TROVAN^Ò/Zithromax^Ò Compliance Pak

Twenty healthy subjects participated in a Phase 1 pharmacokinetic study to assess the safety of the TROVAN^Ò/Zithromax^Ò Compliance Pak.

The adverse events listed in the table above were obtained from the experience of the 20 healthy volunteers that participated in the study and were described as mild to moderate in nature.

Trovafloxacin

Over 6000 patients have been treated with TROVAN in multidose clinical efficacy trials worldwide.

In TROVAN studies, the majority of adverse reactions were described as mild in nature (over 90 were described as mild or moderate). TROVAN was discontinued for adverse events thought related to drug in 5% of patients (dizziness 2.4%, nausea 1.9%, headache 1.1%, and vomiting 1.0%).

Dizziness/lightheadedness on TROVAN is generally mild, lasts for a few hours following a dose, and in most cases, resolves with continued dosing. The incidence of dizziness and lightheadedness in TROVAN patients over 65 years is 3.1% and 0.6%, respectively (See PATIENT INFORMATION).

TROVAN appears to have a low potential for phototoxicity. In clinical trials with TROVAN, only mild, treatment-related phototoxicity was observed in less than 0.03% (2/7096) of patients.

Additional reported drug-related events in clinical trials (remotely, possibly, probably, or unknown) that occurred in <1% of TROVAN-treated patients are:

Application Injection Insertion Site: Application/injection/insertion site device complications, inflammation, pain, edema

Autonomic Nervous: flushing, increased sweating, dry mouth, cold clammy skin, increased saliva

Cardiovascular: peripheral edema, chest pain, thrombophlebitis, hypotension, palpitation, periorbital edema, hypertension, syncope, tachycardia, angina pectoris, bradycardia, peripheral ischemia, edema, dizziness postural

Central Peripheral Nervous System: confusion, paresthesia, vertigo, hypoesthesia, ataxia, convulsions, dysphonia, hypertonia, migraine, involuntary muscle contractions, speech disorder, encephalopathy, abnormal gait, hyperkinesia, hypokinesia, tongue paralysis, abnormal coordination, tremor, dyskinesia

Gastrointestinal: altered bowel habit, constipation, Clostridium difficile-associated diarrhea, dyspepsia, flatulence, loose stools, gastritis, dysphagia, increased appetite, gastroenteritis, rectal disorder, colitis, pseudomembranous colitis, enteritis, eructation, gastrointestinal disorder, melena, hiccup

Oral Cavity: gingivitis, stomatitis, altered saliva, tongue disorder, tongue edema, tooth disorder, chelitis, halitosis

General Other: fever, fatigue, pain, asthenia, moniliasis, hot flushes, back pain, chills, infection (bacterial, fungal), malaise, sepsis, alcohol intolerance, allergic reaction, anaphylactoid reaction, drug (other) toxicity/reaction, weight increase, weight decrease

Hematopoietic: anemia, granulocytopenia, hemorrhage unspecified, leukopenia, prothrombin decreased, thrombocythemia, thrombocytopenia

Liver Biliary: increased hepatic enzymes, hepatic function abnormal, bilirubinemia, discolored feces, jaundice

Metabolic Nutritional: hyperglycemia, thirst

Musculoskeletal: arthralgia, muscle cramps, myalgia, muscle weakness, skeletal pain, tendinitis, arthropathy

Psychiatric: anxiety, anorexia, agitation, nervousness, somnolence, insomnia, depression, amnesia, concentration impaired, depersonalization, dreaming abnormal, emotional lability, euphoria, hallucination, impotence, libido decreased-male, paroniria, thinking abnormal

Reproductive: Female: leukorrhea, menstrual disorder; Male: balanoposthitis

Respiratory: dyspnea, rhinitis, sinusitis, bronchospasm, coughing, epistaxis, respiratory insufficiency, upper respiratory tract infection, respiratory disorder, asthma, hemoptysis, hypoxia, stridor

Skin/Appendages: pruritus ani, skin disorder, skin ulceration, angioedema, dermatitis, dermatitis fungal, photosensitivity skin reaction, seborrhea, skin exfoliation, urticaria

Special Senses: taste perversion, eye pain, abnormal vision, conjunctivitis, photophobia, conjuctival hemorrhage, hyperacusis, scotoma, tinnitus, visual field defect, diplopia, xerophthalmia

Urinary System: dysuria, face edema, micturition frequency, interstitial nephritis, renal failure acute, renal function abnormal, urinary incontinence

Azithromycin

In clinical trials, most of the reported side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Approximately 0.7% of the patients from the multiple-dose clinical trials discontinued ZITHROMAX^Ò (azithromycin) therapy because of treatment-related side effects. Most of the side effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain. Rarely but potentially serious side effects were angioedema and cholestatic jaundice.

Single-1 gram dose regimen: Overall the most common side effects in patients receiving a single-dose regimen of 1 gram of ZITHROMAX^Ò were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen.

Side effects that occurred in patients on the single one-gram dosing regimen of ZITHROMAX^Ò with a frequency of 1% or greater included diarrhea-loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%).

Laboratory Changes Trovafloxacin

Changes in laboratory parameters, without regard to drug relationship, occurring in ³1% of TROVAN-treated patients were: decreased hemoglobin and hematocrit; increased platelets; decreased and increased WBC; eosinophilia; increased ALT (SGPT), AST (SGOT), and alkaline phosphatase; decreased protein and albumin; increased BUN and creatinine; decreased sodium; and bicarbonate. It is not known whether these abnormalities were caused by the drug or the underlying condition being treated.

