Ofloxacin Tablets Product Monograph

INDICATIONS AND CLINICAL USE

OFLOXACIN TABLETS (ofloxacin) is indicated for the treatment of adults with the following infections caused by susceptible strains of the designated microorganisms:

Lower Respiratory Tract Infections: including pneumonia and acute exacerbation of chronic bronchitis due to Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis.

Urinary Tract Infections: UNCOMPLICATED CYSTITIS due to Escherichia coli, Klebsiella pneumoniae or Proteus mirabilis.

COMPLICATED URINARY TRACT INFECTIONS due to Escherichia coli, Klebsiella pneumoniae or Proteus mirabilis.

Prostatitis: due to Escherichia coli.

Sexually Transmitted Diseases (See WARNINGS): 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: Ofloxacin is not effective in the treatment of syphilis. All patients with gonorrhoea should have an initial serologic test for syphilis and a follow–up serologic test after three months (see WARNINGS).

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 ofloxacin 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 of this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ofloxacin 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

Ofloxacin is contraindicated in persons with a history of hypersensitivity to ofloxacin or members of the quinolone group of antibacterial agents.

WARNINGS

The safety and efficacy of ofloxacin in children, adolescents (under the age of 18 years), pregnant women and lactating women has not been established. (See PRECAUTIONS; Use in Children, Use in Pregnancy and Nursing Mothers.)

The oral administration of ofloxacin has produced lesions in weight bearing articular cartilage and lameness in several species of immature animals (see TOXICOLOGY; Other Studies). Consequently, OFLOXACIN TABLETS (ofloxacin) 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.

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 of uncertain etiology have been reported in patients receiving therapy with quinolones including, extremely rarely, 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 after appearance of a skin rash or any other sign of hypersensitivity and supportive measures instituted. (See 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. 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 (eg. severe cerebral arteriosclerosis, epilepsy, etc.) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (eg. certain drug therapy, renal dysfunction, etc.). (See PRECAUTIONS and ADVERSE REACTIONS).

Vision Disorders

If vision disorder occurs in association with the use of OFLOXACIN TABLETS, consult an eye specialist immediately. A modest increase in risk of developing Retinal Detachment was found in association with the use of Fluoroquinolones in some observational studies; however, a causal relationship to the drug has not been clearly established.

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 oral antibacterial drug effective against C. difficile. (See ADVERSE REACTIONS).

PRECAUTIONS

General

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 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 HUMAN PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

Allergic Reactions

Moderate to severe phototoxicity reactions have been observed in patients who are exposed to direct sunlight while receiving some drugs in this class including ofloxacin. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity (eg. 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 nursing females a single 200 mg 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).

Patients with Special Diseases and Conditions

CNS Disorders

As with all 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

As with other quinolones, disturbances of blood glucose including symptomatic hyper–and hypoglycemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g. glyburide/glibenclamide, etc.,) or with insulin. In these patients careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with ofloxacin, the patient should discontinue ofloxacin immediately and appropriate ancillary measures should be instituted. (See PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS).

Drug Interactions

Antacids, Sucralfate, Metal Cations and Multivitamins: Quinolones have the potential to form stable complexes with many metal ions. Administration of oral quinolones with antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent cations such as iron; or multivitamins containing zinc 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 ofloxacin administration.

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 had not been studied.

Cyclosporine: Elevated serum levels of cyclosporine have been reported following concomitant use 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 nonsterodial 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 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 (PT) (or other appropriate test(s) of coagulation) should be 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 and an antidiabetic agent, careful monitoring of blood glucose is recommended when these agents are used concomitantly.

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:

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

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

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 µg/mL. In 7 hours, the level had fallen to 16.2 µg/mL, and by 24 hours to 2.7 µg/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 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 OFLOXACIN TABLETS (ofloxacin) is 200 mg to 400 mg orally every 12 hours as described in the DOSAGE CHART.

Antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent cations such as iron; or multivitamins containing zinc should not be taken within the two-hour period before, or within the two-hour period after oral administration of ofloxacin (see PRECAUTIONS).

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:

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.

Women: 0.85 x the value calculated in 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

Proper/Common Name: Ofloxacin

Chemical Name(s): (±)-9-fluoro-2,3-dihydro-3-methyl-I0-(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 odorless 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 pKa: 5.74 (COOH) and pKa₂: 7.90 (CH₃-N). The pH is 7.16 (saturated solution). The melting point is 260 - 270°C.

