PERK

OFO
(Copyright 2000 - PERK)

Technical Literature

 Categories: Antibacterials; Anti-Infectives; Antibiotics; Antimicrobials; Bronchitis; Chlamydia; Chronic Bronchitis; Cystitis; Eye, Ear, Nose, & Throat Preparations; Fluoroquinolones; Gonorrhea; H. Influenzae Pneumonia; Ophthalmics; Pneumonia; Prostatitis; Respiratory Tract Infections; Sexually Transmitted Diseases; Skin Infections; Urethritis; Urinary Antibacterial; Urinary Tract Infections; Tuberculosis; Pregnancy Category C;

Cost of Therapy: India-Rs. 111.72 (Perk) US-$43.09 (Urinary Infections; Tablet; 200 mg; 2/day; 7 days) vs. Potential Cost of $4,090.49 (DRG 320, Urinary Tract Infections)

Table of Contents:

Description
Clinical Pharmacology
Indications and Usage
Contraindications
Precautions
Drug Interactions
Adverse Reactions
Overdosage
Dosage and Administration
Animal Pharmacology
How Supplied
 

Description:

OFO Tablets are a synthetic broad-spectrum antimicrobial agent for oral administration. Chemically, ofloxacin, a fluorinated carboxyquinolone, is the racemate, ()-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. Its empirical formula is C18H20FN3O4, and its molecular weight is 361.4. Ofloxacin is an off-white to pale yellow crystalline powder. The molecule exists as a zwitterion at the pH conditions in the small intestine. 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 and freely soluble in aqueous solutions with pH above 9. Ofloxacin has the potential to form stable coordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Fe+3 > Al+3 > Cu+2 > Ni+2> Pb+2 > Zn+2 > Mg+2> Ca+2 > Ba+2.

Tablets: OFO tablets contain the following inactive ingredients: anhydrous lactose, corn starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and may also contain synthetic yellow iron oxide.

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.

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. Absorption of ofloxacin after single or multiple doses of 100 to 400 mg is predictable, and the amount of drug absorbed increases proportionately with the dose.

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. TABLE 1 shows 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 oral doses of 400 mg.

TABLE 1 -

Oral Dose

Serum Concentration 2 hours after admin. (mcg/ml)

Area Under the Curve (AUC(0-00)) (mcgh/ml)

200 mg single dose

1.5

14.1

300 mg single dose

2.4

21.2

400 mg single dose

2.9

31.4

400 mg steady state

4.6

61.0

 

Steady-state concentrations were attained after four oral doses and 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 doses, peak serum levels of 2.2 mcg/ml and 3.6 mcg/ml, respectively, are predicted at steady-state.

Elimination of ofloxacin is primarily by renal excretion. Approximately 65% of a dose is excreted renally within 48 h. Studies indicate that <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 is excreted in the feces. This indicates a small degree of biliary excretion of ofloxacin.

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

Microbiology

Ofloxacin has in vitroactivity against a broad spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria. Ofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations. Ofloxacin is thought to exert a bactericidal effect on susceptible microorganisms by inhibiting DNA gyrase, an essential enzyme that is a critical catalyst in the duplication, transcription, and repair of bacterial DNA.

Cross-resistance has been observed between ofloxacin and other fluoroquinolones. There is generally no cross-resistance between ofloxacin and other classes of antibacterial agents such as beta-lactams or aminoglycosides.

Ofloxacin has been shown to be active against most strains of the following organisms both in vitro and in specific clinical infections; (See INDICATIONS AND USAGE).

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.

Resistance to ofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9to 10-11). To date, emergence of resistance has been relatively uncommon in clinical practice. With the exception of Pseudomonas aeruginosa (10%), less than a 4% rate of resistance emergence has been reported for most other species. Although cross-resistance has been observed between ofloxacin and other fluoroquinolones, some organisms resistant to other quinolones may be susceptible to ofloxacin.

Aerobes, Gram-Positive: Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae.

Aerobes, Gram-Negative: Enterobacter cloacae, Haemophilus influenzae, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens*

Anaerobic Species: Propionibacterium acnes

*Efficacy for this organism was studied in fewer than 10 infections

 

Indications and Usage:

OFO tablets are indicated for the treatment of adults with mild to moderate infections caused by susceptible strains of the designated microorganisms in the infections listed below

Lower Respiratory Tract

Acute bacterial exacerbations of chronic bronchitis due toHaemophilus influenzae or Streptococcus pneumoniae.

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

Skin and Skin Structures

Uncomplicated skin and skin structure infections due toStaphylococcus aureus, Streptococcus pyogenes, or Proteus mirabilis.*

Sexually Transmitted Diseases (See WARNINGS).

Acute, uncomplicated urethral and cervical gonorrhea due toNeisseria gonorrhoeae.

