Linezolid Hetero

Linezolid Hetero

linezolid

Manufacturer:

Hetero Labs

Distributor:

Medicell Pharma
Full Prescribing Info
Contents
Linezolid.
Description
Each film coated tablet contains Linezolid 600 mg.
Linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.
The empirical formula is C16H20FN3O4. Its molecular weight is 337.35.
Excipients/Inactive Ingredients: Lactose Monohydrate (Pharmatose 200M), Maize Starch (Extra white maize starch), Hydroxypropyl cellulose (Klucel LXF), Hydroxypropyl cellulose (Klucel LF), Lactose Monohydrate (Super Tab 11SD), Sodium Starch Glycolate (Primojel), Magnesium Stearate (Ligamed-MF-2-V), Opadry White 03B58895, Purified Water.
Action
Pharmacotherapeutic Group: Other antibacterials. ATC Code: J 01 X X 08.
Pharmacology: Pharmacodynamics: General Properties: Linezolid is a synthetic, antibacterial agent which belongs to a new class of antibiotics, the oxazolidinones, with in vitro activity against aerobic Gram positive bacteria, certain Gram negative bacteria and anaerobic micro-organisms. It selectively inhibits bacterial protein synthesis via a unique mechanism of action. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex which is an essential component of the translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for majority of strains.
The in vitro postantibiotic effect (PAE) of linezolid for Staphylococcus aureus was approximately 2 hours. When measured in animal models, the in vivo PAE was 3.6 to 3.9 hours for Staphylococcus aureus and Streptococcus pneumoniae, respectively. In animal studies, the key pharmacodynamic parameter for efficacy was the time that the linezolid plasma levels exceeded the minimum inhibitory concentration (MIC) of the infecting organism. Linezolid was efficacious when plasma levels exceeded the MIC of the infecting organism for a minimum of 40% of the dosing interval.
Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, as described in Indications/Uses.
Aerobic and facultative Gram-positive microorganisms: Enterococcus faecium (vancomycin-resistant strains only); Staphylococcus aureus (including methicillin-resistant strains); Streptococcus agalactiae; Streptococcus pneumoniae (penicillin-susceptible strains only); Streptococcus pyogenes.
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for linezolid. However, the safety and effectiveness of linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic and facultative Gram-positive microorganisms: Enterococcus faecalis (including vancomycin-resistant strains); Enterococcus faecium (vancomycin-susceptible strains); Staphylococcus epidermidis (including methicillin-resistant strains); Staphylococcus haemolyticus; Streptococcus pneumoniae (penicillin-resistant strains); Viridans group streptococci.
Aerobic and facultative Gram-negative microorganisms: Pasteurella multocida.
Breakpoints: The following MIC breakpoints separate susceptible from non-susceptible isolates: (See Table 1.)

