Floxin Tablets 300mg Product Monograph

INDICATIONS AND CLINICAL USE

FLOXIN (ofloxacin) Tablets are indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms:

Lower Respiratory Tract Infections:

Pneumonia and acute exacerbation of chronic bronchitis due to Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis.

Prostatitis: due to Escherichia coli.

Sexually Transmitted Diseases:

Acute uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Urethritis/cervicitis due to

Chlamydia trachomatis, or mixed infections due to Neisseria gonorrhoeae and Chlamydia trachomatis.

Note: FLOXIN Tablets are not effective in the treatment of syphilis. All patients with gonorrhea should have an initial serologic test for syphilis and a follow-up serologic test after three months (see WARNINGS).

Acute pelvic inflammatory disease of mild to moderate severity appropriate for outpatient management when due to

Neisseria gonorrhoeae and/or Chlamydia trachomatis.

Note: Empiric therapy for pelvic inflammatory disease must provide broad spectrum coverage of likely pathogens such as N. gonorrhoeae, C. trachomatis, anaerobes, Gardnerella vaginalis, Haemophilus influenzae, enteric gram-negative rods and Streptococcus agalactae. FLOXIN Tablets have demonstrated clinical effectiveness only against N. gonorrhoeae and C. trachomatis; therefore, consideration should be given to inclusion of additional agents if FLOXIN Tablets are used empirically for the treatment of pelvic inflammatory infection.

Note: Clinical trials with FLOXIN Tablet therapy have not provided information regarding intermediate and long-term outcomes.

Skin and Skin Structure Infections:

Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes.

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. Therapy with FLOXIN Tablets may be initiated before results of these tests are known; once the results of bacteriological testing become known, therapy should be adjusted if required.

As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with FLOXIN Tablets. 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.

If anaerobic organisms are suspected of or known to be contributing to the infection, appropriate therapy for anaerobic pathogens should be considered.

CONTRAINDICATIONS

FLOXIN (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 antibacterial agents. Ofloxacin is also contraindicated in persons with a history of tendinitis or tendon rupture associated with the use of any member of the quinolone group of antimicrobial agents.

WARNINGS

THE SAFETY AND EFFICACY OF FLOXIN (OFLOXACIN) TABLETS IN CHILDREN, ADOLESCENTS

(UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN

ESTABLISHED. (SEE PRECAUTIONS; USE IN CHILDREN, USE IN PREGNANCY, AND NURSING

MOTHERS.)

The oral administration of FLOXIN (ofloxacin) Tablets has produced lesions in weight-bearing articular cartilage and lameness in several species of immature animals (see TOXICOLOGY: REPRODUCTION AND TERATOLOGY,

Other Studies). Consequently, FLOXIN Tablets should not be used in pre-pubertal patients. Syphilis:

Ofloxacin is not effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with ofloxacin should have a follow-up serologic test for syphilis after three months and, if positive, treatment with an appropriate antimicrobial should be instituted.

Hypersensitivity Reactions:

Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions have been reported in patients receiving therapy with quinolones, including ofloxacin. These reactions often occur following the first dose. Some reactions were accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling, etc.), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria/hives, itching and other serious skin reactions. A few patients had a history of hypersensitivity reactions. The drug should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management as clinically indicated. (See PRECAUTIONS and ADVERSE

REACTIONS.)

Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology have been reported in patients receiving therapy with quinolones including ofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome, etc.); vasculitis, arthralgia, myalgia, serum sickness; allergic pneumonitis; interstitial nephritis, acute renal insufficiency/failure; hepatitis, jaundice, acute hepatic necrosis/failure; anemia including hemolytic and aplastic, thrombocytopenia including thrombotic thrombocytopenic purpura, leukopenia, agranulocytosis, pancytopenia, and/or other hematologic abnormalities. The administration of ofloxacin should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity and supportive measures instituted. (See PRECAUTIONS and ADVERSE REACTIONS.) CNS Effects:

Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ofloxacin. Quinolones, including ofloxacin, may also cause central nervous system stimulation which may lead to: tremors, restlessness/agitation, nervousness/anxiety, lightheadedness, confusion, hallucinations, paranoia and depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving ofloxacin, the drug should be discontinued and appropriate measures instituted. Insomnia may be more common with ofloxacin than some other products in the quinolone class. As with all quinolones, ofloxacin should be used with caution in patients with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy, etc.) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction, etc.). (See PRECAUTIONS and ADVERSE REACTIONS.)

Peripheral Neuropathy:

Rare 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 quinolones, including ofloxacin.

Ofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation in order to prevent the development of an irreversible condition.

Gastrointestinal Effects:

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ofloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis". After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile. (See ADVERSE REACTIONS.)

Musculoskeletal Effects:

Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including ofloxacin. Post-marketing surveillance reports indicate that the risk may be increased in patients receiving concomitant corticosteroids, especially the elderly (see

PRECAUTIONS). Ofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. Tendon rupture can occur during or after therapy with quinolones, including ofloxacin (see

CONTRAINDICATIONS).

