ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

Inhixa 2,000 IU (20 mg)/0.2 mL solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

10,000 IU/mL (100 mg/mL) solution for injection

Each pre-filled syringe contains enoxaparin sodium 2,000 IU anti-Xa activity (equivalent to 20 mg) in
0.2 mL water for injections.

For the full list of excipients, see section 6.1.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

3. PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe (injection).

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI), in
combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be
managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.
In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is 2,000 IU
(20 mg) once daily by subcutaneous (SC) injection. Preoperative initiation (2 hours before surgery) of
enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk surgery.

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 In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of
7-10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the patient
no longer has significantly reduced mobility.
In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by SC injection preferably started 12 hours before surgery. If there is a need for
earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high risk patient waiting
for a deferred orthopaedic surgery), the last injection should be administered no later than 12 hours prior to
surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis
up to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal
or pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by SC injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered SC either as a once daily injection of 150 IU/kg (1.5 mg/kg) or as
twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is 100 IU/kg
(1 mg/kg) every 12 hours by SC injection administered in combination with antiplatelet therapy. Treatment

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should be maintained for a minimum of 2 days and continued until clinical stabilization. The usual duration
of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325 mg/day
long-term regardless of treatment strategy.

For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous (IV)
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) SC dose followed by 100 IU/kg (1 mg/kg)
administered SC every 12 hours (maximum 10,000 IU (100 mg) for each of the first two SC doses).
Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg to 325 mg once daily) should be
administered concomitantly unless contraindicated. The recommended duration of treatment is 8 days or
until hospital discharge, whichever comes first. When administered in conjunction with a thrombolytic
(fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and
30 minutes after the start of fibrinolytic therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last dose of enoxaparin sodium SC was given less than
8 hours before balloon inflation, no additional dosing is needed. If the last SC administration
was given more than 8 hours before balloon inflation, an IV bolus of 30 IU/kg (0.3 mg/kg)
enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below “renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥75 years of age, an initial IV bolus must not be used.
Initiate dosing with 75 IU/kg (0.75 mg/kg) SC every 12 hours (maximum 7,500 IU (75 mg) for each of the
first two SC doses only, followed by 75 IU/kg (0.75 mg/kg) SC dosing for the remaining doses). For dose in
elderly patients with impaired kidney function, see below “renal impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):

Indication Dosing regimen

Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) SC once daily

Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight SC once daily

Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight SC once daily

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Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) IV bolus plus 100 IU/kg
(1 mg/kg) body weight SC and then 100 IU/kg
(1 mg/kg) body weight SC every 24 hours

Treatment of acute STEMI (patients over 75) No IV initial bolus, 100 IU/kg (1 mg/kg) body
weight SC and then 100 IU/kg (1 mg/kg) body
weight SC every 24 hours
The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thrombo-embolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by SC injection.
For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The disposable pre-filled syringe is ready for immediate use.

The use of a tuberculin syringe or equivalent is recommended when using ampoules or multidose vials to
assure withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, use the graduated pre-filled syringes to reach the
required volume by discarding the excess before injection. Please be aware that in some cases it is not
possible to achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be
rounded up to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. After
administration, the injection site should not be rubbed.

Note for the pre-filled syringes fitted with an automatic safety system: The safety system is triggered at the
end of the injection (see instructions in section 6.6).

In case of self-administration, patient should be advised to follow instructions provided in the patient
information leaflet included in the pack of this medicinal product.

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IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For IV injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an IV line. It should not be mixed or co-administered
with other medicinal products. To avoid the possible mixture of enoxaparin sodium with other medicinal
products, the IV access chosen should be flushed with a sufficient amount of sodium chloride 9 mg/ml
(0.9%) or 5% glucose in water for injections prior to and following the IV bolus administration of
enoxaparin sodium to clear the port of the medicinal product. Enoxaparin sodium may be safely administered
with normal sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the IV line.

Additional bolus for PCI when last SC administration was given more than 8 hours before balloon inflation
For patients being managed with PCI, an additional IV bolus of 30 IU/kg (0.3 mg/kg) is to be administered if
last SC administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/ml (0.9%) solution for
injection or 5% glucose in water for injections) as follows:
Withdraw 30 mL from the infusion bag with a syringe and discard the liquid. Inject the complete contents of
the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe into the 20 mL remaining in the bag. Gently mix
the contents of the bag. Withdraw the required volume of diluted solution with a syringe for administration
into the IV line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through IV line after dilution is completed at a concentration of 300 IU (3 mg) /mL.

Weight Required dose Volume to inject when diluted

30 IU/kg (0.3 mg/kg) to a final concentration of
300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10
105 3,150 31.5 10.5
110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12

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 125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
 At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
 At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.
Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.

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Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH) or to any of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (>100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-
induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a
case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments
are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism,
any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on treatment), platelet count

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should be measured. Patients must be aware that these symptoms may occur and if so, that they should inform
their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach a
sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

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Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If the treatment with
enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours
after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after
a careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg ) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

Renal impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the
risk of bleeding. In these patients, careful clinical monitoring is advised, and biological monitoring by anti-
Xa activity measurement might be considered (see sections 4.2 and 5.2).
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

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In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.

Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:
- Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,

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 - Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
 Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

 Medicinal products increasing potassium levels:

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in

12
patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) SC once daily for prophylaxis of DVT following surgery or
in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or without PE,
patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg) SC dose every 12 hours
or a 150 IU/kg (1.5 mg/kg) SC dose once a day. In the clinical trials for treatment of unstable angina and
non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) SC every 12 hours, and in the clinical
study for treatment of acute STEMI enoxaparin sodium regimen was a 3,000 IU (30 mg) IV bolus followed
by 100 IU/kg (1 mg/kg) SC every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see section 4.4 and 'Description of selected adverse reactions' below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000
to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be estimated from
available data). Within each system organ class, adverse reactions are presented in order of decreasing
seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*
Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury *
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema
Uncommon: Bullous dermatitis
Rare: Alopecia*

13
 Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as: organic
lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting haemostasis
(see sections 4.4 and 4.5).

System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in

organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and unstable acute STEMI
without PE PE in angina and
patients non-Q-wave
with active MI
cancer
Very common: Common: Very Common b: Common: Common:
Blood Haemorrhag Haemorrha common: Haemorrha Haemorrhag Haemorrhag
and eα ge α Haemorrhag ge eα eα
lymphat eα Rare:
ic Rare: Retroperiton Uncommon:
system Retroperiton Uncommon: eal Intracranial
disorde eal Intracranial haemorrhage haemorrhage
rs haemorrhage haemorrhage ,
, Retroperiton
Retroperiton eal
eal haemorrhage
haemorrhage
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

14
Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)
System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in
organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and PE unstable acute STEMI
without PE in patients angina and
with active non-Q-wave
cancer MI
Blood Very common: Uncommon Very common: Unknown: Uncommon: Common:
and Thrombocyto : Thrombocyto Thrombocyt Thrombo- Thrombocyto
lympha sisβ Thrombo- sisβ openia cytopenia sisβ
tic cytopenia Thrombo-
system Common: Common: cytopenia
disorde Thrombo- Thrombo- Very rare:
rs cytopenia cytopenia Immuno-
allergic
thrombo-
cytopenia
β
: Platelet increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after IV, extracorporeal or SC administration may lead to
haemorrhagic complications. Following oral administration of even large doses, it is unlikely that enoxaparin
sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow IV injection of protamine. The dose of
protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the anticoagulant
effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the previous
8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be administered if
enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it
has been determined that a second dose of protamine is required. After 12 hours of the enoxaparin sodium
injection, protamine administration may not be required. However, even with high doses of protamine, the
anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about 60%) (see the
prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

15
Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

Pharmacodynamic effects

Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery, 179
patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin sodium
4,000 IU (40 mg) SC, were randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU
(40 mg) (n=90) once a day SC or to placebo (n=89) for 3 weeks. The incidence of DVT during extended
prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no PE was reported. No
major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium
4,000 IU (40 mg) Placebo
once a day SC once a day SC
n (%) n (%)
All treated extended prophylaxis 90 (100) 89 (100)
patients
Total VTE 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo =0.008
#p value versus placebo =0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) SC were randomised to a post-
discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day SC or to placebo
(n=131) for 3 weeks. Similar to the first study the incidence of VTE during extended prophylaxis was
significantly lower for enoxaparin sodium compared to placebo for both total VTE (enoxaparin sodium 21
[16%] versus placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium 8 [6.1%] versus placebo
28 [21.4%]; p=<0.001). No difference in major bleeding was found between the enoxaparin sodium and the
placebo group.

16
Extended prophylaxis of DVT following cancer surgery
A double-blind, multicenter trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or
pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) SC) daily for 6 to 10 days and were
then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days. Bilateral
venography was performed between days 25 and 31, or sooner if symptoms of venous thromboembolism
occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis for four weeks after
surgery for abdominal or pelvic cancer significantly reduced the incidence of venographically demonstrated
thrombosis, as compared with enoxaparin sodium prophylaxis for one week. The rates of venous
thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the placebo group and 4.8%
(n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three months [13.8% vs. 5.5%
(n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other complications during the
double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicenter, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day SC was compared to placebo in the prophylaxis of DVT in medical patients with
severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days).
This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day SC, enoxaparin
sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are provided
in the table below.

Enoxaparin Enoxaparin sodium Placebo

sodium 4,000 IU (40 mg)
2,000 IU (20 mg) once a day SC n (%)
once a day SC n (%)
n (%)
All treated medical 287 (100) 291(100) 288 (100)
patients during acute
illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to
be thromboembolic in origin
* p value versus placebo =0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without PE

In a multicenter, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once

17
a day SC, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours SC, or (iii) heparin IV bolus
(5,000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total
of 900 patients were randomised in the study and all patients were treated. All patients also received warfarin
sodium (dose adjusted according to prothrombin time to achieve an INR of 2.0 to 3.0), commencing within
72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days.
Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the
targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard
heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy
data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium Heparin

150 IU/kg 100 IU/kg aPTT adjusted IV
(1.5 mg/kg) once a (1 mg/kg) twice a therapy
day SC day SC n (%)
n (%) n (%)
All treated DVT 298 (100) 312 (100) 290 (100)
patients with or
without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
*The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

18
 Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

Enoxaparin all regimens

Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)
*All data with 95% CI

Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicenter study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either SC enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated heparin
adjusted based on aPTT. Patients had to be treated in hospital for a minimum of 2 days and a maximum of
8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be
followed up to 30 days. In comparison with heparin, enoxaparin sodium significantly reduced the combined
incidence of angina pectoris, myocardial infarction and death, with a decrease of 19.8 to 16.6% (relative risk
reduction of 16.2%) on day 14. This reduction in the combined incidence was maintained after 30 days (from
23.3 to 19.8%; relative risk reduction of 15%).

19
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the SC
injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicenter study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) IV bolus plus a 100 IU/kg
(1 mg/kg) SC dose followed by an SC injection of 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated
heparin adjusted based on aPTT for 48 hours. All patients were also treated with acetylsalicylic acid for a
minimum of 30 days. The enoxaparin sodium dosing strategy was adjusted for severe renally impaired
patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin sodium were given
until hospital discharge or for a maximum of eight days (whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no
additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of
30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last SC administration given more than 8 hours before
balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p=0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage (a
measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group (10.1%)
as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of treatment
with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the
enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

Hepatic impairment

Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single

20
and repeated SC administration and after single IV administration. The quantitative determination of anti-Xa
and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods.

Absorption

The absolute bioavailability of enoxaparin sodium after SC injection, based on anti-Xa activity, is close to
100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after SC injection and achieves
approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single SC administration of 2,000 IU, 4,000 IU,
100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

A 3,000 IU (30 mg) IV bolus immediately followed by a 100 IU/kg (1 mg/kg) SC every 12 hours provided
initial maximum anti-Xa activity level of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of
steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated SC administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily
regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about
15% higher than after a single dose. After repeated SC administration of the 100 IU/kg (1 mg/kg) twice daily
regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single
dose and mean maximum and trough anti-Xa activity levels of about 1.2 and 0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated SC administration no accumulation takes
place.

Plasma anti-IIa activity after SC administration is approximately ten-fold lower than anti-Xa activity. The
mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following SC injection and
reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of 100 IU/kg (1 mg/kg) twice daily
and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerization to lower
molecular weight species with much reduced biological potency.

Elimination

Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after a
150 IU /kg (1.5 mg/kg) 6-hour IV infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single SC dose to about 7 hours
after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

21
Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated SC
4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine clearance
<30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated SC
4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) IV dose however, AUC was two-fold higher than control.

Weight
After repeated SC 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is marginally
higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese control
subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-adjusted
clearance in obese subjects with SC dosing.

When non-weight adjusted dosing was administered, it was found after a single-SC 4,000 IU (40 mg) dose,
that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men
(<57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week SC toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week
SC and IV toxicity studies both in rats, and monkeys.

Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at SC doses of enoxaparin sodium up to 30 mg/kg/day did not
reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was found to have no effect
on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day.

22
6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections

6.2 Incompatibilities

SC injection

Do not mix with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

Enoxaparin sodium may be safely administered with sodium chloride 9mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

6.3 Shelf life

Pre-filled syringe

3 years

Diluted medicinal product with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in
water for injections.

8 hours

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

6.5 Nature and contents of container

0.2 mL of solution in:

- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a blue polypropylene plunger rod. The syringe can be additionally
equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe Passive
needle guard.

Packs of:
- 1, 2, 6, 10, 20 and 50 pre-filled syringe(s)
- 2, 6, 10, 20, 50 and 90 pre-filled syringes with needle guard
- 6, 10 and 20 pre-filled syringes with manual needle guard
- 2 and 6 pre-filled syringes with UltraSafe Passive needle guard

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

INSTRUCTIONS FOR USE: PRE-FILLED SYRINGE

23
How to give yourself an injection of Inhixa with a pre-filled syringe without needle guard

If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

24
8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out.

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with needle guard

Your pre-filled syringe has a needle guard attached to it in order to protect you from needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

25
Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Push hard the plunger. The needle guard, which is in the form of a plastic cylinder, will be activated
automatically and it will completely cover the needle.

26
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with UltraSafe Passive needle guard

Your pre-filled syringe has UltraSafe Passive needle guard attached to it in order to protect you from needle
stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your stomach, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

27
Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Let go of the plunger and allow the syringe to move up until the entire needle is guarded and locks
into place.

28
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with manually activated needle guard

Your pre-filled syringe has a manually activated needle guard attached to it in order to protect you from
needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from your
belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

29
6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Firmly hold the syringe tube with one hand (A). With the other hand hold the base, “wings” of the
syringe (B), and pull the base until you hear a clicking sound (C). Now the used needle is completely
protected.

30
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/001
EU/1/16/1132/002
EU/1/16/1132/011
EU/1/16/1132/012
EU/1/16/1132/021
EU/1/16/1132/023
EU/1/16/1132/033
EU/1/16/1132/034
EU/1/16/1132/051
EU/1/16/1132/053
EU/1/16/1132/054
EU/1/16/1132/064
EU/1/16/1132/065
EU/1/16/1132/085
EU/1/16/1132/090
EU/1/16/1132/095
EU/1/16/1132/117

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

31
1. NAME OF THE MEDICINAL PRODUCT

Inhixa 4,000 IU (40 mg)/0.4 mL solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

10,000 IU/mL (100 mg/mL) solution for injection

Each pre-filled syringe contains enoxaparin sodium 4,000 IU anti-Xa activity (equivalent to 40 mg) in
0.4 mL water for injections.

For the full list of excipients, see section 6.1.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

3. PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe (injection).

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI), in
combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be
managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.
In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is 2,000 IU
(20 mg) once daily by subcutaneous (SC) injection. Preoperative initiation (2 hours before surgery) of
enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk surgery.

32
 In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of 7-
10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the patient no
longer has significantly reduced mobility.
In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by SC injection preferably started 12 hours before surgery. If there is a need for
earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high risk patient waiting
for a deferred orthopaedic surgery), the last injection should be administered no later than 12 hours prior to
surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis
up to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal
or pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by SC injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered SC either as a once daily injection of 150 IU/kg (1.5 mg/kg) or as
twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is 100 IU/kg
(1 mg/kg) every 12 hours by SC injection administered in combination with antiplatelet therapy. Treatment

33
should be maintained for a minimum of 2 days and continued until clinical stabilization. The usual duration
of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325 mg/day
long-term regardless of treatment strategy.

For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous (IV)
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) SC dose followed by 100 IU/kg (1 mg/kg)
administered SC every 12 hours (maximum 10,000 IU (100 mg) for each of the first two SC doses).
Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg to 325 mg once daily) should be
administered concomitantly unless contraindicated. The recommended duration of treatment is 8 days or
until hospital discharge, whichever comes first. When administered in conjunction with a thrombolytic
(fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and
30 minutes after the start of fibrinolytic therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last dose of enoxaparin sodium SC was given less than
8 hours before balloon inflation, no additional dosing is needed. If the last SC administration
was given more than 8 hours before balloon inflation, an IV bolus of 30 IU/kg (0.3 mg/kg)
enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below “renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥75 years of age, an initial IV bolus must not be used.
Initiate dosing with 75 IU/kg (0.75 mg/kg) SC every 12 hours (maximum 7,500 IU (75 mg) for each of the
first two SC doses only, followed by 75 IU/kg (0.75 mg/kg) SC dosing for the remaining doses). For dose in
elderly patients with impaired kidney function, see below “renal impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):

Indication Dosing regimen

Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) SC once daily

Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight SC once daily

Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight SC once daily

34
Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) IV bolus plus 100 IU/kg
(1 mg/kg) body weight SC and then 100 IU/kg
(1 mg/kg) body weight SC every 24 hours

Treatment of acute STEMI (patients over 75) No IV initial bolus, 100 IU/kg (1 mg/kg) body
weight SC and then 100 IU/kg (1 mg/kg) body
weight SC every 24 hours
The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thrombo-embolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by SC injection.
For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The disposable pre-filled syringe is ready for immediate use.

The use of a tuberculin syringe or equivalent is recommended when using ampoules or multidose vials to
assure withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, use the graduated pre-filled syringes to reach the
required volume by discarding the excess before injection. Please be aware that in some cases it is not
possible to achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be
rounded up to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. After
administration, the injection site should not be rubbed.

Note for the pre-filled syringes fitted with an automatic safety system: The safety system is triggered at the
end of the injection (see instructions in section 6.6).

In case of self-administration, patient should be advised to follow instructions provided in the patient
information leaflet included in the pack of this medicinal product.

35
IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For IV injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an IV line. It should not be mixed or co-administered
with other medicinal products. To avoid the possible mixture of enoxaparin sodium with other medicinal
products, the IV access chosen should be flushed with a sufficient amount of sodium chloride 9 mg/ml
(0.9%) or glucose in water for injections prior to and following the IV bolus administration of enoxaparin
sodium to clear the port of the medicinal product. Enoxaparin sodium may be safely administered with
normal sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the IV line.

Additional bolus for PCI when last SC administration was given more than 8 hours before balloon inflation
For patients being managed with PCI, an additional IV bolus of 30 IU/kg (0.3 mg/kg) is to be administered if
last SC administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/ml (0.9%) solution for
injection or 5% glucose in water for injections) as follows:
Withdraw 30 mL from the infusion bag with a syringe and discard the liquid. Inject the complete contents of
the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe into the 20 mL remaining in the bag. Gently mix
the contents of the bag. Withdraw the required volume of diluted solution with a syringe for administration
into the IV line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through IV line after dilution is completed at a concentration of 300 IU (3 mg) /mL.

Weight Required dose Volume to inject when diluted

30 IU/kg (0.3 mg/kg) to a final concentration of
300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10
105 3,150 31.5 10.5
110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12

36
 125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
 At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
 At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.
Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.

37
Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH) or to any of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (>100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-
induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a
case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments
are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism,
any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on treatment), platelet count

38
should be measured. Patients must be aware that these symptoms may occur and if so, that they should inform
their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach a
sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,

39
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If the treatment with
enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours
after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after
a careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg ) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

Renal impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the
risk of bleeding. In these patients, careful clinical monitoring is advised, and biological monitoring by anti-
Xa activity measurement might be considered (see sections 4.2 and 5.2).

40
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.
In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.

Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:

41
 - Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,
- Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
 Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

 Medicinal products increasing potassium levels:

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

42
Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in
patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) SC once daily for prophylaxis of DVT following surgery or
in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or without PE,
patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg) SC dose every 12 hours
or a 150 IU/kg (1.5 mg/kg) SC dose once a day. In the clinical trials for treatment of unstable angina and
non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) SC every 12 hours, and in the clinical
study for treatment of acute STEMI enoxaparin sodium regimen was a 3,000 IU (30 mg) IV bolus followed
by 100 IU/kg (1 mg/kg) SC every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see section 4.4 and 'Description of selected adverse reactions' below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000
to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be estimated from
available data). Within each system organ class, adverse reactions are presented in order of decreasing
seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*
Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury *
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema

43
 Uncommon: Bullous dermatitis
Rare: Alopecia*
Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as: organic
lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting haemostasis
(see sections 4.4 and 4.5).

System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in

organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and unstable acute STEMI
without PE PE in angina and
patients non-Q-wave
with active MI
cancer
Very common: Common: Very Common b: Common: Common:
Blood Haemorrhag Haemorrha common: Haemorrha Haemorrhag Haemorrhag
and eα ge α Haemorrhag ge eα eα
lymphat eα Rare:
ic Rare: Retroperiton Uncommon:
system Retroperiton Uncommon: eal Intracranial
disorde eal Intracranial haemorrhage haemorrhage
rs haemorrhage haemorrhage ,
, Retroperiton
Retroperiton eal
eal haemorrhage
haemorrhage
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

44
Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)
System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in
organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and PE unstable acute STEMI
without PE in patients angina and
with active non-Q-wave
cancer MI
Blood Very common: Uncommon Very common: Unknown: Uncommon: Common:
and Thrombocyto : Thrombocyto Thrombocyt Thrombo- Thrombocyto
lympha sisβ Thrombo- sisβ openia cytopenia sisβ
tic cytopenia Thrombo-
system Common: Common: cytopenia
disorde Thrombo- Thrombo- Very rare:
rs cytopenia cytopenia Immuno-
allergic
thrombo-
cytopenia
β
: Platelet increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after IV, extracorporeal or SC administration may lead to
haemorrhagic complications. Following oral administration of even large doses, it is unlikely that enoxaparin
sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow IV injection of protamine. The dose of
protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the anticoagulant
effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the previous
8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be administered if
enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it
has been determined that a second dose of protamine is required. After 12 hours of the enoxaparin sodium
injection, protamine administration may not be required. However, even with high doses of protamine, the
anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about 60%) (see the
prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

45
Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

Pharmacodynamic effects

Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery, 179
patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin sodium
4,000 IU (40 mg) SC, were randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU
(40 mg) (n=90) once a day SC or to placebo (n=89) for 3 weeks. The incidence of DVT during extended
prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no PE was reported. No
major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium
4,000 IU (40 mg) Placebo
once a day SC once a day SC
n (%) n (%)
All treated extended prophylaxis 90 (100) 89 (100)
patients
Total VTE 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo =0.008
#p value versus placebo =0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) SC were randomised to a post-
discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day SC or to placebo
(n=131) for 3 weeks. Similar to the first study the incidence of VTE during extended prophylaxis was
significantly lower for enoxaparin sodium compared to placebo for both total VTE (enoxaparin sodium 21
[16%] versus placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium 8 [6.1%] versus placebo
28 [21.4%]; p=<0.001). No difference in major bleeding was found between the enoxaparin sodium and the
placebo group.

46
Extended prophylaxis of DVT following cancer surgery
A double-blind, multicenter trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or
pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) SC) daily for 6 to 10 days and were
then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days. Bilateral
venography was performed between days 25 and 31, or sooner if symptoms of venous thromboembolism
occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis for four weeks after
surgery for abdominal or pelvic cancer significantly reduced the incidence of venographically demonstrated
thrombosis, as compared with enoxaparin sodium prophylaxis for one week. The rates of venous
thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the placebo group and 4.8%
(n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three months [13.8% vs. 5.5%
(n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other complications during the
double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicenter, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day SC was compared to placebo in the prophylaxis of DVT in medical patients with
severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days).
This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day SC, enoxaparin
sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are provided
in the table below.

Enoxaparin Enoxaparin sodium Placebo

sodium 4,000 IU (40 mg)
2,000 IU (20 mg) once a day SC n (%)
once a day SC n (%)
n (%)
All treated medical 287 (100) 291(100) 288 (100)
patients during acute
illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to
be thromboembolic in origin
* p value versus placebo =0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without PE

47
In a multicenter, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once
a day SC, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours SC, or (iii) heparin IV bolus
(5,000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total
of 900 patients were randomised in the study and all patients were treated. All patients also received warfarin
sodium (dose adjusted according to prothrombin time to achieve an INR of 2.0 to 3.0), commencing within
72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days.
Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the
targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard
heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy
data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium Heparin

150 IU/kg 100 IU/kg aPTT adjusted IV
(1.5 mg/kg) once a (1 mg/kg) twice a therapy
day SC day SC n (%)
n (%) n (%)
All treated DVT 298 (100) 312 (100) 290 (100)
patients with or
without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
*The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

48
 Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

Enoxaparin all regimens

Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)
*All data with 95% CI

Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicenter study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either SC enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated heparin
adjusted based on aPTT. Patients had to be treated in hospital for a minimum of 2 days and a maximum of
8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be
followed up to 30 days. In comparison with heparin, enoxaparin sodium significantly reduced the combined
incidence of angina pectoris, myocardial infarction and death, with a decrease of 19.8 to 16.6% (relative risk
reduction of 16.2%) on day 14. This reduction in the combined incidence was maintained after 30 days (from
23.3 to 19.8%; relative risk reduction of 15%).

49
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the SC
injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicenter study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) IV bolus plus a 100 IU/kg
(1 mg/kg) SC dose followed by an SC injection of 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated
heparin adjusted based on aPTT for 48 hours. All patients were also treated with acetylsalicylic acid for
a minimum of 30 days. The enoxaparin sodium dosing strategy was adjusted for severe renally impaired
patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin sodium were given
until hospital discharge or for a maximum of eight days (whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no
additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of
30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last SC administration given more than 8 hours before
balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p=0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage
(a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group
(10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of
treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the
enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

Hepatic impairment

Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

50
5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single
and repeated SC administration and after single IV administration. The quantitative determination of anti-Xa
and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods.

Absorption

The absolute bioavailability of enoxaparin sodium after SC injection, based on anti-Xa activity, is close to
100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after SC injection and achieves
approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single SC administration of 2,000 IU, 4,000 IU,
100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

A 3,000 IU (30 mg) IV bolus immediately followed by a 100 IU/kg (1 mg/kg) SC every 12 hours provided
initial maximum anti-Xa activity level of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of
steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated SC administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily
regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about
15% higher than after a single dose. After repeated SC administration of the 100 IU/kg (1 mg/kg) twice daily
regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single
dose and mean maximum and trough anti-Xa activity levels of about 1.2 and 0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated SC administration no accumulation takes
place.

Plasma anti-IIa activity after SC administration is approximately ten-fold lower than anti-Xa activity. The
mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following SC injection and
reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of 100 IU/kg (1 mg/kg) twice daily
and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerization to lower
molecular weight species with much reduced biological potency.

Elimination

51
Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after
a 150 IU /kg (1.5 mg/kg) 6-hour IV infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single SC dose to about 7 hours
after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated SC
4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine clearance
<30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated SC
4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) IV dose however, AUC was two-fold higher than control.

Weight
After repeated SC 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is marginally
higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese control
subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-adjusted
clearance in obese subjects with SC dosing.

When non-weight adjusted dosing was administered, it was found after a single-SC 4,000 IU (40 mg) dose,
that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men
(<57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week SC toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week
SC and IV toxicity studies both in rats, and monkeys.

52
Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at SC doses of enoxaparin sodium up to 30 mg/kg/day did not
reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was found to have no effect
on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections

6.2 Incompatibilities

SC injection

Do not mix with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

Enoxaparin sodium may be safely administered with sodium chloride 9mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

6.3 Shelf life

Pre-filled syringe

3 years

Diluted medicinal product with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in
water for injections.

8 hours

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

6.5 Nature and contents of container

0.4 mL of solution in:

- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a yellow polypropylene plunger rod. The syringe can be additionally
equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe Passive
needle guard.

Packs of:
- 2, 5, 6, 10, 20, 30 and 50 pre-filled syringes
- 2, 5, 6, 10, 20, 30, 50 and 90 pre-filled syringes with needle guard
- 2, 6, 10, 20 and 50 pre-filled syringes with manual needle guard
- 2 and 6 pre-filled syringes with UltraSafe Passive needle guard

53
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

INSTRUCTIONS FOR USE: PRE-FILLED SYRINGE

How to give yourself an injection of Inhixa with a pre-filled syringe without needle guard

If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

54
7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out.

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with needle guard

Your pre-filled syringe has a needle guard attached to it in order to protect you from needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.

55
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Push hard the plunger. The needle guard, which is in the form of a plastic cylinder, will be activated
automatically and it will completely cover the needle.

56
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with UltraSafe Passive needle guard

Your pre-filled syringe has UltraSafe Passive needle guard attached to it in order to protect you from needle
stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your stomach, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

57
Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Let go of the plunger and allow the syringe to move up until the entire needle is guarded and locks
into place.

58
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with manually activated needle guard

Your pre-filled syringe has a manually activated needle guard attached to it in order to protect you from
needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from your
belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

59
6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Firmly hold the syringe tube with one hand (A). With the other hand hold the base, “wings” of the
syringe (B), and pull the base until you hear a clicking sound (C). Now the used needle is completely
protected.

60
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/003
EU/1/16/1132/004
EU/1/16/1132/013
EU/1/16/1132/014
EU/1/16/1132/024
EU/1/16/1132/025
EU/1/16/1132/035
EU/1/16/1132/036
EU/1/16/1132/043
EU/1/16/1132/044
EU/1/16/1132/052
EU/1/16/1132/055
EU/1/16/1132/056
EU/1/16/1132/066
EU/1/16/1132/067
EU/1/16/1132/068
EU/1/16/1132/086
EU/1/16/1132/091
EU/1/16/1132/096
EU/1/16/1132/097
EU/1/16/1132/098
EU/1/16/1132/116

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

61
1. NAME OF THE MEDICINAL PRODUCT

Inhixa 6,000 IU (60 mg)/0.6 mL solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

10,000 IU/mL (100 mg/mL) solution for injection

Each pre-filled syringe contains enoxaparin sodium 6,000 IU anti-Xa activity (equivalent to 60 mg) in 0.6
mL water for injections.

For the full list of excipients, see section 6.1.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

3. PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe (injection).

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI), in
combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be
managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.
In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is 2,000 IU
(20 mg) once daily by subcutaneous (SC) injection. Preoperative initiation (2 hours before surgery) of
enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk surgery.

62
 In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of
7-10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the patient
no longer has significantly reduced mobility.
In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by SC injection preferably started 12 hours before surgery. If there is a need for
earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high risk patient waiting
for a deferred orthopaedic surgery), the last injection should be administered no later than 12 hours prior to
surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis
up to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal
or pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by SC injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered SC either as a once daily injection of 150 IU/kg (1.5 mg/kg) or as
twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is 100 IU/kg
(1 mg/kg) every 12 hours by SC injection administered in combination with antiplatelet therapy. Treatment

63
should be maintained for a minimum of 2 days and continued until clinical stabilization. The usual duration
of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325 mg/day
long-term regardless of treatment strategy.

