LEVOFLOXACIN- levofloxacin_tablet, film coated

Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology ( 12. The mean +/- SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following administration of the oral tablets, are summarized in Table 8. Table 8: Mean +/- SD Levofloxacin PK Parameters Regimen max (mcg/mL) max (h) AUC (mcgh/mL) CL/F 1 Vd/F 2 1/2 (h) CL R Single dose 3 3 4 Multiple dose 3 4 500 mg oral tablet single dose, effects of gender and age: 5 6 7 8 500 mg oral single dose tablet, patients with renal impairment: 1 2 3 4 5 6 7 8 Absorption Distribution In vitro Elimination Metabolism Excretion Specific Populations Geriatric Patients [see Use in Specific Populations ( 8. 5 Pediatric Patients 0 to 24 max [see Dosage and Administration ( 2. 2 Male and Female Subjects Racial or Ethnic Groups Patients with Renal Impairment [see Dosage and Administration ( 2. Patients with Hepatic Impairment [see Use in Specific Populations ( 8. Patients with Bacterial Infection Drug Interaction Studies [see Drug Interactions ( 7 Mechanism of Action Resistance in vitro -9 -10 Antimicrobial Activity in vitro in vitro Indications and Usage ( 1 Aerobic bacteria Enterococcus faecalis 1 Gram-Negative Bacteria Enterobacter cloacae 1 Streptococcus pneumoniae isolates are isolates resistant to two or more of the following antibiotics: penicillin (MIC >=2 mcg/mL), 2 nd Escherichia coli Haemophilus influenzae Other microorganisms Chlamydophila pneumoniae in vitro but their clinical significance is unknown in vitro Aerobic bacteria Staphylococcus haemolyticus streptococci Gram-Negative Bacteria Acinetobacter baumannii Anaerobic bacteria Clostridium perfringens Susceptibility Tests.

Levofloxacin is a fluoroquinolone antibacterial indicated in adults (18 years of age and older) with infections caused by designated, susceptible bacteria and in pediatric patients where indicated ( 1 12. 15 Levofloxacin tablets are indicated in adult patients for the treatment of nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae. Pseudomonas aeruginosa [see Clinical Studies ( 14. 1) Levofloxacin tablets are indicated in adult patients for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae [see Dosage and Administration ( 2. nd Levofloxacin tablets are indicated in adult patients for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae [see Dosage and Administration ( 2. Levofloxacin tablets are indicated in adult patients for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, Proteus mirabilis [see Clinical Studies ( 14. Levofloxacin tablets are indicated in adult patients for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus, Streptococcus pyogenes. Levofloxacin tablets are indicated in adult patients for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, Staphylococcus epidermidis [see Clinical Studies ( 14. 6 Levofloxacin tablets are indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis [see Dosage and Administration ( 2. [see Clinical Studies ( 14. 9 Levofloxacin tablets are indicated for treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis Y. pestis [see Dosage and Administration ( 2. 2 [see Clinical Studies ( 14. Levofloxacin tablets are indicated in adult patients for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis [see Clinical Studies ( 14. 7 Levofloxacin tablets are indicated in adult patients for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa [see Clinical Studies (14. Levofloxacin tablets are indicated in adult patients for the treatment of acute pyelonephritis caused by Escherichia coli, [see Clinical Studies (14. 8 Levofloxacin tablets are indicated in adult patients for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus. [see Warnings and Precautions ( 5. 15 Levofloxacin tablets are indicated in adult patients for the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB) due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis. 15 Levofloxacin tablets are indicated in adult patients for the treatment of acute bacterial sinusitis (ABS) due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis [see Clinical Studies ( 14. 15 To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin tablets and other antibacterial drugs, levofloxacin tablets 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. Culture and susceptibility testing [see Microbiology ( 12. Pseudomonas aeruginosa.

