PRODUCT MONOGRAPH

NOVO-OFLOXACIN (Ofloxacin) Tablets Antibacterial Agent Novopharm Ltd. Date of Preparation: Toronto, Canada May 22, 2001

Control #059346

PRODUCT MONOGRAPH

NOVO-OFLOXACIN (Ofloxacin) 200 mg, 300 mg and 400 mg Tablets

ACTIONS AND CLINICAL PHARMACOLOGY

NOVO-OFLOXACIN (ofloxacin) is a broad-spectrum, synthetic fluoroquinolone antibacterial agent for oral administration. Ofloxacin is thought to exert a bactericidal effect on susceptible bacterial cells by inhibiting the essential bacterial enzyme, DNA gyrase, a critical catalyst in the duplication, transcription and repair of bacteria. The pharmacokinetic profile of ofloxacin tablets is comparable to the profile of ofloxacin administered i.v. The bioavailability of ofloxacin in the tablet formulation is approximately 98%. Ofloxacin is rapidly and completely absorbed from the upper small bowel following oral administration. The pharmacokinetic parameters of oral ofloxacin following single doses of 200, 300 and 400 mg and multiple doses of 400 mg to healthy 70 to 80 kg males are summarized in Table 1. Table 1

The following are mean peak serum concentrations in healthy 49 to 102 kg male volunteers after single and multiple doses of 200 and 400 mg of ofloxacin i.v. (see Table 2). Table 2

*at 7th day of therapy A comparative, single-dose, crossover bioavailability study was performed on NOVO- OFLOXACIN (ofloxacin) 400 mg Tablets and Floxin(tm) 400 mg Tablets. The mean pharmacokinetic data calculated for the two ofloxacin formulations are tabulated below in Table 3 V(10) :

Table 3

T

MAX

T1/2

* expressed as arithmetic mean (CV%) only.

* *Floxin(tm) is manufactured by Ortho-McNeil Inc. (Canada) Elimination is mainly by renal excretion. Ofloxacin undergoes minimal biotransformation.

INDICATIONS AND CLINICAL USE

NOVO-OFLOXACIN (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. 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: Acute, uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae. Cervicitis / urethritis due to Chlamydia trachomatis or mixed infections due to Neisseria gonorrhoeae and Chlamydia trachomatis.

Note

: NOVO-OFLOXACIN is not effective in the treatment of syphilis. All patients with gonorrhoea should have an initial serologic test for syphilis and 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 a N. gonorrhoeae, C. trachomatis, anaerobes, Gardnerella vaginalis, Haemophilus influenzae, enteric gram-negative rods and Streptococcus agalactae. Ofloxacin has demonstrated clinical effectiveness only against N. gonorrhoea and C. trachomatis; therefore, consideration should be given to inclusion of additional agents if NOVO-OFLOXACIN is used empirically for the treatment of pelvic inflammatory infection.

Note

: Clinical trials with ofloxacin 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 and 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 NOVO-OFLOXACIN (ofloxacin) 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 ofloxacin. 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

NOVO-OFLOXACIN (ofloxacin) Tablets are 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 should not be used in prepubertal 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 3 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, i.v. 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 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 CNS 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 (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).

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 a highly concentrated urine.

Renal/Hepatic

: Administer NOVO-OFLOXACIN (ofloxacin) Tablets 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 (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 nursing 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 under 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, Multivitamins, etc.

: 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 2-hour period before or within the 2-hour period after oral 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 has 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 (NSAIDs)

: 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 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.

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 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.

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

at 7th day of therapy Steady state concentrations are achieved with both ofloxacin tablets and i.v. 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 ofloxacin tablets, peak plasma levels of 2.2 ug/mL and 3.6 ug/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 q12 h for seven days were 2.9 and 0.5 ug/mL, respectively. Following intravenous doses of 400 mg of ofloxacin q12 h, the mean peak and trough plasma steady-state levels ranged, in two different studies, from 5.5 to 7.2 ug/mL and 1.2 to 1.9 ug/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). The mean AUC(0-12) attained after the intravenous administration of 400 mg over 60 min was 43.5 ugCh/mL; the mean AUC(0-l2) attained after the oral administration of 400 mg was 41.2 ugCh/mL (two one- sided t-test, 90% confidence interval was 103-109). [See graph] 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 h following the administration of a single 200 mg oral dose of ofloxacin to 12 healthy volunteers, the average urine ofloxacin concentration was approximately 220 ug/mL. Between 12 and 24 h after administration, the average urine ofloxacin level was approximately 34 ug/mL.