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

Urinary Tract

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.*

Prostate

Prostatitis due to Escherichia coli.

* Although treatment of infections due to this organism in this infection demonstrated a clinically acceptable overall outcome, efficacy was demonstrated in fewer than 10 infections.

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 results become available, appropriate therapy should be continued.

As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ofloxacin. 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 contributing to the infection, appropriate therapy for anaerobic pathogens should be administered like OFO-T Tablets & Suspension (Ofloxacin + Tinidazole).

Contraindications:

Ofloxacin is contraindicated in persons with a history of hypersensitivity to ofloxacin, to other quinolones, or to any of the components in this medication.

Precautions:

General

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

Administer ofloxacin with caution in the presence of renal or hepatic insufficiency/impairment.

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., skin eruption, etc.) occurs.

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

As with other quinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported

As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Information for Patients

Tablets: Patients should be advised:

--to drink fluids liberally if able to take fluids by the oral route.

--that ofloxacin should not be taken with food.

--that ofloxacin may cause neurologic adverse effects (e.g., dizziness, lightheadedness, etc.) 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.

--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, etc.), or any other symptom of an allergic reaction.

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

--that mineral supplements, vitamins with iron or minerals, calcium-, aluminum- or magnesium-based antacids or sucralfate should not be taken within the two-hour period before or within the two-hour period after taking ofloxacin.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Ofloxacin was not mutagenic in the Ames test, in vitro and in vivo cytogenetic assay, sister chromatid exchange (Chinese Hamster and human cell lines), unscheduled DNA synthesis (UDS) assay using human fibroblasts, the dominant lethal assay, or mouse micronucleus assay. In fertility studies in rats, ofloxacin did not affect male or female fertility or morphological or reproductive performance at oral dosing up to 360 mg/kg/day (equivalent to 4000 times the maximum recommended daily ophthalmic dose).

Pregnancy

Teratogenic Effects: Pregnancy Category C: Ofloxacin has been shown to have an embryocidal effect in rats and in rabbits when given in doses of 810 mg/kg/day (equivalent to 9000 times the maximum recommended daily ophthalmic dose) and 160 mg/kg/day (equivalent to 1800 times the maximum recommended daily ophthalmic dose). These dosages resulted in decreased fetal body weight and increased fetal mortality in rats and rabbits, respectively. Minor fetal skeletal variations were reported in rats receiving doses of 810 mg/kg/day. Ofloxacin has not been shown to be teratogenic at doses as high as 810 mg/kg/day and 160 mg/kg/day when administered to pregnant rats and rabbits, respectively.

Nonteratogenic Effects: Additional studies in rats with doses up to 360 mg/kg/day during late gestation showed no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn.

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

Nursing Mothers

In nursing women a single 200 mg oral dose of ofloxacin resulted in concentrations of ofloxacin in milk that were similar to those found in plasma. It is not known whether ofloxacin is excreted in human milk following topical ophthalmic administration. Because of the potential for 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

Should be used with caution in children above six months.

There is no evidence that the oral dosage form of ofloxacin has any effect on weight bearing joints.

Drug Interactions:

Antacids, Sucralfate, Metal Cations, Multivitamins: Tablets: 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 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.

Caffeine: Interactions between ofloxacin and caffeine have not been detected.

Cimetidine: Cimetidine has demonstrated interference with the elimination of some quinolones. This interference has resulted in significant increases in half-life and AUC of some quinolones. The potential for interaction between ofloxacin and cimetidine has not been studied.

Cyclosporine: Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with some other quinolones. The potential for interaction between ofloxacin and cyclosporine has not been studied.

Drugs metabolized by Cytochrome P450 enzymes: Most quinolone antimicrobial drugs inhibit cytochrome P450 enzyme activity. This may result in a prolonged half-life for some drugs that are also metabolized by this system (e.g., cyclosporine, theophylline/methylxanthines, warfarin, etc.) 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.

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: Although concurrent administration of some quinolones with theophylline may result in impaired elimination of theophylline, the extent of such impairment varies among different quinolones. Steady-state theophylline levels may increase when ofloxacin and theophylline are administered concurrently. In a pharmacokinetic study involving 15 healthy male subjects, steady-state peak theophylline concentration increased by an average of approximately 9%, and the AUC increased by an average of approximately 13% when oral ofloxacin and theophylline were administered concurrently. In clinical trials with intravenous ofloxacin, theophylline concentrations were determined in 41 patients who were treated with both drugs. In 38 patients, no apparent elevation in the serum theophylline was discernible. Marginal increases above the theophylline therapeutic range were reported in 3 patients; clinical toxicity was, however, not reported in these three patients. Generally, patients receiving theophylline in clinical trials of the intravenous formulation of ofloxacin reported nausea more frequently than those patients not receiving theophylline. As with some other quinolones, concomitant administration of ofloxacin may prolong the half-life of theophylline, elevate serum theophylline levels, and may increase the risk of theophylline-related adverse reactions. Theophylline levels should be closely monitored and theophylline dosage adjustments made, if appropriate, when ofloxacin is co-administered.

