8/3/2020 Metalyse 10,000 units - Summary of Product Characteristics (SmPC) - print friendly - (emc)

Metalyse 10,000 units

Summary of Product Characteristics Updated 25-Oct-2017 | Boehringer Ingelheim Limited
1. Name of the medicinal product
Metalyse 10,000 units powder and solvent for solution for injection
2. Qualitative and quantitative composition
Each vial contains 10,000 units (50 mg) tenecteplase.
Each pre-filled syringe contains 10 ml solvent.
The reconstituted solution contains 1,000 units (5 mg) tenecteplase per ml.
Potency of tenecteplase is expressed in units (U) by using a reference standard which is specific for tenecteplase and is
not comparable with units used for other thrombolytic agents.
Tenecteplase is a fibrin-specific plasminogen activator produced in a Chinese hamster ovary cell line by recombinant
DNA technology.
For a full list of excipients, see section 6.1.
3. Pharmaceutical form
Powder and solvent for solution for injection.
The powder is white to off-white.
The solvent is clear and colourless.
The reconstituted preparation is a clear and colourless to slightly yellow solution.
4. Clinical particulars
4.1 Therapeutic indications

Metalyse is indicated in adults for the thrombolytic treatment of suspected myocardial infarction with persistent ST
elevation or recent left Bundle Branch Block within 6 hours after the onset of acute myocardial infarction (AMI)
symptoms.

4.2 Posology and method of administration

Posology
Metalyse should be prescribed by physicians experienced in the use of thrombolytic treatment and with the facilities to
monitor that use.
Treatment with Metalyse should be initiated as soon as possible after onset of symptoms.
Metalyse should be administered on the basis of body weight, with a maximum dose of 10,000 units (50 mg
tenecteplase). The volume required to administer the correct dose can be calculated from the following scheme:

Patients' body weight Tenecteplase Tenecteplase Corresponding volume of

category reconstituted solution
(U) (mg)
(kg) (ml)

< 60 6,000 30 6

≥ 60 to < 70 7,000 35 7

≥ 70 to < 80 8,000 40 8

≥ 80 to < 90 9,000 45 9

≥ 90 10,000 50 10

For details see section 6.6: Special precautions for disposal and other handling

Elderly (≥ 75 years)
Metalyse should be administered with caution in the elderly (≥ 75 years) due to a higher bleeding risk (see information on
bleeding in section 4.4 and on the STREAM study in section 5.1).
Paediatric population
The safety and efficacy of Metalyse in children (below 18 years) have not been established. No data are available.

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Method of administration
The required dose should be administered as a single intravenous bolus over approximately 10 seconds.
A pre-existing intravenous line may be used for administration of Metalyse in sodium chloride 9 mg/ml (0.9%) solution
only. Metalyse is incompatible with glucose solution.
No other medicinal product should be added to the injection solution.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Adjunctive therapy
Antithrombotic adjunctive therapy with platelet inhibitors and anticoagulants should be administered according to the
current relevant treatment guidelines for the management of patients with ST-elevation myocardial infarction.
For coronary intervention see section 4.4.
Unfractionated heparin and enoxaparin have been used as antithrombotic adjunctive therapy in clinical studies with
Metalyse.
Acetylsalicylic acid should be initiated as soon as possible after symptom onset and continued with lifelong treatment
unless it is contraindicated.

4.3 Contraindications

Metalyse must not be administered to patients with a history of an anaphylactic (i.e. life-threatening) reaction to any of
the constituents (i.e. tenecteplase or any excipient) or gentamicin (a trace residue from the manufacturing process). If
treatment with Metalyse is nevertheless considered to be necessary, facilities for resuscitation should be immediately
available in case of need.
Furthermore, Metalyse is contraindicated in the following situations because thrombolytic therapy is associated with a
higher risk of bleeding:
- Significant bleeding disorder either at present or within the past 6 months
- Patients receiving effective oral anticoagulant treatment, e.g. warfarin sodium (INR > 1.3) (see section 4.4, subsection
“Bleeding”)
- Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
- Known haemorrhagic diathesis
- Severe uncontrolled hypertension
- Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months
(this includes any trauma associated with the current AMI)
- Recent trauma to the head or cranium
- Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks
- Acute pericarditis and/or subacute bacterial endocarditis
- Acute pancreatitis
- Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active
hepatitis
- Active peptic ulceration
- Arterial aneurysm and known arterial/venous malformation
- Neoplasm with increased bleeding risk
- Any known history of haemorrhagic stroke or stroke of unknown origin
- Known history of ischaemic stroke or transient ischaemic attack in the preceding 6 months
- Dementia

4.4 Special warnings and precautions for use

Coronary intervention
If primary percutaneous coronary intervention (PCI) is scheduled according to the current relevant treatment guidelines,
tenecteplase (see section 5.1 ASSENT-4 study) should not be given.
Patients who cannot undergo primary PCI within one hour as recommended by guidelines and receive tenecteplase as
primary coronary recanalization treatment should be transferred without delay to a coronary intervention capable facility
for angiography and timely adjunctive coronary intervention within 6-24 hours or earlier if medically indicated (see
section 5.1 STREAM study).