For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous (IV)
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) SC dose followed by 100 IU/kg (1 mg/kg)
administered SC every 12 hours (maximum 10,000 IU (100 mg) for each of the first two SC doses).
Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg to 325 mg once daily) should be
administered concomitantly unless contraindicated. The recommended duration of treatment is 8 days or
until hospital discharge, whichever comes first. When administered in conjunction with a thrombolytic
(fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and
30 minutes after the start of fibrinolytic therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last dose of enoxaparin sodium SC was given less than
8 hours before balloon inflation, no additional dosing is needed. If the last SC administration
was given more than 8 hours before balloon inflation, an IV bolus of 30 IU/kg (0.3 mg/kg)
enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below “renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥75 years of age, an initial IV bolus must not be used.
Initiate dosing with 75 IU/kg (0.75 mg/kg) SC every 12 hours (maximum 7,500 IU (75 mg) for each of the
first two SC doses only, followed by 75 IU/kg (0.75 mg/kg) SC dosing for the remaining doses). For dose in
elderly patients with impaired kidney function, see below “renal impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):

Indication Dosing regimen

Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) SC once daily

Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight SC once daily

Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight SC once daily

64
Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) IV bolus plus 100 IU/kg
(1 mg/kg) body weight SC and then 100 IU/kg
(1 mg/kg) body weight SC every 24 hours

Treatment of acute STEMI (patients over 75) No IV initial bolus, 100 IU/kg (1 mg/kg) body
weight SC and then 100 IU/kg (1 mg/kg) body
weight SC every 24 hours
The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thrombo-embolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by SC injection.
For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The disposable pre-filled syringe is ready for immediate use.

The use of a tuberculin syringe or equivalent is recommended when using ampoules or multidose vials to
assure withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, use the graduated pre-filled syringes to reach the
required volume by discarding the excess before injection. Please be aware that in some cases it is not
possible to achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be
rounded up to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. After
administration, the injection site should not be rubbed.

Note for the pre-filled syringes fitted with an automatic safety system: The safety system is triggered at the
end of the injection (see instructions in section 6.6).

In case of self-administration, patient should be advised to follow instructions provided in the patient
information leaflet included in the pack of this medicinal product.

65
IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For IV injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an IV line. It should not be mixed or co-administered
with other medicinal products. To avoid the possible mixture of enoxaparin sodium with other medicinal
products, the IV access chosen should be flushed with a sufficient amount of sodium chloride 9 mg/ml
(0.9%) or 5% glucose in water for injections prior to and following the IV bolus administration of
enoxaparin sodium to clear the port of the medicinal product. Enoxaparin sodium may be safely administered
with normal sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the IV line.

Additional bolus for PCI when last SC administration was given more than 8 hours before balloon inflation
For patients being managed with PCI, an additional IV bolus of 30 IU/kg (0.3 mg/kg) is to be administered if
last SC administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/ml (0.9%) solution for
injection or 5% glucose in water for injections) as follows:
Withdraw 30 mL from the infusion bag with a syringe and discard the liquid. Inject the complete contents of
the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe into the 20 mL remaining in the bag. Gently mix
the contents of the bag. Withdraw the required volume of diluted solution with a syringe for administration
into the IV line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through IV line after dilution is completed at a concentration of 300 IU (3 mg) /mL.

Weight Required dose Volume to inject when diluted

30 IU/kg (0.3 mg/kg) to a final concentration of
300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10
105 3,150 31.5 10.5
110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12

66
 125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
 At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
 At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.
Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.

67
Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH) or to any of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (>100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-
induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a
case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments
are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism,
any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on treatment), platelet count

68
should be measured. Patients must be aware that these symptoms may occur and if so, that they should inform
their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach a
sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,

69
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If the treatment with
enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours
after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after
a careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg ) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

Renal impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the
risk of bleeding. In these patients, careful clinical monitoring is advised, and biological monitoring by anti-
Xa activity measurement might be considered (see sections 4.2 and 5.2).

70
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.
In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.

Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:

71
 - Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,
- Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
 Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

 Medicinal products increasing potassium levels:

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

72
Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in
patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) SC once daily for prophylaxis of DVT following surgery or
in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or without PE,
patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg) SC dose every 12 hours
or a 150 IU/kg (1.5 mg/kg) SC dose once a day. In the clinical trials for treatment of unstable angina and
non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) SC every 12 hours, and in the clinical
study for treatment of acute STEMI enoxaparin sodium regimen was a 3,000 IU (30 mg) IV bolus followed
by 100 IU/kg (1 mg/kg) SC every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see section 4.4 and 'Description of selected adverse reactions' below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000
to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be estimated from
available data). Within each system organ class, adverse reactions are presented in order of decreasing
seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*
Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury *
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema

73
 Uncommon: Bullous dermatitis
Rare: Alopecia*
Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as: organic
lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting haemostasis
(see sections 4.4 and 4.5).

System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in

organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and unstable acute STEMI
without PE PE in angina and
patients non-Q-wave
with active MI
cancer
Very common: Common: Very Common b: Common: Common:
Blood Haemorrhag Haemorrha common: Haemorrha Haemorrhag Haemorrhag
and eα ge α Haemorrhag ge eα eα
lymphat eα Rare:
ic Rare: Retroperiton Uncommon:
system Retroperiton Uncommon: eal Intracranial
disorde eal Intracranial haemorrhage haemorrhage
rs haemorrhage haemorrhage ,
, Retroperiton
Retroperiton eal
eal haemorrhage
haemorrhage
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

74
Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)
System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in
organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and PE unstable acute STEMI
without PE in patients angina and
with active non-Q-wave
cancer MI
Blood Very common: Uncommon Very common: Unknown: Uncommon: Common:
and Thrombocyto : Thrombocyto Thrombocyt Thrombo- Thrombocyto
lympha sisβ Thrombo- sisβ openia cytopenia sisβ
tic cytopenia Thrombo-
system Common: Common: cytopenia
disorde Thrombo- Thrombo- Very rare:
rs cytopenia cytopenia Immuno-
allergic
thrombo-
cytopenia
β
: Platelet increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after IV, extracorporeal or SC administration may lead to
haemorrhagic complications. Following oral administration of even large doses, it is unlikely that enoxaparin
sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow IV injection of protamine. The dose of
protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the anticoagulant
effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the previous
8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be administered if
enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it
has been determined that a second dose of protamine is required. After 12 hours of the enoxaparin sodium
injection, protamine administration may not be required. However, even with high doses of protamine, the
anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about 60%) (see the
prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

75
Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

Pharmacodynamic effects

Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery, 179
patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin sodium
4,000 IU (40 mg) SC, were randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU
(40 mg) (n=90) once a day SC or to placebo (n=89) for 3 weeks. The incidence of DVT during extended
prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no PE was reported. No
major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium
4,000 IU (40 mg) Placebo
once a day SC once a day SC
n (%) n (%)
All treated extended prophylaxis 90 (100) 89 (100)
patients
Total VTE 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo =0.008
#p value versus placebo =0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) SC were randomised to a post-
discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day SC or to placebo
(n=131) for 3 weeks. Similar to the first study the incidence of VTE during extended prophylaxis was
significantly lower for enoxaparin sodium compared to placebo for both total VTE (enoxaparin sodium 21
[16%] versus placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium 8 [6.1%] versus placebo
28 [21.4%]; p=<0.001). No difference in major bleeding was found between the enoxaparin sodium and the
placebo group.

76
Extended prophylaxis of DVT following cancer surgery
A double-blind, multicenter trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or
pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) SC) daily for 6 to 10 days and were
then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days. Bilateral
venography was performed between days 25 and 31, or sooner if symptoms of venous thromboembolism
occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis for four weeks after
surgery for abdominal or pelvic cancer significantly reduced the incidence of venographically demonstrated
thrombosis, as compared with enoxaparin sodium prophylaxis for one week. The rates of venous
thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the placebo group and 4.8%
(n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three months [13.8% vs. 5.5%
(n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other complications during the
double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicenter, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day SC was compared to placebo in the prophylaxis of DVT in medical patients with
severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days).
This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day SC, enoxaparin
sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are provided
in the table below.

Enoxaparin Enoxaparin sodium Placebo

sodium 4,000 IU (40 mg)
2,000 IU (20 mg) once a day SC n (%)
once a day SC n (%)
n (%)
All treated medical 287 (100) 291(100) 288 (100)
patients during acute
illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to
be thromboembolic in origin
* p value versus placebo =0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without PE

In a multicenter, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once

77
a day SC, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours SC, or (iii) heparin IV bolus
(5,000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total
of 900 patients were randomised in the study and all patients were treated. All patients also received warfarin
sodium (dose adjusted according to prothrombin time to achieve an INR of 2.0 to 3.0), commencing within
72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days.
Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the
targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard
heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy
data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium Heparin

150 IU/kg 100 IU/kg aPTT adjusted IV
(1.5 mg/kg) once a (1 mg/kg) twice a therapy
day SC day SC n (%)
n (%) n (%)
All treated DVT 298 (100) 312 (100) 290 (100)
patients with or
without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
*The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

78
 Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

Enoxaparin all regimens

Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)
*All data with 95% CI

Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicenter study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either SC enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated heparin
adjusted based on aPTT. Patients had to be treated in hospital for a minimum of 2 days and a maximum of
8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be
followed up to 30 days. In comparison with heparin, enoxaparin sodium significantly reduced the combined
incidence of angina pectoris, myocardial infarction and death, with a decrease of 19.8 to 16.6% (relative risk
reduction of 16.2%) on day 14. This reduction in the combined incidence was maintained after 30 days (from
23.3 to 19.8%; relative risk reduction of 15%).

79
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the SC
injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicenter study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) IV bolus plus a 100 IU/kg
(1 mg/kg) SC dose followed by an SC injection of 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated
heparin adjusted based on aPTT for 48 hours. All patients were also treated with acetylsalicylic acid for
a minimum of 30 days. The enoxaparin sodium dosing strategy was adjusted for severe renally impaired
patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin sodium were given
until hospital discharge or for a maximum of eight days (whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no
additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of
30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last SC administration given more than 8 hours before
balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p=0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage
(a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group
(10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of
treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the
enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

Hepatic impairment

Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single

80
and repeated SC administration and after single IV administration. The quantitative determination of anti-Xa
and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods.

Absorption

The absolute bioavailability of enoxaparin sodium after SC injection, based on anti-Xa activity, is close to
100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after SC injection and achieves
approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single SC administration of 2,000 IU, 4,000 IU,
100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

A 3,000 IU (30 mg) IV bolus immediately followed by a 100 IU/kg (1 mg/kg) SC every 12 hours provided
initial maximum anti-Xa activity level of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of
steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated SC administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily
regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about
15% higher than after a single dose. After repeated SC administration of the 100 IU/kg (1 mg/kg) twice daily
regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single
dose and mean maximum and trough anti-Xa activity levels of about 1.2 and 0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated SC administration no accumulation takes
place.

Plasma anti-IIa activity after SC administration is approximately ten-fold lower than anti-Xa activity. The
mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following SC injection and
reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of 100 IU/kg (1 mg/kg) twice daily
and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerization to lower
molecular weight species with much reduced biological potency.

Elimination

Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after
a 150 IU /kg (1.5 mg/kg) 6-hour IV infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single SC dose to about 7 hours
after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

81
Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated SC
4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine clearance
<30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated SC
4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) IV dose however, AUC was two-fold higher than control.

Weight
After repeated SC 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is marginally
higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese control
subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-adjusted
clearance in obese subjects with SC dosing.

When non-weight adjusted dosing was administered, it was found after a single-SC 4,000 IU (40 mg) dose,
that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men
(<57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week SC toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week
SC and IV toxicity studies both in rats, and monkeys.

Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at SC doses of enoxaparin sodium up to 30 mg/kg/day did not
reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was found to have no effect
on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day.

82
6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections

6.2 Incompatibilities

SC injection

Do not mix with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

Enoxaparin sodium may be safely administered with sodium chloride 9mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

6.3 Shelf life

Pre-filled syringe

3 years

Diluted medicinal product with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in
water for injections.

8 hours

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

6.5 Nature and contents of container

0.6 mL of solution in:

- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and an orange polypropylene plunger rod. The syringe can be
additionally equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe
Passive needle guard.

Packs of:
- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes
- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes with needle guard
- 6, 10, 12, 20, 24 and 50 pre-filled syringes with manual needle guard
- 2 and 10 pre-filled syringes with UltraSafe Passive needle guard

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

INSTRUCTIONS FOR USE: PRE-FILLED SYRINGE

83
How to give yourself an injection of Inhixa with a pre-filled syringe without needle guard

If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

84
8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out.

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with needle guard

Your pre-filled syringe has a needle guard attached to it in order to protect you from needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

85
Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Push hard the plunger. The needle guard, which is in the form of a plastic cylinder, will be activated
automatically and it will completely cover the needle.

86
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with UltraSafe Passive needle guard

Your pre-filled syringe has UltraSafe Passive needle guard attached to it in order to protect you from needle
stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your stomach, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

87
Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Let go of the plunger and allow the syringe to move up until the entire needle is guarded and locks
into place.

88
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with manually activated needle guard

Your pre-filled syringe has a manually activated needle guard attached to it in order to protect you from
needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from your
belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

89
6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Firmly hold the syringe tube with one hand (A). With the other hand hold the base, “wings” of the
syringe (B), and pull the base until you hear a clicking sound (C). Now the used needle is completely
protected.

90
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/005
EU/1/16/1132/006
EU/1/16/1132/015
EU/1/16/1132/016
EU/1/16/1132/026
EU/1/16/1132/027
EU/1/16/1132/028
EU/1/16/1132/037
EU/1/16/1132/038
EU/1/16/1132/045
EU/1/16/1132/046
EU/1/16/1132/057
EU/1/16/1132/058
EU/1/16/1132/083
EU/1/16/1132/087
EU/1/16/1132/092
EU/1/16/1132/099
EU/1/16/1132/100
EU/1/16/1132/101
EU/1/16/1132/102
EU/1/16/1132/111
EU/1/16/1132/118
EU/1/16/1132/119
EU/1/16/1132/120

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

91
Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

92
1. NAME OF THE MEDICINAL PRODUCT

Inhixa 8,000 IU (80 mg)/0.8 mL solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

10,000 IU/mL (100 mg/mL) solution for injection

Each pre-filled syringe contains enoxaparin sodium 8,000 IU anti-Xa activity (equivalent to 80 mg) in
0.8 mL water for injections.

For the full list of excipients, see section 6.1.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

3. PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe (injection).

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI), in
combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be
managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.
In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is 2,000 IU
(20 mg) once daily by subcutaneous (SC) injection. Preoperative initiation (2 hours before surgery) of
enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk surgery.

93
 In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of
7-10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the patient
no longer has significantly reduced mobility.
In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by SC injection preferably started 12 hours before surgery. If there is a need for
earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high risk patient waiting
for a deferred orthopaedic surgery), the last injection should be administered no later than 12 hours prior to
surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis
up to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal
or pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by SC injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered SC either as a once daily injection of 150 IU/kg (1.5 mg/kg) or as
twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is 100 IU/kg
(1 mg/kg) every 12 hours by SC injection administered in combination with antiplatelet therapy. Treatment

94
should be maintained for a minimum of 2 days and continued until clinical stabilization. The usual duration
of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325 mg/day
long-term regardless of treatment strategy.

For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous (IV)
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) SC dose followed by 100 IU/kg (1 mg/kg)
administered SC every 12 hours (maximum 10,000 IU (100 mg) for each of the first two SC doses).
Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg to 325 mg once daily) should be
administered concomitantly unless contraindicated. The recommended duration of treatment is 8 days or
until hospital discharge, whichever comes first. When administered in conjunction with a thrombolytic
(fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and
30 minutes after the start of fibrinolytic therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last dose of enoxaparin sodium SC was given less than
8 hours before balloon inflation, no additional dosing is needed. If the last SC administration
was given more than 8 hours before balloon inflation, an IV bolus of 30 IU/kg (0.3 mg/kg)
enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below “renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥75 years of age, an initial IV bolus must not be used.
Initiate dosing with 75 IU/kg (0.75 mg/kg) SC every 12 hours (maximum 7,500 IU (75 mg) for each of the
first two SC doses only, followed by 75 IU/kg (0.75 mg/kg) SC dosing for the remaining doses). For dose in
elderly patients with impaired kidney function, see below “renal impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):

Indication Dosing regimen

Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) SC once daily

Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight SC once daily

Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight SC once daily

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Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) IV bolus plus 100 IU/kg
(1 mg/kg) body weight SC and then 100 IU/kg
(1 mg/kg) body weight SC every 24 hours

Treatment of acute STEMI (patients over 75) No IV initial bolus, 100 IU/kg (1 mg/kg) body
weight SC and then 100 IU/kg (1 mg/kg) body
weight SC every 24 hours
The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thrombo-embolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by SC injection.
For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The disposable pre-filled syringe is ready for immediate use.

The use of a tuberculin syringe or equivalent is recommended when using ampoules or multidose vials to
assure withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, use the graduated pre-filled syringes to reach the
required volume by discarding the excess before injection. Please be aware that in some cases it is not
possible to achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be
rounded up to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. After
administration, the injection site should not be rubbed.

Note for the pre-filled syringes fitted with an automatic safety system: The safety system is triggered at the
end of the injection (see instructions in section 6.6).

In case of self-administration, patient should be advised to follow instructions provided in the patient
information leaflet included in the pack of this medicinal product.

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IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For IV injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an IV line. It should not be mixed or co-administered
with other medicinal products. To avoid the possible mixture of enoxaparin sodium with other medicinal
products, the IV access chosen should be flushed with a sufficient amount of sodium chloride 9 mg/ml
(0.9%) or 5% glucose in water for injections prior to and following the IV bolus administration of
enoxaparin sodium to clear the port of the medicinal product. Enoxaparin sodium may be safely administered
with normal sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the IV line.

Additional bolus for PCI when last SC administration was given more than 8 hours before balloon inflation
For patients being managed with PCI, an additional IV bolus of 30 IU/kg (0.3 mg/kg) is to be administered if
last SC administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/ml (0.9%) solution for
injection or 5% glucose in water for injections) as follows:
Withdraw 30 mL from the infusion bag with a syringe and discard the liquid. Inject the complete contents of
the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe into the 20 mL remaining in the bag. Gently mix
the contents of the bag. Withdraw the required volume of diluted solution with a syringe for administration
into the IV line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through IV line after dilution is completed at a concentration of 300 IU (3 mg) /mL.

Weight Required dose Volume to inject when diluted

30 IU/kg (0.3 mg/kg) to a final concentration of
300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10
105 3,150 31.5 10.5
110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12

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 125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
 At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
 At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.
Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.

98
Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH) or to any of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (>100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-
induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a
case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments
are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism,
any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on treatment), platelet count

99
should be measured. Patients must be aware that these symptoms may occur and if so, that they should inform
their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach a
sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,

100
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If the treatment with
enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours
after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after a
careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg ) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

Renal impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the
risk of bleeding. In these patients, careful clinical monitoring is advised, and biological monitoring by anti-
Xa activity measurement might be considered (see sections 4.2 and 5.2).

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Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.
In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.

Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:

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 - Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,
- Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
 Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

 Medicinal products increasing potassium levels:

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

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Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in
patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) SC once daily for prophylaxis of DVT following surgery or
in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or without PE,
patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg) SC dose every 12 hours
or a 150 IU/kg (1.5 mg/kg) SC dose once a day. In the clinical trials for treatment of unstable angina and
non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) SC every 12 hours, and in the clinical
study for treatment of acute STEMI enoxaparin sodium regimen was a 3,000 IU (30 mg) IV bolus followed
by 100 IU/kg (1 mg/kg) SC every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see section 4.4 and 'Description of selected adverse reactions' below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000
to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be estimated from
available data). Within each system organ class, adverse reactions are presented in order of decreasing
seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*
Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury *
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema

104
 Uncommon: Bullous dermatitis
Rare: Alopecia*
Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as: organic
lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting haemostasis
(see sections 4.4 and 4.5).

System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in

organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and unstable acute STEMI
without PE PE in angina and
patients non-Q-wave
with active MI
cancer
Very common: Common: Very Common b: Common: Common:
Blood Haemorrhag Haemorrha common: Haemorrha Haemorrhag Haemorrhag
and eα ge α Haemorrhag ge eα eα
lymphat eα Rare:
ic Rare: Retroperiton Uncommon:
system Retroperiton Uncommon: eal Intracranial
disorde eal Intracranial haemorrhage haemorrhage
rs haemorrhage haemorrhage ,
, Retroperiton
Retroperiton eal
eal haemorrhage
haemorrhage
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

105
Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)
System Prophylaxis in Prophylaxis Treatment in Extended Treatment Treatment in
organ surgical in medical patients with treatment of in patients patients with
class patients patients DVT with or DVT and with acute STEMI
without PE PE in unstable
patients angina and
with active non-Q-
cancer wave MI
Blood Very common: Uncommon: Very common: Unknown: Uncommon Common:
and Thrombocyto Thrombo- Thrombocyto Thromboc : Thrombocyto
lympha sisβ cytopenia sisβ ytopenia Thrombo- sisβ
tic cytopenia Thrombo-
system Common: Common: cytopenia
disorde Thrombo- Thrombo- Very rare:
rs cytopenia cytopenia Immuno-
allergic
thrombo-
cytopenia
β
: Platelet increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after IV, extracorporeal or SC administration may lead to
haemorrhagic complications. Following oral administration of even large doses, it is unlikely that enoxaparin
sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow IV injection of protamine. The dose of
protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the anticoagulant
effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the previous
8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be administered if
enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it
has been determined that a second dose of protamine is required. After 12 hours of the enoxaparin sodium
injection, protamine administration may not be required. However, even with high doses of protamine, the
anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about 60%) (see the
prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

106
Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

Pharmacodynamic effects

Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery, 179
patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin sodium
4,000 IU (40 mg) SC, were randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU
(40 mg) (n=90) once a day SC or to placebo (n=89) for 3 weeks. The incidence of DVT during extended
prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no PE was reported. No
major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium
4,000 IU (40 mg) Placebo
once a day SC once a day SC
n (%) n (%)
All treated extended prophylaxis 90 (100) 89 (100)
patients
Total VTE 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo =0.008
#p value versus placebo =0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) SC were randomised to a post-
discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day SC or to placebo
(n=131) for 3 weeks. Similar to the first study the incidence of VTE during extended prophylaxis was
significantly lower for enoxaparin sodium compared to placebo for both total VTE (enoxaparin sodium 21
[16%] versus placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium 8 [6.1%] versus placebo
28 [21.4%]; p=<0.001). No difference in major bleeding was found between the enoxaparin sodium and the
placebo group.

107
Extended prophylaxis of DVT following cancer surgery
A double-blind, multicenter trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or
pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) SC) daily for 6 to 10 days and were
then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days. Bilateral
venography was performed between days 25 and 31, or sooner if symptoms of venous thromboembolism
occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis for four weeks after
surgery for abdominal or pelvic cancer significantly reduced the incidence of venographically demonstrated
thrombosis, as compared with enoxaparin sodium prophylaxis for one week. The rates of venous
thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the placebo group and 4.8%
(n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three months [13.8% vs. 5.5%
(n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other complications during the
double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicenter, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day SC was compared to placebo in the prophylaxis of DVT in medical patients with
severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days).
This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day SC, enoxaparin
sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are provided
in the table below.

Enoxaparin Enoxaparin sodium Placebo

sodium 4,000 IU (40 mg)
2,000 IU (20 mg) once a day SC n (%)
once a day SC n (%)
n (%)
All treated medical 287 (100) 291(100) 288 (100)
patients during acute
illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to
be thromboembolic in origin
* p value versus placebo =0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without PE

In a multicenter, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once

108
a day SC, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours SC, or (iii) heparin IV bolus
(5,000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total
of 900 patients were randomised in the study and all patients were treated. All patients also received warfarin
sodium (dose adjusted according to prothrombin time to achieve an INR of 2.0 to 3.0), commencing within
72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days.
Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the
targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard
heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy
data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium Heparin

150 IU/kg 100 IU/kg aPTT adjusted IV
(1.5 mg/kg) once a (1 mg/kg) twice a therapy
day SC day SC n (%)
n (%) n (%)
All treated DVT 298 (100) 312 (100) 290 (100)
patients with or
without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
*The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

109
 Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

Enoxaparin all regimens

Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)
*All data with 95% CI

Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicenter study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either SC enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated heparin
adjusted based on aPTT. Patients had to be treated in hospital for a minimum of 2 days and a maximum of
8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be
followed up to 30 days. In comparison with heparin, enoxaparin sodium significantly reduced the combined
incidence of angina pectoris, myocardial infarction and death, with a decrease of 19.8 to 16.6% (relative risk
reduction of 16.2%) on day 14. This reduction in the combined incidence was maintained after 30 days (from
23.3 to 19.8%; relative risk reduction of 15%).

110
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the SC
injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicenter study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) IV bolus plus a 100 IU/kg
(1 mg/kg) SC dose followed by an SC injection of 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated
heparin adjusted based on aPTT for 48 hours. All patients were also treated with acetylsalicylic acid for a
minimum of 30 days. The enoxaparin sodium dosing strategy was adjusted for severe renally impaired
patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin sodium were given
until hospital discharge or for a maximum of eight days (whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no
additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of
30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last SC administration given more than 8 hours before
balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p=0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage (a
measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group (10.1%)
as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of treatment
with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the
enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

Hepatic impairment

Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single

111
and repeated SC administration and after single IV administration. The quantitative determination of anti-Xa
and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods.

Absorption

The absolute bioavailability of enoxaparin sodium after SC injection, based on anti-Xa activity, is close to
100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after SC injection and achieves
approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single SC administration of 2,000 IU, 4,000 IU,
100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

A 3,000 IU (30 mg) IV bolus immediately followed by a 100 IU/kg (1 mg/kg) SC every 12 hours provided
initial maximum anti-Xa activity level of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of
steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated SC administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily
regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about
15% higher than after a single dose. After repeated SC administration of the 100 IU/kg (1 mg/kg) twice daily
regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single
dose and mean maximum and trough anti-Xa activity levels of about 1.2 and 0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated SC administration no accumulation takes
place.

Plasma anti-IIa activity after SC administration is approximately ten-fold lower than anti-Xa activity. The
mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following SC injection and
reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of 100 IU/kg (1 mg/kg) twice daily
and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerization to lower
molecular weight species with much reduced biological potency.

Elimination

Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after a
150 IU /kg (1.5 mg/kg) 6-hour IV infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single SC dose to about 7 hours
after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

112
Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated SC
4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine clearance
<30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated SC
4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) IV dose however, AUC was two-fold higher than control.

Weight
After repeated SC 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is marginally
higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese control
subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-adjusted
clearance in obese subjects with SC dosing.

When non-weight adjusted dosing was administered, it was found after a single-SC 4,000 IU (40 mg) dose,
that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men
(<57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week SC toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week
SC and IV toxicity studies both in rats, and monkeys.

Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at SC doses of enoxaparin sodium up to 30 mg/kg/day did not
reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was found to have no effect
on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day.

113
6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections

6.2 Incompatibilities

SC injection

Do not mix with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

Enoxaparin sodium may be safely administered with sodium chloride 9mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

6.3 Shelf life

Pre-filled syringe

3 years

Diluted medicinal product with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in
water for injections.

8 hours

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

6.5 Nature and contents of container

0.8 mL of solution in:

- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a red polypropylene plunger rod. The syringe can be
additionally equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe
Passive needle guard.
.

Packs of:
- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes
- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes with needle guard
- 6, 10, 12, 20, 24 and 50 pre-filled syringes with manual needle guard
- 2 and 10 pre-filled syringes with UltraSafe Passive needle guard

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

INSTRUCTIONS FOR USE: PRE-FILLED SYRINGE

114
How to give yourself an injection of Inhixa with a pre-filled syringe without needle guard

If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

115
8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out.

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with needle guard

Your pre-filled syringe has a needle guard attached to it in order to protect you from needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

116
Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Push hard the plunger. The needle guard, which is in the form of a plastic cylinder, will be activated
automatically and it will completely cover the needle.

117
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with UltraSafe Passive needle guard

Your pre-filled syringe has UltraSafe Passive needle guard attached to it in order to protect you from needle
stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your stomach, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

118
Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Let go of the plunger and allow the syringe to move up until the entire needle is guarded and locks
into place.

119
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with manually activated needle guard

Your pre-filled syringe has a manually activated needle guard attached to it in order to protect you from
needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from your
belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

120
6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Firmly hold the syringe tube with one hand (A). With the other hand hold the base, “wings” of the
syringe (B), and pull the base until you hear a clicking sound (C). Now the used needle is completely
protected.

121
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/007
EU/1/16/1132/008
EU/1/16/1132/017
EU/1/16/1132/018
EU/1/16/1132/029
EU/1/16/1132/030
EU/1/16/1132/039
EU/1/16/1132/040
EU/1/16/1132/047
EU/1/16/1132/048
EU/1/16/1132/059
EU/1/16/1132/060
EU/1/16/1132/084
EU/1/16/1132/088
EU/1/16/1132/093
EU/1/16/1132/103
EU/1/16/1132/104
EU/1/16/1132/105
EU/1/16/1132/106
EU/1/16/1132/112
EU/1/16/1132/113
EU/1/16/1132/121
EU/1/16/1132/122
EU/1/16/1132/123

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

122
Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

123
1. NAME OF THE MEDICINAL PRODUCT

Inhixa 10,000 IU (100 mg)/1 mL solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

10,000 IU/mL (100 mg/mL) solution for injection

Each pre-filled syringe contains enoxaparin sodium 10,000 IU anti-Xa activity (equivalent to 100 mg) in
1 mL water for injections.

For the full list of excipients, see section 6.1.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

3. PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe (injection).

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI), in
combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be
managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.
In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is 2,000 IU
(20 mg) once daily by subcutaneous (SC) injection. Preoperative initiation (2 hours before surgery) of
enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk surgery.

124
 In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of
7-10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the patient
no longer has significantly reduced mobility.
In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by SC injection preferably started 12 hours before surgery. If there is a need for
earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high risk patient waiting
for a deferred orthopaedic surgery), the last injection should be administered no later than 12 hours prior to
surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis
up to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal
or pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by SC injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered SC either as a once daily injection of 150 IU/kg (1.5 mg/kg) or as
twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is 100 IU/kg
(1 mg/kg) every 12 hours by SC injection administered in combination with antiplatelet therapy. Treatment

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should be maintained for a minimum of 2 days and continued until clinical stabilization. The usual duration
of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325 mg/day
long-term regardless of treatment strategy.

For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous (IV)
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) SC dose followed by 100 IU/kg (1 mg/kg)
administered SC every 12 hours (maximum 10,000 IU (100 mg) for each of the first two SC doses).
Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg to 325 mg once daily) should be
administered concomitantly unless contraindicated. The recommended duration of treatment is 8 days or
until hospital discharge, whichever comes first. When administered in conjunction with a thrombolytic
(fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and
30 minutes after the start of fibrinolytic therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last dose of enoxaparin sodium SC was given less than
8 hours before balloon inflation, no additional dosing is needed. If the last SC administration
was given more than 8 hours before balloon inflation, an IV bolus of 30 IU/kg (0.3 mg/kg)
enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below “renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥75 years of age, an initial IV bolus must not be used.
Initiate dosing with 75 IU/kg (0.75 mg/kg) SC every 12 hours (maximum 7,500 IU (75 mg) for each of the
first two SC doses only, followed by 75 IU/kg (0.75 mg/kg) SC dosing for the remaining doses). For dose in
elderly patients with impaired kidney function, see below “renal impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):

Indication Dosing regimen

Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) SC once daily

Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight SC once daily

Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight SC once daily

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Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) IV bolus plus 100 IU/kg
(1 mg/kg) body weight SC and then 100 IU/kg
(1 mg/kg) body weight SC every 24 hours

Treatment of acute STEMI (patients over 75) No IV initial bolus, 100 IU/kg (1 mg/kg) body
weight SC and then 100 IU/kg (1 mg/kg) body
weight SC every 24 hours
The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thrombo-embolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by SC injection.
For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The disposable pre-filled syringe is ready for immediate use.

The use of a tuberculin syringe or equivalent is recommended when using ampoules or multidose vials to
assure withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, use the graduated pre-filled syringes to reach the
required volume by discarding the excess before injection. Please be aware that in some cases it is not
possible to achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be
rounded up to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. After
administration, the injection site should not be rubbed.

Note for the pre-filled syringes fitted with an automatic safety system: The safety system is triggered at the
end of the injection (see instructions in section 6.6).

In case of self-administration, patient should be advised to follow instructions provided in the patient
information leaflet included in the pack of this medicinal product.

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IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single IV bolus injection immediately followed by a SC
injection.
For IV injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an IV line. It should not be mixed or co-administered
with other medicinal products. To avoid the possible mixture of enoxaparin sodium with other medicinal
products, the IV access chosen should be flushed with a sufficient amount of sodium chloride 9 mg/ml
(0.9%) or 5% glucose in water for injections prior to and following the IV bolus administration of
enoxaparin sodium to clear the port of the medicinal product. Enoxaparin sodium may be safely administered
with normal sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the IV line.

