LINEZOLID- linezolid_tablet, film coated

Linezolid is an antibacterial drug [see Microbiology ( 12. 4 ) In a randomized, positive-and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single Linezolid 600 mg dose via a 1 hour IV infusion, a single Linezolid 1,200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1,200 mg Linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time. The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults Dose of Linezolid C max mcg/mL C min mcg/mL T max hrs AUC* mcgh/mL t 1/2 hrs CL mL/min 400 mg tablet single dose dagger 8. 20 146 every 12 hours 11. 69 110 600 mg tablet single dose 12. 26 127 every 12 hours 21. 40 80 600 mg IV injection double dagger single dose 12. 40 138 every 12 hours 15. 80 123 600 mg oral suspension single dose 11. 60 141 * 0en dashinfinity 0en dash t dagger double dagger C max min max max 1/2 Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean Standard Deviation, n=16) Absorption Linezolid is extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously without dose adjustment. Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1. 5 hours to 2. 2 hours and C max 0-infinity Distribution Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration-independent. The volume of distribution of linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers. Metabolism Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite A is presumed to be formed via an enzymatic pathway whereas metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. In vitro studies have demonstrated that linezolid is minimally metabolized and may be mediated by human cytochrome P450. However, the metabolic pathway of linezolid is not fully understood. Excretion Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min which suggests net tubular reabsorption. Virtually no linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B, and 3% as metabolite A. A small degree of nonlinearity in clearance was observed with increasing doses of linezolid, which appears to be due to lower renal and nonrenal clearance of linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life. Geriatric Patients The pharmacokinetics of linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary. Pediatric Patients The pharmacokinetics of linezolid following a single intravenous dose were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from 12 through 17 years, and in pediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of linezolid are summarized in Table 9 for the pediatric populations studied and healthy adult subjects after administration of single intravenous doses. The C max ss Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed every 8 hours relative to adolescents or adults dosed every 12 hours. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg every 8 hours. Pediatric patients 12 years and older should receive 600 mg every 12 hours [ see Dosage and Administration ( 2 Table 9. Pharmacokinetic Parameters of Linezolid in Pediatrics and Adults Following a Single Intravenous Infusion of 10 mg/kg or 600 mg Linezolid (Mean: (%CV); [Min, Max Values]) Age Group C max mcg/mL V ss L/kg AUC mcgh/mL t 1/2 hrs CL mL/min/kg Neonatal Patients Pre-term** 12. 81 (24%) 108 (47%) 5. 0 (52%) <1 week (N=9) dagger [9. 05] [41, 191] [2. 0] Full-term*** 11. 78 (20%) 55 (47%) 3. 8 (55%) <1 week (N=10) dagger [8. 96] [19, 103] [1. 8] Full-term*** >=1 week to <=28 days dagger 12. 66 (29%) 34 (21%) 1. 1 (22%) Infant Patients >28 days to <3 Months (N=12) dagger 11. 79 (26%) 33 (26%) 1. 4 (32%) Pediatric Patients 3 months through 11 years dagger 15. 69 (28%) 58 (54%) 2. 8 (53%) Adolescent Subjects and Patients 12 through 17 years double dagger 16. 61 (15%) 95 (44%) 4. 1 (53%) Adult Subjects section 12. 65 (16%) 91 (33%) 4. 7 (34%) (N=29) [8. 84] [53, 155] [1. 3] *AUC = Single dose AUC 0en dashinfinity **In this data set, “pre-term” is defined as <34 weeks gestational age (Note: Only 1 patient enrolled was pre-term with a postnatal age between 1 week and 28 days) *** In this data set, “full-term” is defined as >=34 weeks gestational age dagger Dose of 10 mg/kg double dagger Dose of 600 mg or 10 mg/kg up to a maximum of 600 mg section C max ss 1/2 Gender Females have a slightly lower volume of distribution of linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender does not appear to be necessary. Renal Impairment The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal impairment; however, the two primary metabolites of linezolid accumulate in patients with renal impairment, with the amount of accumulation increasing with the severity of renal dysfunction (see Table 10). The pharmacokinetics of linezolid and its two metabolites have also been studied in patients with end-stage renal disease (ESRD) receiving hemodialysis. In the ESRD study, 14 patients were dosed with linezolid 600 mg every 12 hours for 14. 