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Bleeding
The most common complication encountered during tenecteplase therapy is bleeding. The concomitant use of heparin
anticoagulation may contribute to bleeding. As fibrin is lysed during tenecteplase therapy, bleeding from recent puncture
site may occur. Therefore, thrombolytic therapy requires careful attention to all possible bleeding sites (including catheter
insertion sites, arterial and venous puncture sites, cutdown sites and needle puncture sites). The use of rigid catheters
as well as intramuscular injections and non-essential handling of the patient should be avoided during treatment with
tenecteplase.
Most frequently haemorrhage at the injection site, and occasionally genitourinary and gingival bleeding were observed.
Should serious bleeding occur, in particular cerebral haemorrhage, concomitant heparin administration should be
terminated immediately. Administration of protamine should be considered if heparin has been administered within 4
hours before the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use
of transfusion products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be
considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/l is
desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative. In the following
conditions, the risk of tenecteplase therapy may be increased and should be weighed against the anticipated benefits:
- Systolic blood pressure > 160 mm Hg
- Cerebrovascular disease
- Recent gastrointestinal or genitourinary bleeding (within the past 10 days)
- High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
- Any known recent (within the past 2 days) intramuscular injection
- Advanced age, i.e. over 75 years
- Low body weight < 60 kg
- Patients receiving oral anticoagulants: The use of Metalyse may be considered when dosing or time since the last
intake of anticoagulant treatment makes residual efficacy unlikely and if appropriate test(s) of anticoagulant activity for
the product(s) concerned show no clinically relevant activity on the coagulation system (e.g. INR ≤ 1.3 for vitamin K
antagonists or other relevant test(s) for other oral anticoagulants are within the respective upper limit of normal).
Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is recommended that antiarrhythmic
therapy for bradycardia and/or ventricular tachyarrhythmias (pacemaker, defibrillator) is available when tenecteplase is
administered.
GPIIb/IIIa antagonists
Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.
Hypersensitivity/Re-administration
No sustained antibody formation to the tenecteplase molecule has been observed after treatment. However there is no
systematic experience with re-administration of tenecteplase. Caution is needed when administering tenecteplase to
persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients,
or to gentamicin (a residue from the manufacturing process). If an anaphylactoid reaction occurs, the injection should be
discontinued immediately and appropriate therapy should be initiated. In any case, tenecteplase should not be re-
administered before assessment of haemostatic factors like fibrinogen, plasminogen and alpha2-antiplasmin.
Paediatric population
Metalyse is not recommended for use in children (below 18 years) due to a lack of data on safety and efficacy.

4.5 Interaction with other medicinal products and other forms of interaction

No formal interaction studies with tenecteplase and medicinal products commonly administered in patients with AMI
have been performed. However, the analysis of data from more than 12,000 patients treated during phase I, II and III did
not reveal any clinically relevant interactions with medicinal products commonly used in patients with AMI and
concomitantly used with tenecteplase.
Medicinal products that affect coagulation or those that alter platelet function (e.g. ticlopidine, clopidogrel, LMWH) may
increase the risk of bleeding prior to, during or after tenecteplase therapy.
Concomitant use of GPIIb/IIIa antagonists increases bleeding risk.

4.6 Fertility, pregnancy and lactation

Pregnancy
There is a limited amount of data from the use of Metalyse in pregnant women. Nonclinical data performed with
tenecteplase have shown bleeding with secondary mortality of dams due to the known pharmacological activity of the

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active substance and in a few cases abortion and resorption of the foetus occurred (effects only have been observed
with repeated dose administration). Tenecteplase is not considered to be teratogenic (please see section 5.3).
The benefit of treatment must be evaluated against the potential risks in case of myocardial infarction during pregnancy.
Breast-feeding
It is not known if tenecteplase is excreted in human milk. Breast-feeding should be discarded within the first 24 hours
after thrombolytic therapy.
Fertility
Clinical data as well as nonclinical studies on fertility are not available for tenecteplase (Metalyse).