The solubility of ofloxacin in human urine is estimated to be between 7000 and 9000 ug/mL. The maximum expected urinary concentrations of ofloxacin after administration of a 400 mg oral dose is 400 ug/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 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 tablets is reduced in patients with impaired renal function (creatinine clearance rate # 50 mL/min), and dosage adjustment is necessary. (See DOSAGE & ADMINISTRATION)

MEAN PHARMACOKlNETlC PARAMETERS FOR OFLOXACIN FOLLOWING A SINGLE 300 MG DOSE IN HEALTHY VOLUNTEERS AND IN PATIENTS WITH RENAL INSUFFICIENCY

max

Food:

The effect of food on absorption of ofloxacin has not been studied.

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.

Acute Toxicity:

TOXICOLOGY

For both sexes LD50 is estimated to be >70 mg/kg

Subchronic Toxicity:

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:

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 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:

Arthropathy:

MAJOR FINDINGS

FOLLOWING SINGLE DOSES

PARAMETER

CONCENTRATION

(ug/mL or ug/g)

DOSE LEVELS

(mg/kg)

AVERAGE DOSE LEVELS

(mg/kg/day)

AVERAGE DOSE LEVELS

(mg/kg/day)

STUDY

STUDY

STUDY

RESPONSE

STUDY

RESPONSE

REFERENCES

1. Ball P. Overview of experience with ofloxacin in respiratory tract infection. Scand J Infect Dis 1990; 68(Suppl):56-63.

2. Batteiger BE, Jones RB, White A. Efficacy and safety of ofloxacin in the treatment of nongonococcal sexually transmitted disease. Am J Med 1989; 87(Suppl 6C):755-75.

3. Boslego JW, Hicks CB, Greenup R et al. A prospective randomized trial of ofloxacin vs. doxycycline in the treatment of uncomplicated male urethritis. Sex Transm Dis 1988; 15(4):186-91.

4. Corrado ML. Worldwide clinical experience with ofloxacin in urologic cases. Urol 1991; 37(3) (Supp):28-32.

5. Cox CE. Ofloxacin in the management of complicated urinary tract infections, including prostatitis. Amer J Med 1989; 87(Suppl 6C): 615-618.

6. Felmingham D, O'Hare MD, Robbins, MJ et al. Comparative in vitro studies with 4- Quinolone antimicrobials. Drugs Exper Clin Res 1985; X1(5):317-29.

7. Fenelon LE, Mumtaz G, Redgway GL. The in-vitro antibiotic susceptibility of

chlamydia pneumoniae.

J Antibmicrob Chemother 1990; 26:763-7.

Fox AR, and Phillips I. The antibiotic sensitivity of the bacteroides fragilis group in the United Kingdom. J Antibmicrob Chemother 1987; 20:477-88. Fuchs PC, Barry AL, Jones RN et al. Proposed disk diffusion susceptibility criteria for ofloxacin. J Clin Microb 1985; 22:310-1. Fung-Tomc J, Desiderio J, Tsai Y et al. In vitro and in vivo antibacterial activities of BMY 40062, a new fluoronaphthyridone. Antimicrob Agents Chemother 1989; 30:906- 14. Furuhama K, Akahane K, Kato M et al. 10-Day oral nephrotoxicity study of DL-8280, a. synthetic antibacterial agent, in rabbits. Chemo ther (Tokyo) 1984; 32 (Suppl 1):1142-7. Gentry LO, Rodriguez-Gomez G, Zeluff BJ, et al. A comparative evaluation of oral ofloxacin versus intravenous cefotaxime therapy for serious skin and skin structure infections. Amer J Med 1989; 87(Suppl 6C):57S 6C-60S. Goldstein EJC, Citron DM. Comparative activities of cefuroxime, amoxicillin-clavulanic acid, ciprofloxacin, enoxacin, and ofloxacin against aerobic and anaerobic bacteria isolate from bites wounds. Antimicrob Agents Chemother 1988; 32:1143-8. Hooper DC, Wolfson JS. Fluoroquinolone antimicrobial agents. N Eng J Med 1991; 324(6):384-94. Kato M, Ohno H, Yoshida M, et al. 26-Week chronic oral toxicity of dL-8280, a new synthetic antibacterial agent, in rats. Chemo Ther (Tokyo) 1984; 32(Suppl):1121-41. Kato M, Onodera T. Relationship between occurrence of arthropathy by antibacterial drugs and maturity of cartilage abstract. J Toxicol Sci 1985; 10(3):270. Kenny GV, Cartwright FD. Susceptibility of mycoplasma pneumoniae to several new quinolones, tetracycline, and erythromycin. Antimicrob Agents Chemother 1991; 35:587-9. Kenny GE, Hooton TM, Roberts MC, et al. Susceptibilities of genital mycoplasma to the newer quinolones as determined by the agar dilution method. Antimicrob Agents Chemother 1989; 33:103-7. Kurzynski TA, Boehm DM, Rott-Petri JS et al. Antimicrobial susceptibilities of bordetella species isolated in a multicenter pertussis surveillance project. Antimicrob Agents Chemother 1988; 32:137-40. Leysen DC, Haemers A, Pattyn SR. Mycobacteria and the new quinolones. Antimicrob Agents Chemother 1989; 33:1-5. Lipsky B, Tack K, Kuo C, et al. Ofloxacin treatment of chlamydia pneumoniae (Strain TWAR) lower respiratory tract infections. Am J Med 1990; 89:722-4. Lode H, Hoffken G, Olschewski P et al. Pharmacokinetics of ofloxacin after parenteral and oral administration. Antimicrob Agents Chemother 1987; 31:1338-42. Lutz Jr FB. Single-dose efficacy of ofloxacin in uncomplicated gonorrhea. Amer J Med 1989; 87(Suppl 6C):695-745. Mayer D and Bruch K. No indications for the mutagenicity of ofloxacin. Infection 1986; 14(Suppl. 1):108-9. Monk JP, Campoli-Richards DM. Ofloxacin a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 1987; 33:346-391. 26 National Committee for Clinical Laboratory Standards. Methods for dilution; antimicrobial susceptibility tests for bacteria that grow aerobically--Second Edition; Approved Standard. NCCLS Document M7-A2. Villanova 1990; PA:NCCLS.

