Trovan Tablets (Trovafloxacin Mesylate)
Action: Trovan is available as tablets (trovafloxacin) for oral administration and as an i.v. (alatrofloxacin injection), a prodrug of trovafloxacin, for i.v. administration.
Trovafloxacin, a synthetic broad-spectrum antimicrobial agent of the fluoronaphthyridone class related to fluoroquinolones, has a bactericidal mode of action. This action of trovafloxacin results from interference with the enzyme DNA gyrase, an essential component for the synthesis of bacterial DNA, without significantly affecting the activity of eucaryotic topoisomerase II. Trovafloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive aerobic, anaerobic and atypical bacteria.
Fluoroquinolones, including trovafloxacin, differ in chemical structure and mode of action from other classes of antimicrobial agents such as b-lactam antibiotics, aminoglycosides, and macrolides. Therefore, microorganisms resistant to these latter classes of antimicrobial agents may be susceptible to fluoroquinolones. For example, b-lactamase production and alterations in penicillin-binding proteins have no effect on trovafloxacin activity. Conversely, microorganisms resistant to fluoroquinolones may be susceptible to other classes of antimicrobial agents.
Although cross-resistance has been observed between trovafloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to trovafloxacin. Conversely, some microorganisms resistant to trovafloxacin may be susceptible to other fluoroquinolones.
Clinical Pharmacology: Absorption: Oral: Trovafloxacin is well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 88%.
Trovafloxacin tablets may be administered without regard to food. When trovafloxacin tablets are given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations over 3 to 4 hours after dosing rather than 1 to 2 hours. However, there is no apparent alteration in C max or AUC.
Alatrofloxacin is rapidly and completely converted in vivo to trovafloxacin following i.v. administration. Serum concentrations of alatrofloxacin are below detectable levels within 5 minutes of completion of a 1-hour infusion.
Pharmacokinetics : The mean pharmacokinetic parameters (±SD) of trovafloxacin after single and multiple 100 and 200 mg oral doses, and 1-hour i.v. infusions of alatrofloxacin in doses of 200 and 300mg (trovafloxacin equivalents).
Trovafloxacin drug exposure after oral administration of trovafloxacin is dose-proportional in the dose range of 30 to 1000 mg or after i.v. administration of alatrofloxacin in the dose range of 30 to 400 mg (trovafloxacin equivalents). Steady-state concentrations are achieved by the third daily oral dose of trovafloxacin or i.v. dose of alatrofloxacin with an accumulation factor of approximately 1.3 times the single dose concentrations.
Special Population Pharmacokinetics: Geriatrics: In adult subjects, the pharmacokinetics of trovafloxacin is not affected by age (range 19 to 78 years).
Children: Limited information is available in the pediatric population. The pharmacokinetics of trovafloxacin has not been fully characterized in pediatric population less than 18 years of age.
Gender: There are no significant differences in trovafloxacin pharmacokinetics between males and females when differences in body weight are taken into account. After single 200 mg doses, trovafloxacin C max and AUC 0-¥ were 60% and 32% higher, respectively, in healthy females compared to healthy males. Following repeated daily administration of 200 mg for 7 days, the C max for trovafloxacin was 38% higher and AUC 0-24 was 16% higher in healthy females compared to healthy males. The clinical implication of the increases in serum levels of trovafloxacin in females has not been established.
Renal Insufficiency: The pharmacokinetics of trovafloxacin is not affected by renal impairment. Trovafloxacin serum concentrations are not significantly altered in subjects with severe renal insufficiency (creatinine clearance < 20 mL/min), including patients on hemodialysis .
Chronic Hepatic Disease (cirrhosis): Following repeated administration of 100 mg for 7 days to patients with mild cirrhosis (Child-Pugh Class A), the AUC 0-24 for trovafloxacin was increased approximately 45% compared to matched controls. Repeated administration of 200mg for 7 days to patients with moderate cirrhosis (Child-Pugh Class B) resulted in an increase of approximately 50% in AUC 0-24 compared to matched controls. There appeared to be no significant effect on trovafloxacin C max for either group. The oral clearance of trovafloxacin was reduced by approximately 30% in both cirrhosis groups, which corresponded to prolongation of half-life by 2to 2.5hours (25to 30% increase) compared to controls. There are no pharmacokinetic, safety or efficacy data in patients with severe cirrhosis (Child-Pugh Class C),
Metabolism: Trovafloxacin is metabolized in the liver by conjugation (the role of cytochrome P450 oxidative metabolism of trovafloxacin is minimal) and is eliminated primarily in the bile, with 2.5% of the dose being found in the serum in the form of the active N-acetyl metabolite. Thirteen percent of the administered dose appears in the urine in the form of the ester glucuronide and 9% appears in the feces as the N-acetyl metabolite. Other minor metabolites (diacid, sulfamate, hydroxycarboxylic acid) have been identified in both urine and feces in small amounts.
Distribution: Trovafloxacin is widely distributed throughout the body. Concentrations of trovafloxacin following either oral or i.v. administration are generally greater in tissues than in plasma or serum. The mean plasma protein bound fraction, which is concentration-independent, in plasma samples is approximately 76%.
