TROVAFLOXACIN

THE SAFETY AND EFFECTIVENESS OF TROVAFLOXACIN IN PEDIATRIC PATIENTS AND ADOLESCENTS LESS THAN 18 YEARS OF AGE PREGNANT WOMEN AND NURSING WOMEN HAVE NOT BEEN ESTABLISHED (See

PRECAUTIONS

As with other members of the quinolone class, trovafloxacin has caused arthropathy and/or chondrodysplasia in immature rats and dogs. The significance of these findings to humans is unknown (See CLINICAL PHARMACOLOGY: ANIMAL PHARMACOLOGY).

Convulsions, increased intracranial pressure and psychosis have been reported in patients receiving quinolones. Quinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, and insomnia. These reactions may occur following the first dose. If these reactions occur in patients receiving trovafloxacin or alatrofloxacin, the drug should be discontinued and appropriate measures instituted (See

PRECAUTIONS

As with other quinolones, TROVAN should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral atherosclerosis, epilepsy, and other factors that predispose to seizures (See ADVERSE REACTIONS).

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones. These reactions may occur following the first dose. Some reactions have been 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, itching, and other serious skin reactions.

TROVAN should be discontinued 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

Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving therapy with all antimicrobials. 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 or failure; hepatitis, jaundice, acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

Although not seen in TROVAN clinical trials, ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. TROVAN 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 during or after therapy with quinolones.

AZITHROMYCIN

Serious allergic reactions, including angioedema and anaphylaxis, have been reported rarely in patients on azithromycin therapy (See CONTRAINDICATIONS). Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is unknown at present.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

General

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including both TROVAN and ZITHROMAX, 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 flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is the 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).

Neither trovafloxacin nor azithromycin has been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonoccocal urethritis/cervicitis or gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with sexually transmitted urethritis/cervicitis or gonorrhea should have a serologic test for syphilis at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests should be initiated if infection is confirmed.

General

Trovafloxacin

Moderate to severe phototoxicity reactions have been observed in patients who are exposed to direct sunlight while receiving some drugs in the quinolone class. Therapy should be discontinued if phototoxicity (e.g., a skin eruption, etc.) occurs.

The safety and efficacy of TROVAN in patients with severe cirrhosis (Child-Pugh Class C) have not been studied.

During the post-marketing period, TROVAN-associated liver enzyme abnormalities and/or symptomatic hepatitis have occurred during short-term or long-term therapy. Liver enzyme abnormalities have been reported in both men and women. Liver failure (including acute hepatic necrosis with eosinophilic infiltration) has also been reported rarely. Symptomatic pancreatitis has been reported on therapy. Clinicians should monitor liver function tests and pancreatic tests in patients who develop symptoms consistent with hepatitis and/or pancreatitis as clinically indicated.

Azithromycin

Because azithromycin is principally eliminated via the liver, caution should be exercised when azithromycin is administered to patients with impaired hepatic function. There are no data regarding azithromycin usage in patients with renal impairment; thus, caution should be exercised when prescribing azithromycin in these patients. The following adverse events have not been reported in clinical trials with azithromycin, an azalide; however, they have been reported with macrolide products: ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, in individuals with prolonged QT intervals.

Information for Patients

Patients should be advised:

† that TROVAN Tablets may be taken without regard to meals;

† that vitamins or minerals containing iron, aluminum- or magnesium-base antacids, antacids containing citric acid buffered with sodium citrate, sucralfate or Videx^Ò (Didanosine) chewable/ buffered tablets, buffered powder for oral solution, or pediatric powder for oral solution, should be taken at least two hours before or two hours after taking TROVAN Tablets (See DRUG INTERACTIONS);

† that TROVAN may cause lightheadedness and/or dizziness. Dizziness and/or lightheadedness was the most common adverse reaction reported, and for females under 45 years, it was reported significantly more frequently than in other groups. The incidence of dizziness may be substantially reduced if TROVAN Tablets are taken at bedtime or with food. Patients should know how they react to trovafloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination (See

WARNINGS

† that TROVAN^Ò/Zithromax^Ò Compliance Pak has been associated with nausea, vomiting, and diarrhea within 2 hours of administration. Nausea was the most common adverse event, seen in 10/20 (50%) of participants in a pharmacokinetic, trial followed by abdominal pain seen in 5/20 (25%) of the study subjects;