5 days (see Table 11). Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal impairment. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of linezolid in patients with renal impairment should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by hemodialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid. Approximately 30% of a dose was eliminated in a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis. Parameter Healthy Subjects CL CR Moderate Renal Impairment 30 < CL CR Severe Renal Impairment 10 < CL CR LINEZOLID AUC 0- infinity 110 (22) 128 (53) 127 (66) t 1/2 6. 7) METABOLITE A AUC 0-48 7. 6) METABOLITE B 1 AUC 0-48 30. 5) 203 (92) t 1/2 6. 9) 1 Table 11. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Subjects with End-Stage Renal Disease (ESRD) After the Administration of 600 mg Linezolid Every 12 Hours for 14. 5 Days Parameter ESRD Subjects 1 LINEZOLID AUC 0-12 181 (52. 4) METABOLITE A AUC 0-12 153 (40. 6) t 1/2 15. 5) METABOLITE B 2 AUC 0-12 356 (99. 7) t 1/2 34. 1) 1 2 The pharmacokinetics of linezolid are not altered in patients (n=7) with mild-to-moderate hepatic impairment (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild-to-moderate hepatic impairment. The pharmacokinetics of linezolid in patients with severe hepatic impairment have not been evaluated. Drug Interactions Drugs Metabolized by Cytochrome P450 Linezolid is not an inducer of cytochrome P450 (CYP450) in rats. In addition, linezolid does not inhibit the activities of clinically significant human CYP isoforms (e. , 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major enzymes. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen. Antibacterial Drugs Aztreonam Gentamicin Antioxidants The potential for drug-drug interactions with linezolid and the antioxidants Vitamin C and Vitamin E was studied in healthy volunteers. Subjects were administered a 600 mg oral dose of linezolid on Day 1, and another 600 mg dose of linezolid on Day 8. On Days 2 to 9, subjects were given either Vitamin C (1,000 mg/day) or Vitamin E (800 IU/ day). The AUC 0-infinity Strong CYP 3A4 Inducers Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid C max 0-12 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 Some individuals receiving Linezolid may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or dopaminergic agents. Commonly used drugs such as phenylpropanolamine and pseudoephedrine have been specifically studied. Initial doses of adrenergic agents, such as dopamine or epinephrine, should be reduced and titrated to achieve the desired response. Tyramine: 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 [ see Patient Counseling Information ( 17 Pseudoephedrine HCl or phenylpropanolamine HCl: 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 [ see Warnings and Precautions (5. 6) and Drug Interactions (7) Serotonergic Agents Dextromethorphan: 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. Mechanism of Action Linezolid is a synthetic antibacterial agent of the oxazolidinone class, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. 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 essential for bacterial reproduction. 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 the majority of isolates. Resistance In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant Enterococcus faecium Staphylococcus aureus cfr Interaction with Other Antimicrobial Drugs In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin. Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro [see Indications and Usage ( 1 Gram-positive bacteria Enterococcus faecium Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes The following in vitro data are available, but their clinical significance is unknown. Greater than 90% of the following bacteria exhibit an in vitro MIC less than or equal to the linezolid-susceptible breakpoint for organisms of similar genus. The safety and effectiveness of linezolid in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Enterococcus faecalis Enterococcus faecium Staphylococcus epidermidis Staphylococcus haemolyticus Viridans group streptococci Gram-negative bacteria Pasteurella multocida Susceptibility Testing.