Trovafloxacin was found in measurable concentrations in the breast milk of 3 lactating women. The average measurable breast milk concentration was 0.8 µg/mL (range 0.3 to 2.1 µg/mL) after single i.v. alatrofloxacin (300 mg trovafloxacin equivalents) and repeated oral trovafloxacin (200 mg) doses.
Excretion: The terminal elimination half-life of trovafloxacin is approximately 11 hours. Approximately 50% of an oral dose is excreted unchanged (43% in the feces and 6% in the urine). After multiple 200 mg doses to healthy subjects, mean (±SD) cumulative urinary trovafloxacin concentrations were 12.1 ± 3.4 µg/mL. With these levels of trovafloxacin in urine, crystals of trovafloxacin have not been observed in the urine of human subjects.
Action: Trovan Is Available As Tablets (trovafloxacin) For Oral Administration And As An I.v. (alatrofloxacin Injection), A Prodrug Of Trovafloxacin, For I.v. Administration.
Trovafloxacin, A Synthetic Broad-spectrum Antimicrobial Agent Of The Fluoronaphthyridone Class Related To Fluoroquinolones, Has A Bactericidal Mode Of Action. This Action Of Trovafloxacin Results From Interference With The Enzyme DNA Gyrase, An Essential Component For The Synthesis Of Bacterial DNA, Without Significantly Affecting The Activity Of Eucaryotic Topoisomerase II. Trovafloxacin Has In Vitro Activity Against A Wide Range Of Gram-negative And Gram-positive Aerobic, Anaerobic And Atypical Bacteria.
Fluoroquinolones, Including Trovafloxacin, Differ In Chemical Structure And Mode Of Action From Other Classes Of Antimicrobial Agents Such As B-lactam Antibiotics, Aminoglycosides, And Macrolides. Therefore, Microorganisms Resistant To These Latter Classes Of Antimicrobial Agents May Be Susceptible To Fluoroquinolones. For Example, B-lactamase Production And Alterations In Penicillin-binding Proteins Have No Effect On Trovafloxacin Activity. Conversely, Microorganisms Resistant To Fluoroquinolones May Be Susceptible To Other Classes Of Antimicrobial Agents.
Although Cross-resistance Has Been Observed Between Trovafloxacin And Some Other Fluoroquinolones, Some Microorganisms Resistant To Other Fluoroquinolones May Be Susceptible To Trovafloxacin. Conversely, Some Microorganisms Resistant To Trovafloxacin May Be Susceptible To Other Fluoroquinolones.
Clinical Pharmacology: Absorption: Oral: Trovafloxacin Is Well Absorbed From The Gastrointestinal Tract After Oral Administration. The Absolute Bioavailability Is Approximately 88%.
Trovafloxacin Tablets May Be Administered Without Regard To Food. When Trovafloxacin Tablets Are Given Concomitantly With Food, There Is A Delay In The Absorption Of The Drug, Resulting In Peak Concentrations Over 3 To 4 Hours After Dosing Rather Than 1 To 2 Hours. However, There Is No Apparent Alteration In C Max Or AUC.
Alatrofloxacin Is Rapidly And Completely Converted In Vivo To Trovafloxacin Following I.v. Administration. Serum Concentrations Of Alatrofloxacin Are Below Detectable Levels Within 5 Minutes Of Completion Of A 1-hour Infusion.
Pharmacokinetics : The Mean Pharmacokinetic Parameters (±SD) Of Trovafloxacin After Single And Multiple 100 And 200 Mg Oral Doses, And 1-hour I.v. Infusions Of Alatrofloxacin In Doses Of 200 And 300mg (trovafloxacin Equivalents).
Trovafloxacin Drug Exposure After Oral Administration Of Trovafloxacin Is Dose-proportional In The Dose Range Of 30 To 1000 Mg Or After I.v. Administration Of Alatrofloxacin In The Dose Range Of 30 To 400 Mg (trovafloxacin Equivalents). Steady-state Concentrations Are Achieved By The Third Daily Oral Dose Of Trovafloxacin Or I.v. Dose Of Alatrofloxacin With An Accumulation Factor Of Approximately 1.3 Times The Single Dose Concentrations.
Special Population Pharmacokinetics: Geriatrics: In Adult Subjects, The Pharmacokinetics Of Trovafloxacin Is Not Affected By Age (range 19 To 78 Years).
Children: Limited Information Is Available In The Pediatric Population. The Pharmacokinetics Of Trovafloxacin Has Not Been Fully Characterized In Pediatric Population Less Than 18 Years Of Age.
Gender: There Are No Significant Differences In Trovafloxacin Pharmacokinetics Between Males And Females When Differences In Body Weight Are Taken Into Account. After Single 200 Mg Doses, Trovafloxacin C Max And AUC 0-¥ Were 60% And 32% Higher, Respectively, In Healthy Females Compared To Healthy Males. Following Repeated Daily Administration Of 200 Mg For 7 Days, The C Max For Trovafloxacin Was 38% Higher And AUC 0-24 Was 16% Higher In Healthy Females Compared To Healthy Males. The Clinical Implication Of The Increases In Serum Levels Of Trovafloxacin In Females Has Not Been Established.
