Fluoroquinolones, including FLOXIN®, 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). To reduce the development of drug-resistant bacteria and maintain the effectiveness of FLOXIN® (ofloxacin tablets) Tablets and other antibacterial drugs, FLOXIN® (ofloxacin tablets) Tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION FLOXIN® (ofloxacin tablets) Tablets is a synthetic broad-spectrum antimicrobial agent for oral administration. Chemically, ofloxacin, a fluorinated carboxyquinolone, is the racemate, (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7 oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. The chemical structure is: Its empirical formula is C18H20FN3O4, and its molecular weight is 361. 4 Ofloxacin is an off-white to pale yellow crystalline powder. The molecule exists as a zwitterion at the pH conditions in the small intestine.
The relative solubility characteristics of ofloxacin at room temperature, as defined by USP nomenclature, indicate that ofloxacin is considered to be soluble in aqueous solutions with pH between 2 and 5. It is sparingly to slightly soluble in aqueous solutions with pH 7 (solubility falls to 4 mg/mL) and freely soluble in aqueous solutions with pH above 9. Ofloxacin has the potential to form stable coordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Fe+3 > Al+3 > Cu +2 > Ni+2 > Pb+2 > Zn+2 > Mg+2 > Ca+2 > Ba+2.
1 FLOXIN® Tablets contain the following inactive ingredients: anhydrous lactose, modified corn starch, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and may also contain synthetic yellow iron oxide. CLINICAL PHARMACOLOGY Following oral administration, the bioavailability of ofloxacin in the tablet formulation is approximately 98%. Maximum serum concentrations are achieved one to two hours after an oral dose.
Absorption of ofloxacin after single or multiple doses of 200 to 400 mg is predictable, and the amount of drug absorbed increases proportionately with the dose. Ofloxacin has biphasic elimination. Following multiple oral doses at steady-state administration, the half-lives are approximately 4-5 hours and 20-25 hours. However, the longer half-life represents less than 5% of the total AUC. Accumulation at steady-state can be estimated using a half-life of 9 hours. The total clearance and volume of distribution are approximately similar after single or multiple doses.
Elimination is mainly by renal excretion. The following are mean peak serum concentrations in healthy 70-80 kg male volunteers after single oral doses of 200, 300, or 400 mg of ofloxacin or after multiple oral doses of 400 mg. Steady-state concentrations were attained after four oral doses, and the area under the curve (AUC) was approximately 40% higher than the AUC after single doses. Therefore, after multiple-dose administration of 200 mg and 300 mg doses, peak serum levels of 2. 2 ? g/mL and 3. 6 ? g/mL, respectively, are predicted at steady-state.
In vitro, approximately 32% of the drug in plasma is protein bound. The single dose and steady-state plasma profiles of ofloxacin injection were comparable in extent of exposure (AUC) to those of ofloxacin tablets when the injectable and tablet formulations of ofloxacin were administered in equal doses (mg/mg) to the same group of subjects.
The mean steady-state AUC(0-12) attained after the intravenous administration of 400 mg over 60 min was 43. 5 ? g•h/mL; the mean steady-state AUC(0-12) attained after the oral administration of 400 mg was 41. 2 ? g•h/mL (twoone-sided t-test, 90% confidence interval was 103-109). (See following chart. )
2 Between 0 and 6 h following the administration of a single 200 mg oral dose of ofloxacin to 12 healthy volunteers, the average urine ofloxacin concentration was approximately 220 ? g/mL. Between 12 and 24 hours after administration, the average urine ofloxacin level was approximately 34 ? g/mL. Following oral administration of recommended therapeutic doses, ofloxacin has been detected in blister fluid, cervix, lung tissue, ovary, prostatic fluid, prostatic tissue, skin, and sputum.
The mean concentration of ofloxacin in each of these various body fluids and tissues after one or more doses was 0. 8 to 1. 5 times the concurrent plasma level. Inadequate data are presently available on the distribution or levels of ofloxacin in the cerebrospinal fluid or brain tissue. Ofloxacin has a pyridobenzoxazine ring that appears to decrease the extent of parent compound metabolism. Between 65% and 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hours of dosing.
Studies indicate that less than 5% of an administered dose is recovered in the urine as the desmethyl or N-oxide metabolites. Four to eight percent of an ofloxacin dose is excreted in the feces. This indicates a small degree of biliary excretion of ofloxacin. The administration of FLOXIN® with food does not affect the Cmax and AUC? of the drug, but Tmax is prolonged. Clearance of ofloxacin is reduced in patients with impaired renal function (creatinine clearance rate.