600 mg Film-Coated Tablet

Linezolid
Servalin
Antibacterial
2068517
Linezolid Lactic acidosis

Servalin
Lactic acidosis has been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis
including recurrent nausea or vomiting, abdominal pain, a low bicarbonate level, or hyperventilation while receiving linezolid
should receive immediate medical attention. If lactic acidosis occurs, the benefits of continued use of linezolid should be
600 mg Film-Coated Tablet weighed against the potential risks.
Antibacterial Mitochondrial dysfunction
Linezolid inhibits mitochondrial protein synthesis. Adverse events, such as lactic acidosis, anaemia and neuropathy (optic
and peripheral), may occur as a result of this inhibition; these events are more common when the drug is used longer than
FORMULATION 28 days.
Each film-coated tablet contains:
Linezolid ............600 mg Serotonin syndrome
Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and serotonergic agents,
DRUG DESCRIPTION: including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported. Co-administration of
Linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[[3-[3- linezolid and serotonergic agents is therefore contraindicated (see section Contraindications) except where administration of
Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide. linezolid and concomitant serotonergic agents is essential. In those cases patients should be closely observed for signs and
The empirical formula is C16H20 FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below: symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or
O symptoms occur physicians should consider discontinuing either one or both agents; if the concomitant serotonergic agent is
withdrawn, discontinuation symptoms can occur.
O
N N H Peripheral and optic neuropathy
O * N CH3 Peripheral neuropathy, as well as optic neuropathy and optic neuritis sometimes progressing to loss of vision, have been
H reported in patients treated with Linezolid tablets 600mg; these reports have primarily been in patients treated for longer than
F the maximum recommended duration of 28 days.
O
THERAPEUTIC INDICATIONS All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour
Nosocomial pneumonia vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an
Community acquired pneumonia ophthalmologist as necessary. If any patients are taking Linezolid tablets 600mg for longer than the recommended 28 days,
Linezolid tablets 600mg is indicated in adults for the treatment of community acquired pneumonia and nosocomial their visual function should be regularly monitored.
pneumonia when known or suspected to be caused by susceptible Gram positive bacteria. In determining whether Linezolid
tablets 600mg is an appropriate treatment, the results of microbiological tests or information on the prevalence of resistance If peripheral or optic neuropathy occurs, the continued use of Linezolid tablets 600mg should be weighed against the
to antibacterial agents among Gram positive bacteria should be taken into consideration (See section Pharmacodynamic potential risks.
properties). There may be an increased risk of neuropathies when linezolid is used in patients currently taking or who have recently taken
Linezolid is not active against infections caused by Gram negative pathogens. Specific therapy against Gram negative antimycobacterial medications for the treatment of tuberculosis.
organisms must be initiated concomitantly if a Gram negative pathogen is documented or suspected.
Complicated skin and soft tissue infections (see section Special warnings and precautions for use) Linezolid tablets 600mg Convulsions
is indicated in adults for the treatment of complicated skin and soft tissue infections only when microbiological testing has Convulsions have been reported to occur in patients when treated with Linezolid tablets 600mg. In most of these cases, a
established that the infection is known to be caused by susceptible Gram positive bacteria. history of seizures or risk factors for seizures was reported. Patients should be advised to inform their physician if they have a
Linezolid is not active against infections caused by Gram negative pathogens. Linezolid should only be used in patients with history of seizures.
complicated skin and soft tissue infections with known or possible co-infection with Gram negative organisms if there are no
alternative treatment options available (see section Special warnings and precautions for use). In these circumstances Monoamine oxidase inhibitors
treatment against Gram negative organisms must be initiated concomitantly. Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI); however, at the doses used for antibacterial
Linezolid should only be initiated in a hospital environment and after consultation with a relevant specialist such as a therapy, it does not exert an anti-depressive effect. There are very limited data from drug interaction studies and on the safety
microbiologist or infectious diseases specialist. of linezolid when administered to patients with underlying conditions and/or on concomitant medications which might put
Consideration should be given to official guidance on the appropriate use of antibacterial agents. them at risk from MAO inhibition. Therefore, linezolid is not recommended for use in these circumstances unless close
observation and monitoring of the recipient is possible (see sections Contraindications and Interaction with other medicinal
POSOLOGY AND METHOD OF ADMINISTRATION products and other forms of interaction).