PRECAUTIONS

General:

Prescribing FLOXIN (ofloxacin) Tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Periodic assessment of organ system functions including renal, hepatic, and hematopoietic is advisable during prolonged therapy. (See WARNINGS and ADVERSE REACTIONS.)

Adequate hydration of patients receiving ofloxacin should be maintained to prevent the formation of a highly concentrated urine.

Renal/Hepatic:

Administer ofloxacin with caution in the presence of renal or hepatic insufficiency/impairment. In patients with known or suspected renal or hepatic insufficiency/impairment, careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of ofloxacin may be reduced. Alteration of the dosage regimen is necessary for patients with impairment of renal function (creatinine clearance # 50 mL/min). (See

PHARMACOLOGY, HUMAN PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Phototoxicity Reactions:

Moderate to severe phototoxicity reactions have been observed in patients exposed to direct sunlight while receiving some drugs in this class including ofloxacin. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity (e.g., a skin eruption, etc.) occurs.

Use in Pregnancy:

Doses equivalent to 50 and 10 times the maximum therapeutic 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 maximum intended human dose (based on mg/m²).

Safety and efficacy have not been established in pregnant women. Ofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. (See WARNINGS.)

Nursing Mothers:

In lactating females, a single 200 mg oral dose resulted in concentrations of ofloxacin in milk which 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.)

Use in Children:

Safety and effectiveness in children and adolescents below the age of 18 years have not been established. Ofloxacin causes arthropathy (arthrosis) and osteochondrosis in juvenile animals of several species. (See WARNINGS.)

Geriatric Use:

In phase 2/3 clinical trials with ofloxacin, 688 patients (14.2%) were $ 65 years of age. Of these, 436 patients (9.0%)

were between the ages of 65 and 74 and 252 patients (5.2%) were 75 years or older. There was no apparent difference in the frequency or severity of adverse reactions in elderly adults compared with younger adults. The pharmacokinetic properties of ofloxacin in elderly subjects are similar to those in younger subjects. Drug absorption appears to be unaffected by age. Dosage adjustment is necessary for elderly patients with impaired renal function (creatinine clearance rate # 50 mL/min) due to reduced clearance of ofloxacin. In comparative studies, the frequency of most drug-related nervous system events in patients $ 65 years of age were comparable for ofloxacin and control drugs. The only differences identified were an increase in reports of insomnia (3.9% vs 1.5%) and headache (4.7% vs 1.8%) with ofloxacin. It is important to note that these geriatric safety data are extracted from 44 comparative studies where the adverse reaction information from 20 different controls (other antibiotics or placebo) were pooled for comparison with ofloxacin. The clinical significance of such a comparison is not clear. (See CLINICAL PHARMACOLOGY and

DOSAGE AND ADMINISTRATION.)

Elderly patients may be more sensitive to drug-associated effects on the QT interval. Therefore, precaution should be taken when using ofloxacin with concomitant drugs that can result in prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia). (See PRECAUTIONS, QT Interval Prolongation/Torsades de Pointes.)

Patients with Special Diseases and Conditions:

CNS Disorders:

As with other quinolones, ofloxacin should be used with caution in any patient with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy, etc.) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction, etc.). (See WARNINGS and PRECAUTIONS, Drug Interactions.)

Disturbances of Blood Glucose:

A possible interaction between oral hypoglycemic drugs (e.g., glyburide/glibenclamide) or with insulin and fluoroquinolone antimicrobial agents, including ofloxacin, have been reported resulting in a potentiation of the hypoglycemic action of these drugs. The mechanism for this interaction is not known. In these patients careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with ofloxacin, discontinue ofloxacin immediately and initiate appropriate therapy. (See Drug Interactions and ADVERSE

REACTIONS.)

QT Interval Prolongation/Torsades de Pointes:

QT interval prolongation and episodes of torsades de pointes have been reported in patients receiving quinolones, including very rare reports involving ofloxacin. This drug should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine, procainamide), or class III (amiodarone, sotalol) antiarrhythmic 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 any product containing any of these components (e.g. Videx® [didanosine]) may substantially interfere with the absorption of oral 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 oral ofloxacin 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 following 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, etc.) when co-administered with quinolones. The extent of this inhibition varies among different quinolones. (See other drug interactions.)

Nonsteroidal anti-inflammatory drugs: The concomitant administration of a nonsteroidal anti-inflammatory drug with a quinolone, including ofloxacin, may increase the risk of CNS stimulation and convulsive seizures. (See WARNINGS.)

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 given 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 and theophylline are co-administered. Adverse reactions (including seizures, etc.) 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 antibiotic is administered concomitantly with warfarin or its derivatives, the prothrombin time or other suitable coagulation test should be closely monitored and the dose of warfarin modified as appropriate.

