ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adult Patients. The safety of ZYVOX formulations was evaluated in 2046 adult patients enrolled in seven Phase comparator-controlled clinical trials, who were treated for up to 28 days. In these studies, 85% of the adverse events reported with ZYVOX were described as mild to moderate in intensity. Table 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 ZYVOX 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%).Table 6. Incidence (%) of Adverse Events Reported in >=2% of Adult Patients in Comparator-Controlled Clinical Trials with ZYVOXEventZYVOX(n=2046)All Comparators Comparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone g IV q12h; clarithromycin 250 mg PO q12h; dicloxacillin 500 mg PO q6h; oxacillin g IV q6h; vancomycin g IV q12h. (n=2001)Diarrhea8.36.3Headache6.55.5Nausea6.24.6Vomiting3.72.0Insomnia2.51.7Constipation2.22.1Rash2.02.2Dizziness2.01.9Fever1.62.1Other adverse events reported in Phase and Phase studies included oral moniliasis, vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain, pruritus, and tongue discoloration.Table shows the incidence of drug-related adverse events reported in at least 1% of adult patients in these trials by dose of ZYVOX.Table 7. Incidence (%) of Drug-Related Adverse Events Occurring in >1% of Adult Patients Treated with ZYVOX in Comparator-Controlled Clinical TrialsUncomplicated Skin and Skin Structure InfectionsAll Other IndicationsAdverse EventZYVOX 400 mg PO q12h(n=548)Clarithromycin 250 mg PO q12h(n=537)ZYVOX 600 mg q12h(n=1498)All Other ComparatorsComparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone g IV q12h; dicloxacillin 500 mg PO q6h; oxacillin g IV q6h; vancomycin g IV q12h. (n=1464)% of patients with drug-related adverse event25.419.620.414.3% of patients discontinuing due to drug-related adverse eventsThe most commonly reported drug-related adverse events leading to discontinuation in patients treated with ZYVOX were nausea, headache, diarrhea, and vomiting. 3.52.42.11.7Diarrhea5.34.84.02.7Nausea3.53.53.31.8Headache2.72.21.91.0Taste alteration1.82.00.90.2Vaginal moniliasis1.61.31.00.4Fungal infection 1.50.20.1<0.1Abnormal liver function tests0.401.30.5Vomiting0.90.41.20.4Tongue discoloration1.100.20Dizziness1.11.50.40.3Oral moniliasis0.401.10.4. Pediatric Patients. The safety of ZYVOX formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged through 17 years (146 of these 248 were age through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 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 ZYVOX 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 to (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 shows the incidence of adverse events reported in at least 2% of pediatric patients treated with ZYVOX in these trials.Table 8. Incidence (%) of Adverse Events Reported in >=2% of Pediatric Patients Treated with ZYVOX in Comparator-Controlled Clinical TrialsUncomplicated Skin and Skin Structure InfectionsPatients through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h. All Other IndicationsPatients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6-24h, depending on age and renal clearance. EventZYVOX(n=248)Cefadroxil(n 251)ZYVOX(n 215)Vancomycin(n=101)Fever2.93.614.114.1Diarrhea7.88.010.812.1Vomiting2.96.49.49.1Sepsis008.07.1Rash1.61.27.015.2Headache6.54.00.90Anemia005.67.1Thrombocytopenia004.72.0Upper respiratory infection3.75.24.21.0Nausea3.73.21.90Dyspnea003.31.0Reaction at site of injection or of vascular catheter003.35.1Trauma3.34.82.82.0Pharyngitis2.91.60.51.0Convulsion002.82.0Hypokalemia002.83.0Pneumonia002.82.0Thrombocythemia002.82.0Cough2.44.00.90Generalized abdominal pain 2.42.80.92.0Localized abdominal pain 2.42.80.51.0Apnea002.32.0Gastrointestinal bleeding002.31.0Generalized edema002.31.0Loose stools1.60.82.33.0Localized pain2.01.60.90Skin disorder2.000.91.0Table shows the incidence of drug-related adverse events reported in more than 1% of pediatric patients (and more than patient) in either treatment group in the comparator-controlled Phase trials.Table 9. Incidence (%) of Drug-related Adverse Events Occurring in >1% of Pediatric Patients (and >1 Patient) in Either Treatment Group in Comparator-Controlled Clinical TrialsEventUncomplicated Skin and Skin Structure InfectionsPatients through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h. All Other IndicationsPatients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6-24h, depending on age and renal clearance. ZYVOX(n=248)Cefadroxil(n=251)ZYVOX(n=215)Vancomycin(n=101)% of patients with >=1 drug-related adverse event19.214.118.834.3% of patients discontinuing due to drug-related adverse event1.62.40.96.1Diarrhea5.75.23.86.1Nausea3.32.01.40Headache2.40.800Loose stools1.20.81.90Thrombocytopenia001.90Vomiting1.22.41.91.0Generalized abdominal pain1.61.200Localized abdominal pain1.61.200Anemia001.41.0Eosinophilia0.40.41.40Rash0.41.21.47.1Vertigo1.20.400Oral moniliasis000.94.0Fever000.53.0Pruritus at non-application site0.4002.0Anaphylaxis00010.1These reports were of red-man syndrome, which were coded as anaphylaxis. Laboratory Changes. ZYVOX 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 comparator-controlled trials, the percentage of adult patients who developed 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 ZYVOX and 1.5% (range among studies: 0.4 to 7.0%) with comparator. In study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with ZYVOX and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from through 17 years, the percentage of patients who developed substantially low platelet count was 0% with ZYVOX and 0.4% with cefadroxil. Thrombocytopenia associated with the use of ZYVOX appears to be dependent on duration of therapy, (generally greater than 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 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in compassionate use program for ZYVOX; the role of linezolid in these events cannot be determined (see WARNINGS).Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between ZYVOX 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 10, 11, 12, and 13.Table 10. 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 ZYVOXLaboratory Assay Uncomplicated Skin and Skin Structure InfectionsAll Other IndicationsZYVOX400 mg q12hClarithromycin250 mg q12hZYVOX600 mg q12hAll Other ComparatorsComparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone g IV q12h; dicloxacillin 500 mg PO q6h; oxacillin g IV q6h; vancomycin g IV q12h. Hemoglobin (g/dL)0.90.07.16.6Platelet count (x 103/mm3)0.70.83.01.8WBC (x 103/mm3)0.20.62.21.3Neutrophils (x 103/mm3)0.00.21.11.2Table 11. Percent of Adult Patients who Experienced at Least One Substantially Abnormal>2 Upper Limit of Normal (ULN) for values normal at baseline;>2 ULN and >2 baseline for values abnormal at baseline. Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with ZYVOXLaboratory Assay Uncomplicated Skin and Skin Structure InfectionsAll Other IndicationsZYVOX400 mg q12hClarithromycin250 mg q12hZYVOX600 mg q12hAll OtherComparatorsComparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone g IV q12h; dicloxacillin 500 mg PO q6h; oxacillin g IV q6h; vancomycin g IV q12h. AST (U/L)1.71.35.06.8ALT (U/L)1.71.79.69.3LDH (U/L)0.20.21.81.5Alkaline phosphatase (U/L)0.20.23.53.1Lipase (U/L)2.82.64.34.2Amylase (U/L)0.20.22.42.0Total bilirubin (mg/dL)0.20.00.91.1BUN (mg/dL)0.20.02.11.5Creatinine (mg/dL)0.20.00.20.6Table 12. 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 ZYVOXLaboratory Assay Uncomplicated Skin and Skin Structure InfectionsPatients through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h. All Other IndicationsPatients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6-24h, depending on age and renal clearance. ZYVOXCefadroxilZYVOXVancomycinHemoglobin (g/dL)0.00.015.712.4Platelet count (x 103/mm3)0.00.412.913.4WBC (x 103/mm3)0.80.812.410.3Neutrophils (x 103/mm3)1.20.85.94.3Table 13. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal>2 Upper Limit of Normal (ULN) for values normal at baseline; >2 ULN and >2 (>1.5 for total bilirubin) baseline for values abnormal at baseline. Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with ZYVOXLaboratory Assay Uncomplicated Skin and Skin Structure InfectionsPatients through 11 years of age received ZYVOX 10 mg/kg PO q12h or cefadroxil 15 mg/kg PO q12h. Patients 12 years or older received ZYVOX 600 mg PO q12h or cefadroxil 500 mg PO q12h. All Other IndicationsPatients from birth through 11 years of age received ZYVOX 10 mg/kg IV/PO q8h or vancomycin 10 to 15 mg/kg IV q6-24h, depending on age and renal clearance. ZYVOXCefadroxilZYVOXVancomycinALT (U/L)0.00.010.112.5Lipase (U/L)0.41.2------Amylase (U/L)------0.61.3Total bilirubin (mg/dL)------6.35.2Creatinine (mg/dL)0.40.02.41.0. Postmarketing Experience. Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported during postmarketing use of ZYVOX (see WARNINGS). Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with ZYVOX. Lactic acidosis has been reported with the use of ZYVOX (see PRECAUTIONS). 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. Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and ZYVOX (see PRECAUTIONS). Convulsions have been reported with the use of ZYVOX (see PRECAUTIONS). Anaphylaxis, angioedema, and bullous skin disorders such as those described as Stevens Johnson syndrome have been reported. 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to ZYVOX, or combination of these factors. Because they are reported voluntarily from population of unknown size, estimates of frequency cannot be made and causal relationship cannot be precisely established.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

