Mirabegron (In ) 25 mg, Solifenacin Succinate 5 mg (ER) Tablets

Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle.

Absorption — After oral administration of solifenacin succinate in healthy volunteers, peak plasma concentrations (C max) of solifenacin were reached within 3 to 8 hours after administration and, at steady-state, ranged from 32.3 to 62.9 ng/mL for the 5 and 10 mg solifenacin succinate tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, with plasma concentrations of solifenacin proportional to the dose administered.

Effect of Food — Solifenacin succinate may be administered without regard to meals. A single 10 mg dose administration of solifenacin succinate with food increased C maxand AUC of solifenacin by 4% and 3%, respectively.

Distribution — Solifenacin is approximately 98% ( in vivo) bound to human plasma proteins, principally to α 1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600 L.

Elimination — The elimination half-life (t 1/2) of solifenacin following chronic dosing is approximately 45-68 hours.

Metabolism — Solifenacin is extensively metabolized in the liver. The primary pathway for elimination is by way of CYP3A4; however, alternate metabolic pathways exist. The primary metabolic routes of solifenacin are through N-oxidation of the quinuclidin ring and 4R-hydroxylation of the tetrahydroisoquinoline ring. One pharmacologically active metabolite (4R-hydroxy solifenacin), occurring at low concentrations and unlikely to contribute significantly to clinical activity, and three pharmacologically inactive metabolites (N-glucuronide and the N-oxide and 4R-hydroxy-N-oxide of solifenacin) have been found in human plasma after oral dosing.

Excretion — Following the administration of 10 mg of 14C-solifenacin succinate to healthy volunteers, 69% of the radioactivity was recovered in the urine and 23% in the feces over 26 days. Less than 15% (as mean value) of the dose was recovered in the urine as intact solifenacin. The major metabolites identified in urine were N-oxide of solifenacin, 4R-hydroxy solifenacin, and 4R-hydroxy-N-oxide of solifenacin and, in feces, 4R-hydroxy solifenacin.

Geriatric Patients — Multiple dose studies of Solifenacin succinate tablets in geriatric volunteers (65 to 80 years) showed that C max, AUC and t 1/2values of solifenacin were 20-25% higher compared to the younger adult volunteers (18 to 55 years). [See Use in Specific Populations( 8.5)] .

Patients with Renal Impairment — In studies with solifenacin succinate 10 mg, there was a 2.1-fold increase in AUC and a 1.6-fold increase in t 1/2of solifenacin in patients with severe renal impairment compared to subjects with normal renal function [see Use in Specific Populations( 8.6)] .

Patients with Hepatic Impairment — In studies with solifenacin succinate 10 mg, there was a 2-fold increase in the t 1/2and a 35% increase in AUC of solifenacin in patients with moderate hepatic impairment compared to subjects with normal hepatic function [see Use in Specific Populations( 8.7)] . Solifenacin succinate tablets have not been studied in patients with severe hepatic impairment.

Strong CYP3A4 Inhibitors — In a crossover study, following blockade of CYP3A4 by coadministration of the strong CYP3A4 inhibitor, ketoconazole 400 mg once daily for 21 days, the mean C maxand AUC of solifenacin increased by 1.5 and 2.7-fold, respectively [see Dosage and Administration ( 2.4) and Drug Interactions( 7.1)] .

CYP3A4 Inducers — Because solifenacin is a substrate of CYP3A4, inducers of CYP3A4 may decrease the concentration of solifenacin.

Warfarin — In a crossover study, subjects received a single oral dose of warfarin 25 mg on the 10 th day of dosing with either solifenacin succinate 10 mg or matching placebo once daily for 16 days. For R-warfarin, when it was coadministered with solifenacin succinate, the mean C maxincreased by 3% and AUC decreased by 2%. For S-warfarin, when it was coadministered with solifenacin succinate, the mean C maxand AUC increased by 5% and 1%, respectively.