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The studies used to define the previously mentioned breakpoints were standard NCCLS (National Committee for Clinical Laboratory Standards) microdilution and agar diffusion methods.
Susceptibility: The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections.
Resistance: Linezolid's mechanism of action differs from that of other antibiotic classes (e.g., the aminoglycosides, beta-lactams, folic acid antagonists, glycopeptides, lincosamides, quinolones, rifamycins, streptogramins, tetracyclines and chloramphenicol). Therefore, there is no cross resistance between linezolid and these classes of drug. Linezolid is active against pathogens that are susceptible or resistant to such antibiotics.
Pharmacokinetics: Linezolid tablets 600mg primarily contains (s)-linezolid which is biologically active and is metabolised to form inactive derivatives.
Absorption: Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 2 hours of dosing. Absolute oral bioavailability of linezolid (oral and intravenous dosing in a crossover study) is complete (approximately 100%). Absorption is not significantly affected by food and absorption from the oral suspension is similar to 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 been determined to be 15.1 [2.5] mg/l and 3.68 [2.68] mg/l, respectively.
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] mg/l and 6.15 [2.94] mg/l, respectively. Steady-state conditions are achieved by the second day of dosing.
Distribution: Volume of distribution at steady-state averages at about 40-50 litres in healthy adults and approximates to total body water. Plasma protein binding is about 31% and is not concentration dependent.
Linezolid concentrations have been determined in various fluids from a limited number of subjects in volunteer studies 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. 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 Cmax, respectively. In a small study of subjects with ventricular-peritoneal shunts and essentially non-inflamed meninges, the ratio of linezolid in cerebrospinal fluid to plasma at Cmax was 0.7:1.0 after multiple linezolid dosing.
Biotransformation: Linezolid is primarily metabolised by oxidation of the morpholine ring resulting mainly in the formation of two inactive open-ring carboxylic acid derivatives; the aminoethoxyacetic acid metabolite (PNU-142300) and the hydroxyethyl glycine metabolite (PNU-142586). The hydroxyethyl glycine metabolite (PNU-142586) is the predominant human metabolite and is believed to be formed by a non-enzymatic process. The aminoethoxyacetic acid metabolite (PNU-142300) is less abundant. Other minor, inactive metabolites have been characterised.
Elimination: In patients with normal renal function or mild to moderate renal insufficiency, linezolid is primarily excreted under steady-state conditions in the urine as PNU-142586 (40%), parent drug (30%) and PNU-142300 (10%). Virtually no parent drug is found in the faeces whilst approximately 6% and 3% of each dose appears as PNU-142586 and PNU-142300, respectively. The elimination half-life of linezolid averages at about 5-7 hours.
Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. A small degree of non-linearity in clearance is observed with increasing doses of linezolid. This appears to be due to lower renal and non-renal clearance at higher linezolid concentrations. However, the difference in clearance is small and is not reflected in the apparent elimination half-life.
Special populations: Renal impairment: After single doses of 600 mg, there was a 7-8 fold increase in exposure to the two primary metabolites of linezolid in the plasma of patients with severe renal insufficiency (i.e. creatinine clearance < 30 ml/min). However, there was no increase in AUC of parent drug. Although there is some removal of the major metabolites of linezolid by haemodialysis, metabolite plasma levels after single 600 mg doses were still considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency.
In 24 patients with severe renal insufficiency, 21 of whom were on regular haemodialysis, peak plasma concentrations of the two major metabolites after several days dosing were about 10 fold those seen in patients with normal renal function. Peak plasma levels of linezolid were not affected.
The clinical significance of these observations has not been established as limited safety data are currently available (see Dosage & Administration).
Hepatic impairment: Limited data indicate that the pharmacokinetics of linezolid, PNU-142300 and PNU-142586 are not altered in patients with mild to moderate hepatic insufficiency (i.e. Child-Pugh class A or B). The pharmacokinetics of linezolid in patients with severe hepatic insufficiency (i.e. Child-Pugh class C) have not been evaluated. However, as linezolid is metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism (see Dosage & Administration).
Paediatric population (< 18 years old): In children 1 week to 12 years old, administration of 10 mg/kg every 8 hours daily gave exposure approximating to that achieved with 600 mg twice daily in adults.
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 clearance increases rapidly over that period.
In adolescents (12 to 17 years old), linezolid pharmacokinetics were similar to that in adults following a 600mg dose. Therefore, adolescents administered 600 mg every 12 hours daily will have similar exposure to that observed in adults receiving the same dosage.