Additional bolus for PCI when last SC administration was given more than 8 hours before balloon inflation
For patients being managed with PCI, an additional IV bolus of 30 IU/kg (0.3 mg/kg) is to be administered if
last SC administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/ml (0.9%) solution for
injection or 5% glucose in water for injections) as follows:
Withdraw 30 mL from the infusion bag with a syringe and discard the liquid. Inject the complete contents of
the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe into the 20 mL remaining in the bag. Gently mix
the contents of the bag. Withdraw the required volume of diluted solution with a syringe for administration
into the IV line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through IV line after dilution is completed at a concentration of 300 IU (3 mg) /mL.

Weight Required dose Volume to inject when diluted

30 IU/kg (0.3 mg/kg) to a final concentration of
300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10
105 3,150 31.5 10.5
110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12

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 125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
 At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
 At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.
Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.

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Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH) or to any of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (>100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-
induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a
case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments
are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism,
any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on treatment), platelet count

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should be measured. Patients must be aware that these symptoms may occur and if so, that they should inform
their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach
a sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

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Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If the treatment with
enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours
after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma
formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after a
careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg ) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

Renal impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the
risk of bleeding. In these patients, careful clinical monitoring is advised, and biological monitoring by anti-
Xa activity measurement might be considered (see sections 4.2 and 5.2).
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

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In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.

Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:
- Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,

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 - Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
 Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

 Medicinal products increasing potassium levels:

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in

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patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) SC once daily for prophylaxis of DVT following surgery or
in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or without PE,
patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg) SC dose every 12 hours
or a 150 IU/kg (1.5 mg/kg) SC dose once a day. In the clinical trials for treatment of unstable angina and
non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) SC every 12 hours, and in the clinical
study for treatment of acute STEMI enoxaparin sodium regimen was a 3,000 IU (30 mg) IV bolus followed
by 100 IU/kg (1 mg/kg) SC every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see section 4.4 and 'Description of selected adverse reactions' below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000
to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be estimated from
available data). Within each system organ class, adverse reactions are presented in order of decreasing
seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*
Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury *
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema
Uncommon: Bullous dermatitis
Rare: Alopecia*

135
 Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as: organic
lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting haemostasis
(see sections 4.4 and 4.5).
System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in
organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and unstable acute STEMI
without PE PE in angina and
patients non-Q-wave
with active MI
cancer
Very common: Common: Very Common b: Common: Common:
Blood Haemorrhag Haemorrha common: Haemorrha Haemorrhag Haemorrhag
and eα ge α Haemorrhag ge eα eα
lymphat eα Rare:
ic Rare: Retroperiton Uncommon:
system Retroperiton Uncommon: eal Intracranial
disorde eal Intracranial haemorrhage haemorrhage
rs haemorrhage haemorrhage ,
, Retroperiton
Retroperiton eal
eal haemorrhage
haemorrhage
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

136
Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)
System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in
organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and PE unstable acute STEMI
without PE in patients angina and
with active non-Q-wave
cancer MI
Blood Very common: Uncommon: Very common: Unknown: Uncommon: Common:
and Thrombocyto Thrombo- Thrombocyto Thrombocyt Thrombo- Thrombocyto
lympha sisβ cytopenia sisβ openia cytopenia sisβ
tic Thrombo-
system Common: Common: cytopenia
disorde Thrombo- Thrombo- Very rare:
rs cytopenia cytopenia Immuno-
allergic
thrombo-
cytopenia
β
: Platelet increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after IV, extracorporeal or SC administration may lead to
haemorrhagic complications. Following oral administration of even large doses, it is unlikely that enoxaparin
sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow IV injection of protamine. The dose of
protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the anticoagulant
effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the previous
8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be administered if
enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it
has been determined that a second dose of protamine is required. After 12 hours of the enoxaparin sodium
injection, protamine administration may not be required. However, even with high doses of protamine, the
anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about 60%) (see the
prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

137
Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

Pharmacodynamic effects
Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery, 179
patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin sodium
4,000 IU (40 mg) SC, were randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU
(40 mg) (n=90) once a day SC or to placebo (n=89) for 3 weeks. The incidence of DVT during extended
prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no PE was reported. No
major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium
4,000 IU (40 mg) Placebo
once a day SC once a day SC
n (%) n (%)
All treated extended prophylaxis 90 (100) 89 (100)
patients
Total VTE 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo =0.008
#p value versus placebo =0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) SC were randomised to a post-
discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day SC or to placebo
(n=131) for 3 weeks. Similar to the first study the incidence of VTE during extended prophylaxis was
significantly lower for enoxaparin sodium compared to placebo for both total VTE (enoxaparin sodium 21
[16%] versus placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium 8 [6.1%] versus placebo
28 [21.4%]; p=<0.001). No difference in major bleeding was found between the enoxaparin sodium and the
placebo group.

Extended prophylaxis of DVT following cancer surgery

138
A double-blind, multicenter trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or
pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) SC) daily for 6 to 10 days and were
then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days. Bilateral
venography was performed between days 25 and 31, or sooner if symptoms of venous thromboembolism
occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis for four weeks after
surgery for abdominal or pelvic cancer significantly reduced the incidence of venographically demonstrated
thrombosis, as compared with enoxaparin sodium prophylaxis for one week. The rates of venous
thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the placebo group and 4.8%
(n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three months [13.8% vs. 5.5%
(n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other complications during the
double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicenter, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day SC was compared to placebo in the prophylaxis of DVT in medical patients with
severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days).
This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day SC, enoxaparin
sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are provided
in the table below.

Enoxaparin Enoxaparin sodium Placebo

sodium 4,000 IU (40 mg)
2,000 IU (20 mg) once a day SC n (%)
once a day SC n (%)
n (%)
All treated medical 287 (100) 291(100) 288 (100)
patients during acute
illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to
be thromboembolic in origin
* p value versus placebo =0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without PE

In a multicenter, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once
a day SC, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours SC, or (iii) heparin IV bolus

139
(5,000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total
of 900 patients were randomised in the study and all patients were treated. All patients also received warfarin
sodium (dose adjusted according to prothrombin time to achieve an INR of 2.0 to 3.0), commencing within
72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days.
Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the
targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard
heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy
data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium Heparin

150 IU/kg 100 IU/kg aPTT adjusted IV
(1.5 mg/kg) once a (1 mg/kg) twice a therapy
day SC day SC n (%)
n (%) n (%)
All treated DVT 298 (100) 312 (100) 290 (100)
patients with or
without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
*The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

140
 Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

Enoxaparin all regimens

Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)
*All data with 95% CI

Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicenter study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either SC enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated heparin
adjusted based on aPTT. Patients had to be treated in hospital for a minimum of 2 days and a maximum of
8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be
followed up to 30 days. In comparison with heparin, enoxaparin sodium significantly reduced the combined
incidence of angina pectoris, myocardial infarction and death, with a decrease of 19.8 to 16.6% (relative risk
reduction of 16.2%) on day 14. This reduction in the combined incidence was maintained after 30 days (from
23.3 to 19.8%; relative risk reduction of 15%).

141
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the SC
injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicenter study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) IV bolus plus a 100 IU/kg
(1 mg/kg) SC dose followed by an SC injection of 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated
heparin adjusted based on aPTT for 48 hours. All patients were also treated with acetylsalicylic acid for
a minimum of 30 days. The enoxaparin sodium dosing strategy was adjusted for severe renally impaired
patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin sodium were given
until hospital discharge or for a maximum of eight days (whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no
additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of
30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last SC administration given more than 8 hours before
balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p=0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage
(a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group
(10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of
treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the
enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

Hepatic impairment

Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single

142
and repeated SC administration and after single IV administration. The quantitative determination of anti-Xa
and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods.

Absorption

The absolute bioavailability of enoxaparin sodium after SC injection, based on anti-Xa activity, is close to
100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after SC injection and achieves
approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single SC administration of 2,000 IU, 4,000 IU,
100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

A 3,000 IU (30 mg) IV bolus immediately followed by a 100 IU/kg (1 mg/kg) SC every 12 hours provided
initial maximum anti-Xa activity level of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of
steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated SC administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily
regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about
15% higher than after a single dose. After repeated SC administration of the 100 IU/kg (1 mg/kg) twice daily
regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single
dose and mean maximum and trough anti-Xa activity levels of about 1.2 and 0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated SC administration no accumulation takes
place.

Plasma anti-IIa activity after SC administration is approximately ten-fold lower than anti-Xa activity. The
mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following SC injection and
reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of 100 IU/kg (1 mg/kg) twice daily
and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerization to lower
molecular weight species with much reduced biological potency.

Elimination

Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after a
150 IU /kg (1.5 mg/kg) 6-hour IV infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single SC dose to about 7 hours
after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

143
Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated SC
4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine clearance
<30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated SC
4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) IV dose however, AUC was two-fold higher than control.

Weight
After repeated SC 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is marginally
higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese control
subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-adjusted
clearance in obese subjects with SC dosing.

When non-weight adjusted dosing was administered, it was found after a single-SC 4,000 IU (40 mg) dose,
that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men
(<57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week SC toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week
SC and IV toxicity studies both in rats, and monkeys.

Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at SC doses of enoxaparin sodium up to 30 mg/kg/day did not
reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was found to have no effect
on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day.

144
6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections

6.2 Incompatibilities

SC injection
Do not mix with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

Enoxaparin sodium may be safely administered with sodium chloride 9mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

6.3 Shelf life

Pre-filled syringe

3 years

Diluted medicinal product with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in
water for injections.

8 hours

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

6.5 Nature and contents of container

1 mL of solution in:
- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a black polypropylene plunger rod. The syringe can be
additionally equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe
Passive needle guard.

Packs of:
- 2, 6, 10, 12, 20, 24, 30, 50 and 90 pre-filled syringes
- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes with needle guard
- 6, 10, 12, 20, 24 and 50 pre-filled syringes with manual needle guard
- 2 and 10 pre-filled syringes with UltraSafe Passive needle guard

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

INSTRUCTIONS FOR USE: PRE-FILLED SYRINGE

145
How to give yourself an injection of Inhixa with a pre-filled syringe without needle guard

If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

146
8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out.

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with needle guard

Your pre-filled syringe has a needle guard attached to it in order to protect you from needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

147
Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Push hard the plunger. The needle guard, which is in the form of a plastic cylinder, will be activated
automatically and it will completely cover the needle.

148
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with UltraSafe Passive needle guard

Your pre-filled syringe has UltraSafe Passive needle guard attached to it in order to protect you from needle
stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your stomach, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

149
Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Let go of the plunger and allow the syringe to move up until the entire needle is guarded and locks
into place.

150
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with manually activated needle guard

Your pre-filled syringe has a manually activated needle guard attached to it in order to protect you from
needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from your
belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

151
6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Firmly hold the syringe tube with one hand (A). With the other hand hold the base, “wings” of the
syringe (B), and pull the base until you hear a clicking sound (C). Now the used needle is completely
protected.

152
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/009
EU/1/16/1132/010
EU/1/16/1132/019
EU/1/16/1132/020
EU/1/16/1132/022
EU/1/16/1132/031
EU/1/16/1132/032
EU/1/16/1132/041
EU/1/16/1132/042
EU/1/16/1132/049
EU/1/16/1132/050
EU/1/16/1132/061
EU/1/16/1132/062
EU/1/16/1132/063
EU/1/16/1132/089
EU/1/16/1132/094
EU/1/16/1132/107
EU/1/16/1132/108
EU/1/16/1132/109
EU/1/16/1132/110
EU/1/16/1132/114
EU/1/16/1132/115
EU/1/16/1132/124
EU/1/16/1132/125
EU/1/16/1132/126

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

153
Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

154
1. NAME OF THE MEDICINAL PRODUCT

Inhixa 12,000 IU (120 mg)/0.8 mL solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains enoxaparin sodium 12,000 IU anti-Xa activity (equivalent to 120 mg) in
0.8 mL water for injections.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe (injection).

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI),
in combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to
be managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.
 In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is
2,000 IU (20 mg) once daily by subcutaneous injection. Preoperative initiation (2 hours before surgery)
of enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk surgery.
In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of
7-10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the patient
no longer has significantly reduced mobility.

155
 In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by subcutaneous injection preferably started 12 hours before surgery. If there
is a need for earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high risk
patient waiting for a deferred orthopaedic surgery), the last injection should be administered no later
than 12 hours prior to surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis
up to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal or
pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by subcutaneous injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered subcutaneously either as a once daily injection of 150 IU/kg
(1.5 mg/kg) or as twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
 For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is
100 IU/kg (1 mg/kg) every 12 hours by subcutaneous injection administered in combination with
antiplatelet therapy. Treatment should be maintained for a minimum of 2 days and continued until
clinical stabilization. The usual duration of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325 mg/day
long-term regardless of treatment strategy.

156
 For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) subcutaneous dose followed by 100 IU/kg
(1 mg/kg) administered subcutaneously every 12 hours (maximum 10,000 IU (100 mg) for each of the
first two subcutaneous doses). Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg
to 325 mg once daily) should be administered concomitantly unless contraindicated. The
recommended duration of treatment is 8 days or until hospital discharge, whichever comes first. When
administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin
sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic
therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last dose of enoxaparin sodium was given less than
8 hours before balloon inflation, no additional dosing is needed. If the last subcutaneous
administration was given more than 8 hours before balloon inflation, an intravenous bolus of
30 IU/kg (0.3 mg/kg) enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.
No data are available.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below “renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥ 75 years of age, an initial intravenous bolus must not be
used. Initiate dosing with 75 IU/kg (0.75 mg/kg) subcutaneous injection every 12 hours (maximum 7,500 IU
(75 mg) for each of the first two subcutaneous doses only, followed by 75 IU/kg (0.75 mg/kg) subcutaneous
dosing for the remaining doses). For dose in elderly patients with impaired kidney function, see below “renal
impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
< 15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):
Indication Dosing regimen
Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) subcutaneously once daily
Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight subcutaneously once daily
Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight subcutaneously once daily
Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) intravenous bolus plus 100 IU/kg
(1 mg/kg) body weight subcutaneously and then 100 IU/kg
(1 mg/kg) body weight subcutaneously every 24 hours
Treatment of acute STEMI (patients over 75) No intravenous initial bolus, 100 IU/kg (1 mg/kg) body
weight subcutaneously and then 100 IU/kg (1 mg/kg) body
weight subcutaneously every 24 hours
The recommended dose adjustments do not apply to the haemodialysis indication.

157
Moderate and mild renal impairment
Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thrombo-embolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by subcutaneous injection.
 For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately
followed by a subcutaneous injection.
 For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The disposable pre-filled syringe is ready for immediate use.

The use of a tuberculin syringe or equivalent is recommended when using ampoules or multidose vials to
assure withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, the graduated pre-filled syringes should be used
to reach the required volume by discarding the excess before injection. In some cases it is not possible to
achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be rounded up
to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. The injection
site should not be rubbed after administration.

Note for the pre-filled syringes fitted with an automatic safety system: The safety system is triggered at the
end of the injection (see instructions in section 6.6).

In case of self-administration, patient should be advised to follow instructions provided in the patient
information leaflet included in the pack of this medicinal product.

IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately followed
by a subcutaneous injection.
For intravenous injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or
co-administered with other medicinal products. To avoid the possible mixture of enoxaparin sodium with
other medicinal products, the intravenous access chosen should be flushed with a sufficient amount of
sodium chloride 9 mg/ml (0.9%) or 5% glucose in water for injections prior to and following the intravenous

158
bolus administration of enoxaparin sodium to clear the port of the medicinal product. Enoxaparin sodium
may be safely administered with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in
water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the intravenous line.

Additional bolus for PCI when last subcutaneous administration was given more than 8 hours before balloon
inflation
For patients being managed with PCI, an additional intravenous bolus of 30 IU/kg (0.3 mg/kg) is to be
administered if last subcutaneous administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/ml (0.9%) solution for
injection or 5% glucose in water for injections) as follows:
30 mL of solution should be withdrawn from the infusion bag with a syringe and discarded. The complete
contents of the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe should be injected into the 20 mL
remaining in the bag. The contents of the bag should be gently mixed. Then, the required volume of diluted
solution should be withdrawn with a syringe for administration into the intravenous line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through intravenous line after dilution is completed at a concentration of

300 IU (3 mg)/mL.

Weight Required dose Volume to inject when diluted

30 IU/kg (0.3 mg/kg) to a final concentration of
300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10
105 3,150 31.5 10.5
110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12
125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

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Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
 At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
 At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.
Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.
Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

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4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH) or to any of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (> 100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (> 100 days) of
heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in
such a case must be made only after a careful benefit risk assessment and after non-heparin alternative
treatments are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism,
any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on treatment), platelet count
should be measured. Patients must be aware that these symptoms may occur and if so, that they should inform
their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

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Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach
a sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

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Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last intravenous/subcutaneous enoxaparin sodium injection. If the
treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than
6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or
hematoma formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after
a careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

Renal impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the
risk of bleeding. In these patients, careful clinical monitoring is advised, and biological monitoring by
anti-Xa activity measurement might be considered (see sections 4.2 and 5.2).
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
< 15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

163
In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (< 45 kg) and low-weight men (< 57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI > 30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.

Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:
- Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,

164
 - Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

Medicinal products increasing potassium levels

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in
patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical

165
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) subcutaneously once daily for prophylaxis of DVT following
surgery or in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or
without PE, patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg)
subcutaneous dose every 12 hours or a 150 IU/kg (1.5 mg/kg) subcutaneous dose once a day. In the clinical
trials for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg
(1 mg/kg) subcutaneously every 12 hours, and in the clinical study for treatment of acute STEMI enoxaparin
sodium regimen was a 3,000 IU (30 mg) intravenous bolus followed by 100 IU/kg (1 mg/kg) subcutaneously
every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see section 4.4 and 'Description of selected adverse reactions' below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000) or not known (cannot be
estimated from available data). Within each system organ class, adverse reactions are presented in order of
decreasing seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*
Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury*
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema
Uncommon: Bullous dermatitis
Rare: Alopecia*

166
 Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as:
organic lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting
haemostasis (see sections 4.4 and 4.5).

System Prophylaxis Prophylaxis Treatment Extended Treatment in Treatment in

organ class in surgical in medical in patients treatment of patients with patients with
patients patients with DVT DVT and PE unstable acute STEMI
with or in patients angina and
without PE with active non-Q-wave
cancer MI
Blood and Very Common: Very Common b: Common: Common:
lymphatic common: Haemorrha common: Haemorrhag Haemorrhag Haemorrhage
system Haemorrhag ge α Haemorrha e eα α

disorders eα ge α
Rare: Uncommon:
Rare: Uncommon Retroperiton Intracranial
Retroperiton : eal haemorrhage,
eal Intracranial haemorrhage Retroperitone
haemorrhage haemorrhag al
e, haemorrhage
Retroperiton
eal
haemorrhag
e
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

167
 Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)
System Prophylaxis Prophylaxi Treatment Extended Treatment in Treatment in
organ class in surgical s in in patients treatment of patients with patients with
patients medical with DVT DVT and PE unstable acute STEMI
patients with or in patients angina and
without PE with active non-Q-wave
cancer MI
Blood and Very Uncommon Very Unknown: Uncommon: Common:
lymphatic common: : Thrombo- common: Thrombocyt Thrombo- Thrombocyto
system Thrombocyto cytopenia Thrombo- openia cytopenia sisβ Thrombo-
disorders sisβ cytosisβ cytopenia
Very rare:
Common: Immuno-
Common: Thrombo- allergic
Thrombo- cytopenia thrombo-
cytopenia cytopenia
β
: Platelet increased > 400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after intravenous, extracorporeal or subcutaneous

administration may lead to haemorrhagic complications. Following oral administration of even large doses, it
is unlikely that enoxaparin sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow intravenous injection of protamine. The dose
of protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the
anticoagulant effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the
previous 8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be
administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine
administration, or if it has been determined that a second dose of protamine is required. After 12 hours of the
enoxaparin sodium injection, protamine administration may not be required. However, even with high doses
of protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about
60%) (see the prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

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Pharmacodynamic effects

Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery,
179 patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin
sodium 4,000 IU (40 mg) subcutaneously, were randomised to a post-discharge regimen of either enoxaparin
sodium 4,000 IU (40 mg) (n = 90) once a day subcutaneously or to placebo (n = 89) for 3 weeks. The
incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to
placebo, no PE was reported. No major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium Placebo

4,000 IU (40 mg) once a day once a day
subcutaneously subcutaneously
n (%) n (%)
All treated extended prophylaxis patients 90 (100) 89 (100)
Total VTE 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo = 0.008
#p value versus placebo = 0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) subcutaneously were
randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n = 131) once a day
subcutaneously or to placebo (n = 131) for 3 weeks. Similar to the first study the incidence of VTE during
extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo for both total VTE
(enoxaparin sodium 21 [16%] versus placebo 45 [34.4%]; p = 0.001) and proximal DVT (enoxaparin sodium
8 [6.1%] versus placebo 28 [21.4%]; p =< 0.001). No difference in major bleeding was found between the
enoxaparin sodium and the placebo group.

Extended prophylaxis of DVT following cancer surgery

A double-blind, multicentre trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or

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pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) subcutaneously) daily for 6 to 10 days
and were then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days.
Bilateral venography was performed between days 25 and 31, or sooner if symptoms of venous
thromboembolism occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis
for four weeks after surgery for abdominal or pelvic cancer significantly reduced the incidence of
venographically demonstrated thrombosis, as compared with enoxaparin sodium prophylaxis for one week.
The rates of venous thromboembolism at the end of the double-blind phase were 12.0 % (n = 20) in the
placebo group and 4.8% (n = 8) in the enoxaparin sodium group; p = 0.02. This difference persisted at three
months [13.8% vs. 5.5% (n = 23 vs 9), p = 0.01]. There were no differences in the rates of bleeding or other
complications during the double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicentre, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day subcutaneously was compared to placebo in the prophylaxis of DVT in medical patients
with severely restricted mobility during acute illness (defined as walking distance of < 10 meters for
≤ 3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥ 75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day subcutaneously,
enoxaparin sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are
provided in the table below.

Enoxaparin sodium Enoxaparin sodium Placebo

2,000 IU (20 mg) 4,000 IU (40 mg)
once a day once a day
subcutaneously subcutaneously n (%)
n (%) n (%)
All treated medical patients 287 (100) 291 (100) 288 (100)
during acute illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin
* p value versus placebo = 0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without PE

In a multicentre, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once
a day subcutaneously, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours subcutaneously,
or (iii) heparin intravenous bolus (5,000 IU) followed by a continuous infusion (administered to achieve an
aPTT of 55 to 85 seconds). A total of 900 patients were randomised in the study and all patients were treated.
All patients also received warfarin sodium (dose adjusted according to prothrombin time to achieve an INR
of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy,
and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was administered for a minimum
of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were

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equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT
and/or PE). The efficacy data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium Heparin

150 IU/kg (1.5 mg/kg) 100 IU/kg (1 mg/kg) aPTT adjusted
once a day twice a day Intravenous Therapy
subcutaneously subcutaneously n (%)
n (%) n (%)
All treated DVT patients 298 (100) 312 (100) 290 (100)
with or without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
*The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

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 Enoxaparin all regimens
Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)
*All data with 95% CI

Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicentre study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either subcutaneous enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or intravenous
unfractionated heparin adjusted based on aPTT. Patients had to be treated in hospital for a minimum of
2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital
discharge. The patients had to be followed up to 30 days. In comparison with heparin, enoxaparin sodium
significantly reduced the combined incidence of angina pectoris, myocardial infarction and death, with a
decrease of 19.8 to 16.6% (relative risk reduction of 16.2%) on day 14. This reduction in the combined
incidence was maintained after 30 days (from 23.3 to 19.8%; relative risk reduction of 15%).
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the
subcutaneous injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicentre study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) intravenous bolus plus
a 100 IU/kg (1 mg/kg) subcutaneous dose followed by an subcutaneous injection of 100 IU/kg (1 mg/kg)
every 12 hours or intravenous unfractionated heparin adjusted based on aPTT for 48 hours. All patients were
also treated with acetylsalicylic acid for a minimum of 30 days. The enoxaparin sodium dosing strategy was
adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The subcutaneous
injections of enoxaparin sodium were given until hospital discharge or for a maximum of eight days
(whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no

172
additional dosing, if last subcutaneous administration given less than 8 hours before balloon inflation,
intravenous bolus of 30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last subcutaneous administration given
more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p < 0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p < 0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p = 0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage
(a measure of net clinical benefit) was significantly lower (p < 0.0001) in the enoxaparin sodium group
(10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of
treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p < 0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the
enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

Hepatic impairment

Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single
and repeated subcutaneous administration and after single intravenous administration. The quantitative
determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic
methods.

Absorption

The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is
close to 100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after subcutaneous injection and
achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single subcutaneous administration of
2,000 IU, 4,000 IU, 100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

173
A 3,000 IU (30 mg) intravenous bolus immediately followed by a 100 IU/kg (1 mg/kg) subcutaneous every
12 hours provided initial maximum anti-Xa activity level of 1.16 IU/mL (n = 16) and average exposure
corresponding to 88% of steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated subcutaneous administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once
daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio
about 15% higher than after a single dose. After repeated subcutaneous administration of the 100 IU/kg
(1 mg/kg) twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65%
higher than after a single dose and mean maximum and trough anti-Xa activity levels of about 1.2 and
0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated subcutaneous administration no
accumulation takes place.

Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa
activity. The mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following
subcutaneous injection and reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of
100 IU/kg (1 mg/kg) twice daily and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerisation to lower
molecular weight species with much reduced biological potency.

Elimination

Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after a
150 IU /kg (1.5 mg/kg) 6-hour intravenous infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single subcutaneous dose to about
7 hours after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment

174
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated
subcutaneous 4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine
clearance < 30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated
subcutaneous 4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) intravenous dose however, AUC was two-fold higher than control.

Weight
After repeated subcutaneous 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is
marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese
control subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-
adjusted clearance in obese subjects with subcutaneous dosing.

When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 4,000 IU
(40 mg) dose, that anti-Xa exposure is 52% higher in low-weight women (< 45 kg) and 27% higher in
low-weight men (< 57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the
26-week subcutaneous and intravenous toxicity studies both in rats, and monkeys.

Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin sodium up to
30 mg/kg/day did not reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was
found to have no effect on fertility or reproductive performance of male and female rats at subcutaneous
doses up to 20 mg/kg/day.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections

6.2 Incompatibilities

SC injection

Do not mix with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

175
Enoxaparin sodium may be safely administered with sodium chloride 9 mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

6.3 Shelf life

Pre-filled syringe

3 years

Diluted medicinal product with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in
water for injections.

8 hours

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

6.5 Nature and contents of container

0.8 mL of solution in a clear, colourless type I neutral glass syringe barrel with fixed needle and needle
shield closed by chlorobutyl rubber stopper and a purple polypropylene plunger rod. The syringe can be
additionally equipped with needle guard.

Packs of:
- 2, 10 and 30 pre-filled syringes,
- 10 and 30 pre-filled syringes with needle guard.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

INSTRUCTIONS FOR USE: PRE-FILLED SYRINGE

How to give yourself an injection of Inhixa with a pre-filled syringe without needle guard

If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.

176
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out.

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

177
When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with needle guard

Your pre-filled syringe has a needle guard attached to it in order to protect you from needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

178
8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Push hard the plunger. The needle guard, which is in the form of a plastic cylinder, will be activated
automatically and it will completely cover the needle.

11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

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EU/1/16/1132/069
EU/1/16/1132/073
EU/1/16/1132/075
EU/1/16/1132/076
EU/1/16/1132/077

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

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1. NAME OF THE MEDICINAL PRODUCT

Inhixa 15,000 IU (150 mg)/1 mL solution for injection in pre-filled syringe

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains enoxaparin sodium 15,000 IU anti-Xa activity (equivalent to 150 mg) in
1 mL water for injections.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection in pre-filled syringe (injection).

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI),
in combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to
be managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.
 In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is
2,000 IU (20 mg) once daily by subcutaneous injection. Preoperative initiation (2 hours before
surgery) of enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk
surgery.

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 In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of
7-10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the
patient no longer has significantly reduced mobility.
 In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by subcutaneous injection preferably started 12 hours before surgery. If there
is a need for earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high
risk patient waiting for a deferred orthopaedic surgery), the last injection should be administered no
later than 12 hours prior to surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis
up to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal or
pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by subcutaneous injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered subcutaneously either as a once daily injection of 150 IU/kg
(1.5 mg/kg) or as twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
 For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is
100 IU/kg (1 mg/kg) every 12 hours by subcutaneous injection administered in combination with

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 antiplatelet therapy. Treatment should be maintained for a minimum of 2 days and continued until
clinical stabilization. The usual duration of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325 mg/day
long-term regardless of treatment strategy.

 For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) subcutaneous dose followed by 100 IU/kg
(1 mg/kg) administered subcutaneously every 12 hours (maximum 10,000 IU (100 mg) for each of the
first two subcutaneous doses). Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg
to 325 mg once daily) should be administered concomitantly unless contraindicated. The
recommended duration of treatment is 8 days or until hospital discharge, whichever comes first. When
administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin
sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic
therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last dose of enoxaparin sodium was given less than
8 hours before balloon inflation, no additional dosing is needed. If the last subcutaneous
administration was given more than 8 hours before balloon inflation, an intravenous bolus of
30 IU/kg (0.3 mg/kg) enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.
No data are available.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below “renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥ 75 years of age, an initial intravenous bolus must not be
used. Initiate dosing with 75 IU/kg (0.75 mg/kg) subcutaneous injection every 12 hours (maximum 7,500 IU
(75 mg) for each of the first two subcutaneous doses only, followed by 75 IU/kg (0.75 mg/kg) subcutaneous
dosing for the remaining doses). For dose in elderly patients with impaired kidney function, see below “renal
impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
< 15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):
Indication Dosing regimen
Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) subcutaneously once daily
Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight subcutaneously once daily
Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight subcutaneously once daily

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Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) intravenous bolus plus 100 IU/kg
(1 mg/kg) body weight subcutaneously and then 100 IU/kg
(1 mg/kg) body weight subcutaneously every 24 hours
Treatment of acute STEMI (patients over 75) No intravenous initial bolus, 100 IU/kg (1 mg/kg) body
weight subcutaneously and then 100 IU/kg (1 mg/kg) body
weight subcutaneously every 24 hours
The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thrombo-embolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by subcutaneous injection.
 For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately
followed by a subcutaneous injection.
 For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The disposable pre-filled syringe is ready for immediate use.

The use of a tuberculin syringe or equivalent is recommended when using ampoules or multidose vials to
assure withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, the graduated pre-filled syringes should be used
to reach the required volume by discarding the excess before injection. In some cases it is not possible to
achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be rounded up
to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. The injection
site should not be rubbed after administration.

Note for the pre-filled syringes fitted with an automatic safety system: The safety system is triggered at the
end of the injection (see instructions in section 6.6).

In case of self-administration, patient should be advised to follow instructions provided in the patient
information leaflet included in the pack of this medicinal product.

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IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately followed
by a subcutaneous injection.
For intravenous injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or
co-administered with other medicinal products. To avoid the possible mixture of enoxaparin sodium with
other medicinal products, the intravenous access chosen should be flushed with a sufficient amount of
sodium chloride 9 mg/ml (0.9%) or 5% glucose in water for injections prior to and following the intravenous
bolus administration of enoxaparin sodium to clear the port of the medicinal product. Enoxaparin sodium
may be safely administered with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in
water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the intravenous line.

Additional bolus for PCI when last subcutaneous administration was given more than 8 hours before balloon
inflation
For patients being managed with PCI, an additional intravenous bolus of 30 IU/kg (0.3 mg/kg) is to be
administered if last subcutaneous administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/ml (0.9%) solution for
injection or 5% glucose in water for injections) as follows:
30 mL of solution should be withdrawn from the infusion bag with a syringe and discarded. The complete
contents of the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe should be injected into the 20 mL
remaining in the bag. The contents of the bag should be gently mixed. Then, the required volume of diluted
solution should be withdrawn with a syringe for administration into the intravenous line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through intravenous line after dilution is completed at a concentration of

300 IU (3 mg)/mL.

Weight Required dose Volume to inject when diluted

30 IU/kg (0.3 mg/kg) to a final concentration of
300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10
105 3,150 31.5 10.5

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 110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12
125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
 At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
 At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.

