LINEZOLID- linezolid_tablet, film coated

Linezolid is an antibacterial drug [( see Microbiology ( 12. 4 In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single linezolid 600 mg dose via a 1 hour IV infusion, a single linezolid 1200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1200 mg linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time. The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults max min max 1/2 400 mg tablet single dosedagger 8. 20 146 every 12 hours 11 3. 69 110 600 mg tablet single dose 12. 26 127 every 12 hours 21. 40 80 600 mg IV injection double dagger Single dose 12. 40 138 every 12 hours 15. 80 123 600 mg oral suspension Single dose 11 --- 0. 60 141 0 to infinity 0 to tau max min max max 1\2 Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean +/- Standard Deviation, n=16) Absorption max 0 to infinity Distribution Metabolism in vitro In vitro Excretion Specific Populations Geriatric Patients Pediatric Patients max ss [see Dosage and Administration ( 2 Table 9. Pharmacokinetic Parameters of Linezolid in Pediatrics and Adults Following a Single Intravenous Infusion of 10 mg/kg or 600 mg Linezolid (Mean: (%CV); [Min, Max Values]) max ss ½ Neonatal Patients dagger 12. 81 (24%) 108 (47%) 5. 6 (46%) 2 (52%) Full-term*** dagger 11. 78 (20%) 55 (47%) 3 (55%) 3. 8 (55%) Full-term*** dagger 12. 66 (29%) 34 (21%) 1. 1 (22%) Infant Patients dagger 11 (27%) 0. 79 (26%) 33 (26%) 1. 4 (32%) Pediatric Patients dagger 15. 69 (28%) 58 (54%) 2. 8 (53%) Adolescent Subjects and Patients double dagger 16. 61 (15%) 95 (44%) 4. 1 (53%) Adult Subjects section 12. 65 (16%) 91 (33%) 4. 7 (34%) * AUC = Single dose AUC 0 to infinity max ss 1/2 Gender Renal Impairment Table 10. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Patients with Varying Degrees of Renal Impairment After a Single 600 mg Oral Dose of Linezolid Healthy Subjects CL CR Moderate Renal Impairment 30 < CL CR CR LINEZOLID AUC 0-infinity 110 (22) 128 (53) 127 (66) t 1/2 6. 7) METABOLITE A AUC 0-48 7. 6) METABOLITE B 1 AUC 0-48 30. 5) 203 (92) t 1/2 6. 9) 1 Table 11. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Subjects with End-Stage Renal Disease (ESRD) After the Administration of 600 mg Linezolid Every 12 Hours for 14. 5 Days Parameter 1 LINEZOLID AUC 0-12 181 (52. 4) METABOLITE A AUC 0-12 153 (40. 6) t 1/2 15. 5) METABOLITE B 2 AUC 0-12 356 (99. 7) t 1/2 34. 1) 1 2 Hepatic Impairment 0 to infinity max 0 to 12 see Patient Counseling Information ( 17 see Warnings and Precautions ( 5. 6 7 Mechanism of Action in vitro Mechanisms of Resistance In vitro cfr Interaction with Other Antimicrobial Drugs In vitro in vitro [see Indications and Usage ( 1 Gram-positive bacteria Enterococcus faecium Staphylococcus aureus in vitro in vitro Gram-negative bacteria Susceptibility Test Methods in vitro Dilution techniques 1,2 Diffusion techniques 2,3 Table 12. Susceptibility Test Interpretive Criteria for Linezolid Pathogen Susceptibility Interpretive Criteria Minimal Inhibitory Concentrations (MIC in mcg/mL) Disk Diffusion (Zone Diameters in mm) S I R S I R Enterococcus <=2 4 >=8 >=23 21-22 <=20 Staphylococcus a <=4 -- >=8 >=21 -- <=20 Streptococcus pneumoniae b <=2 -- -- >=21 -- -- Streptococcus S pneumoniae b <=2 -- -- >=21 -- -- S=susceptible, I=intermediate, R=resistant a b A report of "Susceptible" indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate Quality Control 1,2,3 Table 13. Acceptable Quality Control Ranges for Linezolid Minimum Inhibitory Ranges (MIC in mcg/mL) Disk Diffusion Ranges Zone Diameters (mm) Enterococcus faecalis Staphylococcus aureus Staphylococcus aureus Streptococcus pneumoniae a a Streptococcus S.

Linezolid is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Linezolid is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [see Warnings and Precautions ( 5. 4 Linezolid is an oxazolidinone-class antibacterial indicated in adults for the treatment of the following infections caused by susceptible Gram-positive bacteria: Nosocomial pneumonia ( 1. 4 Nosocomial pneumonia [see Clinical Studies ( 14 Community-acquired pneumonia [see Clinical Studies ( 14 Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, Staphylococcus aureus Streptococcus pyogenes Streptococcus agalactiae. [see Clinical Studies ( 14 Uncomplicated skin and skin structure infections Staphylococcus aureus Streptococcus pyogenes [see Clinical Studies ( 14 Vancomycin-resistant Enterococcus faecium see Clinical Studies ( 14 To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid and other antibacterial drugs, linezolid should be used only to treat 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.