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

Summary of the safety profile

Haemorrhage is a very common undesirable effect associated with the use of tenecteplase. The type of haemorrhage is
predominantly superficial at the injection site. Ecchymoses are observed commonly but usually do not require any
specific action. Death and permanent disability are reported in patients who have experienced stroke (including
intracranial bleeding) and other serious bleeding episodes.
Tabulated list of adverse reactions
Adverse reactions listed below are classified according to frequency and system organ class. Frequency groupings are
defined according to the following convention: 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), Very rare (<1/10,000), Not known (cannot be estimated from the available
data).
Table 1 displays the frequency of adverse reactions.

System organ class Adverse reaction

Immune system disorders

Rare Anaphylactoid reaction (including rash, urticaria, bronchospasm, laryngeal oedema)

Nervous system disorders

Uncommon Intracranial haemorrhage (such as cerebral haemorrhage, cerebral haematoma,

haemorrhagic stroke, haemorrhagic transformation stroke, intracranial haematoma,
subarachnoid haemorrhage) including associated symptoms as somnolence,
aphasia, hemiparesis, convulsion

Eye disorders

Uncommon Eye haemorrhage

Cardiac disorders

Uncommon Reperfusion arrhythmias (such as asystole, accelerated idioventricular arrhythmia,

arrhythmia, extrasystoles, atrial fibrillation, atrioventricular first degree to
atrioventricular block complete, bradycardia, tachycardia, ventricular arrhythmia,
ventricular fibrillation, ventricular tachycardia) occur in close temporal relationship to
treatment with tenecteplase. Reperfusion arrhythmias may lead to cardiac arrest,
can be life threatening and may require the use of conventional antiarrhythmic
therapies.

Rare Pericardial haemorrhage

Vascular disorders

Very common Haemorrhage

Rare Embolism (thrombotic embolisation)

Respiratory, thoracic and mediastinal disorders

Common Epistaxis

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Rare Pulmonary haemorrhage

Gastrointestinal disorders

Common Gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer

haemorrhage, rectal haemorrhage, haematemesis, melaena, mouth haemorrhage)

Uncommon Retroperitoneal haemorrhage (such as retroperitoneal haematoma)

Not known Nausea, vomiting

Skin and subcutaneous tissue disorders

Common Ecchymosis

Renal and urinary disorders

Common Urogenital haemorrhage (such as haematuria, haemorrhage urinary tract)

General disorders and administration site conditions

Common Injection site haemorrhage, puncture site haemorrhage

Investigations

Rare Blood pressure decreased

Not known Body temperature increased

Injury, poisoning and procedural complications

Not known Fat embolism, which may lead to corresponding consequences in the organs
concerned

As with other thrombolytic agents, the following events have been reported as sequelae of myocardial infarction and/or
thrombolytic administration:
- very common: hypotension, heart rate and rhythm disorders, angina pectoris
- common: recurrent ischaemia, cardiac failure, myocardial infarction, cardiogenic shock, pericarditis, pulmonary oedema
- uncommon: cardiac arrest, mitral valve incompetence, pericardial effusion, venous thrombosis, cardiac tamponade,
myocardial rupture
- rare: pulmonary embolism
These cardiovascular events can be life-threatening and may lead to death.
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:
United Kingdom
Yellow Card Scheme
Website: [Link]/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL – Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: [Link]
e-mail: medsafety@[Link]
Malta
ADR Reporting
Website: [Link]/adrportal
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4.9 Overdose

In the event of overdose there may be an increased risk of bleeding. In case of severe prolonged bleeding substitution
therapy may be considered (plasma, platelets), see also section 4.4.
5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, enzymes; ATC code: B01A D11