Antidiabetic Agents (e.g. insulin, glyburide/glibenclamide, etc.): Since disturbances of blood glucose including hyperglycemia and hypoglycemia have been reported in patients treated concurrently with quinolones, including ofloxacin, and an antidiabetic agent, careful monitoring of blood glucose is recommended when these agents are used concomitantly. (See PRECAUTIONS, Disturbances of Blood Glucose and Information to be provided to the Patient.)

Interactions with Laboratory or Diagnostic Testing:

Some quinolones, including ofloxacin, 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.

Information to be provided to the Patient:

Patients should be advised:

— that antibacterial drugs including FLOXIN (ofloxacin) Tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When FLOXIN (ofloxacin) Tablets are prescribed to treat a 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 FLOXIN (ofloxacin) Tablets or other antibacterial drugs in the future.

— that ofloxacin may cause changes in the electrocardiogram (QTc interval prolongation),

— that ofloxacin should be avoided in patients receiving class IA (e.g. quinidine, procainamide) or class III (e.g.

amiodarone, sotalol) antiarrhythmic agents,

— that ofloxacin should be used with caution in subjects receiving drugs that affect the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants,

— to inform their physicians of any personal or family history of QTc prolongation or proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial ischemia,

— that peripheral neuropathies have been associated with ofloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or vibration develop, they should discontinue treatment and contact their physicians.

— to drink fluids liberally;

— that mineral supplements, vitamins with iron or minerals, calcium-, aluminum-, or magnesium-based antacids, sucralfate or Videx® and/or Videx EC® (didanosine) should not be taken within the two-hour period before or within the two-hour period after taking ofloxacin (See PRECAUTIONS, Drug Interactions);

— that ofloxacin can be taken without regard to meals;

— that ofloxacin may cause neurologic adverse effects (e.g., dizziness, lightheadedness) and that patients should know how they react to ofloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination (See WARNINGS and ADVERSE REACTIONS);

— to discontinue treatment and inform their physician if they experience pain, inflammation, or rupture of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded;

— that ofloxacin may be associated with hypersensitivity reactions, even following the first dose, to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face; tightness of the throat, hoarseness), or any other symptom of an allergic reaction (See WARNINGS and ADVERSE REACTIONS);

— to avoid excessive sunlight or artificial ultraviolet light while receiving ofloxacin and to discontinue therapy if phototoxicity (e.g., skin eruption) occurs;

— that if they are diabetic and are being treated with insulin or an oral hypoglycemic drug, to discontinue ofloxacin immediately if a hypoglycemic reaction occurs and consult a physician (See PRECAUTIONS: General and Drug

Interactions);

— that convulsions have been reported in patients taking quinolones, including ofloxacin, and to notify their physician before taking this drug if there is a history of this condition.

— that safety and efficacy of ofloxacin have not been established in pregnant women. Ofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

— that in nursing women concentrations of ofloxacin in milk were similar to those found in plasma. Therefore, because of the potential for serious adverse reactions from ofloxacin in nursing infants, a decision should be made to discontinue nursing or discontinue the drug.

ADVERSE REACTIONS

Clinical Trials Experience:

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% Vomiting 1%

Insomnia 3% Dizziness 3%

Rash 1% Pruritus 1%

External genital Vaginitis 1%

pruritus in women 1% Headache 3%

Diarrhea 1% Dysgeusia 1%

In clinical trials, the most frequently reported adverse events, regardless of relationship to drug, were:

Nausea 10% Insomnia 7%

Vomiting 4% Headache 9%

Diarrhea 4% Vaginitis 5%

External genital Dizziness 5%

pruritus in women 6%

Additional events occurring in clinical trials at rates of 1 - 3% and less than 1% regardless of relationship to drug or route of administration were :

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 Geriatrics:

In phase 2/3 clinical trials with ofloxacin, 688 patients (14.2%) were $ 65 years of age. Of these, 436 patients (9.0%) were between the ages of 65 and 74 and 252 patients (5.2%) were 75 years or older. There was no apparent difference in the frequency or severity of adverse reactions in elderly adults compared with younger adults. In comparative studies, the frequency of most drug-related nervous system events in patients $ 65 years of age were comparable for ofloxacin and control drugs. The only differences identified were an increase in reports of insomnia (3.9% vs 1.5%) and headache (4.7% vs 1.8%) with ofloxacin. It is important to note that these geriatric safety data are extracted from 44 comparative studies where the adverse reaction information from 20 different controls (other antibiotics or placebo) were pooled for comparison with ofloxacin. The clinical significance of such a comparison is not clear.

Worldwide Marketing Experience:

Additional adverse events regardless of relationship to drug were reported from worldwide marketing experience with quinolones, including ofloxacin.

