Prescription Drug Information: Trovan

TROVAN- trovafloxacin mesylate tablet, film coated
TROVAN- trovafloxacin mesylate injection, solution, concentrate
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.

DESCRIPTION

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:

Image from Drug Label Content

Its empirical formula is C20 H15 F3 N4 O3 •CH3 SO3 H 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:

Image from Drug Label Content
(click image for full-size original)

Its empirical formula is C26 H25 F3 N6 O5 •CH3 SO3 H 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.

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.)

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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
*
Single dose: AUC(0–∞), multiple dose: AUC(0–24)
trovafloxacin equivalents
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.

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