Community-acquired Pneumonia due to Haemophilus influenzae or Streptococcus pneumoniae .

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

Acute, uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae.

Nongonococcal urethritis and cervicitis due to Chlamydia trachomatis.

Mixed infections of the urethra and cervix due to Chlamydia trachomatis and Neisseria gonorrhoeae.

Acute pelvic inflammatory disease (including severe infection) due to Chlamydia trachomatis and/or Neisseria gonorrhoeae.

NOTE: If anaerobic microorganisms are suspected of contributing to the infection, appropriate therapy for anaerobic pathogens should be administered.

Uncomplicated cystitis due to Citrobacter diversus, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa.

Complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Citrobacter diversus  , or Pseudomonas aeruginosa.

Prostatitis due to Escherichia coli .

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.

CONTRAINDICATIONS:

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

CLINICAL PHARMACOLOGY:

 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. Ofloxacin has biphasic elimination. Following multiple oral doses at steady-state administration, accumulation at steady-state can be estimated using a half-life of 9 hours. Elimination is mainly by renal excretion. Four to eight percent of an Ofloxacin dose is excreted in the feces. This indicates a small degree of biliary excretion of Ofloxacin. Following oral administration of recommended therapeutic doses, Ofloxacin has been detected in blister fluid, cervix, lung tissue, ovary, prostatic fluid, prostatic tissue, skin, and sputum. The mean concentration of Ofloxacin in each of these various body fluids and tissues after one or more doses was 0.8 to 1.5 times the concurrent plasma level. Inadequate data are presently available on the distribution or levels of Ofloxacin in the cerebrospinal fluid or brain tissue. The administration of Ofloxacin with food does not affect the C _max and AUC _(infinity) of the drug, but T _max is prolonged. Clearance of Ofloxacin is reduced in patients with impaired renal function (creatinine clearance rate </= 50 mL/min), and dosage adjustment is necessary. The rate of oral absorption is unaffected by age or gender. 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.

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. Fluoroquinolones, including ofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and (beta)-lactam antibiotics, including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials. Cross-resistance has been observed between Ofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to ofloxacin.

Ofloxacin has been shown to be active against most strains of the following microorganisms:

Aerobic gram-positive microorganisms: Staphylococcus aureus (methicillin-susceptible strains), Streptococcus pneumoniae (penicillin-susceptible strains),

Streptococcus pyogenes,

Aerobic gram-negative microorganisms: Citrobacter (diversus) koser, Enterobacter aerogenes, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Neisseria gonorrhoeae, Proteus mirabilis, Pseudomonas aeruginosa.

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

Other microorganisms: Chlamydia trachomatis

WARNINGS:

THE SAFETY AND EFFICACY OF OFLOXACIN IN PEDIATRIC PATIENTS AND ADOLESCENTS (UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED.

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 (e.g., severe cerebral arteriosclerosis, epilepsy) 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.

Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions have been reported in patients receiving therapy with quinolones, including Ofloxacin. 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.

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.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Ofloxacin, and may range in severity from mild to life-threatening. 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 colitis.

Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported with Ofloxacin and other quinolones. Ofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon.

Ofloxacin has not been shown to be 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.

PRECAUTIONS:

 General: Adequate hydration of patients receiving Ofloxacin should be maintained to prevent the formation of highly concentrated urine. 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.

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) occurs.

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. If a hypoglycemic reaction occurs in a patient being treated with Ofloxacin, discontinue ofloxacin immediately.

Pregnancy: Pregnancy Category C. There are, however, no adequate and well-controlled studies in pregnant women. Ofloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: 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.

Pediatric Use: Safety and effectiveness in pediatric patients and adolescents below the age of 18 years have not been established. Ofloxacin causes arthropathy (arthrosis) and osteochondrosis in juvenile animals of several species.

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 chewable/buffered tablets or the pediatric powder for oral solution may substantially interfere with the absorption of quinolones resulting in systemic levels considerably lower than desired. These agents should not be taken within the two-hour period before or within the two-hour period after Ofloxacin administration.

Drugs metabolized by Cytochrome P450 enzymes: Most quinolone antimicrobial drugs inhibit cytochrome P450 enzyme activity. This may result in a prolonged half-life for some drugs that are also metabolized by this system (e.g., cyclosporine, theophylline/methylxanthines, warfarin) when co-administered with quinolones. The extent of this inhibition varies among different quinolones.

Non-steroidal anti-inflammatory drugs: The concomitant administration of a non-steroidal anti-inflammatory drug with a quinolone, including ofloxacin, may increase the risk of CNS stimulation and convulsive seizures.

Theophylline : 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.

Warfarin : If a quinolone antimicrobial is administered concomitantly with warfarin or its derivatives, the prothrombin time or other suitable coagulation test should be closely monitored.

Antidiabetic agents (e.g., insulin, glyburide/glibenclamide) : Since disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concurrently with quinolones and an antidiabetic agent, careful monitoring of blood glucose is recommended when these agents are used concomitantly.

SIDE EFFECTS:

The following events were considered likely to be drug-related in patients receiving multiple doses of Ofloxacin: nausea 3%, insomnia 3%, headache 1%, dizziness 1%, diarrhea 1%, vomiting 1%, rash 1%, pruritus 1%, external genital pruritus in women 1%, vaginitis 1%, dysgeusia 1%.

The most frequently reported adverse events, regardless of relationship to drug, were: nausea 10%, headache 9%, insomnia 7%, external genital pruritus in women 6%, dizziness 5%, vaginitis 5%, diarrhea 4%, vomiting 4%.

The following events, regardless of relationship to drug, occurred in 1 to 3% of patients: Abdominal pain and cramps, chest pain, decreased appetite, dry mouth, dysgeusia, fatigue, flatulence, gastrointestinal distress, nervousness, pharyngitis, pruritus, fever, rash, sleep disorders, somnolence, trunk pain, vaginal discharge, visual disturbances, and constipation.

OVERDOSAGE: Information on overdosage with Ofloxacin is limited. In the event of an acute overdose, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Ofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.  

DOSAGE AND ADMINISTRATION:

 The usual dose of Ofloxacin tablets is 200 mg to 400 mg orally every 12 h as described in the following dosing chart. These recommendations apply to patients with normal renal function (i.e., creatinine clearance > 50 mL/min).

Patients with Normal Renal Function:

Patients with Impaired Renal Function: Dosage should be adjusted for patients with a creatinine clearance </= 50 mL/min. After a normal initial dose, dosage should be adjusted as follows:

When only the serum creatinine is known, the following formula may be used to estimate creatinine clearance.

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.

How Supplied: Each Pack of Ruz-Ofloxacin 200 mg or 300 mg tablets contain 20 tablets in 2 blisters.

storage: Store in well-closed containers. Store below 30°C.

Reference: Reference: PDR 2000, page 2149-2153

                  USPDI for Professional Health Care, 2004, Page 1380-1397

                  Martindale 2005, Page 239-240