Posology Use with tyramine-rich foods
Linezolid tablets 600mg solution for infusion, film-coated tablets or oral suspension may be used as initial therapy. Patients Patients should be advised against consuming large amounts of tyramine-rich foods (see section Interaction with other
who commence treatment on the parenteral formulation may be switched to either oral presentation when clinically medicinal products and other forms of interaction).
indicated. In such circumstances, no dose adjustment is required as linezolid has an oral bioavailability of approximately
100%. Superinfection
Recommended dosage and duration of treatment for adults: The effects of linezolid therapy on normal flora have not been evaluated in clinical trials.
The duration of treatment is dependent on the pathogen, the site of infection and its severity, and on the patient's clinical The use of antibiotics may occasionally result in an overgrowth of non-susceptible organisms. For example, approximately 3%
response. of patients receiving the recommended linezolid doses experienced drug-related candidiasis during clinical trials. Should
The following recommendations for duration of therapy reflect those used in the clinical trials. Shorter treatment regimens superinfection occur during therapy, appropriate measures should be taken.
may be suitable for some types of infection but have not been evaluated in clinical trials.
The maximum treatment duration is 28 days. The safety and effectiveness of linezolid when administered for periods longer Special populations
than 28 days have not been established. (see section Special warnings and precautions for use). Linezolid should be used with special caution in patients with severe renal insufficiency and only when the anticipated benefit
No increase in the recommended dosage or duration of treatment is required for infections associated with concurrent is considered to outweigh the theoretical risk (see sections Posology and method of administration and Pharmacokinetic
bacteraemia. properties).
The dose recommendation for the solution for infusion and the tablets/granules for oral suspension are identical and are as It is recommended that linezolid should be given to patients with severe hepatic insufficiency only when the perceived benefit
follows: outweighs the theoretical risk (see sections Posology and method of administration and Pharmacokinetic properties).

Infections Dosage Duration of treatment Impairment of fertility

Linezolid reversibly decreased fertility and induced abnormal sperm morphology in adult male rats at exposure levels
approximately equal to those expected in humans; possible effects of linezolid on the human male reproductive system are
Nosocomial pneumonia not known (see section Preclinical safety data).
600 mg twice daily 10-14 Consecutive days
Clinical trials
Community acquired pneumonia The safety and effectiveness of linezolid when administered for periods longer than 28 days have not been established.
Controlled clinical trials did not include patients with diabetic foot lesions, decubitus or ischaemic lesions, severe burns or
Complicated skin and soft tissue infections 600 mg twice daily gangrene. Therefore, experience in the use of linezolid in the treatment of these conditions is limited.

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Pediatric population:
Monoamine oxidase inhibitors
The safety and efficacy of linezolid in children aged (< 18 years old) has not been established.
Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAOI). There are very limited data from drug
Elderly: interaction studies and on the safety of linezolid when administered to patients on concomitant medications that might put
No dose adjustment is required. them at risk from MAO inhibition. Therefore, linezolid is not recommended for use in these circumstances unless close
observation and monitoring of the recipient is possible (see sections Contraindications and Special warnings and precautions
Renal impairment: for use).
No dose adjustment is required (see sections Special warnings and precautions for use and Pharmacokinetic properties).
Severe renal impairment (i.e. CLCR < 30 ml/min): Potential interactions producing elevation of blood pressure
No dose adjustment is required. Due to the unknown clinical significance of higher exposure (up to 10 fold) to the two In normotensive healthy volunteers, linezolid enhanced the increases in blood pressure caused by pseudoephedrine and
primary metabolites of linezolid in patients with severe renal insufficiency, linezolid should be used with special caution in phenylpropanolamine hydrochloride. Co-administration of linezolid with either pseudoephedrine or phenylpropanolamine
these patients and only when the anticipated benefit is considered to outweigh the theoretical risk. resulted in mean increases in systolic blood pressure of the order of 30-40 mmHg, compared with 11-15 mmHg increases with
As approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis, linezolid should be given after linezolid alone, 14-18 mmHg with either pseudoephedrine or phenylpropanolamine alone and 8-11 mmHg with placebo.
dialysis in patients receiving such treatment. The primary metabolites of linezolid are removed to some extent by Similar studies in hypertensive subjects have not been conducted. It is recommended that doses of drugs with a vasopressive
haemodialysis, but the concentrations of these metabolites are still very considerably higher following dialysis than those action, including dopaminergic agents, should be carefully titrated to achieve the desired response when co-administered with
observed in patients with normal renal function or mild to moderate renal insufficiency. linezolid.