Linezolid is an oxazolidinone-class antibacterial indicated in adults and children for the treatment of the following infections caused by susceptible Gram-positive bacteria: Nosocomial pneumonia (1. 1); Community-acquired pneumonia ( 1. 4 Enterococcus faecium 1. 5 Limitations of Use ( 1. 6 Linezolid tablets are not indicated for the treatment of Gram-negative infections. The safety and efficacy of linezolid tablets formulations given for longer than 28 days have not been evaluated in controlled clinical trials. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Linezolid formulations and other antibacterial drugs, Linezolid should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 7 Linezolid is indicated for the treatment of nosocomial pneumonia caused by Staphylococcus aureus Streptococcus pneumoniae see Clinical Studies ( 14 Linezolid is indicated for the treatment of community-acquired pneumonia caused by Streptococcus pneumoniae Staphylococcus aureus see Clinical Studies ( 14 Linezolid is indicated for the treatment of complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus Streptococcus pyogenes Streptococcus agalactiae see Clinical Studies ( 14 Linezolid is indicated for the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus Streptococcus pyogenes see Clinical Studies ( 14 Linezolid is indicated for the treatment of vancomycin-resistant Enterococcus faecium see Clinical Studies ( 14 Linezolid is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [ see Warnings and Precautions ( 5. 4 The safety and efficacy of linezolid formulations given for longer than 28 days have not been evaluated in controlled clinical trials [ see Clinical Studies ( 14 To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid and other antibacterial drugs, linezolid should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Dosage, Route, and Frequency of Administration Infection Pediatric Patients Adults and Adolescents Duration (days Nosocomial pneumonia 10 mg/kg intravenous or oral every 8 hours 600 mg intravenous or oral every 12 hours 10 to 14 Community-acquired pneumonia, including concurrent bacteremia Complicated skin and skin structure infections Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia 10 mg/kg intravenous or oral every 8 hours 600 mg intravenous or oral every 12 hours 14 to 28 Uncomplicated skin and skin structure infections less than 5 yrs: 10 mg/kg oral every 8 hours Adults: 400 mg oral every 12 hours 10 to 14 The recommended dosage for Linezolid formulations for the treatment of infections is described in Table 1. Dosage Guidelines for Linezolid Dosage, Route and Frequency of Administration Recommended Duration of Treatment (consecutive days) Infection* Pediatric Patientsdagger (Birth through 11 Years of Age) Adults and Adolescents (12 Years and Older) Nosocomial pneumonia 10 mg/kg intravenously or oral double dagger 600 mg intravenously or oral double dagger 10 to 14 Community-acquired pneumonia, including concurrent bacteremia Complicated skin and skin structure infections Vancomycin-resistant Enterococcus faecium 10 mg/kg intravenously or oral double dagger 600 mg intravenously or oral double dagger 14 to 28 Uncomplicated skin and skin structure infections less than 5 yrs: 10 mg/kg oral double dagger double dagger Adults: 400 mg oral double dagger double dagger 10 to 14 * Due to the designated pathogens [ see Indications and Usage (1) dagger Neonates less than days see Use in Specific Populations (8. 4) Clinical Pharmacology (12. 3 double dagger Oral dosing using either Linezolid Tablets or Linezolid for Oral Suspension [ see How Supplied/Storage and Handling (16).

Most common adverse reactions (>5% of adult and/or pediatric patients treated with Linezolid) include: diarrhea, vomiting, headache, nausea, and anemia. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults The safety of Linezolid formulations was evaluated in 2,046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. Incidence (%) of Treatmenten dashEmergent Adverse Reactions Occurring in >1% of Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials ADVERSE REACTIONS Uncomplicated Skin and Skin Structure Infections All Other Indications Linezolid 400 mg by mouth every 12 hours (n=548) Clarithromycin 250 mg by mouth every 12 hours (n=537) Linezolid 600 mg every 12 hours (n=1,498) All Other Comparators* (n=1,464) Headache 8. 4 Diarrhea 8. 6 Vomiting 2. 3 Dizziness 2. 4 Taste alteration 1. 3 Vaginal moniliasis 1. 5 Oral moniliasis 0. 0 Abnormal liver function tests 0. 8 Fungal infection 1. 2 Tongue discoloration 1. 