Linezolid

1 INDICATIONS AND USAGE Linezolid for Oral Suspension 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. 2); Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis ( 1. 3); Uncomplicated skin and skin structure infections ( 1. 4); Vancomycin-resistant Enterococcus faecium infections. ( 1. 5) Limitations of Use ( 1.6 ): • Linezolid is not indicated for the treatment of Gram-negative infections. • The safety and efficacy of linezolid 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. ( 1.7 ) 1.1 Nosocomial Pneumonia Linezolid is indicated for the treatment of nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [see Clinical Studies ( 14 )]. 1.2 Community-acquired Pneumonia Linezolid is indicated for the treatment of community-acquired pneumonia caused by Streptococcus pneumoniae , including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only) [see Clinical Studies ( 14 )]. 1.3 Complicated Skin and Skin Structure Infections Linezolid is indicated for the treatment of complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes , or Streptococcus agalactiae . Linezolid has not been studied in the treatment of decubitus ulcers [see Clinical Studies ( 14 )]. 1.4 Uncomplicated Skin and Skin Structure Infections Linezolid is indicated for the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes [see Clinical Studies ( 14 )]. 1.5 Vancomycin-resistant Enterococcus faecium Infections Linezolid is indicated for the treatment of vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia [see Clinical Studies ( 14 )]. 1.6 Limitations of Use • 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 )]. 1.7 Usage 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.

2 DOSAGE AND ADMINISTRATION Dosage, Route, and Frequency of Administration Infection Pediatric Patients (Birth through 11 years of age) Adults and Adolescents (12 years and older) Duration (Days) Nosocomial pneumonia Community-acquired pneumonia, including concurrent bacteremia 10 mg/kg intravenous or oral every 8 hours 600 mg intravenous or oral every 12 hours 10 to 14 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 5 to 11 yrs: 10 mg/kg oral every 12 hours Adults: 400 mg oral every 12 hours Adolescents: 600 mg oral every 12 hours 10 to 14 2.1 General Dosage and Administration The recommended dosage for linezolid formulations for the treatment of infections is described in Table 1. Table 1. Dosage Guidelines for Linezolid Infection Due to the designated pathogens [see Indications and Usage ( 1 )]. Dosage, Route, and Frequency of Administration Recommended Duration of Treatment (Consecutive Days) Pediatric Patients Neonates less than 7 days: Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of 10 mg/kg every 8 hours regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life [see Use in Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.3 )]. (Birth through 11 Years of Age) Adults and Adolescents (12 Years and Older) Nosocomial pneumonia 10 mg/kg intravenously or oral Oral dosing using either linezolid tablets or Linezolid for Oral Suspension [see How Supplied/Storage and Handling ( 16 )]. every 8 hours 600 mg intravenously 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 intravenously or oral every 8 hours 600 mg intravenously 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 5 to 11 yrs: 10 mg/kg oral every 12 hours Adults: 400 mg oral every 12 hours Adolescents: 600 mg oral every 12 hours 10 to 14 No dose adjustment is necessary when switching from intravenous to oral administration. 2.5 Constitution of Oral Suspension Linezolid for Oral Suspension is supplied as a powder for constitution. Gently tap bottle to loosen powder. Add a total of 123 mL distilled water in two portions. After adding the first half, shake vigorously to wet all of the powder. Then add the second half of the water and shake vigorously to obtain a uniform suspension. After constitution, each 5 mL of the suspension contains 100 mg of linezolid. Before using, gently mix by inverting the bottle 3 to 5 times. Do not shake . Store constituted suspension at room temperature. Use within 21 days after constitution.