Therefore, linezolid should be used with special caution in patients with severe renal insufficiency who are undergoing Potential serotonergic interactions
dialysis and only when the anticipated benefit is considered to outweigh the theoretical risk. The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered
To date, there is no experience of linezolid administration to patients undergoing continuous ambulatory peritoneal dialysis dextromethorphan (two 20 mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion,
(CAPD) or alternative treatments for renal failure (other than haemodialysis). delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia) have been observed in normal subjects receiving
linezolid and dextromethorphan.
Hepatic impairment:
No dose adjustment is required. However, there are limited clinical data and it is recommended that linezolid should be used Post marketing experience: there has been one report of a patient experiencing serotonin syndrome-like effects while taking
in such patients only when the anticipated benefit is considered to outweigh the theoretical risk (see sections Special linezolid and dextromethorphan which resolved on discontinuation of both medications.
warnings and precautions for use and Pharmacokinetic properties). During clinical use of linezolid with serotonergic agents, including antidepressants such as selective serotonin reuptake
Method of administration: inhibitors (SSRIs), cases of serotonin syndrome have been reported. Therefore, while co-administration is contraindicated,
The recommended linezolid dosage should be administered orally twice daily. management of patients for whom treatment with linezolid and serotonergic agents is essential, is described in section Special
Route of administration: Oral use. warnings and precautions for use.
The film-coated tablets may be taken with or without food. Use with tyramine-rich foods
No significant pressor response was observed in subjects receiving both linezolid and less than 100 mg tyramine. This
CONTRAINDICATIONS suggests that it is only necessary to avoid ingesting excessive amounts of food and beverages with a high tyramine content
Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g. (e.g. mature cheese, yeast extracts, undistilled alcoholic beverages and fermented soya bean products such as soy sauce).
phenelzine, isocarboxazid, selegiline, moclobemide) or within two weeks of taking any such medicinal product.
Unless there are facilities available for close observation and monitoring of blood pressure, linezolid should not be Drugs metabolised by cytochrome P450
administered to patients with the following underlying clinical conditions or on the following types of concomitant Linezolid is not detectably metabolised by the cytochrome P450 (CYP) enzyme system and it does not inhibit any of the
medications: clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not induce P450
- Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, isoenzymes in rats. Therefore, no CYP450-induced drug interactions are expected with linezolid.
schizoaffective disorder, acute confusional states.
- Patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin Rifampicin
5-HT1 receptor agonists (triptans), directly and indirectly acting sympathomimetic agents (including the adrenergic The effect of rifampicin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers administered
bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressive agents (e.g. epinephrine, norepinephrine), linezolid 600 mg twice daily for 2.5 days with and without rifampicin 600 mg once daily for 8 days. Rifampicin decreased the
dopaminergic agents (e.g. dopamine, dobutamine), pethidine or buspirone. linezolid Cmax and AUC by a mean 21% [90% CI, 15, 27] and a mean 32% [90% CI, 27, 37], respectively. The mechanism of
Animal data suggest that linezolid and its metabolites may pass into breast milk and, accordingly, breast-feeding should be this interaction and its clinical significance are unknown.
discontinued prior to and throughout administration (see section Fertility, pregnancy and lactation).
Warfarin
SPECIAL WARNINGS AND PRECAUTIONS FOR USE When warfarin was added to linezolid therapy at steady-state, there was a 10% reduction in mean maximum INR on co-
Myelosuppression administration with a 5% reduction in AUC INR. There are insufficient data from patients who have received warfarin and
Myelosuppression (including anaemia, leucopenia, pancytopenia and thrombocytopenia) has been reported in patients linezolid to assess the clinical significance, if any, of these findings.
receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected haematologic FERTILITY, PREGNANCY AND LACTATION
parameters have risen toward pretreatment levels. The risk of these effects appears to be related to the duration of Pregnancy
treatment. There are limited data from the use of linezolid in pregnant women. Studies in animals have shown reproductive toxicity.
Elderly patients treated with linezolid may be at greater risk of experiencing blood dyscrasias than younger patients.
A potential risk for humans exists.
Thrombocytopenia may occur more commonly in patients with severe renal insufficiency, whether or not on dialysis. Linezolid should not be used during pregnancy unless clearly necessary i.e. only if the potential benefit outweighs the
Therefore, close monitoring of blood counts is recommended in patients who: have pre-existing anaemia, granulocytopenia theoretical risk.
or thrombocytopenia; are receiving concomitant medications that may decrease haemoglobin levels, depress blood counts
or adversely affect platelet count or function; have severe renal insufficiency; receive more than 10-14 days of therapy. Breast-feeding
Linezolid should be administered to such patients only when close monitoring of haemoglobin levels, blood counts and Animal data suggest that linezolid and its metabolites may pass into breast milk and, accordingly, breast-feeding should be
platelet counts is possible. discontinued prior to and throughout administration.