Enterococcus faecium The recommended dosage for linezolid for the treatment of infections is described in Table 1. Dosage Guidelines for Linezolid Infection* Pediatric Patients dagger Adults and Adolescent (12 Years and Older) Nosocomial pneumonia double dagger double dagger Community-acquired pneumonia, including concurrent bacteremia Complicated skin and skin structure infections Vancomycin-resistant Enterococcus faecium , 10 mg/kg intravenously or oral double dagger double dagger Uncomplicated skin and skin structure infections less than 5 yrs: 10 mg/kg oral double dagger double dagger Adults: 400 mg oral double dagger double dagger * Due to the designated pathogens [see Indications and Usage ( 1 dagger Neonates less than 7 days: [see Use in Specific Populations ( 8. 3 [see How Supplied/Storage and Handling ( 16.

Most common adverse reactions (>5% of adult patients treated with linezolid) include: diarrhea, vomiting, headache, nausea, and anemia. ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults: Table 2. Incidence (%) of Treatmenten dashEmergent Adverse Reactions Occurring in >1% of Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials ADVERSE REACTIONS All Other Indications Linezolid 400 mg by mouth every 12 hours (n=548) (n=537) (n=1498) Headache 8. 4 Diarrhea 8. 6 ADVERSE REACTIONS All Other Indications Linezolid 400 mg by mouth every 12 hours (n=548) Clarithromycin 250 mg by mouth every 12 hours (n=537) (n=1498) Vomiting 2 1. 3 Dizziness 2. 4 Taste alteration 1. 3 Vaginal moniliasis 1. 5 Oral moniliasis 0. 7 1 Abnormal liver function tests 0. 8 Fungal infection 1. 2 Tongue discoloration 1. 3 0 Localized abdominal pain 1. 8 Generalized abdominal pain 0. 2 1 * Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g Pediatric Patients: Table 3. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in > 1% of Pediatric Patients (and >1 Patient) in Either Treatment Group in Comparator-Controlled Clinical Trials ADVERSE REACTIONS * All Other Indications dagger Diarrhea 7. 1 Vomiting 2. 1 Headache 6. 9 0 Anemia 0 0 5. 1 Thrombocytopenia 0 0 4. 7 2 Nausea 3. 9 0 Generalized abdominal pain 2. 9 2 Localized abdominal pain 2. 5 1 Loose stools 1. 3 3 Eosinophilia 0. 9 1 Pruritus at non-application site 0. 4 2 Vertigo 1. 4 0 0 * Patients 5 through 11 years of age received linezolid 10 mg/kg by mouth every 12 hours or cefadroxil 15 mg/kg by mouth every 12 hours. Patients 12 years or older received linezolid 600 mg by mouth every 12 hours or cefadroxil 500 mg by mouth every 12 hours. Laboratory Abnormalities: [see Warning and Precautions (5. Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between linezolid and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 4, 5, 6, and 7. Percent of Adult Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid Laboratory Assay All Other Indications dagger Hemoglobin (g/dL) 0. 6 Platelet count (x10 3 3 0. 8 WBC (x 10 3 3 0. 3 Neutrophils (x10 3 3 0 0. 2 * <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. Percent of Adult Patients who Experienced at Least One Substantially Abnormal* Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid All Other Indications dagger AST (U/L) 1. 8 ALT (U/L) 1. 3 LDH (U/L) 0. 5 All Other Indications dagger Alkaline phosphatase (U/L) 0. 1 Lipase (U/L) 2. 2 Amylase (U/L) 0. 4 2 Total bilirubin(mg/dL) 0. 1 BUN (mg/dL) 0. 5 Creatinine (mg/dL) 0. 6 * >2 x Upper Limit of Normal (ULN) for values normal at baseline; Table 6. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Hematology Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid dagger double dagger Cefadroxil Hemoglobin (g/dL) 0 0 15. 4 Platelet count (x10 3 3 0 0. 4 WBC (x 10 3 3 0. 3 Neutrophils (x10 3 3 1. 3 * <75% (<50% for neutrophils) of Lower Limit of Normal (LLN) for values normal at baseline; Table 7. Percent of Pediatric Patients who Experienced at Least One Substantially Abnormal* Serum Chemistry Laboratory Value in Comparator-Controlled Clinical Trials with Linezolid dagger double dagger ALT (U/L) 0 0 10. 5 Lipase (U/L) 0. 2 --- --- Amylase (U/L) --- --- 0. 3 Total bilirubin --- --- 6. 2 Creatinine (mg/dL) 0. 4 1 * >2 x Upper Limit of Normal (ULN) for values normal at baseline; >2 x ULN and >2 (>1. 5 for The following adverse reactions have been identified during postapproval use of linezolid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 7 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 8 [see Warnings and Precautions ( 5.