† 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 TROVAN may be associated with hypersensitivity reactions, even following the first dose, and to discontinue the drug at the first sign of a skin rash, hives, or other skin reactions, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face, tightness of the throat, hoarseness) or other symptoms of an allergic reaction (See

WARNINGS

† to avoid excessive sunlight or artificial ultraviolet light (e.g., tanning beds) while taking TROVAN and to discontinue therapy if phototoxicity (e.g., sunburn-like reaction or skin eruption) occurs;

† that ZITHROMAX^Ò for oral suspension in single 1-g packets can be taken with or without food after constitution;

† that they should not take aluminum- and magnesium-containing antacids and azithromycin simultaneously;

† that they should discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur.

Drug Interactions

Trovafloxacin

No significant interactions with theophylline, cimetidine, digoxin, warfarin, or cyclosporine have been observed with TROVAN Tablets (See CLINICAL PHARMACOLOGY).

Minor pharmacokinetic interactions without clinical significance have been observed with co-administration of TROVAN Tablets with caffeine, omeprazole and calcium carbonate (See CLINICAL PHARMACOLOGY).

Antacids, Sucralfate, and Iron: The absorption of oral trovafloxacin is significantly reduced by the concomitant administration of some antacids containing magnesium or aluminum, citric acid/sodium citrate (Bicitra^Ò), as well as sucralfate, and iron (as ferrous ions). These agents, as well as formulations containing divalent or trivalent cations or other buffering ingredients, such as Videx^{Ò, (} Didanosine), chewable/buffered or the pediatric oral solution, should be taken at least two hours before or two hours after oral trovafloxacin administration (See CLINICAL PHARMACOLOGY).

Morphine: Co-administration of intravenous morphine significantly reduces the absorption of oral trovafloxacin. Intravenous morphine should be administered at least 2 hours after oral TROVAN dosing in the fasted state and at least 4 hours after oral TROVAN is taken with food. Trovafloxacin administration had no effect on the pharmacokinetics of morphine or its metabolite, morphine-6-b-glucuronide (See CLINICAL PHARMACOLOGY).

Azithromycin

Aluminum- and magnesium-containing antacids reduce the peak serum levels (rate) but not the AUC (extent) of azithromycin (500 mg) absorption.

Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin (500 mg) absorption.

Azithromycin (500 mg Day 1, 250 mg Days 2-5) did not affect the plasma levels or pharmacokinetics of theophylline administered as a single intravenous dose. The effect of azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple doses resulting in therapeutic steady-state levels of theophylline is not known. However, concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. Therefore, until further data are available, prudent medical practice dictates careful monitoring of plasma theophylline levels in patients receiving azithromycin and theophylline concomitantly.

Azithromycin (500 mg Day 1, 250 mg Days 2-5) did not affect the prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.

The following drug interactions have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, they have been observed with macrolide products. Until further data are developed regarding drug interactions when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised:

Digoxin - elevated digoxin levels.

Ergotamine or dihydroergotamine - acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.

Triazolam - decreases the clearance of triazolam and thus may increase the pharmacologic effect of triazolam.

Drugs metabolized by the cytochrome P⁴⁵⁰ system - elevations of serum carbamazepine, cyclosporine, hexobarbital, and phenytoin levels.

Laboratory Test Interactions

There are no reported laboratory test interactions.

Carcinogenesis Mutagenesis, Impairment of Fertility

Trovafloxacin

Trovan did not shorten the time to development of UV-induced skin tumors in hairless albino (Skh-1) mice; thus, it was not photo co-carcinogenic in this model. These mice received oral trovafloxacin and concurrent irradiation with simulated sunlight 5 days per week for 40 weeks followed by a 12-week treatment-free observation period. The daily dose of UV radiation used in this study was approximately 30% of the minimal dose of UV radiation that would induce erythema in Caucasian humans. The median time to the development of skin tumors in the hairless mice (42-43 weeks) was similar in the vehicle control group and those given 10 or 30 mcg/kg of trovafloxacin daily. At a dose level of 30 mg/kg/day, the mice had skin trovafloxacin concentrations of approximately 7 mg/g. Following multiple 200 mg daily doses of trovafloxacin, the amount in human skin is estimated maximally to be about 3 mcg/g, based upon peak plasma concentrations measured at this dose level and the skin to serum penetration ratio approximately 1.0.

