Floxin (Ofloxacin)

FLOXIN®

Janssen-Ortho

Ofloxacin

Antibacterial

Action And Clinical Pharmacology: 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.

Pharmacokinetics: 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.

Elimination is mainly by renal excretion. Ofloxacin undergoes minimal biotransformation.

Indications And Clinical Uses: 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 H. influenzae or S. pneumoniae, M. catarrhalis.

Urinary Tract Infections: Uncomplicated cystitis due to E. coli, K. pneumoniae or P. mirabilis. Complicated urinary tract infections due to E. coli, K. pneumoniae or P. mirabilis.

Prostatitis: due to E. coli.

Sexually Transmitted Diseases: Acute, uncomplicated urethral and cervical gonorrhea due to N. gonorrheae. Urethritis/cervicitis due to C. trachomatis, or mixed infections due to N. gonorrheae and C. trachomatis.

Note: Ofloxacin is not effective in the treatment of syphilis. All patients with gonorrhea should have an initial serologic test for syphilis and a follow-up serologic test after 3 months (see Warnings).

Acute pelvic inflammatory disease of mild to moderate severity appropriate for outpatient management when due to N. gonorrhea and/or C. trachomatis.

Note: Empiric therapy for pelvic inflammatory disease must provide broad spectrum coverage of likely pathogens such as N. gonorrhea, C. trachomatis, anaerobes, G. vaginalis, H. influenzae, enteric gram-negative rods and S. agalactae. Ofloxacin has demonstrated clinical effectiveness only against N. gonorrhea and C. trachomatis, therefore, consideration should be given to inclusion of additional agents if 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 S. aureus or S. 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 in this class, some strains of P. 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.

Contra-Indications: Persons with a history of hypersensitivity to ofloxacin or members of the quinolone group of antibacterial agents.

Manufacturers’ Warnings In Clinical States: 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, Children, Pregnancy, Lactation).

The oral administration of ofloxacin has produced lesions in weight-bearing articular cartilage and lameness in several species of immature animals. 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 Effects).

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 Effects).

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 Effects).

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 C. 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 Effects).

Precautions: General: Periodic assessment of organ system functions, including renal, hepatic and hematopoietic, is advisable during prolonged therapy (see Warnings and Adverse Effects).

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

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

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.

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/m.

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).

Lactation: 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 Effects).

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 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 Drug Interactions and Adverse Effects).

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 with 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 coadministered with quinolones. The extent of this inhibition varies among different quinolones (see other Drug Interactions).

Nonsteroidal Anti-inflammatory Drugs (NSAIDs): The concomitant administration of an NSAID 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 coadministered. 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 i.v. formulations. The incidence of drug-related adverse reactions in patients during phase 2 and 3 clinical trials was 11%. Among patients receiving multiple-dose therapy, 4% discontinued ofloxacin due to adverse experiences.

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

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

The following laboratory abnormalities appeared in ³1% 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, ALT.

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.

Adverse Events

Body System Adverse Event

Special Senses diplopia, nystagmus, blurred vision, disturbances of: taste, smell, hearing and equilibrium, usually reversible following discontinuation

Nervous System nightmares; suicidal thoughts or acts, disorientation, psychotic reactions, paranoia; phobia, agitation, restlessness, aggressiveness/hostility, manic reaction, emotional lability; peripheral neuropathy, ataxia, incoordination; possible exacerbation of: myasthenia gravis and extrapyramidal disorders; dysphasia, lightheadedness (see Warnings and Precautions)

Cardiovascular cerebral thrombosis, pulmonary edema, tachycardia, hypotension/shock, syncope

Respiratory bronchospasm, dyspnea, allergic pneumonitis, stridor

Gastrointestinal hepatic dysfunction including: hepatic necrosis, hepatitis, jaundice (cholestatic or hepatocellular); intestinal perforation; pseudomembranous colitis, gastrointestinal hemorrhage; hiccough, painful oral mucosa, pyrosis (see Warnings)

Genital/Reproductive vaginal candidiasis

Urinary anuria, polyuria, renal failure, renal calculi, urinary retention, interstitial nephritis, hematuria (see Warnings and Precautions)

Skin/Hypersensitivity anaphylactic/anaphylactoid reactions/shock; purpura, serum sickness, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, photosensitivity, toxic epidermal necrolysis, erythema nodosum, hyperpigmentation, conjunctivitis, vesiculobullous eruption (see Warnings and Precautions)

Endocrine/Metabolic hyper- or hypoglycemia, especially in diabetic patients on insulin or oral hypoglycemic agents (see Precautions, General and Drug Interactions)

Hematopoietic anemia, including hemolytic and aplastic; hemorrhage, pancytopenia, agranulocytosis, leukopenia, reversible bone marrow depression, thrombocytopenia, thrombotic thrombocytopenic purpura, petechiae, ecchymosis/bruising (see Warnings)

Musculoskeletal tendonitis/rupture; weakness

Laboratory Abnormalities Hematopoietic: prolongation of prothrombin time Serum Chemistry: acidosis, elevation of: serum triglycerides, serum cholesterol, serum potassium, liver function tests including: GGTP, LDH, bilirubin Urinary: albuminuria, candiduria

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 Overdose: Symptoms: Information on overdosage with ofloxacin is limited. One incident of accidental overdosage has been reported. In this case, an adult female received 3 g of ofloxacin i.v. over 45 minutes. A blood sample obtained 15 minutes after the completion of the infusion revealed an ofloxacin level of 39.3 g/mL. In 7 hours, the level had fallen to 16.2 g/mL, and by 24 hours to 2.7 g/mL. During the infusion, the patient developed drowsiness, nausea, dizziness, hot and cold flushes, subjective facial swelling and numbness, slurring of speech, and mild to moderate disorientation. All complaints except the dizziness subsided within 1 hour after discontinuation of the infusion. The dizziness, most bothersome while standing, resolved in approximately 9 hours. Laboratory testing reportedly revealed no clinically significant changes in routine parameters in this patient.

Treatment: 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.

Antacids containing calcium, magnesium or aluminum; sucralfate; divalent or trivalent cations such as iron; or multivitamins containing zinc should not be taken within the 2-hour period before or within the 2-hour period after oral administration of ofloxacin (see Precautions).

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

72xserum creatinine (mg/dL)

Women: 0.85xthe value calculated for men.

Males:

Creatinine clearance (mL/s)= Weight (kg)x(140-age)

49xserum creatinine (mmol/L)

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

72xserum creatinine (mg/dL)

Females: 0.85xabove value.

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.

Availability And Storage: 200 mg: Each light yellow, film-coated tablet, engraved with FLOXIN and 200 mg, contains: ofloxacin 200 mg. Nonmedicinal ingredients: anhydrous lactose, cornstarch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide and titanium dioxide. Bottles of 50.

300 mg: Each white, film-coated tablet, engraved with FLOXIN and 300 mg, contains: ofloxacin 300 mg. Nonmedicinal ingredients: anhydrous lactose, cornstarch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide. Bottles of 50.

400 mg: Each pale gold, film-coated tablet, engraved with FLOXIN and 400 mg, contains: ofloxacin 400 mg. Nonmedicinal ingredients: anhydrous lactose, cornstarch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide and titanium dioxide. Bottles of 50.

Store in well-closed containers. Store at controlled room temperature (15 to 30°C).

FLOXIN® Janssen-Ortho Ofloxacin Antibacterial

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