Administer levofloxacin tablets to pediatric patients weighing 30 kg and greater only ( 2. 2 Dosage in Adult and Pediatric Patients with Creatinine Clearance greater than or equal to 50 mL/minute (2. 2) Type of Infection Dose Every 24 hours Duration (days) Adjust dose for creatinine clearance less than 50 mL/minute ( 2. 3 The usual dose of levofloxacin tablets is 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1. These recommendations apply to patients with creatinine clearance >= 50 mL/minute. For patients with creatinine clearance less than 50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration ( 2. 3 Table 1: Dosage of Levofloxacin Tablets in Adult Patients with Creatinine Clearance greater than or equal to 50 mL/minute) Type of Infection* Dosed Every 24 hours Duration (days) dagger double dagger double dagger double dagger section section section Þ,ß Þ,ß ß ß à paragraph # # # * [see Indications and Usage ( 1)]. dagger double dagger Staphylococcus aureus, Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae [see Indications and Usage ( 1. 2 section Streptococcus pneumoniae Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and Usage ( 1. 3 paragraph Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis E. coli, # Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; E. anthracis [see Clinical Studies ( 14. 9 ß [see Warnings and Precautions ( 5. 12 Use in Specific Populations ( 8. 9 à Yersinia pestis The dosage of levofloxacin tablets for inhalational anthrax (post-exposure) and plague in pediatric patients who weigh 30 kg or greater is described below in Table 2. Levofloxacin tablets cannot be administered to patients who weigh less than 30 kg because of the limitations of the available strength. Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg. Table 2 Levofloxacin Tablets Dosage in Pediatric Patients Weighing 30 kg or greater with Inhalational Anthrax (Post-Exposure) and Plague* Type of Infection * Dose Frequency Duration dagger Inhalational Anthrax (post-exposure) double dagger,section Pediatric patients weighing 50 kg or greater 500 mg every 24 hours 60 days section Pediatric patients weighing 30 kg to less than 50 kg 250 mg every 12 hours 60 days section Plague paragraph Pediatric patients weighing 50 kg or greater 500 mg every 24 hours 10 to 14 days Pediatric patients weighing 30 kg to less than 50 kg 250 mg every 12 hours 10 to 14 days * Bacillus anthracis [see Indications and Usage ( 1. 13 Yersinia pestis [see Indications and Usage ( 1. 14 dagger double dagger B. section [see Warnings and Precautions ( 5. 4 and Clinical Studies ( 14. 9 Yersinia pestis. Administer levofloxacin tablets with caution in patients with renal impairment. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced in these patients. [see Use in Specific Populations ( 8. 6 Table 3: Dosage Adjustment in Adult Patients with Renal Impairment (Creatinine Clearance less than 50 mL/minute) Creatinine Clearance greater than or equal to Creatinine Clearance 20 to 49 mL/minute Creatinine Clearance 10 to 19 mL/minute Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD) 750 mg every 750 mg every 48 hours 750 mg initial dose, then 500 mg every 48 hours 750 mg initial dose, 500 mg every 500 mg initial dose, then 250 mg every 24 hours 500 mg initial dose, then 250 mg every 48 hours 500 mg initial dose, then 250 mg every 48 hours 250 mg every No dosage adjustment required 250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required No information Levofloxacin tablets should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions ( 7. Levofloxacin tablets can be administered without regard to food. Adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions (6. 1 and Patient Counseling Information ( 17).

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS,TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS
Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3)] o Central nervous system effects [see Warnings and Precautions (5. 4)] Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions [see Warnings and Precautions (5. 1)] [see Warnings and Precautions ( 5. Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions (5. 15 [see Indications and Usage (1. 12)] o Acute bacterial exacerbation of chronic bronchitis [see Indications and Usage ( 1. 13)] o Acute bacterial sinusitis [see Indications and Usage ( 1. 14)] WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS See full prescribing information for complete boxed warning Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together ( 5. 1 ), including: (5. 2) o Peripheral neuropathy (5. 3) o Central nervous system effects (5. 4) Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions (5. 1 ) [see Warnings and Precautions ( 5. 15 ), reserve levofloxacin for use in patients who have no alternative treatment options for the following indications: (1. 13) o Acute bacterial sinusitis (1.