Trovafloxacin was not mutagenic in the Ames Salmonella reversion assay or CHO HGPRT mammalian cell gene mutation assay and it was not clastogenic in mitogen-stimulated human lymphocytes or mouse bone marrow cells. A mouse micronucleus test conducted with alatrofloxacin was also negative. The positive response observed in the E. coli bacterial mutagenicity assay may be due to the inhibition of DNA gyrase by trovafloxacin.

Trovafloxacin and alatrofloxacin did not affect the fertility of male or female rats at oral and I. V. doses of 75 mg/kg/day and 50 mg/kg/day, respectively. These doses are 15 and 10 times the recommended maximum human dose based on mg/kg or approximately 2 times based on mg/m². However, oral doses of trovafloxacin at 200 mg/kg/day (40 times the recommended maximum human dose based on mg/kg or about 6 times based on mg/m²) were associated with increased preimplantation loss in rats.

Azithromycin

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay.

Pregnancy:Teratogenic Effects

Trovafloxacin

Pregnancy Category C: An increase in skeletal variations was observed in rat fetuses after daily oral 75 mg/kg maternal doses of trovafloxacin (approximately 15 times the highest recommended human dose based on mg/kg or two times based upon body surface area) were administered during organogenesis. However, fetal skeletal variations were not observed in rats dosed orally with 15 mg/kg trovafloxacin. Evidence of fetotoxicity (increased perinatal mortality and decreased body weights) was also observed in rats at 75 mg/kg. Daily oral doses of trovafloxacin at 45 mg/kg (approximately 9 times the highest recommended human dose based on mg/kg or 2.7 times based upon body surface area) in the rabbit were not associated with an increased incidence of fetal skeletal variations or malformations.

An increase in skeletal variations and malformations was observed in rat fetuses after daily intravenous doses of alatrofloxacin at >/=20 mg/kg/day (approximately 4 times the highest recommended human dose based on mg/kg or 0.6 times based upon body surface area) were administered to dams during organogenesis. In the rabbit, an increase in fetal skeletal malformations was also observed when 20 mg/kg/day (approximately equal to the highest recommended human dose based upon body surface area) of alatrofloxacin was given intravenously during the period of organogenesis. Intravenous dosing of alatrofloxacin at 6.5 mg/kg in the rat or rabbit was not associated with an increased incidence of skeletal variations or malformations. Fetotoxicity and fetal skeletal malformations have been associated with other quinolones.

Oral doses of trovafloxacin >5 mg/kg were associated with an increased gestation time in rats, and several dams at 75 mg/kg experienced uterine dystocia.

There are no adequate and well controlled studies in pregnant women. TROVAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (See

WARNINGS

Azithromycin

Pregnancy Category B: Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose levels (i.e. 200 mg/kg/day). These doses, based on a mg/m² basis, are estimated to be 4 and 2 times, respectively, the human daily dose of 500 mg.

No evidence of impaired fertility or harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.

Nursing Mothers

Trovafloxacin

Trovafloxacin is excreted in human milk and was found in measurable concentrations in the milk of lactating subjects (See CLINICAL PHARMACOLOGY: Distribution).

Because of the potential for unknown effects from trovafloxacin in nursing infants from mothers taking trovafloxacin, 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.

Azithromycin

It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of the TROVAN/ZITHROMAX Compliance Pak in pediatric populations less than 18 years of age have not been established. Quinolones, including trovafloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species (See

WARNINGS

Geriatric Use

Trovafloxacin

In multiple-dose clinical trials of trovafloxacin, 27% of patients were ³65 years of age and 12% of patients were ³75 years of age. The overall incidence of drug-related adverse reactions, including central nervous system and gastrointestinal side effects, was less in the ³65 year group than the other age groups.

Azithromycin

Pharmacokinetic parameters in older volunteers (65-85 years old) were similar to those in younger volunteers (18-40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen (See CLINICAL PHARMACOLOGY).

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