Boston Healthcare Consulting

CLINICAL PHARMACOLOGY

Pharmacokinetics

Tablets and Intravenous Infusion

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) to the same group of subjects. The mean steady-state AUC_(0-12) attained after the intravenous administration of 400 mg over 60 min was 43.5 mcg·h/ml; the mean steady-state AUC_(0-12) attained after the oral administration of 400 mg was 41.2 mcg·h/ml (two one-sided t-test, 90% confidence interval was 103-109).

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 mcg/ml. Between 12 and 24 hours after administration, the average urine ofloxacin level was approximately 34 mcg/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 hours, as compared to approximately 6 hours in younger adults. Drug absorption, however, appears to be unaffected by age.

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

Tablets: Ofloxacin has a pyridobenzoxazine ring that appears to decrease the extent of parent compound metabolism. Between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing. Studies indicate that less than 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. The administration of ofloxacin with food does not affect the C_max and AUC _¥ of the drug, but T_max is prolonged.

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 200 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.

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.

Intravenous Infusion: 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 mcg/ml, respectively; the concentrations at 12 hours (h) after dosing were 0.3 and 0.7 mcg/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 mcg/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 mcg/ml and 1.2 to 1.9 mcg/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.

Ophthalmic Solution

Serum, urine and tear concentrations of ofloxacin were measured in 30 healthy women at various time points during a ten-day course of treatment with ofloxacin ophthalmic solution. The mean serum ofloxacin concentration ranged from 0.4 ng/ml to 1.9 ng/ml. Maximum ofloxacin concentration increased from 1.1 ng/ml on day one to 1.9 ng/ml on day 11 after 4 times daily dosing for 10½ days. Maximum serum ofloxacin concentrations after ten days of topical ophthalmic dosing were more than 1000 times lower than those reported after standard oral doses of ofloxacin.

Tear ofloxacin concentrations ranged from 5.7 to 31 mcg/g during the 40 minute period following the last dose on day 11. Mean tear concentration measured four hours after topical ophthalmic dosing was 9.2 mcg/g.

Corneal tissue concentrations of 4.4 mcg/ml were observed four hours after beginning topical ocular application of two drops of ofloxacin ophthalmic solution every 30 minutes. Ofloxacin was excreted in the urine primarily unmodified.

Otic Solution

Drug concentrations in serum (in subjects with tympanostomy tubes and perforated tympanic membranes), in otorrhea, and in mucosa of the middle ear (in subjects with perforated tympanic membranes) were determined following otic administration of ofloxacin solution. In two single-dose studies, mean ofloxacin serum concentrations were low in adult patients with tympanostomy tubes, with and without otorrhea, after otic administration of a 0.3% solution (4.1 ng/ml (n=3) and 5.4 ng/ml (n=5), respectively). In adults with perforated tympanic membranes, the maximum serum drug level of ofloxacin detected was 10 ng/ml after administration of a 0.3% solution. Ofloxacin was detectable in the middle ear mucosa of some adult subjects with perforated tympanic membranes (11 of 16 subjects). The variability of ofloxacin concentration in middle ear mucosa was high. The concentrations ranged from 1.2 to 602 mcg/g after otic administration of a 0.3% solution. Ofloxacin was present in high concentrations in otorrhea (389 - 2850 mcg/g, n=13) 30 minutes after otic administration of a 0.3% solution in subjects with chronic suppurative otitis media and perforated tympanic membranes. However, the measurement of ofloxacin in the otorrhea does not necessarily reflect the exposure of the middle ear to ofloxacin.

Microbiology

Tablet and Intravenous Infusion

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 specific clinical infections; (See INDICATIONS AND USAGE).

Gram-Positive Aerobes: Staphylococcus aureus, Streptococcus pneumoniae, streptococcus pyogenes.

Gram-Negative Aerobes: Citrobacter diversus, Enterobacter aerogenes, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Neisseria gonorrhoeae, Proteus mirabilis, Pseudomonas aeruginosa

Other: Chlamydia trachomatis

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

Ofloxacin exhibits in vitro minimum inhibitory concentrations (MIC's) of 2 mcg/ml or less against most (³90%) 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:

Gram-Positive Aerobes: Staphylococcus epidermidis (excluding methicillin-resistant strains), Staphylococcus haemolyticus, Staphylococcus saprophyticus

Gram-Negative Aerobes: Acinetobacter calcoaceticus, Aeromonas caviae, Aeromonas hydrophila, Bordetella parapertussis, Bordetella pertussis, Citrobacter freundii, Enterobacter cloacae, Haemophilus ducreyi, Klebsiella oxytoca, Moraxella catarrhalis, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Serratia marcescens, Vibrio parahaemolyticus

Anaerobes: Clostridium perfringens, Gardnerella vaginalis

Other Organisms: Chlamydia pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis (including multiple drug-resistant strains), Mycoplasma hominis, Mycoplasma pneumoniae, Ureaplasma urealyticum

Ofloxacin has not been shown to be active against Treponema pallidum. (See WARNINGS).