If significant myelosuppression occurs during linezolid therapy, treatment should be stopped unless it is considered
Fertility
absolutely necessary to continue therapy, in which case intensive monitoring of blood counts and appropriate management
In animal studies, linezolid caused a reduction in fertility (see section Preclinical safety data).
strategies should be implemented.
In addition, it is recommended that complete blood counts (including haemoglobin levels, platelets, and total and EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
differentiated leucocyte counts) should be monitored weekly in patients who receive linezolid regardless of baseline blood Patients should be warned about the potential for dizziness or symptoms of visual impairment (as described in section Special
count. warnings and precautions for use and Undesirable effects) whilst receiving linezolid and should be advised not to drive or
In compassionate use studies, a higher incidence of serious anaemia was reported in patients receiving linezolid for more operate machinery if any of these symptoms occurs.
than the maximum recommended duration of 28 days. These patients more often required blood transfusion. Cases of
anaemia requiring blood transfusion have also been reported post marketing, with more cases occurring in patients who UNDESIRABLE EFFECTS
received linezolid therapy for more than 28 days. The table below provides a listing of adverse drug reactions with frequency based on all-causality data from clinical studies
Cases of sideroblastic anaemia have been reported post-marketing. Where time of onset was known, most patients had that enrolled more than 2,000 adult patients who received the recommended linezolid doses for up to 28 days.
received linezolid therapy for more than 28 days. Most patients fully or partially recovered following discontinuation of Those most commonly reported were diarrhoea (8.4%), headache (6.5%), nausea (6.3%) and vomiting (4.0%).
linezolid with or without treatment for their anaemia. The most commonly reported drug-related adverse events which led to discontinuation of treatment were headache,
diarrhoea, nausea and vomiting. About 3% of patients discontinued treatment because they experienced a drug-related
Mortality imbalance in a clinical trial in patients with catheter-related Gram positive bloodstream infections
adverse event.
Excess mortality was seen in patients treated with linezolid, relative to vancomycin/dicloxacillin/oxacillin, in an open-label
Additional adverse reactions reported from post-marketing experience are included in the table with frequency category 'Not
study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs 58/363 (16.0%)]. The main
known', since the actual frequency cannot be estimated from the available data.
factor influencing the mortality rate was the Gram positive infection status at baseline. Mortality rates were similar in patients
The following undesirable effects have been observed and reported during treatment with linezolid with the following
with infections caused purely by Gram positive organisms (odds ratio 0.96; 95% confidence interval: 0.58-1.59) but were
significantly higher (p=0.0162) in the linezolid arm in patients with any other pathogen or no pathogen at baseline (odds ratio frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to
2.48; 95% confidence interval: 1.38-4.46). The greatest imbalance occurred during treatment and within 7 days following <1/1,000); very rare (<1/10,000); Not known (cannot be estimated from the available data)
discontinuation of study drug. More patients in the linezolid arm acquired Gram negative pathogens during the study and
died from infection caused by Gram negative pathogens and polymicrobial infections. Therefore, in complicated skin and System Organ Common Uncommon Rare Very Rare Frequency not known
soft tissue infections linezolid should only be used in patients with known or possible co-infection with Gram negative Class (≥1/100 to <1/10) (≥1/1,000 to <1/100) (≥1/10,000 to <1/1,000) (<1/10,000) (cannot be estimated
organisms if there are no alternative treatment options available (see section Therapeutic indications). In these from available data)
circumstances treatment against Gram negative organisms must be initiated concomitantly. Infections and candidiasis, vaginitis antibiotic-associated
Antibiotic-associated diarrhoea and colitis infestations oral candidiasis, colitis, including
Antibiotic-associated diarrhoea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium vaginal candidiasis, pseudomembranous
difficile- associated diarrhoea, has been reported in association with the use of nearly all antibiotics including linezolid and fungal infections colitis
may range in severity from mild diarrhoea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who
Blood and the anaemia †
leucopenia, pancytopenia
develop serious diarrhoea during or after the use of linezolid. If antibiotic-associated diarrhoea or antibiotic-associated colitis
lymphatic neutropenia,
is suspected or confirmed, ongoing treatment with antibacterial agents, including linezolid, should be discontinued and
system thrombocytopenia,
adequate therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in this
disorders eosinophilia
situation.