ANIMAL PHARMACOLOGY. 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 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 male at this dose level at 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 male rats after 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.These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.Linezolid did not affect the fertility or reproductive performance of adult female rats. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses >= 50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7-fold greater than mean AUCs observed in pediatric patients aged months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day through postnatal day 5), neonatal exposure (postnatal days to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Pharmacokinetics. The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous (IV) doses are summarized in Table 1. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours (q12h) are shown in Figure 1.Table 1. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in AdultsDose of LinezolidCmax ug/mLCmin ug/mLTmax hrsAUC AUC for single dose AUC0-; for multiple-dose AUC0- ug h/mLt1/2 hrsCLmL/minCmax Maximum plasma concentration; Cmin Minimum plasma concentration; Tmax Time to Cmax; AUC Area under concentration-time curve; t1/2 Elimination half-life; CL Systemic clearance400 mg tablet single dose Data dose-normalized from 375 mg every 12 hours 8.10(1.83)11.00(4.37)---3.08(2.25)1.52(1.01)1.12(0.47)55.10(25.00)73.40(33.50)5.20(1.50)4.69(1.70)146(67)110(49)600 mg tablet single dose every 12 hours 12.70(3.96)21.20(5.78)---6.15(2.94)1.28(0.66)1.03(0.62)91.40(39.30)138.00(42.10)4.26(1.65)5.40(2.06)127(48)80(29)600 mg IV injectionData dose-normalized from 625 mg, IV dose was given as 0.5-hour infusion. single dose every 12 hours 12.90(1.60)15.10(2.52)---3.68(2.36)0.50(0.10)0.51(0.03)80.20(33.30)89.70(31.00)4.40(2.40)4.80(1.70)138(39)123(40)600 mg oral suspension single dose11.00(2.76)---0.97(0.88)80.80(35.10)4.60(1.71)141(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 rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately to 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 Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0- values 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 limited number of subjects in Phase volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2 to and for 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 is presumed to be formed via an enzymatic pathway whereas metabolite is mediated by 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 renal clearance of linezolid is low (average 40 mL/min) and 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.. Special Populations. Geriatric. 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. The pharmacokinetics of linezolid following single IV 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 week through 12 years. The pharmacokinetic parameters of linezolid are summarized in Table for the pediatric populations studied and healthy adult subjects after administration of single IV doses.The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, clearance of linezolid varies as function of age. With the exclusion of pre-term neonates less than one week of age, 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 shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is wider 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 hours (q8h) relative to adolescents or adults dosed every 12 hours (q12h). Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h (see DOSAGE AND ADMINISTRATION).Table 2. Pharmacokinetic Parameters of Linezolid in Pediatrics and Adults Following Single Intravenous Infusion of 10 mg/kg or 600 mg Linezolid (Mean: (%CV); [Min, Max Values])Age GroupCmax ug/mLVss L/kgAUC AUC Single dose AUC0- ug h/mLt 1/2 hrsCLmL/min/kgCmax Maximum plasma concentration; Vss= Volume of distribution; AUC Area under concentration-time curve; t1/2 Apparent elimination half-life; CL Systemic clearance normalized for body weightNeonatal Patients Pre-termIn this data set, pre-term is defined as <34 weeks gestational age (Note: Only patient enrolled was pre-term with postnatal age between week and 28 days) 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-termIn this data set, full-term is defined as >=34 weeks gestational age 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 >= 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 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 yearsDose of 600 mg or 10 mg/kg up to 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 SubjectsDose normalized to 600 mg (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 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 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 Insufficiency. The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal insufficiency; however, the two primary metabolites of linezolid may accumulate in patients with renal insufficiency, with the amount of accumulation increasing with the severity of renal dysfunction (see Table 3). The clinical significance of accumulation of these two metabolites has not been determined in patients with severe renal insufficiency. Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal insufficiency. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of linezolid in patients with renal insufficiency should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by dialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid. Approximately 30% of dose was eliminated in 3-hour dialysis session beginning hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis.Table 3. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites and in Patients with Varying Degrees of Renal Insufficiency After Single 600-mg Oral Dose of LinezolidParameterHealthy Subjects CLCR 80 mL/minModerate Renal Impairment 30 CLCR 80 mL/minSevere Renal Impairment 10 CLCR 30 mL/minHemodialysis-DependentOff Dialysisbetween hemodialysis sessions On DialysisNA Not applicableLinezolidAUC0-, ug h/mL110 (22)128 (53)127 (66)141 (45)83 (23)t1/2, hours6.4 (2.2)6.1 (1.7)7.1 (3.7)8.4 (2.7)7.0 (1.8)Metabolite AAUC0-48, ug h/mL7.6 (1.9)11.7 (4.3)56.5 (30.6)185 (124)68.8 (23.9)t1/2, hours6.3 (2.1)6.6 (2.3)9.0 (4.6)NANAMetabolite BAUC0-48, ug h/mL30.5 (6.2)51.1 (38.5)203 (92)467 (102)239 (44)t1/2, hours6.6 (2.7)9.9 (7.4)11.0 (3.9)NANA. Hepatic Insufficiency. The pharmacokinetics of linezolid are not altered in patients (n=7) with mild-to-moderate hepatic insufficiency (Child-Pugh class or B). On the basis of the available information, no dose adjustment is recommended for patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of linezolid in patients with severe hepatic insufficiency have not been evaluated.. Drug-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.. Antibiotics. 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.Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in study of 16 healthy adult males. Volunteers were administered oral linezolid 600 mg twice daily for doses with and without rifampin 600 mg once daily for days. Co-administration of rifampin with linezolid resulted in 21% decrease in linezolid Cmax [90% CI, 15% 27%] and 32% decrease in linezolid AUC0-12 [90% CI, 27% 37%]. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes (see PRECAUTIONS, Drug Interactions). Monoamine Oxidase Inhibition. Linezolid is reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.Adrenergic Agents: 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 PRECAUTIONS, Information for Patients).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 PRECAUTIONS, Drug Interactions). 