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.

Otic Solution

Ofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Ofloxacin exerts its antibacterial activity by inhibiting DNA gyrase, a bacterial topoisomerase. DNA gyrase is an essential enzyme which controls DNA topology and assists in DNA replication, repair, deactivation, and transcription. 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 microorganisms, both in vitro and clinically in otic infections as described in the INDICATIONS AND USAGE.

Aerobes, Gram-Positive: Staphylococcus aureus, Streptococcus pneumoniae

Aerobes, Gram-Negative: Haemophilus influenzae, Moraxella catarrhalis, Proteus mirabilis, Pseudomonas aeruginosa

Susceptibility Testing

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 MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method¹ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ofloxacin powder. The MIC values should be interpreted according to the criteria in TABLE 2.

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 MIC values in TABLE 3.

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 procedure² requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-mcg 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-mcg ofloxacin disk should be interpreted according to TABLE 4.

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-mcg ofloxacin disk should provide the following zone diameters in these laboratory test quality control strains (see TABLE 5).

CLINICAL STUDIES

Ophthalmic Solution

Conjunctivitis: In a randomized, double-masked, multicenter clinical trial, ofloxacin ophthalmic solution was superior to its vehicle after 2 days of treatment in patients with conjunctivitis and positive conjunctival cultures. Clinical outcomes for the trial demonstrated a clinical improvement rate of 86% (54/63) for the ofloxacin treated group versus 72% (48/67) for the placebo treated group after 2 days of therapy. Microbiological outcomes for the same clinical trial demonstrated an eradication rate for causative pathogens of 65% (41/63) for the ofloxacin treated group versus 25% (17/67) for the vehicle treated group after two days of therapy. Please note that microbiologic eradication does not always correlate with clinical outcome in anti-infective trials.

Corneal Ulcers: In a randomized, double-masked, multi-center clinical trial of 140 subjects with positive cultures, ofloxacin ophthalmic solution treated subjects had an overall clinical success rate (complete reepithelialization and no progression of the infiltrate for two consecutive visits) of 82% (61/74) compared to 80% (53/66) for the fortified antibiotic group, consisting of 1.5% tobramycin and 10% cefazolin solutions. The median time to clinical success was 11 days for the ofloxacin treated group and 10 days for the fortified treatment group.

INDICATIONS AND USAGE

Tablets and Intravenous Infusion

Ofloxacin tablets and IV are 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- (For Intravenous Infusion: when intravenous administration offers a route of administration advantageous to the patient, [e.g., patient cannot tolerate an oral dosage form]). 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.

* Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studies 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.

Ophthalmic Solution

Ofloxacin ophthalmic solution is indicated for the treatment of infections caused by susceptible strains of the following bacteria in the conditions listed below:

Gram-positive bacteria: Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae.

Gram-negative bacteria: Enterobacter cloacae, Haemophilus influenzae, Proteus mirabilis, Pseudomonas aeruginosa.

Gram-positive bacteria: Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae.

Gram-negative bacteria: Pseudomonas aeruginosa, Serratia marcescens*.

Anaerobic species: Propionibacterium acnes.

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

Otic Solution

Ofloxacin otic solution 0.3% is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below:

Otitis Externa: in adults and pediatric patients, one year and older, due to Staphylococcus aureus and Pseudomonas aeruginosa.

Chronic Suppurative Otitis Media: in patients 12 years and older with perforated tympanic membranes due to Staphylococcus aureus, Proteus mirabilis, and Pseudomonas aeruginosa.

Acute Otitis Media: in pediatric patients one year and older with tympanostomy tubes due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa.

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.

WARNINGS

Tablets and Intravenous Infusion

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 PRECAUTIONS, Pediatric Use, Pregnancy, Nursing Mothers).

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/m² 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).

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).

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, 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, General, PRECAUTIONS, Information for Patients, DRUG INTERACTIONS 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 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 agents.

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 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.

Ophthalmic Solution

NOT FOR INJECTION.