6 ADVERSE REACTIONS 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 Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ()] Peripheral and Optic Neuropathy [see Warnings and Precautions ()] Serotonin Syndrome [see Warnings and Precautions ()] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ()] Lactic Acidosis [see Warnings and Precautions ()] Convulsions [see Warnings and Precautions ()] Rhabdomyolysis [see Warnings and Precautions ()] Hypoglycemia [see Warnings and Precautions ()] Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions ()] 6.1 Clinical Trials Experience 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. Of the patients treated for uncomplicated skin and skin structure infections (uSSSIs), 25.4% of linezolid-treated and 19.6% of comparator-treated patients experienced at least one drug-related adverse event. For all other indications, 20.4% of linezolid-treated and 14.3% of comparator-treated patients experienced at least one drug-related adverse event. Table 2 shows the incidence of all-causality, treatment-emergent adverse reactions reported in at least 1% of adult patients in these trials by dose of linezolid. Table 2. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in >1% of Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials Uncomplicated Skin and Skin Structure Infections All Other Indications ADVERSE REACTIONS 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=1498) All Other Comparators 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. (n=1464) Headache 8.8 8.4 5.7 4.4 Diarrhea 8.2 6.1 8.3 6.4 Nausea 5.1 4.5 6.6 4.6 Vomiting 2.0 1.5 4.3 2.3 Dizziness 2.6 3.0 1.8 1.5 Rash 1.1 1.1 2.3 2.6 Anemia 0.4 0 2.1 1.4 Taste alteration 1.8 2.0 1.0 0.3 Vaginal moniliasis 1.8 1.3 1.1 0.5 Oral moniliasis 0.5 0 1.7 1.0 Abnormal liver function tests 0.4 0.2 1.6 0.8 Fungal infection 1.5 0.2 0.3 0.2 Tongue discoloration 1.3 0 0.3 0 Localized abdominal pain 1.3 0.6 1.2 0.8 Generalized abdominal pain 0.9 0.4 1.2 1.0 Of the patients treated for uSSSIs, 3.5% of linezolid-treated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 2.1% of linezolid-treated and 1.7% of comparator-treated patients. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting. 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% (13/215) in the linezolid arm and 3% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established. Of the pediatric patients treated for uSSSIs, 19.2% of linezolid-treated and 14.1% of comparator-treated patients experienced at least one drug-related adverse event. For all other indications, 18.8% of linezolid-treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event. Table 3 shows the incidence of all-causality, treatment-emergent adverse reactions reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled Phase 3 trials. Table 3. 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 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. All Other Indications Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously or by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance. Linezolid (n=248) Cefadroxil (n=251) Linezolid (n=215) Vancomycin (n=101) Diarrhea 7.8 8.0 10.8 12.1 Vomiting 2.9 6.4 9.4 9.1 Headache 6.5 4.0 0.9 0 Anemia 0 0 5.6 7.1 Thrombocytopenia 0 0 4.7 2.0 Nausea 3.7 3.2 1.9 0 Generalized abdominal pain 2.4 2.8 0.9 2.0 Localized abdominal pain 2.4 2.8 0.5 1.0 Loose stools 1.6 0.8 2.3 3.0 Eosinophilia 0.4 0.8 1.9 1.0 Pruritus at non-application site 0.8 0.4 1.4 2.0 Vertigo 1.2 0.4 0 0 Of the pediatric patients treated for uSSSIs, 1.6% of linezolid-treated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 0.9% of linezolid-treated and 6.1% of comparator-treated patients. 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%) with linezolid and 1.5% (range among studies: 0.4 to 7%) 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 ( 5.1 )]. 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 hematologic or serum chemistry value is presented in Tables 4, 5, 6, and 7. Table 4. Percent of Adult Patients who Experienced at Least One Substantially Abnormal <75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; <75% (<50% for neutrophils) of LLN and of baseline for values abnormal at baseline. Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid 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 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. Hemoglobin (g/dL) 0.9 0.0 7.1 6.6 Platelet count (x 10 3 /mm 3 ) 0.7 0.8 3.0 1.8 WBC (x 10 3 /mm 3 ) 0.2 0.6 2.2 1.3 Neutrophils (x 10 3 /mm 3 ) 0.0 0.2 1.1 1.2 Table 5. Percent of Adult Patients who Experienced at Least One Substantially Abnormal >2 x Upper Limit of Normal (ULN) for values normal at baseline; >2 x ULN and >2 x baseline for values abnormal at baseline. Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid 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 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. AST (U/L) 1.7 1.3 5.0 6.8 ALT (U/L) 1.7 1.7 9.6 9.3 LDH (U/L) 0.2 0.2 1.8 1.5 Alkaline phosphatase (U/L) 0.2 0.2 3.5 3.1 Lipase (U/L) 2.8 2.6 4.3 4.2 Amylase (U/L) 0.2 0.2 2.4 2.0 Total bilirubin (mg/dL) 0.2 0.0 0.9 1.1 BUN (mg/dL) 0.2 0.0 2.1 1.5 Creatinine (mg/dL) 0.2 0.0 0.2 0.6 Table 6. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal <75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; <75% (<50% for neutrophils) of LLN and <75% (<50% for neutrophils, <90% for hemoglobin if baseline <LLN) of baseline for values abnormal at baseline. Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Laboratory Assay Uncomplicated Skin and Skin Structure Infections 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. All Other Indications Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously or by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6-24 hours, depending on age and renal clearance. Linezolid Cefadroxil Linezolid Vancomycin Hemoglobin (g/dL) 0.0 0.0 15.7 12.4 Platelet count (x 10 3 /mm 3 ) 0.0 0.4 12.9 13.4 WBC (x 10 3 /mm 3 ) 0.8 0.8 12.4 10.3 Neutrophils (x 10 3 /mm 3 ) 1.2 0.8 5.9 4.3 Table 7. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal >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. Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Laboratory Assay Uncomplicated Skin and Skin Structure Infections 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. All Other Indications Patients from birth through 11 years of age received linezolid 10 mg/kg intravenously or by mouth every 8 hours or vancomycin 10 to 15 mg/kg intravenously every 6-24 hours, depending on age and renal clearance. Linezolid Cefadroxil Linezolid Vancomycin ALT (U/L) 0.0 0.0 10.1 12.5 Lipase (U/L) 0.4 1.2 --- --- Amylase (U/L) --- --- 0.6 1.3 Total bilirubin (mg/dL) --- --- 6.3 5.2 Creatinine (mg/dL) 0.4 0.0 2.4 1.0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval 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: • Anaphylaxis, angioedema, bullous skin disorders including severe cutaneous adverse reactions (SCAR) such as toxic epidermal necrolysis and Stevens-Johnson syndrome, and hypersensitivity vasculitis. • 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 )]; sideroblastic anemia. • Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision [see Warnings and Precautions ( 5.2 )]. • 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 )]. • Lactic acidosis [see Warnings and Precautions ( 5.7 )]. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy. • Convulsions [see Warnings and Precautions ( 5.8 )]. • Rhabdomyolysis [see Warnings and Precautions ( 5.9 )]. • Hypoglycemia, including symptomatic episodes [see Warnings and Precautions ( 5.10 )]. • Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [see Warnings and Precautions ( 5.11 )]. • 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.

12.3 Pharmacokinetics 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. Table 8. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults Dose of Linezolid C max mcg/mL C min mcg/mL T max hrs AUC AUC for single dose = AUC 0-∞ ; for multiple-dose = AUC 0-τ mcg • h/mL t 1/2 hrs CL mL/min 400 mg tablet single dose Data dose-normalized from 375 mg 8.10 --- 1.52 55.10 5.20 146 (1.83) (1.01) (25.00) (1.50) (67) every 12 hours 11.00 3.08 1.12 73.40 4.69 110 (4.37) (2.25) (0.47) (33.50) (1.70) (49) 600 mg tablet single dose 12.70 --- 1.28 91.40 4.26 127 (3.96) (0.66) (39.30) (1.65) (48) every 12 hours 21.20 6.15 1.03 138.00 5.40 80 (5.78) (2.94) (0.62) (42.10) (2.06) (29) 600 mg IV injection Data dose-normalized from 625 mg, intravenous dose was given as 0.5-hour infusion. C max = Maximum plasma concentration; C min = Minimum plasma concentration; T max = Time to C max ; AUC = Area under concentration-time curve; t 1/2 = Elimination half-life; CL = Systemic clearance single dose 12.90 --- 0.50 80.20 4.40 138 (1.60) (0.10) (33.30) (2.40) (39) every 12 hours 15.10 3.68 0.51 89.70 4.80 123 (2.52) (2.36) (0.03) (31.00) (1.70) (40) 600 mg oral suspension single dose 11.00 --- 0.97 80.80 4.60 141 (2.76) (0.88) (35.10) (1.71) (45) 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 is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC 0-∞ is similar under both conditions. 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. Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2 to 1 and the ratio of linezolid in sweat relative to plasma was 0.55 to 1. 