In paediatric patients with ventriculoperitoneal shunts who were administered linezolid 10mg/kg either 12 hourly or 8 hourly, variable cerebrospinal fluid (CSF) linezolid concentrations were observed following either single or multiple dosing of linezolid. Therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empirical treatment of paediatric patients with central nervous system infections is not recommended.
Elderly: The pharmacokinetics of linezolid are not significantly altered in elderly patients aged 65 and over.
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 attributed to body weight differences. However, because the mean half life of linezolid is not significantly different in males and females, plasma concentrations in females are not expected to substantially rise above those known to be well tolerated and, therefore, dose adjustments are not required.
Toxicology: Preclinical safety data: Linezolid decreased fertility and reproductive performance of male rats at exposure levels approximately equal to those expected in humans. In sexually mature animals these effects were reversible. The reversible effects on fertility were mediated by altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. The presence of abnormal sperm in the epididymis was accompanied by epithelial cell hypertrophy and hyperplasia.
Epididymal hypertrophy was not observed in dogs treated for 1 month, although changes in the weights of prostate, testes and epididymis were apparent.
Sexually mature male rats showed slightly decreased fertility following oral treatment as juveniles throughout most of their period of sexual development (50 mg/kg/day from postnatal days 7 to 36, and 100 mg/kg/day from days 37 to 55), at exposures up to 1.7 times the mean AUC in pediatric patients aged 3 months to 11 years. Decreased fertility was not observed following shorter treatment periods in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5 to 21), or juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats following treatment on postnatal days 22 to 35.
Reproductive toxicity studies in mice and rats showed no evidence of a teratogenic effect at exposure levels 4 times or equivalent, respectively, to those expected 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 genetic predisposition to sternal variations in the strain of mice. In rats, slight maternal toxicity was noted at exposures lower than expected clinical exposures. Mild fetal toxicity, manifested as decreased fetal body weights, reduced ossification of sternebrae, reduced pup survival and mild maturational delays were noted. When mated, these same pups showed evidence of a reversible dose-related increase in pre-implantation loss with a corresponding decrease in fertility.
Linezolid was also not teratogenic in rabbits when administered twice daily at total oral doses up to 15 mg/kg/day (0.06 times the clinical exposure, based on AUC). Maternal toxicity (clinical signs, reduced body weight gain and food consumption) occurred at 5 and 15 mg/kg/day, and reduced fetal body weight occurred at 15 mg/kg/day. Linezolid exposures were low due to the characteristic sensitivity of rabbits to antibiotics.
Linezolid and its metabolites are excreted into the milk of lactating rats and the concentrations observed were higher than those in maternal plasma.
Linezolid produced reversible myelosuppression in adult and juvenile rats and dogs.
In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was 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-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats administered Linezolid at 80 mg/kg/day for 6 months, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to a spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of a common background change.
Indications/Uses
Linezolid is indicated for the treatment of adults (12 years and older) and pediatric patients (birth through 11 years of age) with the following infections caused by the susceptible strains of the designated Gram-positive bacteria only. Linezolid is not indicated for the treatment of Gram-negative infections. Specific Gram-negative therapy is required if a concomitant Gram- negative pathogen is documented or suspected (see Precautions and Pharmacology: Pharmacodynamics under Actions).
Community-acquired pneumonia caused by Streptococcus pneumoniae (penicillin-sensitive strain only), including cases with concurrent bacteraemia, or Staphylococcus aureus (methicillin-sensitive strain only).
Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-sensitive and methicillin-resistant strains) or Streptococcus pneumoniae (penicillin-sensitive strains only).
Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-sensitive strains only) or Streptococcus pyogenes.
Complicated skin and skin structure infections, caused by Staphylococcus aureus (methicillin-sensitive and methicillin resistant strains), Streptococcus pyogenes or Streptococcus agalactiae.
Vancomycin-resistant Enterococcus faecium including cases with concurrent bacteraemia.
Linezolid should not be initiated as a first line therapy for community acquired pneumonia or uncomplicated skin infection, but may be considered if resistant strains are suspected or proven or in presence of drug allergy.
Dosage/Direction for Use
Posology: Linezolid tablets 600mg solution for infusion, film-coated tablets or oral suspension may be used as initial therapy. Patients who commence treatment on the parenteral formulation may be switched to either oral presentation when clinically indicated. In such circumstances, no dose adjustment is required as linezolid has an oral bioavailability of approximately 100%.
Recommended dosage and duration of treatment for adults: Patients whose therapy is started with linezolid injection may be switched to linezolid tablets or linezolid for oral suspension, with no dosage adjustment. (See Table 2.)