Renal Insufficiency: The Pharmacokinetics Of Trovafloxacin Is Not Affected By Renal Impairment. Trovafloxacin Serum Concentrations Are Not Significantly Altered In Subjects With Severe Renal Insufficiency (creatinine Clearance < 20 ML/min), Including Patients On Hemodialysis .
Chronic Hepatic Disease (cirrhosis): Following Repeated Administration Of 100 Mg For 7 Days To Patients With Mild Cirrhosis (Child-Pugh Class A), The AUC 0-24 For Trovafloxacin Was Increased Approximately 45% Compared To Matched Controls. Repeated Administration Of 200mg For 7 Days To Patients With Moderate Cirrhosis (Child-Pugh Class B) Resulted In An Increase Of Approximately 50% In AUC 0-24 Compared To Matched Controls. There Appeared To Be No Significant Effect On Trovafloxacin C Max For Either Group. The Oral Clearance Of Trovafloxacin Was Reduced By Approximately 30% In Both Cirrhosis Groups, Which Corresponded To Prolongation Of Half-life By 2to 2.5hours (25to 30% Increase) Compared To Controls. There Are No Pharmacokinetic, Safety Or Efficacy Data In Patients With Severe Cirrhosis (Child-Pugh Class C),
Metabolism: Trovafloxacin Is Metabolized In The Liver By Conjugation (the Role Of Cytochrome P450 Oxidative Metabolism Of Trovafloxacin Is Minimal) And Is Eliminated Primarily In The Bile, With 2.5% Of The Dose Being Found In The Serum In The Form Of The Active N-acetyl Metabolite. Thirteen Percent Of The Administered Dose Appears In The Urine In The Form Of The Ester Glucuronide And 9% Appears In The Feces As The N-acetyl Metabolite. Other Minor Metabolites (diacid, Sulfamate, Hydroxycarboxylic Acid) Have Been Identified In Both Urine And Feces In Small Amounts.
Distribution: Trovafloxacin Is Widely Distributed Throughout The Body. Concentrations Of Trovafloxacin Following Either Oral Or I.v. Administration Are Generally Greater In Tissues Than In Plasma Or Serum. The Mean Plasma Protein Bound Fraction, Which Is Concentration-independent, In Plasma Samples Is Approximately 76%.
Trovafloxacin Was Found In Measurable Concentrations In The Breast Milk Of 3 Lactating Women. The Average Measurable Breast Milk Concentration Was 0.8 µg/mL (range 0.3 To 2.1 µg/mL) After Single I.v. Alatrofloxacin (300 Mg Trovafloxacin Equivalents) And Repeated Oral Trovafloxacin (200 Mg) Doses.
Excretion: The Terminal Elimination Half-life Of Trovafloxacin Is Approximately 11 Hours. Approximately 50% Of An Oral Dose Is Excreted Unchanged (43% In The Feces And 6% In The Urine). After Multiple 200 Mg Doses To Healthy Subjects, Mean (±SD) Cumulative Urinary Trovafloxacin Concentrations Were 12.1 ± 3.4 µg/mL. With These Levels Of Trovafloxacin In Urine, Crystals Of Trovafloxacin Have Not Been Observed In The Urine Of Human Subjects.
Trovafloxacin tablets and alatrofloxacin injection are contraindicated in persons with a history of hypersensitivity to trovafloxacin, alatrofloxacin or any member of the quinolone class of antimicrobial agents.
Hepatic Effects: Trovafloxacin tablets and alatrofloxacin i.v.-associated liver enzyme abnormalities, symptomatic hepatitis, jaundice, and liver failure (including rare reports of acute hepatic necrosis with eosinophilic infiltration, liver transplantation and/or death) have been reported with both short-term, as short as 2 days, and long-term drug exposure in men and women. In some cases Trovan-associated liver failure appears to be an idiosyncratic hypersensitivity reaction and is therefore unpredictable. However, Trovan can also have a direct toxic effect on the liver. Trovan use exceeding 2 weeks in duration is associated with a significantly increased risk of serious liver injury. Liver injury has also been reported following Trovan re-exposure. Clinicians should monitor liver function tests (e.g., AST, ALT, bilirubin) in all Trovan recipients. Clinicians should consider discontinuing Trovan use in those patients who develop liver function test abnormalities. Note, however, that because Trovan-associated liver failure appears to be unpredictable, the reliability of liver function monitoring in managing this risk is uncertain. Trovan should be discontinued immediately if clinical signs and symptoms consistent with liver dysfunction develop. Trovan should be reserved for use in hospitalized patients with serious life-threatening infections. Trovan should not be used when safer, alternative antimicrobial therapy will be effective.
Children, Pregnancy and Lactation : The safety and efficacy of Trovan in children, pregnant women and nursing women have not been established.
Chondrotoxic Effects: 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.
Hypersensitivity: Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving quinolone therapy including Trovan. 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, i.v. fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.
Serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology have been reported in patients receiving therapy with all antibiotics including Trovan. 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.