 Resistance
System Organ Common Uncommon Rare Very Rare Frequency not known Cross resistance
Class (≥1/100 to <1/10) (≥1/1,000 to <1/100) (≥1/10,000 to <1/1,000) (<1/10,000) (cannot be estimated Linezolid's mechanism of action differs from those of other antibiotic classes. In vitro studies with clinical isolates (including
from available data) methicillin-resistant staphylococci, vancomycin-resistant enterococci, and penicillin- and erythromycin-resistant streptococci)
indicate that linezolid is usually active against organisms which are resistant to one or more other classes of antimicrobial
Immune anaphylaxis agents.
system Resistance to linezolid is associated with point mutations in the 23S rRNA.
disorders As documented with other antibiotics when used in patients with difficult to treat infections and/or for prolonged periods,
Metabolism hyponatraemia lactic acidosis emergent decreases in susceptibility have been observed with linezolid. Resistance to linezolid has been reported in
and nutrition enterococci, Staphylococcus aureus and coagulase negative staphylococci. This generally has been associated with
disorders prolonged courses of therapy and the presence of prosthetic materials or undrained abscesses. When antibiotic-resistant
Psychiatric insomnia organisms are encountered in the hospital it is important to emphasize infection control policies.
disorders Information from clinical trials
Studies in the paediatric population:
Nervous headache, taste convulsions, serotonin syndrome, In an open study, the efficacy of linezolid (10 mg/kg q8h) was compared to vancomycin (10- 15mg/kg q6- 24h) in treating
system perversion hypoaesthesia, peripheral neuropathy
infections due to suspected or proven resistant gram-positive pathogens (including nosocomial pneumonia, complicated skin
disorders (metallic taste), paraesthesia
dizziness and skin structure infections, catheter related bacteraemia, bacteraemia of unknown source, and other infections), in
children from birth to 11 years. Clinical cure rates in the clinically evaluable population were 89.3% (134/150) and 84.5%
Eye disorders blurred vision changes in visual field optic neuropathy,
(60/71) for linezolid and vancomycin, respectively (95%CI: -4.9, 14.6).
defect optic neuritis, loss of
vision, changes in visual Pharmacokinetic properties
acuity, changes in colour Linezolid tablets 600mg primarily contains (s)-linezolid which is biologically active and is metabolised to form inactive
vision derivatives.
Ear and tinnitus Absorption
labyrinth Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 2
disorders hours of dosing. Absolute oral bioavailability of linezolid (oral and intravenous dosing in a crossover study) is complete
Cardiac arrhythmia (approximately 100%). Absorption is not significantly affected by food and absorption from the oral suspension is similar to
disorders (tachycardia) that achieved with the film-coated tablets.
Plasma linezolid Cmax and Cmin (mean and [SD]) at steady-state following twice daily intravenous dosing of 600 mg have
Vascular hypertension transient ischaemic been determined to be 15.1 [2.5] mg/l and 3.68 [2.68] mg/l, respectively.
disorders attacks, phlebitis,
In another study following oral dosing of 600 mg twice daily to steady-state, Cmax and Cmin were determined to be 21.2 [5.8]
thrombophlebitis
mg/l and 6.15 [2.94] mg/l, respectively. Steady-state conditions are achieved by the second day of dosing.
Gastrointestinal diarrhoea, nausea, pancreatitis, gastritis, superficial tooth
disorders vomiting, localised abdominal distention, discolouration Distribution
or general abdominal dry mouth, glossitis, Volume of distribution at steady-state averages at about 40-50 litres in healthy adults and approximates to total body water.
pain, constipation, loose stools, stomatitis, Plasma protein binding is about 31% and is not concentration dependent.
dyspepsia tongue discolouration Linezolid concentrations have been determined in various fluids from a limited number of subjects in volunteer studies
or disorder following multiple dosing. The ratio of linezolid in saliva and sweat relative to plasma was 1.2:1.0 and 0.55:1.0, respectively.