In clinical trials using multiple-dose therapy, ophthalmologic abnormalities including cataracts and multiple punctate lenticular opacities have been noted in patients undergoing treatment with other quinolones. The relationship of the drugs to these events is not presently established.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Information on overdosage with ofloxacin is limited. One incident of accidental overdosage has been reported. In this case, an adult female received 3 grams of ofloxacin intravenously over 45 minutes. A blood sample obtained 15 minutes after the completion of the infusion revealed an ofloxacin level of 39.3 :g/mL. In 7 hours, the level had fallen to 16.2

:g/mL, and by 24 h to 2.7 :g/mL. During the infusion, the patient developed drowsiness, nausea, dizziness, hot and cold flushes, subjective facial swelling and numbness, slurring of speech, and mild to moderate disorientation. All complaints except the dizziness subsided within 1 hour after discontinuation of the infusion. The dizziness, most bothersome while standing, resolved in approximately 9 hours. Laboratory testing reportedly revealed no clinically significant changes in routine parameters in this patient.

In the event of acute overdose, the patient should be observed and appropriate hydration maintained. Ofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.

DOSAGE AND ADMINISTRATION

General

The dosing 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 Dosage Adjustment for Renal Impairment.

The usual dose of FLOXIN (ofloxacin) Tablets is described in the following Dosage Chart.

Antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent cations such as iron;

multivitamins containing zinc; or any product containing any of these components (e.g. Videx® [didanosine]) should not be taken within the two-hour period before or within the two-hour period after oral administration of ofloxacin. (See

PRECAUTIONS.)

Dosage Chart - FLOXIN Tablets (Patients with Normal Renal Function)

_____________________________________________________________________________________________________________________

Unit Daily Infection Description Dose Frequency Duration Dose _____________________________________________________________________________________________________________________

Lower Respiratory Exacerbation of

Tract Infections Chronic Bronchitis or 400 mg q12h 10 days 800 mg

Pneumonia

Sexually Trans- Acute, uncomplicated

mitted Diseases gonorrhea 400 mg single 1 day 400 mg dose

Cervicitis/urethritis

due to C. trachomatis

or mixed infections 300 mg q12h 7 days 600 mg due to C. trachomatis

and N. gonorrhoeae

Acute Pelvic

Inflammatory Disease 400 mg q12h 10-14 days 800 mg

Skin and Skin Uncomplicated 400 mg q12h 10 days 800 mg Structure

Infections

Complicated 400 mg q12h 10 days 800 mg

Prostatitis 300 mg q12h 6 weeks 600 mg _____________________________________________________________________________________________________________________

Dosage Adjustment For Renal Impairment:

Dosage should be adjusted in patients with a creatinine clearance value of less than or equal to 50 mL/min.

After a normal initial dose, the dosing interval should be adjusted as follows:

Creatinine Maintenance

Clearance Unit Dose Frequency

________________________________________________________________________

20-50 mL/min as recommended q24h

in the Dosage Chart

< 20 mL/min ½ recommended q24h

dose in Dosage

Chart

________________________________________________________________________

When only the serum creatinine is known, the following formula may be used to estimate creatinine clearance. The serum creatinine should represent steady-state renal function.

Men: Creatinine clearance (mL/min) = Weight (kg) x (140 - age) x 1.2

serum creatinine (µmol/L)

Women: 0.85 x the value calculated for men.

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.

PHARMACEUTICAL INFORMATION

Drug Substance:

Common Name: Ofloxacin

Chemical Name: (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-

piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine

-6-carboxylic acid

Structural Formula:

Molecular Formula: C18H20FN3O4

Molecular Weight: 361.4

Description:

Ofloxacin, a fluorinated carboxyquinolone, occurs as off-white to pale yellow crystals or crystalline powder. It is odourless and has a bitter taste. The relative solubility characteristics of ofloxacin at room temperature, as defined by

USP nomenclature, indicate that ofloxacin is considered to be soluble in aqueous solutions with pH between 2 and 5.

It is sparingly to slightly soluble in aqueous solutions with pH 7 (solubility falls to 4 mg/mL) and freely soluble in aqueous solutions with pH above 9. In addition, it is freely soluble in glacial acetic acid, sparingly soluble in chloroform and slightly soluble in methanol, ethanol and acetone. The pKa's are pKa₁: 5.74 (COOH) and pKa₂: 7.90 (CH3-N.). The pH is 7.16 (saturated solution). The melting point is 260^o-270^oC.

Composition:

The core tablet composition of the two FLOXIN ofloxacin Tablet formulations (300 and 400 mg) is qualitatively identical. The 300 mg and 400 mg dosage forms are film-coated white and pale gold, respectively.

Each FLOXIN Tablet contains the following inactive ingredients: anhydrous lactose, corn starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide. The 400 mg tablets also contain synthetic yellow iron oxide.

Stability and Storage Recommendations:

FLOXIN Tablets should be stored in well-closed containers. Store at controlled room temperature (15 - 30^oC).