Mechanism of action
Tenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PA by modifications at
three sites of the protein structure. It binds to the fibrin component of the thrombus (blood clot) and selectively converts
thrombus-bound plasminogen to plasmin, which degrades the fibrin matrix of the thrombus. Tenecteplase has a higher
fibrin specificity and greater resistance to inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.
Pharmacodynamic effects
After administration of tenecteplase dose dependent consumption of α2-antiplasmin (the fluid-phase inhibitor of plasmin)
with consequent increase in the level of systemic plasmin generation have been observed. This observation is consistent
with the intended effect of plasminogen activation. In comparative studies a less than 15% reduction in fibrinogen and a
less than 25% reduction in plasminogen were observed in subjects treated with the maximum dose of tenecteplase
(10,000 U, corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in fibrinogen and
plasminogen levels. No clinically relevant antibody formation was detected at 30 days.
Clinical efficacy and safety
Patency data from the phase I and II angiographic studies suggest that tenecteplase, administered as a single
intravenous bolus, is effective in dissolving blood clots in the infarct-related artery of subjects experiencing an AMI on a
dose related basis.
ASSENT-2
A large scale mortality trial (ASSENT-2) in approx. 17,000 patients showed that tenecteplase is therapeutically
equivalent to alteplase in reducing mortality (6.2% for both treatments, at 30 days, upper limit of the 95% CI for the
relative risk ratio 1.124) and that the use of tenecteplase is associated with a significantly lower incidence of non-
intracranial bleedings (26.4% vs. 28.9%, p=0.0003). This translates into a significantly lower need of transfusions (4.3%
vs. 5.5%, p=0.0002). Intracranial haemorrhage occurred at a rate of 0.93% vs. 0.94% for tenecteplase and alteplase,
respectively.
Coronary patency and limited clinical outcome data showed that AMI patients have been successfully treated later than 6
hours after symptom onset.
ASSENT-4
The ASSENT-4 PCI study was designed to show if in 4000 patients with large myocardial infarctions pre-treatment with
full dose tenecteplase and concomitant single bolus of up to 4,000 IU unfractionated heparin administered prior to
primary PCI to be performed within 60 to 180 minutes leads to better outcomes than primary PCI alone. The trial was
prematurely terminated with 1667 randomised patients due to a numerically higher mortality in the facilitated PCI group
receiving tenecteplase. The occurrence of the primary endpoint, a composite of death or cardiogenic shock or
congestive heart failure within 90 days, was significantly higher in the group receiving the exploratory regimen of
tenecteplase followed by routine immediate PCI: 18.6% (151/810) compared to 13.4% (110/819) in the PCI only group,
p=0.0045. This significant difference between the groups for the primary endpoint at 90 days was already present in-
hospital and at 30 days.
Numerically all of the components of the clinical composite endpoint were in favour of the PCI only regimen: death: 6.7%
vs. 4.9% p=0.14; cardiogenic shock: 6.3% vs. 4.8% p=0.19; congestive heart failure: 12.0% vs. 9.2% p=0.06
respectively. The secondary endpoints re-infarction and repeat target vessel revascularisation were significantly
increased in the group pre-treated with tenecteplase: re-infarction: 6.1% vs. 3.7% p=0.0279; repeat target vessel
revascularisation: 6.6% vs. 3.4% p=0.0041.
The following adverse events occurred more frequently with tenecteplase prior to PCI: intracranial haemorrhage: 1% vs.
0% p=0.0037; stroke: 1.8% vs. 0% p<0.0001; major bleeds: 5.6% vs. 4.4% p=0.3118; minor bleeds: 25.3% vs. 19.0% p=
0.0021; blood transfusions: 6.2% vs. 4.2% p=0.0873; abrupt vessel closure: 1.9% vs. 0.1% p=0.0001.
STREAM study
The STREAM study was designed to evaluate the efficacy and safety of a pharmaco-invasive strategy versus a strategy
of standard primary PCI in patients presenting with ST elevation acute myocardial infarction within 3 hours of onset of
symptoms not able to undergo primary PCI within one hour of first medical contact. The pharmaco-invasive strategy
consisted of early fibrinolytic treatment with bolus tenecteplase and additional antiplatelet and anticoagulant therapy
followed by angiography within 6-24 hours or rescue coronary intervention.
The study population consisted of 1,892 patients randomised by means of an interactive voice response system. The
primary endpoint, a composite of death or cardiogenic shock or congestive heart failure or re-infarction within 30 days,
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was observed in 12.4% (116/939) of the pharmaco-invasive arm versus 14.3% (135/943) in the primary PCI arm (relative
risk 0.86 (0.68-1.09)).
Single components of the primary composite endpoint for the pharmaco-invasive strategy versus primary PCI
respectively were observed with the following frequencies:

Pharmaco-invasive Primary PCI p

(n=944) (n=948)

Composite death, shock, congestive heart 116/939 (12.4%) 135/943 (14.3%) 0.21
failure, re-infarction

All-cause mortality 43/939 (4.6%) 42/946 (4.4%) 0.88

Cardiogenic shock 41/939 (4.4%) 56/944 (5.9%) 0.13
Congestive heart failure 57/939 (6.1%) 72/943 (7.6%) 0.18
Re-infarction 23/938 (2.5%) 21/944 (2.2%) 0.74