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. Specific Populations : 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 and the volume of distribution (V ss ) of linezolid are similar regardless of age in pediatric patients. However, plasma clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, weight-based clearance is most rapid in the youngest age groups ranging from < 1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and a shorter half-life as compared with adults. As the age of pediatric patients increases, the weight-based clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is increased inter-subject variability in linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as compared with adults. 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 AUC = Single dose AUC 0-∞ ** 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 mcg ● h/mL t 1/2 hrs CL mL/min/kg Neonatal Patients Pre-term ˂ 1 week (N=9) Dose of 10 mg/kg 12.7 (30%) [9.6, 22.2] 0.81 (24%) [0.43, 1.05] 108 (47%) [41, 191] 5.6 (46%) [2.4, 9.8] 2.0 (52%) [0.9, 4.0] Full-term *** < 1 week (N=10) 11.5 (24%) [8.0, 18.3] 0.78 (20%) [0.45, 0.96] 55 (47%) [19, 103] 3.0 (55%) [1.3, 6.1] 3.8 (55%) [1.5, 8.8] Full-term *** ≥ 1 week to ≤ 28 days (N=10) 12.9 (28%) [7.7, 21.6] 0.66 (29%) [0.35, 1.06] 34 (21%) [23, 50] 1.5 (17%) [1.2, 1.9] 5.1 (22%) [3.3, 7.2] Infant Patients > 28 days to < 3 Months (N=12) 11.0 (27%) [7.2, 18.0] 0.79 (26%) [0.42, 1.08] 33 (26%) [17, 48] 1.8 (28%) [1.2, 2.8] 5.4 (32%) [3.5, 9.9] Pediatric Patients 3 months through 11 years (N=59) 15.1 (30%) [6.8, 36.7] 0.69 (28%) [0.31, 1.50] 58 (54%) [19, 153] 2.9 (53%) [0.9, 8.0] 3.8 (53%) [1.0, 8.5] Adolescent Subjects and Patients 12 through 17 years Dose of 600 mg or 10 mg/kg up to a maximum of 600 mg (N=36) 16.7 (24%) [9.9, 28.9] 0.61 (15%) [0.44, 0.79] 95 (44%) [32, 178] 4.1 (46%) [1.3, 8.1] 2.1 (53%) [0.9, 5.2] Adult Subjects Dose normalized to 600 mg C max = Maximum plasma concentration; Vss= Volume of distribution; AUC = Area under concentration-time curve; t 1/2 = Apparent elimination half-life; CL = Systemic clearance normalized for body weight (N= 29) 12.5 (21%) [8.2, 19.3] 0.65 (16%) [0.45, 0.84] 91 (33%) [53, 155] 4.9 (35%) [1.8, 8.3] 1.7 (34%) [0.9, 3.3] 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. Table 10. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Patients with Varying Degrees of Renal Impairment After a Single 600 mg Oral Dose of Linezolid Parameter Healthy Subjects CL CR > 80 mL/min Moderate Renal Impairment 30 < CL CR < 80 mL/min Severe Renal Impairment 10 < CL CR < 30 mL/min LINEZOLID AUC 0-∞ , mcg h/mL 110 (22) 128 (53) 127 (66) t 1/2 , hours 6.4 (2.2) 6.1 (1.7) 7.1 (3.7) METABOLITE A AUC 0-48 , mcg h/mL 7.6 (1.9) 11.7 (4.3) 56.5 (30.6) t 1/2 , hours 6.3 (2.1) 6.6 (2.3) 9.0 (4.6) METABOLITE B Metabolite B is the major metabolite of linezolid. AUC 0-48 , mcg h/mL 30.5 (6.2) 51.1 (38.5) 203 (92) t 1/2 , hours 6.6 (2.7) 9.9 (7.4) 11.0 (3.9) 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 Between hemodialysis sessions. LINEZOLID AUC 0-12 , mcg h/mL (after last dose) 181 (52.3) t 1/2 , h (after last dose) 8.3 (2.4) METABOLITE A AUC 0-12 , mcg h/mL (after last dose) 153 (40.6) t 1/2 , h (after last dose) 15.9 (8.5) METABOLITE B Metabolite B is the major metabolite of linezolid. AUC 0-12 , mcg h/mL (after last dose) 356 (99.7) t 1/2 , h (after last dose) 34.8 (23.1) Hepatic Impairment : 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.g., 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 : The pharmacokinetics of linezolid or aztreonam are not altered when administered together. Gentamicin : The pharmacokinetics of linezolid or gentamicin are not altered when administered together. 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 2-9, subjects were given either Vitamin C (1,000 mg/day) or Vitamin E (800 IU/ day). The AUC 0-∞ of linezolid increased 2.3% when co-administered with Vitamin C and 10.9% when co‑administered with Vitamin E. No linezolid dose adjustment is recommended during co-administration with Vitamin C or Vitamin E. 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 [90% CI, 15% to 27%] and a 32% decrease in linezolid AUC 0-12 [90% CI, 27% to 37%]. The clinical significance of this interaction is unknown. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) could cause a similar or smaller decrease in linezolid exposure. 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 )]. 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 every 12 hours 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 to 79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively. 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. figure-1