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 Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.
Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH) or to any of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (> 100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (> 100 days) of
heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in
such a case must be made only after a careful benefit risk assessment and after non-heparin alternative
treatments are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.

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The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with
cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous
thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on
treatment), platelet count should be measured. Patients must be aware that these symptoms may occur and if
so, that they should inform their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach
a sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

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Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last intravenous/subcutaneous enoxaparin sodium injection. If the
treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than
6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or
hematoma formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after
a careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

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Renal impairment

In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the
risk of bleeding. In these patients, careful clinical monitoring is advised, and biological monitoring by
anti-Xa activity measurement might be considered (see sections 4.2 and 5.2).
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
< 15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.
In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (< 45 kg) and low-weight men (< 57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI > 30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially
‘sodium-free’.

Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

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4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:
- Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,
- Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

Medicinal products increasing potassium levels

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

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4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in
patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) subcutaneously once daily for prophylaxis of DVT following
surgery or in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or
without PE, patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg)
subcutaneous dose every 12 hours or a 150 IU/kg (1.5 mg/kg) subcutaneous dose once a day. In the clinical
trials for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg
(1 mg/kg) subcutaneously every 12 hours, and in the clinical study for treatment of acute STEMI enoxaparin
sodium regimen was a 3,000 IU (30 mg) intravenous bolus followed by 100 IU/kg (1 mg/kg) subcutaneously
every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see section 4.4 and 'Description of selected adverse reactions' below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000) or not known (cannot be
estimated from available data). Within each system organ class, adverse reactions are presented in order of
decreasing seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*
Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders

192
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury*
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema
Uncommon: Bullous dermatitis
Rare: Alopecia*
Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as:
organic lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting
haemostasis (see sections 4.4 and 4.5).

193
 System Prophylaxis Prophylaxis Treatment Extended Treatment in Treatment in
organ class in surgical in medical in patients treatment of patients with patients with
patients patients with DVT DVT and PE unstable acute STEMI
with or in patients angina and
without PE with active non-Q-wave
cancer MI
Blood and Very Common: Very Common b: Common: Common:
lymphatic common: Haemorrha common: Haemorrhag Haemorrhag Haemorrhage
system Haemorrhag ge α Haemorrha e eα α

disorders eα ge α
Rare: Uncommon:
Rare: Uncommon Retroperiton Intracranial
Retroperiton : eal haemorrhage,
eal Intracranial haemorrhage Retroperitone
haemorrhage haemorrhag al
e, haemorrhage
Retroperiton
eal
haemorrhag
e
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)

System Prophylaxis in Prophylaxis Treatment Extended Treatment in Treatment in
organ class surgical in medical in patients treatment of patients with patients with
patients patients with DVT DVT and PE unstable acute STEMI
with or in patients angina and
without PE with active non-Q-wave
cancer MI
Blood and Very common: Uncommon Very Unknown: Uncommon: Common:
lymphatic Thrombocytos : Thrombo- common: Thrombocyt Thrombo- Thrombocytos
system isβ cytopenia Thrombo- openia cytopenia isβ Thrombo-
disorders cytosisβ cytopenia
Very rare:
Common: Common: Immuno-
Thrombo- Thrombo- allergic
cytopenia cytopenia thrombo-
cytopenia
β
: Platelet increased > 400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after intravenous, extracorporeal or subcutaneous

administration may lead to haemorrhagic complications. Following oral administration of even large doses, it
is unlikely that enoxaparin sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow intravenous injection of protamine. The dose
of protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the
anticoagulant effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the
previous 8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be
administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine
administration, or if it has been determined that a second dose of protamine is required. After 12 hours of the
enoxaparin sodium injection, protamine administration may not be required. However, even with high doses
of protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about
60%) (see the prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

Pharmacodynamic effects

Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery,
179 patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin
sodium 4,000 IU (40 mg) subcutaneously, were randomised to a post-discharge regimen of either enoxaparin

195
sodium 4,000 IU (40 mg) (n = 90) once a day subcutaneously or to placebo (n = 89) for 3 weeks. The
incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to
placebo, no PE was reported. No major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium Placebo

4,000 IU (40 mg) once a day once a day
subcutaneously subcutaneously
n (%) n (%)
All treated extended prophylaxis patients 90 (100) 89 (100)
Total VTE 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo = 0.008
#p value versus placebo = 0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) subcutaneously were
randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n = 131) once a day
subcutaneously or to placebo (n = 131) for 3 weeks. Similar to the first study the incidence of VTE during
extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo for both total VTE
(enoxaparin sodium 21 [16%] versus placebo 45 [34.4%]; p = 0.001) and proximal DVT (enoxaparin sodium
8 [6.1%] versus placebo 28 [21.4%]; p =< 0.001). No difference in major bleeding was found between the
enoxaparin sodium and the placebo group.

Extended prophylaxis of DVT following cancer surgery

A double-blind, multicentre trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or
pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) subcutaneously) daily for 6 to 10 days
and were then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days.
Bilateral venography was performed between days 25 and 31, or sooner if symptoms of venous
thromboembolism occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis
for four weeks after surgery for abdominal or pelvic cancer significantly reduced the incidence of
venographically demonstrated thrombosis, as compared with enoxaparin sodium prophylaxis for one week.
The rates of venous thromboembolism at the end of the double-blind phase were 12.0 % (n = 20) in the
placebo group and 4.8% (n = 8) in the enoxaparin sodium group; p = 0.02. This difference persisted at three
months [13.8% vs. 5.5% (n = 23 vs 9), p = 0.01]. There were no differences in the rates of bleeding or other
complications during the double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicentre, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day subcutaneously was compared to placebo in the prophylaxis of DVT in medical patients
with severely restricted mobility during acute illness (defined as walking distance of < 10 meters for
≤ 3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥ 75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day subcutaneously,
enoxaparin sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are
provided in the table below.

196
 Enoxaparin sodium Enoxaparin sodium Placebo
2,000 IU (20 mg) 4,000 IU (40 mg)
once a day once a day
subcutaneously subcutaneously n (%)
n (%) n (%)
All treated medical patients 287 (100) 291 (100) 288 (100)
during acute illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin
* p value versus placebo = 0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without PE

In a multicentre, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once
a day subcutaneously, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours subcutaneously,
or (iii) heparin intravenous bolus (5,000 IU) followed by a continuous infusion (administered to achieve an
aPTT of 55 to 85 seconds). A total of 900 patients were randomised in the study and all patients were treated.
All patients also received warfarin sodium (dose adjusted according to prothrombin time to achieve an INR
of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy,
and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was administered for a minimum
of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were
equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT
and/or PE). The efficacy data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium Heparin

150 IU/kg (1.5 mg/kg) 100 IU/kg (1 mg/kg) aPTT adjusted
once a day twice a day Intravenous Therapy
subcutaneously subcutaneously n (%)
n (%) n (%)
All treated DVT patients 298 (100) 312 (100) 290 (100)
with or without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
*The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

197
Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

Enoxaparin all regimens

Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)

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 *All data with 95% CI

Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicentre study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either subcutaneous enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or intravenous
unfractionated heparin adjusted based on aPTT. Patients had to be treated in hospital for a minimum of
2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital
discharge. The patients had to be followed up to 30 days. In comparison with heparin, enoxaparin sodium
significantly reduced the combined incidence of angina pectoris, myocardial infarction and death, with a
decrease of 19.8 to 16.6% (relative risk reduction of 16.2%) on day 14. This reduction in the combined
incidence was maintained after 30 days (from 23.3 to 19.8%; relative risk reduction of 15%).
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the
subcutaneous injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicentre study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) intravenous bolus plus
a 100 IU/kg (1 mg/kg) subcutaneous dose followed by an subcutaneous injection of 100 IU/kg (1 mg/kg)
every 12 hours or intravenous unfractionated heparin adjusted based on aPTT for 48 hours. All patients were
also treated with acetylsalicylic acid for a minimum of 30 days. The enoxaparin sodium dosing strategy was
adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The subcutaneous
injections of enoxaparin sodium were given until hospital discharge or for a maximum of eight days
(whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no
additional dosing, if last subcutaneous administration given less than 8 hours before balloon inflation,
intravenous bolus of 30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last subcutaneous administration given
more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p < 0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p < 0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p = 0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage
(a measure of net clinical benefit) was significantly lower (p < 0.0001) in the enoxaparin sodium group
(10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of
treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p < 0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in
the enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

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Hepatic impairment

Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single
and repeated subcutaneous administration and after single intravenous administration. The quantitative
determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic
methods.

Absorption

The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is
close to 100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after subcutaneous injection and
achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single subcutaneous administration of
2,000 IU, 4,000 IU, 100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

A 3,000 IU (30 mg) intravenous bolus immediately followed by a 100 IU/kg (1 mg/kg) subcutaneous every
12 hours provided initial maximum anti-Xa activity level of 1.16 IU/mL (n = 16) and average exposure
corresponding to 88% of steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated subcutaneous administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once
daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio
about 15% higher than after a single dose. After repeated subcutaneous administration of the 100 IU/kg
(1 mg/kg) twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65%
higher than after a single dose and mean maximum and trough anti-Xa activity levels of about 1.2 and
0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated subcutaneous administration no
accumulation takes place.

Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa
activity. The mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following
subcutaneous injection and reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of
100 IU/kg (1 mg/kg) twice daily and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

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Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerisation to lower
molecular weight species with much reduced biological potency.

Elimination

Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after a
150 IU /kg (1.5 mg/kg) 6-hour intravenous infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single subcutaneous dose to about
7 hours after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated
subcutaneous 4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine
clearance < 30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated
subcutaneous 4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) intravenous dose however, AUC was two-fold higher than control.

Weight
After repeated subcutaneous 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is
marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese
control subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-
adjusted clearance in obese subjects with subcutaneous dosing.

When non-weight adjusted dosing was administered, it was found after a single- subcutaneous 4,000 IU
(40 mg) dose, that anti-Xa exposure is 52% higher in low-weight women (< 45 kg) and 27% higher in
low-weight men (< 57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

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5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the
26-week subcutaneous and intravenous toxicity studies both in rats, and monkeys.

Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin sodium up to
30 mg/kg/day did not reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was
found to have no effect on fertility or reproductive performance of male and female rats at subcutaneous
doses up to 20 mg/kg/day.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for injections

6.2 Incompatibilities

SC injection

Do not mix with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

Enoxaparin sodium may be safely administered with sodium chloride 9 mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

6.3 Shelf life

Pre-filled syringe

3 years

Diluted medicinal product with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose in
water for injections.

8 hours

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

6.5 Nature and contents of container

1 mL of solution in a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a dark blue polypropylene plunger rod. The syringe can be
additionally equipped with needle guard.

Packs of:
- 2, 10 and 30 pre-filled syringes,
- 10 and 30 pre-filled syringes with needle guard.

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Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

INSTRUCTIONS FOR USE: PRE-FILLED SYRINGE

How to give yourself an injection of Inhixa with a pre-filled syringe without needle guard

If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

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7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out.

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with needle guard

Your pre-filled syringe has a needle guard attached to it in order to protect you from needle stick injury.
If you are able to give this medicinal product to yourself, your doctor or nurse will show you how to do this.
Do not try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your
doctor or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicinal product. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicinal product if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicinal product. Change the place where you inject each
time from the right to the left side of your abdomen (belly). This medicinal product should be
injected just under the skin on your abdomen, but not too near the belly button or any scar tissue (at
least 5 cm away from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.

204
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold

8) Press down on the plunger with your thumb. This will inject the medicinal product into the fatty
tissue of the abdomen. Make sure you hold the skin fold throughout the injection

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Push hard the plunger. The needle guard, which is in the form of a plastic cylinder, will be activated
automatically and it will completely cover the needle.

205
11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/070
EU/1/16/1132/074
EU/1/16/1132/078
EU/1/16/1132/079
EU/1/16/1132/080

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

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1. NAME OF THE MEDICINAL PRODUCT

Inhixa 30,000 IU (300 mg)/3 mL solution for injection in multidose container

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains enoxaparin sodium 30,000 IU anti-Xa activity (equivalent to 300 mg) in 3.0 mL water for
injections.

Each mL contains 10,000 IU (100 mg) enoxaparin sodium.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

Excipient(s) with known effect

Benzyl alcohol (45 mg in 3.0 mL)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism (VTE).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI),
in combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to
be managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.

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 In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is
2,000 IU (20 mg) once daily by subcutaneous injection. Preoperative initiation (2 hours before
surgery) of enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk
surgery.
In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of
7-10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the
patient no longer has significantly reduced mobility.
 In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by subcutaneous injection preferably started 12 hours before surgery. If there
is a need for earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high
risk patient waiting for a deferred orthopaedic surgery), the last injection should be administered no
later than 12 hours prior to surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis up
to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal or
pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by subcutaneous injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered subcutaneously either as a once daily injection of 150 IU/kg (1.5
mg/kg) or as twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

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Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
 For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is
100 IU/kg (1 mg/kg) every 12 hours by subcutaneous injection administered in combination with
antiplatelet therapy. Treatment should be maintained for a minimum of 2 days and continued until
clinical stabilization. The usual duration of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75-325 mg/day
long-term regardless of treatment strategy.

 For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) subcutaneous dose followed by 100 IU/kg
(1 mg/kg) administered subcutaneously every 12 hours (maximum 10,000 IU (100 mg) for each of the
first two subcutaneous doses). Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg
to 325 mg once daily) should be administered concomitantly unless contraindicated. The
recommended duration of treatment is 8 days or until hospital discharge, whichever comes first. When
administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin
sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic
therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last subcutaneous dose of enoxaparin sodium was given
less than 8 hours before balloon inflation, no additional dosing is needed. If the last
subcutaneous administration was given more than 8 hours before balloon inflation, an
intravenous bolus of 30 IU/kg (0.3 mg/kg) enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.
No data are available.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below paragraph “Renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥75 years of age, an initial intravenous bolus must not be
used. Initiate dosing with 75 IU/kg (0.75 mg/kg) subcutaneously every 12 hours (maximum 7,500 IU
(75 mg) for each of the first two subcutaneous doses only, followed by 75 IU/kg (0.75 mg/kg) subcutaneous
dosing for the remaining doses). For dose in elderly patients with impaired kidney function, see below “renal
impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):

Indication Dosing regimen

Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) subcutaneously once daily

Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight subcutaneously once daily

209
Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight subcutaneously once daily

Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) intravenous bolus plus 100 IU/kg
(1 mg/kg) body weight subcutaneously and then 100 IU/kg
(1 mg/kg) body weight subcutaneously every 24 hours
Treatment of acute STEMI (patients over 75) No intravenous initial bolus, 100 IU/kg (1 mg/kg) body
weight subcutaneously and then 100 IU/kg (1 mg/kg) body
weight subcutaneously every 24 hours

The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Inhixa multidose vial contains benzyl alcohol and must not be used in newborn babies and premature
neonates (see section 4.3).

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thromboembolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by subcutaneous injection.
 For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately
followed by a subcutaneous injection.
 For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The use of a tuberculin syringe or equivalent is recommended when using multidose vials to assure
withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, the graduated pre-filled syringes should be used
to reach the required volume by discarding the excess before injection. In some cases it is not possible to
achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be rounded up
to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. The injection
site should not be rubbed after administration.

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IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately followed
by a subcutaneous injection.
For intravenous injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or co-
administered with other medicinal products. To avoid the possible mixture of enoxaparin sodium with other
medicinal products, the intravenous access chosen should be flushed with a sufficient amount of sodium
chloride 9 mg/mL (0.9%) solution for infusion or 5% glucose in water for injections prior to and following
the intravenous bolus administration of enoxaparin sodium to clear the port of the medicinal product.
Enoxaparin sodium may be safely administered with sodium chloride 9 mg/mL (0.9%) solution for infusion
or 5% glucose in water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the intravenous line.

Additional bolus for PCI when last subcutaneous administration was given more than 8 hours before balloon
inflation
For patients being managed with PCI, an additional intravenous bolus of 30 IU/kg (0.3 mg/kg) is to be
administered if last subcutaneous administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/mL (0.9%) solution
for infusion or 5% glucose in water for injections) as follows:
30 mL of the solution should be withdrawn from the infusion bag with a syringe and discarded. The
complete contents of the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe should be injected into the
20 mL remaining in the bag. The contents of the bag should be gently mixed. Then, the required volume of
diluted solution should be withdrawn with a syringe for administration into the intravenous line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through intravenous line after dilution is completed at a concentration of 300 IU
(3 mg)/mL.

Required dose Volume to inject when diluted to a final

Weight
30 IU/kg (0.3 mg/kg) concentration of 300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10
105 3,150 31.5 10.5

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 110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12
125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
 At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
 At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.

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 Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.
Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH), to benzyl alcohol or any other of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).
Because of the content of benzyl alcohol (see section 6.1), enoxaparin sodium multiple dose vial formulation
must not be given to newborns or premature neonates (see sections 4.4 and 4.6).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (>100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-
induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such
a case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments
are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

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The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with
cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous
thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on
treatment), platelet count should be measured. Patients must be aware that these symptoms may occur and if
so, that they should inform their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach
a sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

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Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last intravenous/ subcutaneous enoxaparin sodium injection. If the
treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than
6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or
hematoma formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after
a careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg ) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

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Renal impairment

 In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which
increases the risk of bleeding. In these patients, careful clinical monitoring is advised, and biological
monitoring by anti-Xa activity measurement might be considered (see sections 4.2 and 5.2).
 Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in
extra corporeal circulation during haemodialysis.
In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Benzyl alcohol

Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in
neonates (“Gasping Syndrome”) (see section 4.3). The minimum amount of benzyl alcohol at which toxicity
may occur is not known. Benzyl alcohol may also cause toxic reactions in infants and children up to 3 years
old, due to increased risk of accumulation.
High volumes of medicinal products containing benzyl alcohol should be used with caution and only if
necessary in patients with liver or kidney impairment, or in pregnant women, because of the risk of
accumulation of benzyl alcohol and its toxicity (metabolic acidosis).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose within the recommended dose
range, that is to say essentially ‘sodium-free’.

Acute generalized exanthematous pustulosis

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Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:
- Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,
- Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
 Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

 Medicinal products increasing potassium levels

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

As benzyl alcohol may cross the placenta, it is recommended to use a formulation that does not contain
benzyl alcohol.

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Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in
patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) subcutaneously once daily for prophylaxis of DVT following
surgery or in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or
without PE, patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg)
subcutaneous dose every 12 hours or a 150 IU/kg (1.5 mg/kg) subcutaneous dose once a day. In the clinical
trials for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg
(1 mg/kg) subcutaneously every 12 hours, and in the clinical study for treatment of acute STEMI enoxaparin
sodium regimen was a 3,000 IU (30 mg) intravenous bolus followed by 100 IU/kg (1 mg/kg) subcutaneously
every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see sections 4.4 and ”Description of selected adverse reactions” below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be
estimated from available data). Within each system organ class, adverse reactions are presented in order of
decreasing seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*

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Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury *
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema
Uncommon: Bullous dermatitis
Rare: Alopecia*
Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as:
organic lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting
haemostasis (see sections 4.4 and 4.5).

219
 System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in
organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and PE unstable acute STEMI
without PE in patients angina and
with active non-Q-wave
cancer MI
Blood Very common: Common: Very Common b: Common: Common:
and Haemorrhageα Haemorrhag common: Haemorrhage Haemorrhage Haemorrhageα
lympha eα Haemorrhage α
α
tic Rare: Uncommon:
system Retroperitonea Rare: Intracranial
disorde l haemorrhage Uncommon: Retroperiton haemorrhage,
rs Intracranial eal Retroperitone
haemorrhage, haemorrhage al
Retroperitone haemorrhage
al
haemorrhage
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)

System Prophylaxis in Prophylaxis Treatment in Extended Treatment in Treatment in
organ surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and PE unstable acute STEMI
without PE in patients angina and
with active non-Q-wave
cancer MI
Blood Very common: Uncommon: Very Unknown: Uncommon: Common:
and Thrombo- Thrombo- common: Thrombocyto Thrombo- Thrombocytos
lympha cytosisβ cytopenia Thrombo- penia cytopenia isβ Thrombo-
tic cytosisβ cytopenia
system Common: Very rare:
disorde Thrombo- Common: Immuno-
rs cytopenia Thrombo- allergic
cytopenia thrombo-
cytopenia
β
: Platelet increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in
neonates (“Gasping Syndrome”) (see section 4.3).
Benzyl alcohol may also cause toxic reactions in infants and children up to 3 years old, due to increased risk
of accumulation (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after intravenous, extracorporeal or subcutaneous

administration may lead to haemorrhagic complications. Following oral administration of even large doses, it
is unlikely that enoxaparin sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow intravenous injection of protamine. The dose
of protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the
anticoagulant effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the
previous 8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be
administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine
administration, or if it has been determined that a second dose of protamine is required. After 12 hours of the
enoxaparin sodium injection, protamine administration may not be required. However, even with high doses
of protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about
60%) (see the prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

Pharmacodynamic effects

Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery,
179 patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin
sodium 4,000 IU (40 mg) subcutaneously, were randomised to a post-discharge regimen of either enoxaparin

221
sodium 4,000 IU (40 mg) (n=90) once a day subcutaneously or to placebo (n=89) for 3 weeks. The incidence
of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no
PE was reported. No major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium
Placebo
4,000 IU (40 mg) once a day
once a day subcutaneously
subcutaneously
n (%)
n (%)
All treated extended prophylaxis patients 90 (100) 89 (100)
Total VTE (%) 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo =0.008
#p value versus placebo =0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) subcutaneously were
randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day
subcutaneously or to placebo (n=131) for 3 weeks. Similar to the first study the incidence of VTE during
extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo for both total VTE
(enoxaparin sodium 21 [16%] versus placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium
8 [6.1%] versus placebo 28 [21.4%]; p=<0.001). No difference in major bleeding was found between the
enoxaparin sodium and the placebo group.

Extended prophylaxis of DVT following cancer surgery

A double-blind, multicentre trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or
pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) subcutaneously) daily for 6 to 10 days
and were then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days.
Bilateral venography was performed between days 25 and 31, or sooner if symptoms of venous
thromboembolism occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis
for four weeks after surgery for abdominal or pelvic cancer significantly reduced the incidence of
venographically demonstrated thrombosis, as compared with enoxaparin sodium prophylaxis for one week.
The rates of venous thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the
placebo group and 4.8% (n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three
months [13.8% vs. 5.5% (n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other
complications during the double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicentre, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day subcutaneously was compared to placebo in the prophylaxis of DVT in medical patients
with severely restricted mobility during acute illness (defined as walking distance of <10 meters for
≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day subcutaneously,
enoxaparin sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are
provided in the table below.

Enoxaparin sodium Enoxaparin sodium Placebo

2,000 IU (20 mg) 4,000 IU (40 mg) n (%)

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 once a day once a day
subcutaneously subcutaneously
n (%) n (%)
All treated medical patients 287 (100) 291(100) 288 (100)
during acute illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin
* p value versus placebo = 0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without PE

In a multicentre, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once
a day subcutaneously, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours subcutaneously, or
(iii) heparin intravenous bolus (5,000 IU) followed by a continuous infusion (administered to achieve an
aPTT of 55 to 85 seconds). A total of 900 patients were randomised in the study and all patients were treated.
All patients also received warfarin sodium (dose adjusted according to prothrombin time to achieve an INR
of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy,
and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was administered for a minimum
of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were
equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT
and/or PE). The efficacy data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium

Heparin
150 IU/kg (1.5 mg/kg) 100 IU/kg (1 mg/kg)
aPTT Adjusted Intravenous
once a day twice a day
Therapy
subcutaneously subcutaneously
n (%)
n (%) n (%)
All treated DVT patients 298 (100) 312 (100) 290 (100)
with or without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
* The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526

223
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

Enoxaparin all regimens

Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)
*All data with 95% CI

224
Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicentre study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either subcutaneous enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or intravenous
unfractionated heparin adjusted based on aPTT. Patients had to be treated in hospital for a minimum of
2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital
discharge. The patients had to be followed up to 30 days. In comparison with heparin, enoxaparin sodium
significantly reduced the combined incidence of angina pectoris, myocardial infarction and death, with a
decrease of 19.8 to 16.6% (relative risk reduction of 16.2%) on day 14. This reduction in the combined
incidence was maintained after 30 days (from 23.3 to 19.8%; relative risk reduction of 15%).
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the
subcutaneous injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicentre study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) intravenous bolus plus
a 100 IU/kg (1 mg/kg) subcutaneously dose followed by an subcutaneous injection of 100 IU/kg (1 mg/kg)
every 12 hours or intravenous unfractionated heparin adjusted based on aPTT for 48 hours. All patients were
also treated with acetylsalicylic acid for a minimum of 30 days. The enoxaparin sodium dosing strategy was
adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The subcutaneous
injections of enoxaparin sodium were given until hospital discharge or for a maximum of eight days
(whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no
additional dosing, if last subcutaneous administration given less than 8 hours before balloon inflation,
intravenous bolus of 30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last subcutaneous administration given
more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p=0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage
(a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group
(10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of
treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in
the enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

Hepatic impairment

225
Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single
and repeated subcutaneous administration and after single intravenous administration. The quantitative
determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic
methods.

Absorption

The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is
close to 100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after subcutaneous injection and
achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single subcutaneous administration of
2,000 IU, 4,000 IU, 100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

A 3,000 IU (30 mg) intravenous bolus immediately followed by a 100 IU/kg (1 mg/kg) subcutaneous every
12 hours provided initial maximum anti-Xa activity level of 1.16 IU/mL (n=16) and average exposure
corresponding to 88% of steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated subcutaneous administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once
daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio
about 15% higher than after a single dose. After repeated subcutaneous administration of the 100 IU/kg
(1 mg/kg) twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65%
higher than after a single dose and mean maximum and trough anti-Xa activity levels of about 1.2 and
0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated subcutaneous administration no
accumulation takes place.

Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa
activity. The mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following
subcutaneous injection and reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of
100 IU/kg (1 mg/kg) twice daily and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

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Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerisation to lower
molecular weight species with much reduced biological potency.

Elimination

Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after a
150 IU /kg (1.5 mg/kg) 6-hour intravenous infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single subcutaneous dose to about
7 hours after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated
subcutaneous 4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine
clearance <30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated
subcutaneous 4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) intravenous dose however, AUC was two-fold higher than control.

Weight
After repeated subcutaneous 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is
marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese
control subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-
adjusted clearance in obese subjects with subcutaneous dosing.

When non-weight adjusted dosing was administered, it was found after a single- subcutaneous 4,000 IU
(40 mg) dose, that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-
weight men (<57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

227
5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the
26-week subcutaneous and intravenous toxicity studies both in rats, and monkeys.

Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin sodium up to
30 mg/kg/day did not reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was
found to have no effect on fertility or reproductive performance of male and female rats at subcutaneous
doses up to 20 mg/kg/day.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzyl alcohol
Water for injections

6.2 Incompatibilities

SC injection

Should not be mixed with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

This medicinal product must not be mixed with other medicinal products except those mentioned in section
6.6.

6.3 Shelf life

3 years

After first opening

Chemical and physical in-use stability has been demonstrated for 28 days at 25 °C.
From a microbiological point of view, once opened, the medicinal product may be stored for a maximum of
28 days below 25 °C. Other in-use storage times and conditions are the responsibility of the user.

After dilution with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for
injection.

Chemical and physical in-use stability has been demonstrated for 8 hours at 25 °C.
From a microbiological point of view, unless the method of dilution precludes the risk of microbial
contamination, the medicinal product should be used immediately. If not used immediately, in-use storage
times and conditions are the responsibility of user.

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

For storage conditions after first opening and dilution of the medicinal product, see section 6.3.

228
6.5 Nature and contents of container

3 mL of solution in clear, colourless type I glass vial sealed with rubber injection stopper and white
aluminium-plastic cap in a cardboard box.

Pack-sizes of 1 vial containing 3 mL.

6.6 Special precautions for disposal and other handling

Enoxaparin sodium may be safely administered with sodium chloride 9 mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/071

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

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1. NAME OF THE MEDICINAL PRODUCT

Inhixa 50,000 IU (500 mg)/5 mL solution for injection in multidose container

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains enoxaparin sodium 50,000 IU anti-Xa activity (equivalent to 500 mg) in 5.0 mL water for
injections.

Each mL contains 10,000 IU (100 mg) enoxaparin sodium.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

Excipient(s) with known effect

Benzyl alcohol (75 mg in 5.0 mL)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism (VTE).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI), in
combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be
managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.

230
 In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is
2,000 IU (20 mg) once daily by subcutaneous injection. Preoperative initiation (2 hours before
surgery) of enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk
surgery.
In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of
7-10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the
patient no longer has significantly reduced mobility.
 In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by subcutaneous injection preferably started 12 hours before surgery. If there
is a need for earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high
risk patient waiting for a deferred orthopaedic surgery), the last injection should be administered no
later than 12 hours prior to surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis up
to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal or
pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by subcutaneous injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered subcutaneously either as a once daily injection of 150 IU/kg
(1.5 mg/kg) or as twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

231
Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
 For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is
100 IU/kg (1 mg/kg) every 12 hours by subcutaneous injection administered in combination with
antiplatelet therapy. Treatment should be maintained for a minimum of 2 days and continued until
clinical stabilization. The usual duration of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75-325 mg/day
long-term regardless of treatment strategy.
 For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) subcutaneous dose followed by 100 IU/kg
(1 mg/kg) administered subcutaneously every 12 hours (maximum 10,000 IU (100 mg) for each of the
first two subcutaneous doses). Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg
to 325 mg once daily) should be administered concomitantly unless contraindicated. The
recommended duration of treatment is 8 days or until hospital discharge, whichever comes first. When
administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin
sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic
therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last subcutaneous dose of enoxaparin sodium was given
less than 8 hours before balloon inflation, no additional dosing is needed. If the last
subcutaneous administration was given more than 8 hours before balloon inflation, an
intravenous bolus of 30 IU/kg (0.3 mg/kg) enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.
No data are available.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below paragraph “Renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥75 years of age, an initial intravenous bolus must not be
used. Initiate dosing with 75 IU/kg (0.75 mg/kg) subcutaneously every 12 hours (maximum 7,500 IU
(75 mg) for each of the first two subcutaneous doses only, followed by 75 IU/kg (0.75 mg/kg) subcutaneous
dosing for the remaining doses). For dose in elderly patients with impaired kidney function, see below “renal
impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):

Indication Dosing regimen

Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) subcutaneously once daily

Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight subcutaneously once daily

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Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight subcutaneously once daily

Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) intravenous bolus plus 100 IU/kg
(1 mg/kg) body weight subcutaneously and then 100 IU/kg
(1 mg/kg) body weight subcutaneously every 24 hours

Treatment of acute STEMI (patients over 75) No intravenous initial bolus, 100 IU/kg (1 mg/kg) body
weight subcutaneously and then 100 IU/kg (1 mg/kg) body
weight subcutaneously every 24 hours

The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Inhixa multidose vial contains benzyl alcohol and must not be used in newborn babies and premature
neonates (see section 4.3).

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thromboembolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by subcutaneous injection.
 For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately
followed by a subcutaneous injection.
 For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The use of a tuberculin syringe or equivalent is recommended when using multidose vials to assure
withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, the graduated pre-filled syringes should be used
to reach the required volume by discarding the excess before injection. In some cases it is not possible to
achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be rounded up
to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. The injection
site should not be rubbed after administration.

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IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately followed
by a subcutaneous injection.
For intravenous injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or co-
administered with other medicinal products. To avoid the possible mixture of enoxaparin sodium with other
medicinal products, the intravenous access chosen should be flushed with a sufficient amount of sodium
chloride 9 mg/mL (0.9%) solution for infusion or 5% glucose in water for injection prior to and following the
intravenous bolus administration of enoxaparin sodium to clear the port of the medicinal product. Enoxaparin
sodium may be safely administered with sodium chloride 9 mg/mL (0.9%) solution for infusion or 5%
glucose in water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the intravenous line.