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Paediatric population: Linezolid Hetero film coated tablets are not recommended for use in paediatrics.
Elderly: No dose adjustment is required.
Renal impairment: No dose adjustment is required (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Severe renal impairment (i.e. CLCR < 30 ml/min): No dose adjustment is required. Due to the unknown clinical significance of higher exposure (up to 10 fold) to the two primary metabolites of linezolid in patients with severe renal insufficiency, linezolid should be used with special caution in these patients and only when the anticipated benefit is considered to outweigh the theoretical risk.
As approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis, linezolid should be given after dialysis in patients receiving such treatment. The primary metabolites of linezolid are removed to some extent by haemodialysis, but the concentrations of these metabolites are still very considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency.
Therefore, linezolid should be used with special caution in patients with severe renal insufficiency who are undergoing dialysis and only when the anticipated benefit is considered to outweigh the theoretical risk.
To date, there is no experience of linezolid administration to patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or alternative treatments for renal failure (other than haemodialysis).
Hepatic impairment: No dose adjustment is required. However, there are limited clinical data and it is recommended that linezolid should be used in such patients only when the anticipated benefit is considered to outweigh the theoretical risk (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Method of administration: The recommended linezolid dosage should be administered orally twice daily.
Route of administration: Oral use.
The film-coated tablets may be taken with or without food.
Overdosage
No specific antidote is known.
No cases of overdose have been reported. However, the following information may prove useful: Supportive care is advised together with maintenance of glomerular filtration. Approximately 30% of a linezolid dose is removed during 3 hours of haemodialysis, but no data are available for the removal of linezolid by peritoneal dialysis or haemoperfusion.
The two primary metabolites of linezolid are also removed to some extent by haemodialysis.
Signs of toxicity in rats following doses of 3000 mg/kg/day linezolid were decreased activity and ataxia whilst dogs treated with 2000 mg/kg/day experienced vomiting and tremors.
Contraindications
Linezolid is contraindicated in patients who have previously demonstrated hypersensitivity to linezolid or any of the other product components.
Monoamine Oxidase Inhibitors: Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.
Potential Interactions Producing Elevation of Blood Pressure: Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (e.g., pseudoephedrine, phenylpropanolamine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine) (see Interactions).
Potential Serotonergic Interactions: Unless patients are carefully observed for signs and/or symptoms of serotonin syndrome, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine or buspirone (see Interactions).
Special Precautions
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all antibacterial agents, including linezolid, and may range in severity from mild to life-threatening.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.
Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Myelosuppression: Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatments level. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.
Lactic Acidosis: Lactic acidosis has been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving Linezolid should receive immediate medical evaluation.
Prescribing Linezolid in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Peripheral and Optic Neuropathy: Peripheral and optic neuropathy have been reported in patients treated with linezolid, primarily those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration.
If symptoms of visual impairment appear, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking linezolid for extended periods (greater than or equal to 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with linezolid. If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients should be weighed against the potential risks.
Convulsions: Convulsions have been reported to occur rarely in patients when treated with linezolid. In most of these cases, a history of seizures or risk factors for seizures were reported.
Serotonin syndrome: Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been reported.
Where administration of linezolid and concomitant serotonergic agents is clinically appropriate, patients should be closely observed for signs and symptoms of serotonin syndrome such as cognitive dysfunction, hyperpyrexia, hyperreflexia and incoordination. If signs or symptoms occur, physicians should consider discontinuation of either one or both agents. If the concomitant serotonergic agent is withdrawn, discontinuation symptoms can be observed.
Linezolid has not been studied in patients with uncontrolled hypertension, phaeochromocytoma, carcino id syndrome, or untreated hyperthyroidism.
The safety and efficacy of Linezolid formulations given for longer than 28 days have not been evaluated in controlled clinical trials.
In healthy volunteers, co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid Cmax and a 32% decrease in linezolid AUC (see Interactions). The clinical significance of this interaction is unknown.
Use in Gram-negative pathogens: Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. Specific Gram-negative therapy is required if a concomitant Gram-negative pathogen is documented or suspected. Linezolid should be used with special caution in patients at high risk for life threatening systemic infections, such as those with infections related to central venous catheters in intensive care units. Linezolid is not approved for the treatment of patients with catheter-related bloodstream infections.
Clinical Trial in Catheter-Related Gram-Positive Bloodstream Infections: An open-label, randomized clinical trial was conducted in adult patients with catheter-related Gram-positive bloodstream infections comparing linezolid (600 mg q12h IV/PO) to vancomycin 1 g IV q12h or oxacillin 2 g IV q6h/dicloxacillin 500 mg PO q6h with a treatment duration of 7 to 28 days. The mortality rates in this study were 78/363 (21.5%) and 58/363 (16.0%) on linezolid and the comparator, respectively. Based on results from a logistic regression, the estimated odds ratio is 1.426 [95%CI 0.970, 2.098]. While causality has not been established, this observed imbalance occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline. Patients randomized to linezolid who had only a Gram-positive infection at baseline, including the subgroup of patients with Gram-positive bacteremia experienced a survival rate similar to the comparator.
Effects on Ability to Drive and Use Machines: The effect of linezolid on the ability to drive or operate machinery has not been systematically evaluated.
Use In Pregnancy & Lactation
Reproductive studies performed in mice and rats treated with linezolid showed no evidence of teratogenic effects. Mild fetal toxicity was observed in mice only at maternally toxic dose levels. In rats, fetal toxicity was manifested as decreased fetal body weights and reduced ossification of sternebrae (which is often seen in association with decreased body weights). Reduced pup survival and mild maturational delays occurred in rats. When mated, these same pups showed evidence of a reversible, dose- related increase in pre-implantation loss. There are no adequate and well-controlled studies in pregnant women. Therefore, linezolid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Linezolid decreased the fertility of male rats.
Linezolid transferred into the breast milk of lactating laboratory rats. It is not known whether linezolid is excreted in human milk.
Therefore, caution should be exercised when linezolid is administered to a nursing woman.
Adverse Reactions
Adverse events: Clinical Trials: Adverse events considered drug-related in controlled clinical trials with an incidence of at least 1% were: abdominal pain/cramp/distension, abnormal hematology tests, abnormal liver function tests, diarrhea, headache, moniliasis, nausea, taste alteration, and vomiting.
Adult Patients: The safety of linezolid formulations was evaluated in 2046 patients enrolled in seven phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. In these studies, 85% of the adverse events reported with LINEZOLID were described as mild to moderate in intensity. Table 3 shows the incidence of adverse events reported in at least 2% of patients in these trials. The most common adverse events in patients treated with LINEZOLID were diarrhea (incidence across studies: 2.8% to 11.0%), headache (incidence across studies: 0.5% to 11.3%), and nausea (incidence across studies: 3.4% to 9.6%). (See Tables 3 and 4.)