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 days) with two doses of PPA (25 mg) or PSE (60 mg) given 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 to hours after the second dose of PPA or PSE, and returned to baseline to 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.Serotonergic Agents: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 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.. MICROBIOLOGY. Linezolid is synthetic antibacterial agent of new class of antibiotics, the oxazolidinones, 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 inhibits bacterial protein synthesis through mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of functional 70S initiation complex, which is an essential component of the bacterial 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 the majority of strains.In clinical trials, resistance to linezolid developed in patients infected with Enterococcus faecium (4 patients received 200 mg q12h, lower than the recommended dose, and patients received 600 mg q12h). In compassionate use program, resistance to linezolid developed in patients with E. faecium and in patient with Enterococcus faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at frequency of x 10 -9 to x 10 -11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to linezolid during its clinical use have been published.1 In one report nosocomial spread of vancomycin- and linezolid-resistant E. faecium occurred 2. There has been report of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during its clinical use.3 The linezolid resistance in these organisms was associated with point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. When antibiotic-resistant organisms are encountered in the hospital, it is important to emphasize infection control policies.4, Resistance to linezolid has not been reported in Streptococcus spp., including Streptococcus pneumoniae.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 and in clinical infections, as described in the INDICATIONS AND USAGE section.. Aerobic and facultative Gram-positive microorganisms. Enterococcus faecium (vancomycin-resistant strains only) Staphylococcus aureus (including methicillin-resistant strains) Streptococcus agalactiae Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP]MDRSP refers to isolates resistant to two or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole. 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 Viridans group streptococci. Aerobic and facultative Gram-negative microorganisms Pasteurella multocida. Susceptibility Testing Methods. NOTE: Susceptibility testing by dilution methods requires the use of linezolid susceptibility powder.When available, the results of in vitro susceptibility tests should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.. Dilution Techniques. Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using standardized procedure. Standardized procedures are based on dilution method 6,7 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of linezolid powder. The MIC values should be interpreted according to criteria provided in Table 4.. Diffusion Techniques. Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 7, requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 ug of linezolid to test the susceptibility of microorganisms to linezolid. The disk diffusion interpretive criteria are provided in Table 4.Table 4. Susceptibility Interpretive Criteria for LinezolidPathogenSusceptibility Interpretive Criteria Minimal Inhibitory Concentrations(MIC in ug/mL)Disk Diffusion(Zone Diameters in mm)SIRSIREnterococcus spp<= 24>=8>= 2321-22<=20Staphylococcus spp The current absence of data on resistant strains precludes defining any categories other than Susceptible. Strains yielding test results suggestive of nonsusceptible category should be retested, and if the result is confirmed, the isolate should be submitted to reference laboratory for further testing. <=4------>= 21------Streptococcus pneumoniae<=2These interpretive standards for S. pneumoniae and Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with to 5% lysed horse blood inoculated with direct colony suspension and incubated in ambient air at 35C for 20 to 24 hours. ------>= 21These zone diameter interpretive standards are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood inoculated with direct colony suspension and incubated in 5% CO2 at 35C for 20 to 24 hours. ------Streptococcus spp other than pneumoniae <=2 ------>= 21 ------A report of Susceptible indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. report of Resistant indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.. Quality Control. Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard linezolid powder should provide the following range of values noted in Table 5. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.Table 5. Acceptable Quality Control Ranges for Linezolid to be Used in Validation of Susceptibility Test ResultsQC StrainAcceptable Quality Control RangesMinimum Inhibitory Concentration(MIC in ug/mL)Disk Diffusion(Zone Diameters in mm)Enterococcus faecalisATCC 292121 4Not applicableStaphylococcus aureusATCC 292131 4Not applicableStaphylococcus aureusATCC 25923Not applicable25 32Streptococcus pneumoniaeATCC 49619This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae.0.50 2This quality control range for S. pneumoniae is applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with to 5% lysed horse blood inoculated with direct colony suspension and incubated in ambient air at 35C for 20 to 24 hours. 25 34This quality control zone diameter range is applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood inoculated with direct colony suspension and incubated in 5% CO2 at 35C for 20 to 24 hours. Graph.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. Adults. Vancomycin-Resistant Enterococcal Infections. Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in randomized, multi-center, double-blind trial comparing high dose of ZYVOX (600 mg) with low dose of ZYVOX (200 mg) given every 12 hours (q12h) either intravenously (IV) or orally for 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 0.05 level.Table 15. Cure Rates at the Test-of-Cure Visit for ITT Adult Patients with Documented Vancomycin-Resistant Enterococcal Infections at BaselineSource of InfectionCuredZYVOX600 mg q12hn/N (%)ZYVOX200 mg q12hn/N (%)Any site39/58 (67)24/46 (52)Any site with associated bacteremia10/17 (59)4/14 (29)Bacteremia of unknown origin5/10 (50)2/7 (29)Skin and skin structure9/13 (69)5/5 (100)Urinary tract12/19 (63)12/20 (60)Pneumonia 2/3 (67)0/1 (0)OtherIncludes sources of infection such as hepatic abscess, biliary sepsis, necrotic gall bladder, pericolonic abscess, pancreatitis, and catheter-related infection. 11/13 (85)5/13 (39). Nosocomial Pneumonia. Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in randomized, multi-center, double-blind trial. Patients were treated for to 21 days. One group received ZYVOX I.V. Injection 600 mg q12h, and the other group received vancomycin g q12h IV. Both groups received concomitant aztreonam (1 to g every hours IV), 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. modified intent-to-treat (MITT) analysis of 94 linezolid-treated patients and 83 vancomycin-treated patients included subjects who had 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 16.Table 16. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Nosocomial PneumoniaPathogenCuredZYVOXn/N (%)Vancomycinn/N (%)Staphylococcus aureus23/38 (61)14/23 (61)Methicillin-resistant S. aureus 13/22 (59)7/10 (70)Streptococcus pneumoniae9/9 (100)9/10 (90). Pneumonia caused by multi-drug resistant S.pneumoniae (MDRSPMDRSP refers to isolates resistant to two or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole. ). ZYVOX was studied for the treatment of community-acquired (CAP) and hospital-acquired (HAP) pneumonia due to MDRSP by pooling clinical data from seven comparative and non-comparative Phase and Phase studies involving adult and pediatric patients. The pooled MITT population consisted of all patients with S.pneumoniae isolated at baseline; the pooled ME population consisted of patients satisfying criteria for microbiologic evaluability. The pooled MITT population with CAP included 15 patients (41%) with severe illness (risk classes IV and V) as assessed by prediction rule11. The pooled clinical cure rates for patients with CAP due to MDRSP were 35/48 (73%) in the MITT and 33/36 (92%) in the ME populations respectively. The pooled clinical cure rates for patients with HAP due to MDRSP were 12/18 (67%) in the MITT and 10/12 (83%) in the ME populations respectively. Table 17. Clinical cure rates for 36 microbiologically-evaluable patients with CAP due to MDRSP who were treated with ZYVOX (stratified by antibiotic susceptibility) Susceptibility ScreeningClinical Curen/Nn= pooled number of patients treated successfully; N= pooled number of patients having MDRSP isolates that exhibited resistance to the listed antibiotic (%)Penicillin-resistant 14/16882nd generation cephalosporin-resistant2nd-generation cephalosporin tested was cefuroxime 19/2286Macrolide-resistantmacrolide tested was erythromycin 29/3097Tetracycline-resistant22/2492Trimethoprim/sulfamethoxazole-resistant18/2186. Complicated Skin and Skin Structure Infections. Adult patients with clinically documented complicated skin and skin structure infections were enrolled in randomized, multi-center, double-blind, double-dummy trial comparing study medications administered IV followed by medications given orally for total of 10 to 21 days of treatment. One group of patients received ZYVOX I.V. Injection 600 mg q12h followed by ZYVOX Tablets 600 mg q12h; the other group received oxacillin g every hours (q6h) IV followed by dicloxacillin 500 mg q6h 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. 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 18.Table 18. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Complicated Skin and Skin Structure InfectionsPathogenCuredZYVOXn/N (%)Oxacillin/Dicloxacillinn/N (%)Staphylococcus aureus73/83 (88)72/84 (86)Methicillin-resistant S. aureus 2/3 (67)0/0 (-)Streptococcus agalactiae6/6 (100)3/6 (50)Streptococcus pyogenes18/26 (69)21/28 (75)A separate study provided additional experience with the use of ZYVOX in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. This was randomized, open-label trial in hospitalized adult patients with documented or suspected MRSA infection.One group of patients received ZYVOX I.V. Injection 600 mg q12h followed by ZYVOX Tablets 600 mg q12h. The other group of patients received vancomycin g q12h IV. Both groups were treated for to 28 days, and could receive concomitant aztreonam or gentamicin if clinically indicated. The cure rates in microbiologically evaluable patients with MRSA skin and skin structure infection were 26/33 (79%) for linezolid-treated patients and 24/33 (73%) for vancomycin-treated patients.. Diabetic Foot Infections. Adult diabetic patients with clinically documented complicated skin and skin structure infections (diabetic foot infections) were enrolled in randomized (2:1 ratio), multi-center, open-label trial comparing study medications administered IV or orally for total of 14 to 28 days of treatment. One group of patients received ZYVOX 600 mg q12h IV or orally; the other group received ampicillin/sulbactam 1.5 to g IV or amoxicillin/clavulanate 500 to 875 mg every to 12 hours (q8-12h) orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to g every hours (q6h) was used for the intravenous regimen. Patients in the comparator group could also be treated with vancomycin g q12h IV 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 to g q8-12h IV. 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. critical post-hoc analysis focused on 121 linezolid-treated and 60 comparator-treated patients who had 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 19.Table 19. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Diabetic Foot InfectionsPathogenCuredZYVOXn/N (%)Comparatorn/N (%)Staphylococcus aureus49/63 (78)20/29 (69)Methicillin-resistant S. aureus 12/17 (71)2/3 (67)Streptococcus agalactiae25/29 (86)9/16 (56). Pediatric Patients. Infections Due to Gram-positive Organisms. safety and efficacy study provided experience on the use of ZYVOX in pediatric patients for the treatment of nosocomial pneumonia, complicated skin and skin structure infections, catheter-related bacteremia, bacteremia of unidentified source, and other infections due to Gram-positive bacterial pathogens, including methicillin-resistant and -susceptible Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Pediatric patients ranging in age from birth through 11 years with infections caused by the documented or suspected Gram-positive organisms were enrolled in randomized, open-label, comparator-controlled trial. One group of patients received ZYVOX I.V. Injection 10 mg/kg every hours (q8h) followed by ZYVOX for Oral Suspension 10 mg/kg q8h. second group received vancomycin 10 to 15 mg/kg IV every to 24 hours, depending on age and renal clearance. Patients who had confirmed VRE infections were placed in third arm of the study and received ZYVOX 10 mg/kg q8h IV and/or orally. All patients were treated for total of 10 to 28 days and could receive concomitant Gram-negative antibiotics if clinically indicated. In the intent-to-treat (ITT) population, there were 206 patients randomized to linezolid and 102 patients randomized to vancomycin. One hundred seventeen (57 %) linezolid-treated patients and 55 (54%) vancomycin-treated patients were clinically evaluable. The cure rates in ITT patients were 81% in patients randomized to linezolid and 83% in patients randomized to vancomycin (95% Confidence Interval of the treatment difference; -13%, 8%). The cure rates in clinically evaluable patients were 91% in linezolid-treated patients and 91% in vancomycin-treated patients (95% CI; -11%, 11%). Modified intent-to-treat (MITT) patients included ITT patients who, at baseline, had Gram-positive pathogen isolated from the site of infection or from blood. The cure rates in MITT patients were 80% in patients randomized to linezolid and 90% in patients randomized to vancomycin (95% CI; -23%, 3%). The cure rates for ITT, MITT, and clinically evaluable patients are presented in Table 20. After the study was completed, 13 additional patients ranging from days through 16 years of age were enrolled in an open-label extension of the VRE arm of the study. Table 21 provides clinical cure rates by pathogen for microbiologically evaluable patients including microbiologically evaluable patients with vancomycin-resistant Enterococcus faecium from the extension of this study.Table 20. Cure Rates at the Test-of-Cure Visit for Intent to Treat, Modified Intent to Treat, and Clinically Evaluable Pediatric Patients by Baseline DiagnosisPopulationITTMITTMITT ITT patients with an isolated Gram-positive pathogen at baseline Clinically EvaluableZYVOXn/N (%)Vancomycinn/N (%)ZYVOXn/N (%)Vancomycinn/N (%)ZYVOXn/N (%)Vancomycinn/N (%)Any diagnosis150/186 (81)69/83 (83)86/108 (80)44/49 (90)106/117 (91)49/54 (91)Bacteremia of unidentified source22/29 (76)11/16 (69)8/12 (67)7/8 (88)14/17 (82)7/9 (78)Catheter-related bacteremia30/41 (73)8/12 (67)25/35 (71)7/10 (70)21/25(84)7/9 (78)Complicated skin and skin structure infections61/72 (85)31/34 (91)37/43 (86)22/23 (96)46/49 (94)26/27 (96)Nosocomial pneumonia13/18 (72)11/12 (92)5/6 (83)4/4 (100)7/7 (100)5/5 (100)Other infections24/26 (92)8/9 (89)11/12 (92)4/4 (100)18/19 (95)4/4 (100)Table 21. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Pediatric Patients with Infections due to Gram-positive PathogensPathogenMicrobiologically EvaluableZYVOXn/N (%)Vancomycinn/N (%)Vancomycin-resistant Enterococcus faecium 6/8 (75)Includes data from patients enrolled in the open-label extension of this study. 0/0 (-)Staphylococcus aureus36/38 (95)23/24 (96)Methicillin-resistant S. aureus 16/17 (94)9/9 (100)Streptococcus pyogenes2/2 (100)1/2 (50).