ADVERSE REACTIONS
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 [see Warnings and Precautions ( 5. 5) [see Warnings and Precautions ( 5. 6) [see Warnings and Precautions ( 5. 7 [see Warnings and Precautions ( 5. 8) [see Warnings and Precautions ( 5. 9 Clostridium difficile- [see Warnings and Precautions ( 5. 10) [see Warnings and Precautions ( 5. 11 [see Warnings and Precautions ( 5. 12 [see Warnings and Precautions ( 5. 13 [see Warnings and Precautions ( 5. 14) [see Warnings and Precautions ( 5. 15) [see Dosage and Administration ( 2. 5 The most common reactions (>=3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness ( 6. 2 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. [see Indications and Usage (1) Table 4: Common (>=1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin # System/Organ Class Adverse Reaction % (N=7,537) Infections and Infestations Psychiatric Disorders * [see Warnings and Precautions (5. 4)] Nervous System Disorders [see Warnings and Precautions (5. 4)] Respiratory, Thoracic and Mediastinal Disorders [see Warnings and Precautions (5. 7)] Gastrointestinal Disorders Skin and Subcutaneous Tissue Disorders [see Warnings and Precautions (5. 7)] Reproductive System and Breast Disorders dagger General Disorders and Administration Site Conditions * dagger # Table 5: Less Common (0. 1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7,537) System/Organ Class Adverse Reaction Infections and Infestations Blood and Lymphatic System Disorders [see Warnings and Precautions (5. 6)] Immune System Disorders [see Warnings and Precautions (5. 7)] Metabolism and Nutrition Disorders [see Warnings and Precautions (5. 13)] Psychiatric Disorders * [see Warnings and Precautions (5. 4)] * * Nervous System Disorders [see Warnings and Precautions (5. 4)] [see Warnings and Precautions (5. 3)] * Respiratory, Thoracic and Mediastinal Disorders Cardiac Disorders Vascular Disorders Gastrointestinal Disorders C. difficile [see Warnings and Precautions (5. 10)] Hepatobiliary Disorders Skin and Subcutaneous Tissue Disorders [see Warnings and Precautions (5. 7)] Musculoskeletal and Connective Tissue Disorders [see Warnings and Precautions (5. 2)] Renal and Urinary Disorders [see Warnings and Precautions (5. 6)] * Table 6 lists adverse reactions that have been identified during post-approval use of levofloxacin. 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. Table 6: Postmarketing Reports Of Adverse Drug Reactions System/Organ Class Adverse Reaction Blood and Lymphatic System Disorders [see Warnings and Precautions ( 5. 6 Immune System Disorders [see Warnings and Precautions ( 5. 7 Psychiatric Disorders [see Warnings and Precautions ( 5. 4 Nervous System Disorders [see Warnings and Precautions (5. 5 [see Warnings and Precautions ( 5. 4 Eye Disorders Ear and Labyrinth Disorders Cardiac Disorders [see Warnings and Precautions ( 5. 11 Vascular Disorders Respiratory, Thoracic and Mediastinal Disorders [see Warnings and Precautions ( 5. 6 Hepatobiliary Disorders [see Warnings and Precautions ( 5. 8 )] Skin and Subcutaneous Tissue Disorders [see Warnings and Precautions (5. 6)] [see Warnings and Precautions (5. 14)] Musculoskeletal and Connective Tissue Disorders [see Warnings and Precautions ( 5. 2 Renal and Urinary Disorders [see Warnings and Precautions ( 5. 6 General Disorders and Administration Site Conditions Investigations.

Levofloxacin tablets are contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials [see Warnings and Precautions ( 5. 3 Known hypersensitivity to levofloxacin or other quinolones ( 4 5.

