OFLOXACIN

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of ofloxacin tablets, USP and other antibacterial drugs, ofloxacin tablets, USP 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. Ofloxacin tablets, USP are indicated for the treatment of adults with mild to moderate infections (unless otherwise indicated) caused by susceptible strains of the designated microorganisms in the infections listed below. Please see DOSAGE AND ADMINISTRATION for specific recommendations. Acute Bacterial Exacerbations of Chronic Bronchitis (ABECB) due to Haemophilus influenzae or Streptococcus pneumoniae . Because fluoroquinolones, including ofloxacin, have been associated with serious adverse reactions (see Warnings ), - and for some patients ABECB is self-limiting, reserve ofloxacin for treatment of ABECB in patients who have no alternative treatment options . Community-Acquired Pneumonia due to Haemophilus influenzae or Streptococcus pneumoniae . Uncomplicated Skin and Skin Structure Infections due to methicillin-susceptible Staphylococcus aureus, Streptococcus pyogenes, or Proteus mirabilis. Acute, Uncomplicated Urethral and Cervical Gonorrhea due to Neisseria gonorrhoeae (see WARNINGS ). Nongonococcal Urethritis and Cervicitis due to Chlamydia trachomatis (see WARNINGS ). Mixed Infections of the Urethra and Cervix due to Chlamydia trachomatis and Neisseria gonorrhoeae (see WARNINGS ). Acute Pelvic Inflammatory Disease (including severe infection) due to Chlamydia trachomatis and/or Neisseria gonorrhoeae (see WARNINGS ). NOTE: If anaerobic microorganisms are suspected of contributing to the infection, appropriate therapy for anaerobic pathogens should be administered. Uncomplicated Cystitis due to Citrobacter diversus, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa. Because fluoroquinolones, including ofloxacin, have been associated with serious adverse reactions (see WARNINGS ), and for some patients uncomplicated cystitis is self-limiting, reserve ofloxacin for treatment of uncomplicated cystitis in patients who have no alternative treatment options. Complicated Urinary Tract Infections due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Citrobacter diversus,* or Pseudomonas aeruginosa.* Prostatitis due to Escherichia coli. * = Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to ofloxacin, USP. Therapy with ofloxacin, USP may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued. As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ofloxacin, USP. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.

DOSAGE AND ADMINISTRATION The usual dose of ofloxacin tablets is 200 mg to 400 mg orally every 12 h as described in the following dosing chart. These recommendations apply to patients with normal renal function (i.e., creatinine clearance > 50 mL/min). For patients with altered renal function (i.e., creatinine clearance < 50 mL/min), see the Patients With Impaired Renal Function subsection. Infection† Unit Dose Frequency Duration Daily Dose Acute Bacterial Exacerbation of Chronic Bronchitis 400 mg q12h 10 days 800 mg Comm. Acquired Pneumonia 400 mg q12h 10 days 800 mg Uncomplicated Skin and Skin Structure Infections 400 mg q12h 10 days 800 mg Acute, Uncomplicated Urethral and Cervical Gonorrhea 400 mg single dose 1 day 400 mg Nongonococcal Cervicitis/Urethritis due to C. trachomatis 300 mg q12h 7 days 600 mg Mixed Infection of the Urethra and Cervix due to C. trachomatis and N. gonorrhoeae 300 mg q12h 7 days 600 mg Acute Pelvic Inflammatory Disease 400 mg q12h 10 to 14 days 800 mg Uncomplicated Cystitis due to E. coli or K. pneumoniae 200 mg q12h 3 days 400 mg Uncomplicated Cystitis due to Other Approved Pathogens 200 mg q12h 7 days 400 mg Complicated UTI’s 200 mg q12h 10 days 400 mg Prostatitis due to E. coli 300 mg q12h 6 weeks 600 mg † DUE TO THE DESIGNATED PATHOGENS (see INDICATIONS AND USAGE ). Antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent cations such as iron; or multivitamins containing zinc; or didanosine, chewable/buffered tablets or the pediatric powder for oral solution should not be taken within the two-hour period before or within the two-hour period after taking ofloxacin (see PRECAUTIONS ). Patients With Impaired Renal Function Dosage should be adjusted for patients with a creatinine clearance < 50 mL/min. After a normal initial dose, dosage should be adjusted as follows: Creatinine Clearance Maintenance Dose Frequency 20 to 50 mL/min the usual recommended unit dose q24h < 20 mL/min ½ the usual recommended unit dose q24h When only the serum creatinine is known, the following formula may be used to estimate creatinine clearance. Women: 0.85 x the value calculated for men. The serum creatinine should represent a steady-state of renal function. Patients With Cirrhosis: The excretion of ofloxacin may be reduced in patients with severe liver function disorders (e.g., cirrhosis with or without ascites). A maximum dose of 400 mg of ofloxacin per day should therefore not be exceeded. ofloxacin-fig3-formula

