FLOXIN® (ofloxacin injection) I.V. is a synthetic, broad-spectrum antimicrobial agent for intravenous 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. The chemical structure is:

Its empirical formula is C ₁₈ H ₂₀ FN ₃ O ₄ , and its molecular weight is 361.4. Ofloxacin is an off-white to pale yellow crystalline powder. 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 (solubility falls to 4 mg/mL) 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 .

FLOXIN I.V. IN SINGLE-USE VIALS is a sterile, preservative-free aqueous solution of ofloxacin with pH ranging from 3.5 to 5.5. FLOXIN I.V. IN PRE-MIXED BOTTLES and IN PRE-MIXED FLEXIBLE CONTAINERS are sterile, preservative-free aqueous solutions of ofloxacin with pH ranging from 3.8 to 5.8. The color of FLOXIN I.V. may range from light yellow to amber. This does not adversely affect product potency. FLOXIN I.V. IN SINGLE-USE VIALS contains ofloxacin in Water for Injection. FLOXIN I.V. IN PRE-MIXED BOTTLES and IN PRE-MIXED FLEXIBLE CONTAINERS are dilute, non-pyrogenic, nearly isotonic pre-mixed solutions that contain ofloxacin in 5% Dextrose (D ₅ W). Hydrochloric acid and sodium hydroxide may have been added to adjust the pH.

The flexible container is fabricated from a specially formulated non-plasticized, thermoplastic copolyester (CR3). The amount of water that can permeate from the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the flexible container can leach out certain of the container's chemical components in very small amounts within the expiration period. The suitability of the container material has been confirmed by tests in animals according to USP biological tests for plastic containers.

Following a single 60-minute intravenous infusion of 200 mg or 400 mg of ofloxacin to normal volunteers, the mean maximum plasma concentrations attained were 2.7 and 4.0 µg/mL, respectively; the concentrations at 12 hours (h) after dosing were 0.3 and 0.7 µg/mL, respectively.

Steady-state concentrations were attained after four doses, and the area under the curve (AUC) was approximately 40% higher than the AUC after a single dose. The mean peak and trough plasma steady-state levels attained following intravenous administration of 200 mg of ofloxacin q 12 h for seven days were 2.9 and 0.5 µg/mL, respectively. Following intravenous doses of 400 mg of ofloxacin q 12 h, the mean peak and trough plasma steady-state levels ranged, in two different studies, from 5.5 to 7.2 µg/mL and 1.2 to 1.9 µg/mL, respectively.

Following 7 days of intravenous administration, the elimination half-life of ofloxacin was 6 h (range 5 to 10 h). The total clearance and the volume of distribution were approximately 15 L/h and 120 L, respectively.

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.

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 µg·h/mL; the mean AUC _(0-12) attained after the oral administration of 400 mg was 41.2 µg·h/mL (two one-sided t-test, 90% confidence interval was 103-109). [See following chart.]

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 µg/mL. Between 12 and 24 h after administration, the average urine ofloxacin level was approximately 34 µg/mL.

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.

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 was 7 to 8 h, as compared to approximately 6 h in younger adults.

Clearance of ofloxacin is reduced in patients with impaired renal function (creatinine clearance </= 50 mL/min), and dosage adjustment is necessary. (See PRECAUTIONS : General and DOSAGE AND ADMINISTRATION .)

Microbiology

Ofloxacin has in vitro activity 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.

Ofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the section

The following in vitro data are available, but their clinical significance is unknown.

Ofloxacin exhibits in vitro minimum inhibitory concentrations (MIC's) of 2 µg/mL or less against most (>/=90%) strains of the following microorganisms; however, the safety and effectiveness of ofloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:

Ofloxacin is not active against Treponema pallidum . (See .)

Many strains of other streptococcal species, Enterococcus species, and anaerobes are resistant to ofloxacin.

Resistance to ofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10 ^-9 to 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.

Susceptibility Tests

Dilution techniques:

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method ¹ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ofloxacin powder. The MIC values should be interpreted according to the following criteria:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ofloxacin powder should provide the following MIC values:

Diffusion techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure ² requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-µg ofloxacin to test the susceptibility of microorganisms to ofloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg ofloxacin disk should be interpreted according to the following criteria:

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ofloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-µg ofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:

FLOXIN (ofloxacin injection) I.V. is indicated for the treatment of adults with mild to moderate infections (unless otherwise indicated) caused by susceptible strains of the designated microorganisms in the infections listed below - when intravenous administration offers a route of administration advantageous to the patient, (e.g., patient cannot tolerate an oral dosage form). Please see DOSAGE AND ADMINISTRATION for specific recommendations.