Geriatrics: 5. 5 17 Pediatrics: 5. 10 Lactation: Risk Summary (see Data). Data Animal Data Risk Summary (see Data) [see Use in Specific Populations (8. 4) Clinical Pharmacology (12. 3) [see Dosage and Administration (2. 2) Pediatric Use (8. 4) Clinical Studies (14. 2) Data Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions ( 5. 2 Inhalational Anthrax (Post-Exposure) [see Indications and Usage (1. 7), Dosage and Administration ( 2. 2 ) and Clinical Studies ( 14. Plague Yersinia pestis (Y. pestis) [see Indications and Usage ( 1. 10 Pharmacokinetics following intravenous administration [see Clinical Pharmacology ( 12. 9) Dosage in Pediatric Patients with Inhalational Anthrax or Plague see Dosage and Administration ( 2. 2 Adverse Reactions [see Dosage and Administration ( 2. [see Dosage and Administration ( 2. 2 Table 7: Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial Follow-up Period Levofloxacin N = 1,340 Non-Fluoroquinolone * N = 893 p-value dagger 60 days 28 (2. 038 1 year double dagger 46 (3. 025 * dagger double dagger adverse reactions reported in pediatric patients in clinical trials, adverse reactions reported in adults during clinical trials or post-marketing experience [see Adverse Reactions ( 6)] Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as levofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing levofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning; Warnings and Precautions ( 5. 3) [see Warnings and Precautions ( 5. 8 [see Warnings and Precautions ( 5. 9 [see Warnings and Precautions ( 5. 11 [see Clinical Pharmacology ( 12. Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with renal impairment (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of levofloxacin are not required following hemodialysis or CAPD [see Dosage and Administration ( 2. 3 Pharmacokinetic studies in patients with hepatic impairment have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.

Interacting Drug Interaction 2. 3 While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of levofloxacin tablets with antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. Tablets with antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine may substantially interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired. These agents should be taken at least two hours before or two hours after oral levofloxacin administration. No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for R- and S- warfarin was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed. However, there have been reports during the postmarketing experience in patients that levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions ( 6. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered [see Warnings and Precautions ( 5. 2 17) [see Warnings and Precautions ( 5. 4 No significant effect of levofloxacin on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed. However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when levofloxacin is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions ( 5. No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in a clinical study involving healthy volunteers. However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones. Levofloxacin C max e max 1/2 No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in a clinical study involving healthy volunteers. Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin. Therefore, no dosage adjustment for levofloxacin or digoxin is required when administered concomitantly. No significant effect of probenecid or cimetidine on the C max 1/2 R Some fluoroquinolones, including levofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.

OVERDOSAGE
In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.
NONCLINICAL TOXICOLOGY
In a lifetime bioassay in rats, levofloxacin exhibited no carcinogenic potential following daily dietary administration for 2 years; the highest dose (100 mg/kg/day) was 1. 4 times the Maximum Recommended Human Dose (MRHD) (750 mg) after normalization for total body surface area. Levofloxacin did not shorten the time to tumor development of UV-induced skin tumors in hairless albino (Skh-1) mice at any levofloxacin dose level and was therefore not photo-carcinogenic under conditions of this study. Dermal levofloxacin concentrations in the hairless mice ranged from 25 to 42 mcg/g at the highest levofloxacin dose level (300 mg/kg/day) used in the photo-carcinogenicity study. By comparison, dermal levofloxacin concentrations in human subjects receiving 750 mg of levofloxacin averaged approximately 11. 8 mcg/g at C max (S. typhimurium E. coli) in vitro Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions (5. 12)] In vitro in vivo.