CNS and Psychiatric Effects: Convulsions, increased intracranial pressure and psychosis have been reported in patients receiving quinolones. Quinolones, including trovafloxacin, may also cause CNS stimulation which may lead to tremors, restlessness, 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.
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.
Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Trovan, 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 C. 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.
Musculoskeletal Effects: 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.
General: Trovafloxacin tablets and alatrofloxacin injection use exceeding 2 weeks in duration is associated with a significantly increased risk of serious liver injury.
Symptomatic pancreatitis has been reported in patients on Trovan therapy. Clinicians should monitor pancreatic tests as clinically indicated in patients who develop symptoms consistent with pancreatitis.
Bolus or rapid (£30 minutes) i.v. infusion may cause seizures or hypotension (which in some cases may also be a manifestation of an allergic/anaphylactic reaction, or a manifestation of a histamine-release phenomenon, i.e., Red Man's Syndrome. After dilution with an appropriate diluent, alatrofloxacin should be administered by slow i.v. infusion over a period of 60minutes.
Trovan may cause dizziness (including lightheadedness). Dizziness (including lightheadedness) was the most common adverse reaction reported and, for females under 45 years, it was reported significantly more often than in other groups. The incidence of dizziness may be reduced if trovafloxacin tablets are taken at bedtime.
Dizziness (including lightheadedness) on Trovan is generally mild, lasts for a few hours following a dose and, in most cases, resolves with continued dosing.
Occupational Hazards: Patients should know how they react to trovafloxacin before they operate an automobile or machinery or engage in activities requiring mental alertness and coordination . Phototoxicity: Moderate to severe phototoxicity reactions have been observed in patients who were exposed to direct sunlight while receiving some drugs in this class. Excessive exposure to sunlight or artificial UV light should be avoided and Trovan therapy should be discontinued if phototoxicity (e.g., a skin eruption, etc.) occurs. In a study of skin response to ultraviolet and visible radiation in 50 healthy volunteers, trovafloxacin tablets 200 mg daily were shown to have a lower potential of producing phototoxic reactions than two other quinolones (although greater than placebo) as measured by the minimum erythematous dose (MED), the dose of irradiation at which erythema is observed after administration of the standard doses of the antibacterial agent.
Photocarcinogenicity: Some fluoroquinolones are known to be photocarcinogenic. 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. The clinical significance of these findings, particularly for short-term use, is not known.
Geriatrics: In multiple-dose clinical trials of trovafloxacin, 26% were elderly patients (³65 years of age). The overall incidence of drug-related adverse reactions, including CNS and gastrointestinal side effects, was less in the elderly than the other age groups.
Patients with Impaired Renal Function: The pharmacokinetics of trovafloxacin is not affected by renal impairment. Trovafloxacin serum concentrations are not significantly altered in subjects with severe renal insufficiency (creatinine clearance <20 mL/min), including patients on hemodialysis (see Pharmacology and Dosage).
Patients with Chronic Hepatic Disease (cirrhosis): Patients with Mild-moderate Hepatic Impairment: In patients with mild-moderate hepatic impairment (Child-Pugh Class A and B) there are no pharmacokinetic data for the 300 mg dose. Since Trovan is eliminated by the liver and the potential for accumulation is unknown, use of the 300 mg dose should be considered in these patients only if the benefits outweigh the risk.
For use of the 200 mg dose, the potential for increased AUC due to reduced elimination should be taken into account when the use of Trovan is considered for these patients.
Patients with Severe Hepatic Impairment: There are no pharmacokinetic, safety or efficacy data in patients with severe cirrhosis (Child-Pugh Class C) and therefore the use of Trovan in these patients is not recommended.
Pregnancy : 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.
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 twice the based upon BSA) 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 75mg/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 BSA) 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 i.v. doses of alatrofloxacin at ³20 mg/kg/day (approximately 4 times the highest recommended human dose based on mg/kg or 0.6 times based upon BSA) were administered to dams during organogenesis. In the rabbit, an increase in fetal skeletal malformations was also observed when 20mg/kg/day (approximately equal to the highest recommended human dose based upon BSA) of alatrofloxacin was given i.v. during the period of organogenesis. I.V. 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 >5mg/kg were associated with an increased gestation time in rats and several dams at 75 mg/kg experienced uterine dystocia.
Lactation : Trovafloxacin is excreted in human milk. Because of the potential for unknown effects from trovafloxacin in infants being nursed by mothers taking Trovan, a decision should be made either to discontinue nursing or to discontinue the drug, taking into consideration the importance of therapy with Trovan to the mother.
Children: The safety and efficacy of trovafloxacin 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).
Drug Interactions : When trovafloxacin tablets are administered, the systemic bioavailability of trovafloxacin is significantly reduced by the concomitant administration of some antacids containing magnesium and aluminum hydroxide, sucralfate, vitamins and minerals containing divalent metal cations and concomitant i.v. administration of morphine.