WARNINGS Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including ofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting ofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions (see Warnings ) Discontinue ofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones. Tendinitis and Tendon Rupture Fluoroquinolones, including ofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon and has been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur within hours or days of starting ofloxacin, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have been reported in patients taking fluoroquinolones who do not have the above risk factors. Discontinue ofloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture (see Adverse Reactions ). Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Peripheral Neuropathy Fluoroquinolones, including ofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including ofloxacin. Symptoms may occur soon after initiation of norfloxacin and may be irreversible in some patients (see WARNINGS ). Discontinue ofloxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including ofloxacin, in patients who have previously experienced peripheral neuropathy (see Adverse Reactions ). Central Nervous System Effects Psychiatric Adverse Reactions: Fluoroquinolones, including ofloxacin, have been associated with an increased risk of psychiatric adverse reactions toxic psychoses or hallucinations; agitation; delirium, confusion, disorientation, or disturbances in attention; nervousness or restlessness, memory impairment. If these reactions occur in…

CONTRAINDICATIONS Ofloxacin tablets are contraindicated in persons with a history of hypersensitivity associated with the use of ofloxacin or any member of the quinolone group of antimicrobial agents.

Drug Interactions Antacids, Sucralfate, Metal Cations, Multivitamins Quinolones form chelates with alkaline earth and transition metal cations. Administration of quinolones with antacids containing calcium, magnesium, or aluminum, with sucralfate, with divalent or trivalent cations such as iron, or with multivitamins containing zinc or with didanosine, chewable/buffered tablets or the pediatric powder for oral solution may substantially interfere with the absorption of quinolones resulting in systemic levels considerably lower than desired. These agents should not be taken within the two-hour period before or within the two-hour period after ofloxacin administration (see DOSAGE AND ADMINISTRATION ). Caffeine Interactions between ofloxacin and caffeine have not been detected. Cimetidine Cimetidine has demonstrated interference with the elimination of some quinolones. This interference has resulted in significant increases in half-life and AUC of some quinolones. The potential for interaction between ofloxacin and cimetidine has not been studied. Cyclosporine Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with some other quinolones. The potential for interaction between ofloxacin and cyclosporine has not been studied. Drugs Metabolized by Cytochrome P450 Enzymes Most quinolone antimicrobial drugs inhibit cytochrome P450 enzyme activity. This may result in a prolonged half-life for some drugs that are also metabolized by this system (e.g., cyclosporine, theophylline/methylxanthines, warfarin) when coadministered with quinolones. The extent of this inhibition varies among different quinolones (see other Drug Interactions ). Non Steroidal Anti-Inflammatory Drugs The concomitant administration of a non-steroidal anti-inflammatory drug with a quinolone, including ofloxacin, may increase the risk of CNS stimulation and convulsive seizures (see WARNINGS and PRECAUTIONS , General ). Probenecid The concomitant use of probenecid with certain other quinolones has been reported to affect renal tubular secretion. The effect of probenecid on the elimination of ofloxacin has not been studied. Theophylline Steady-state theophylline levels may increase when ofloxacin and theophylline are administered concurrently. As with other quinolones, concomitant administration of ofloxacin may prolong the half-life of theophylline, elevate serum theophylline levels, and increase the risk of theophylline-related adverse reactions. Theophylline levels should be closely monitored and theophylline dosage adjustments made, if appropriate, when ofloxacin is coadministered. Adverse reactions (including seizures) may occur with or without an elevation in the serum theophylline level (see WARNINGS and PRECAUTIONS , General ). Warfarin Some quinolones have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. Therefore, if a quinolone antimicrobial is administered concomitantly with warfarin or its derivatives, the prothrombin time or other suitable coagulation test should be closely monitored. Antidiabetic Agents (e.g., Insulin, Glyburide/Glibenclamide) Since disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concurrently with quinolones and an antidiabetic agent, careful monitoring of blood glucose is recommended when these agents are used concomitantly (see PRECAUTIONS , General and Information for Patients ).

Pregnancy Teratogenic Effects Pregnancy Category C Ofloxacin has not been shown to have any teratogenic effects at oral doses as high as 810 mg/kg/day (11 times the recommended maximum human dose based on mg/m 2 or 50 times based on mg/kg) and 160 mg/kg/day (4 times the recommended maximum human dose based on mg/m 2 or 10 times based on mg/kg) when administered to pregnant rats and rabbits, respectively. Additional studies in rats with oral doses up to 360 mg/kg/day (5 times the recommended maximum human dose based on mg/m 2 or 23 times based on mg/kg) demonstrated no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn. Doses equivalent to 50 and 10 times the recommended maximum human dose of ofloxacin (based on mg/kg) were fetotoxic (i.e., decreased fetal body weight and increased fetal mortality) in rats and rabbits, respectively. Minor skeletal variations were reported in rats receiving doses of 810 mg/kg/day, which is more than 10 times higher than the recommended maximum human dose based on mg/m 2 . There are, however, no adequate and well-controlled studies in pregnant women. Ofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see WARNINGS ).