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. ZYVOX formulations are contraindicated for use in patients who have known 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 or (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), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine) (see PRECAUTIONS, Drug 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 PRECAUTIONS, General and Drug Interactions).

DESCRIPTION SECTION.

DESCRIPTION. ZYVOX I.V. Injection, ZYVOX Tablets, and ZYVOX for Oral Suspension contain linezolid, which is 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, and its chemical structure is represented below:ZYVOX I.V. Injection is supplied as ready-to-use sterile isotonic solution for intravenous infusion. Each mL contains mg of linezolid. Inactive ingredients are sodium citrate, citric acid, and dextrose in an aqueous vehicle for intravenous administration. The sodium (Na+) content is 0.38 mg/mL (5 mEq per 300-mL bag; 3.3 mEq per 200-mL bag; and 1.7 mEq per 100-mL bag).ZYVOX Tablets for oral administration contain 400 mg or 600 mg linezolid as film-coated compressed tablets. Inactive ingredients are corn starch, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, and carnauba wax. The sodium (Na+) content is 1.95 mg per 400-mg tablet and 2.92 mg per 600-mg tablet (0.1 mEq per tablet, regardless of strength).ZYVOX for Oral Suspension is supplied as an orange-flavored granule/powder for constitution into suspension for oral administration. Following constitution, each mL contains 100 mg of linezolid. Inactive ingredients are sucrose, citric acid, sodium citrate, microcrystalline cellulose and carboxymethylcellulose sodium, aspartame, xanthan gum, mannitol, sodium benzoate, colloidal silicon dioxide, sodium chloride, and flavors (see PRECAUTIONS, Information for Patients). The sodium (Na+) content is 8.52 mg per mL (0.4 mEq per mL).. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The recommended dosage for ZYVOX formulations for the treatment of infections is described in Table 14.Table 14. Dosage Guidelines for ZYVOXInfectionDue to the designated pathogens (see INDICATIONS AND USAGE)Dosage and Route of AdministrationRecommended Duration of Treatment (consecutive days)Pediatric PatientsNeonates <7 days: Most pre-term neonates 7 days of age (gestational age 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 dosing regimen of 10 mg/kg q12h. Consideration may be given to the use of 10 mg/kg q8h regimen in neonates with sub-optimal clinical response. All neonatal patients should receive 10 mg/kg q8h by days of life (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric). (Birth through 11 Years of Age)Adults and Adolescents (12 Years and Older)Complicated skin and skin structure infections10 mg/kg IV or oralOral dosing using either ZYVOX Tablets or ZYVOX for Oral Suspension q8h600 mg IV or oral q12h10 to 14Community-acquired pneumonia, including concurrent bacteremiaNosocomial pneumoniaVancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia10 mg/kg IV or oral q8h600 mg IV or oral q12h 14 to 28Uncomplicated skin and skin structure infections<5 yrs: 10 mg/kg oral q8h5-11 yrs: 10 mg/kg oral q12hAdults: 400 mg oral q12hAdolescents: 600 mg oral q12h10 to 14Adult patients with infection due to MRSA should be treated with ZYVOX 600 mg q12h.In limited clinical experience, out of (83%) pediatric patients with infections due to Gram-positive pathogens with MICs of ug/mL treated with ZYVOX had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with sub-optimal clinical response, particularly those with pathogens with MIC of ug/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric and PRECAUTIONS, Pediatric Use).In controlled clinical trials, the protocol-defined duration of treatment for all infections ranged from to 28 days. Total treatment duration was determined by the treating physician based on site and severity of the infection, and on the patients clinical response.No dose adjustment is necessary when switching from intravenous to oral administration. Patients whose therapy is started with ZYVOX I.V. Injection may be switched to either ZYVOX Tablets or Oral Suspension at the discretion of the physician, when clinically indicated.. Intravenous Administration. ZYVOX I.V. Injection is supplied in single-use, ready-to-use infusion bags (see HOW SUPPLIED for container sizes). Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired.ZYVOX I.V. Injection should be administered by intravenous infusion over period of 30 to 120 minutes. Do not use this intravenous infusion bag in series connections. Additives should not be introduced into this solution. If ZYVOX I.V. Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product. In particular, physical incompatibilities resulted when ZYVOX I.V. Injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when ZYVOX I.V. Injection was combined with ceftriaxone sodium.If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of ZYVOX I.V. Injection with an infusion solution compatible with ZYVOX I.V. Injection and with any other drug(s) administered via this common line (see Compatible Intravenous Solutions).. Compatible Intravenous Solutions. 5% Dextrose Injection, USP0.9% Sodium Chloride Injection, USPLactated Ringers Injection, USPKeep the infusion bags in the overwrap until ready to use. Store at room temperature. Protect from freezing. ZYVOX I.V. Injection may exhibit yellow color that can intensify over time without adversely affecting potency.. 5% Dextrose Injection, USP. 0.9% Sodium Chloride Injection, USP. Lactated Ringers Injection, USP. Constitution of Oral Suspension. ZYVOX for Oral Suspension is supplied as powder/granule for constitution. Gently tap bottle to loosen powder. Add 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 uniform suspension. After constitution, each mL of the suspension contains 100 mg of linezolid. Before using, gently mix by inverting the bottle to times. DO NOT SHAKE. Store constituted suspension at room temperature. Use within 21 days after constitution.

DRUG & OR LABORATORY TEST INTERACTIONS SECTION.

Drug-Laboratory Test Interactions. There are no reported drug-laboratory test interactions.

DRUG INTERACTIONS SECTION.

Drug Interactions. (see also CLINICAL PHARMACOLOGY, Drug-Drug Interactions). Monoamine Oxidase Inhibition. Linezolid is reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.Adrenergic Agents: Some individuals receiving ZYVOX may experience 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.Serotonergic Agents: Co-administration of linezolid and serotonergic agents was not associated with serotonin syndrome in Phase 1, or studies. Spontaneous reports of serotonin syndrome associated with co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported. Patients who are treated with ZYVOX and concomitant serotonergic agents should be closely observed as described in the PRECAUTIONS, General Section.Strong CYP450 Inducers: In study in healthy volunteers, co-administration of rifampin with oral linezolid resulted in 21% decrease in linezolid Cmax and 32% decrease in linezolid AUC0-12. The clinical significance of this interaction is unknown. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) could cause similar or smaller decrease in linezolid exposure (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).

