Trovan
Trovan - General Information
Trovan (sold as Trovan® by Pfizer) is a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was withdrawn from the market due to the risk of hepatotoxicity. It had better gram-positive bacterial coverage and less gram-negative coverage than the previous fluoroquinolones. [Wikipedia]
Pharmacology of Trovan
Trovan is a broad spectrum antibiotic that inhibits DNA supercoiling in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It is not used widely due to the risk of hepatotoxicity. It tends to have better gram-positive bacterial coverage and less gram-negative coverage than the previous fluoroquinolones. Mechanism of action of fluoroquinolones including trovafloxacin is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines. Therefore fluoroquinolones may be active against pathogens that are resistant to these antibiotics. There is no cross-resistance between trovafloxacin and the mentioned classes of antibiotics. The overall results obtained from in vitro synergy studies, testing combinations of trovafloxacin with beta-lactams and aminoglycosides, indicate that synergy is strain specific and not commonly encountered. This agrees with results obtained previously with other fluoroquinolones. Resistance to trovafloxacin in vitro develops slowly via multiple-step mutation in a manner similar to other fluoroquinolones. Resistance to trovafloxacin in vitro occurs at a general frequency of between 1x10-7 to 10-10. Although cross-resistance has been observed between trovafloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to trovafloxacin.
Trovan 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 VidexÒ (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;
• 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 ;
• that TROVANÒ/ZithromaxÒ 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;
• 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 ZITHROMAXÒ 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.
Trovan Interactions
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%.
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).
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.
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.
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.
Minor pharmacokinetic interactions without clinical significance have been observed with co-administration of TROVAN Tablets with caffeine, omeprazole and calcium carbonate.
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 (BicitraÒ), 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 VidexÒ, ( Didanosine), chewable/buffered or the pediatric oral solution, should be taken at least two hours before or two hours after oral trovafloxacin administration.
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.
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.
Trovan Contraindications
TROVAN is contraindicated in persons with a history of hypersensitivity to trovafloxacin, alatrofloxacin, quinolone antimicrobial agents, or any other components of these products.
ZITHROMAX is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or any macrolide antibiotic.
Additional information about Trovan
Trovan Indication: For treatment of infections caused by susceptible strains of the designated microorganisms in uncomplicated urethral gonorrhea in males and endocervical and rectal gonorrhea in females caused by Neisseria gonorrhoeae as well as non gonoccocal urethritis and cervicitis due to Chlamydia trachomatis.
Mechanism Of Action: Trovan is a fluoronaphthyridone related to the fluoroquinolones with in vitro activity against a wide range of gram-negative and gram-positive aerobic and anaerobic microorganisms. The bactericidal action of trovafloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription, and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division.
Drug Interactions: Not Available
Food Interactions: Not Available
Generic Name: Trovafloxacin
Synonyms: TVFX; Trovafloxacin mesylate
Drug Category: Anti-Infectives; Fluoroquinolones
Drug Type: Small Molecule; Approved; Withdrawn
Other Brand Names containing Trovafloxacin: Trovan;
Absorption: Well-absorbed from the gastrointestinal tract after oral administration and does not depend on concomitant food intake. The absolute bioavailability is approximately 88%.
Toxicity (Overdose): Symptoms of overdose include convulsions, decreased activity, diarrhea, sleepiness, tremors, and/or vomiting.
Protein Binding: The mean plasma protein bound fraction is approximately 76%, and is concentration-independent.
Biotransformation: Metabolism Trovafloxacin is metabolized by conjugation (the role of cytochrome P450 oxidative metabolism of trovafloxacin is minimal). The major metabolites include the ester glucuronide, which appears in the urine (13% of the administered dose); and the N -acetyl metabolite, which appears in the feces and serum (9% and 2.5% of the administered dose, respectively). Other minor metabolites include diacid, hydroxycarboxylic acid, and sulfamate, which have been identified in both the feces and the urine in small amounts (< 4% of the administered dose).
Half Life: Following oral administration, half-life ranged from 9.1 hours to 12.2 hours over the dosage range of 100 to 200 mg tablets. Following intravenous infusion, half-life ranged from 9.4 to 12.7 hours over a dosage range of 100 to 300 mg.
Dosage Forms of Trovan: Tablet Oral
Liquid Intravenous
Chemical IUPAC Name: 7-[(1R,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid
Chemical Formula: C20H15F3N4O3
Trovafloxacin on Wikipedia: https://en.wikipedia.org/wiki/Trovafloxacin
Organisms Affected: Enteric bacteria and other eubacteria