Nursing Mothers In lactating females, a single oral 200 mg dose of ofloxacin resulted in concentrations of ofloxacin in milk that were similar to those found in plasma. Because of the potential for serious adverse reactions from ofloxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see WARNINGS and ADVERSE REACTIONS ).

ADVERSE REACTIONS The following is a compilation of the data for ofloxacin based on clinical experience with both the oral and intravenous formulations. The incidence of drug-related adverse reactions in patients during Phase 2 and 3 clinical trials was 11%. Among patients receiving multiple-dose therapy, 4% discontinued ofloxacin due to adverse experiences. In clinical trials, the following events were considered likely to be drug-related in patients receiving multiple doses of ofloxacin: nausea 3%, insomnia 3%, headache 1%, dizziness 1%, diarrhea 1%, vomiting 1%, rash 1%, pruritus 1%, external genital pruritus in women 1%, vaginitis 1%, dysgeusia 1%. In clinical trials, the most frequently reported adverse events, regardless of relationship to drug, were: nausea 10%, headache 9%, insomnia 7%, external genital pruritus in women 6%, dizziness 5%, vaginitis 5%, diarrhea 4%, vomiting 4%. In clinical trials, the following events, regardless of relationship to drug, occurred in 1 to 3% of patients: abdominal pain and cramps, chest pain, decreased appetite, dry mouth, dysgeusia, fatigue, flatulence, gastrointestinal distress, nervousness, pharyngitis, pruritus, fever, rash, sleep disorders, somnolence, trunk pain, vaginal discharge, visual disturbances, and constipation. Additional events, occurring in clinical trials at a rate of less than 1%, regardless of relationship to drug, were: Body as a Whole: asthenia, chills, malaise, extremity pain, pain, epistaxis Cardiovascular System: cardiac arrest, edema, hypertension, hypotension, palpitations, vasodilation Gastrointestinal System: dyspepsia Genital/Reproductive System: burning, irritation, pain and rash of the female genitalia; dysmenorrhea; menorrhagia; metrorrhagia Musculoskeletal System: arthralgia, myalgia Nervous System: seizures, anxiety, cognitive change, depression, dream abnormality, euphoria, hallucinations, paresthesia, syncope, vertigo, tremor, confusion Nutritional/Metabolic: thirst, weight loss Respiratory System: respiratory arrest, cough, rhinorrhea Skin/Hypersensitivity: angioedema, diaphoresis, urticaria, vasculitis Special Senses: decreased hearing acuity, tinnitus, photophobia Urinary System: dysuria, urinary frequency, urinary retention The following laboratory abnormalities appeared in ≥ 1% of patients receiving multiple doses of ofloxacin. It is not known whether these abnormalities were caused by the drug or the underlying conditions being treated. Hematopoietic: anemia, leukopenia, leukocytosis, neutropenia, neutrophilia, increased band forms, lymphocytopenia, eosinophilia, lymphocytosis, thrombocytopenia, thrombocytosis, elevated ESR Hepatic: elevated: alkaline phosphatase, AST (SGOT), ALT (SGPT) Serum Chemistry: hyperglycemia, hypoglycemia, elevated creatinine, elevated BUN Urinary: glucosuria, proteinuria, alkalinuria, hyposthenuria, hematuria, pyuria Postmarketing Adverse Events Additional adverse events, regardless of relationship to drug, reported from worldwide marketing experience with quinolones, including ofloxacin: Clinical Cardiovascular System: cerebral thrombosis, pulmonary edema, tachycardia, hypotension/shock, syncope, torsade de pointes. Endocrine/Metabolic: hyper- or hypoglycemia, especially in diabetic patients on insulin or oral hypoglycemic agents (see PRECAUTIONS , General and Drug Interactions ). Gastrointestinal System: hepatic dysfunction including: hepatic necrosis, jaundice (cholestatic or hepatocellular), hepatitis; intestinal perforation; hepatic failure (including fatal cases); pseudomembranous colitis (the onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment), GI hemorrhage; hiccough, painful oral mucosa, pyrosis (see WARNINGS ). Genital/Reproductive System: vaginal candidiasis Hematopoietic: anemia, including hemolytic and aplastic; hemorrhage, pancytopenia, agranulocytosis, leukopenia, reversible bone marrow depression, thrombocytopenia, thrombotic thrombocytopenic purpura, petechiae…