Trovan

• Cheshire Pharm. Systems

• Pfizer U.S. Pharmaceuticals Group

• Roerig

Trovan® HAS BEEN ASSOCIATED WITH SERIOUS LIVER INJURY LEADING TO LIVER TRANSPLANTATION AND/OR DEATH. Trovan-ASSOCIATED LIVER INJURY HAS BEEN REPORTED WITH BOTH SHORT-TERM AND LONG-TERM DRUG EXPOSURE. 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. Trovan SHOULD BE RESERVED FOR USE IN PATIENTS WITH SERIOUS, LIFE- OR LIMB-THREATENING INFECTIONS WHO RECEIVE THEIR INITIAL THERAPY IN AN IN-PATIENT HEALTH CARE FACILITY (I.E., HOSPITAL OR LONG-TERM NURSING CARE FACILITY). Trovan SHOULD NOT BE USED WHEN SAFER, ALTERNATIVE ANTIMICROBIAL THERAPY WILL BE EFFECTIVE. (SEE WARNINGS.)

Trovan is available as Trovan Tablets (trovafloxacin mesylate) for oral administration and as Trovan I.V. (alatrofloxacin mesylate injection), a prodrug of trovafloxacin, for intravenous administration.

After intravenous administration, alatrofloxacin is rapidly converted to trovafloxacin. Plasma concentrations of alatrofloxacin are below quantifiable levels within 5 to 10 minutes of completion of a 1 hour infusion.

Absorption

Trovafloxacin is well-absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 88%. For comparable dosages, no dosage adjustment is necessary when switching from parenteral to oral administration (Figure 1). (See DOSAGE AND ADMINISTRATION.)

Figure 1. Mean trovafloxacin serum concentrations determined following 1 hour intravenous infusions of alatrofloxacin at daily doses of 200 mg (trovafloxacin equivalents) to healthy male volunteers and following daily oral administration of 200 mg trovafloxacin for 7 days to six male and six female healthy young volunteers.

Pharmacokinetics

The mean pharmacokinetic parameters (±SD) of trovafloxacin after single and multiple 100 mg and 200 mg oral doses and 1 hour intravenous infusions of alatrofloxacin in doses of 200 and 300 mg (trovafloxacin equivalents) appear in the chart below.

Serum concentrations of trovafloxacin are dose proportional after oral administration of trovafloxacin in the dose range of 30 to 1000 mg or after intravenous administration of alatrofloxacin in the dose range of 30 to 400 mg (trovafloxacin equivalents). Steady state concentrations are achieved by the third daily oral or intravenous dose of trovafloxacin with an accumulation factor of approximately 1.3 times the single dose concentrations.

Oral absorption of trovafloxacin is not altered by concomitant food intake; therefore, it can be administered without regard to food.

The systemic exposure to trovafloxacin (AUC0–∞) administered as crushed tablets via nasogastric tube into the stomach was identical to that of orally administered intact tablets. Administration of concurrent enteral feeding solutions had no effect on the absorption of trovafloxacin given via nasogastric tube into the stomach. When trovafloxacin was administered as crushed tablets into the duodenum via nasogastric tube, the AUC0–∞ and peak serum concentration (Cmax) were reduced by 30% relative to the orally administered intact tablets. Time to peak serum level (Tmax) was also decreased from 1.7 hrs to 1.1 hrs.

Distribution

The mean plasma protein bound fraction is approximately 76%, and is concentration-independent. Trovafloxacin is widely distributed throughout the body. Rapid distribution of trovafloxacin into tissues results in significantly higher trovafloxacin concentrations in most target tissues than in plasma or serum.

Presence in Breast Milk

Trovafloxacin was found in measurable concentrations in the breast milk of three lactating subjects. The average measurable breast milk concentration was 0.8 µg/mL (range: 0.3–2.1 µg/mL) after single I.V. alatrofloxacin (300 mg trovafloxacin equivalents) and repeated oral trovafloxacin (200 mg) doses.

Metabolism

Trovafloxacin is metabolized by conjugation (the role of cytochrome P450 oxidative metabolism of trovafloxacin is minimal). 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 (2.5% of the dose is found in the serum as the active N-acetyl metabolite). Other minor metabolites (diacid, sulfamate, hydroxycarboxylic acid) have been identified in both urine and feces in small amounts (<4% of the administered dose).

Excretion

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.