Additional bolus for PCI when last subcutaneous administration was given more than 8 hours before balloon
inflation
For patients being managed with PCI, an additional intravenous bolus of 30 IU/kg (0.3 mg/kg) is to be
administered if last subcutaneous administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/mL (0.9%) solution
for infusion or 5% glucose in water for injections) as follows:
30 mL of the solution should be withdrawn from the infusion bag with a syringe and discarded. The
complete contents of the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe should be injected into the
20 mL remaining in the bag. The contents of the bag should be gently mixed. Then, the required volume of
diluted solution should be withdrawn with a syringe for administration into the intravenous line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through intravenous line after dilution is completed at a concentration of 300 IU (3
mg)/mL.

Volume to inject when diluted to

Required dose
Weight a final concentration of
30 IU/kg (0.3 mg/kg)
300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10

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 105 3,150 31.5 10.5
110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12
125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
 At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
 At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.

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 Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.
Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH), to benzyl alcohol or any other of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).
Because of the content of benzyl alcohol (see section 6.1), enoxaparin sodium multiple dose vial formulation
must not be given to newborns or premature neonates (see sections 4.4 and 4.6).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (>100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-
induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such
a case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments
are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

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The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with
cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous
thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on
treatment), platelet count should be measured. Patients must be aware that these symptoms may occur and if
so, that they should inform their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach
a sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

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Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last intravenous/ subcutaneous enoxaparin sodium injection. If the
treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than
6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or
hematoma formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after
a careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg ) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

Renal impairment

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 In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which
increases the risk of bleeding. In these patients, careful clinical monitoring is advised, and biological
monitoring by anti-Xa activity measurement might be considered (see sections 4.2 and 5.2).
 Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in
extra corporeal circulation during haemodialysis.
In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Benzyl alcohol

Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in
neonates (“Gasping Syndrome”) (see section 4.3). The minimum amount of benzyl alcohol at which toxicity
may occur is not known. Benzyl alcohol may also cause toxic reactions in infants and children up to 3 years
old, due to increased risk of accumulation.
High volumes of medicinal products containing benzyl alcohol should be used with caution and only if
necessary in patients with liver or kidney impairment, or in pregnant women, because of the risk of
accumulation of benzyl alcohol and its toxicity (metabolic acidosis).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose within the recommended dose
range, that is to say essentially ‘sodium-free’.

Acute generalized exanthematous pustulosis

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Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:
- Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,
- Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
 Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

 Medicinal products increasing potassium levels

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

As benzyl alcohol may cross the placenta, it is recommended to use a formulation that does not contain
benzyl alcohol.

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Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in
patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) subcutaneously once daily for prophylaxis of DVT following
surgery or in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or
without PE, patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg)
subcutaneous dose every 12 hours or a 150 IU/kg (1.5 mg/kg) subcutaneous dose once a day. In the clinical
trials for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg
(1 mg/kg) subcutaneously every 12 hours, and in the clinical study for treatment of acute STEMI enoxaparin
sodium regimen was a 3,000 IU (30 mg) intravenous bolus followed by 100 IU/kg (1 mg/kg) subcutaneously
every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see sections 4.4 and “Description of selected adverse reactions” below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be
estimated from available data). Within each system organ class, adverse reactions are presented in order of
decreasing seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*

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Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury *
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema
Uncommon: Bullous dermatitis
Rare: Alopecia*
Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as:
organic lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting
haemostasis (see sections 4.4 and 4.5).

242
 System Prophylaxis Prophylaxis Treatment in Extended Treatment in Treatment in
organ in surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and unstable acute STEMI
without PE PE in angina and
patients non-Q-wave
with active MI
cancer
Blood Very Common: Very Common b: Common: Common:
and common: Haemorrhag common: Haemorrhag Haemorrhage Haemorrhage
lymphati Haemorrhage eα Haemorrhage e α α
α α
c system
disorder Rare: Uncommon:
s Rare: Uncommon: Retroperitone Intracranial
Retroperitone Intracranial al haemorrhage,
al haemorrhage, haemorrhage Retroperitone
haemorrhage Retroperitone al
al haemorrhage
haemorrhage
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)

System Prophylaxis Prophylaxis Treatment in Extended Treatment in Treatment in
organ in surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and PE unstable acute STEMI
without PE in patients angina and
with active non-Q-wave
cancer MI
Blood Very Uncommon: Very common: Unknown: Uncommon: Common:
and common: Thrombo- Thrombo- Thrombocyto Thrombo- Thrombocytos
lympha Thrombo- cytopenia cytosisβ penia cytopenia isβ Thrombo-
β
tic cytosis cytopenia
system Common: Very rare:
disorde Common: Thrombo- Immuno-
rs Thrombo- cytopenia allergic
cytopenia thrombo-
cytopenia
β
: Platelet increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in
neonates (“Gasping Syndrome”) (see section 4.3).
Benzyl alcohol may also cause toxic reactions in infants and children up to 3 years old, due to increased risk
of accumulation (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

243
4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after intravenous, extracorporeal or subcutaneous

administration may lead to haemorrhagic complications. Following oral administration of even large doses, it
is unlikely that enoxaparin sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow intravenous injection of protamine. The dose
of protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the
anticoagulant effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the
previous 8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be
administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine
administration, or if it has been determined that a second dose of protamine is required. After 12 hours of the
enoxaparin sodium injection, protamine administration may not be required. However, even with high doses
of protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about
60%) (see the prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

Pharmacodynamic effects

Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery,
179 patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin
sodium 4,000 IU (40 mg) subcutaneously, were randomised to a post-discharge regimen of either enoxaparin

244
sodium 4,000 IU (40 mg) (n=90) once a day subcutaneously or to placebo (n=89) for 3 weeks. The incidence
of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no
PE was reported. No major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium
Placebo
4,000 IU (40 mg) once a day
once a day subcutaneously
subcutaneously
n (%)
n (%)
All treated extended prophylaxis patients 90 (100) 89 (100)
Total VTE (%) 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo =0.008
#p value versus placebo =0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) subcutaneously were
randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day
subcutaneously or to placebo (n=131) for 3 weeks. Similar to the first study the incidence of VTE during
extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo for both total VTE
(enoxaparin sodium 21 [16%] versus placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium
8 [6.1%] versus placebo 28 [21.4%]; p=<0.001). No difference in major bleeding was found between the
enoxaparin sodium and the placebo group.

Extended prophylaxis of DVT following cancer surgery

A double-blind, multicentre trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or
pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) subcutaneously) daily for 6 to 10 days
and were then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days.
Bilateral venography was performed between days 25 and 31, or sooner if symptoms of venous
thromboembolism occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis
for four weeks after surgery for abdominal or pelvic cancer significantly reduced the incidence of
venographically demonstrated thrombosis, as compared with enoxaparin sodium prophylaxis for one week.
The rates of venous thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the
placebo group and 4.8% (n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three
months [13.8% vs. 5.5% (n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other
complications during the double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicentre, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day subcutaneously was compared to placebo in the prophylaxis of DVT in medical patients
with severely restricted mobility during acute illness (defined as walking distance of <10 meters for
≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day subcutaneously,
enoxaparin sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are
provided in the table below.

Enoxaparin sodium Enoxaparin sodium Placebo

2,000 IU (20 mg) 4,000 IU (40 mg) n (%)

245
 once a day once a day
subcutaneously subcutaneously
n (%) n (%)
All treated medical patients 287 (100) 291(100) 288 (100)
during acute illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin
* p value versus placebo = 0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without PE

In a multicentre, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once
a day subcutaneously, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours subcutaneously, or
(iii) heparin intravenous bolus (5,000 IU) followed by a continuous infusion (administered to achieve an
aPTT of 55 to 85 seconds). A total of 900 patients were randomised in the study and all patients were treated.
All patients also received warfarin sodium (dose adjusted according to prothrombin time to achieve an INR
of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy,
and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was administered for a minimum
of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were
equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT
and/or PE). The efficacy data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium

Heparin
150 IU/kg (1.5 mg/kg) 100 IU/kg (1 mg/kg)
aPTT Adjusted Intravenous
once a day twice a day
Therapy
subcutaneously subcutaneously
n (%)
n (%) n (%)
All treated DVT patients 298 (100) 312 (100) 290 (100)
with or without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
* The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526

246
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

Enoxaparin all regimens

Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)
*All data with 95% CI

247
Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicentre study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either subcutaneous enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or intravenous
unfractionated heparin adjusted based on aPTT. Patients had to be treated in hospital for a minimum of
2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital
discharge. The patients had to be followed up to 30 days. In comparison with heparin, enoxaparin sodium
significantly reduced the combined incidence of angina pectoris, myocardial infarction and death, with a
decrease of 19.8 to 16.6% (relative risk reduction of 16.2%) on day 14. This reduction in the combined
incidence was maintained after 30 days (from 23.3 to 19.8%; relative risk reduction of 15%).
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the
subcutaneous injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicentre study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) intravenous bolus plus a
100 IU/kg (1 mg/kg) subcutaneous dose followed by an subcutaneous injection of 100 IU/kg (1 mg/kg) every
12 hours or intravenous unfractionated heparin adjusted based on aPTT for 48 hours. All patients were also
treated with acetylsalicylic acid for a minimum of 30 days. The enoxaparin sodium dosing strategy was
adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The subcutaneous
injections of enoxaparin sodium were given until hospital discharge or for a maximum of eight days
(whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no
additional dosing, if last subcutaneous administration given less than 8 hours before balloon inflation,
intravenous bolus of 30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last subcutaneous administration given
more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p=0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage
(a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group
(10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of
treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in
the enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

Hepatic impairment

248
Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single
and repeated subcutaneous administration and after single intravenous administration. The quantitative
determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic
methods.

Absorption

The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is
close to 100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after subcutaneous injection and
achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single subcutaneous administration of
2,000 IU, 4,000 IU, 100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

A 3,000 IU (30 mg) intravenous bolus immediately followed by a 100 IU/kg (1 mg/kg) subcutaneous every
12 hours provided initial maximum anti-Xa activity level of 1.16 IU/mL (n=16) and average exposure
corresponding to 88% of steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated subcutaneous administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once
daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio
about 15% higher than after a single dose. After repeated subcutaneous administration of the 100 IU/kg
(1 mg/kg) twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65%
higher than after a single dose and mean maximum and trough anti-Xa activity levels of about 1.2 and
0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated subcutaneous administration no
accumulation takes place.

Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa
activity. The mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following
subcutaneous injection and reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of
100 IU/kg (1 mg/kg) twice daily and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

249
Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerisation to lower
molecular weight species with much reduced biological potency.

Elimination

Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after a
150 IU /kg (1.5 mg/kg) 6-hour intravenous infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single subcutaneous dose to about
7 hours after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated
subcutaneous 4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine
clearance <30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated
subcutaneous 4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) intravenous dose however, AUC was two-fold higher than control.

Weight
After repeated subcutaneous 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is
marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese
control subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-
adjusted clearance in obese subjects with subcutaneous dosing.

When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 4,000 IU
(40 mg) dose, that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-
weight men (<57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

250
5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the
26-week subcutaneous and intravenous toxicity studies both in rats, and monkeys.

Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin sodium up to
30 mg/kg/day did not reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was
found to have no effect on fertility or reproductive performance of male and female rats at subcutaneous
doses up to 20 mg/kg/day.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzyl alcohol
Water for injections

6.2 Incompatibilities

SC injection

Should not be mixed with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

This medicinal product must not be mixed with other medicinal products except those mentioned in section
6.6.

6.3 Shelf life

3 years

After first opening

Chemical and physical in-use stability has been demonstrated for 28 days at 25 °C.
From a microbiological point of view, once opened, the medicinal product may be stored for a maximum of
28 days below 25 °C. Other in-use storage times and conditions are the responsibility of the user.

After dilution with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for
injection.

Chemical and physical in-use stability has been demonstrated for 8 hours at 25 °C.
From a microbiological point of view, unless the method of dilution precludes the risk of microbial
contamination, the medicinal product should be used immediately. If not used immediately, in-use storage
times and conditions are the responsibility of user.

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

For storage conditions after first opening and dilution of the medicinal product, see section 6.3.

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6.5 Nature and contents of container

5 mL of solution in clear, colourless type I glass vial sealed with rubber injection stopper and grey
aluminium-plastic cap in a cardboard box.

Pack-sizes of 5 vials containing 5 mL.

6.6 Special precautions for disposal and other handling

Enoxaparin sodium may be safely administered with sodium chloride 9 mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/072

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

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1. NAME OF THE MEDICINAL PRODUCT

Inhixa 100,000 IU (1000 mg)/10 mL solution for injection in multidose container

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains enoxaparin sodium 100,000 IU anti-Xa activity (equivalent to 1000 mg) in 10.0 mL water
for injections.

Each mL contains 10,000 IU (100 mg) enoxaparin sodium.

Enoxaparin sodium is a biological substance obtained by alkaline depolymerisation of heparin benzyl ester
derived from porcine intestinal mucosa.

Excipient(s) with known effect

Benzyl alcohol (150 mg in 10.0 mL)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection

Clear, colourless to pale yellow solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Inhixa is indicated in adults for:

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular
those undergoing orthopaedic or general surgery including cancer surgery.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart
failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased
risk of venous thromboembolism (VTE).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require
thrombolytic therapy or surgery.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer.
Prevention of thrombus formation in extra corporeal circulation during haemodialysis.
Acute coronary syndrome:
 Treatment of unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI),
in combination with oral acetylsalicylic acid.
 Treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to
be managed medically or with subsequent percutaneous coronary intervention (PCI).

4.2 Posology and method of administration

Posology

Prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients
Individual thromboembolic risk for patients can be estimated using validated risk stratification model.

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 In patients at moderate risk of thromboembolism, the recommended dose of enoxaparin sodium is
2,000 IU (20 mg) once daily by subcutaneous injection. Preoperative initiation (2 hours before
surgery) of enoxaparin sodium 2,000 IU (20 mg) was proven effective and safe in moderate risk
surgery.
In moderate risk patients, enoxaparin sodium treatment should be maintained for a minimal period of
7-10 days whatever the recovery status (e.g. mobility). Prophylaxis should be continued until the
patient no longer has significantly reduced mobility.
 In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU
(40 mg) once daily given by subcutaneous injection preferably started 12 hours before surgery. If there
is a need for earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high
risk patient waiting for a deferred orthopaedic surgery), the last injection should be administered no
later than 12 hours prior to surgery and resumed 12 hours after surgery.
o For patients who undergo major orthopaedic surgery an extended thromboprophylaxis up
to 5 weeks is recommended.
o For patients with a high venous thromboembolism (VTE) risk who undergo abdominal or
pelvic surgery for cancer an extended thromboprophylaxis up to 4 weeks is
recommended.

Prophylaxis of venous thromboembolism in medical patients

The recommended dose of enoxaparin sodium is 4,000 IU (40 mg) once daily by subcutaneous injection.
Treatment with enoxaparin sodium is prescribed for at least 6 to 14 days whatever the recovery status
(e.g. mobility). The benefit is not established for a treatment longer than 14 days.

Treatment of DVT and PE

Enoxaparin sodium can be administered subcutaneously either as a once daily injection of 150 IU/kg
(1.5 mg/kg) or as twice daily injections of 100 IU/kg (1 mg/kg).
The regimen should be selected by the physician based on an individual assessment including evaluation of
the thromboembolic risk and of the risk of bleeding. The dose regimen of 150 IU/kg (1.5 mg/kg)
administered once daily should be used in uncomplicated patients with low risk of VTE recurrence. The dose
regimen of 100 IU/kg (1 mg/kg) administered twice daily should be used in all other patients such as those
with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis.

Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy
should be initiated when appropriate (see “Switch between enoxaparin sodium and oral anticoagulants” at
the end of section 4.2).

In the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of
its recurrence in patients with active cancer, physicians should carefully assess the individual
thromboembolic and bleeding risks of the patient.
The recommended dose is 100 IU/kg (1 mg/kg) administered twice daily by SC injections for 5 to 10 days,
followed by a 150 IU/kg (1.5 mg/kg) once daily SC injection up to 6 months. The benefit of continuous
anticoagulant therapy should be reassessed after 6 months of treatment.

Prevention of thrombus formation during haemodialysis

The recommended dose is 100 IU/kg (1 mg/kg) of enoxaparin sodium.
For patients with a high risk of haemorrhage, the dose should be reduced to 50 IU/kg (0.5 mg/kg) for double
vascular access or 75 IU/kg (0.75 mg/kg) for single vascular access.

During haemodialysis, enoxaparin sodium should be introduced into the arterial line of the circuit at the
beginning of the dialysis session. The effect of this dose is usually sufficient for a 4-hour session; however, if
fibrin rings are found, for example after a longer than normal session, a further dose of 50 IU to 100 IU/kg
(0.5 to 1 mg/kg) may be given.

No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during
haemodialysis sessions.

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Acute coronary syndrome: treatment of unstable angina and NSTEMI and treatment of acute STEMI
 For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is
100 IU/kg (1 mg/kg) every 12 hours by subcutaneous injection administered in combination with
antiplatelet therapy. Treatment should be maintained for a minimum of 2 days and continued until
clinical stabilization. The usual duration of treatment is 2 to 8 days.
Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading
dose of 150–300 mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75-325 mg/day
long-term regardless of treatment strategy.
 For treatment of acute STEMI, the recommended dose of enoxaparin sodium is a single intravenous
bolus of 3,000 IU (30 mg) plus a 100 IU/kg (1 mg/kg) subcutaneous dose followed by 100 IU/kg
(1 mg/kg) administered subcutaneously every 12 hours (maximum 10,000 IU (100 mg) for each of the
first two subcutaneous doses). Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75 mg
 to 325 mg once daily) should be administered concomitantly unless contraindicated. The
recommended duration of treatment is 8 days or until hospital discharge, whichever comes first. When
administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin
sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic
therapy.
o For dose in patients ≥ 75 years of age, see paragraph “Elderly”.
o For patients managed with PCI, if the last subcutaneous dose of enoxaparin sodium was given
less than 8 hours before balloon inflation, no additional dosing is needed. If the last
subcutaneous administration was given more than 8 hours before balloon inflation, an
intravenous bolus of 30 IU/kg (0.3 mg/kg) enoxaparin sodium should be administered.

Special populations

Paediatric population
The safety and efficacy of enoxaparin sodium in paediatric population have not been established.
No data are available.

Elderly
For all indications except STEMI, no dose reduction is necessary in the elderly patients, unless kidney
function is impaired (see below paragraph “Renal impairment” and section 4.4).
For treatment of acute STEMI in elderly patients ≥75 years of age, an initial intravenous bolus must not be
used. Initiate dosing with 75 IU/kg (0.75 mg/kg) subcutaneously every 12 hours (maximum 7,500 IU
(75 mg) for each of the first two subcutaneous doses only, followed by 75 IU/kg (0.75 mg/kg) subcutaneous
dosing for the remaining doses). For dose in elderly patients with impaired kidney function, see below “renal
impairment” and section 4.4.

Hepatic impairment
Limited data are available in patients with hepatic impairment (see sections 5.1 and 5.2) and caution should
be used in these patients (see section 4.4).

Renal impairment (see sections 4.4 and 5.2)

Severe renal impairment
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra
corporeal circulation during haemodialysis.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):

Indication Dosing regimen

Prophylaxis of venous thromboembolic disease 2,000 IU (20 mg) subcutaneously once daily

Treatment of DVT and PE 100 IU/kg (1 mg/kg) body weight subcutaneously once daily

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Extended treatment of DVT and PE in patients 100 IU/kg (1 mg/kg) body weight SC once daily
with active cancer
Treatment of unstable angina and NSTEMI 100 IU/kg (1 mg/kg) body weight subcutaneously once daily

Treatment of acute STEMI (patients under 75) 1 x 3,000 IU (30 mg) intravenous bolus plus 100 IU/kg
(1 mg/kg) body weight subcutaneously and then 100 IU/kg
(1 mg/kg) body weight subcutaneously every 24 hours

Treatment of acute STEMI (patients over 75) No intravenous initial bolus, 100 IU/kg (1 mg/kg) body
weight subcutaneously and then 100 IU/kg (1 mg/kg) body
weight subcutaneously every 24 hours

The recommended dose adjustments do not apply to the haemodialysis indication.

Moderate and mild renal impairment

Although no dose adjustment is recommended in patients with moderate (creatinine clearance
30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment, careful clinical monitoring
is advised.

Inhixa multidose vial contains benzyl alcohol and must not be used in newborn babies and premature
neonates (see section 4.3).

Method of administration

Inhixa is not indicated for intramuscular use and should not be administered by this route.

For the prophylaxis of venous thromboembolic disease following surgery, treatment of DVT and PE,
extended treatment of DVT and PE in patients with active cancer, treatment of unstable angina and
NSTEMI, enoxaparin sodium should be administered by subcutaneous injection.
 For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately
followed by a subcutaneous injection.
 For the prevention of thrombus formation in the extra corporeal circulation during haemodialysis, it is
administered through the arterial line of a dialysis circuit.

The use of a tuberculin syringe or equivalent is recommended when using multidose vials to assure
withdrawal of the appropriate volume of the medicinal product.

SC injection technique

Injection should be made preferably when the patient is lying down. Enoxaparin sodium is administered by
deep SC injection.

When using pre-filled syringes, the air bubble should not be expelled from the syringe before the injection in
order to avoid the loss of the medicinal product. When the quantity of the medicinal product to be injected
requires to be adjusted based on the patient’s body weight, the graduated pre-filled syringes should be used
to reach the required volume by discarding the excess before injection. In some cases it is not possible to
achieve an exact dose due to the graduations on the syringe, and in such case the volume shall be rounded up
to the nearest graduation.

The administration should be alternated between the left and right anterolateral or posterolateral abdominal
wall.

The whole length of the needle should be introduced vertically into a skin fold gently held between the
thumb and index finger. The skin fold should not be released until the injection is complete. The injection
site should not be rubbed after administration.

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IV (bolus) injection (for acute STEMI indication only)

For acute STEMI, treatment is to be initiated with a single intravenous bolus injection immediately followed
by a subcutaneous injection.
For intravenous injection, either the multidose vial or pre-filled syringe can be used.
Enoxaparin sodium should be administered through an intravenous line. It should not be mixed or co-
administered with other medicinal products. To avoid the possible mixture of enoxaparin sodium with other
medicinal products, the intravenous access chosen should be flushed with a sufficient amount of sodium
chloride 9 mg/mL (0.9%) solution for infusion or 5% glucose in water for injection prior to and following the
intravenous bolus administration of enoxaparin sodium to clear the port of the medicinal product. Enoxaparin
sodium may be safely administered with sodium chloride 9 mg/mL (0.9%) solution for infusion or 5%
glucose in water for injections.

Initial 3,000 IU (30 mg) bolus

For the initial 3,000 IU (30 mg) bolus, using an enoxaparin sodium graduated pre-filled syringe, the
excessive volume has to be expelled to retain only 3,000 IU (30 mg) in the syringe. The 3,000 IU (30 mg)
dose can then be directly injected into the intravenous line.

Additional bolus for PCI when last subcutaneous administration was given more than 8 hours before balloon
inflation
For patients being managed with PCI, an additional intravenous bolus of 30 IU/kg (0.3 mg/kg) is to be
administered if last subcutaneous administration was given more than 8 hours before balloon inflation.

In order to assure the accuracy of the small volume to be injected, it is recommended to dilute the medicinal
product to 300 IU/mL (3 mg/mL).
To obtain a 300 IU/mL (3 mg/mL) solution, using a 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe,
it is recommended to use a 50 mL infusion bag (i.e. using either sodium chloride 9 mg/mL (0.9%) solution
for infusion or 5% glucose in water for injections) as follows:
30 mL of the solution should be withdrawn from the infusion bag with a syringe and discarded. The
complete contents of the 6,000 IU (60 mg) enoxaparin sodium pre-filled syringe should be injected into the
20 mL remaining in the bag. The contents of the bag should be gently mixed. Then, the required volume of
diluted solution should be withdrawn with a syringe for administration into the intravenous line.

After dilution is completed, the volume to be injected can be calculated using the following formula [volume
of diluted solution (mL) = patient weight (kg) x 0.1] or using the table below. It is recommended to prepare
the dilution immediately before use.

Volume to be injected through intravenous line after dilution is completed at a concentration of 300 IU (3
mg)/mL.

Volume to inject when diluted to

Required dose
Weight a final concentration of
30 IU/kg (0.3 mg/kg)
300 IU (3 mg)/mL
[kg] IU [mg] [mL]
45 1,350 13.5 4.5
50 1,500 15 5
55 1,650 16.5 5.5
60 1,800 18 6
65 1,950 19.5 6.5
70 2,100 21 7
75 2,250 22.5 7.5
80 2,400 24 8
85 2,550 25.5 8.5
90 2,700 27 9
95 2,850 28.5 9.5
100 3,000 30 10

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 105 3,150 31.5 10.5
110 3,300 33 11
115 3,450 34.5 11.5
120 3,600 36 12
125 3,750 37.5 12.5
130 3,900 39 13
135 4,050 40.5 13.5
140 4,200 42 14
145 4,350 43.5 14.5
150 4,500 45 15

Arterial line injection

It is administered through the arterial line of a dialysis circuit for the prevention of thrombus formation in the
extra corporeal circulation during haemodialysis.

Switch between enoxaparin sodium and oral anticoagulants

Switch between enoxaparin sodium and vitamin K antagonists (VKA)

Clinical monitoring and laboratory tests [prothrombin time expressed as the International Normalised Ratio
(INR)] must be intensified to monitor the effect of VKA.
As there is an interval before the VKA reaches its maximum effect, enoxaparin sodium therapy should be
continued at a constant dose for as long as necessary in order to maintain the INR within the desired
therapeutic range for the indication in two successive tests.
For patients currently receiving a VKA, the VKA should be discontinued and the first dose of enoxaparin
sodium should be given when the INR has dropped below the therapeutic range.

Switch between enoxaparin sodium and direct oral anticoagulants (DOAC)

For patients currently receiving enoxaparin sodium, discontinue enoxaparin sodium and start the DOAC 0 to
2 hours before the time that the next scheduled administration of enoxaparin sodium would be due as per
DOAC label.
For patients currently receiving a DOAC, the first dose of enoxaparin sodium should be given at the time the
next DOAC dose would be taken.

Administration in spinal/epidural anaesthesia or lumbar puncture

Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of
neuraxial haematomas (see section 4.4).
- At doses used for prophylaxis
A puncture-free interval of at least 12 hours shall be kept between the last injection of enoxaparin
sodium at prophylactic doses and the needle or catheter placement.
For continuous techniques, a similar delay of at least 12 hours should be observed before removing
the catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 24 hours.
The 2 hours preoperative initiation of enoxaparin sodium 2,000 IU (20 mg) is not compatible with
neuraxial anaesthesia.
- At doses used for treatment
A puncture-free interval of at least 24 hours shall be kept between the last injection of enoxaparin
sodium at curative doses and the needle or catheter placement (see also section 4.3).
For continuous techniques, a similar delay of 24 hours should be observed before removing the
catheter.
For patients with creatinine clearance [15-30] mL/min, consider doubling the timing of
puncture/catheter placement or removal to at least 48 hours.

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 Patients receiving the twice daily doses (i.e. 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg
(1 mg/kg) twice-daily) should omit the second enoxaparin sodium dose to allow a sufficient delay
before catheter placement or removal.
Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial
hematoma will be avoided.
Likewise, consider not using enoxaparin sodium until at least 4 hours after the spinal/epidural puncture or
after the catheter has been removed. The delay must be based on a benefit-risk assessment considering both
the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors.

4.3 Contraindications

Enoxaparin sodium is contraindicated in patients with:

 Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular
weight heparins (LMWH), to benzyl alcohol or any other of the excipients listed in section 6.1;
 History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in
the presence of circulating antibodies (see also section 4.4 );
 Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent
haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding,
recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous
malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities;
 Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for
treatment in the previous 24 hours (see section 4.4).
Because of the content of benzyl alcohol (see section 6.1), enoxaparin sodium multiple dose vial formulation
must not be given to newborns or premature neonates (see sections 4.4 and 4.6).

4.4 Special warnings and precautions for use

Traceability

LMWHs are biological medicinal products. In order to improve the traceability of biological medicinal
products, the name and the batch number of the administered product should be clearly recorded.

General

Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal
products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities,
units, dose and clinical efficacy and safety. This results in differences in pharmacokinetics and associated
biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance
with the instructions for use specific to each proprietary medicinal product are therefore required.

History of HIT (>100 days)

Use of enoxaparin sodium in patients with a history of immune mediated HIT within the past 100 days or in
the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist
several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-
induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such
a case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments
are considered (e.g. danaparoid sodium or lepirudin).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered
on a case-by-case basis and careful monitoring is recommended.

259
The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually
appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with
cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with
enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous
thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on
treatment), platelet count should be measured. Patients must be aware that these symptoms may occur and if
so, that they should inform their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50 % of the initial
value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another
non-heparin anticoagulant alternative treatment.

Haemorrhage

As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the
haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with
increased potential for bleeding, such as:
- impaired haemostasis,
- history of peptic ulcer,
- recent ischemic stroke,
- severe arterial hypertension,
- recent diabetic retinopathy,
- neuro- or ophthalmologic surgery,
- concomitant use of medicinal products affecting haemostasis (see section 4.5).

Laboratory tests

At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding
time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of
fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT)
may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium
antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium
activity.

Spinal/Epidural anaesthesia or lumbar puncture

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of
enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and
spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis.
These events are rare with enoxaparin sodium dose regimens 4,000 IU (40 mg) once daily or lower. The risk
of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant
use of additional medicinal products affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal
surgery or spinal deformity.

To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and
epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of
enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best
performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach
a sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance
[15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is
more prolonged (see section 4.2).

260
Should the physician decide to administer anticoagulation in the context of epidural or spinal
anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and
symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or
weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they
experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected,
initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though
such treatment may not prevent or reverse neurological sequelae.

Skin necrosis/cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment
discontinuation.

Percutaneous coronary revascularization procedures

To minimise the risk of bleeding following the vascular instrumentation during the treatment of unstable
angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin
sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure
device is used, the sheath can be removed immediately. If a manual compression method is used, sheath
should be removed 6 hours after the last intravenous/ subcutaneous enoxaparin sodium injection. If the
treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than
6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or
hematoma formation.

Acute infective endocarditis

Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of
cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after
a careful individual benefit risk assessment.

Mechanical prosthetic heart valves

The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with
mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in
patients with mechanical prosthetic heart valves who have received enoxaparin sodium for
thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit
the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal
and foetal death.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart
valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic
heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg ) twice daily) to reduce the risk of
thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal
and foetal death. There have been isolated post-marketing reports of valve thrombosis in pregnant women
with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis.
Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.

Elderly

No increased bleeding tendency is observed in the elderly with the prophylactic dose ranges. Elderly patients
(especially patients eighty years of age and older) may be at an increased risk for bleeding complications
with the therapeutic dose ranges. Careful clinical monitoring is advised and dose reduction might be
considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).

Renal impairment

261
 In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which
increases the risk of bleeding. In these patients, careful clinical monitoring is advised, and biological
monitoring by anti-Xa activity measurement might be considered (see sections 4.2 and 5.2).
 Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance
<15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in
extra corporeal circulation during haemodialysis.
In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin
sodium is significantly increased, a dose adjustment is recommended for therapeutic and prophylactic dose
ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and
mild (creatinine clearance 50-80 mL/min) renal impairment.

Hepatic impairment

Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased
potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with
liver cirrhosis and not recommended (see section 5.2).

Low weight

An increase in exposure of enoxaparin sodium with prophylactic doses (non-weight adjusted) has been
observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of
bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).

Obese patients

Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in
obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose
adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8),
particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic
acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should
be monitored regularly especially in patients at risk.

Benzyl alcohol

Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in
neonates (“Gasping Syndrome”) (see section 4.3). The minimum amount of benzyl alcohol at which toxicity
may occur is not known. Benzyl alcohol may also cause toxic reactions in infants and children up to 3 years
old, due to increased risk of accumulation.
High volumes of medicinal products containing benzyl alcohol should be used with caution and only if
necessary in patients with liver or kidney impairment, or in pregnant women, because of the risk of
accumulation of benzyl alcohol and its toxicity (metabolic acidosis).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose within the recommended dose
range, that is to say essentially ‘sodium-free’.

Acute generalized exanthematous pustulosis

262
Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in
association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions
appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as
appropriate).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended

Medicinal products affecting haemostasis (see section 4.4)

It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin
sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used
with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products
such as:
- Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including
ketorolac,
- Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and
anticoagulants (see section 4.2).