AVAILABILITY OF DOSAGE FORMS

FLOXIN ofloxacin Tablets are supplied as 300 mg white and 400 mg pale gold, film-coated tablets. Each tablet is engraved with 'FLOXIN' and the appropriate strength. FLOXIN Tablets are packaged in bottles of 50 tablets in the following configurations:

300 mg tablets - bottles of 50

400 mg tablets - bottles of 50

MICROBIOLOGY

Ofloxacin is a quinolone antimicrobial agent. The mechanism of action of ofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination.

Ofloxacin is active in vitro against a broad spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria

(Table 1). Ofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.

Ofloxacin is not inhibited by $-lactamase enzymes.

TABLE 1

CUMULATIVE PERCENT OF STRAINS INHIBITED AT THE

INDICATED CONCENTRATIONS OF OFLOXACIN

Genera or Species

No. of

Isolates

Tested

MIC (µg/mL)

0.062 0.125 0.25 0.5 1.0 2 4 8 16 32 64 128

Enterococcus

(Streptococcus faecalis) Enterococcus spp.

Staphylococcus aureus (including methicillin- resistant strains)

Staphylococcus epidermidis (including methicillin- resistant strains)

Staphylococcus

saprophyticus

Staphylococcus spp.

Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Streptococci (serogroups A, B, C)

Clostridium perfringens Clostridium welchii

Clostridium spp.

Peptococcus species

Peptostreptococcus species Acinetobacter calcoaceticus Acinetobacter species Aeromonas hydrophila Aeromonas species

Moraxella catarrhalis^*

Bordetella parapertussis Bordetella pertussis

Campylobacter jejuni Citrobacter diversus Citrobacter freundii

Citrobacter spp.

Enterobacter aerogenes Enterobacter cloacae Enterobacter spp.

Escherichia coli

Hemophilus ducreyi

Hemophilus influenzae Hemophilus parainfluenzae Klebsiella pneumoniae Klebsiella oxytoca

Klebsiella spp.

Neisseria gonorrhoeae Neisseria meningitidis Plesiomonas shigelloides Plesiomonas species Proteus mirabilis

Proteus vulgaris

Proteus morganii** Providencia rettgeri

Providencia stuartii

$10

$10

$10

>90

.

* This species was previously referred to as Branhamella catarrhalis ** In some references this species is referred to as Morganella morganii

TABLE 1 (contd.)

CUMULATIVE PERCENT OF STRAINS INHIBITED AT THE

INDICATED CONCENTRATIONS OF OFLOXACIN

* Includes Bacteroides intermedius

Many strains of other streptococcal species, Enterococcus species and anaerobes are resistant to ofloxacin. Ofloxacin has not been shown to be active against Treponema pallidum. (See WARNINGS.)

Resistance:

The mode of action of quinolone antibiotics is different from that of other major classes of antibiotics. Organisms resistant to non-quinolone antibiotics may be sensitive to quinolones. Ofloxacin has been shown to be active against many microorganisms resistant to other antimicrobials, including penicillins, cephalosporins, aminoglycosides, macrolides, tetracyclines, chloramphenicol, and isoniazid.

Resistance to ofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10^-9 to 10^-11). Organisms acquiring resistance to the older quinolones, such as nalidixic acid and cinoxacin, have been shown to be susceptible to ofloxacin. Although cross-resistance has been observed between ofloxacin and other fluoroquinolones such as norfloxacin, ciprofloxacin and enoxacin, some organisms resistant to other quinolones may be susceptible to ofloxacin.

Susceptibility Testing

Dilution Techniques:

Quantitiative methods are used to determine antimicrobial minimal inhibitory concentrations ( MIC values). These MIC values provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure. Standardized procedures are based on a dilution method²⁶ (broth or agar)

or equivalent with standardized inoculum concentrations and standardized concentrations of ofloxacin powder. The

MIC values should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae and Neisseria gonorrhoeae

MIC (µg/mL)^a Interpretation

< 2 Susceptible (S)

4 Intermediate (I)

> 8 Resistant (R)

^a For testing Streptococcus pneumoniae, these interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.

For testing Haemophilus influenzae: ^b

MIC (µg/mL) Interpretation ^c

< 0.2 Susceptible (S)

^b This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae using Haemophilus Test Medium.

^c The current absence of data on resistant strains precludes defining any categories other than “Susceptible.” Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Neisseria gonorrhoeae: ^d

MIC (µg/mL) Interpretation

< 0.25 Susceptible (S)

0.5–1 Intermediate (I)

> 2 Resistant (R)

^d These interpretive standards are applicable only to agar dilution tests using GC agar base and 1% defined growth supplement incubated in 5% CO₂.

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. A 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 a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A 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.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ofloxacin powder should provide the following MIC values:

Microorganism MIC (µg/mL)

E. coli ATCC 25922 0.015–0.12

S. aureus ATCC 29213 0.12–1

P. aeruginosa ATCC 27853 1–8

H. influenzae ATCC 49247^e 0.016–0.06

N. gonorrhoeae ATCC 49226^f 0.004–0.016

Streptococcus pneumoniae ATCC 49619^g 1–4

^e This quality control range is applicable only to H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium.