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Pediatric Patients: The safety of LINEZOLID formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two phase 3 comparator-controlled clinical trials and were treated for up to 28 days. In these studies, 83% and 99%, respectively, of the adverse events reported with LINEZOLID were described as mild to moderate in intensity. In the study of hospitalized pediatric patients (birth through 11 years) with Gram-positive infections, who were randomized 2 to 1 (linezolid: vancomycin), mortality was 6.0% (13/215) in the linezolid arm and 3.0% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established. Table 5 shows the incidence of adverse events reported in at least 2% of pediatric patients treated with LINEZOLID in these trials. Table 6 shows the incidence of drug-related adverse events reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled phase 3 trials. (See Tables 5 and 6.)

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Laboratory Abnormalities: Linezolid has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hours for up to 28 days. In phase 3 comparator-controlled trials, the percentage of adult patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3 to 10.0%) with Linezolid and 1.5% (range among studies: 0.4 to 7.0%) with a comparator. In a study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with Linezolid and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with Linezolid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of Linezolid appears to be dependent on duration of therapy, (generally greater than 2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for Linezolid; the role of linezolid in these events cannot be determined (see Precautions).
Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between LINEZOLID and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal haematologic or serum chemistry value is presented in Tables 7, 8, 9 & 10. (See Tables 7, 8, 9 and 10.)