Concomitant use with caution

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
 Other medicinal products affecting haemostasis such as:
- Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose
(cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in
acute coronary syndrome due to the risk of bleeding,
- Dextran 40,
- Systemic glucocorticoids.

 Medicinal products increasing potassium levels

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin
sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third
trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data
have shown that enoxaparin passage through the placenta is minimal.
Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or
excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there
is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the
risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart
valves (see section 4.4).

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before

(see section 4.4).

As benzyl alcohol may cross the placenta, it is recommended to use a formulation that does not contain
benzyl alcohol.

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Breast-feeding

It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the
passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is
unlikely. Inhixa can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on
fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in
clinical trials. These included 1,776 for prophylaxis of DVT following orthopaedic or abdominal surgery in
patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT in acutely ill medical
patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment
of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.

Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The
enoxaparin sodium dose was 4,000 IU (40 mg) subcutaneously once daily for prophylaxis of DVT following
surgery or in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or
without PE, patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg)
subcutaneous dose every 12 hours or a 150 IU/kg (1.5 mg/kg) subcutaneous dose once a day. In the clinical
trials for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg
(1 mg/kg) subcutaneously every 12 hours, and in the clinical study for treatment of acute STEMI enoxaparin
sodium regimen was a 3,000 IU (30 mg) intravenous bolus followed by 100 IU/kg (1 mg/kg) subcutaneously
every 12 hours.

In clinical trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported
reactions (see sections 4.4 and “Description of selected adverse reactions” below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is
similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin
treatment (see section 4.4).

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials and reported in post-marketing experience (* indicates
reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to <1/1,000); and very rare (< 1/10,000) or not known (cannot be
estimated from available data). Within each system organ class, adverse reactions are presented in order of
decreasing seriousness.

Blood and the lymphatic system disorders

Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*

264
Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was
complicated by organ infarction or limb ischaemia (see section 4.4).

Immune system disorders

Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of
neurologic injuries including long-term or permanent paralysis (see section 4.4).

Hepatobiliary disorders
Very common: Hepatic enzyme increases (mainly transaminases > 3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury *
Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

Common: Urticaria, pruritus, erythema
Uncommon: Bullous dermatitis
Rare: Alopecia*
Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have
been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve
after a few days and should not cause treatment discontinuation.
Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema,
haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site

Investigations
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).

Description of selected adverse reactions

Haemorrhages
These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients). Some of
these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the
haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥ 2 g/dL or
transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always
considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as:
organic lesions liable to bleed, invasive procedures or the concomitant use of medicinal products affecting
haemostasis (see sections 4.4 and 4.5).

265
 System Prophylaxis Prophylaxis Treatment in Extended Treatment in Treatment in
organ in surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and unstable acute STEMI
without PE PE in angina and
patients non-Q-wave
with active MI
cancer
Blood Very Common: Very Common b: Common: Common:
and common: Haemorrhag common: Haemorrhag Haemorrhage Haemorrhage
lymphati Haemorrhage eα Haemorrhage e α α
α α
c system
disorder Rare: Uncommon:
s Rare: Uncommon: Retroperitone Intracranial
Retroperitone Intracranial al haemorrhage,
al haemorrhage, haemorrhage Retroperitone
haemorrhage Retroperitone al
al haemorrhage
haemorrhage
α
: such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and
gastro-intestinal haemorrhage.
b
: frequency based on a retrospective study on a registry including 3526 patients (see section 5.1)

Thrombocytopenia and thrombocytosis (see section 4.4 monitoring of platelet counts)

System Prophylaxis Prophylaxis Treatment in Extended Treatment in Treatment in
organ in surgical in medical patients with treatment of patients with patients with
class patients patients DVT with or DVT and PE unstable acute STEMI
without PE in patients angina and
with active non-Q-wave
cancer MI
Blood Very Uncommon: Very common: Unknown: Uncommon: Common:
and common: Thrombo- Thrombo- Thrombocyto Thrombo- Thrombocytos
lympha Thrombo- cytopenia cytosisβ penia cytopenia isβ Thrombo-
β
tic cytosis cytopenia
system Common: Very rare:
disorde Common: Thrombo- Immuno-
rs Thrombo- cytopenia allergic
cytopenia thrombo-
cytopenia
β
: Platelet increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).

Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in
neonates (“Gasping Syndrome”) (see section 4.3).
Benzyl alcohol may also cause toxic reactions in infants and children up to 3 years old, due to increased risk
of accumulation (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

266
4.9 Overdose

Signs and symptoms

Accidental overdose with enoxaparin sodium after intravenous, extracorporeal or subcutaneous

administration may lead to haemorrhagic complications. Following oral administration of even large doses, it
is unlikely that enoxaparin sodium will be absorbed.

Management

The anticoagulant effects can be largely neutralised by the slow intravenous injection of protamine. The dose
of protamine depends on the dose of enoxaparin sodium injected; 1 mg protamine neutralises the
anticoagulant effect of 100 IU (1 mg) of enoxaparin sodium, if enoxaparin sodium was administered in the
previous 8 hours. An infusion of 0.5 mg protamine per 100 IU (1 mg) of enoxaparin sodium may be
administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine
administration, or if it has been determined that a second dose of protamine is required. After 12 hours of the
enoxaparin sodium injection, protamine administration may not be required. However, even with high doses
of protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralised (maximum about
60%) (see the prescribing information for protamine salts).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, heparin group. ATC code: B01A B05

Inhixa is a biosimilar medicinal product. Detailed information is available on the website of the European
Medicines Agency [Link]

Pharmacodynamic effects

Enoxaparin is a LMWH with a mean molecular weight of approximately 4,500 daltons, in which the
antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is
the sodium salt.

In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg)
and low anti-IIa or anti thrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant
activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.

Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have
been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of
endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand
factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute
to the overall antithrombotic effect of enoxaparin sodium.
When used as prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used
as curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolic disease associated with surgery

Extended prophylaxis of VTE following orthopaedic surgery

In a double blind study of extended prophylaxis for patients undergoing hip replacement surgery,
179 patients with no venous thromboembolic disease initially treated, while hospitalised, with enoxaparin
sodium 4,000 IU (40 mg) subcutaneously, were randomised to a post-discharge regimen of either enoxaparin

267
sodium 4,000 IU (40 mg) (n=90) once a day subcutaneously or to placebo (n=89) for 3 weeks. The incidence
of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no
PE was reported. No major bleeding occurred.
The efficacy data are provided in the table below.

Enoxaparin sodium
Placebo
4,000 IU (40 mg) once a day
once a day subcutaneously
subcutaneously
n (%)
n (%)
All treated extended prophylaxis patients 90 (100) 89 (100)
Total VTE (%) 6 (6.6) 18 (20.2)
Total DVT (%) 6 (6.6)* 18 (20.2)
Proximal DVT (%) 5 (5.6)# 7 (8.8)
*p value versus placebo =0.008
#p value versus placebo =0.537

In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery
initially treated, while hospitalised, with enoxaparin sodium 4,000 IU (40 mg) subcutaneously were
randomised to a post-discharge regimen of either enoxaparin sodium 4,000 IU (40 mg) (n=131) once a day
subcutaneously or to placebo (n=131) for 3 weeks. Similar to the first study the incidence of VTE during
extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo for both total VTE
(enoxaparin sodium 21 [16%] versus placebo 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium
8 [6.1%] versus placebo 28 [21.4%]; p=<0.001). No difference in major bleeding was found between the
enoxaparin sodium and the placebo group.

Extended prophylaxis of DVT following cancer surgery

A double-blind, multicentre trial, compared a four-week and a one-week regimen of enoxaparin sodium
prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or
pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) subcutaneously) daily for 6 to 10 days
and were then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days.
Bilateral venography was performed between days 25 and 31, or sooner if symptoms of venous
thromboembolism occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis
for four weeks after surgery for abdominal or pelvic cancer significantly reduced the incidence of
venographically demonstrated thrombosis, as compared with enoxaparin sodium prophylaxis for one week.
The rates of venous thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the
placebo group and 4.8% (n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three
months [13.8% vs. 5.5% (n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other
complications during the double-blind or follow-up periods.

Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce
limitation of mobility

In a double blind multicentre, parallel group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU
(40 mg) once a day subcutaneously was compared to placebo in the prophylaxis of DVT in medical patients
with severely restricted mobility during acute illness (defined as walking distance of <10 meters for
≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or
complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at
least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy,
and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for
6 to 14 days (median duration 7 days). When given at a dose of 4,000 IU (40 mg) once a day subcutaneously,
enoxaparin sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are
provided in the table below.

Enoxaparin sodium Enoxaparin sodium Placebo

2,000 IU (20 mg) 4,000 IU (40 mg) n (%)

268
 once a day once a day
subcutaneously subcutaneously
n (%) n (%)
All treated medical patients 287 (100) 291(100) 288 (100)
during acute illness
Total VTE (%) 43 (15.0) 16 (5.5)* 43 (14.9)
Total DVT (%) 43 (15.0) 16 (5.5) 40 (13.9)
Proximal DVT (%) 13 (4.5) 5 (1.7) 14 (4.9)
VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin
* p value versus placebo = 0.0002

At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the
enoxaparin sodium 4,000 IU (40 mg) treatment group versus the placebo treatment group.
The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7%
and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium
4,000 IU (40 mg) group.

Treatment of DVT with or without pulmonary embolism

In a multicentre, parallel group study, 900 patients with acute lower extremity DVT with or without PE were
randomised to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once
a day subcutaneously, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours subcutaneously, or
(iii) heparin intravenous bolus (5,000 IU) followed by a continuous infusion (administered to achieve an
aPTT of 55 to 85 seconds). A total of 900 patients were randomised in the study and all patients were treated.
All patients also received warfarin sodium (dose adjusted according to prothrombin time to achieve an INR
of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy,
and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was administered for a minimum
of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were
equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT
and/or PE). The efficacy data are provided in the table below.

Enoxaparin sodium Enoxaparin sodium

Heparin
150 IU/kg (1.5 mg/kg) 100 IU/kg (1 mg/kg)
aPTT Adjusted Intravenous
once a day twice a day
Therapy
subcutaneously subcutaneously
n (%)
n (%) n (%)
All treated DVT patients 298 (100) 312 (100) 290 (100)
with or without PE
Total VTE (%) 13 (4.4)* 9 (2.9)* 12 (4.1)
DVT only (%) 11 (3.7) 7 (2.2) 8 (2.8)
Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4)
PE (%) 2 (0.7) 2 (0.6) 4 (1.4)
VTE = venous thromboembolic event (DVT and/or PE)
* The 95% confidence intervals for the treatment differences for total VTE were:
- enoxaparin sodium once a day versus heparin (-3.0 to 3.5)
- enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).

Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group,
1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.

Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its
recurrence in patients with active cancer

In clinical trials with limited number of patients, reported rates of recurrent VTE in patients treated with
enoxaparin given once or twice daily for 3 to 6 months appear comparable to those with warfarin.

Effectiveness in real-life setting was assessed in a cohort of 4,451 patients with symptomatic VTE and active
cancer from the multinational registry RIETE of patients with VTE and other thrombotic conditions. 3,526

269
patients received SC enoxaparin up to 6 months and 925 patients received tinzaparin or dalteparin SC.
Among the 3,526 patients receiving enoxaparin treatment, 891 patients were treated with 1.5 mg/kg once
daily as initial therapy and extended treatment up to 6 months (once daily alone), 1,854 patients received
initial 1.0 mg/kg twice daily regimen and extended treatment up to 6 months (twice daily alone), and 687
patients received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily-
once daily) as the extended treatment up to 6 months. The mean and median duration of treatment until
regimen change was 17 days and 8 days, respectively. There was no significant difference for VTE
recurrence rate between the two treatments groups (see table), with enoxaparin meeting the prespecified
criterion for non inferiority of 1.5 (HR adjusted by relevant covariates 0.817, 95% CI: 0.499-1.336). There
was no statistically significant difference between the two treatment groups with regards to the relative risks
of major (fatal or non-fatal) bleeding and all-cause death (see table).

Table. Efficacy and safety outcomes in the RIETECAT study

Adjusted hazard ratios

Enoxaparin Other LMWH
Outcome enoxaparin / other LMWH
n=3526 n=925
[95% confidence interval]
VTE recurrence 70 (2.0%) 23 (2.5%) 0.817, [ 0.499-1.336]
Major bleeding 111 (3.1%) 18 (1.9%) 1.522, [ 0.899-2.577]
Non-major bleeding 87 (2.5%) 24 (2.6%) 0.881, [0.550-1.410]
Overall death 666 (18.9%) 157 (17.0%) 0.974, [ 0.813-1.165]

An overview of outcomes per treatment regimen used in the RIETECAT study among 6-month completers is
provided below:

Table. 6-month outcomes in patients completing 6-month treatment, by different regimens

Enoxaparin all regimens

Outcome Enoxapa Enoxapar EU-
N (%) rin all Enoxapa Enoxapar authorized
Enoxapa Enoxapa in More
(95% CI) regimens rin BID in OD to LMWHs
rin OD rin BID than one
to OD BID
switch
N=1432 N=444 N=529 N=406 N=14 N=39 N=428
70 33 22 10 1 4 23
Recurrence (4.9%) (7.4%) (4.2%) (2.5%) (7.1%) (10.3%) (5.4%)
of VTE (3.8%- (5.0%- (2.5%- (0.9%- (0%- (0.3%- (3.2%-
6.0%) 9.9%) 5.9%) 4.0%) 22.6%) 20.2%) 7.5%)
Major 111 31 52 21 1 6 18
bleeding (7.8%) (7.0%) (9.8%) (5.2%) (7.1%) (15.4%) (4.2%)
(fatal and (6.4%- (4.6%- (7.3%- (3.0%- (0%- (3.5%- (2.3%-
non-fatal) 9.1%) 9.4%) 12.4%) 7.3%) 22.6%) 27.2%) 6.1%)
Non-major 87 26 33 23 1 4 24
bleedings of (6.1%) (5.9%) (6.2%) (5.7%) (7.1%) (10.3%) (5.6%)
clinical (4.8%- (3.7%- (4.2%- (3.4%- (0%- (0.3%- (3.4%-
significance 7.3%) 8.0%) 8.3%) 7.9%) 22.6%) 20.2%) 7.8%)
666 175 323 146 6 16 157
All-cause (46.5%) (39.4%) (61.1%) (36.0%) (42.9%) (41.0%) (36.7%)
death (43.9%- (34.9%- (56.9%- (31.3%- (13.2%- (24.9%- (32.1%-
49.1%) 44.0%) 65.2%) 40.6%) 72.5%) 57.2%) 41.3%)
Fatal PE or 48 7 35 5 1 11
0
fatal (3.4%) (1.6%) (6.6%) (1.2%) (2.6%) 2.6%)
(0%)
bleeding (2.4%- (0.4%- (4.5%- (0.2%- (0%- (1.1%-
-
related death 4.3%) 2.7%) 8.7%) 2.3%) 7.8%) 4.1%)
*All data with 95% CI

270
Treatment of unstable angina and non ST elevation myocardial infarction

In a large multicentre study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave
myocardial infarction were randomised to receive in association with acetylsalicylic acid (100 to 325 mg
once daily), either subcutaneous enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or intravenous
unfractionated heparin adjusted based on aPTT. Patients had to be treated in hospital for a minimum of
2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital
discharge. The patients had to be followed up to 30 days. In comparison with heparin, enoxaparin sodium
significantly reduced the combined incidence of angina pectoris, myocardial infarction and death, with a
decrease of 19.8 to 16.6% (relative risk reduction of 16.2%) on day 14. This reduction in the combined
incidence was maintained after 30 days (from 23.3 to 19.8%; relative risk reduction of 15%).
There were no significant differences in major haemorrhages, although a haemorrhage at the site of the
subcutaneous injection was more frequent.

Treatment of acute ST-segment elevation myocardial infarction

In a large multicentre study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were
randomised to receive either enoxaparin sodium in a single 3,000 IU (30 mg) intravenous bolus plus a
100 IU/kg (1 mg/kg) subcutaneous dose followed by an subcutaneous injection of 100 IU/kg (1 mg/kg) every
12 hours or intravenous unfractionated heparin adjusted based on aPTT for 48 hours. All patients were also
treated with acetylsalicylic acid for a minimum of 30 days. The enoxaparin sodium dosing strategy was
adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The subcutaneous
injections of enoxaparin sodium were given until hospital discharge or for a maximum of eight days
(whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded
investigational medicinal product. Therefore, for patients on enoxaparin sodium, the PCI was to be
performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e. no
additional dosing, if last subcutaneous administration given less than 8 hours before balloon inflation,
intravenous bolus of 30 IU/ kg (0.3 mg/kg) enoxaparin sodium, if the last subcutaneous administration given
more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary
end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after
randomization [9.9 percent in the enoxaparin sodium group, as compared with 12.0 percent in the
unfractionated heparin group] with a 17 percent relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at
48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as
compared with treatment with unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups
including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of
fibrinolytic administered, and time to treatment with the investigational medicinal product.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in
patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent
reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, p=0.27 for
interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage
(a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group
(10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of
treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium
group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in
the enoxaparin sodium group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial
haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was
maintained over a 12 month follow-up period.

Hepatic impairment

271
Based on literature data the use of enoxaparin sodium 4,000 IU (40 mg) in cirrhotic patients (Child-Pugh
class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the
literature studies may have limitations. Caution should be used in patients with hepatic impairment as these
patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have
been performed in cirrhotic patients (Child Pugh class A, B nor C).

5.2 Pharmacokinetic properties

General characteristics

The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time
course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dose ranges after single
and repeated subcutaneous administration and after single intravenous administration. The quantitative
determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic
methods.

Absorption

The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is
close to 100%.

Different doses and formulations and dosing regimens can be used.

The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after subcutaneous injection and
achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single subcutaneous administration of
2,000 IU, 4,000 IU, 100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.

A 3,000 IU (30 mg) intravenous bolus immediately followed by a 100 IU/kg (1 mg/kg) subcutaneous every
12 hours provided initial maximum anti-Xa activity level of 1.16 IU/mL (n=16) and average exposure
corresponding to 88% of steady-state levels. Steady-state is achieved on the second day of treatment.

After repeated subcutaneous administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once
daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio
about 15% higher than after a single dose. After repeated subcutaneous administration of the 100 IU/kg
(1 mg/kg) twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65%
higher than after a single dose and mean maximum and trough anti-Xa activity levels of about 1.2 and
0.52 IU/mL, respectively.

Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic
parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dose ranges.
Intra-patient and inter-patient variability is low. Following repeated subcutaneous administration no
accumulation takes place.

Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa
activity. The mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following
subcutaneous injection and reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of
100 IU/kg (1 mg/kg) twice daily and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution

The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 litres and is close to the blood
volume.

Biotransformation

272
Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerisation to lower
molecular weight species with much reduced biological potency.

Elimination

Enoxaparin sodium is a low clearance substance with a mean anti-Xa plasma clearance of 0.74 L/h after a
150 IU /kg (1.5 mg/kg) 6-hour intravenous infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single subcutaneous dose to about
7 hours after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion
of active and non-active fragments 40% of the dose.

Special populations

Elderly
Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not
different in elderly subjects compared to younger subjects when renal function is normal. However, since
renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin
sodium (see sections 4.2 and 4.4).

Hepatic impairment
In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg)
once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic
impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII
level secondary to a reduced synthesis of ATIII in patients with hepatic impairment.

Renal impairment
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been
observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function.
Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance
50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated
subcutaneous 4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine
clearance <30 mL/min), the AUC at steady state is significantly increased on average by 65% after repeated
subcutaneous 4,000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).

Haemodialysis
Enoxaparin sodium pharmacokinetics appeared similar than control population, after a single 25 IU, 50 IU or
100 IU/kg (0.25, 0.50 or 1.0 mg/kg) intravenous dose however, AUC was two-fold higher than control.

Weight
After repeated subcutaneous 150 IU/kg (1.5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is
marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese
control subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-
adjusted clearance in obese subjects with subcutaneous dosing.

When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 4,000 IU
(40 mg) dose, that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-
weight men (<57 kg) when compared to normal weight control subjects (see section 4.4).

Pharmacokinetic interactions

No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when
administered concomitantly.

273
5.3 Preclinical safety data

Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse reactions at
15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the
26-week subcutaneous and intravenous toxicity studies both in rats, and monkeys.

Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse
lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte
chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.

Studies conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin sodium up to
30 mg/kg/day did not reveal any evidence of teratogenic effects or foetotoxicity. Enoxaparin sodium was
found to have no effect on fertility or reproductive performance of male and female rats at subcutaneous
doses up to 20 mg/kg/day.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzyl alcohol
Water for injections

6.2 Incompatibilities

SC injection

Should not be mixed with other medicinal products.

IV (bolus) injection (for acute STEMI indication only)

This medicinal product must not be mixed with other medicinal products except those mentioned in section
6.6.

6.3 Shelf life

3 years

After first opening

Chemical and physical in-use stability has been demonstrated for 28 days at 25 °C.
From a microbiological point of view, once opened, the medicinal product may be stored for a maximum of
28 days below 25 °C. Other in-use storage times and conditions are the responsibility of the user.

After dilution with sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for
injection.

Chemical and physical in-use stability has been demonstrated for 8 hours at 25 °C.
From a microbiological point of view, unless the method of dilution precludes the risk of microbial
contamination, the medicinal product should be used immediately. If not used immediately, in-use storage
times and conditions are the responsibility of user.

6.4 Special precautions for storage

Store below 25 °C. Do not freeze.

For storage conditions after first opening and dilution of the medicinal product, see section 6.3.

274
6.5 Nature and contents of container

10 mL of solution in clear, colourless type I glass vial sealed with rubber injection stopper and white
aluminium-plastic cap in a cardboard box.

Pack-sizes of 1 or 5 vials containing 10 mL.

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

Enoxaparin sodium may be safely administered with sodium chloride 9 mg/ml (0.9%) solution for injection
or 5% glucose in water for injections (see section 4.2).

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/081
EU/1/16/1132/082

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15/09/2016

Date of latest renewal: 26/08/2021

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines
Agency [Link]

275
 ANNEX II

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND

MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE

USE OF THE MEDICINAL PRODUCT

276
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) of the biological active substance(s)

Shenzhen Techdow Pharmaceutical Co., Ltd.

No. 19, Gaoxinzhongyi Road, Hi-tech Industrial Park,
Nanshan District,
Shenzhen City,
Guangdong Province,
518057, People’s Republic of China

Shenzhen Hepalink Pharmaceutical Group Co., Ltd.

No. 1 Rongtian Road, Kengzi Sub-district
Pingshan District, Shenzhen
518122, People’s Republic of China

Name and address of the manufacturer responsible for batch release

SciencePharma spółka z ograniczoną odpowiedzialnością

Chełmska 30/34
00-725 Warsaw
Poland

The printed package leaflet of the medicinal product must state the name and address of the manufacturer
responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION

 Periodic safety update reports (PSURs)

The requirements for submission of PSURs for this medicinal product are set out in the list of Union
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any
subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE

USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and
interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and
any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of an

277
important (pharmacovigilance or risk minimisation) milestone being reached.

278
 ANNEX III

LABELLING AND PACKAGE LEAFLET

279
A. LABELLING

280
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (Packs of 1, 2, 6, 10, 20, 50 or 90)

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 2,000 IU (20 mg)/0.2 mL solution for injection in pre-filled syringe

enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled syringe (0.2 mL) contains 2,000 IU (20 mg) enoxaparin sodium

3. LIST OF EXCIPIENTS

Water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

1 pre-filled syringe
2 pre-filled syringes
6 pre-filled syringes
10 pre-filled syringes
20 pre-filled syringes
50 pre-filled syringes
2 pre-filled syringes with needle guard
6 pre-filled syringes with needle guard
10 pre-filled syringes with needle guard
20 pre-filled syringes with needle guard
50 pre-filled syringes with needle guard
90 pre-filled syringes with needle guard
6 pre-filled syringes with manual needle guard
10 pre-filled syringes with manual needle guard
20 pre-filled syringes with manual needle guard
2 pre-filled syringes with UltraSafe Passive needle guard
6 pre-filled syringes with UltraSafe Passive needle guard

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For single use only.

Read the package leaflet before use.
Subcutaneous, intravenous use.
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

281
Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The diluted solution must be used within 8 hours.

9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/021
EU/1/16/1132/001
EU/1/16/1132/033
EU/1/16/1132/002
EU/1/16/1132/064
EU/1/16/1132/011
EU/1/16/1132/034
EU/1/16/1132/012
EU/1/16/1132/023
EU/1/16/1132/065
EU/1/16/1132/051
EU/1/16/1132/085
EU/1/16/1132/090
EU/1/16/1132/095
EU/1/16/1132/053
EU/1/16/1132/054
EU/1/16/1132/117

13. BATCH NUMBER

Lot

282
14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 2,000 IU (20 mg)/0.2 mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

283
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 2,000 IU (20 mg)/0.2 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Techdow

3. EXPIRY DATE

4. BATCH NUMBER

5. OTHER

284
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 2,000 IU (20 mg)/0.2 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

285
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON OF (Packs of 2, 5, 6, 10, 20, 30, 50 or 90)

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 4,000 IU (40 mg) /0.4 mL solution for injection in pre-filled syringe
enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled syringe (0.4 mL) contains 4,000 IU (40 mg) enoxaparin sodium

3. LIST OF EXCIPIENTS

Water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

2 pre-filled syringes
5 pre-filled syringes
6 pre-filled syringes
10 pre-filled syringes
20 pre-filled syringes
30 pre-filled syringes
50 pre-filled syringes
2 pre-filled syringes with needle guard
5 pre-filled syringes with needle guard
6 pre-filled syringes with needle guard
10 pre-filled syringes with needle guard
20 pre-filled syringes with needle guard
30 pre-filled syringes with needle guard
50 pre-filled syringes with needle guard
90 pre-filled syringes with needle guard
2 pre-filled syringes with manual needle guard
6 pre-filled syringes with manual needle guard
10 pre-filled syringes with manual needle guard
20 pre-filled syringes with manual needle guard
50 pre-filled syringes with manual needle guard
2 pre-filled syringes with UltraSafe Passive needle guard
6 pre-filled syringes with UltraSafe Passive needle guard

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For single use only.

Read the package leaflet before use.
Subcutaneous, intravenous use.

286
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The diluted solution must be used within 8 hours.

9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/003
EU/1/16/1132/066
EU/1/16/1132/035
EU/1/16/1132/004
EU/1/16/1132/116
EU/1/16/1132/043
EU/1/16/1132/068
EU/1/16/1132/013
EU/1/16/1132/067
EU/1/16/1132/036
EU/1/16/1132/014
EU/1/16/1132/024
EU/1/16/1132/044
EU/1/16/1132/025
EU/1/16/1132/052
EU/1/16/1132/096

287
EU/1/16/1132/086
EU/1/16/1132/091
EU/1/16/1132/097
EU/1/16/1132/098
EU/1/16/1132/055
EU/1/16/1132/056

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 4,000 IU (40 mg)/0.4 mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

288
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 4,000 IU (40 mg) /0.4 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Techdow

3. EXPIRY DATE

4. BATCH NUMBER

5. OTHER

289
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 4,000 IU (40 mg) /0.4 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

290
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON OF (Packs of 2, 6, 10, 12, 20, 24, 30 or 50)

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 6,000 IU (60 mg)/0.6 mL solution for injection in pre-filled syringe

enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled syringe (0.6 mL) contains 6,000 IU (60 mg) enoxaparin sodium

3. LIST OF EXCIPIENTS

Water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

2 pre-filled syringes
6 pre-filled syringes
10 pre-filled syringes
12 pre-filled syringes
20 pre-filled syringes
24 pre-filled syringes
30 pre-filled syringes
50 pre-filled syringes
2 pre-filled syringes with needle guard
6 pre-filled syringes with needle guard
10 pre-filled syringes with needle guard
12 pre-filled syringes with needle guard
20 pre-filled syringes with needle guard
24 pre-filled syringes with needle guard
30 pre-filled syringes with needle guard
50 pre-filled syringes with needle guard
6 pre-filled syringes with manual needle guard
10 pre-filled syringes with manual needle guard
12 pre-filled syringes with manual needle guard
20 pre-filled syringes with manual needle guard
24 pre-filled syringes with manual needle guard
50 pre-filled syringes with manual needle guard
2 pre-filled syringes with UltraSafe Passive needle guard
10 pre-filled syringes with UltraSafe Passive needle guard

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For single use only.

Read the package leaflet before use.

291
Subcutaneous, intravenous use.
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The diluted solution must be used within 8 hours.

9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/005
EU/1/16/1132/037
EU/1/16/1132/006
EU/1/16/1132/045
EU/1/16/1132/083
EU/1/16/1132/015
EU/1/16/1132/038
EU/1/16/1132/016
EU/1/16/1132/026
EU/1/16/1132/027
EU/1/16/1132/028
EU/1/16/1132/046
EU/1/16/1132/111
EU/1/16/1132/087
EU/1/16/1132/092

292
EU/1/16/1132/099
EU/1/16/1132/100
EU/1/16/1132/101
EU/1/16/1132/102
EU/1/16/1132/057
EU/1/16/1132/058
EU/1/16/1132/118
EU/1/16/1132/119
EU/1/16/1132/120

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 6,000 IU (60 mg)/0.6 mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

293
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 6,000 IU (60 mg)/0.6 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Techdow

3. EXPIRY DATE

4. BATCH NUMBER

5. OTHER

294
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 6,000 IU (60 mg)/0.6 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

295
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON OF (Packs of 2, 6, 10, 12, 20, 24, 30 or 50)

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 8,000 IU (80 mg)/0.8 mL solution for injection in pre-filled syringe

enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled syringe (0.8 mL) contains 8,000 IU (80 mg) enoxaparin sodium

3. LIST OF EXCIPIENTS

Water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

2 pre-filled syringes
6 pre-filled syringes
10 pre-filled syringes
12 pre-filled syringes
20 pre-filled syringes
24 pre-filled syringes
30 pre-filled syringes
50 pre-filled syringes
2 pre-filled syringes with needle guard
6 pre-filled syringes with needle guard
10 pre-filled syringes with needle guard
12 pre-filled syringes with needle guard
20 pre-filled syringes with needle guard
24 pre-filled syringes with needle guard
30 pre-filled syringes with needle guard
50 pre-filled syringes with needle guard
6 pre-filled syringes with manual needle guard
10 pre-filled syringes with manual needle guard
12 pre-filled syringes with manual needle guard
20 pre-filled syringes with manual needle guard
24 pre-filled syringes with manual needle guard
50 pre-filled syringes with manual needle guard
2 pre-filled syringes with UltraSafe Passive needle guard
10 pre-filled syringes with UltraSafe Passive needle guard

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For single use only.

Read the package leaflet before use.

296
Subcutaneous, intravenous use.
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The diluted solution must be used within 8 hours.

9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/007
EU/1/16/1132/039
EU/1/16/1132/008
EU/1/16/1132/047
EU/1/16/1132/084
EU/1/16/1132/017
EU/1/16/1132/040
EU/1/16/1132/018
EU/1/16/1132/029
EU/1/16/1132/112
EU/1/16/1132/030
EU/1/16/1132/048
EU/1/16/1132/113
EU/1/16/1132/088
EU/1/16/1132/093

297
EU/1/16/1132/103
EU/1/16/1132/104
EU/1/16/1132/105
EU/1/16/1132/106
EU/1/16/1132/059
EU/1/16/1132/060
EU/1/16/1132/121
EU/1/16/1132/122
EU/1/16/1132/123

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 8,000 IU (80 mg)/0.8 mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

298
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 8,000 IU (80 mg)/0.8 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Techdow

3. EXPIRY DATE

4. BATCH NUMBER

5. OTHER

299
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 8,000 IU (80 mg)/0.8 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

300
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON OF (Packs of 2, 6, 10, 12, 20, 24, 30, 50 or 90)

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 10,000 IU (100 mg)/1 mL solution for injection in pre-filled syringe

enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled syringe (1 mL) contains 10,000 IU (100 mg) enoxaparin sodium

3. LIST OF EXCIPIENTS

Water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

2 pre-filled syringes
6 pre-filled syringes
10 pre-filled syringes
12 pre-filled syringes
20 pre-filled syringes
24 pre-filled syringes
30 pre-filled syringes
50 pre-filled syringes
90 pre-filled syringes
2 pre-filled syringes with needle guard
6 pre-filled syringes with needle guard
10 pre-filled syringes with needle guard
12 pre-filled syringes with needle guard
20 pre-filled syringes with needle guard
24 pre-filled syringes with needle guard
30 pre-filled syringes with needle guard
50 pre-filled syringes with needle guard
6 pre-filled syringes with manual needle guard
10 pre-filled syringes with manual needle guard
12 pre-filled syringes with manual needle guard
20 pre-filled syringes with manual needle guard
24 pre-filled syringes with manual needle guard
50 pre-filled syringes with manual needle guard
2 pre-filled syringes with UltraSafe Passive needle guard
10 pre-filled syringes with UltraSafe Passive needle guard

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For single use only.