^f This quality control range is applicable only to N. gonorrhoeae ATCC 49226 tested by an agar dilution procedure using GC agar base with 1% defined growth supplement incubated in 5% CO₂.

^g This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.

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 procedure³⁹ requires the use of standard inoculum concentrations. This procedure uses paper disks impregnated with 5-µg ofloxacin to test the susceptibility of microorganisms to ofloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg ofloxacin disk should be interpreted according to the following criteria:

For testing aerobic microorganisms other than H. influenzae and N. gonorrhoeae: ^h

Zone Diameter (mm) Interpretation

> 16 Susceptible (S)

13–15 Intermediate (I)

< 12 Resistant (R)

^h For testing Streptococcus pneumoniae, these zone diameter standards are applicable only to disk diffusion tests using

Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in 5% CO₂.

For testing H. influenzae: ⁱ

Zone Diameter (mm) Interpretation ^j

> 16 Susceptible (S)

ⁱ This zone diameter standard is applicable only to disk diffusion tests with H. influenzae using Haemophilus Test Medium incubated in 5% CO2.

^j The current absence of data on resistant strains precludes defining any categories other than “susceptible.” Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing N. gonorrhoeae: ^k

Zone Diameter (mm) Interpretation

> 31 Susceptible (S)

25–30 Intermediate (I)

< 24 Resistant (R)

^k These zone diameter standards are applicable only to disk diffusion tests using GC agar base and 1% defined growth supplement incubated in 5% CO₂.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ofloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-µg ofloxacin disk should provide the following zone diameters in these laboratory test quality control strains.

Microorganism Zone Diameter (mm)

E. coli ATCC 25922 29–33

P. aeruginosa ATCC 27853 17–21

H. influenzae ATCC 49247 ^l 31–40

N. gonorrhoeae ATCC 49226 ^m 43–51

S. aureus ATCC 25923 24–28

Streptococcus pneumoniae ATCC 49619 ⁿ 16–21

^l This quality control range is applicable only to H. influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium incubated in 5% CO₂.

^m This quality control range is applicable only to N. gonorrhoeae ATCC 49226 tested by a disk diffusion procedure using GC agar base with 1% defined growth supplement incubated in 5% CO₂.

ⁿ This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood and incubated in 5% CO₂.

PHARMACOLOGY

ANIMAL PHARMACOLOGY:

A summary of the major findings obtained from pharmacology studies with ofloxacin is presented below:

The major effects of ofloxacin on the central nervous system or gastrointestinal tract were observed either at relatively high oral doses (>100 mg/kg) or following rapid bolus intravenous injection. Human oral doses of 200 to

400 mg (per 50-60 kg individuals) are equivalent to 4-8 mg/kg. Some of the effects were, in addition, species specific.

HUMAN PHARMACOLOGY:

Pharmacokinetics:

The pharmacokinetic profile of FLOXIN (ofloxacin) Tablets is comparable to the profile of ofloxacin administered intravenously. Following oral administration, the bioavailability of ofloxacin in the tablet formulation is approximately 98%. Maximum serum concentrations are achieved one to two hours after an oral dose. Absorption of ofloxacin after single or multiple doses of 200 to 400 mg is predictable, and the amount of drug absorbed increases proportionately with the dose.

The following are mean peak serum concentrations in healthy 70-80 kg male volunteers after single oral doses of

200, 300, or 400 mg of ofloxacin or after multiple doses of 400 mg.

Dose C_max:g/mL

± S.D.

AUC0-last pt.

:g x h/mL

± S.D.

Tmax

± S.D.

t1/2

200 mg -single dose 1.7 ± 0.3 14.1 ± 2.3 1.5 ± 0.3 4.9

300 mg -single dose 2.6 ± 0.4 21.2 ± 2.5 1.7 ± 0.5 4.6

400 mg -single dose 3.7 ± 0.7 31.4 ± 4.7 1.8 ± 0.6 3.8

400 mg -steady state 5.0 ± 1.0 62.9 ± 14.4 1.7 ± 0.5 5.2

The following are mean peak serum concentrations in healthy 49-102 kg male volunteers after single and multiple doses of 200 and 400 mg of intravenous ofloxacin.

Dose

C_max:g/mL ± S.D.

AUC0-last pt.

