Floxin I.V.

FLOXIN (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.

THE SAFETY AND EFFICACY OF OFLOXACIN IN CHILDREN, ADOLESCENTS (UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (SEE PEDIATRIC USE, USE IN PREGNANCY, AND NURSING MOTHERS SUBSECTIONS IN THE PRECAUTIONS SECTION.)

In the immature rat, the oral administration of ofloxacin at 5 to 16 times the recommended maximum human dose based on mg/kg or 1-3 times based on mg/m 2 increased the incidence and severity of osteochondrosis. The lesions did not regress after 13 weeks of drug withdrawal. Other quinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY .)

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). (See PRECAUTIONS : General , Information for Patients , Drug Interactions and ADVERSE 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), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria/hives, itching, and other serious skin reactions. A few patients had a history of hypersensitivity reactions. The drug should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated. (See PRECAUTIONS and ADVERSE REACTIONS .)

Serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including 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); 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 drug should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity and supportive measures instituted. (See PRECAUTIONS : Information for Patients and ADVERSE REACTIONS .)

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 any antibacterial agent.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate 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 clinically effective against C. difficile colitis. (See ADVERSE REACTIONS .)

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. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. Tendon rupture can occur at any time during or after therapy with ofloxacin.

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. Patients treated with ofloxacin for gonorrhea should have a follow-up serologic test for syphilis after three months and, if positive, treatment with an appropriate antimicrobial should be instituted.

General:

Because a rapid or bolus intravenous injection may result in hypotension, OFLOXACIN INJECTION SHOULD ONLY BE ADMINISTERED BY SLOW INTRAVENOUS INFUSION OVER A PERIOD OF 60 MINUTES. (See DOSAGE AND ADMINISTRATION .)

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. 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. In patients with impaired renal function (creatinine clearance </= 50 mg/mL), alteration of the dosage regimen is necessary. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION .)

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 (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). (See WARNINGS and Drug Interactions .)

A possible interaction between oral hypoglycemic drugs (e.g., glyburide/glibenclamide) or with insulin and fluoroquinolone antimicrobial agents have been reported resulting in a potentiation of the hypoglycemic action of these drugs. The mechanism for this interaction is not known. If a hypoglycemic reaction occurs in a patient being treated with ofloxacin, discontinue ofloxacin immediately and consult a physician. (See Drug Interactions and ADVERSE REACTIONS .)

As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy. (See WARNINGS and ADVERSE REACTIONS .)

Information for Patients:

Patients should be advised:

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

-- that ofloxacin may cause neurologic adverse effects (e.g., dizziness, lightheadedness) 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 (See WARNINGS and ADVERSE REACTIONS );

-- 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), or any other symptom of an allergic reaction (See WARNINGS and ADVERSE REACTIONS );

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

-- to discontinue treatment and inform their physician if they experience pain, inflammation, or rupture of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded;

-- that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent, to discontinue ofloxacin immediately if a hypoglycemic reaction occurs and consult a physician (See PRECAUTIONS : General and Drug Interactions );

-- that convulsions have been reported in patients taking quinolones, including ofloxacin, and to notify their physician before taking this drug if there is a history of this condition.

Drug Interactions:

Antacids, Sucralfate, Metal Cations, Multi-Vitamins:   There are no data concerning an interaction of intravenous quinolones with oral antacids, sucralfate, multi-vitamins, or metal cations. However, no quinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line. (See DOSAGE AND 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) when co-administered with quinolones. The extent of this inhibition varies among different quinolones. (See other Drug Interactions .)

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. (See WARNINGS and PRECAUTIONS : General .)

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 administered 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, if appropriate, when ofloxacin is co-administered. Adverse reactions (including seizures) 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 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 (See PRECAUTIONS : General and Information for Patients .)

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Long-term studies to determine the carcinogenic potential of ofloxacin have not been conducted.

Ofloxacin was not mutagenic in the Ames bacterial test, in vitro and in vivo cytogenetic assay, sister chromatid exchange (Chinese Hamster and Human Cell Lines), unscheduled DNA Repair (UDS) using human fibroblasts, dominant lethal assays, or mouse micronucleus assay. Ofloxacin was positive in the UDS test using rat hepatocytes and Mouse Lymphoma Assay.

Pregnancy: Teratogenic Effects. Pregnancy Category C.

Ofloxacin has not been shown to have any teratogenic effects at oral doses as high as 810 mg/kg/day (11 times the recommended maximum human dose based on mg/m 2 or 50 times based on mg/kg) and 160 mg/kg/day (4 times the recommended maximum human dose based on mg/m 2 or 10 times based on mg/kg) when administered to pregnant rats and rabbits, respectively. Additional studies in rats with oral doses up to 360 mg/kg/day (5 times the recommended maximum human dose based on mg/m 2 or 23 times based on mg/kg) demonstrated no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn. Doses equivalent to 50 and 10 times the recommended maximum human 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 recommended maximum human dose based on mg/m 2 .

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. (See WARNINGS .)

Nursing Mothers:

In lactating females, a single oral 200-mg dose of ofloxacin resulted in concentrations of ofloxacin in milk that 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 .)

Pediatric Use:

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 .)

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

In the event of acute overdose, the patient should be observed and appropriate hydration maintained. Ofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.

SINGLE-USE VIALS:

FLOXIN (ofloxacin injection) I.V. is supplied in single-use vials. Each vial contains a concentrated solution with the equivalent of 400 mg of ofloxacin.

40 mg/mL, 10 mL vials (NDC 0062-1550-01)

FLOXIN I.V. SINGLE-USE VIALS are manufactured for ORTHO-McNEIL PHARMACEUTICAL, INC. by Schering-Plough Products, Inc., Manati, PR 00674.

PRE-MIXED IN FLEXIBLE CONTAINERS:

FLOXIN (ofloxacin injection) I.V. PRE-MIXED IN FLEXIBLE CONTAINERS is supplied as a single-use, pre-mixed solution in 50 mL and 100 mL flexible containers. Each contains a dilute solution with the equivalent of 200 mg or 400 mg of ofloxacin, respectively, in 5% Dextrose (D 5 W).

4 mg/mL (200 mg), 50 mL flexible container (NDC 0062-1553-01)

4 mg/mL (400 mg), 100 mL flexible container (NDC 0062-1552-02)

FLOXIN I.V. PRE-MIXED IN FLEXIBLE CONTAINERS is manufactured for ORTHO-McNEIL, PHARMACEUTICAL, INC. by Abbott Laboratories, North Chicago, IL 60064.

FLOXIN (ofloxacin injection) I.V. in SINGLE-USE VIALS should be stored at controlled room temperature 59°F to 86°F (15°C to 30°C) and protected from light. FLOXIN I.V. PRE-MIXED IN FLEXIBLE CONTAINERS should be stored at or below 77°F or 25°C; however, brief exposure up to 104°F or 40°C does not adversely affect the product. Avoid excessive heat and protect from freezing and light.

Also Available:

TABLETS

Ofloxacin is also available as FLOXIN TABLETS (ofloxacin tablets) 200, 300 and 400 mg.

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. (See WARNINGS .) 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/m 2 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.

Rx only.

FLOXIN is a trademark of ORTHO-McNEIL PHARMACEUTICAL, INC. U.S. Patent No. 4,382,892