Trovan Tablets
Trovan Tablets contain trovafloxacin mesylate, a synthetic broad-spectrum antibacterial agent for oral administration. Chemically, trovafloxacin mesylate, a fluoronaphthyridone related to the fluoroquinolone antibacterials, is (1α, 5α, 6α) - 7 - (6 - amino - 3 - azabicyclo[3.1.0]hex - 3 - yl) - 1 - (2,4 - difluorophenyl) - 6 - fluoro - 1,4 - dihydro - 4 - oxo - 1,8 - naphthyridine - 3 - carboxylic acid, monomethanesulfonate. Trovafloxacin mesylate differs from other quinolone derivatives by having a 1,8-naphthyridine nucleus.
The chemical structure is:
Its empirical formula is C20H15F3N4O3•CH3SO3H and its molecular weight is 512.46.
Trovafloxacin mesylate is a white to off-white powder.
Trovafloxacin mesylate is available in 100 mg and 200 mg (trovafloxacin equivalent) blue, film-coated tablets. Trovan Tablets contain microcrystalline cellulose, cross-linked sodium carboxymethylcellulose and magnesium stearate. The tablet coating is a mixture of hydroxypropylcellulose, hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol and FD&C blue #2 aluminum lake.
Trovan I.V.
Trovan I.V. contains alatrofloxacin mesylate, the L-alanyl-L-alanyl prodrug of trovafloxacin mesylate. Chemically, alatrofloxacin mesylate is (1α, 5α, 6α) - L - alanyl - N - [3 - [6 - carboxy - 8 - (2,4 - difluorophenyl) - 3 - fluoro - 5,8 - dihydro - 5 - oxo - 1,8 - naphthyridine - 2 - yl] - 3 - azabicyclo[3.1.0]hex - 6 - yl] - L - alaninamide, monomethanesulfonate. It is intended for administration by intravenous infusion.
Following intravenous administration, the alanine substituents in alatrofloxacin are rapidly hydrolyzed in vivo to yield trovafloxacin. (See CLINICAL PHARMACOLOGY.)
The chemical structure is:
Its empirical formula is C26H25F3N6O5•CH3SO3H and its molecular weight is 654.62.
Alatrofloxacin mesylate is a white to light yellow powder.
Trovan I.V. is available in 40 mL and 60 mL single use vials as a sterile, preservative-free aqueous concentrate of 5 mg trovafloxacin/mL as alatrofloxacin mesylate intended for dilution prior to intravenous administration of doses of 200 mg or 300 mg of trovafloxacin, respectively. (See HOW SUPPLIED.)
The formulation contains Water for Injection, and may contain sodium hydroxide or hydrochloric acid for pH adjustment. The pH range for the 5 mg/mL aqueous concentrate is 3.5 to 4.3.
Trovan - Clinical Pharmacology
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.
| TROVAFLOXACIN PHARMACOKINETIC PARAMETERS |
|---|
|
Cmax
(µg/mL) |
Tmax
(hrs) |
AUC
(µg•h/mL) |
T½
(hrs) |
Vdss
(L/Kg) |
CL
(mL/hr/Kg) |
CLr
(mL/hr/Kg) |
|---|
| Cmax=Maximum serum concentration; Tmax=Time to Cmax; AUC=Area under concentration vs. time curve; T1/2=serum half-life; Vdss=Volume of distribution; Cl=Total clearance; Clr=Renal clearance |
|
| Trovafloxacin 100 mg |
|
|
|
|
|
|
|
| Single dose |
1.0±0.3 |
0.9±0.4 |
11.2±2.2 |
9.1 |
— |
— |
— |
| Multiple dose |
1.1±0.2 |
1.0±0.5 |
11.8±1.8 |
10.5 |
— |
— |
— |
| Trovafloxacin 200 mg |
|
|
|
|
|
|
|
| Single dose |
2.1±0.5 |
1.8±0.9 |
26.7±7.5 |
9.6 |
— |
— |
— |
| Multiple dose |
3.1±1.0 |
1.2±0.5 |
34.4±5.7 |
12.2 |
— |
— |
— |
| Alatrofloxacin 200 mg |
|
|
|
|
|
|
|
| Single dose |
2.7±0.4 |
1.0±0.0 |
28.1±5.1 |
9.4 |
1.2±0.2 |
93.0±17.4 |
6.5±3.5 |
| Multiple dose |
3.1±0.6 |
1.0±0.0 |
32.2±7.3 |
11.7 |
1.3±0.1 |
81.7±17.8 |
8.6±2.4 |
| Alatrofloxacin 300 mg† |
|
|
|
|
|
|
|
| Single dose |
3.6±0.6 |
1.3±0.4 |
46.1±5.2 |
11.2 |
1.2±0.1 |
84.6±6.0 |
6.9±0.5 |
| Multiple dose |
4.4±0.6 |
1.2±0.2 |
46.3±3.9 |
12.7 |
1.4±0.1 |
84.5±11.1 |
8.4±1.8 |
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.