Composition

In addition to ofloxacin, each tablet contains the non–medicinal ingredients microcrystalline cellulose, methylcellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, polydextrose, hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide and carnauba wax. The 200 mg and 400 mg tablets also contain yellow ferric oxide.

Stability and Storage Recommendations

OFLOXACIN TABLETS should be stored in well closed containers. Store at room temperature (15 - 30°C). Protect from light.

AVAILABILITY OF DOSAGE FORMS

200 mg: Each light yellow, oval, biconvex, film–coated tablet, engraved 200 on one side, contains 200 mg ofloxacin. Available in bottles of 100 and 250, and unit dose packages of 100.

300 mg: Each white, oval, biconvex, film–coated tablet, engraved 300 on one side, contains 300 mg ofloxacin. Available in bottles of 100 and 250, and unit dose packages of 100.

400 mg: Each yellow, oval, biconvex, film–coated tablet, engraved 400 on one side, contains 400 mg ofloxacin. Available in bottles of 100 and 250, and unit dose packages of 100.

MICROBIOLOGY

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 β–lactamase enzymes.

TABLE 1: CUMMULATIVE PERCENT OF STRAINS INHIBITED AT THE INDICATED CONCENTRATIONS OF OFLOXACIN

* This species was previously referred to as Branhamella catarrhalis

** In some references this species is referred to as Morganella morganii

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, enoxacin, and ciprofloxacin, some organisms resistant to other quinolones may be susceptible to ofloxacin.

Susceptibility Testing

Diffusion techniques: The National Committee for Clinical Laboratory Standards (NCCLS) approved procedure (M2-A4--Performance Standards for Antimicrobial Disk Susceptibility Tests 1990) has been recommended for use with the 5-mg ofloxacin disk to test susceptibility to ofloxacin. Interpretation involves correlation of the diameters obtained in the disk test with minimum inhibitory concentrations (MIC) for ofloxacin. Other quinolone antibacterial disks should not be substituted when performing susceptibility tests for ofloxacin because of spectrum differences with ofloxacin. The 5-µg ofloxacin disk should be used for all in vitro testing of isolates using diffusion techniques.

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

A report of “susceptible” indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of “moderately susceptible” suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids in which ofloxacin levels are much higher than in plasma. A report of “resistant” indicates that achievable concentrations of ofloxacin are unlikely to be inhibitory and other therapy should be selected.

Standardized procedures require the use of laboratory control organisms. The 5-µg ofloxacin disk should give the following zone diameter:

Dilution Techniques: Broth and agar dilution methods, such as those recommended by the NCCLS (M7-A2--Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically 1990), may be used to determine the minimum inhibitory concentrations (MIC) of ofloxacin. MIC test results should be interpreted according to the following criteria:

As with standard diffusion methods, dilution procedures require the use of laboratory control organisms. Standard ofloxacin powder should give the following MIC values:

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

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.

Steady–state concentrations are achieved 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, peak plasma levels of 2.2 µg/mL and 3.6 µg/mL, respectively, are predicted at steady–state.

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 oral 200 mg dose of ofloxacin to 12 healthy volunteers, the average urine ofloxacin concentration was approximately 220 µg/mL. Between 12 and 24 hours after administration, the average urine ofloxacin level was approximately 34 µg/mL.

The solubility of ofloxacin in human urine is estimated to be between 7000 and 9000 µg/mL. The maximum expected urinary concentrations of ofloxacin after administration of a 400 mg dose is 400 µg/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% to 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 the administration of oral doses of ofloxacin to healthy, elderly volunteers (64 - 74 years of age) with normal renal function, the apparent half–life of ofloxacin is 7 to 8 hours, compared to approximately 6 hours in younger male adults. Drug absorption, however, appears to be unaffected by age.

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 DOSAGE AND ADMINISTRATION).

Food: The absorption of ofloxacin is not affected when administered with food.

Caffeine: Interactions between ofloxacin and caffeine have not been detected. See PRECAUTIONS (Drug Interactions) 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.

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

TOXICOLOGY

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.

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 vaseline or gel ointment, ofloxacin is neither phototoxic nor photo–allergenic 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:

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