Cardiac mortality 31/939 (3.3%) 32/946 (3.4%) 0.92

The observed incidence of major and of minor non-ICH bleeds were similar in both groups:

Pharmaco-invasive Primary PCI p

(n=944) (n=948)

Major non-ICH bleed 61/939 (6.5%) 45/944 (4.8%) 0.11

Minor non-ICH bleed 205/939 (21.8%) 191/944 (20.2%) 0.40

Incidence of total strokes and intracranial haemorrhage

Pharmaco-invasive Primary PCI p

(n=944) (n=948)

Total stroke (all types) 15/939 (1.6%) 5/946 (0.5%) 0.03*

Intracranial haemorrhage 9/939 (0.96%) 2/946 (0.21%) 0.04**

Intracranial haemorrhage after protocol
amendment to half dose in patients ≥ 75
years : 4/747 (0.5%) 2/758 (0.3%) 0.45

* the incidences in both groups are those expected in STEMI patients treated by fibrinolytics or primary PCI (as observed
in previous studies).
** the incidence in the pharmaco-invasive group is as expected for fibrinolysis with tenecteplase (as observed in previous
studies).
After the dose reduction of tenecteplase by half in patients ≥ 75 years there was no further intracranial hemorrhage (0 of
97 patients) (95% CI: 0.0-3.7) versus 8.1% (3 of 37 patients) (95% CI: 1.7-21.9) prior to dose reduction. The bounds of
the confidence interval of the observed incidences prior and after dose reduction are overlapping.
In patients ≥ 75 years the observed incidence of the primary efficacy composite end point for the pharmaco-invasive
strategy and primary PCI were as follows: before dose reduction 11/37 (29.7%) (95% CI: 15.9- 47.0) versus 10/32
(31.3%) (95% CI: 16.1-50.0), after dose reduction: 25/97 (25.8%) (95% CI: 17.4-35.7) versus 25/88 (24.8%) (95% CI:
19.3-39.0). In both groups the bounds of the confidence interval of the observed incidences prior and post dose
reduction are overlapping.

5.2 Pharmacokinetic properties

Absorption and distribution

Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen. Following intravenous
bolus administration of 30 mg tenecteplase in patients with acute myocardial infarction, the initially estimated
tenecteplase plasma concentration was 6.45 ± 3.60 μg/mL (mean ± SD). The distribution phase represents 31% ± 22%
to 69% ± 15% (mean ± SD) of the total AUC following the administration of doses ranges from 5 to 50 mg.
Data on tissue distribution were obtained in studies with radioactively labelled tenecteplase in rats. The main organ to
which tenecteplase distributed was the liver. It is not known whether and to which extent tenecteplase binds to plasma
proteins in humans. The mean residence time (MRT) in the body is approximately 1 h and the mean (± SD) volume of
distribution at the steady-state (Vss) ranged from 6.3 ± 2 L to 15 ± 7 L.
Biotransformation
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Tenecteplase is cleared from circulation by binding to specific receptors in the liver followed by catabolism to small
peptides. Binding to hepatic receptors is, however, reduced compared to native t-PA, resulting in a prolonged half-life.
Elimination
After single intravenous bolus injection of tenecteplase in patients with acute myocardial infarction, tenecteplase antigen
exhibits biphasic elimination from plasma. There is no dose dependence of tenecteplase clearance in the therapeutic
dose range. The initial, dominant half-life is 24 ± 5.5 (mean ±SD) min, which is 5 times longer than native t-PA. The
terminal half-life is 129 ± 87 min, and plasma clearance is 119 ± 49 ml/min.
Increasing body weight resulted in a moderate increase of tenecteplase clearance, and increasing age resulted in a
slight decrease of clearance. Women exhibit in general lower clearance than men, but this can be explained by the
generally lower body weight of women.
Linearity/Non-Linearity
The dose linearity analysis based on AUC suggested that tenecteplase exhibits non-linear pharmacokinetics in the dose
range studied, i.e. 5 to 50 mg.
Renal and hepatic impairment
Because elimination of tenecteplase is through the liver, it is not expected that renal dysfunction will affect its the
pharmacokinetics. This is also supported by animal data. However, the effect of renal and hepatic dysfunction on
pharmacokinetics of tenecteplase in humans has not been specifically investigated. Accordingly, there is no guidance for
the adjustment to tenecteplase dose in patients with hepatic and severe renal insufficiency.