The safety and effectiveness of the intravenous formulation in treating patients with severe infections have not been established.

NOTE: IN THE ABSENCE OF VOMITING OR OTHER FACTORS INTERFERING WITH THE ABSORPTION OF ORALLY ADMINISTERED DRUG, PATIENTS RECEIVE ESSENTIALLY THE SAME SYSTEMIC ANTIMICROBIAL THERAPY AFTER EQUIVALENT DOSES OF OFLOXACIN ADMINISTERED BY EITHER THE ORAL OR THE INTRAVENOUS ROUTE. THEREFORE, THE INTRAVENOUS FORMULATION DOES NOT PROVIDE A HIGHER DEGREE OF EFFICACY OR MORE POTENT ANTIMICROBIAL ACTIVITY THAN AN EQUIVALENT DOSE OF THE ORAL FORMULATION OF OFLOXACIN.

Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae or Streptococcus pneumoniae .

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 . (See .)

Nongonococcal urethritis and cervicitis due to Chlamydia trachomatis . (See .)

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

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

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 .

*= Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients.

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.

CONTRAINDICATIONS

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.

PRECAUTIONS

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 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 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 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 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 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 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 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 .)

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 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 .)

ADVERSE REACTIONS

The following is a compilation of the data for ofloxacin based on clinical experience with both the oral and intravenous 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%, headache 1%, dizziness 1%, diarrhea 1%, vomiting 1%, rash 1%, pruritus 1%, external genital pruritus in women 1%, vaginitis 1%, dysgeusia 1%.

Local injection site reactions (phlebitis, swelling, erythema) were reported in approximately 2% of patients treated with the 3.63 mg/mL final infusion concentration of intravenous ofloxacin used in the clinical safety trials. The final infusion concentration of intravenous ofloxacin in the commercially available intravenous preparations is 4.0 mg/mL. To date, individuals administered the 4.0 mg/mL concentration of the intravenous ofloxacin have demonstrated clinically acceptable rates of local injection site reactions. Due to the small difference in concentration, significant differences in local site reactions are unexpected with the 4.0 mg/mL concentration.

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.

Additional events, occurring in clinical trials at a rate of less than 1%, regardless of relationship to drug, were:

The following laboratory abnormalities appeared in >/= 1.0% 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.

Post-Marketing Adverse Events:

Additional adverse events, regardless of relationship to drug, reported from worldwide marketing experience with quinolones, including ofloxacin:

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.

CRYSTALLURIA and CYLINDRURIA HAVE BEEN REPORTED with other quinolones.

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

FLOXIN I.V. should only be administered by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

CAUTION: RAPID OR BOLUS INTRAVENOUS INFUSION MUST BE AVOIDED. Ofloxacin injection should be infused intravenously slowly over a period of not less than 60 minutes. (See PRECAUTIONS .)

Single-use vials require dilution prior to administration. (See PREPARATION FOR ADMINISTRATION .)

The usual dose of FLOXIN (ofloxacin injection) I.V. is 200 mg to 400 mg administered by slow infusion over 60 minutes every 12 h as described in the following dosing chart. These recommendations apply to patients with mild to moderate infection and 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.

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.

Men: Creatinine clearance (mL/min) =       Weight (kg) x (140-age)    
                                                            72 x serum creatinine (mg/dL)

Women: 0.85 x 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.

PREPARATION OF OFLOXACIN INJECTION FOR ADMINISTRATION

FLOXIN I.V. IN SINGLE-USE VIALS:

FLOXIN I.V. is supplied in single-use vials containing a concentrated ofloxacin solution with the equivalent of 400 mg of ofloxacin in Water for Injection. The 10 mL vials contain 40 mg of ofloxacin/mL. THESE FLOXIN I.V. SINGLE-USE VIALS MUST BE FURTHER DILUTED WITH AN APPROPRIATE SOLUTION PRIOR TO INTRAVENOUS ADMINISTRATION. ( See COMPATIBLE INTRAVENOUS SOLUTIONS .) The concentration of the resulting diluted solution should be 4 mg/mL prior to administration.

