FACTIVE

FACTIVE- gemifloxacin mesylate tablet
Merus Labs International Inc.

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones, including FACTIVE ® , have been associated with with disabling and potentially irreversible serious adverse reactions that have occurred together (See WARNINGS) including:

  • Tendinitis and tendon rupture
  • Peripheral neuropathy
  • Central nervous system effects

Discontinue FACTIVE immediately and avoid the use of fluoroquinolones, including FACTIVE, in patients who experience any of these serious adverse reactions (See WARNINGS ).

  • Fluoroquinolones, including FACTIVE, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid FACTIVE in patients with known history of myasthenia gravis (See WARNINGS ).
  • Because fluoroquinolones, including FACTIVE, have been associated with serious adverse reactions (See WARNINGS), reserve FACTIVE for use in patients who have no alternative treatment options for acute bacterial exacerbation of chronic bronchitis (See INDICATIONS AND USAGE).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of FACTIVE and other antibacterial drugs, FACTIVE should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

FACTIVE (gemifloxacin mesylate) is a synthetic broad-spectrum antibacterial agent for oral administration. Gemifloxacin, a compound related to the fluoroquinolone class of antibiotics, is available as the mesylate salt in the sesquihydrate form. Chemically, gemifloxacin is (R,S)-7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

The mesylate salt is a white to light brown solid with a molecular weight of 485.49. Gemifloxacin is considered freely soluble at neutral pH (350 μg/mL at 37ºC, pH 7.0). Its empirical formula is C18 H20 FN5 O4 •CH4 O3 S and its chemical structure is:

Gemifloxacin Mesylate
(click image for full-size original)

Each white to off-white, oval, film-coated FACTIVE tablet has breaklines and GE 320 debossed on both faces and contains gemifloxacin mesylate equivalent to 320 mg gemifloxacin. The inactive ingredients are crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of gemifloxacin are approximately linear over the dose range from 40 mg to 640 mg. There was minimal accumulation of gemifloxacin following multiple oral doses up to 640 mg a day for 7 days (mean accumulation <20%). Following repeat oral administration of 320 mg gemifloxacin once daily, steady-state is achieved by the third day of dosing.

Absorption and Bioavailability

Gemifloxacin, given as an oral tablet, is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of gemifloxacin were observed between 0.5 and 2 hours following oral tablet administration and the absolute bioavailability of the 320 mg tablet averaged approximately 71% (95% CI 60%-84%). Following repeat oral doses of 320 mg to healthy subjects, the mean ± SD maximal gemifloxacin plasma concentrations (Cmax) and systemic drug exposure (AUC (0-24)) were 1.61 ± 0.51 μg/mL (range 0.70-2.62 μg/mL) and 9.93 ± 3.07 μg•hr/mL (range 4.71-20.1 μg•hr/mL), respectively. In patients with respiratory and urinary tract infections (n=1423), similar estimates of systemic drug exposure were determined using a population pharmacokinetics analysis (geometric mean AUC (0-24), 8.36 μg•hr/mL; range 3.2 – 47.7 μg•hr/mL).

The pharmacokinetics of gemifloxacin were not significantly altered when a 320 mg dose was administered with a high-fat meal. Therefore FACTIVE tablets may be administered without regard to meals.

Distribution

In vitro binding of gemifloxacin to plasma proteins in healthy subjects is approximately 60 to 70% and is concentration independent. After repeated doses, the in vivo plasma protein binding in healthy elderly and young subjects ranged from 55% to 73% and was unaffected by age. Renal impairment does not significantly affect the protein binding of gemifloxacin. The blood-to-plasma concentration ratio of gemifloxacin was 1.2:1. The geometric mean for Vdss/F is 4.18 L/kg (range, 1.66 – 12.12 L/kg).

Gemifloxacin is widely distributed throughout the body after oral administration. Concentrations of gemifloxacin in bronchoalveolar lavage fluid exceed those in the plasma. Gemifloxacin penetrates well into lung tissue and fluids. After five daily doses of 320 mg gemifloxacin, concentrations in plasma, bronchoalveolar macrophages, epithelial lining fluid and bronchial mucosa at approximately 2 hours were as in Table 1.

Table 1. Gemifloxacin Concentrations in Plasma and Tissues (320 mg Oral Dosing)
Tissue Concentration (mean ± SD) Ratio compared with plasma(mean ± SD)
Plasma 1.40 (0.442) μg/mL
Bronchoalveolar Macrophages 107 (77) μg/g 90.5 (106.3)
Epithelial Lining Fluid 2.69 (1.96) μg/mL 1.99 (1.32)
Bronchial Mucosa 9.52 (5.15) μg/g 7.21 (4.03)

Metabolism

Gemifloxacin is metabolized to a limited extent by the liver. The unchanged compound is the predominant drug-related component detected in plasma (approximately 65%) up to 4 hours after dosing. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin. Cytochrome P450 enzymes do not play an important role in gemifloxacin metabolism, and the metabolic activity of these enzymes is not significantly inhibited by gemifloxacin.

Excretion

Gemifloxacin and its metabolites are excreted via dual routes of excretion. Following oral administration of gemifloxacin to healthy subjects, a mean (± SD) of 61 ± 9.5% of the dose was excreted in the feces and 36 ± 9.3% in the urine as unchanged drug and metabolites. The mean (± SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6-17.6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin. The mean (± SD) plasma elimination half-life at steady state following 320 mg to healthy subjects was approximately 7 ± 2 hours (range 4-12 hours).

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