5.3 Preclinical safety data

Intravenous single dose administration in rats, rabbits and dogs resulted only in dose-dependent and reversible
alterations of the coagulation parameters with local haemorrhage at the injection site, which was regarded as a
consequence of the pharmacodynamic effect of tenecteplase. Multiple-dose toxicity studies in rats and dogs confirmed
these above-mentioned observations, but the study duration was limited to two weeks by antibody formation to the
human protein tenecteplase, which resulted in anaphylaxis.
Safety pharmacology data in cynomolgus monkeys revealed reduction of blood pressure followed by changes of ECG,
but these occurred at exposures that were considerably higher than the clinical exposure.
With regard to the indication and the single dose administration in humans, reproductive toxicity testing was limited to an
embryotoxicity study in rabbits, as a sensitive species. Tenecteplase induced total litter deaths during the mid-embryonal
period. When tenecteplase was given during the mid- or late-embryonal period maternal animals showed vaginal
bleeding on the day after the first dose. Secondary mortality was observed 1-2 days later. Data on the foetal period are
not available.
Mutagenicity and carcinogenicity are not expected for this class of recombinant proteins and genotoxicity and
carcinogenicity testing were not necessary.
No local irritation of the blood vessel was observed after intravenous, intra-arterial or paravenous administration of the
final formulation of tenecteplase.
6. Pharmaceutical particulars
6.1 List of excipients

Powder
L-arginine
Phosphoric acid
Polysorbate 20.
Trace residue from manufacturing process: Gentamicin
Solvent
Water for injections.

6.2 Incompatibilities

Metalyse is incompatible with glucose infusion solutions.

6.3 Shelf life

Shelf life as packaged for sale

2 years
Reconstituted solution
Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C and 8 hours at 30°C.
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From a microbiological point of view, the reconstituted solution should be used immediately. If not used immediately, in-
use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24
hours at 2-8°C.

6.4 Special precautions for storage

Do not store above 30°C. Keep the container in the outer carton in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of container

20 ml glass vial type I, with a coated (B2-42) grey rubber stopper and a flip-off cap filled with powder for solution for
injection. Each vial 50 mg tenecteplase.
10 ml plastic pre-filled syringe with 10 ml of solvent.
Sterile vial adapter.
Sterile needle for single use.

6.6 Special precautions for disposal and other handling

Metalyse should be reconstituted by adding the complete volume of water for injections from the pre-filled syringe to the
vial containing the powder for injection.
1. Ensure that the appropriate vial size is chosen according to the body weight of the patient.

Patients' body weight Volume of reconstituted Tenecteplase Tenecteplase

category solution
(U) (mg)
(kg) (ml)

< 60 6 6,000 30

≥ 60 to < 70 7 7,000 35

≥ 70 to < 80 8 8,000 40

≥ 80 to < 90 9 9,000 45

≥ 90 10 10,000 50

2. Check that the cap of the vial is still intact.

3. Remove the flip-off cap from the vial.
4. Remove the tip-cap from the syringe. Then immediately screw the pre-filled syringe on the vial adapter and penetrate
the vial stopper in the middle with the spike of the vial adapter.
5. Add the water for injections into the vial by pushing the syringe plunger down slowly to avoid foaming.
6. Reconstitute by swirling gently.
7. The reconstituted preparation results in a colourless to pale yellow, clear solution. Only clear solution without particles
should be used.
8. Directly before the solution will be administered, invert the vial with the syringe still attached, so that the syringe is
below the vial.
9. Transfer the appropriate volume of reconstituted solution of Metalyse into the syringe, based on the patient's weight.
10. Disconnect the syringe from the vial adapter.
11. Metalyse is to be administered to the patient, intravenously in about 10 seconds. It should not be administered in a
line containing glucose.
12. Any unused solution should be discarded.
Alternatively the reconstitution can be performed with the included needle.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
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Germany
8. Marketing authorisation number(s)
EU/1/00/169/006

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 23 February 2001
Date of last renewal: 23 February 2006
10. Date of revision of the text
October 2017
Detailed information on this medicinal product is available on the website of the European Medicines Agency
[Link]
Company Contact Details
Boehringer Ingelheim Limited
Address WWW
Ellesfield Avenue, Bracknell, Berkshire, RG12 8YS [Link]

Telephone Fax
+44 (0)1344 424 600 +44 (0)1344 741 298

Medical Information Direct Line Medical Information e-mail

+44 (0)1344 742579 medinfo@[Link]

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