3 0 Localized abdominal pain 1. 8 Generalized abdominal pain 0. 0 * Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours. 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 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. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in >1% of Pediatric Patients (and >1 Patient) in Either Treatment Group in Comparator-Controlled Clinical Trials ADVERSE REACTIONS Uncomplicated Skin and Skin Structure Infections * All Other Indications dagger Linezolid (n=248) Cefadroxil (n=251) Linezolid (n=215) Vancomycin (n=101) Diarrhea 7. 1 Vomiting 2. 1 Headache 6. 9 0 Anemia 0 0 5. 1 Thrombocytopenia 0 0 4. 9 0 Generalized abdominal pain 2. 0 Localized abdominal pain 2. 0 Loose stools 1. 0 Eosinophilia 0. 0 Pruritus at non-application site 0. 0 Vertigo 1. 4 0 0 * Patients 5 through 11 years of age received Linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours. Patients 12 years or older received Linezolid 600 mg by mouth every 12 hours or cefadroxil 500 mg by mouth every 12 hours. 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. 0%) with Linezolid and 1. 5% (range among studies: 0. 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 Warnings and Precautions ( 5. Percent of Adult Patients who Experienced at Least One Substantially Abnormal * Laboratory Assay Uncomplicated Skin and Skin Structure Infections All Other Indications Linezolid 400 mg every 12 hours Clarithromycin 250 mg every 12 hours Linezolid 600 mg every 12 hours All Other Comparators dagger Hemoglobin (g/dL) 0. 6 Platelet count (x 10 3 3 0. 8 WBC (x 10 3 3 0. 3 Neutrophils (x 10 3 3 0. 2 * < dagger Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours. Percent of Adult Patients who Experienced at Least One Substantially Abnormal * Laboratory Assay Uncomplicated Skin and Skin Structure Infections All Other Indications Linezolid 400 mg every 12 hours Clarithromycin 250 mg every 12 hours Linezolid 600 mg every 12 hours All Other Comparators dagger AST (U/L) 1. 8 ALT (U/L) 1. 3 LDH (U/L) 0. 5 Alkaline phosphatase (U/L) 0. 1 Lipase (U/L) 2. 2 Amylase (U/L) 0. 0 Total bilirubin (mg/dL) 0. 1 BUN (mg/dL) 0. 5 Creatinine (mg/dL) 0. 6 * > > dagger Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal * Laboratory Assay Uncomplicated Skin and Skin Structure Infections dagger All Other Indications double dagger Linezolid Cefadroxil Linezolid Vancomycin Hemoglobin (g/dL) 0. 4 Platelet count (x 10 3 3 0. 4 WBC (x 10 3 3 0. 3 Neutrophils (x 10 3 3 1. 3 * < < dagger Patients 5 through 11 years of age received Linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours. double dagger Patients from birth through 11 years of age received Linezolid 10 mg/kg intravenously by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal * Laboratory Assay Uncomplicated Skin and Skin Structure Infections dagger All Other Indications double dagger Linezolid Cefadroxil Linezolid Vancomycin ALT (U/L) 0. 5 Lipase (U/L) 0. 2 -- -- Amylase (U/L) -- -- 0. 3 Total bilirubin (mg/dL) -- -- 6. 2 Creatinine (mg/dL) 0. 0 * >2 x Upper Limit of Normal (ULN) for values normal at baseline; >2 x ULN and >2 (>1. 5 for total bilirubin) x baseline for values abnormal at baseline. dagger Patients 5 through 11 years of age received Linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours. Patients 12 years or older received Linezolid 600 mg mouth every 12 hours or cefadroxil 500 mg by mouth every 12 hours. double dagger Patients from birth through 11 years of age received Linezolid 10 mg/kg intravenously/by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance. The following adverse reactions have been identified during postapproval use of Linezolid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia). Thrombocytopenia has been reported more often in patients with severe renal impairment and in patients with moderate to severe hepatic impairment [ see Warnings and Precautions ( 5. 1 Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision [ see Warnings and Precautions ( 5. 2 Lactic acidosis [ see Warnings and Precautions ( 5. 7 Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, and Linezolid [ see Warnings and Precautions ( 5. 3 Convulsions [ see Warnings and Precautions ( 5. 8 Anaphylaxis, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, and hypersensitivity vasculitis. Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome. Hypoglycemia, including symptomatic episodes [ see Warnings and Precautions ( 5. 9 Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion(SIADH) [ see Warnings and Precautions ( 5.