:g x h/mL

± S.D. T_max t_1/2

200 mg -single dose 2.29 ± 0.5 12.20 ± 1.8 1.0 5.29

200 mg -steady state* 2.89 ± 0.5 12.96 ± 1.6 ---- 5.15

400 mg -single dose 4.49 ± 0.8 25.28 ± 3.30 1.0 5.50

400 mg -steady state* 5.47 64.55 ± 15.0 1.1 6.05

* at 7^th day of therapy

Steady-state concentrations are achieved with both FLOXIN Tablets and intravenous ofloxacin after four doses. The area under the curve (AUC) was approximately 40% higher than the AUC after single doses. Therefore, after multiple-dose administration of 200 mg and 300 mg FLOXIN Tablets, peak plasma levels of 2.2 :g/mL and 3.6

:g/mL, respectively, are predicted at steady state. The mean peak and trough plasma steady state levels attained following intravenous administration of 200 mg of ofloxacin q12h for seven days were 2.9 and 0.5 :g/mL, respectively. Following intravenous doses of 400 mg of ofloxacin q12h, the mean peak and trough plasma steady state levels ranged, in two different studies, from 5.5 to 7.2 :g/mL and 1.2 to 1.9 :g/mL, respectively.

The single dose and steady state plasma profiles of ofloxacin injection were comparable in extent of exposure

(AUC) to those of ofloxacin tablets when the injectable and tablet formulations of ofloxacin were administered in equal doses (mg/mg) to the same group of subjects. The mean steady-state AUC_(0-12) attained after the intravenous administration of 400 mg over 60 min was 43.5 :g x h/mL; the mean steady-state AUC_(0-12) attained after the oral administration of 400 mg was 41.2 :g x h/mL (two one-sided t-test, 90% confidence interval was 103-109). [See graph below.]

Metabolism and Excretion:

Ofloxacin has biphasic elimination. Following multiple oral doses at steady-state administration, the half-lives are approximately 4-5 hours and 20-25 hours. However, the longer half-life represents less than 5% of the total AUC. Accumulation at steady-state can be estimated using a half-life of 9 hours. The total clearance and volume of distribution are approximately similar after single or multiple doses.

Elimination is mainly by renal excretion. Between 0 and 6 hours following the administration of a single 200 mg oral dose of ofloxacin to 12 healthy volunteers, the average urine ofloxacin concentration was approximately 220

:g/mL. Between 12 and 24 hours after administration, the average urine ofloxacin level was approximately 34

:g/mL.

Urinary Concentration(:g/mL) Time following single doses Hours Post Dose 100 mg 300 mg

0 - 2 78 228

2 - 4 115 260

4 - 6 65 287

6 - 8 75 271

8 - 12 62 202

The solubility of ofloxacin in human urine is estimated to be between 7000 and 9000 :g/mL. The maximum expected urinary concentrations of ofloxacin after administration of a 400 mg oral dose is 400 :g/mL, approximately 20 times less than the equilibrium solubility. Ofloxacin crystals have not been observed to date in urine of any subject.

Ofloxacin undergoes minimal biotransformation. Ofloxacin has a pyridobenzoxazine ring that appears to decrease the extent of parent compound metabolism. Between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. Studies indicate that less than 5% of an administered dose is recovered in the urine as the desmethyl or N-oxide metabolites. Four to eight percent of an ofloxacin dose (oral/parenteral) is excreted in the feces. This indicates a small degree of biliary secretion of ofloxacin.

CNS Effects:

No evidence of an effect of ofloxacin on the electrical activity of the brain has been demonstrated. Ofloxacin does not alter the metabolism of glucose in the central nervous system based on positron emission tomography. It does not affect the electrical patterns of brain function based on EEGs.

Factors Influencing the Pharmacokinetics:

Age (elderly):

Following oral administration to healthy elderly subjects (65-81 years of age), maximum plasma concentrations are usually achieved one to two hours after single and multiple twice-daily doses, indicating that the rate of oral absorption is unaffected by age or gender. Mean peak plasma concentrations in elderly subjects were 9-21% higher than those observed in younger subjects. Gender differences in the pharmacokinetic properties of elderly subjects have been observed. Peak plasma concentrations were 114% and 54% higher in elderly females compared to elderly males following single and multiple twice daily doses. [This interpretation was based on study results collected from two separate studies.] Plasma concentrations increase dose-dependently with the increase in doses after single oral dose and at steady state. No differences were observed in the volume of distribution values between elderly and younger subjects. As in younger subjects, elimination is mainly by renal excretion as unchanged drug in elderly subjects, although less drug is recovered from renal excretion in elderly subjects. Consistent with younger subjects, less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites in the elderly. A longer plasma half-life of approximately 6.4 to 7.4 hours was observed in elderly subjects, compared with

4 to 5 hours for young subjects. Slower elimination of ofloxacin is observed in elderly subjects as compared with younger subjects which may be attributable to the reduced renal function and renal clearance observed in the elderly subjects. Because ofloxacin is known to be substantially excreted by the kidney, and elderly patients are more likely to have decreased renal function, dosage adjustment is necessary for elderly patients with impaired renal function as recommended for all patients. (See PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION.)

Impaired Renal Function:

Clearance of ofloxacin is reduced in patients with impaired renal function (creatinine clearance rate # 50 mL/min), and dosage adjustment is necessary. (See PRECAUTIONS: General and DOSAGE AND

ADMINISTRATION.)