GENERAL PRECAUTIONS SECTION.

General. Lactic Acidosis. Lactic acidosis has been reported with the use of ZYVOX. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or low bicarbonate level while receiving ZYVOX should receive immediate medical evaluation.. Serotonin Syndrome. Spontaneous reports of serotonin syndrome associated with the co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported (see PRECAUTIONS, Drug Interactions).Where administration of ZYVOX 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 (see package insert of the specified agent(s) for description of the associated discontinuation symptoms).. Peripheral and Optic Neuropathy. Peripheral and optic neuropathy have been reported in patients treated with ZYVOX, 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. Visual blurring has been reported in some patients treated with ZYVOX for less than 28 days. If patients experience symptoms of visual impairment, 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 ZYVOX for extended periods (>= months) and in all patients reporting new visual symptoms regardless of length of therapy with ZYVOX. If peripheral or optic neuropathy occurs, the continued use of ZYVOX in these patients should be weighed against the potential risks.. Convulsions. Convulsions have been reported in patients when treated with linezolid. In some of these cases, history of seizures or risk factors for seizures was reported.The use of antibiotics may promote the overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.ZYVOX has not been studied in patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism.The safety and efficacy of ZYVOX formulations given for longer than 28 days have not been evaluated in controlled clinical trials.Prescribing ZYVOX in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

GERIATRIC USE SECTION.

Geriatric Use. Of the 2046 patients treated with ZYVOX in Phase 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.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Tablets. ZYVOX Tablets are available as follows:600 mg (white, capsule-shaped, film-coated tablets printed with ZYVOX 600 mg) 20 tablets in HDPE bottleNDC 21695-399-20. Storage of ZYVOX Formulations. Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Protect from light. Keep bottles tightly closed to protect from moisture. It is recommended that the infusion bags be kept in the overwrap until ready to use. Protect infusion bags from freezing.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. ZYVOX formulations are indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms (see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION and CLINICAL STUDIES). Linezolid is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if concomitant Gram-negative pathogen is documented or suspected (see WARNINGS).Vancomycin-Resistant Enterococcus faecium infections, including cases with concurrent bacteremia. (see CLINICAL STUDIES)Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), or Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]).Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae. ZYVOX has not been studied in the treatment of decubitus ulcers.Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible only) or Streptococcus pyogenes.Community-acquired pneumonia caused by Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]MDRSP refers to isolates resistant to two or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole. ), including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible strains only).To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZYVOX and other antibacterial drugs, ZYVOX 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.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Patients should be advised that:ZYVOX may be taken with or without food.They should inform their physician if they have history of hypertension.Large quantities of foods or beverages with high tyramine content should be avoided while taking ZYVOX. Quantities of tyramine consumed should be less than 100 mg per meal. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses (0 to 15 mg tyramine per ounce); fermented or air-dried meats (0.1 to mg tyramine per ounce); sauerkraut (8 mg tyramine per ounces); soy sauce (5 mg tyramine per teaspoon); tap beers (4 mg tyramine per 12 ounces); red wines (0 to mg tyramine per ounces). The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.9,10 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.Phenylketonurics: Each mL of the 100 mg/5 mL ZYVOX for Oral Suspension contains 20 mg phenylalanine. The other ZYVOX formulations do not contain phenylalanine. Contact your physician or pharmacist.They should inform their physician if they experience changes in vision.They should inform their physician if they have history of seizures.Diarrhea is 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.Patients should be counseled that antibacterial drugs including ZYVOX should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZYVOX is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ZYVOX or other antibacterial drugs in the future.. ZYVOX may be taken with or without food.. They should inform their physician if they have history of hypertension.. Large quantities of foods or beverages with high tyramine content should be avoided while taking ZYVOX. Quantities of tyramine consumed should be less than 100 mg per meal. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses (0 to 15 mg tyramine per ounce); fermented or air-dried meats (0.1 to mg tyramine per ounce); sauerkraut (8 mg tyramine per ounces); soy sauce (5 mg tyramine per teaspoon); tap beers (4 mg tyramine per 12 ounces); red wines (0 to mg tyramine per ounces). The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.9,10 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.. Phenylketonurics: Each mL of the 100 mg/5 mL ZYVOX for Oral Suspension contains 20 mg phenylalanine. The other ZYVOX formulations do not contain phenylalanine. Contact your physician or pharmacist.. They should inform their physician if they experience changes in vision.. They should inform their physician if they have history of seizures.. Diarrhea is 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.

NONTERATOGENIC EFFECTS SECTION.

Non-teratogenic Effects In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). dose of 450 mg/kg/day (6.5-fold the estimated human exposure level 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.In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold 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, finding often seen in association with decreased fetal body weights. Slight 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 dose of 15 mg/kg/day (0.06-fold 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, survival of pups was decreased on postnatal days to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.

NURSING MOTHERS SECTION.

Nursing Mothers. Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZYVOX is administered to nursing woman.

OVERDOSAGE SECTION.

OVERDOSAGE. In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In Phase clinical trial, approximately 30% of dose of linezolid was removed during 3-hour hemodialysis session beginning 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 3000 mg/kg/day and 2000 mg/kg/day, respectively.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 600 mg Tablet Bottle Label. NDC 21695-399-2020 TabletsRx onlyZYVOX(R)(linezolid) tablets600 mgPfizerDistributed byPharmacia Upjohn CoDivision of Pfizer Inc, NY, NY 10017Repackaged by:Rebel Distributors CorpThousand Oaks, CA 91320. Zyvox 600 mg.

PEDIATRIC USE SECTION.

Pediatric Use. The safety and effectiveness of ZYVOX 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 comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years (see INDICATIONS AND USAGE and CLINICAL STUDIES):nosocomial pneumoniacomplicated skin and skin structure infectionscommunity-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from months through 12 years)vancomycin-resistant Enterococcus faecium infectionsThe safety and effectiveness of ZYVOX for the treatment of pediatric patients with the following infection have been established in comparator-controlled study in pediatric patients ranging in age from through 17 years (see CLINICAL STUDIES):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 Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, linezolid clearance is function of age. Excluding neonates less than week of age, 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 shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence, mean clearance values approach those observed for the adult population. There is wider inter-subject variability in linezolid clearance and in 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 q8h relative to adolescents or adults dosed q12h. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h.Recommendations for the dosage regimen for pre-term neonates less than days of age (gestational age less than 34 weeks) are based on pharmacokinetic data from pre-term neonates. Most of these pre-term neonates have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. Therefore, these pre-term neonates should be initiated with dosing regimen of 10 mg/kg q12h. Consideration may be given to the use of 10 mg/kg q8h regimen in neonates with sub-optimal clinical response. All neonatal patients should receive 10 mg/kg q8h by days of life (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric and DOSAGE AND ADMINISTRATION ).In limited clinical experience, out of (83%) pediatric patients with infections due to Gram-positive pathogens with MICs of ug/mL treated with ZYVOX had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with sub-optimal clinical response, particularly those with pathogens with MIC of ug/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric and DOSAGE AND ADMINISTRATION).. 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 months through 12 years). vancomycin-resistant Enterococcus faecium infections. uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.