CLINICAL STUDIES
Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for a total of 7 to 15 days to intravenous imipenem/cilastatin (500 to 1000 mg every 6 to 8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7 to 15 days. Levofloxacin-treated patients received an average of 7 days of intravenous therapy (range: 1 to 16 days); comparator-treated patients received an average of 8 days of intravenous therapy (range: 1 to 19 days). Pseudomonas aeruginosa S. aureus Table 9: Clinical Success Rates and Bacteriological Eradication Rates (Nosocomial Pneumonia) Pathogen N Levofloxacin No. (%) of Patients Microbiologic/ Clinical Outcomes N Imipenem/Cilastatin No. (%) of Patients Microbiologic/ Clinical Outcomes * P. aeruginosa dagger S. marcescens E. pneumoniae double dagger H. influenzae S. pneumoniae * S. aureus dagger double dagger Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days. Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%). The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydophila pneumoniae Mycoplasma pneumoniae Legionella pneumophila Table 10: Bacteriological Eradication Rates Across 2 Community Acquired Pneumonia Clinical Studies Pathogen No. Pathogens Bacteriological Eradication Rate (%) H. pneumoniae S. catarrhalis H. parainfluenzae K. pneumoniae Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae Streptococcus pneumoniae nd Table 11: Clinical and Bacterial Success Rates for Levofloxacin-Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy) Screening Susceptibility Clinical Success Bacteriological Success * n/N dagger % n/N double dagger % Penicillin-resistant 2 nd Cephalosporin resistant Macrolide-resistant Trimethoprim/Sulfamethoxazole resistant Tetracycline-resistant * dagger double dagger Table 12: Clinical Success and Bacteriologic Eradication Rates for Resistant Streptococcus pneumoniae Type of Resistance Clinical Success Bacteriologic Eradication To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg, IV or orally, every day for five days or levofloxacin 500 mg IV or orally, every day for 10 days. Table 13: Bacteriological Eradication Rates (Community-Acquired Pneumonia) S. pneumoniae 19/20 (95%) Haemophilus influenzae 12/12 (100%) Haemophilus parainfluenzae 10/10 (100%) Mycoplasma pneumoniae 26/27 (96%) Chlamydophila pneumoniae 13/15 (87%) Levofloxacin is approved for the treatment of acute bacterial sinusitis (ABS) using either 750 mg by mouth x 5 days or 500 mg by mouth once daily x 10 to 14 days. To evaluate the safety and efficacy of a high dose short course of levofloxacin, 780 outpatient adults with clinically and radiologically determined acute bacterial sinusitis were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg by mouth once daily for five days to levofloxacin 500 mg by mouth once daily for 10 days. Table 14: Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis) Pathogen Levofloxacin 750 mg x 5 days Levofloxacin 500 mg x 10 days Streptococcus pneumoniae * 25/27 (92. 6%) 26/27 (96. 3%) Haemophilus influenzae * 19/21 (90. 5%) 25/27 (92. 6%) Moraxella catarrhalis * 10/11 (90. 9%) 13/13 (100%) * Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for complicated skin and skin structure infections. The patients were randomized to receive either levofloxacin 750 mg once daily (IV followed by oral), or an approved comparator for a median of 10 +/- 4. As is expected in complicated skin and skin structure infections, surgical procedures were performed in the levofloxacin and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the levofloxacin-treated patients and 44% of the comparator-treated patients, either shortly before or during antibiotic treatment and formed an integral part of therapy for this indication. Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB 3 Table 15: Bacteriological Eradication Rates (Chronic Bacterial Prostatitis) Levofloxacin (N=136) Ciprofloxacin (N=125) Pathogen N Eradication N Eradication E. coli 15 14 (93. 3%) 11 9 (81. faecalis 54 39 (72. 2%) 44 33 (75. epidermidis * 11 9 (81. 8%) 14 11 (78. epidermidis To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 1,109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from November 2004 to April 2006 comparing levofloxacin 750 mg IV or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10 days (563 patients). Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded. Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-therapy visit in patients with a pathogen identified at baseline. The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of levofloxacin and 5 to 9 days after the last dose of active ciprofloxacin. Table 16: Bacteriological Eradication at Test-of-Cure Levofloxacin Ciprofloxacin Overall Difference [95% CI] n/N % n/N % Levofloxacin- mITT Population * Overall (cUTI or AP) 252/333 75. 