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

Teratogenic Effects en dash Pregnancy Category C (see Non-teratogenic Effects). Non-teratogenic Effects 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 linezolid is administered to a nursing woman. The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years [see Indications and Usage ( 1 12. 3 14 nosocomial pneumonia Enterococcus faecium The safety and effectiveness of linezolid for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years [see Clinical Studies ( 14 uncomplicated skin and skin structure infections caused by Staphylococcus aureus Streptococcus pyogenes [see Dosage and Administration ( 2. 3 [see Clinical Pharmacology ( 12. 3 2 Of the 2046 patients treated with linezolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

OVERDOSAGE
In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3000 mg/kg/day and 2000 mg/kg/day, respectively.
NONCLINICAL TOXICOLOGY
Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro in vitro in vivo 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.
CLINICAL STUDIES
Nosocomial Pneumonia Table 14. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Nosocomial Pneumonia Pathogen Cured Linezolid n/N (%) Vancomycin n/N (%) Staphylococcus aureus 23/38 (61) 14/23 (61) Methicillin-resistant S. aureus 13/22 (59) 7/10 (70) Streptococcus pneumoniae 9/9 (100) 9/10 (90) Complicated Skin and Skin Structure Infections Adult patients with clinically documented complicated skin and skin structure infections were enrolled in a randomized, multi-center, double-blind, double-dummy trial comparing study medications administered intravenously followed by medications given orally for a total of 10 to 21 days of treatment. One group of patients received linezolid I. Injection 600 mg every 12 hours followed by linezolid tablets 600 mg every 12 hours; the other group received oxacillin 2 g every 6 hours intravenously followed by dicloxacillin 500 mg every 6 hours orally. Patients could receive concomitant aztreonam if clinically indicated. There were 400 linezolid-treated and 419 oxacillin-treated patients enrolled in the study. Two hundred forty-five (61%) linezolid-treated patients and 242 (58%) oxacillin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 90% in linezolid-treated patients and 85% in oxacillin-treated patients. A modified intent-to-treat (MITT) analysis of 316 linezolid-treated patients and 313 oxacillin-treated patients included subjects who met all criteria for study entry. The cure rates in the MITT analysis were 86% in linezolid-treated patients and 82% in oxacillin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 15. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Complicated Skin and Skin Structure Infections Pathogen Cured Linezolid n/N (%) Oxacillin/Dicloxacillin n/N (%) Staphylococcus aureus S. aureus Streptococcus agalactiae Streptococcus pyogenes A separate study provided additional experience with the use of linezolid in the treatment of methicillin-resistant Staphylococcus aureus One group of patients received linezolid I. Injection 600 mg every 12 hours followed by linezolid tablets 600 mg every 12 hours. The other group of patients received vancomycin 1 g every 12 hours intravenously. Both groups were treated for 7 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 Pathogen Cured Linezolid n/N (%) Comparator n/N (%) Staphylococcus aureus S. aureus Streptococcus agalactiae Vancomycin-Resistant Enterococcal Infections Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multi-center, double-blind trial comparing a high dose of linezolid (600 mg) with a low dose of linezolid (200 mg) given every 12 hours either intravenously (IV) or orally for 7 to 28 days. Patients could receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to high-dose linezolid and 66 to low-dose linezolid. The intent-to-treat (ITT) population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in the high-dose arm and 52 in the low-dose arm. Cure Rates at the Test-of-Cure Visit for ITT Adult Patients with Documented Vancomycin-Resistant Enterococcal Infections at Baseline Source of Infection Cured 12 hours n/N (%) *Includes sources of infection such as hepatic abscess, biliary sepsis, necrotic gall bladder, pericolonic abscess, pancreatitis, and catheter-related infection. Infections due to Gram-positive Bacteria Staphylococcus aureus Enterococcus faecium. Enterococcus faecium Table 18. Cure Rates at the Test-of-Cure Visit for Intent-to-Treat, Modified Intent-to-Treat, and Clinically Evaluable Pediatric Patients for the Overall Population by select Baseline Diagnosis Population ITT MITT* Clinical Evaluable Linezolid n/N (%) Vancomycin n/N (%) Linezolid n/N (%) Vancomycin n/N (%) Linezolid n/N (%) Vancomycin n/N (%) * Table 19. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Pediatric Patients with Infections due to Gram-positive Pathogens Enterococcus faecium S.
REFERENCES
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard en dash Twelfth Edition

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LINEZOLID- linezolid_tablet, film coated Product manual source documgent