Ofloxacin ophthalmic solution should not be injected subconjunctivally, nor should it be introduced directly into the anterior chamber of the eye.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones, including ofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria, and itching. A rare occurrence of Stevens-Johnson syndrome, which progressed to toxic epidermal necrolysis, has been reported in a patient who was receiving topical ophthalmic ofloxacin. If an allergic reaction to ofloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management, including intubation should be administered as clinically indicated.

Otic Solution

NOT FOR OPHTHALMIC USE.

NOT FOR INJECTION.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones, including ofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria, and itching. If an allergic reaction to ofloxacin is suspected, stop the drug. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management, including intubation, should be administered as clinically indicated.

PRECAUTIONS

General

Intravenous Infusion

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).

Tablets and Intravenous Infusion

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).

Intravenous Infusion: 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).

Ophthalmic Solution

As with other anti-infectives, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. Ofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity reaction.

The systemic administration of quinolones, including ofloxacin, has led to lesions or erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species. Ofloxacin, administered systemically at 10 mg/kg/day in young dogs (equivalent to 110 times the maximum recommended daily adult ophthalmic dose) has been associated with these types of effects.

Otic Solution

As with other anti-infective preparations, prolonged use may result in over-growth of nonsusceptible organisms, including fungi. If the infection is not improved after one week, cultures should be obtained to guide further treatment. If otorrhea persists after a full course of therapy, or if two or more episodes of otorrhea occur within six months, further evaluation is recommended to exclude an underlying condition such as cholesteatoma, foreign body, or a tumor.

The systemic administration of quinolones, including ofloxacin at doses much higher than given or absorbed by the otic route, has led to lesions or erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species.

Young growing guinea pigs dosed in the middle ear with 0.3% ofloxacin otic solution showed no systemic effects, lesions or erosions of the cartilage in weight-bearing joints, or other signs of arthropathy. No drug-related structural or functional changes of the cochlea and no lesions in the ossicles were noted in the guinea pig following otic administration of 0.3% ofloxacin for one month.

No signs of local irritation were found when 0.3% ofloxacin was applied topically in the rabbit eye. Ofloxacin was also shown to lack dermal sensitizing potential in the guinea pig maximization study.

Information for Patients

Tablets and Intravenous Infusion

Ophthalmic Solution

Avoid contaminating the applicator tip with material from the eye, fingers or other source.

Systemic quinolones, including ofloxacin, have been associated with hypersensitivity reactions, even following a single dose. Discontinue use immediately and contact your physician at the first sign of a rash or allergic reaction.

Otic Solution

Avoid contaminating the applicator tip with material from the fingers or other sources. This precaution is necessary if the sterility of the drops is to be preserved. Systemic quinolones, including ofloxacin, have been associated with hypersensitivity reactions, even following a single dose. Discontinue use immediately and contact your physician at the first sign of a rash or allergic reaction.

Otitis Externa: Prior to administration of ofloxacin otic in patients with otitis externa, the solution should be warmed by holding the bottle in the hand for one or two minutes to avoid dizziness which may result from the instillation of a cold solution. The patient should lie with the affected ear upward, and then the drops should be instilled. This position should be maintained for five minutes to facilitate penetration of the drops into the ear canal. Repeat, if necessary, for the opposite ear (see DOSAGE AND ADMINISTRATION).

Acute Otitis Media and Chronic Suppurative Otitis Media: In pediatric patients (from 1 to 12 years old) with acute otitis media with tympanostomy tubes and in patients with chronic suppurative otitis media with perforated tympanic membranes, prior to administration, the solution should be warmed by holding the bottle in the hand for one or two minutes to avoid dizziness which may result from the instillation of a cold solution. The patient should lie with the affected ear upward, and then the drops should be instilled. The tragus should then be pumped 4 times by pushing inward to facilitate penetration of the drops into the middle ear. This position should be maintained for five minutes. Repeat, if necessary, for the opposite ear (see DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, and 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 assay, or mouse micronucleus assay. Ofloxacin was positive in the UDS test using rat hepatocyte, and Mouse Lymphoma Assay.

Otic Solution: Long-term studies to determine the carcinogenic potential of ofloxacin have not been conducted. Ofloxacin was not mutagenic in the Ames test, the sister chromatid exchange assay (Chinese hamster and human cell lines), the unscheduled DNA synthesis (UDS) assay using human fibroblasts, the dominant lethal assay, or the mouse micronucleus assay. Ofloxacin was positive in the rat hepatocyte UDS assay, and in the mouse lymphoma assay. In rats, ofloxacin did not affect male or female reproductive performance at oral doses up to 360 mg/kg/day. This would be over 1000 times the maximum recommended clinical dose, based upon body surface area, assuming total absorption of ofloxacin from the ear of a patient treated with ofloxacin otic twice per day.