MEAN PHARMACOKINETIC PARAMETERS FOR OFLOXACIN FOLLOWING A SINGLE 300 MG DOSE

IN HEALTHY VOLUNTEERS AND IN PATIENTS WITH RENAL INSUFFICIENCY

PARAMETER

Group Creatinine

Clearance

(mL/min/1.73m²) C_max

(mg/L)

Tmax

(h)

t1/2

(h)

AUC (mgCh/L)

Renal Clearance L/hr

% Dose Urinary Recovery 0-120 hr (%)

I

II

III

$ 50

10 - 49

< 10

3.55 ± 0.60

3.69 ± 1.0

4.20 ± 1.3

1.8 ± 0.7

2.2 ± 1.0

1.5 ± 0.4

6.51

16.38

21.67

40.43 ± 10.5

83.24 ± 29.4

152.45 ± 32.3

6.2

1.3

N/A

74.3

28.5

6.7

Food:

The administration of FLOXIN with food prolongs the time to peak concentration (T_max) by approximately one hour, slightly reduces the peak concentration (C_max) by approximately 17% but has no statistically significant effect on the extent of absorption (AUC) of the drug.

Caffeine:

Interactions between ofloxacin and caffeine have not been detected.

See PRECAUTIONS for effects on administration with food, antacids and multivitamins.

Serum Protein Binding:

In vitro, approximately 32% of the drug in serum is protein bound.

Tissue Concentration:

The following are mean concentrations of ofloxacin in various body fluids and tissues after one or more oral doses.

Concentration Hours

Fluid/ (µg/mL or Post Dose Dosage Tissue µg/g) Dosing (mg) Amount

Sputum 3.1 1-2 400 single dose

5.7 4 400 steady state

Lung 4.5 6-7 400 two doses tissue 6.7 2.5 200 steady state

Skin 3.4 2-2.5 300 single dose

Blister 4.7 6 600 single dose fluid

Prostatic 3.9 2.5 200 single dose tissue

Prostatic 7.2 7 300 two doses fluid

Ovary 5.5 1-6 300 single dose

Cervix 5.6 2 300 single dose

Gall- 3.1 4 200 single dose bladder

tissue

Bile 2.9 3-4 200 single dose

There is inadequate evidence to establish the extent of distribution to cerebrospinal fluid or brain tissue.

TOXICOLOGY

Acute Toxicity:

Acute Toxicity (contd.):

^a For both sexes LD₅₀ is estimated to be >70 mg/kg Subchronic Toxicity:

Subchronic Toxicity: (contd.)

Subchronic Toxicity: (contd.)

Chronic Toxicity:

Carcinogenicity:

As with most drugs of this class, long-term studies to determine the carcinogenic potential have not been conducted.

Mutagenicity:

The mutagenic potential of ofloxacin was evaluated in Ames Rec-Assay, in vivo Cytogenetic, Sister Chromatid

Exchange (Chinese Hamster and Human Cell Lines), Unscheduled DNA Repair and Dominant Lethal Studies.

Only the Rec-Assay had a positive finding indicating a potential for ofloxacin to produce primary DNA damage in

Bacillus subtilis. Ofloxacin, nalidixic acid and pipemidic acid inhibited M45 (rec-) slightly more than H17 (rec+).

Kenamycin inhibited both mutants in a similar manner, and mitomycin C inhibited MH5 to a greater degree than it inhibited H17.

In contrast ofloxacin had no effect on the DNA of eukaryotes. There was no evidence of either point mutations or of in vitro or in vivo chromosome mutation.

REPRODUCTION AND TERATOLOGY

Fertility:

Teratology and Embryotoxicity:

Teratology and Embryotoxicity (contd.): 44

Perinatal and Postnatal:

Other Studies:

The results of special toxicity studies indicated that ofloxacin demonstrated no evidence of ocular toxicity in rats, no antigenicity or ototoxicity in guinea pigs.

Ofloxacin is not nephrotoxic when administered orally for 10 days to rabbits (4/group; 0, 50, 200 mg/kg/day) at dosage levels of 50 or 200 mg/kg/day. Crystalluria was not observed in any animals treated with ofloxacin. In petroleum jelly or gel ointment, ofloxacin is neither phototoxic nor photoallergenic in guinea pigs.

Reduced serum globulin and protein levels have been observed in animals treated with quinolones. In one ofloxacin study, minor decreases in serum globulin and protein levels were noted in female cynomolgus monkeys dosed orally with 40 mg/kg ofloxacin daily for one year. These changes, however, were considered to be within normal limits for monkeys.

A series of special studies was conducted in rats and dogs to evaluate the arthropathic effects of ofloxacin. The lesion induced by ofloxacin and other quinolones is described as an irreversible blister, erosion or increased synovial fluid of the diarthric joint cartilage that may lead to permanent lameness. Results of these studies are as follows:

Arthropathy:

Arthropathy (contd.):

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