| Fluid or Tissue |
Tissue-Fluid/Serum Ratio (Range) |
|---|
|
| Respiratory |
|
| bronchial macrophages (multiple dose) |
24.1 (9.6–41.8) |
| lung mucosa |
1.1 (0.7–1.5) |
| lung epithelial lining fluid (multiple dose) |
5.8 (1.1–17.5) |
| whole lung |
2.1 (0.42–5.03) |
| Skin, Musculoskeletal |
|
| skin |
1.0 (0.20–1.88) |
| subcutaneous tissue |
0.4 (0.15–0.68) |
| skin blister fluid |
0.7–0.9 (blister/plasma) |
| skeletal muscle |
1.5 (0.50–2.90) |
| bone |
1.0 (0.55–1.67) |
| Gastrointestinal |
|
| colonic tissue |
0.7 (0.0–1.47) |
| peritoneal fluid |
0.4 (0.0–1.25) |
| bile |
15.4 (11.9–21.0) |
| Central Nervous System |
|
| cerebrospinal fluid (CSF), adults |
0.25 (0.03–0.33) |
| cerebrospinal fluid (CSF), children |
0.28 |
| Reproductive |
|
| prostatic tissue |
1.0 (0.5–1.6) |
| cervix (multiple dose) |
0.6 (0.5–0.7) |
| ovary |
1.6 (0.3–2.2) |
| fallopian tube |
0.7 (0.2–1.1) |
| myometrium (multiple dose) |
0.6 (0.4–0.8) |
| uterus |
0.6 (0.3–0.8) |
| vaginal fluid (multiple dose) |
4.7 (0.8–20.8) |
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
GeriatricIn adult subjects, the pharmacokinetics of trovafloxacin are not affected by age (range 19–78 years).
PediatricLimited 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.
GenderThere 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.)
Chronic Hepatic DiseaseFollowing 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.)
Renal InsufficiencyThe 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.
Photosensitivity PotentialIn 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.)
Drug-drug InteractionsThe 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:
| MIC (µg/mL) |
Interpretation |
|---|
| ≤2.0 |
Susceptible (S) |
| 4.0 |
Intermediate (I) |
| ≥8.0 |
Resistant (R) |
For testing Haemophilus spp.
| MIC (µg/mL) |
Interpretation |
|---|
|
| ≤1.0 |
Susceptible (S) |
For testing Streptococcus spp. including Streptococcus pneumoniae:
| MIC (µg/mL) |
Interpretation |
|---|
| ≤1.0 |
Susceptible (S) |
| 2.0 |
Intermediate (I) |
| ≥4.0 |
Resistant (R) |
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:
| Microorganism |
MIC Range (µg/mL) |
|---|
|
| Escherichia coli ATCC 25922 |
0.004–0.016 |
| Staphylococcus aureus ATCC 29213 |
0.008–0.03 |
| Pseudomonas aeruginosa ATCC 27853 |
0.25–2.0 |
| Enterococcus faecalis ATCC 29212 |
0.06–0.25 |
| Haemophilus influenzae ATCC 49247 |
0.004–0.016 |
| Streptococcus pneumoniae ATCC 49619 |
0.06–0.25 |
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:
| Zone Diameter (mm) |
Interpretation |
|---|
| ≥17 |
Susceptible (S) |
| 14–16 |
Intermediate (I) |
| ≤13 |
Resistant (R) |
For testing Haemophilus spp.:
| Zone Diameter (mm) |
Interpretation |
|---|
|
| ≥22 |
Susceptible (S) |
For testing Streptococcus spp. including Streptococcus pneumoniae:
| Zone Diameter (mm) |
Interpretation |
|---|
| ≥19 |
Susceptible (S) |
| 18–16 |
Intermediate (I) |
| ≤15 |
Resistant (R) |
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:
| Microorganism |
Zone Diameter Range (mm) |
|---|
|
| Escherichia coli ATCC 25922 |
29–36 |
| Staphylococcus aureus ATCC 25923 |
29–35 |
| Pseudomonas aeruginosa ATCC 27853 |
21–27 |
| Haemophilus influenzae ATCC 49247 |
32–39 |
| Streptococcus pneumoniae ATCC 49619 |
25–32 |
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:
| MIC (µg/mL) |
Interpretation |
|---|
| ≤2.0 |
Susceptible (S) |
| 4.0 |
Intermediate (I) |
| ≥8.0 |
Resistant (R) |
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:
| Microorganism |
MIC (µg/mL) |
|---|
|
| Bacteroides fragilis ATCC 25285 |
0.125–0.5 |
| Bacteroides thetaiotamicron ATCC 29741 |
0.25–1.0 |
| Eubacterium lentum ATCC 43055 |
0.25–1.0 |
Indications and Usage for Trovan
Trovan is indicated for the treatment of patients initiating therapy in in-patient health care facilities (i.e., hospitals and long term nursing care facilities) with serious, life- or limb-threatening infections caused by susceptible strains of the designated microorganisms in the conditions listed below. (See DOSAGE AND ADMINISTRATION.)