Pregnancy, Teratogenic Effects, Pregnancy Category C

Ofloxacin had 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/m² or 50 times based on mg/kg) and 160 mg/kg/day (4 times the reommended maximum human dose based on mg/m² 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/m² 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 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/m².

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.)

Otic Solution: Ofloxacin has been shown to have an embryocidal effect in rats at a dose of 810 mg/kg/day and in rabbits at 160 mg/kg/day.

These dosages resulted in decreased fetal body weights 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.

Ofloxacin has not been shown to have any adverse effects on the developing embryo or fetus at doses relevant to the amount of ofloxacin that will be delivered ototopically at the recommended clinical doses.

Nonteratogenic Effects

Otic Solution: Additional studies in the rat demonstrated that doses up to 360 mg/kg/day during late gestation had no adverse effects on late fetal develoopment, labor, delivery, lactation, neonatal viability, or growth of the newborn. There are, however, no adequate and well-controlled studies in pregnant women. Ofloxacin otic should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

In lactating females, 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 and otic administration. 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).

Otic Solution: No changes in hearing function occurred in 30 pediatric subjects treated with ofloxacin otic and tested for audiometric parameters. Although safety and efficacy have been demonstrated in pediatric patients one year and older, safety and effectiveness in infants below the age of one year have not been established. Although quinolones, including ofloxacin, have been shown to cause arthropathy in immature animals after systemic administration, young growing guinea pigs dosed in the middle ear with 0.3% ofloxacin otic solution for one month showed no systemic effects, quinolone-induced lesions, erosions of the cartilage in weight-bearing joints, or other signs of arthropathy.

DRUG INTERACTIONS

Tablets and Intravenous Infusion

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. (See DOSAGE AND ADMINISTRATION). Intravenous Infusion: There are no data concerning an interaction of intravenous quinolones with oral antacids, sucralfate, multivitamins, 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 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 theoplylline 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 PRECAUTIONS, Information for the Patient).

Ophthalmic Solution

Specific drug interaction studies have not been conducted with oflaxacin ophthalmic solution. However, the systemic administration of some quinolones has been shown to elevate plasma concentrations of theophylline, interfere with the metabolism of caffeine, and enhance the effects of the oral anticoagulant warfarin and its derivatives, and has been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.

Otic Solution

Specific drug interaction studies have not been conducted with ofloxacin otic.

ADVERSE REACTIONS

Tablets and Intravenous Infusion

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%.

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:

Body as a Whole: Asthenia, chills, malaise, extremity pain, pain, epistaxis.

Cardiovascular System: Cardiac arrest, edema, hypertension, hypotension, palpitations, vasodilation.

Gastrointestinal System: Dyspepsia.

Genital/Reproductive System: Burning, irritation, pain and rash of the female genitalia, dysmenorrhea, menorrhagia, metrorrhagia.

Musculoskeletal System: Arthralgia, myalgia.

Nervous System: Seizures, anxiety, cognitive change, depression, dream abnormality, euphoria, hallucinations, paresthesia, syncope, vertigo, tremor, confusion.

Nutritional/Metabolic: Thirst, weight loss.

Respiratory System: Respiratory arrest, cough, rhinorrhea.

Skin/Hypersensitivity: Angiodema, diaphoresis, urticaria, vasculitis.

Special Senses: Decreased hearing acuity, tinnitus, photophobia.

Urinary System: Dysuria, urinary frequency, urinary retention.

The following laboratory abnormalities appeared in ³ 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.

Hematopoietic: Anemia, leukopenia, leukocytosis, neutropenia, neutrophilia, increased band forms, lymphocytopenia, eosinophilia, lymphocytosis, thrombocytopenia, thrombocytosis, elevated ESR.

Hepatic: Elevated: alkaline phosphatase, AST (SGOT), ALT (SGPT).

Serum Chemistry: Hyperglycemia, hypoglycemia, elevated creatinine, elevated BUN.

Urinary: Glucosuria, proteinuria, alkalinuria, hyposthenuria, hematuria, pyuria.