Hepato-biliary abnormal liver increased total bilirubin The ratio for epithelial lining fluid and alveolar cells of the lung was 4.5:1.0 and 0.15:1.0, when measured at steady-state
disorders function test; Cmax, respectively.
increased AST, In a small study of subjects with ventricular-peritoneal shunts and essentially non-inflamed meninges, the ratio of linezolid in
ALT or alkaline cerebrospinal fluid to plasma at Cmax was 0.7:1.0 after multiple linezolid dosing.
phosphatase Biotransformation
Skin and pruritus, rash urticaria, dermatitis, bullous disorders such as Linezolid is primarily metabolised by oxidation of the morpholine ring resulting mainly in the formation of two inactive open-
subcutaneous diaphoresis those described as ring carboxylic acid derivatives; the aminoethoxyacetic acid metabolite (PNU-142300) and the hydroxyethyl glycine
tissue disorders Stevens-Johnson metabolite (PNU-142586). The hydroxyethyl glycine metabolite (PNU-142586) is the predominant human metabolite and is
syndrome and toxic believed to be formed by a non-enzymatic process. The aminoethoxyacetic acid metabolite (PNU-142300) is less abundant.
epidermal necrolysis, Other minor, inactive metabolites have been characterised.
angioedema, alopecia
Elimination
Renal and urinary increased BUN renal failure, In patients with normal renal function or mild to moderate renal insufficiency, linezolid is primarily excreted under steady-state
disorders increased creatinine, conditions in the urine as PNU-142586 (40%), parent drug (30%) and PNU-142300 (10%). Virtually no parent drug is found
polyuria in the faeces whilst approximately 6% and 3% of each dose appears as PNU-142586 and PNU-142300, respectively. The
Reproductive vulvovaginal disorder elimination half-life of linezolid averages at about 5-7 hours.
system and breast Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. A small degree of non-linearity in
disorders clearance is observed with increasing doses of linezolid. This appears to be due to lower renal and non-renal clearance at
General disorders fever, localised pain chills, fatigue, injection higher linezolid concentrations. However, the difference in clearance is small and is not reflected in the apparent elimination
and administration site pain, increased half-life.
site conditions thirst
Special populations
Investigations Chemistry Chemistry
Increased LDH, Increased sodium or Renal impairment: After single doses of 600 mg, there was a 7-8 fold increase in exposure to the two primary metabolites of
creatine kinase, calcium. Decreased linezolid in the plasma of patients with severe renal insufficiency (i.e. creatinine clearance < 30 ml/min). However, there was
lipase, amylase or non fasting glucose. no increase in AUC of parent drug. Although there is some removal of the major metabolites of linezolid by haemodialysis,
non fasting glucose. Increased or metabolite plasma levels after single 600 mg doses were still considerably higher following dialysis than those observed in
Decreased total decreased chloride. patients with normal renal function or mild to moderate renal insufficiency.
protein, albumin, In 24 patients with severe renal insufficiency, 21 of whom were on regular haemodialysis, peak plasma concentrations of the
sodium or calcium. two major metabolites after several days dosing were about 10 fold those seen in patients with normal renal function. Peak
Increased or Haematology plasma levels of linezolid were not affected.
decreased Increased reticulocyte The clinical significance of these observations has not been established as limited safety data are currently available.
potassium or count.
bicarbonate. Decreased Hepatic impairment: Limited data indicate that the pharmacokinetics of linezolid, PNU-142300 and PNU-142586 are not
neutrophils. altered in patients with mild to moderate hepatic insufficiency (i.e. Child-Pugh class A or B). The pharmacokinetics of linezolid
Haematology in patients with severe hepatic insufficiency (i.e. Child-Pugh class C) have not been evaluated. However, as linezolid is
Increased metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its
neutrophils metabolism.
or eosinophils.
Decreased Paediatric population (< 18 years old): There are insufficient data on the safety and efficacy of linezolid in children and
haemoglobin, adolescents (< 18 years old) and therefore, use of linezolid in this age group is not recommended.
haematocrit or Further studies are needed to establish safe and effective dosage recommendations. Pharmacokinetic studies indicate that
red blood cell count. after single and multiple doses in children (1 week to 12 years), linezolid clearance (based on kg body weight) was greater in
Increased or paediatric patients than in adults, but decreased with increasing age.
decreased platelet In children 1 week to 12 years old, administration of 10 mg/kg every 8 hours daily gave exposure approximating to that
or white blood cell achieved with 600 mg twice daily in adults.
counts. In neonates up to 1 week of age, the systemic clearance of linezolid (based on kg body weight) increases rapidly in the first
week of life. Therefore, neonates given 10 mg/kg every 8 hours daily will have the greatest systemic exposure on the first day
after delivery. However, excessive accumulation is not expected with this dosage regimen during the first week of life as
† See below clearance increases rapidly over that period.