Known hypersensitivity to linezolid or any of the other product components. 1 Patients taking any monoamine oxidase inhibitors (MAOI) or within two weeks of taking an MAOI. 2 Linezolid formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components. Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e. , phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.

Risk Summary Available data from published and postmarketing case reports with linezolid use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. When administered during organogenesis, linezolid did not cause malformations in mice, rats, or rabbits at maternal exposure levels approximately 6. 5 times (mice), equivalent to (rats), or 0. 06 times (rabbits) the clinical therapeutic exposure, based on AUCs. However, embryo-fetal lethality was observed in mice at 6. 5 times the estimated human exposure. When female rats were dosed during organogenesis through lactation, postnatal survival of pups was decreased at doses approximately equivalent to the estimated human exposure based on AUCs ( see Data. The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In mice, embryo-fetal toxicities were observed only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). An oral dose of 450 mg/kg/day given from Gestation Day (GD) 6 to 16 (6. 5 times the estimated human exposure based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion. Neither maternal nor embryo-fetal toxicities were observed at doses up to 150 mg/kg/day. Fetal malformations were not observed. In rats, fetal toxicity was observed at 15 and 50 mg/kg/day administered orally from GD 6 to 17 (exposures 0. 22 times to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day. In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at an oral dose of 15 mg/kg/day given from GD 6 to 20 (0. 06 times the estimated human exposure based on AUCs). When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation (GD 6 through Lactation Day 20), survival of pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss. Risk Summary Linezolid is present in breast milk. Based on data from available published case reports, the daily dose of linezolid that the infant would receive from breastmilk would be approximately 6% to 9% of the recommended therapeutic infant dose (10 mg/kg every 8 hours). There is no information on the effects of linezolid on the breastfed infant; however, diarrhea and vomiting were the most common adverse reactions reported in clinical trials in infants receiving linezolid therapeutically [ see Adverse Reactions ( 6. 1 (see Clinical Considerations). Clinical Considerations Advise lactating women to monitor a breastfed infant for diarrhea and vomiting. Infertility Males Based on findings from studies in rats, linezolid may reversibly impair fertility in male patients [ see Nonclinical Toxicology ( 13. The safety and effectiveness of Linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years [see Indications and Usage (1 Clinical Pharmacology (12. 3 Clinical Studies (14) nosocomial pneumonia complicated skin and skin structure infections community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years) vancomycin-resistant Enterococcus faecium infections The safety and effectiveness of Linezolid for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years [see Clinical Studies (14) uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended. The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in preterm (gestational age <34 weeks) neonates <7 days of age, linezolid clearance is often lower than in full-term neonates <7 days of age. Consequently, preterm neonates <7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours [see Dosage and Administration (2. 1) Clinical Pharmacology (12. 3 In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with Linezolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response [see Clinical Pharmacology (12. 3) Dosage and Administration (2)] Of the 2,046 patients treated with Linezolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Monoamine oxidase inhibitors and potential for interaction with adrenergic and serotonergic agents. 3 Linezolid is a reversible, nonselective inhibitor of monoamine oxidase [ see Contraindications (4. 2) Clinical Pharmacology (12. 3) Linezolid has the potential for interaction with adrenergic and serotonergic agents [ see Warnings and Precautions (5. 6 Clinical Pharmacology (12.

OVERDOSAGE
In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3,000 mg/kg/day and 2,000 mg/kg/day, respectively.
NONCLINICAL TOXICOLOGY
Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro in vitro in utero Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose-and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss, and suppression of body weight gain, which may have contributed to the observed effects. 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 after 6 months of dosing, 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 spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.
