Ciprofloxacin Extended-release

CIPROFLOXACIN EXTENDED-RELEASE- ciprofloxacin hydrochloride and ciprofloxacin tablet, film coated, extended release
Par Pharmaceuticals, Inc.

WARNING: Fluoroquinolones, including Ciprofloxacin Extended-Release Tablets, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS ).

Fluoroquinolones, including ciprofloxacin extended-release tablets, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid ciprofloxacin extended-release tablets in patients with known history of myasthenia gravis (see WARNINGS ).

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

DESCRIPTION

Ciprofloxacin Extended-Release Tablets contain ciprofloxacin, a synthetic broad-spectrum antimicrobial agent for oral administration. Ciprofloxacin extended-release tablets are coated, bilayer tablets consisting of an immediate-release layer and a matrix type controlled-release layer. The tablets contain a combination of two types of ciprofloxacin drug substance, ciprofloxacin hydrochloride and ciprofloxacin (base). Ciprofloxacin hydrochloride is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)-3-quinolinecarboxylic acid monohydrochloride, monohydrate. The empirical formula of the monohydrate is C17 H18 FN3 O3 • HCl • H2 O and its molecular weight is 385.8. The drug substance is a faintly yellowish to light yellow crystalline substance. The chemical structure of the monohydrate is as follows:

Chemical Structure
(click image for full-size original)

Ciprofloxacin is 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. The empirical formula is C17 H18 FN3 O3 and its molecular weight is 331.3. It is a white to pale yellow crystalline substance and its chemical structure is as follows:

434b702d-figure-02

Ciprofloxacin extended-release tablets are available in 500 mg and 1000 mg (ciprofloxacin equivalent) tablet strengths. Ciprofloxacin extended-release tablets are white, film-coated, oval-shaped tablets. Each ciprofloxacin extended-release 500 mg tablet contains 500 mg of ciprofloxacin* as ciprofloxacin HCl (287.5 mg, calculated as ciprofloxacin on the dried basis) and ciprofloxacin (212.6 mg, calculated on the dried basis). Each ciprofloxacin extended-release 1000 mg tablet contains 1000 mg of ciprofloxacin* as ciprofloxacin HCl (574.9 mg, calculated as ciprofloxacin on the dried basis) and ciprofloxacin (425.2 mg, calculated on the dried basis). The inactive ingredients are colloidal silicon dioxide, crospovidine, D&C Yellow #10, hydrogenated vegetable oil, lactitol, magnesium stearate, microcrystalline cellulose, and succinic acid. The coating contains: hypromellose, maltodextrin, polydextrose, polyethylene glycol, titanium dioxide, and triacetin.

* as ciprofloxacin and ciprofloxacin hydrochloride

CLINICAL PHARMACOLOGY

Absorption

Ciprofloxacin extended-release tablets are formulated to release drug at a slower rate compared to immediate-release tablets. Approximately 35% of the dose is contained within an immediate-release component, while the remaining 65% is contained in a slow-release matrix.

Maximum plasma ciprofloxacin concentrations are attained between 1 and 4 hours after dosing with ciprofloxacin extended-release tablets. In comparison to the 250 mg and 500 mg ciprofloxacin immediate-release BID treatment, the Cmax of ciprofloxacin extended-release tablets 500 mg and 1000 mg once daily are higher than the corresponding BID doses, while the AUCs over 24 hours are equivalent.

The following table compares the pharmacokinetic parameters obtained at steady state for these four treatment regimens (500 mg QD ciprofloxacin extended-release tablets versus 250 mg BID ciprofloxacin immediate-release tablets and 1000 mg QD ciprofloxacin extended-release tablets versus 500 mg BID ciprofloxacin immediate-release).

Ciprofloxacin Pharmacokinetics (Mean ± SD) Following Ciprofloxacin Immediate-Release (IR) Tablets and Ciprofloxacin Extended-Release Tablets Administration
Cmax (mg/L) AUC0-24h (mg•h/L) T1/2 (hr) Tmax (hr) §
§ median (range)
Results of the pharmacokinetic studies demonstrate that ciprofloxacin extended-release tablets may be administered with or without food (for example, high-fat and low-fat meals or under fasted conditions).
ciprofloxacin extended-release 500 mg QD 1.59 ± 0.43 7.97 ± 1.87 6.6 ± 1.4 1.5 (1 – 2.5)
ciprofloxacin IR 250 mg BID 1.14 ± 0.23 8.25 ± 2.15 4.8 ± 0.6 1 (0.5 – 2.5)
ciprofloxacin extended-release 1000 mg QD 3.11 ± 1.08 16.83 ± 5.65 6.31 ± 0.72 2 (1 – 4)
ciprofloxacin IR 500 mg BID 2.06 ± 0.41 17.04 ± 4.79 5.66 ± 0.89 2 (0.5 – 3.5)

Distribution

The volume of distribution calculated for intravenous ciprofloxacin is approximately 2.1 – 2.7 L/kg. Studies with the oral and intravenous forms of ciprofloxacin have demonstrated penetration of ciprofloxacin into a variety of tissues. The binding of ciprofloxacin to serum proteins is 20% to 40%, which is not likely to be high enough to cause significant protein binding interactions with other drugs. Following administration of a single dose of ciprofloxacin extended-release tablets, ciprofloxacin concentrations in urine collected up to 4 hours after dosing averaged over 300 mg/L for both the 500 mg and 1000 mg tablets; in urine excreted from 12 to 24 hours after dosing, ciprofloxacin concentration averaged 27 mg/L for the 500 mg tablet, and 58 mg/L for the 1000 mg tablet.

Metabolism

Four metabolites of ciprofloxacin were identified in human urine. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. The primary metabolites are oxociprofloxacin (M3) and sulfociprofloxacin (M2), each accounting for roughly 3% to 8% of the total dose. Other minor metabolites are desethylene ciprofloxacin (M1), and formylciprofloxacin (M4). The relative proportion of drug and metabolite in serum corresponds to the composition found in urine. Excretion of these metabolites was essentially complete by 24 hours after dosing. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).

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