The following adverse reactions to linezolid were considered to be serious in rare cases: localised abdominal pain, transient In adolescents (12 to 17 years old), linezolid pharmacokinetics were similar to that in adults following a 600mg dose.
ischaemic attacks and hypertension. Therefore, adolescents administered 600 mg every 12 hours daily will have similar exposure to that observed in adults
†In controlled clinical trials where linezolid was administered for up to 28 days, 2.0% of the patients reported anaemia. In a receiving the same dosage.
compassionate use program of patients with life-threatening infections and underlying co-morbidities, the percentage of In paediatric patients with ventriculoperitoneal shunts who were administered linezolid 10mg/kg either 12 hourly or 8 hourly,
patients who developed anaemia when receiving linezolid for ≤ 28 days was 2.5% (33/1326) as compared with 12.3% variable cerebrospinal fluid (CSF) linezolid concentrations were observed following either single or multiple dosing of
(53/430) when treated for >28 days. The proportion of cases reporting drug-related serious anaemia and requiring blood linezolid.
Therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the
transfusion was 9% (3/33) in patients treated for ≤ 28 days and 15% (8/53) in those treated for >28 days.
empirical treatment of paediatric patients with central nervous system infections is not recommended.
Paediatric population
Elderly: The pharmacokinetics of linezolid are not significantly altered in elderly patients aged 65 and over.
Safety data from clinical studies based on more than 500 paediatric patients (from birth to 17 years) do not indicate that the
safety profile of linezolid for paediatric patients differs from that for adult patients. Female patients: Females have a slightly lower volume of distribution than males and the mean clearance is reduced by
approximately 20% when corrected for body weight. Plasma concentrations are higher in females and this can partly be
Reporting of suspected adverse reactions attributed to body weight differences. However, because the mean half life of linezolid is not significantly different in males and
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued females, plasma concentrations in females are not expected to substantially rise above those known to be well tolerated and,
monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected therefore, dose adjustments are not required.
adverse reactions via the Yellow Card Scheme at [Link]/yellowcard
Preclinical safety data
OVERDOSE Linezolid decreased fertility and reproductive performance of male rats at exposure levels approximately equal to those in
No specific antidote is known. humans. In sexually mature animals these effects were reversible. However, these effects did not reverse in juvenile animals
No cases of overdose have been reported. However, the following information may prove useful: treated with linezolid for nearly the entire period of sexual maturation. Abnormal sperm morphology in testis of adult male rats,
Supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a linezolid dose is and epithelial cell hypertrophy and hyperplasia in the epididymis were noted. Linezolid appeared to affect the maturation of rat
removed during 3 hours of haemodialysis, but no data are available for the removal of linezolid by peritoneal dialysis or spermatozoa. Supplementation of testosterone had no effect on linezolid-mediated fertility effects. Epididymal hypertrophy
haemoperfusion. was not observed in dogs treated for 1 month, although changes in the weights of prostate, testes and epididymis were
The two primary metabolites of linezolid are also removed to some extent by haemodialysis. apparent.
Signs of toxicity in rats following doses of 3000 mg/kg/day linezolid were decreased activity and ataxia whilst dogs treated Reproductive toxicity studies in mice and rats showed no evidence of a teratogenic effect at exposure levels 4 times or
with 2000 mg/kg/day experienced vomiting and tremors. equivalent, respectively, to those in humans. The same linezolid concentrations caused maternal toxicity in mice and were
related to increased embryo death including total litter loss, decreased fetal body weight and an exacerbation of the normal
PHARMACOLOGICAL PROPERTIES genetic predisposition to sternal variations in the strain of mice. In rats, slight maternal toxicity was noted at exposures lower
Pharmacodynamic properties than clinical exposures. Mild fetal toxicity, manifested as decreased fetal body weights, reduced ossification of sternebrae,
Pharmacotherapeutic group: Other antibacterials, ATC code: J 01 X X 08. reduced pup survival and mild maturational delays were noted. When mated, these same pups showed evidence of a
General properties reversible dose-related increase in pre-implantation loss with a corresponding decrease in fertility. In rabbits, reduced fetal
Linezolid is a synthetic, antibacterial agent that belongs to a new class of antimicrobials, the oxazolidinones. It has in vitro body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food
activity against aerobic Gram positive bacteria and anaerobic micro-organisms. Linezolid selectively inhibits bacterial consumption) at low exposure levels 0.06 times compared to the expected human exposure based on AUCs. The species is
protein synthesis via a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S of the 50S known to be sensitive to the effects of antibiotics.
subunit) and prevents the formation of a functional 70S initiation complex which is an essential component of the translation Linezolid and its metabolites are excreted into the milk of lactating rats and the concentrations observed were higher than
process. those in maternal plasma.