Warfarin: Some quinolones have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. Therefore, if a quinolone antimicrobial is administered concomitantly with warfarin or its derivatives, the prothrombin time or other suitable coagulation test should be closely monitored.

Antidiabetic agents (e.g.,insulin, glyburide/glibenclamide, 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:

The following is a compilation of the data for ofloxacin based on clinical experience with the oral 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, only 4% discontinued ofloxacin due to adverse experiences.

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

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

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

Overdosage:

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:

Tablets

The usual dose of ofloxacin tablets are 200 mg to 400 mg orally every 12 h as described in the following dosing chart ( TABLE 8). These recommendations apply to patients with normal renal function (i.e., creatinine clearance > 50 ml/min). For patients with altered renal function (i.e., creatinine clearance <= 50 ml/min), see the Patients with Impaired Renal Function subsection.

TABLE 6 - Patients with Normal Renal Function

Infection

Description*

Unit Daily Dose

Frequency

Duration

Dose

Lower Respiratory

Exacerbation of Chronic Bronchitis

400 mg

q12h

10 days

800 mg

Tract

Com. Acq. Pneumonia

400 mg

q12h

10 days

800 mg

Skin and Skin

Uncomplicated infections

400 mg

q12h

10 days

800 mg

Structures Sexually Transmitted Diseases

Acute, uncomplicated gonorrhea

400 mg

single dose

1 day

400 mg

Cervicitis/urethritis due to C. trachomatis

300 mg

q12h

7 days

600 mg

 

Cervicitis/urethritis due to C. trachomatis and N. gonorrhoeae

300 mg

q12h

7 days

600 mg

 

Urinary Tract

Cystitis due to E. coli or K. pneumoniae

200 mg

q12h

3 days

400 mg

Cystitis due to other approved pathogens

200 mg

q12h

7 days

400 mg

 

Complicated UTI's

200 mg

q12h

10 days

400 mg

 

Prostate

Prostatitis due to E. coli

300 mg

q12h

6 wks**

600 mg

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 ofloxacin administrations

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 ( TABLE 7):

TABLE 7 -

Creatinine Clearance

Maintenance Dose

Frequency

10-50 ml/min

the usual recommended unit dose

q24h

< 10 ml/min

1/2 the usual recommended unit dose

q24h

When only the serum creatinine is known, the following formula (TABLE 8) may be used to estimate creatinine clearance.

TABLE 8 - Creatinine clearance (ml/min)

Men: [Weight (kg) (140-age)] [72 serum creatinine (mg/dl)]

Women: 0.85 the value calculated for men.

The serum creatinine should represent a steady-state of renal function.

Patients with Cirrhosis: The excretion of ofloxacin may be reduced in patients with severe liver function disorders (e.g., cirrhosis with or without ascites). A maximum dose of 400 mg of ofloxacin per day should therefore not be exceeded.

Animal Pharmacology:

Ofloxacin, as well as other drugs of the quinolone class, has been shown to cause arthropathies (arthrosis) in immature dogs and rats. In addition, these drugs are associated with an increased incidence of osteochondrosis in rats as compared to the incidence observed in vehicle- treated rats. There is no evidence of arthropathies in fully mature dogs at intravenous doses up to 3 times the recommended maximum human dose (on a mg/m2 basis or 5 times based on a mg/kg basis), for a one-week exposure period.

Long-term, high-dose systemic use of other quinolones in experimental animals has caused lenticular opacities; however, this finding was not observed in any animal studies with ofloxacin.

Reduced serum globulin and protein levels were observed in animals treated with other 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.

Crystalluria and ocular toxicity were not observed in any animals treated with ofloxacin.

How Supplied:

Tablets

OFO tablets are supplied as 100 mg dispersible & 200 mg orange film-coated tablets. Each tablet is distinguished by "OFO" and the appropriate strength. OFO Tablets are packaged in strips of 10 tablets (100 mg) and blisters of 10 tablets (200 mg).

OFO Tablets should be stored in well-closed containers. Store below 86F (30C).

Tablet, Dispersible - Oral - 100 mg

10's

Rs4.98

OFO 100, PERK PHARMACEUTICALS LIMITED

India

Tablet, Plain Coated - Oral - 200 mg

10's

Rs7.98

OFO 200, PERK PHARMACEUTICALS LIMITED

India

Copyright 2000 PERK PHARMACEUTICALS LIMITED

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