The incidence and magnitude of liver function abnormalities with TROVAN were the same as comparator agents except in the only study in which oral TROVAN was administered for 28 days. In this study (chronic bacterial prostatitis) nine percent (13/140) of TROVAN-treated patients experienced elevations of serum transaminases (AST and/or ALT) of >/=3 times the upper limit of normal. These liver function test abnormalities generally developed at the end of, or following completion of, the planned 28-day course of therapy, but were not associated with concurrent elevations of related laboratory measures of hepatic function (such as serum bilirubin, alkaline phosphatase, or lactate dehydrogenase). Patients were asymptomatic with these abnormalities, which generally returned to normal within 1-2 months after discontinuation of therapy (see Trovan Post-Marketing Experience below).

Trovan Post-Marketing Experience

Adverse reactions reported with TROVAN during the post-marketing period include: anaphylaxis, symptomatic hepatitis (some patients experienced an associated peripheral eosinophilia), liver failure (including acute hepatic necrosis with eosinophilic infiltration), Stevens-Johnson Syndrome, and symptomatic pancreatitis.

During the post-marketing period, TROVAN-associated liver enzyme abnormalities and/or symptomatic hepatitis have occurred during short-term or long-term therapy (See PRECAUTIONS).

Laboratory Changes Azithromycin

Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows:

With an incidence of 1-2%, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT, and AST (SGOT).

With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and phosphate.

When follow-up was provided, changes in laboratory tests appeared to be reversible.

In multiple-dose clinical trials involving more than 3000 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of a renal function abnormality.

The systemic availability of trovafloxacin following oral tablet administration is significantly reduced by the concomitant administration of antacids containing aluminum and magnesium salts, sucralfate, vitamins or minerals containing iron, and concomitant intravenous morphine administration.

Administration of trovafloxacin (300 mg p.o.) 30 minutes after administration of an antacid containing magnesium hydroxide and aluminum hydroxide resulted in reductions in systemic exposure to trovafloxacin (AUC) of 66% and peak serum concentration (Cmax) of 60% (See PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION).

Concomitant sucralfate administration (1g) with trovafloxacin 200 mg p.o. resulted in a 70% decrease in trovafloxacin systemic exposure (AUC) and a 77% reduction in peak serum concentration (Cmax) (See PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION).

Concomitant administration of ferrous sulfate (120 mg elemental iron) with trovafloxacin 200 mg p.o. resulted in a 40% reduction in trovafloxacin systemic exposure (AUC) and a 48% decrease in trovafloxacin Cmax (See PRECAUTIONS:Drug Interactions and DOSAGE AND ADMINISTRATION).

Concomitant administration of intravenous morphine (0.15 mg/kg with oral trovafloxacin (200 mg) resulted in a 36% reduction in trovafloxacin AUC and a 46% decrease in trovafloxacin Cmax. Trovafloxacin administration had no effect on the pharmacokinetics of morphine or its pharmacologically active metabolite, morphine6- b-glucuronide (See PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION).

Minor pharmacokinetic interactions that are most likely without clinical significance include calcium carbonate, omeprazole, and caffeine.

Concomitant administration of calcium carbonate (1000 mg) with trovafloxacin 200 mg p.o. resulted in a 20% reduction in trovafloxacin AUC and a 17% reduction in peak serum trovafloxacin concentration (Cmax). A 40-mg dose of omeprazole given 2 hours prior to trovafloxacin (300 mg p.o.) resulted in a 17% reduction in trovafloxacin AUC and a 17% reduction in trovafloxacin peak serum concentration (Cmax).

Administration of trovafloxacin (200 mg) concomitantly with caffeine (200 mg) resulted in a 17% increase in caffeine AUC and a 15% increase in caffeine Cmax. These changes in caffeine exposure are not considered clinically significant.

No significant pharmacokinetic interactions include cimetidine, theophylline, digoxin, warfarin, and cyclosporine.

Cimetidine co-administration (400 mg twice daily for 5 days) with trovafloxacin (200 mg p.o. daily for 3 days) resulted in changes in trovafloxacin AUC and Cmax of less than 5%.

Trovafloxacin (200 mg p.o. daily for 7 days) co-administration with theophylline (300 mg twice daily for 14 days) resulted in no change in theophylline AUC and Cmax.

Trovafloxacin (200 mg p.o. daily for 10 days) co-administration with digoxin (0.25 mg daily for 20 days) did not significantly alter systemic exposure (AUC) to digoxin or the renal clearance of digoxin.

Trovafloxacin (200 mg p.o. daily for 7 days) does not interfere with the pharmacokinetics nor the pharmacodynamics of warfarin (daily for 21 days). Concomitant oral administration of trovafloxacin did not affect the systemic exposure (AUC) or peak plasma concentrations (Cmax) of the S or R isomers of warfarin, nor did it influence prothrombin time.

Trovafloxacin (200 mg p.o. daily for 7 days) co-administration with cyclosporine (daily doses from 150-450 mg for 7 days) resulted in decreases of 10% or less in systemic exposure to cyclosporine (AUC) and in the peak blood concentrations of cyclosporine.

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.

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