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Post marketing: Blood and Lymphatic System Disorders: Reversible anemia, thrombocytopenia, leucopenia, pancytopenia and sideroblastic anemia.
Nervous System Disorders: Peripheral neuropathy, convulsions (see Precautions).
Eye Disorders: Optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with linezolid. These reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days (see Precautions).
Immune System Disorders: Anaphylaxis.
Metabolism and Nutrition Disorders: Lactic acidosis (see Precautions).
Skin and Subcutaneous Tissue Disorders: Rash, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens Johnson syndrome.
Gastrointestinal Disorders: Tongue discoloration. Superficial tooth discoloration has been reported very rarely with the use of linezolid. The discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome.
Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and LINEZOLID.
Drug Interactions
Drugs metabolised by Cytochrome P450: Linezolid is not detectably metabolised by the cytochrome P450 (CYP) enzyme system and it does not induce or inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, no CYP450-induced drug interactions are expected with linezolid. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen.
Antibiotics: The pharmacokinetics of linezolid were not altered when administered together with either aztreonam or gentamicin. The effect of rifampin on the pharmacokinetics of linezolid was studied in sixteen healthy adult male volunteers administered linezolid 600 mg twice daily for 2.5 days with and without rifampin 600 mg once daily for 8 days. Rifampin decreased the linezolid Cmax and AUC by a mean 21% [90% CI, 15, 27] and a mean 32% [90% CI, 27, 37], respectively. The mechanism of this interaction and its clinical significance are unknown (see Precautions).
Monoamine Oxidase Inhibition: Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
Adrenergic Agents: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content (e.g., mature cheese, yeast extracts, undistilled alcoholic beverages and fermented soya bean products such as soy sauce).
A reversible enhancement of the pressor response of either pseudoephedrine HCl (PSE) or phenylpropanolamine HCl (PPA) is observed when linezolid is administered to healthy normotensive subjects. A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, linezolid alone, and the combination of steady-state linezolid (600 mg q12h for 3 days) with two doses of PPA (25 mg) or PSE (60 mg) given 4 hours apart. Heart rate was not affected by any of the treatments.
Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2 to 3 hours after the second dose of PPA or PSE, and returned to baseline 2 to 3 hours after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mm Hg: placebo = 121 (103 to 158); linezolid alone = 120 (107 to 135); PPA alone = 125 (106 to 139); PPA with linezolid = 147 (129 to 176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mm Hg (range: 20-52 mm Hg) and 38 mm Hg (range: 18-79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively. Initial doses of adrenergic agents, such as dopamine or dopamine agonists, should be reduced and titrated to achieve the desired response.
Serotonergic Agents: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan. The effects of other serotonin re-uptake inhibitors have not been studied. However, very rare spontaneous reports of serotonin syndrome with co-administration of linezolid and serotonergic agents have been reported.
Storage
Store below 30°C and protect from moisture.
Patient Counseling Information
Information for Patients: Patients should be advised that: Linezolid may be taken with or without food.
They should inform their physician if they have a history of hypertension.
They should avoid consuming food with high tyramine content.
They should inform their physician if taking medications containing pseudoephedrine HCL or phenylpropanolamine HCL, such as cold remedies and decongestants.
They should inform their physician if taking serotonin re-uptake inhibitors or other antidepressants.
They should inform their physician if they experience changes in vision.
They should inform their physician if they have a history of seizures.
Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
MIMS Class
ATC Classification
J01XX08 - linezolid ; Belongs to the class of other antibacterials. Used in the systemic treatment of infections.
Presentation/Packing
FC tab 600 mg (white to off white, oval shaped, bevel edged, biconvex debossed with 'H' on one side and 'L8' on the other side) x 3 x 10's, 10 x 10's.
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