PHARMACOKINETICS SECTION.

Pharmacokinetics. The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous (IV) doses are summarized in Table 1. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours (q12h) are shown in Figure 1.Table 1. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in AdultsDose of LinezolidCmax ug/mLCmin ug/mLTmax hrsAUC AUC for single dose AUC0-; for multiple-dose AUC0- ug h/mLt1/2 hrsCLmL/minCmax Maximum plasma concentration; Cmin Minimum plasma concentration; Tmax Time to Cmax; AUC Area under concentration-time curve; t1/2 Elimination half-life; CL Systemic clearance400 mg tablet single dose Data dose-normalized from 375 mg every 12 hours 8.10(1.83)11.00(4.37)---3.08(2.25)1.52(1.01)1.12(0.47)55.10(25.00)73.40(33.50)5.20(1.50)4.69(1.70)146(67)110(49)600 mg tablet single dose every 12 hours 12.70(3.96)21.20(5.78)---6.15(2.94)1.28(0.66)1.03(0.62)91.40(39.30)138.00(42.10)4.26(1.65)5.40(2.06)127(48)80(29)600 mg IV injectionData dose-normalized from 625 mg, IV dose was given as 0.5-hour infusion. single dose every 12 hours 12.90(1.60)15.10(2.52)---3.68(2.36)0.50(0.10)0.51(0.03)80.20(33.30)89.70(31.00)4.40(2.40)4.80(1.70)138(39)123(40)600 mg oral suspension single dose11.00(2.76)---0.97(0.88)80.80(35.10)4.60(1.71)141(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 rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately to 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 Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0- values 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 limited number of subjects in Phase volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2 to and for 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 is presumed to be formed via an enzymatic pathway whereas metabolite is mediated by 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 renal clearance of linezolid is low (average 40 mL/min) and 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.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Lactic Acidosis. Lactic acidosis has been reported with the use of ZYVOX. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or low bicarbonate level while receiving ZYVOX should receive immediate medical evaluation.. Serotonin Syndrome. Spontaneous reports of serotonin syndrome associated with the co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported (see PRECAUTIONS, Drug Interactions).Where administration of ZYVOX 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 (see package insert of the specified agent(s) for description of the associated discontinuation symptoms).. Peripheral and Optic Neuropathy. Peripheral and optic neuropathy have been reported in patients treated with ZYVOX, 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. Visual blurring has been reported in some patients treated with ZYVOX for less than 28 days. If patients experience symptoms of visual impairment, 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 ZYVOX for extended periods (>= months) and in all patients reporting new visual symptoms regardless of length of therapy with ZYVOX. If peripheral or optic neuropathy occurs, the continued use of ZYVOX in these patients should be weighed against the potential risks.. Convulsions. Convulsions have been reported in patients when treated with linezolid. In some of these cases, history of seizures or risk factors for seizures was reported.The use of antibiotics may promote the overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.ZYVOX has not been studied in patients with uncontrolled hypertension, pheochromocytoma, carcinoid syndrome, or untreated hyperthyroidism.The safety and efficacy of ZYVOX formulations given for longer than 28 days have not been evaluated in controlled clinical trials.Prescribing ZYVOX in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.. Information for Patients. Patients should be advised that:ZYVOX may be taken with or without food.They should inform their physician if they have history of hypertension.Large quantities of foods or beverages with high tyramine content should be avoided while taking ZYVOX. Quantities of tyramine consumed should be less than 100 mg per meal. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses (0 to 15 mg tyramine per ounce); fermented or air-dried meats (0.1 to mg tyramine per ounce); sauerkraut (8 mg tyramine per ounces); soy sauce (5 mg tyramine per teaspoon); tap beers (4 mg tyramine per 12 ounces); red wines (0 to mg tyramine per ounces). The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.9,10 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.Phenylketonurics: Each mL of the 100 mg/5 mL ZYVOX for Oral Suspension contains 20 mg phenylalanine. The other ZYVOX formulations do not contain phenylalanine. Contact your physician or pharmacist.They should inform their physician if they experience changes in vision.They should inform their physician if they have history of seizures.Diarrhea is 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.Patients should be counseled that antibacterial drugs including ZYVOX should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZYVOX is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ZYVOX or other antibacterial drugs in the future.. ZYVOX may be taken with or without food.. They should inform their physician if they have history of hypertension.. Large quantities of foods or beverages with high tyramine content should be avoided while taking ZYVOX. Quantities of tyramine consumed should be less than 100 mg per meal. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses (0 to 15 mg tyramine per ounce); fermented or air-dried meats (0.1 to mg tyramine per ounce); sauerkraut (8 mg tyramine per ounces); soy sauce (5 mg tyramine per teaspoon); tap beers (4 mg tyramine per 12 ounces); red wines (0 to mg tyramine per ounces). The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.9,10 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.. Phenylketonurics: Each mL of the 100 mg/5 mL ZYVOX for Oral Suspension contains 20 mg phenylalanine. The other ZYVOX formulations do not contain phenylalanine. Contact your physician or pharmacist.. They should inform their physician if they experience changes in vision.. They should inform their physician if they have history of seizures.. Diarrhea is 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.. Drug Interactions. (see also CLINICAL PHARMACOLOGY, Drug-Drug Interactions). Monoamine Oxidase Inhibition. Linezolid is reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.Adrenergic Agents: Some individuals receiving ZYVOX may experience 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.Serotonergic Agents: Co-administration of linezolid and serotonergic agents was not associated with serotonin syndrome in Phase 1, or studies. Spontaneous reports of serotonin syndrome associated with co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported. Patients who are treated with ZYVOX and concomitant serotonergic agents should be closely observed as described in the PRECAUTIONS, General Section.Strong CYP450 Inducers: In study in healthy volunteers, co-administration of rifampin with oral linezolid resulted in 21% decrease in linezolid Cmax and 32% decrease in linezolid AUC0-12. The clinical significance of this interaction is unknown. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) could cause similar or smaller decrease in linezolid exposure (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions) Drug-Laboratory Test Interactions. There are no reported drug-laboratory test interactions.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.Linezolid did not affect the fertility or reproductive performance of adult female rats. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses >= 50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7-fold greater than mean AUCs observed in pediatric patients aged months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day through postnatal day 5), neonatal exposure (postnatal days to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35.. Pregnancy. Teratogenic Effects.. Pregnancy Category C. Linezolid was not teratogenic in mice, rats, or rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.06-fold (in rabbits) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen (see Non-teratogenic Effects). There are no adequate and well-controlled studies in pregnant women. ZYVOX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Non-teratogenic Effects In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). dose of 450 mg/kg/day (6.5-fold the estimated human exposure level 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.In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold 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, finding often seen in association with decreased fetal body weights. Slight 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 dose of 15 mg/kg/day (0.06-fold 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, survival of pups was decreased on postnatal days to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.. Nursing Mothers. Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZYVOX is administered to nursing woman.. Pediatric Use. The safety and effectiveness of ZYVOX 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 comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years (see INDICATIONS AND USAGE and CLINICAL STUDIES):nosocomial pneumoniacomplicated skin and skin structure infectionscommunity-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from months through 12 years)vancomycin-resistant Enterococcus faecium infectionsThe safety and effectiveness of ZYVOX for the treatment of pediatric patients with the following infection have been established in comparator-controlled study in pediatric patients ranging in age from through 17 years (see CLINICAL STUDIES):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 Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, linezolid clearance is function of age. Excluding neonates less than week of age, 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 shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence, mean clearance values approach those observed for the adult population. There is wider inter-subject variability in linezolid clearance and in 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 q8h relative to adolescents or adults dosed q12h. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h.Recommendations for the dosage regimen for pre-term neonates less than days of age (gestational age less than 34 weeks) are based on pharmacokinetic data from pre-term neonates. Most of these pre-term neonates have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. Therefore, these pre-term neonates should be initiated with dosing regimen of 10 mg/kg q12h. Consideration may be given to the use of 10 mg/kg q8h regimen in neonates with sub-optimal clinical response. All neonatal patients should receive 10 mg/kg q8h by days of life (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric and DOSAGE AND ADMINISTRATION ).In limited clinical experience, out of (83%) pediatric patients with infections due to Gram-positive pathogens with MICs of ug/mL treated with ZYVOX had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with sub-optimal clinical response, particularly those with pathogens with MIC of ug/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric and DOSAGE AND ADMINISTRATION).. 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 months through 12 years). vancomycin-resistant Enterococcus faecium infections. uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes Geriatric Use. Of the 2046 patients treated with ZYVOX in Phase 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.