Concurrent administration of trovafloxacin orally with sucralfate or divalent and trivalent cations such as iron or antacids containing magnesium or aluminum, or citric acid buffered with sodium citrate may substantially interfere with the oral absorption of trovafloxacin, resulting in serum and urine levels considerably lower than desired. Therefore, concurrent administration of these agents with trovafloxacin should be avoided. These agents should be administered either 2 hours after or 2 hours before dosing with trovafloxacin.
Concurrent administration of trovafloxacin orally with i.v. morphine may interfere with the oral absorption of trovafloxacin. I.V. morphine should be administered at least 2 hours after oral trovafloxacin dosing in the fasted state and at least 4 hours after oral trovafloxacin is taken with food.
Antacids Containing Magnesium and Aluminum Hydroxide: Administration of trovafloxacin tablets (300 mg) 30 minutes after administration of antacids containing magnesium hydroxide and aluminum hydroxide resulted in reduction of systemic exposure to trovafloxacin (AUC 0-¥) of 66% and peak serum concentration (C max) of 60% .
Sucralfate: Concomitant sucralfate administration (1g) with trovafloxacin 200 mg orally resulted in a 70% decrease in trovafloxacin systemic exposure (AUC 0-¥) and a 77% reduction in peak serum concentration (C max).
Ferrous Ions: Concomitant administration of ferrous sulfate (120 mg elemental iron) with trovafloxacin 200 mg orally resulted in a 40% reduction in trovafloxacin systemic exposure (AUC 0-¥) and a 48% decrease in trovafloxacin C max.
Morphine: Concomitant administration of i.v. morphine (0.15 mg/kg) with trovafloxacin (200 mg orally) resulted in a 46% decrease in trovafloxacin C max and a 36% reduction in the AUC 0-¥. Trovafloxacin administration had no effect on the pharmacokinetics of morphine or its pharmacologically active metabolite, morphine-6-b-glucuronide .
Citric Acid Buffered With Sodium Citrate: Antacids containing citric acid buffered with sodium citrate may reduce the solubility and the absorption of trovafloxacin.
Drugs exhibiting minor pharmacokinetic interactions with Trovan, most likely without clinical significance, are calcium carbonate, omeprazole and caffeine.
Calcium Carbonate: Concomitant administration of calcium carbonate (1000 mg) with trovafloxacin 200 mg orally resulted in a 20% reduction in trovafloxacin AUC 0-¥ and a 17% reduction in peak serum trovafloxacin concentration (C max).
Omeprazole: A 40 mg dose of omeprazole given 2 hours prior to trovafloxacin (300 mg orally) resulted in a 32% and 17% reduction in trovafloxacin C max and AUC 0-¥, respectively.
Caffeine: Administration of trovafloxacin (200 mg) concomitantly with caffeine (200 mg) resulted in a 17% increase in caffeine AUC 0-¥ and a 15% increase in caffeine C max. These changes in caffeine exposure are not considered clinically significant.
In clinical trials, drugs exhibiting no significant pharmacokinetic interactions with Trovan, were cimetidine, theophylline, digoxin, warfarin and cyclosporine; however, there have been postmarketing reports indicating that trovafloxacin and alatrofloxacin enhance the effect of warfarin.
Cimetidine: Cimetidine coadministration (400 mg twice daily for 5days) with trovafloxacin (200 mg orally daily for 3 days) resulted in changes in trovafloxacin AUC 0-¥ and C max of less than 5%.
Theophylline: Trovafloxacin (200 mg orally daily for 7 days) coadministration with theophylline (300 mg twice daily for 14 days) resulted in no change in theophylline AUC 0-¥ and C max.
Digoxin: Trovafloxacin (200 mg orally daily for 10 days) coadministration with digoxin (0.25 mg daily for 20 days) did not significantly alter systemic exposure (AUC 0-¥) to digoxin or the renal clearance of digoxin.
Warfarin: In clinical trials, trovafloxacin (200 mg orally daily for 7days) did 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 0-¥) or peak plasma concentrations (C max) of the S or R isomers of warfarin, nor did it influence prothrombin times.
During the post-marketing experience, as with some other quinolones, there have been reports that trovafloxacin/alatrovafloxacin enhance the effects of warfarin. Prothrombin time, International Normalized Ratio (INR) or other suitable anticoagulation tests should be closely monitored if a quinolone antimicrobial including trovafloxacin/alatrofloxacin is administered concomitantly with warfarin.
Cyclosporine: Trovafloxacin (200 mg orally daily for 7 days) coadministration with cyclosporine (daily doses from 150 to 450 mg for 7days) resulted in decreases of 10% or less in systemic exposure to cyclosporine (AUC 0-¥) and in the peak blood concentrations of cyclosporine.
Disturbances of Blood Glucose: Disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with quinolones, including trovafloxacin, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide/glibenclamide, etc.) or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient receiving trovafloxacin or alatrofloxacin, discontinue the drug immediately and an appropriate therapy should be instituted.
Laboratory Test Interactions : There are no reported laboratory test interactions.
Alatrofloxacin should not be coadministered with any solution containing multivalent cations, e.g., magnesium, through the same i.v. line.