301
Read the package leaflet before use.
Subcutaneous, intravenous use.
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The diluted solution must be used within 8 hours.

9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/009
EU/1/16/1132/041
EU/1/16/1132/010
EU/1/16/1132/049
EU/1/16/1132/063
EU/1/16/1132/022
EU/1/16/1132/019
EU/1/16/1132/042
EU/1/16/1132/020
EU/1/16/1132/031
EU/1/16/1132/114
EU/1/16/1132/032
EU/1/16/1132/050
EU/1/16/1132/115

302
EU/1/16/1132/089
EU/1/16/1132/094
EU/1/16/1132/107
EU/1/16/1132/108
EU/1/16/1132/109
EU/1/16/1132/110
EU/1/16/1132/061
EU/1/16/1132/062
EU/1/16/1132/124
EU/1/16/1132/125
EU/1/16/1132/126

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 10,000 IU (100 mg)/1 mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

303
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 10,000 IU (100 mg) /1 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Techdow

3. EXPIRY DATE

4. BATCH NUMBER

5. OTHER

304
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 10,000 IU (100 mg) /1 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

305
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (Packs of 2, 10 or 30)

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 12,000 IU (120 mg)/0.8 mL solution for injection in pre-filled syringe

enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled syringe (0.8 mL) contains 12,000 IU (120 mg) enoxaparin sodium.

3. LIST OF EXCIPIENTS

Water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

2 pre-filled syringes
10 pre-filled syringes
30 pre-filled syringes
10 pre-filled syringes with needle guard
30 pre-filled syringes with needle guard

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For single use only.

Read the package leaflet before use.
Subcutaneous, intravenous use.
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The diluted solution must be used within 8 hours.

306
9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/069
EU/1/16/1132/076
EU/1/16/1132/075
EU/1/16/1132/077
EU/1/16/1132/073

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 12,000 IU (120 mg)/0.8 mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

307
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 12,000 IU (120 mg)/0.8 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Techdow

3. EXPIRY DATE

4. BATCH NUMBER

5. OTHER

308
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 12,000 IU (120 mg)/0.8 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

309
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (Packs of 2, 10 or 30)

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 15,000 IU (150 mg)/1 mL solution for injection in pre-filled syringe

enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled syringe (1 mL) contains 15,000 IU (150 mg) enoxaparin sodium

3. LIST OF EXCIPIENTS

Water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

2 pre-filled syringes
10 pre-filled syringes
30 pre-filled syringes
10 pre-filled syringes with needle guard
30 pre-filled syringes with needle guard

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For single use only.

Read the package leaflet before use.
Subcutaneous, intravenous use.
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The diluted solution must be used within 8 hours.

310
9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/074
EU/1/16/1132/078
EU/1/16/1132/080
EU/1/16/1132/079
EU/1/16/1132/070

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 15,000 IU (150 mg)/ mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

311
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 15,000 IU (150 mg)/1 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Techdow

3. EXPIRY DATE

4. BATCH NUMBER

5. OTHER

312
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED SYRINGE

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 15,000 IU (150 mg)/1 mL injection

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

313
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX MULTIDOSE CONTAINER

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 30,000 IU (300 mg)/3 mL solution for injection in multidose container

enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each mL contains 10,000 IU (100 mg) enoxaparin sodium.

Each vial (3 mL) contains 30,000 IU (300 mg) enoxaparin sodium.

3. LIST OF EXCIPIENTS

Benzyl alcohol (see leaflet for further information)

Water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Subcutaneous, intravenous use.
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The contents of the multidose vial should be used within 28 days of opening.

314
9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/071

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 30,000 IU (300 mg)/3 mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

315
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

MULTIPLE DOSE CONTAINER

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 30,000 IU (300 mg)/3 mL solution for injection in multidose container

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

316
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX MULTIDOSE CONTAINER

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 50,000 IU (500 mg)/5 mL solution for injection in multidose container

enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each mL contains 10,000 IU (100 mg) enoxaparin sodium.

Each vial (5 mL) contains 50,000 IU (500 mg) enoxaparin sodium.

3. LIST OF EXCIPIENTS

Benzyl alcohol (see leaflet for further information)

Water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

5 vials

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Subcutaneous, intravenous use.
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The contents of the multidose vial should be used within 28 days of opening.

317
9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/072

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 50,000 IU (500 mg)/5 mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

318
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

MULTIPLE DOSE CONTAINER

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 50,000 IU (500 mg)/5 mL solution for injection in multidose container

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

319
PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER BOX MULTIDOSE CONTAINER

1. NAME OF THE MEDICINAL PRODUCT

Inhixa 100,000 IU (1000 mg)/10 mL solution for injection in multidose container

enoxaparin sodium

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each mL contains 10,000 IU (100 mg) enoxaparin sodium.

Each vial (10 mL) contains 100,000 IU (1000 mg) enoxaparin sodium.

3. LIST OF EXCIPIENTS

Benzyl alcohol (see leaflet for further information)

Water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

1 vial
5 vials

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Subcutaneous, intravenous use.
Extracorporeal use (in the dialysis circuit).

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
The contents of the multidose vial should be used within 28 days of opening.

320
9. SPECIAL STORAGE CONDITIONS

Store below 25 °C.

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Techdow Pharma Netherlands B.V.

Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1132/081
EU/1/16/1132/082

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Inhixa 100,000 IU (1000 mg)/10 mL

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN

321
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

MULTIPLE DOSE CONTAINER

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Inhixa 100,000 IU (1000 mg)/10 mL solution for injection in multidose container

enoxaparin sodium
SC, IV and extracorporeal use

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

322
B. PACKAGE LEAFLET

323
 Package leaflet: Information for the user

Inhixa 2,000 IU (20 mg)/0.2 mL solution for injection

Inhixa 4,000 IU (40 mg)/0.4 mL solution for injection
Inhixa 6,000 IU (60 mg)/0.6 mL solution for injection
Inhixa 8,000 IU (80 mg)/0.8 mL solution for injection
Inhixa 10,000 IU (100 mg)/1 mL solution for injection

enoxaparin sodium

Read all of this leaflet carefully before you start using this medicine because it contains important
information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if
their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Inhixa is and what it is used for
2. What you need to know before you use Inhixa
3. How to use Inhixa
4. Possible side effects
5. How to store Inhixa
6. Contents of the pack and other information

1. What Inhixa is and what it is used for

Inhixa contains the active substance called enoxaparin sodium that is a low molecular weight heparin
(LMWH).

Inhixa works in two ways:

1) Stopping existing blood clots from getting bigger. This helps your body to break them down and stop
them causing you harm.
2) Stopping blood clots forming in your blood.

Inhixa can be used to:

 Treat blood clots that are in your blood
 Stop blood clots from forming in your blood in the following situations:
o Before and after an operation
o When you have an acute illness and face period of limited mobility
o If you have experienced a blood clot due to cancer to prevent further clots from forming.
o When you have unstable angina (a condition when not enough blood gets to your heart)
o After a heart attack
 Stop blood clots forming in the tubes of your dialysis machine (used for people with severe kidney
problems).

2. What you need to know before you use Inhixa

Do not use Inhixa
 If you are allergic to enoxaparin sodium or any of the other ingredients of this medicine (listed in
section 6). Signs of an allergic reaction include: rash, swallowing or breathing problems, swelling of
your lips, face, throat or tongue.

324
  If you are allergic to heparin or other low molecular weight heparins such as nadroparin, tinzaparin
or dalteparin.
 If you have had a reaction to heparin that caused a severe drop in the number of your clotting cells
(platelets) - this reaction is called heparin-induced thrombocytopenia - within the last 100 days or if
you have antibodies against enoxaparin in your blood.
 If you are bleeding heavily or have a condition with a high risk of bleeding (such as stomach ulcer,
recent surgery of the brain or eyes), including recent bleeding stroke.
 If you are using Inhixa to treat blood clots in your body and going to receive spinal or epidural
anaesthesia or lumbar puncture within 24 hours.

Warnings and precautions

Inhixa should not be used interchangeably with other medicines belonging to the group of low molecular
weight heparins. This is because they are not exactly the same and do not have the same activity and
instructions for use.

Talk to your doctor or pharmacist before using Inhixa if:

 you have ever had a reaction to heparin that caused a severe drop in the number of your platelets
 you are going to receive spinal or epidural anesthesia or lumbar puncture (see Operations and
Anaesthetics): a delay should be respected between Inhixa use and this procedure
 you have had a heart valve fitted
 you have endocarditis (an infection of the inner lining of the heart)
 you have history of gastric ulcer
 you have had a recent stroke
 you have high blood pressure
 you have diabetes or problems with blood vessels in the eye caused by diabetes (called diabetic
retinopathy)
 you have had an operation recently on your eyes or brain
 you are elderly (over 65 years old) and especially if you are over 75 years old
 you have kidney problems
 you have liver problems
 you are underweight or overweight
 you have high level of potassium in your blood (this may be checked with a blood test)
 you are currently using medicines which affect bleeding (see section below – Other medicines and
Inhixa).

You may have a blood test before you start using this medicine and at intervals while you are using it; this is
to check the level of the clotting cells (platelets) and potassium in your blood.

Children and adolescents

The safety and efficacy of Inhixa has not been evaluated in children or adolescents.

Other medicines and Inhixa

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other
medicines.
 Warfarin – another anticoagulant medicine used for thinning the blood
 Acetylsalicylic acid (also known as aspirin or ASA), clopidogrel or other medicines used to stop
blood clots from forming (see also in section 3, “Changing anticoagulant medicine”)
 Dextran injection – used as a blood replacer
 Ibuprofen, diclofenac, ketorolac or other medicines known as non-steroidal anti-inflammatory agents
which are used to treat pain and swelling in arthritis and other conditions
 Prednisolone, dexamethasone or other medicines used to treat asthma, rheumatoid arthritis and other
conditions
 Medicines which increase potassium level in your blood such as potassium salts, water pills, some
medicines for heart problems.

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Operations and anaesthetics
If you are going to have a spinal puncture or an operation where an epidural or spinal anaesthetic is used, tell
your doctor that you are using Inhixa. See “Do not use Inhixa”. Also, tell your doctor if you have any
problem with your spine or if you ever had spinal surgery.

Pregnancy and breast-feeding

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist
for advice before taking this medicine.
If you are pregnant and have a mechanical heart valve, you may be at an increased risk of developing blood
clots. Your doctor should discuss this with you.

If you are breast-feeding or plan to breast-feed, you should ask your doctor for advice before taking this
medicine.

Driving and using machines

Inhixa does not affect the ability to drive and operate machinery.

Traceability
It is important to keep a record of the batch number of your Inhixa. So, every time you get a new package of
Inhixa, note down the date and the batch number (which is on the packaging after Lot) and keep this
information in a safe place.

Inhixa contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

3. How to use Inhixa

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or
pharmacist if you are not sure.

Having this medicine

 Your doctor or nurse will normally give you Inhixa. This is because it needs to be given as an
injection.
 When you go home, you may need to continue to use Inhixa and give it yourself (see instructions
below on how to do this).
 Inhixa is usually given by injection underneath the skin (subcutaneous).
 Inhixa can be given by injection into your vein (intravenous) after certain types of heart attack or
operation.
 Inhixa can be added to the tube leaving the body (arterial line) at the start of the dialysis session.
Do not inject Inhixa into a muscle.

How much will be given to you

 Your doctor will decide how much Inhixa to give you. The dose will depend on the reason it is being
used.
 If you have problems with your kidneys you may be given a smaller amount of Inhixa.

1. Treating blood clots that are in your blood

 The usual dose is 150 IU (1.5 mg) for every kilogram of your weight once daily or 100 IU (1 mg) for
every kilogram of your weight twice a day.
 Your doctor will decide how long you should receive Inhixa.

2. Stopping blood clots forming in your blood in the following situations:

 Operation or periods of limited mobility due to an illness
 The dose will depend on how likely you are to develop a clot. You will be given 2,000 IU
(20 mg) or 4,000 IU (40 mg) of Inhixa each day.

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  If you are going to have an operation your first injection will be usually given 2 hours or 12 hours
before your operation.
 If you have restricted mobility due to illness, you will normally be given 4,000 IU (40 mg) of
Inhixa each day.
 Your doctor will decide how long you should receive Inhixa.

 After you have had a heart attack

Inhixa can be used for two different types of heart attack called STEMI (ST segment elevation
myocardial infarction) or non-STEMI (NSTEMI). The amount of Inhixa given to you will depend on
your age and the kind of heart attack you have had.

NSTEMI type of heart attack:

 The usual dose is 100 IU (1 mg) for every kilogram of weight every 12 hours.
 Your doctor will normally ask you to take acetylsalicylic acid (aspirin) as well.
 Your doctor will decide how long you should receive Inhixa.

STEMI type of heart attack if you are under 75 years old:

 An initial dose of 3,000 IU (30 mg) of Inhixa will be given as injection into your vein.
 At the same time you will also be given Inhixa as an injection underneath your skin (subcutaneous
injection). The usual dose is 100 IU (1 mg) for every kilogram of your weight, every 12 hours.
 Your doctor will normally ask you to take acetylsalicylic acid (aspirin) as well.
 Your doctor will decide how long you should receive Inhixa.

STEMI type of heart attack if you are 75 years old or older:

 The usual dose is 75 IU (0.75 mg) for every kilogram of your weight, every 12 hours.
 The maximum amount of Inhixa given for the first two injections is 7,500 IU (75 mg).
 Your doctor will decide how long you should receive Inhixa.

For patients having a procedure called percutaneous coronary intervention (PCI):

Depending on when you were last given Inhixa, your doctor may decide to give an additional dose
of Inhixa before the PCI procedure. This is by injection into your vein.

3. Stopping blood clots from forming in the tubes of your dialysis machine
 The usual dose is 100 IU (1 mg) for every kilogram of your weight.
 Inhixa is added to the tube leaving the body (arterial line) at the start of the dialysis session. This
amount is usually enough for a 4-hour session. However, your doctor may give you a further dose
of 50 IU to 100 IU (0.5 to 1 mg) for every kilogram of your weight, if necessary.

How to give yourself an injection of Inhixa with a pre-filled syringe without needle guard

If you are able to give this medicine to yourself, your doctor or nurse will show you how to do this. Do not
try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your doctor
or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicine. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicine if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so, talk to your doctor or nurse.
- Decide where you are going to inject the medicine. Change the place where you inject each time
from the right to the left side of your abdomen (belly). This medicine should be injected just under
the skin on your abdomen, but not too near the belly button or any scar tissue (at least 5 cm away
from these).
- The pre-filled syringe is intended for single use only.

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Instructions on injecting yourself with Inhixa
1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicine into the fatty tissue of the
abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out.

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To avoid bruising, do not rub the injection site after you have injected yourself.

10) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with needle guard

Your pre-filled syringe has a needle guard attached to it in order to protect you from needle stick injury.
If you are able to give this medicine to yourself, your doctor or nurse will show you how to do this. Do not
try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your doctor
or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicine. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicine if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicine. Change the place where you inject each time
from the right to the left side of your abdomen (belly). This medicine should be injected just under
the skin on your abdomen, but not too near the belly button or any scar tissue (at least 5 cm away
from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

329
Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicine into the fatty tissue of the
abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Push hard the plunger. The needle guard, which is in the form of a plastic cylinder, will be activated
automatically and it will completely cover the needle.

11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

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When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with UltraSafe Passive needle guard

Your pre-filled syringe has UltraSafe Passive needle guard attached to it in order to protect you from needle
stick injury.
If you are able to give this medicine to yourself, your doctor or nurse will show you how to do this. Do not
try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your doctor
or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicine. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicine if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicine. Change the place where you inject each time
from the right to the left side of your abdomen (belly). This medicine should be injected just under
the skin on your abdomen, but not too near the belly button or any scar tissue (at least 5 cm away
from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

331
7) Hold the syringe so that the needle is pointing downwards (vertically at a 90º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicine into the fatty tissue of the
abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Let go of the plunger and allow the syringe to move up until the entire needle is guarded and locks
into place.

11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with manually activated needle guard

Your pre-filled syringe has a manually activated needle guard attached to it in order to protect you from
needle stick injury.
If you are able to give this medicine to yourself, your doctor or nurse will show you how to do this. Do not
try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your doctor
or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicine. Do not use if the date has passed.

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- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicine if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicine. Change the place where you inject each time
from the right to the left side of your abdomen (belly). This medicine should be injected just under
the skin on your abdomen, but not too near the belly button or any scar tissue (at least 5 cm away
from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from your
belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold.

333
8) Press down on the plunger with your thumb. This will inject the medicine into the fatty tissue of the
abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Firmly hold the syringe tube with one hand (A). With the other hand hold the base, “wings” of the
syringe (B), and pull the base until you hear a clicking sound (C). Now the used needle is completely
protected.

11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

Changing anticoagulant treatment

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- Changing from Inhixa to blood thinners called vitamin-K antagonists (e.g. warfarin)
Your doctor will ask you to have performed blood tests called INR and tell you when to stop Inhixa
accordingly.

- Changing from blood thinners called vitamin-K antagonists (e.g. warfarin) to Inhixa
Stop taking the vitamin-K antagonist. Your doctor will ask you to have performed blood tests called INR
and tell you when to start Inhixa accordingly.

- Changing from Inhixa to treatment with direct oral anticoagulant (e.g apixaban, dabigatran, edoxaban,
rivaroxaban)
Stop taking Inhixa. Start taking the direct oral anticoagulant 0-2 hours before the time you would have
had the next Inhixa injection, then continue as normal.

- Changing from treatment with direct oral anticoagulant to Inhixa

Stop taking direct oral anticoagulant. Do not start treatment with Inhixa until 12 hours after the final dose
of direct oral anticoagulant.

If you use more Inhixa than you should

If you think that you have used too much or too little Inhixa, tell your doctor, nurse or pharmacist
immediately, even if you have no signs of a problem. If a child accidentally injects or swallows Inhixa, take
the child to a hospital casualty department straight away.

If you forget to use Inhixa

If you forget to give yourself a dose, have it as soon as you remember. Do not give yourself a double dose on
the same day to make up for a forgotten dose. Keeping a diary will help to make sure you do not miss a dose.

If you stop using Inhixa

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.
It is important for you to keep having Inhixa injections until your doctor decides to stop them. If you stop,
you could get a blood clot which can be very dangerous.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Like other anticoagulant medicines (medicines to reduce blood clotting), Inhixa may cause bleeding which
may potentially be life-threatening. In some cases the bleeding may not be obvious.

If you experience any bleeding that does not stop by itself or if you experience signs of excessive bleeding
(exceptional weakness, tiredness, paleness, dizziness, headache or unexplained swelling), consult your doctor
immediately.
Your doctor may decide to keep you under closer observation or change your medicine.

Stop using Inhixa and talk to a doctor or nurse at once if you get any signs of a severe allergic reaction (such
as difficulty breathing, swelling of the lips, mouth, throat or eyes).

Stop using enoxaparin and seek medical attention immediately if you notice any of the following symptoms:
 A red, scaly widespread rash with bumps under the skin and blisters accompanied by fever. The
symptoms usually appear at the initiation of treatment (acute generalised exanthematous pustulosis).

You should tell your doctor straight away

 If you have any sign of blockage of a blood vessel by a blood clot such as:
- cramping pain, redness, warmth, or swelling in one of your legs – these are symptoms of deep
vein thrombosis

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 - breathlessness, chest pain, fainting or coughing up blood – these are symptoms of a pulmonary
embolism
 If you have a painful rash of dark red spots under the skin which do not go away when you put
pressure on them.
Your doctor may ask you to have performed a blood test to check your platelet count.

Overall list of possible side effects:

Very common (may affect more than 1 in 10 people)
 Bleeding.
 Increases in liver enzymes.

Common (may affect up to 1 in 10 people)

 You bruise more easily than usual. This could be because of a blood problem with low platelet
counts.
 Pink patches on your skin. These are more likely to appear in the area you have been injected with
Inhixa.
 Skin rash (hives, urticaria).
 Itchy red skin.
 Bruising or pain at the injection site.
 Decreased red blood cell count.
 High platelet counts in the blood.
 Headache.

Uncommon (may affect up to 1 in 100 people)

 Sudden severe headache. This could be a sign of bleeding in the brain.
 A feeling of tenderness and swelling in your stomach. You may have bleeding in your stomach.
 Large red irregularly shaped skin marks with or without blisters.
 Skin irritation (local irritation).
 Yellowing of your skin or eyes and your urine becoming darker. These may be signs of a liver
problem.

Rare (may affect up to 1 in 1,000 people)

 Severe allergic reaction. The signs may include: a rash, swallowing or breathing problems, swelling
of your lips, face, throat or tongue.
 Increased potassium in your blood. This is more likely to happen in people with kidney problems or
diabetes. Your doctor will be able to check this by carrying out a blood test.
 An increase in the number of white blood cells called eosinophils in your blood. Your doctor will be
able to check this by carrying out a blood test.
 Hair loss.
 Osteoporosis (a condition where your bones are more likely to break) after long-term use.
 Tingling, numbness and muscular weakness (particularly in the lower part of your body) when you
have had a spinal puncture or a spinal anaesthetic.
 Loss of control over your bladder or bowel (so you cannot control when you go to the toilet).
 Hard mass or lump at the injection site.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed
in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix
V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Inhixa

Keep this medicine out of the sight and reach of children.

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Do not use this medicine after the expiry date which is stated on the label and carton. The expiry date refers
to the last day of that month.

Store below 25 °C. Do not freeze.

After dilution the solution should be used within 8 hours.

Do not use this medicine if you notice any visible change in the appearance of the solution.

The Inhixa pre-filled syringes are for single dose use only. Discard any unused medicine.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Inhixa contains

- The active substance is enoxaparin sodium.
Each mL contains 10,000 IU (100 mg) enoxaparin sodium.
Each pre-filled syringe of 0.2 mL contains 2,000 IU (20 mg) of enoxaparin sodium.
Each pre-filled syringe of 0.4 mL contains 4,000 IU (40 mg) of enoxaparin sodium.
Each pre-filled syringe of 0.6 mL contains 6,000 IU (60 mg) of enoxaparin sodium.
Each pre-filled syringe of 0.8 mL contains 8,000 IU (80 mg) of enoxaparin sodium.
Each pre-filled syringe of 1 mL contains 10,000 IU (100 mg) of enoxaparin sodium.
- The other ingredient is water for injections.

What Inhixa looks like and contents of the pack

Inhixa 2,000 IU (20 mg)/0.2 mL is 0.2 mL of solution in:
- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a blue polypropylene plunger rod. The syringe can be additionally
equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe Passive
needle guard.

Supplied in packs of:

- 1, 2, 6, 10, 20 and 50 pre-filled syringe(s)
- 2, 6, 10, 20, 50 and 90 pre-filled syringes with needle guard
- 6,10 and 20 pre-filled syringes with manual needle guard
- 2 and 6 pre-filled syringes with UltraSafe Passive needle guard

Inhixa 4,000 IU (40 mg)/0.4 mL is 0.4 mL of solution in:

- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a yellow polypropylene plunger rod. The syringe can be additionally
equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe Passive
needle guard.

Supplied in packs of:

- 2, 5, 6, 10, 20, 30 and 50 pre-filled syringes
- 2, 5, 6, 10, 20, 30, 50 and 90 pre-filled syringes with needle guard
- 2, 6, 10, 20 and 50 pre-filled syringes with manual needle guard
- 2 and 6 pre-filled syringes with UltraSafe Passive needle guard

Inhixa 6,000 IU (60 mg)/0.6 mL is 0.6 mL of solution in:

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- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and an orange polypropylene plunger rod. The syringe can be
additionally equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe
Passive needle guard.

Supplied in packs of:

- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes
- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes with needle guard
- 6, 10, 12, 20, 24 and 50 pre-filled syringes with manual needle guard
- 2 and 10 pre-filled syringes with UltraSafe Passive needle guard

Inhixa 8,000 IU (80 mg)/0.8 mL is 0.8 mL of solution in:

- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a red polypropylene plunger rod. The syringe can be
additionally equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe
Passive needle guard.

Supplied in packs of:

- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes
- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes with needle guard
- 6, 10, 12, 20, 24 and 50 pre-filled syringes with manual needle guard
- 2 and 10 pre-filled syringes with UltraSafe Passive needle guard

Inhixa 10,000 IU (100 mg)/1 mL is 1 mL of solution in:

- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a black polypropylene plunger rod. The syringe can be
additionally equipped with needle guard or manual needle guard; or
- a clear, colourless type I neutral glass graduated syringe barrel with fixed needle and needle shield
closed by chlorobutyl rubber stopper and a white polycarbonate plunger rod equipped with UltraSafe
Passive needle guard.

Supplied in packs of:

- 2, 6, 10, 12, 20, 24, 30, 50 and 90 pre-filled syringes
- 2, 6, 10, 12, 20, 24, 30 and 50 pre-filled syringes with needle guard
- 6, 10, 12, 20, 24 and 50 pre-filled syringes with manual needle guard
- 2 and 10 pre-filled syringes with UltraSafe Passive needle guard

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Techdow Pharma Netherlands B.V.
Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

Manufacturer

SciencePharma spółka z ograniczoną odpowiedzialnością

Chełmska 30/34
00-725 Warsaw
Poland

338
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

België/Belgique/Belgien Lietuva
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+31 (0)76 531 5388 +37125892152

България Luxembourg/Luxemburg
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+49 (0)30 220 13 6906 +49 (0)30 220 13 6906

Česká republika Magyarország

Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+420255790502 +3618001930
Danmark Malta
Techdow Pharma Netherlands B.V. Mint Health Ltd.
+4578774377 +356 2755 9990

Deutschland Nederland
Mitvertrieb: Techdow Pharma Germany GmbH Techdow Pharma Netherlands B.V.
Potsdamer Platz 1, 10785 Berlin +31208081112
+49 (0)30 98 321 31 00

Eesti Norge
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+37125892152 +4721569855

Ελλάδα Österreich
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+49 (0)30 220 13 6906 +43720230772

España Polska
TECHDOW PHARMA SPAIN, S.L. Techdow Pharma Netherlands B.V.
Tel: +34 91 123 21 16 +49 (0)30 220 13 6906

France Portugal
Viatris Santé Laboratórios Atral, S.A.
+33 4 37 25 75 00 +351308801067

Hrvatska România
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+385 17776255 +49 (0)30 220 13 6906

Ireland Slovenija
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+31208081112 +49 (0)30 220 13 6906

Ísland Slovenská republika

Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+49 (0)30 220 13 6906 +421233331071

Italia Suomi/Finland
Techdow Pharma Italy S.R.L. Techdow Pharma Netherlands B.V.
Tel: +39 0256569157 +358942733040

339
 Κύπρος Sverige
MA Pharmaceuticals Trading Ltd Techdow Pharma Netherlands B.V.
+357 25 587112 +46184445720

Latvija United Kingdom (Northern Ireland)

Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+37125892152 +44 28 9279 2030

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
[Link]

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 Package leaflet: Information for the user

Inhixa 12,000 IU (120 mg)/0.8 mL solution for injection

Inhixa 15,000 IU (150 mg)/1 mL solution for injection

enoxaparin sodium

Read all of this leaflet carefully before you start using this medicine because it contains important
information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if
their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Inhixa is and what it is used for
2. What you need to know before you use Inhixa
3. How to use Inhixa
4. Possible side effects
5. How to store Inhixa
6. Contents of the pack and other information

1. What Inhixa is and what it is used for

Inhixa contains the active substance called enoxaparin sodium that is a low molecular weight heparin
(LMWH).

Inhixa works in two ways:

1) Stopping existing blood clots from getting bigger. This helps your body to break them down and stop
them causing you harm.
2) Stopping blood clots forming in your blood.

Inhixa can be used to:

 Treat blood clots that are in your blood
 Stop blood clots from forming in your blood in the following situations:
o Before and after an operation
o When you have an acute illness and face period of limited mobility
o If you have experienced a blood clot due to cancer to prevent further clots from forming.
o When you have unstable angina (a condition when not enough blood gets to your heart)
o After a heart attack
 Stop blood clots forming in the tubes of your dialysis machine (used for people with severe kidney
problems).

2. What you need to know before you use Inhixa

Do not use Inhixa

 If you are allergic to enoxaparin sodium or any of the other ingredients of this medicine (listed in
section 6). Signs of an allergic reaction include: rash, swallowing or breathing problems, swelling of
your lips, face, throat or tongue.
 If you are allergic to heparin or other low molecular weight heparins such as nadroparin, tinzaparin or
dalteparin.

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 If you have had a reaction to heparin that caused a severe drop in the number of your clotting cells
(platelets) - this reaction is called heparin-induced thrombocytopenia - within the last 100 days or if
you have antibodies against enoxaparin in your blood.
 If you are bleeding heavily or have a condition with a high risk of bleeding (such as stomach ulcer,
recent surgery of the brain or eyes), including recent bleeding stroke.
 If you are using Inhixa to treat blood clots in your body and going to receive spinal or epidural
anaesthesia or lumbar puncture within 24 hours.

Warnings and precautions

Inhixa should not be used interchangeably with other medicines belonging to the group of low molecular
weight heparins. This is because they are not exactly the same and do not have the same activity and
instructions for use.

Talk to your doctor or pharmacist before using Inhixa if:

 you have ever had a reaction to heparin that caused a severe drop in the number of your platelets
 you are going to receive spinal or epidural anesthesia or lumbar puncture (see Operations and
Anaesthetics): a delay should be respected between Inhixa use and this procedure
 you have had a heart valve fitted
 you have endocarditis (an infection of the inner lining of the heart)
 you have history of gastric ulcer
 you have had a recent stroke
 you have high blood pressure
 you have diabetes or problems with blood vessels in the eye caused by diabetes (called diabetic
retinopathy)
 you have had an operation recently on your eyes or brain
 you are elderly (over 65 years old) and especially if you are over 75 years old
 you have kidney problems
 you have liver problems
 you are underweight or overweight
 you have high level of potassium in your blood (this may be checked with a blood test)
 you are currently using medicines which affect bleeding (see section below – Other medicines and
Inhixa).

You may have a blood test before you start using this medicine and at intervals while you are using it; this is
to check the level of the clotting cells (platelets) and potassium in your blood.

Children and adolescents

The safety and efficacy of Inhixa has not been evaluated in children or adolescents.

Other medicines and Inhixa

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other
medicines.
 Warfarin – another anticoagulant medicine used for thinning the blood
 Acetylsalicylic acid (also known as aspirin or ASA), clopidogrel or other medicines used to stop blood
clots from forming (see also in section 3, “Changing anticoagulant medicine”)
 Dextran injection – used as a blood replacer
 Ibuprofen, diclofenac, ketorolac or other medicines known as non-steroidal anti-inflammatory agents
which are used to treat pain and swelling in arthritis and other conditions
 Prednisolone, dexamethasone or other medicines used to treat asthma, rheumatoid arthritis and other
conditions
 Medicines which increase potassium level in your blood such as potassium salts, water pills, some
medicines for heart problems.

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Operations and anaesthetics
If you are going to have a spinal puncture or an operation where an epidural or spinal anaesthetic is used, tell
your doctor that you are using Inhixa. See “Do not use Inhixa”. Also, tell your doctor if you have any
problem with your spine or if you ever had spinal surgery.

Pregnancy and breast-feeding

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist
for advice before taking this medicine.
If you are pregnant and have a mechanical heart valve, you may be at an increased risk of developing blood
clots. Your doctor should discuss this with you.

If you are breast-feeding or plan to breast-feed, you should ask your doctor for advice before taking this
medicine.

Driving and using machines

Inhixa does not affect the ability to drive and operate machinery.

Traceability
It is important to keep a record of the batch number of your Inhixa. So, every time you get a new package of
Inhixa, note down the date and the batch number (which is on the packaging after Lot) and keep this
information in a safe place.