PREGNANCY SECTION.

Pregnancy. Teratogenic Effects.. Pregnancy Category C. Linezolid was not teratogenic in mice, rats, or rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.06-fold (in rabbits) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen (see Non-teratogenic Effects). There are no adequate and well-controlled studies in pregnant women. ZYVOX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Non-teratogenic Effects In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). dose of 450 mg/kg/day (6.5-fold the estimated human exposure level 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.In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold 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, finding often seen in association with decreased fetal body weights. Slight 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 dose of 15 mg/kg/day (0.06-fold 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, survival of pups was decreased on postnatal days to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.

REFERENCES SECTION.

REFERENCES. Gonzales RD, PC Schreckenberger, MB Graham, et al. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. The Lancet 2001;357:1179.Herrero IA, NC Issa, Patel. Nosocomial spread of linezolid-resistant, vancomycin-resistant Enterococcus faecium. The New England Journal of Medicine 2002;346:867-869.Tsiodras S, HS Gold, Sakoulas, et al. Linezolid resistance in clinical isolate of Staphylococcus aureus. The Lancet 2001;358:207-208.Goldman DA, RA Weinstein, RP Wenzel, et al. Strategies to prevent and control the emergence and spread of antimicrobial-resistant microorganisms in hospitals. challenge to hospital leadership. The Journal of the American Medical Association 1996;275:234-240.Centers for Disease Control and Prevention. Guideline for hand hygiene in health-care settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HIPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Morbidity and Mortality Weekly Report 2002;51 (RR-16).National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.National Committee for Clinical Laboratory Standards. Twelfth Informational Supplement. Approved NCCLS Document M100-S12, Vol. 21, No. 1, NCCLS, Wayne, PA, January 2002.National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January 2000.Walker SE et al. Tyramine content of previously restricted foods in monoamine oxidase inhibitor diets. Journal of Clinical Psychopharmacology 1996;16(5):383-388.DaPrada et al. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. Journal of Neural Transmission 1988; [Supplement] 26:31-56.Fine MJ, Auble TE, Yealy DM, et al. Prediction Rule to Identify Low-Risk Patients with Community-Acquired Pneumonia. The New England Journal of Medicine. 1997;336 (4):243-250.. Gonzales RD, PC Schreckenberger, MB Graham, et al. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. The Lancet 2001;357:1179.. Herrero IA, NC Issa, Patel. Nosocomial spread of linezolid-resistant, vancomycin-resistant Enterococcus faecium. The New England Journal of Medicine 2002;346:867-869.. Tsiodras S, HS Gold, Sakoulas, et al. Linezolid resistance in clinical isolate of Staphylococcus aureus. The Lancet 2001;358:207-208.. Goldman DA, RA Weinstein, RP Wenzel, et al. Strategies to prevent and control the emergence and spread of antimicrobial-resistant microorganisms in hospitals. challenge to hospital leadership. The Journal of the American Medical Association 1996;275:234-240.. Centers for Disease Control and Prevention. Guideline for hand hygiene in health-care settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HIPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Morbidity and Mortality Weekly Report 2002;51 (RR-16).. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.. National Committee for Clinical Laboratory Standards. Twelfth Informational Supplement. Approved NCCLS Document M100-S12, Vol. 21, No. 1, NCCLS, Wayne, PA, January 2002.. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January 2000.. Walker SE et al. Tyramine content of previously restricted foods in monoamine oxidase inhibitor diets. Journal of Clinical Psychopharmacology 1996;16(5):383-388.. DaPrada et al. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. Journal of Neural Transmission 1988; [Supplement] 26:31-56.. Fine MJ, Auble TE, Yealy DM, et al. Prediction Rule to Identify Low-Risk Patients with Community-Acquired Pneumonia. The New England Journal of Medicine. 1997;336 (4):243-250.

SPL UNCLASSIFIED SECTION.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZYVOX formulations and other antibacterial drugs, ZYVOX should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

STORAGE AND HANDLING SECTION.

Storage of ZYVOX Formulations. Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Protect from light. Keep bottles tightly closed to protect from moisture. It is recommended that the infusion bags be kept in the overwrap until ready to use. Protect infusion bags from freezing.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects.. Pregnancy Category C. Linezolid was not teratogenic in mice, rats, or rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.06-fold (in rabbits) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen (see Non-teratogenic Effects). There are no adequate and well-controlled studies in pregnant women. ZYVOX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

WARNINGS SECTION.

WARNINGS. 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 pretreatment levels. 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. In adult and juvenile dogs and rats, myelosuppression, reduced extramedullary hematopoiesis in spleen and liver, and lymphoid depletion of thymus, lymph nodes, and spleen were observed (see ANIMAL PHARMACOLOGY).. Mortality Imbalance in an Investigational Study in Patients with Catheter-Related Bloodstream Infections, including those with catheter-site infections. An imbalance in mortality was seen in patients treated with linezolid relative to vancomycin/dicloxacillin/oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs. 58/363 (16.0%); odds ratio 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, but was not seen in patients with Gram-positive infections only.Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections.Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if concomitant Gram-negative pathogen is documented or suspected (see INDICATIONS AND USAGE).Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ZYVOX, 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 and 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.