1. Neu HC, Chin N. In-vitro activity of two new quinolone antimicrobial agents, S025930 and S-25932 compared with that of other agents. J Antimicrob Chemother 1987; 19:175-85.

2. Nomura M, Inage F, Kato M et al. Four-week oral subacute toxicity of DL-8280, A new synthetic antibacterial agent in dogs. Chemo Ther (Tokyo) 1984; 32(Suppl. 1):1105-21.

Ohno H, Inage F, Akahane K et al. Acute toxicity study of DL-8280, a new synthetic antibacterial agent, in mice, rats, dogs and monkeys. Chemo Ther (Tokyo) 1984; 32(Suppl.1):1084-90. Onodera T, Inage F, Yoshida M et al. Four-week oral subacute toxicity of DL-8280, a new synthetic antibacterial agent in rats. Chemo Ther (Tokyo) 1984; 32(Suppl. 1):1091- 104. Phillips I, King A, Shannon K. In vitro properties of the quinolones. The quinolones 1988; 3:83-117. Sanders Jr WE. Ofloxacin in the treatment of lower respiratory tract infections. Postgraduate Medicine A Research Report; McGraw-Hill, Inc. 1992; 1-5. Seibert G, Limbert M, Klesel N. Comparison of the antibacterial in vitro and in vivo activity of ofloxacin (HODE 280 DL 8280) and nalidixic acid analogues. Eur J Clin Microbiol 1983; 2(6):548-53. Shimada H, Ebine Y, Sato T et al. Dominant lethal study in male mice treated with ofloxacin, a new antimicrobial drug. Mutat Res 1985; 144(1):51-5. Stocks JM, Wallace RJ, Griffith DE et al. Ofloxacin in community-acquired lower respiratory infections. Am J Med 1989; 87(suppl 6C): 525-65. Verho M, Malerczyk V, Grotsch H et al. Absence of crystalluria and estimation of renal parameters after oral and intravenous ofloxacin as compared to placebo in healthy volunteers. Drugs Exptl Clin Res 1988; 14:539-45. Wall RA, Mabey DCW, Bello CSS et al. The comparative in vitro activity of twelve 4- quinolone antimicrobials against Haemophilus ducreyi. J Antimicrob Chemother 1985; 16:165-8. Wolfson J, Hooper D. Fluoroquinolone antimicrobial agents. Clin Microb Rev 1989; 378- 424. Floxin Product Monograph for (tm) Tablets and Floxin(tm) I.V. (Ofloxacin) , Ortho-McNeil Inc., Date of Revision: August 22, 1996. Comparative Bioavailability Study of Ofloxacin Tablets in Normal Healthy Volunteers. February 5, 1998. Data on file at Novopharm Limited.