The in vitro postantibiotic effect (PAE) of linezolid for Staphylococcus aureus was approximately 2 hours. When measured Linezolid produced reversible myelosuppression in rats and dogs.
in animal models, the in vivo PAE was 3.6 and 3.9 hours for Staphylococcus aureus and Streptococcus pneumoniae, In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was
respectively. observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-
In animal studies, the key pharmacodynamic parameter for efficacy was the time for which the linezolid plasma level month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of
exceeded the minimum inhibitory concentration (MIC) for the infecting organism. optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 of 3 male rats after 6 months of
Breakpoints dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility distribution. The optic nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve
degeneration reported in aging rats and may be an exacerbation of common background change.
Testing (EUCAST) for staphylococci and enterococci are Susceptible ≤ 4mg/L and Resistant >4 mg/L. For streptococci
Preclinical data, based on conventional studies of repeated-dose toxicity and genotoxicity, revealed no special hazard for
(including S. pneumoniae) the breakpoints are Susceptible ≤ 2 mg/L and Resistant >4 mg/L. humans beyond those addressed in other sections of this package insert. Carcinogenicity / oncogenicity studies have not been
Non-species related MIC breakpoints are Susceptible ≤ 2 mg/L and Resistant > 4 mg/L. Non-species related breakpoints conducted in view of the short duration of dosing and lack of genotoxicity.
have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species.
They are for use only for organisms that have not been given a specific breakpoint and not for those species where HOW SUPPLIED
susceptibility testing is not recommended. LINEZOLID TABLETS 600 mg
Susceptibility White to off white, oval shaped, bevel edged, biconvex film coated tablets debossed with 'H' on one side with score line and
The prevalence of acquired resistance may vary geographically and with time for selected species and local information 'L’ and ‘8' separated by a score line on the other side.
on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when
local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. PACK STYLE: Alu - Alu Blister Pack x 10's (Box of 10's)

STORAGE CONDITION: Store at temperatures not exceeding 30°C.

Category
Susceptible organisms CAUTION: Foods, Drugs, Devices, and Cosmetics Act prohibits dispensing without prescription.
Gram positive aerobes:
ADVERSE DRUG REACTION REPORTING STATEMENT
Enterococcus faecalis
For suspected adverse drug reaction, seek medical attention immediately and report to the FDA at [Link]
Enterococcus faecium*
AND Unilab at +632-8-UNILAB-1 (+632-8-864522-1) for Metro Manila or toll-free +1-800-10-UNILAB-1 for provinces,
Staphylococcus aureus* or email productsafety@[Link].
Coagulase negative staphylococci
Streptococcus agalactiae* By reporting undesirable effects, you can help provide more information on the safety of this medicine.
Streptococcus pneumoniae*
Streptococcus pyogenes* Manufactured by:
Group C streptococci HETERO LABS LIMITED (Unit V)
Group G streptococci Block V and V-A, TSIIC- Formulation SEZ
Gram positive anaerobes: S. Nos. 439, 440, 441 & 458
Polepally Village, Jadcherla Mandal
8-
Clostridium perfringens
Mahaboobnagar District
8- 8 6 4 5 2 2 - 1
Peptostreptococcus anaerobius
Peptostreptococcus species Telangana State, 509301, India

Resistant organisms Imported by:

Haemophilus influenzae CAMBER PHARMACEUTICALS, INC.
Moraxella catarrhalis Unit 503A ITC Bldg.
Registration Number: DRP-10518-01
Neisseria species 337 Sen. Gil Puyat Avenue
Enterobacteriaceae Bel-Air, Makati City, Metro Manila Date of First Authorization: April 2022
Pseudomonas species Distributed by: Date of Revision of Package Insert: October 2023
UNILAB, Inc.
*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications. No. 66 United Street Reg. IPOPHIL UA173499IN01
Whereas linezolid shows some in vitro activity against Legionella, Chlamydia pneumoniae and Mycoplasma pneumoniae, Mandaluyong City
there are insufficient data to demonstrate clinical efficacy. Metro Manila, Philippines 2068517