7 239/318 75. 1) cUTI 168/230 73. 0 157/213 73. 7 AP 84/103 81. 6 82/105 78. 1 Microbiologically Evaluable Population dagger Overall (cUTI or AP) 228/265 86 215/241 89. 5] cUTI 154/185 83. 2 144/165 87. 3 AP 74/80 92. 4 * 5 dagger 5 Table 17: Bacteriological Eradication Rates for Individual Pathogens Recovered From Patients Randomized to Levofloxacin 750 mg QD for 5 Days Treatment Pathogen Bacteriological Eradication Rate (n/N) % Escherichia coli * 155/172 90 Klebsiella pneumoniae 20/23 87 Proteus mirabilis 12/12 100 * E. coli To evaluate the safety and efficacy of the 250 mg dose, 10 day regimen of levofloxacin, 567 patients with uncomplicated UTI, mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from June 1993 to January 1995 comparing levofloxacin 250 mg orally once daily for 10 days (285 patients) with ciprofloxacin 500 mg orally twice daily for 10 days (282 patients). Patients with a resistant pathogen, recurrent UTI, women over age 55 years, and with an indwelling catheter were initially excluded, prior to protocol amendment which took place after 30% of enrollment. Microbiological efficacy was measured by bacteriologic eradication of the baseline organism(s) at 1 to 12 days post-therapy in patients with a pathogen identified at baseline. Table 18: Bacteriological Eradication Overall (cUTI or AP) at Test-Of-Cure* Levofloxacin Ciprofloxacin n/N % n/N % mITT Population dagger 174/209 83. 3 184/219 84. 0 Microbiologically Evaluable Population double dagger 164/177 92. 7 159/171 93. 0 * dagger double dagger The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage ( 1. 2 0 to 24 [see Clinical Pharmacology ( 12. 3) [see Dosage and Administration (2. 2 [see Warnings and Precautions (5. 4 50 6 50 B. anthracis max 0 to 24 Efficacy studies of levofloxacin could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. [see Indications and Usage ( 1. 0 to 24 [see Clinical Pharmacology ( 12. 3 [see Dosage and Administration ( 2. 50 50 Yersinia pestis Y. pestis 0 to 24 Y.
SPL MEDGUIDE SECTION
Levofloxacin What is the most important information I should know about levofloxacin tablets? you should stop taking levofloxacin tablets immediately and get medical help right away. 1.Tendon rupture or swelling of the tendon (tendinitis). Tendon problems can happen in people of all ages who take levofloxacin tablets. Some tendon problems include: 2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). 3. Central Nervous System (CNS) effects. 4. Worsening of myasthenia gravis (a problem that causes muscle weakness). What are levofloxacin tablets? Who should not take levofloxacin tablets? Do not take levofloxacin tablets Before you take levofloxacin tablets, tell your healthcare provider about all of your medical conditions, including if you: Tell your healthcare provider about all the medicines you take, registered registered registered registered registered registered registered registered How should I take levofloxacin tablets? 8 hours or more less than 8 hours “What is the most important information I should know about levofloxacin tablets?”. “What is the most important information I should know about levofloxacin tablets?”. “What is the most important information I should know about levofloxacin tablets?”. “What are the possible side effects of levofloxacin tablets?”. What should I avoid while taking levofloxacin tablets? Do not What are the possible side effects of levofloxacin tablets? Levofloxacin tablets may cause serious side effects, including: “What is the most important information I should know about levofloxacin tablets?” Serious allergic reactions. Liver damage (hepatotoxicity): Aortic aneurysm and dissection: Intestine infection ( Clostridium difficile- Serious heart rhythm changes (QT prolongation and torsades de pointes). Joint Problems. Changes in blood sugar Sensitivity to sunlight (photosensitivity). “What should I avoid while taking levofloxacin tablets?” How should I store levofloxacin tablets? General information about the safe and effective use of levofloxacin tablets. What are the ingredients in levofloxacin tablets? Active ingredient: Inactive ingredients: This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 07/2024 Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

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LEVOFLOXACIN- levofloxacin_tablet, film coated Product manual source documgent