Inhixa contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

3. How to use Inhixa

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or
pharmacist if you are not sure.

Having this medicine

 Your doctor or nurse will normally give you Inhixa. This is because it needs to be given as an
injection.
 When you go home, you may need to continue to use Inhixa and give it yourself (see instructions
below on how to do this).
 Inhixa is usually given by injection underneath the skin (subcutaneous).
 Inhixa can be given by injection into your vein (intravenous) after certain types of heart attack or
operation.
 Inhixa can be added to the tube leaving the body (arterial line) at the start of the dialysis session.
Do not inject Inhixa into a muscle.

How much will be given to you

 Your doctor will decide how much Inhixa to give you. The dose will depend on the reason it is being
used.
 If you have problems with your kidneys you may be given a smaller amount of Inhixa.

1. Treating blood clots that are in your blood

 The usual dose is 150 IU (1.5 mg) for every kilogram of your weight once daily or 100 IU (1 mg) for
every kilogram of your weight twice a day.
 Your doctor will decide how long you should receive Inhixa.

2. Stopping blood clots forming in your blood in the following situations:

 Operation or periods of limited mobility due to an illness
 The dose will depend on how likely you are to develop a clot. You will be given 2,000 IU
(20 mg) or 4,000 IU (40 mg) of Inhixa each day.

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  If you are going to have an operation your first injection will be usually given 2 hours or
12 hours before your operation.
 If you have restricted mobility due to illness, you will normally be given 4,000 IU (40 mg) of
Inhixa each day.
 Your doctor will decide how long you should receive Inhixa.

 After you have had a heart attack

Inhixa can be used for two different types of heart attack called STEMI (ST segment elevation myocardial
infarction) or non-STEMI (NSTEMI). The amount of Inhixa given to you will depend on your age and the
kind of heart attack you have had.

NSTEMI type of heart attack:

 The usual dose is 100 IU (1 mg) for every kilogram of weight every 12 hours.
 Your doctor will normally ask you to take acetylsalicylic acid (aspirin) as well.
 Your doctor will decide how long you should receive Inhixa.

STEMI type of heart attack if you are under 75 years old:

 An initial dose of 3,000 IU (30 mg) of Inhixa will be given as injection into your vein.
 At the same time you will also be given Inhixa as an injection underneath your skin (subcutaneous
injection). The usual dose is 100 IU (1 mg) for every kilogram of your weight, every 12 hours.
 Your doctor will normally ask you to take acetylsalicylic acid (aspirin) as well.
 Your doctor will decide how long you should receive Inhixa.

STEMI type of heart attack if you are 75 years old or older:

 The usual dose is 75 IU (0.75 mg) for every kilogram of your weight, every 12 hours.
 The maximum amount of Inhixa given for the first two injections is 7,500 IU (75 mg).
 Your doctor will decide how long you should receive Inhixa.

For patients having a procedure called percutaneous coronary intervention (PCI):

Depending on when you were last given Inhixa, your doctor may decide to give an additional dose of Inhixa
before the PCI procedure. This is by injection into your vein.

3. Stopping blood clots from forming in the tubes of your dialysis machine
 The usual dose is 100 IU (1 mg) for every kilogram of your weight.
 Inhixa is added to the tube leaving the body (arterial line) at the start of the dialysis session. This
amount is usually enough for a 4-hour session. However, your doctor may give you a further dose of
50 IU to 100 IU (0.5 to 1 mg) for every kilogram of your weight, if necessary.

How to give yourself an injection of Inhixa with a pre-filled syringe without needle guard

If you are able to give this medicine to yourself, your doctor or nurse will show you how to do this. Do not
try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your doctor
or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicine. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicine if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so, talk to your doctor or nurse.
- Decide where you are going to inject the medicine. Change the place where you inject each time
from the right to the left side of your abdomen (belly). This medicine should be injected just under
the skin on your abdomen, but not too near the belly button or any scar tissue (at least 5 cm away
from these).
- The pre-filled syringe is intended for single use only.

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Instructions on injecting yourself with Inhixa
1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicine into the fatty tissue of the
abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out.

345
To avoid bruising, do not rub the injection site after you have injected yourself.

10) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

How to give yourself an injection of Inhixa with a pre-filled syringe with needle guard

Your pre-filled syringe has a needle guard attached to it in order to protect you from needle stick injury.
If you are able to give this medicine to yourself, your doctor or nurse will show you how to do this. Do not
try to inject yourself if you have not been trained to do so. If you are not sure what to do, talk to your doctor
or nurse immediately.

Before injecting yourself with Inhixa

- Check the expiry date on the medicine. Do not use if the date has passed.
- Check if the syringe is not damaged and the liquid inside is clear. If not, use another syringe.
- Do not use this medicine if you notice any change in its appearance.
- Make sure you know how much you are going to inject.
- Check if the last injection caused any redness, change in skin colour, swelling, oozing or is still
painful. If so talk to your doctor or nurse.
- Decide where you are going to inject the medicine. Change the place where you inject each time
from the right to the left side of your abdomen (belly). This medicine should be injected just under
the skin on your abdomen, but not too near the belly button or any scar tissue (at least 5 cm away
from these).
- The pre-filled syringe is intended for single use only.

Instructions on injecting yourself with Inhixa

1) Wash your hands and the area that you will inject with soap and water. Dry them.
2) Sit or lie in a comfortable position so you are relaxed. Make sure you can see the place you are going
to inject. In a lounge chair, recliner, or propped up in bed with pillows is ideal.
3) Choose an area on the right or left side of your stomach. This should be at least 5 cm away from
your belly button and out towards your sides.

Remember: Do not inject yourself within 5 cm of your belly button or around existing scars or bruises.
Change the place where you inject between the left and right sides of your stomach, depending on the area
you were last injected.

4) Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and
remove the pre-filled syringe.
5) Carefully pull off the needle cap from the syringe. Throw away the cap. The syringe is pre-filled and
ready to use.

346
Do not press on the plunger before injecting yourself. Once you have removed the cap, do not allow the
needle to touch anything. This is to make sure the needle stays clean (sterile).

6) Hold the syringe in the hand you write with (like a pencil) and with your other hand, gently pinch the
cleaned area of your abdomen between your forefinger and thumb to make a fold in the skin.

Make sure you hold the skin fold throughout the injection.

7) Hold the syringe so that the needle is pointing downwards (vertically at a 90 º angle). Insert the full
length of the needle into the skin fold.

8) Press down on the plunger with your thumb. This will inject the medicine into the fatty tissue of the
abdomen. Make sure you hold the skin fold throughout the injection.

9) Remove the needle by pulling it straight out. Do not release the pressure on the plunger!

To avoid bruising, do not rub the injection site after you have injected yourself.

10) Push hard the plunger. The needle guard, which is in the form of a plastic cylinder, will be activated
automatically and it will completely cover the needle.

11) Drop the used syringe into the sharps container. Close the container lid tightly and place the
container out of reach of children.

347
When the container is full, dispose of it as your doctor or pharmacist has instructed. Do not put it in
the household rubbish.

Changing anticoagulant treatment

- Changing from Inhixa to blood thinners called vitamin-K antagonists (e.g. warfarin)
Your doctor will ask you to have performed blood tests called INR and tell you when to stop Inhixa
accordingly.

- Changing from blood thinners called vitamin-K antagonists (e.g. warfarin) to Inhixa
Stop taking the vitamin-K antagonist. Your doctor will ask you to have performed blood tests called
INR and tell you when to start Inhixa accordingly.

- Changing from Inhixa to treatment with direct oral anticoagulant (e.g apixaban, dabigatran,
edoxaban, rivaroxaban)
Stop taking Inhixa. Start taking the direct oral anticoagulant 0-2 hours before the time you would have
had the next Inhixa injection, then continue as normal.

- Changing from treatment with direct oral anticoagulant to Inhixa

Stop taking direct oral anticoagulant. Do not start treatment with Inhixa until 12 hours after the final
dose of direct oral anticoagulant.

If you use more Inhixa than you should

If you think that you have used too much or too little Inhixa, tell your doctor, nurse or pharmacist
immediately, even if you have no signs of a problem. If a child accidentally injects or swallows Inhixa, take
the child to a hospital casualty department straight away.

If you forget to use Inhixa

If you forget to give yourself a dose, have it as soon as you remember. Do not give yourself a double dose on
the same day to make up for a forgotten dose. Keeping a diary will help to make sure you do not miss a dose.

If you stop using Inhixa

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.
It is important for you to keep having Inhixa injections until your doctor decides to stop them. If you stop,
you could get a blood clot which can be very dangerous.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Like other anticoagulant medicines (medicines to reduce blood clotting), Inhixa may cause bleeding which
may potentially be life-threatening. In some cases the bleeding may not be obvious.

If you experience any bleeding that does not stop by itself or if you experience signs of excessive bleeding
(exceptional weakness, tiredness, paleness, dizziness, headache or unexplained swelling), consult your doctor
immediately.
Your doctor may decide to keep you under closer observation or change your medicine.

Stop using Inhixa and talk to a doctor or nurse at once if you get any signs of a severe allergic reaction (such
as difficulty breathing, swelling of the lips, mouth, throat or eyes).

Stop using enoxaparin and seek medical attention immediately if you notice any of the following symptoms:
 A red, scaly widespread rash with bumps under the skin and blisters accompanied by fever. The
symptoms usually appear at the initiation of treatment (acute generalised exanthematous pustulosis).

You should tell your doctor straight away

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 If you have any sign of blockage of a blood vessel by a blood clot such as:
- cramping pain, redness, warmth, or swelling in one of your legs – these are symptoms of deep
vein thrombosis
- breathlessness, chest pain, fainting or coughing up blood – these are symptoms of a pulmonary
embolism
 If you have a painful rash of dark red spots under the skin which do not go away when you put
pressure on them.
Your doctor may ask you to have performed a blood test to check your platelet count.

Overall list of possible side effects:

Very common (may affect more than 1 in 10 people)
 Bleeding.
 Increases in liver enzymes.

Common (may affect up to 1 in 10 people)

 You bruise more easily than usual. This could be because of a blood problem with low platelet counts.
 Pink patches on your skin. These are more likely to appear in the area you have been injected with
Inhixa.
 Skin rash (hives, urticaria).
 Itchy red skin.
 Bruising or pain at the injection site.
 Decreased red blood cell count.
 High platelet counts in the blood.
 Headache.

Uncommon (may affect up to 1 in 100 people)

 Sudden severe headache. This could be a sign of bleeding in the brain.
 A feeling of tenderness and swelling in your stomach. You may have bleeding in your stomach.
 Large red irregularly shaped skin marks with or without blisters.
 Skin irritation (local irritation).
 Yellowing of your skin or eyes and your urine becoming darker. These may be signs of a liver
problem.

Rare (may affect up to 1 in 1,000 people)

 Severe allergic reaction. The signs may include: a rash, swallowing or breathing problems, swelling of
your lips, face, throat or tongue.
 Increased potassium in your blood. This is more likely to happen in people with kidney problems or
diabetes. Your doctor will be able to check this by carrying out a blood test.
 An increase in the number of white blood cells called eosinophils in your blood. Your doctor will be
able to check this by carrying out a blood test.
 Hair loss.
 Osteoporosis (a condition where your bones are more likely to break) after long-term use.
 Tingling, numbness and muscular weakness (particularly in the lower part of your body) when you
have had a spinal puncture or a spinal anaesthetic.
 Loss of control over your bladder or bowel (so you cannot control when you go to the toilet).
 Hard mass or lump at the injection site.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed
in this leaflet. You can also report side effects directly via the national reporting system listed in
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Inhixa

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Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton. The expiry date refers
to the last day of that month.

Store below 25 °C. Do not freeze.

After dilution the solution should be used within 8 hours.

Do not use this medicine if you notice any visible change in the appearance of the solution.

The Inhixa pre-filled syringes are for single dose use only. Discard any unused medicine.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Inhixa contains

- The active substance is enoxaparin sodium.
Each mL contains 15,000 IU (150 mg) enoxaparin sodium.
Each pre-filled syringe of 0.8 mL contains 12,000 IU (120 mg) of enoxaparin sodium.
Each pre-filled syringe of 1 mL contains 15,000 IU (150 mg) of enoxaparin sodium.

- The other ingredient is water for injections.

What Inhixa looks like and contents of the pack

Inhixa 12,000 IU (120 mg)/0.8 mL is 0.8 mL of solution in:
- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a purple polypropylene plunger rod. The syringe can be additionally
equipped with needle guard.

Supplied in packs of:

- 2, 10 and 30 pre-filled syringes,
- 10 and 30 pre-filled syringes with needle guard.

Inhixa 15,000 IU (150 mg)/1 mL is 1 mL of solution in:

- a clear, colourless type I neutral glass syringe barrel with fixed needle and needle shield closed by
chlorobutyl rubber stopper and a dark blue polypropylene plunger rod. The syringe can be additionally
equipped with needle guard.

Supplied in packs of:

- 2, 10 and 30 pre-filled syringes,
- 10 and 30 pre-filled syringes with needle guard.
Not all pack sizes may be marketed.

Marketing Authorisation Holder

Techdow Pharma Netherlands B.V.
Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

Manufacturer

SciencePharma spółka z ograniczoną odpowiedzialnością

Chełmska 30/34
00-725 Warsaw

350
Poland

For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

België/Belgique/Belgien Lietuva
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+31 (0)76 531 5388 +37125892152

България Luxembourg/Luxemburg
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+49 (0)30 220 13 6906 +49 (0)30 220 13 6906

Česká republika Magyarország

Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+420255790502 +3618001930
Danmark Malta
Techdow Pharma Netherlands B.V. Mint Health Ltd.
+4578774377 +356 2755 9990

Deutschland Nederland
Mitvertrieb: Techdow Pharma Germany GmbH Techdow Pharma Netherlands B.V.
Potsdamer Platz 1, 10785 Berlin +31208081112
+49 (0)30 98 321 31 00

Eesti Norge
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+37125892152 +4721569855

Ελλάδα Österreich
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+49 (0)30 220 13 6906 +43720230772

España Polska
TECHDOW PHARMA SPAIN, S.L. Techdow Pharma Netherlands B.V.
Tel: +34 91 123 21 16 +49 (0)30 220 13 6906

France Portugal
Viatris Santé Laboratórios Atral, S.A.
+33 4 37 25 75 00 +351308801067

Hrvatska România
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+385 17776255 +49 (0)30 220 13 6906

Ireland Slovenija
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+31208081112 +49 (0)30 220 13 6906

Ísland Slovenská republika

Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+49 (0)30 220 13 6906 +421233331071

Italia Suomi/Finland
Techdow Pharma Italy S.R.L. Techdow Pharma Netherlands B.V.
Tel: +39 0256569157 +358942733040

351
Κύπρος Sverige
MA Pharmaceuticals Trading Ltd Techdow Pharma Netherlands B.V.
+357 25 587112 +46184445720

Latvija United Kingdom (Northern Ireland)

Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+37125892152 +44 28 9279 2030

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
[Link]

352
 Package leaflet: Information for the user

Inhixa 30,000 IU (300 mg)/3 mL solution for injection in multidose container

Inhixa 50,000 IU (500 mg)/5 mL solution for injection in multidose container
Inhixa 100,000 IU (1000 mg)/10 mL solution for injection in multidose container

enoxaparin sodium

Read all of this leaflet carefully before you start using this medicine because it contains important
information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if
their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side
effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Inhixa is and what it is used for
2. What you need to know before you use Inhixa
3. How to use Inhixa
4. Possible side effects
5. How to store Inhixa
6. Contents of the pack and other information

1. What Inhixa is and what it is used for

Inhixa contains the active substance called enoxaparin sodium that is a low molecular weight heparin
(LMWH).

Inhixa works in two ways:

1) Stopping existing blood clots from getting bigger. This helps your body to break them down and stop
them causing you harm.
2) Stopping blood clots forming in your blood.

Inhixa can be used to:

 Treat blood clots that are in your blood
 Stop blood clots from forming in your blood in the following situations:
o Before and after an operation
o When you have an acute illness and face period of limited mobility
o If you have experienced a blood clot due to cancer to prevent further clots from forming.
o When you have unstable angina (a condition when not enough blood gets to your heart)
o After a heart attack
 Stop blood clots forming in the tubes of your dialysis machine (used for people with severe kidney
problems).

2. What you need to know before you use Inhixa

Do not use Inhixa

 If you are allergic to enoxaparin sodium or any of the other ingredients of this medicine (listed in
section 6). Signs of an allergic reaction include: rash, swallowing or breathing problems, swelling of
your lips, face, throat or tongue.
 If you are allergic to heparin or other low molecular weight heparins such as nadroparin, tinzaparin or
dalteparin.

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 If you have had a reaction to heparin that caused a severe drop in the number of your clotting cells
(platelets) - this reaction is called heparin-induced thrombocytopenia - within the last 100 days or if
you have antibodies against enoxaparin in your blood.
 If you are bleeding heavily or have a condition with a high risk of bleeding (such as stomach ulcer,
recent surgery of the brain or eyes), including recent bleeding stroke.
 If you are using Inhixa to treat blood clots in your body and going to receive spinal or epidural
anaesthesia or lumbar puncture within 24 hours.
 If the patient is a premature or newborn baby up to 1 month because of the risk of severe toxicity
including abnormal respiration (“gasping syndrome”).

Warnings and precautions

Inhixa should not be used interchangeably with other medicines belonging to the group of low molecular
weight heparins. This is because they are not exactly the same and do not have the same activity and
instructions for use.

Talk to your doctor or pharmacist before using Inhixa if:

 you have ever had a reaction to heparin that caused a severe drop in the number of your platelets
 you are going to receive spinal or epidural anesthesia or lumbar puncture (see Operations and
Anaesthetics): a delay should be respected between Inhixa use and this procedure
 you have had a heart valve fitted
 you have endocarditis (an infection of the inner lining of the heart)
 you have history of gastric ulcer
 you have had a recent stroke
 you have high blood pressure
 you have diabetes or problems with blood vessels in the eye caused by diabetes (called diabetic
retinopathy)
 you have had an operation recently on your eyes or brain
 you are elderly (over 65 years old) and especially if you are over 75 years old
 you have kidney problems
 you have liver problems
 you are underweight or overweight
 you have high level of potassium in your blood (this may be checked with a blood test)
 you are currently using medicines which affect bleeding (see section below – Other medicines and
Inhixa).

You may have a blood test before you start using this medicine and at intervals while you are using it; this is
to check the level of the clotting cells (platelets) and potassium in your blood.

Children and adolescents

The safety and efficacy of Inhixa has not been evaluated in children or adolescents.

Other medicines and Inhixa

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other
medicines.
 Warfarin – another anticoagulant medicine used for thinning the blood
 Acetylsalicylic acid (also known as aspirin or ASA), clopidogrel or other medicines used to stop blood
clots from forming (see also in section 3, “Changing anticoagulant medicine”)
 Dextran injection – used as a blood replacer
 Ibuprofen, diclofenac, ketorolac or other medicines known as non-steroidal anti-inflammatory agents
which are used to treat pain and swelling in arthritis and other conditions
 Prednisolone, dexamethasone or other medicines used to treat asthma, rheumatoid arthritis and other
conditions
 Medicines which increase potassium level in your blood such as potassium salts, water pills, some
medicines for heart problems.

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Operations and anaesthetics
If you are going to have a spinal puncture or an operation where an epidural or spinal anaesthetic is used, tell
your doctor that you are using Inhixa. See “Do not use Inhixa”. Also, tell your doctor if you have any
problem with your spine or if you ever had spinal surgery.

Pregnancy and breast-feeding

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist
for advice before taking this medicine.
If you are pregnant and have a mechanical heart valve, you may be at an increased risk of developing blood
clots. Your doctor should discuss this with you.

If you are breast-feeding or plan to breast-feed, you should ask your doctor for advice before taking this
medicine.

Driving and using machines

Inhixa does not affect the ability to drive and operate machinery.

Traceability
It is important to keep a record of the batch number of your Inhixa. So, every time you get a new package of
Inhixa, note down the date and the batch number (which is on the packaging after Lot) and keep this
information in a safe place.

Inhixa contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose within the recommended dose range, that
is to say essentially ‘sodium-free’.

Inhixa contains benzyl alcohol

Inhixa contains benzyl alcohol (45 mg/3 mL; 75 mg/5 mL; 150 mg/10 mL). Benzyl alcohol may cause
allergic reactions.

Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called
“gasping syndrome”) in young children.

Do not give to your newborn baby (up to 4 weeks old), unless recommended by your doctor. Do not use for
more than a week in young children (less than 3 years old), unless advised by your doctor or pharmacist.

Ask your doctor or pharmacist for advice if you have a liver or kidney disease, or if you are pregnant or
breast-feeding. This is because large amounts of benzyl alcohol can build-up in your body and may cause
side effects (called “metabolic acidosis”).

3. How to use Inhixa

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or
pharmacist if you are not sure.

Having this medicine

 Your doctor or nurse will normally give you Inhixa. This is because it needs to be given as an
injection.
 When you go home, you may need to continue to use Inhixa and give it yourself.
 Inhixa is usually given by injection underneath the skin (subcutaneous).
 Inhixa can be given by injection into your vein (intravenous) after certain types of heart attack or
operation.
 Inhixa can be added to the tube leaving the body (arterial line) at the start of the dialysis session.
Do not inject Inhixa into a muscle.

355
How much will be given to you
 Your doctor will decide how much Inhixa to give you. The dose will depend on the reason it is being
used.
 If you have problems with your kidneys you may be given a smaller amount of Inhixa.

1. Treating blood clots that are in your blood

 The usual dose is 150 IU (1.5 mg) for every kilogram of your weight once daily or 100 IU (1 mg) for
every kilogram of your weight twice a day.
 Your doctor will decide how long you should receive Inhixa.

2. Stopping blood clots forming in your blood in the following situations:

 Operation or periods of limited mobility due to an illness
 The dose will depend on how likely you are to develop a clot. You will be given 2,000 IU
(20 mg) or 4,000 IU (40 mg) of Inhixa each day.
 If you are going to have an operation your first injection will be usually given 2 hours or 12 hours
before your operation.
 If you have restricted mobility due to illness, you will normally be given 4,000 IU (40 mg) of
Inhixa each day.
 Your doctor will decide how long you should receive Inhixa.

 After you have had a heart attack

Inhixa can be used for two different types of heart attack called STEMI (ST segment elevation myocardial
infarction) or non-STEMI (NSTEMI). The amount of Inhixa given to you will depend on your age and the
kind of heart attack you have had.

NSTEMI type of heart attack:

 The usual dose is 100 IU (1 mg) for every kilogram of weight every 12 hours.
 Your doctor will normally ask you to take acetylsalicylic acid (aspirin) as well.
 Your doctor will decide how long you should receive Inhixa.

STEMI type of heart attack if you are under 75 years old:

 An initial dose of 3,000 IU (30 mg) of Inhixa will be given as injection into your vein.
 At the same time you will also be given Inhixa as an injection underneath your skin (subcutaneous
injection). The usual dose is 100 IU (1 mg) for every kilogram of your weight, every 12 hours.
 Your doctor will normally ask you to take acetylsalicylic acid (aspirin) as well.
 Your doctor will decide how long you should receive Inhixa.

STEMI type of heart attack if you are 75 years old or older:

 The usual dose is 75 IU (0.75 mg) for every kilogram of your weight, every 12 hours.
 The maximum amount of Inhixa given for the first two injections is 7,500 IU (75 mg).
 Your doctor will decide how long you should receive Inhixa.

For patients having a procedure called percutaneous coronary intervention (PCI):

Depending on when you were last given Inhixa, your doctor may decide to give an additional dose of Inhixa
before the PCI procedure. This is by injection into your vein.

3. Stopping blood clots from forming in the tubes of your dialysis machine
 The usual dose is 100 IU (1 mg) for every kilogram of your weight.
 Inhixa is added to the tube leaving the body (arterial line) at the start of the dialysis session. This
amount is usually enough for a 4-hour session. However, your doctor may give you a further dose of
50 IU to 100 IU (0.5 to 1 mg) for every kilogram of your weight, if necessary.

Changing anticoagulant treatment

- Changing from Inhixa to blood thinners called vitamin-K antagonists (e.g. warfarin)

356
 Your doctor will ask you to have performed blood tests called INR and tell you when to stop Inhixa
accordingly.

- Changing from blood thinners called vitamin-K antagonists (e.g. warfarin) to Inhixa
Stop taking the vitamin-K antagonist. Your doctor will ask you to have performed blood tests called
INR and tell you when to start Inhixa accordingly.

- Changing from Inhixa to treatment with direct oral anticoagulant (e.g apixaban, dabigatran,
edoxaban, rivaroxaban)
Stop taking Inhixa. Start taking the direct oral anticoagulant 0-2 hours before the time you would have
had the next Inhixa injection, then continue as normal.

- Changing from treatment with direct oral anticoagulant to Inhixa

Stop taking direct oral anticoagulant. Do not start treatment with Inhixa until 12 hours after the final
dose of direct oral anticoagulant.

If you use more Inhixa than you should

If you think that you have used too much or too little Inhixa, tell your doctor, nurse or pharmacist
immediately, even if you have no signs of a problem. If a child accidentally injects or swallows Inhixa, take
the child to a hospital casualty department straight away.

If you forget to use Inhixa

If you forget to give yourself a dose, have it as soon as you remember. Do not give yourself a double dose on
the same day to make up for a forgotten dose. Keeping a diary will help to make sure you do not miss a dose.

If you stop using Inhixa

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.
It is important for you to keep having Inhixa injections until your doctor decides to stop them. If you stop,
you could get a blood clot which can be very dangerous.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Like other anticoagulant medicines (medicines to reduce blood clotting), Inhixa may cause bleeding which
may potentially be life-threatening. In some cases the bleeding may not be obvious.

If you experience any bleeding that does not stop by itself or if you experience signs of excessive bleeding
(exceptional weakness, tiredness, paleness, dizziness, headache or unexplained swelling), consult your doctor
immediately.
Your doctor may decide to keep you under closer observation or change your medicine.

Stop using Inhixa and talk to a doctor or nurse at once if you get any signs of a severe allergic reaction (such
as difficulty breathing, swelling of the lips, mouth, throat or eyes).

Stop using enoxaparin and seek medical attention immediately if you notice any of the following symptoms:
 A red, scaly widespread rash with bumps under the skin and blisters accompanied by fever. The
symptoms usually appear at the initiation of treatment (acute generalised exanthematous pustulosis).

You should tell your doctor straight away

 If you have any sign of blockage of a blood vessel by a blood clot such as:
- cramping pain, redness, warmth, or swelling in one of your legs – these are symptoms of deep
vein thrombosis
- breathlessness, chest pain, fainting or coughing up blood – these are symptoms of a pulmonary
embolism

357
 If you have a painful rash of dark red spots under the skin which do not go away when you put
pressure on them.
Your doctor may ask you to have performed a blood test to check your platelet count.

Overall list of possible side effects:

Very common (may affect more than 1 in 10 people)
 Bleeding.
 Increases in liver enzymes.

Common (may affect up to 1 in 10 people)

 You bruise more easily than usual. This could be because of a blood problem with low platelet counts.
 Pink patches on your skin. These are more likely to appear in the area you have been injected with
Inhixa.
 Skin rash (hives, urticaria).
 Itchy red skin.
 Bruising or pain at the injection site.
 Decreased red blood cell count.
 High platelet counts in the blood.
 Headache.

Uncommon (may affect up to 1 in 100 people)

 Sudden severe headache. This could be a sign of bleeding in the brain.
 A feeling of tenderness and swelling in your stomach. You may have bleeding in your stomach.
 Large red irregularly shaped skin marks with or without blisters.
 Skin irritation (local irritation).
 Yellowing of your skin or eyes and your urine becoming darker. These may be signs of a liver
problem.

Rare (may affect up to 1 in 1,000 people)

 Severe allergic reaction. The signs may include: a rash, swallowing or breathing problems, swelling of
your lips, face, throat or tongue.
 Increased potassium in your blood. This is more likely to happen in people with kidney problems or
diabetes. Your doctor will be able to check this by carrying out a blood test.
 An increase in the number of white blood cells called eosinophils in your blood. Your doctor will be
able to check this by carrying out a blood test.
 Hair loss.
 Osteoporosis (a condition where your bones are more likely to break) after long-term use.
 Tingling, numbness and muscular weakness (particularly in the lower part of your body) when you
have had a spinal puncture or a spinal anaesthetic.
 Loss of control over your bladder or bowel (so you cannot control when you go to the toilet).
 Hard mass or lump at the injection site.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed
in this leaflet. You can also report side effects directly via the national reporting system listed in
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Inhixa

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton. The expiry date refers
to the last day of that month.

358
Store below 25 °C. Do not freeze.

After first opening

Chemical and physical in-use stability has been demonstrated for 28 days at 25 °C.
From a microbiological point of view, once opened, the medicine may be stored for a maximum of 28 days
below 25 °C. Other in-use storage times and conditions are the responsibility of the user.

After dilution with sodium chloride 9 mg/ml (0.9%) solution for infusion or 5% glucose solution for
injection

Chemical and physical in-use stability has been demonstrated for 8 hours at 25 °C.
From a microbiological point of view, unless the method of dilution precludes the risk of microbial
contamination, the medicine should be used immediately. If not used immediately, in-use storage times and
conditions are the responsibility of user.

Do not use this medicine if you notice any visible change in the appearance of the solution.

Discard any unused medicine.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Inhixa contains

- The active substance is enoxaparin sodium.
Each mL contains 10,000 IU (100 mg) enoxaparin sodium.
One vial (3.0 mL) contains 30,000 IU (300 mg) enoxaparin sodium.
One vial (5.0 mL) contains 50,000 IU (500 mg) enoxaparin sodium.
One vial (10.0 mL) contains 100,000 IU (1000 mg) enoxaparin sodium.
- The other ingredients are benzyl alcohol (see section 2) and water for injections.

What Inhixa looks like and contents of the pack

 3 mL of solution in clear, colourless type I glass vial sealed with rubber injection stopper and white
aluminium-plastic cap in a cardboard box.

Supplied in packs of 1 vial.

 5 mL of solution in clear, colourless type I glass vial sealed with rubber injection stopper and grey
aluminium-plastic cap in a cardboard box.

Supplied in packs of 5 vials.

 10 mL of solution in clear, colourless type I glass vial sealed with rubber injection stopper and white
aluminium-plastic cap in a cardboard box.

Supplied in packs of 1 and 5 vials.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Techdow Pharma Netherlands B.V.
Strawinskylaan 1143, Toren C-11
1077XX Amsterdam
Netherlands

359
Manufacturer

SciencePharma spółka z ograniczoną odpowiedzialnością

Chełmska 30/34
00-725 Warsaw
Poland

For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

België/Belgique/Belgien Lietuva
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+31 (0)76 531 5388 +37125892152

България Luxembourg/Luxemburg
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+49 (0)30 220 13 6906 +49 (0)30 220 13 6906

Česká republika Magyarország

Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+420255790502 +3618001930
Danmark Malta
Techdow Pharma Netherlands B.V. Mint Health Ltd.
+4578774377 +356 2755 9990

Deutschland Nederland
Mitvertrieb: Techdow Pharma Germany GmbH Techdow Pharma Netherlands B.V.
Potsdamer Platz 1, 10785 Berlin +31208081112
+49 (0)30 98 321 31 00

Eesti Norge
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+37125892152 +4721569855

Ελλάδα Österreich
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+49 (0)30 220 13 6906 +43720230772

España Polska
TECHDOW PHARMA SPAIN, S.L. Techdow Pharma Netherlands B.V.
Tel: +34 91 123 21 16 +49 (0)30 220 13 6906

France Portugal
Viatris Santé Laboratórios Atral, S.A.
+33 4 37 25 75 00 +351308801067

Hrvatska România
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+385 17776255 +49 (0)30 220 13 6906

Ireland Slovenija
Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+31208081112 +49 (0)30 220 13 6906

Ísland Slovenská republika

Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.

360
+49 (0)30 220 13 6906 +421233331071

Italia Suomi/Finland
Techdow Pharma Italy S.R.L. Techdow Pharma Netherlands B.V.
Tel: +39 0256569157 +358942733040

Κύπρος Sverige
MA Pharmaceuticals Trading Ltd Techdow Pharma Netherlands B.V.
+357 25 587112 +46184445720

Latvija United Kingdom (Northern Ireland)

Techdow Pharma Netherlands B.V. Techdow Pharma Netherlands B.V.
+37125892152 +44 28 9279 2030

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
[Link]

361