Post-Marketing Adverse Events: Additional adverse events, regardless of relationship to drug, reported from worldwide marketing experience with quinolones, including ofloxacin:

Cardiovascular System: Cerebral thrombosis, pulmonary edema, tachycardia, hypotension/shock, syncope.

Endocrine/Metabolic: Hyper- or hypoglycemia, especially in diabetic patients on insulin or oral hypoglycemic agents (see PRECAUTIONS, General and DRUG INTERACTIONS).

Gastrointestinal System: Hepatic dysfunction including: hepatic necrosis, jaundice (cholestatic or hepatocellular), hepatitis; instestinal perforation; pseudomembranous colitis (the onset of pseudomembranous colitis symptoms may occur during or after anitmicrobial treatment), GI hemorrhage; hiccough, painful oral mucosa, pyrosis (see WARNINGS).

Genital/Reproductive System: Vaginal candidiasis.

Hematopoietic: Anemia, including hemolytic and aplastic; hemorrhage, pancytopenia, agranulocytosis, leukopenia, reversible bone marrow depression, thrombocytopenia, thrombotic thrombocytopenic purpura, petechiae, ecchymosis/burning (see WARNINGS).

Musculoskeletal: Tendinitis/rupture: weakness; rhabdomyolysis.

Nervous System: Nightmares; suicidal thoughts or acts, disorientation, psychotic reactions, paranoia; phobia, agitation, restlessness, agressiveness/hostility, manic reaction, emotional lability; peripheral neuropathy, ataxia, incoordination; possible exacerbation of: myasthenia gravis and extrapyramidal disorders; dysphasia, lightheadedness (See WARNINGS and PRECAUTIONS).

Respiratory System: Dyspnea, bronchospasm, allergic pneumonitis, stridor (see WARNINGS).

Skin/Hypersensitivity: Anaphylactic (-toid) reactions/shock; purpura, serum sickness, erythema multiforme/Stevens-Johnson Syndrome, erythema nodosum, exfoliative dermatitis, hyperpigmentation, toxic epidermal necrolysis, conjunctivitis, photosensitivity, vesiculobullous eruption (see WARNINGS and PRECAUTIONS).

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

Urinary System: Anuria, polyuria, renal calculi, renal failure, interstitial nephritis, hematuria (see WARNINGS and PRECAUTIONS).

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.

CRYSTALLURIA and CYLINDRURIA HAVE BEEN REPORTED with other quinolones.

Intravenous Infusion: 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.

Ophthalmic Solution

The most frequently reported drug-related adverse reaction was transient ocular burning or discomfort. Other reported reactions include stinging, redness, itching, chemical conjunctivitis/keratitis, periocular/facial edema, foreign body sensation, photophobia, blurred vision, tearing, dryness, and eye pain. Rare reports of dizziness have been received.

Otic Solution

In the Phase III registration trials, a total of 885 subjects were treated with ofloxacin otic solution. This included 229 subjects with otitis externa (with intact tympanic membranes) and 656 subjects with acute otitis media with tympanostomy tubes or chronic suppurative otitis media with perforated tympanic membranes. The reported treatment-related adverse events are listed in TABLE 6.

Subjects with Otitis Externa: The treatment-related adverse events listed in TABLE 6 occurred in 1% or more of the subjects with intact tympanic membranes.

The following treatment-related adverse events were each reported in a single subject: dermatitis, eczema, erythematous rash, follicular rash, rash, hypoaesthesia, tinnitus, dyspepsia, hot flushes, flushing, and otorrhagia.

Subjects with Acute Otitis Media with Tympanostomy Tubes and Subjects with Chronic Suppurative Otitis Media with Perforated Tympanic Membranes: The treatment-related adverse events listed in occurred in 1% or more of the subjects with non-intact tympanic membranes.

Other treatment-related adverse reactions reported in subjects with non-intact tympanic membranes included: diarrhea (0.6%), nausea (0.3%), vomiting (0.3%), dry mouth (0.5%), headache (0.3%), vertigo (0.5%), otorrhagia (0.6%), tinnitus (0.3%), fever (0.3%). The following treatment-related adverse events were each reported in a single subject: application site reaction, otitis externa, urticaria, abdominal pain, dysaesthesia, hyperkinesia, halitosis, inflammation, pain, insomnia, coughing, pharyngitis, rhinitis, sinusitis, and tachycardia.

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 39.4 mcg/ml. In 7 h, the level had fallen to 16.2 mcg/ml, and by 24 h to 2.7 mcg/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 an acute overdose, (Tablets: 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 and Intravenous Infusion

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 9):