CLINICAL STUDIES
Nosocomial Pneumonia Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a randomized, multi-center, double-blind trial. Patients were treated for 7 to 21 days. One group received Linezolid I. Injection 600 mg every 12 hours, and the other group received vancomycin 1 g every 12 hours intravenously. Both groups received concomitant aztreonam (1 to 2 g every 8 hours intravenously), which could be continued if clinically indicated. There were 203 linezolid-treated and 193 vancomycin-treated patients enrolled in the study. One hundred twenty-two (60%) linezolid-treated patients and 103 (53%) vancomycin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 57% for linezolid-treated patients and 60% for vancomycin-treated patients. The cure rates in clinically evaluable patients with ventilator-associated pneumonia were 47% for linezolid-treated patients and 40% for vancomycin-treated patients. A modified intent-to-treat (MITT) analysis of 94 linezolid-treated patients and 83 vancomycin-treated patients included subjects who had a pathogen isolated before treatment. The cure rates in the MITT analysis were 57% in linezolid-treated patients and 46% in­ vancomycin­-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 12. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Nosocomial Pneumonia Pathogen Cured Linezolid n/N (%) Vancomycin n/N (%) Staphylococcus aureus 23/38 (61) 14/23 (61) Methicillin-resistant S. aureus 13/22 (59) 7/10 (70) Streptococcus pneumoniae 9/9 (100) 9/10 (90) Complicated Skin and Skin Structure Infections Adult patients with clinically documented complicated skin and skin structure infections were enrolled in a randomized, multi-center, double-blind, double-dummy trial comparing study medications administered intravenously followed by medications given orally for a total of 10 to 21 days of treatment. One group of patients received Linezolid I. Injection 600 mg every 12 hours followed by Linezolid Tablets 600 mg every 12 hours; the other group received oxacillin 2 g every 6 hours intravenously followed by dicloxacillin 500 mg every 6 hours orally. Patients could receive concomitant aztreonam if clinically indicated. There were 400 linezolid-treated and 419 oxacillin-treated patients enrolled in the study. Two hundred forty-five (61%) linezolid-treated patients and 242 (58%) oxacillin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 90% in linezolid-treated patients and 85% in oxacillin-treated patients. A modified intent-to-treat (MITT) analysis of 316 linezolid-treated patients and 313 oxacillin-treated patients included subjects who met all criteria for study entry. The cure rates in the MITT analysis were 86% in linezolid-treated patients and 82% in oxacillin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 13. Pathogen Cured Linezolid n/N (%) Oxacillin/Dicloxacillin n/N (%) Staphylococcus aureus 73/83 (88) 72/84 (86) Methicillin-resistant S. aureus 2/3 (67) 0/0 (-) Streptococcus agalactiae 6/6 (100) 3/6 (50) Streptococcus pyogenes 18/26 (69) 21/28 (75) A separate study provided additional experience with the use of Linezolid in the treatment of methicillin-resistant Staphylococcus aureus Diabetic Foot Infections Adult diabetic patients with clinically documented complicated skin and skin structure infections (“diabetic foot infections”) were enrolled in a randomized (2:1 ratio), multi-center, open-label trial comparing study medications administered intravenously or orally for a total of 14 to 28 days of treatment. One group of patients received Linezolid 600 mg every 12 hours intravenously or orally; the other group received ampicillin/sulbactam 1. 5 to 3 g intravenously or amoxicillin/clavulanate 500 to 875 mg every 8 to 12 hours orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to 2 g every 6 hours was used for the intravenous regimen. Patients in the comparator group could also be treated with vancomycin 1 g every 12 hours intravenously if MRSA was isolated from the foot infection. Patients in either treatment group who had Gram-negative bacilli isolated from the infection site could also receive aztreonam 1 to 2 g every 8 to 12 hours intravenously. All patients were eligible to receive appropriate adjunctive treatment methods, such as debridement and off-loading, as typically required in the treatment of diabetic foot infections, and most patients received these treatments. There were 241 linezolid-treated and 120 comparator-treated patients in the intent-to-treat (ITT) study population. Two hundred twelve (86%) linezolid-treated patients and 105 (85%) comparator-treated patients were clinically evaluable. In the ITT population, the cure rates were 68. 