This parenteral drug product should be inspected visually for discoloration and particulate matter prior to administration.

Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final parenteral solution. Since the vials are for single-use only, any unused portion should be discarded.

Since only limited data are available on the compatibility of ofloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to FLOXIN I.V. in single-use vials or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of FLOXIN I.V. with an infusion solution compatible with FLOXIN I.V. and with any other drug(s) administered via this common line.

Prepare the desired dosage of ofloxacin according to the following chart:

For example, to prepare a 200-mg dose using the 10 mL vial (40 mg/mL), withdraw 5 mL and dilute with a compatible intravenous solution to a total volume of 50 mL.

Compatible Intravenous Solutions:

Any of the following intravenous solutions may be used to prepare a 4 mg/mL ofloxacin solution with the approximate pH values:

FLOXIN I.V. PRE-MIXED IN SINGLE-USE FLEXIBLE CONTAINERS:

FLOXIN I.V. is also supplied in 50 mL and 100 mL flexible containers containing a pre-mixed, ready-to-use ofloxacin solution in D ₅ W for single-use. NO FURTHER DILUTION OF THIS PREPARATION IS NECESSARY. Each 50 mL pre-mixed flexible container already contains a dilute solution with the equivalent of 200 mg of ofloxacin (4 mg/mL) in 5% Dextrose (D ₅ W). Each 100 mL pre-mixed flexible container already contains a dilute solution with the equivalent of 400 mg of ofloxacin (4 mg/mL) in 5% Dextrose (D ₅ W).

This parenteral drug product should be inspected visually for discoloration and particulate matter prior to administration.

Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final parenteral solution. Since the pre-mixed flexible containers are for single-use only, any unused portion should be discarded.

Since only limited data are available on the compatibility of ofloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to FLOXIN I.V. in flexible containers or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of FLOXIN I.V. with an infusion solution compatible with FLOXIN I.V. and with any other drug(s) administered via this common line.

Instructions for the Use of FLOXIN I.V. PRE-MIXED IN FLEXIBLE CONTAINERS:

To open:

1. Tear outer wrap at the notch and remove solution container.

2. Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as the sterility may be compromised.

3. Do not use if the solution is cloudy or a precipitate is present.

4. Use sterile equipment.

5. WARNING: Do not use flexible containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Preparation for administration:

1. Close flow control clamp of administration set.

2. Remove cover from port at bottom of container.

3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.

4. Suspend container from hanger.

5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of FLOXIN I.V. IN PRE-MIXED FLEXIBLE CONTAINERS.

6. Open flow control clamp to expel air from set. Close clamp.

7. Regulate rate of administration with flow control clamp.

Stability of FLOXIN I.V. as Supplied:

When stored under recommended conditions, FLOXIN I.V., as supplied in 10 mL vials, and 50 mL and 100 mL flexible containers, is stable through the expiration date printed on the label.

Stability of FLOXIN I.V. Following Dilution:

FLOXIN I.V., when diluted in a compatible intravenous fluid to a concentration between 0.4 mg/mL and 4 mg/mL, is stable for 72 h when stored at or below 75°F or 24°C and for 14 days when stored under refrigeration at 41°F or 5°C in glass bottles or plastic intravenous containers. Solutions that are diluted in a compatible intravenous solution and frozen in glass bottles or plastic intravenous containers are stable for 6 months when stored at -4°F or -20°C. Once thawed, the solution is stable for up to 14 days, if refrigerated at 36°F to 46°F (2°C to 8°C). THAW FROZEN SOLUTIONS AT ROOM TEMPERATURE (77°F OR 25°C) OR IN A REFRIGERATOR (46°F OR 8°C). DO NOT FORCE THAW BY MICROWAVE IRRADIATION OR WATER BATH IMMERSION. DO NOT REFREEZE AFTER INITIAL THAWING.

HOW SUPPLIED

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 .) 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

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically -- Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December, 1993.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests -- Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December, 1993.

ORTHO-McNEIL PHARMACEUTICAL, INC.

Raritan, NJ USA 08869

© OMP 1998   Revised March 1998            635-10-267-4

PRODUCT PHOTO(S):