Clinical Trial Experience: 6302 patients have been treated with trovafloxacin tablets and alatrofloxacin injection in multidose clinical efficacy trials worldwide (5045 in oral only trials, and 1257 in i.v. to oral trials).
In Trovan multidose studies, the majority of adverse reactions were described as mild in nature (over 90% were described as mild or moderate).
In multidose studies, Trovan was discontinued for adverse events thought related to drug in 5.3% of patients (with the most frequent reasons for discontinuations being dizziness [including lightheadedness] 1.9%, nausea 1.6%, headache 0.9%, and vomiting 0.9%). Women discontinued for treatment-related adverse events more frequently than men (6.9% vs 3.3%, respectively).
In multidose Phase II/III clinical trials involving 6302 patients treated with Trovan and 4825 patients treated with comparators, the incidence of treatment-related adverse events was 26% vs 24%, respectively.
Trovan may cause dizziness (including lightheadedness). Dizziness (including lightheadedness) was the most common adverse reaction reported and, for women under 45 years, it was reported significantly more often than in other groups. The incidence of dizziness may be reduced if trovafloxacin tablets are taken at bedtime (see Precautions).
Dizziness (including 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 Precautions).
Trovan appears to have a low potential for phototoxicity. In single-dose and multidose clinical trials with Trovan, only mild treatment-related phototoxicity was observed in less than 0.03% (2/7096) patients.
In single-dose and multidose trials, additional events that occurred in <1% of treated patients with Trovan (N=7096), are classified as thought to be drug-related (normal type) and thought not to be drug-related.
Cardiovascular: angina, arrhythmia ventricular, bradycardia, chest pain, dizziness postural, edema, hypertension, hypotension, hypotension postural, palpitation, peripheral edema, peripheral ischemia, syncope, tachycardia, thrombophlebitis, arrhythmia atrial, arteritis, bundle branch block, cardiac arrest, cardiac failure, cardiomegaly, cardiomyopathy, cerebrovascular disorder, cyanosis, endocarditis, fibrillation atrial, heart valve disorder, myocardial infarction, ocular hemorrhage, pericardial effusion, peripheral gangrene, tachycardia supraventricular, tachycardia ventricular, vascular disorder, vein varicose .
Central and Peripheral Nervous Systems: abnormal coordination, abnormal gait, ataxia, confusion, convulsions, dyskinesia, dysphonia, encephalopathy, hyperkinesia, hypertonia, hypoesthesia, hypokinesia, migraine, muscle contractions involuntary, myoclonus, paresthesia, speech disorder, tongue paralysis, tremor, vertigo, aphasia, brain herniation, cerebral edema, coma, delirium, generalized spasm, hemiparesis, hypotonia, meningitis, neuralgia, neuropathy, paresis, stupor .
Collagen: aggravated lupus erythromatosus syndrome, Wegener's granulomatosis .
Endocrine: diabetes insipidus, hypothyroidism .
Gastrointestinal: colitis, constipation, diarrhea (C.difficile ), dyspepsia, dysphagia, enteritis, eructation, flatulence, gastritis, gastroenteritis, gastrointestinal disorder, hiccup, increased appetite, loose stools, melena, pseudomembranous colitis, rectal disorder, anus disorder, diseases of esophagus, diverticulitis, esophagitis, fecal incontinence, gastric dilatation, gastric ulcer, gastroesophageal reflux, gastrointestinal hemorrhage, hemorrhoids, ileus, irritable bowel syndrome, intestinal obstruction, intestinal ischemia, pancreatitis, peritonitis .
Hematopoietic: anemia, granulocytopenia, hemorrhage unspecified, leukopenia, prothrombin decreased, thrombocythemia, thrombocytopenia, cerebral hemorrhage, coagulation disorder, disseminated intravascular coagulation, embolism limb, gingival bleeding, hematoma, hemoperitoneum, leukocytosis, lymphadenopathy, lymphangitis, pulmonary embolism, purpura, purpura thrombopenic thrombotic, subarachnoid hemorrhage, thrombosis arterial.
Hypersensitivity/Allergic: allergic reaction, anaphylactoid reaction, angioedema, asthma, bronchospasm, face edema, larynx edema, periorbital edema, stridor, tongue edema, urticaria, contact dermatitis .
Liver/Biliary: bilirubinemia, discolored feces, hepatic function abnormal, hepatitis, hepatocellular damage, increased hepatic enzymes, jaundice, gall bladder/biliary tract disorder, liver fatty, cholecystitis, cholelithiasis, hepatitis cholestatic, hepatic cirrhosis (hepatitis B), infectious hepatitis .
Metabolic/Nutritional: hyperglycemia, thirst, acidosis, alkalosis, amyloidosis, cachexia, dehydration, diabetes mellitus, gout, hypercalcemia, hypercholesterolemia, hyperkalemia, hypernatremia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, ketosis .
Musculoskeletal: arthralgia, arthropathy, muscle cramp, muscle weakness, myalgia, skeletal pain, tendinitis, arthritis, arthrosis, bone disorder, bone fracture, muscle necrosis, myopathy, myositis, osteomyelitis, synovitis .