5% (165/241) in linezolid-treated patients and 64% (77/120) in comparator-treated patients, where those with indeterminate and missing outcomes were considered failures. The cure rates in the clinically evaluable patients (excluding those with indeterminate and missing outcomes) were 83% (159/192) and 73% (74/101) in the linezolid-and comparator-treated patients, respectively. A critical post-hoc analysis focused on 121 linezolid-treated and 60 comparator-treated patients who had a Gram-positive pathogen isolated from the site of infection or from blood, who had less evidence of underlying osteomyelitis than the overall study population, and who did not receive prohibited antimicrobials. Based upon that analysis, the cure rates were 71% (86/121) in the linezolid-treated patients and 63% (38/60) in the comparator-treated patients. None of the above analyses were adjusted for the use of adjunctive therapies. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 14. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Diabetic Foot Infections Pathogen Cured Linezolid n/N (%) Comparator n/N (%) Staphylococcus aureus 49/63 (78) 20/29 (69) Methicillin-resistant S. aureus 12/17 (71) 2/3 (67) Streptococcus agalactiae 25/29 (86) 9/16 (56) Vancomycin-Resistant Enterococcal Infections Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multi-center, double-blind trial comparing a high dose of Linezolid (600 mg) with a low dose of Linezolid (200 mg) given every 12 hours either intravenously (IV) or orally for 7 to 28 days. Patients could receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to high-dose linezolid and 66 to low-dose linezolid. The intent-to-treat (ITT) population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in the high-dose arm and 52 in the low-dose arm. The cure rates for the ITT population with documented vancomycin-resistant enterococcal infection at baseline are presented in Table 15 by source of infection. These cure rates do not include patients with missing or indeterminate outcomes. The cure rate was higher in the high-dose arm than in the low-dose arm, although the difference was not statistically significant at the 0. Cure Rates at the Test-of-Cure Visit for ITT Adult Patients with Documented Vancomycin-Resistant Enterococcal Infections at Baseline Source of Infection Cured Linezolid 600 mg every 12 hours n/N (%) Linezolid 200 mg every 12 hours n/N (%) Any site 39/58 (67) 24/46 (52) Any site with associated bacteremia 10/17 (59) 4/14 (29) Bacteremia of unknown origin 5/10 (50) 2/7 (29) Skin and skin structure 9/13 (69) 5/5 (100) Urinary tract 12/19 (63) 12/20 (60) Pneumonia 2/3 (67) 0/1 (0) Other* 11/13 (85) 5/13 (39) * Includes sources of infection such as hepatic abscess, biliary sepsis, necrotic gall bladder, pericolonic abscess, pancreatitis, and catheter-related infection. Infections due to Gram-positive Bacteria A safety and efficacy study provided experience on the use of Linezolid in pediatric patients for the treatment of nosocomial pneumonia, complicated skin and skin structure infections, and other infections due to Gram-positive bacterial pathogens, including methicillin-resistant and -susceptible Staphylococcus aureus Enterococcus faecium Enterococcus faecium Table 16. Cure Rates at the Test-of-Cure Visit for Intent-to-Treat, Modified Intent-to-Treat, and Clinically Evaluable Pediatric Patients for the Overall Population and by Select Baseline Diagnosis Population ITT MITT* Clinically Evaluable Linezolid n/N (%) Vancomycin n/N (%) Linezolid n/N (%) Vancomycin n/N (%) Linezolid n/N (%) Vancomycin n/N (%) Any diagnosis 150/186 (81) 69/83 (83) 86/108 (80) 44/49 (90) 106/117 (91) 49/54 (91) Complicated skin and skin structure infections 61/72 (85) 31/34 (91) 37/43 (86) 22/23 (96) 46/49 (94) 26/27 (96) Nosocomial pneumonia 13/18 (72) 11/12 (92) 5/6 (83) 4/4 (100) 7/7 (100) 5/5 (100) * MITT = ITT patients with an isolated Gram-positive pathogen at baseline Table 17. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Pediatric Patients with Infections due to Gram-positive Pathogens Pathogen Microbiologically Evaluable Linezolid n/N (%) Vancomycin n/N (%) Vancomycin-resistant Enterococcus faecium 6/8 (75)* 0/0 (-) Staphylococcus aureus 36/38 (95) 23/24 (96) Methicillin-resistant S. aureus 16/17 (94) 9/9 (100) Streptococcus pyogenes 2/2 (100) 1/2 (50) * Includes data from 7 patients enrolled in the open-label extension of this study.

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