Cefixime 200 mg, Erdosteine 300 mg Hard-gelatin capsules

Cefixime is a semisynthetic cephalosporin antibacterial drug [see Microbiology (12.4)].

Cefixime tablets and cefixime for oral suspension, given orally, are about 40% to 50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food. A single 200 mg tablet of cefixime produces an average peak serum concentration of approximately 2 mcg/mL (range 1 to 4 mcg/mL); a single 400 mg tablet produces an average peak concentration of approximately 3.7 mcg/mL (range 1.3 to 7.7 mcg/mL). The cefixime oral suspension produces average peak concentrations approximately 25% to 50% higher than the tablets, when tested in normal adult volunteers. Two hundred and 400 mg doses of cefixime oral suspension produce average peak concentrations of 3 mcg/mL (range 1 to 4.5 mcg/mL) and 4.6 mcg/mL (range 1.9 to 7.7 mcg/mL), respectively, when tested in normal adult volunteers. The area under the time versus concentration curve (AUC) is greater by approximately 10% to 25% with the cefixime for oral suspension than with the tablet after doses of 100 to 400 mg, when tested in normal adult volunteers. This increased absorption should be taken into consideration if the cefixime for oral suspension is to be substituted for the tablet. Because of the lack of bioequivalence, cefixime tablets should not be substituted for cefixime for oral suspension in the treatment of otitis media [see Dosage and Administration (2)]. Cross-over studies of tablet versus suspension have not been performed in children.

The 400 mg cefixime capsule is bioequivalent to the 400 mg cefixime tablet under fasting conditions. However, food reduces the absorption following administration of the capsule by approximately 15% based on AUC and 25% based on Cmax.

Peak serum concentrations occur between 2 and 6 hours following oral administration of a single 200 mg tablet, a single 400 mg cefixime tablet or 400 mg of cefixime for oral suspension. Peak serum concentrations occur between 2 and 5 hours following a single administration of 200 mg of cefixime for oral suspension. Peak serum concentrations occur between 3 and 8 hours following oral administration of a single 400 mg cefixime capsule.

Distribution — Serum protein binding is concentration independent with a bound fraction of approximately 65%. In a multiple dose study conducted with a research formulation which is less bioavailable than the cefixime tablet or cefixime for oral suspension, there was little accumulation of drug in serum or urine after dosing for 14 days. Adequate data on CSF levels of cefixime are not available.

Metabolism and Excretion — There is no evidence of metabolism of cefixime in vivo. Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages 3 to 4 hours but may range up to 9 hours in some normal volunteers.

Specific Populations — Geriatric Patients: Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults. Differences in the pharmacokinetic parameters between 12 young and 12 elderly subjects who received 400 mg of cefixime once daily for 5 days are summarized as follows:

However, these increases were not clinically significant [see Dosage and Administration (2)].

Patients with Renal Impairment: In subjects with moderate impairment of renal function (20 to 40 mL/min creatinine clearance), the average serum half-life of cefixime is prolonged to 6.4 hours. In severe renal impairment (5 to 20 mL/min creatinine clearance), the half-life increased to an average of 11.5 hours. The drug is not cleared significantly from the blood by hemodialysis or peritoneal dialysis. However, a study indicated that with doses of 400 mg of cefixime, patients undergoing hemodialysis have similar blood profiles as subjects with creatinine clearances of 21 to 60 mL/min.

Erdosteine is a prodrug whose active thiol-containing metabolite disrupts disulfide bonds in bronchial mucoproteins, reducing mucus viscosity. The reference also describes experimental antioxidant activity.

Rapid oral absorption is followed by first-pass formation of active metabolite M1. In the cited 300 mg study, parent drug peaked at about 1.18 hours and M1 at 1.48 hours. Their elimination half-lives were approximately 1.46 and 1.62 hours respectively. Parent-drug protein binding averaged 64.5%. Urine contained M1 and sulfate products, while fecal elimination was negligible. These values concern the capsule study, not a fixed combination.