Neoplasms: basal cell carcinoma, bladder carcinoma, carcinoma, colon carcinoma, gastrointestinal neoplasm malignant, hepatic neoplasm malignant, lymphoma malignant, pulmonary carcinoma, renal carcinoma, sarcoma, skin neoplasm malignant, unspecified neoplasms .
Oral Cavity: altered saliva, chelitis, gingivitis, halitosis, stomatitis, tooth disorder, tongue disorder, glossitis, leukoplakia oral, oral hemorrhage, stomatitis/ulcerative, tongue discoloration, tongue ulceration, toothache .
Psychiatric: agitation, amnesia, anorexia, anxiety, concentration impaired, depersonalization, depression, dreaming abnormal, emotional lability, euphoria, hallucination, impotence, insomnia, libido decreased-male, nervousness, paranoid reaction, paroniria, psychosis, somnolence, thinking abnormal, aggressive reaction, dementia, other sexual dysfunction males, personality disorder, suicide attempt, withdrawal syndrome .
Reproductive: balanoposthitis, leukorrhea, menstrual disorder, anorgasmia male, breast pain, breast engorgement, cervical dysplasia, cervicitis, dysmenorrhea, endometrial hyperplasia, endometriosis, epididymitis, exudate nipples, intermenstrual bleeding, menorrhagia, ovarian cyst, pelvic inflammation, penis disorder, perineal pain, pregnancy ectopic, pregnancy unintended, prostatic disorder, salpingitis, testis disorder, uterine inflammation, uterine spasm, vaginal disorder, vaginal hemorrhage, vaginitis atrophic, vulva disorder .
Respiratory: aspiration, coughing, dyspnea, epistaxis, hemoptysis, hypoxia, respiratory disorder, respiratory insufficiency, rhinitis, sinusitis, apnea, atelectasis, bronchitis, emphysema, hyperventilation, laryngitis, otitis media, pharyngitis, pleural effusion, pleurisy, pneumonia eosinophilic, pneumonia, pneumothorax, pulmonary edema, respiratory depression, respiratory tract infection .
Skin/Appendages: dermatitis, dermatitis fungal, skin disorder, photosensitivity skin reaction, pruritus ani/genital, seborrhea, skin exfoliation, skin ulceration, acne, alopecia, bullous eruption, cellulitis, dry skin, erythema nodosum, eczema, furunculosis, nail disorder, otitis externa, psoriasis, skin discoloration, verruca .
Special Senses: abnormal vision, conjunctival hemorrhage, conjunctivitis, diplopia, eye pain, hyperacusis, photophobia, scotoma, taste perversion, tinnitus, visual field defect, xerophthalmia, blepharitis, earache, eye abnormality, hearing impaired, hearing decreased, other ear disorders, lacrimation abnormal, macula lutea degeneration, photopsia, ptosis, scleritis .
Urinary System: dysuria, micturition frequency/disorder, nephritis interstitial, renal failure, renal function abnormal, strangury, urinary incontinence, urinary tract infection, bladder pain, hematuria, hydronephrosis, hypervolemia, nocturia, oliguria, polyuria, renal calculus, renal cyst, renal pain, pyelonephritis, ureteral/urethral disorder, urinary retention .
General/Other: alcohol intolerance, asthenia, back pain, chills, drug (other) toxicity, fatigue, fever, hot flushes, infection (bacterial, fungal), malaise, pain, sepsis, weight decrease, weight increase, abscess, accidental fall/injury, ascites, enlarged abdomen, granulomatous lesion, herpes, infection (other), influenza-like symptoms, motor vehicle accident, multiorgan failure, necrosis ischemic, rigors, subcutaneous emphysema .
Laboratory Test Abnormalities: Changes in laboratory parameters, without regard to drug relationship, occurring in ³1% of trovafloxacin-treated patients in oral studies were: increased platelets, increased WBC; eosinophilia; increased ALT; increased BUN; and decreased bicarbonate. Changes in laboratory parameters, without regard to drug relationship, occurring in ³1% of Trovan treated patients in i.v. to oral studies were: decreased hemoglobin and hematocrit, decreased and increased platelets, decreased and increased WBC, eosinophilia, increased bilirubin, ALT, AST, LDH, and alkaline phosphatase; decreased protein and albumin; increased BUN and creatinine; decreased sodium; decreased and increased potassium and bicarbonate.
In a comparative study where trovafloxacin tablets were administered for 28 days, a higher incidence of liver enzyme elevations was noted on Trovan after 3 to 4 weeks of dosing. These abnormalities generally resolved within 1 to 2 months after the drug was discontinued (see Warnings).
Postmarketing Experience: During the postmarketing period, adverse reactions reported with Trovan during short-term (as short as 2days) or long-term therapy include: anaphylaxis, Red Man's Syndrome, liver enzyme abnormalities, jaundice, Stevens-Johnson syndrome, symptomatic pancreatitis, symptomatic hepatitis (some patients experienced an associated peripheral eosinophilia) liver failure (including rare reports of acute hepatic necrosis with eosinophilic infiltration, liver transplantation and/or death). In some cases Trovan-associated liver failure appears to be an idiosyncratic hypersensitivity reaction and is therefore unpredictable. However, Trovan can also have a direct toxic effect on the liver. Although many of the hepatic events were associated with serious underlying conditions and/or concomitant medications (making causality difficult to assess), some hepatotoxic events were believed to be strongly associated with Trovan exposure.