Nosocomial pneumonia caused by Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, or Staphylococcus aureus. As with other antimicrobials, where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with either an aminoglycoside or aztreonam may be clinically indicated.
Community acquired pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus, Mycoplasma pneumoniae, Moraxella catarrhalis, Legionella pneumophila, or Chlamydia pneumoniae.
Complicated intra-abdominal infections, including post-surgical infections caused by Escherichia coli, Bacteroides fragilis, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Peptostreptococcus species, or Prevotella species.
Gynecologic and pelvic infections including endomyometritis, parametritis, septic abortion and post-partum infections caused by Escherichia coli, Bacteroides fragilis, viridans group streptococci, Enterococcus faecalis, Streptococcus agalactiae, Peptostreptococcus species, Prevotella species, or Gardnerella vaginalis.
Complicated skin and skin structure infections, including diabetic foot infections, caused by Staphylococcus aureus, Streptococcus agalactiae, Pseudomonas aeruginosa, Enterococcus faecalis, Escherichia coli, or Proteus mirabilis. NOTE: Trovan has not been studied in the treatment of osteomyelitis. (See WARNINGS.)
Contraindications
Trovan is contraindicated in persons with a history of hypersensitivity to trovafloxacin, alatrofloxacin, quinolone antimicrobial agents or any other components of these products.
Warnings
(See boxed WARNING.) Trovan-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 AND LONG-TERM DRUG EXPOSURE IN MEN AND WOMEN. 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 Trovan RECIPIENTS WHO DEVELOP SIGNS OR SYMPTOMS CONSISTENT WITH HEPATITIS. CLINICIANS SHOULD CONSIDER DISCONTINUING Trovan IN THOSE PATIENTS WHO DEVELOP LIVER FUNCTION TEST ABNORMALITIES.
THE SAFETY AND EFFECTIVENESS OF TROVAFLOXACIN IN PEDIATRIC PATIENTS AND ADOLESCENTS LESS THAN 18 YEARS OF AGE, PREGNANT WOMEN, AND NURSING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pediatric Use, Pregnancy, and Nursing Mothers subsections.)
As with other members of the quinolone class, trovafloxacin has caused arthropathy and/or chondrodysplasia in immature rats and dogs. The significance of these findings to humans is unknown. (See ANIMAL PHARMACOLOGY.)
Convulsions, increased intracranial pressure and psychosis have been reported in patients receiving quinolones. Quinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares and insomnia. These reactions may occur following the first dose. If these reactions occur in patients receiving trovafloxacin or alatrofloxacin, the drug should be discontinued and appropriate measures instituted. (See PRECAUTIONS: General,Information for Patients, Drug Interactions and ADVERSE REACTIONS.)
As with other quinolones, Trovan should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral atherosclerosis, epilepsy, and other factors that predispose to seizures. (See ADVERSE REACTIONS.)
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with 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, including generalized erythema.
Life-threatening hypotension has been reported with alatrofloxacin administration. This has occurred in patients receiving alatrofloxacin at either the recommended rate of infusion or if given more rapidly. Hypotension may be potentiated with the concomitant administration of anesthetic agents. Alatrofloxacin should only be administered by slow intravenous infusion over a period of 60 minutes. Blood pressure should be monitored closely during infusion.
Trovan should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated. (See PRECAUTIONS and ADVERSE REACTIONS.)
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. 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.
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 Clostridium difficile is the primary cause of "antibiotic-associated colitis."
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. (See ADVERSE REACTIONS.)
Although not seen in Trovan clinical trials, ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Trovan should be discontinued if the patient experiences pain, inflammation or rupture of a tendon. Patients should rest and refrain from exerci