Special Populations

In adult subjects, the pharmacokinetics of trovafloxacin are not affected by age (range 19–78 years).

Limited information is available in the pediatric population (see Distribution). The pharmacokinetics of trovafloxacin have not been fully characterized in pediatric populations less than 18 years of age.

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 Cmax 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 Cmax for trovafloxacin was 38% higher and AUC(0–24) was 16% higher in healthy females compared to healthy males. The clinical importance of the increases in serum levels of trovafloxacin in females has not been established. (See PRECAUTIONS: Information for Patients.)

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 ~45% compared to matched controls. Repeated administration of 200 mg for 7 days to patients with moderate cirrhosis (Child-Pugh Class B) resulted in an increase of ~50% in AUC(0–24) compared to matched controls. There appeared to be no significant effect on trovafloxacin Cmax for either group. The oral clearance of trovafloxacin was reduced ~30% in both cirrhosis groups, which corresponded to prolongation of half life by 2–2.5 hours (25–30% increase) compared to controls. There are no data in patients with severe cirrhosis (Child-Pugh Class C). Dosage adjustment is recommended in patients with mild to moderate cirrhosis. (See DOSAGE AND ADMINISTRATION.)

The pharmacokinetics of trovafloxacin are 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.

In a study of the skin response to ultraviolet and visible radiation conducted in 48 healthy volunteers (12 per group), the minimum erythematous dose (MED) was measured for ciprofloxacin, lomefloxacin, trovafloxacin and placebo before and after drug administration for 5 days. In this study, trovafloxacin (200 mg q.d.) was shown to have a lower potential for producing delayed photosensitivity skin reactions than ciprofloxacin (500 mg b.i.d.) or lomefloxacin (400 mg q.d.), although greater than placebo. (See PRECAUTIONS: Information for Patients.)

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, 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, 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, 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, morphine-6-β-glucuronide. (See PRECAUTIONS: Drug Interactions, 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 were seen when Trovan was co-administered with 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) did not interfere with either the pharmacokinetics or 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 times. (See PRECAUTIONS: Drug Interactions.)

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.

Microbiology

Trovafloxacin 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. 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 1×10-7 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.

Trovafloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic gram-positive microorganisms
Enterococcus faecalis (many strains are only moderately susceptible)
Staphylococcus aureus (methicillin-susceptible strains)
Streptococcus agalactiae
Streptococcus pneumoniae (penicillin-susceptible strains)
Viridans group streptococci

Aerobic gram-negative microorganisms
Escherichia coli
Gardnerella vaginalis
Haemophilus influenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis
Pseudomonas aeruginosa

Anaerobic microorganisms
Bacteroides fragilis
Peptostreptococcus species
Prevotella species

Other microorganisms
Chlamydia pneumoniae
Legionella pneumophila
Mycoplasma pneumoniae

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

Trovafloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of ≤2 µg/mL against most (90%) strains of the following microorganisms; however, the safety and effectiveness of trovafloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms
Streptococcus pneumoniae (penicillin resistant strains)

Aerobic gram-negative microorganisms
Citrobacter freundii
Enterobacter aerogenes
Morganella morganii
Proteus vulgaris

Anaerobic microorganisms
Bacteroides distasonis
Bacteroides ovatus
Clostridium perfringens

Other microorganisms
Mycoplasma hominis
Ureaplasma urealyticum

NOTE: Mycobacterium tuberculosis and Mycobacterium avium-intracellulare complex organisms are commonly resistant to trovafloxacin.

NOTE: The activity of trovafloxacin against Treponema pallidum has not been evaluated; however, other quinolones are not active against Treponema pallidum. (See WARNINGS.)

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of trovafloxacin mesylate powder. The MIC values should be interpreted according to the following criteria:

For testing non-fastidious aerobic organisms:

For testing Haemophilus spp.1

For testing Streptococcus spp. including Streptococcus pneumoniae2:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard trovafloxacin mesylate powder should provide the following MIC values:

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with trovafloxacin mesylate equivalent to 10 µg trovafloxacin to test the susceptibility of microorganisms to trovafloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a trovafloxacin mesylate disk (equivalent to 10 µg trovafloxacin) should be interpreted according to the following criteria:

The following zone diameter interpretive criteria should be used for testing non-fastidious aerobic organisms:

For testing Haemophilus spp.3:

For testing Streptococcus spp. including Streptococcus pneumoniae4:

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for trovafloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the trovafloxacin mesylate equivalent to 10-µg trovafloxacin disk should provide the following zone diameters in these laboratory quality control strains:

Anaerobic Techniques: For anaerobic bacteria, the susceptibility to trovafloxacin as MICs can be determined by standardized test methods3. The MIC values obtained should be interpreted according to the following criteria:

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized trovafloxacin mesylate powder should provide the following MIC values:

Trovan Tablets and Injection are being distributed only to hospitals and long term nursing care facilities for patients initiating therapy in these facilities

Tablets

Trovan (trovafloxacin mesylate) Tablets are available as blue, film-coated tablets. The 100 mg tablets are round and contain trovafloxacin mesylate equivalent to 100 mg trovafloxacin. The 200 mg tablets are modified oval-shaped and contain trovafloxacin mesylate equivalent to 200 mg trovafloxacin.

Trovan Tablets are packaged and in unit dose blister strips in the following configurations:

100-mg tablets: color: blue; shape: round; debossing: "PFIZER" on one side and "378" on the other
  Bottles of 30 (NDC 0049-3780-30)
  Unit Dose/40 tablets (NDC 0049-3780-43)

200-mg tablets: color: blue; shape: modified oval; debossing: "PFIZER" on one side and "379" on the other
  Bottles of 30 (NDC 0049-3790-30)
  Unit Dose/40 tablets (NDC 0049-3790-43)

Trovan Tablets should be stored at 15°C to 30°C (59°F to 86°F) in airtight containers (USP).

Injection

Trovan is also available for intravenous administration as the prodrug, Trovan I.V. (alatrofloxacin mesylate injection), in the following configurations:

Single-use vials containing a clear, colorless to pale-yellow concentrated solution of alatrofloxacin mesylate equivalent to 5 mg trovafloxacin/mL.

  5 mg/mL, 40 mL, 200 mg
  Unit dose package (NDC 0049-3890-28)

  5 mg/mL, 60 mL, 300 mg
  Unit dose package (NDC 0049-3900-28)

Trovan I.V. should be stored at 15°C to 30°C (59°F to 86°F). Protect From Light. Do Not Freeze.

Trovafloxacin is excreted into human milk. Quinolone-induced cartilage erosion and arthropathies that have been observed in juvenile animals render some concern over its possible toxic effects on the developing joints of nursing infants. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Trovafloxacin was detectable in the breast milk of three lactating women. The average breast milk concentration was 0.8 mcg/mL (range 0.3 to 2.1 mcg/mL) after single intravenous alatrofloxacin 300 mg and repeated oral trovafloxacin 200 mg doses.

Summary of Use during Lactation

No information is available on the clinical use of trovafloxacin during breastfeeding; however, amounts in breastmilk appear to be low. Fluoroquinolones have traditionally not been used in infants because of concern about adverse effects on the infants' developing joints. However, recent studies indicate little risk.[1][2] The calcium in milk might prevent absorption of the small amounts of fluoroquinolones in milk,[3] but insufficient data exist to prove or disprove this assertion. Use of trovafloxacin is acceptable in nursing mothers with monitoring of the infant for possible effects on the gastrointestinal flora, such as diarrhea or candidiasis (thrush, diaper rash). However, it is preferable to use an alternate drug for which safety information is available.

Drug Levels

Maternal Levels. The manufacturer reports that trovafloxacin was found in the breast milk of three lactating subjects. The average measurable breast milk concentration was 0.8 mcg/mL (range 0.3 to 2.1 mcg/mL) after a single intravenous alatrofloxacin dose equivalent to 300 mg of trovafloxacin. Further details on the study are not available.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Ciprofloxacin, Levofloxacin

References

1. Gurpinar AN, Balkan E, Kilic N et al. The effects of a fluoroquinolone on the growth and development of infants. J Int Med Res. 1997;25:302-6. PMID: 9364293

2. van den Oever HL, Versteegh FG, Thewessen EA et al. Ciprofloxacin in preterm neonates: case report and review of the literature. Eur J Pediatr. 1998;157:843-5. PMID: 9809826

3. Fleiss PM. The effect of maternal medications on breast-feeding infants. J Hum Lact. 1992;8:7. Letter. PMID: 1558663

LactMed Record Number

272

Last Revision Date

20170808

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.