Symptoms and Treatment: Information on overdosage with trovafloxacin tablets and alatrofloxacin injection in humans is limited. In the event of acute oral overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given symptomatic and supportive treatment. Adequate hydration should be maintained. Trovafloxacin is not efficiently removed from the body after hemodialysis.
Tablets and I.V.: The recommended dosage for trovafloxacin tablets or alatrofloxacin injection for the treatment of infections is described in TableIII. Doses of Trovan are administered once daily. Trovan should not usually be administered for more than 2weeks. Trovan use exceeding 2 weeks in duration is associated with a significantly increased risk of serious liver injury (see Warnings and Adverse Effects). Follow the Dosage Guidelines table (see Table III) for the recommended dosage regimens for each indication.
Patients whose therapy is started with alatrofloxacin i.v. may be switched to trovafloxacin tablets when clinically indicated at the discretion of the physician. In certain patients with serious life-threatening infections, trovafloxacin tablets may be considered appropriate in-hospital therapy, when the treating physician believes that the benefit of the product for the patient outweighs the potential risk.
Impaired Renal Function: No adjustment in the dosage of Trovan is necessary in patients with impaired renal function (see Pharmacology).
Chronic Hepatic Disease (cirrhosis): Patients With Mild-moderate Hepatic Impairment: In patients with mild-moderate hepatic impairment (Child-Pugh Class A and B) there are no pharmacokinetic data for the 300 mg dose. Since Trovan is eliminated by the liver and the potential for accumulation is unknown, use of the 300 mg dose should be considered in these patients only if the benefits outweigh the risk.
For use of the 200 mg dose, the potential for increased AUC due to reduced elimination should be taken into account when the use of Trovan is considered for these patients (see Pharmacology, Warnings and Precautions).
Patients with Severe Hepatic Impairment: There are no pharmacokinetic, safety or efficacy data in patients with severe cirrhosis (Child-Pugh Class C) and therefore the use of Trovan in these patients is not recommended.
Administration: Tablets: Trovafloxacin tablets may be taken without regard to food.
Concurrent administration of trovafloxacin orally with sucralfate or divalent and trivalent cations such as iron or antacids containing magnesium or aluminum, or citric acid buffered with sodium citrate may substantially interfere with the oral absorption of trovafloxacin, resulting in serum and urine levels considerably lower than desired. Therefore, concurrent administration of these agents with trovafloxacin should be avoided. Single dose bioavailability studies have shown that antacids may be administered either 2 hours after or 2hours before dosing with trovafloxacin without a significant decrease in bioavailability (see Precautions).
Concurrent administration of trovafloxacin orally with i.v. morphine may interfere with the oral absorption of trovafloxacin. I.V. morphine should be administered at least 2 hours after oral trovafloxacin dosing in the fasted state and at least 4 hours after oral trovafloxacin is taken with food (see Precautions).
Alatrofloxacin i.v. should only be administered by i.v. infusion. It is not for i.m., intrathecal, intraperitoneal, or s.c. administration.
Single-use vials require dilution prior to administration.
This parenteral drug product should be inspected visually for discoloration and particulate matter prior to dilution and administration. Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final parenteral solution.
Compatibility: Alatrofloxacin i.v. should not be diluted with 0.9% sodium chloride injection, USP (normal saline), alone or in combination with other diluents. A precipitate may form under these conditions. In addition, alatrofloxacin i.v. should not be diluted with Lactated Ringer's injection, USP. However, as listed above, Lactated Ringer's and 5% dextrose injection, USP, is a compatible solution and it is acceptable to use.
0.9% sodium chloride injection, USP (normal saline), can be used for flushing i.v. lines prior to or after administration of alatrofloxacin i.v.
Alatrofloxacin should not be coadministered with any solution containing multivalent cations, e.g., magnesium, through the same i.v. line.
Tablets: 100 mg: Each standard round convex, blue tablet, engraved with the word “Pfizer” on one side and “378” or “TVN 100” on the reverse side, contains: trovafloxacin mesylate equivalent to trovafloxacin 100 mg. Nonmedicinal ingredients: crosslinked sodium carboxymethyl cellulose, magnesium stearate and microcrystalline cellulose; coating: FD&C Blue No.2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide. Bottles of 100. Unit dose packages.
200 mg: Each modified oval, blue tablet, engraved with the word “Pfizer” on one side and “379” or “TVN 200” on the reverse side, contains: trovafloxacin mesylate equivalent to trovafloxacin 200 mg. Nonmedicinal ingredients: crosslinked sodium carboxymethyl cellulose, magnesium stearate and microcrystalline cellulose; coating: FD&C Blue No.2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide. Bottles of 100. Unit dose packages.
Store at controlled room temperature between 15 and 30°C.
Search for a drug
Trovan Tablets
Trovafloxacin Mesylate
Antibacterial
