Mirabegron 50 mg, Solifenacin Succinate 5 mg Hard-gelatin capsules

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.

Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — The median Tmax of mirabegron following oral administration of a single dose of mirabegron for extended-release oral suspension in pediatric patients under fed state was 4-5 hours. Population pharmacokinetic analysis predicted that the median Tmax of mirabegron for extended-release oral suspension at steady-state was 3-4 hours.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — In the fasted state, steady-state mirabegron AUC increased by 120% relative to the fed state in pediatric patients receiving MYRBETRIQ. Fasted Cmax and AUC increased by 170% and 80%, respectively, compared to the fed state following administration of mirabegron for extended-release oral suspension in healthy volunteers.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — Mirabegron volume of distribution was relatively large in pediatric patients (the range of mean Vz/F under fed state in pediatric patients across studies: 4895-13726 L) and increased with increasing body weight.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — The mean terminal elimination half-life (t1/2) of mirabegron is approximately 26 to 31 hours in pediatric patients.

Metabolism — Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of 14C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor.

Although, in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination. In healthy subjects who were genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT), and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — Population pharmacokinetic model predicted that mirabegron clearance in pediatric patients increased with body weight.

Pediatric Patients — In patients 3 to less than 18 years of age, age was not predicted to affect mirabegron pharmacokinetic parameters after accounting for differences in body weight [see Use in Specific Populations ( 8.4 )].

Mirabegron for Pediatric Neurogenic Detrusor Overactivity (NDO) — Gender has no meaningful impact on mirabegron pharmacokinetics in the pediatric population from 3 to less than 18 years of age.

Race — The pharmacokinetics of mirabegron were comparable between Caucasians and African-American Blacks. Cross studies comparison showed that the exposure in Japanese subjects were higher than that in North American subjects. However, when the Cmax and AUC were normalized for dose and body weight, the difference was smaller.

Patients with Renal Impairment — Following single-dose administration of 100 mg mirabegron in adult volunteers with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m2 as estimated by MDRD), mean mirabegron Cmax and AUC were increased by 6% and 31% relative to adult volunteers with normal renal function. In adult volunteers with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2), Cmax and AUC were increased by 23% and 66%, respectively. In adult volunteers with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), mean Cmax and AUC values were 92% and 118% higher compared to healthy subjects with normal renal function. Mirabegron has not been studied in adult patients with End- Stage Renal Disease (ESRD) (eGFR less than 15 mL/min/1.73 m2) or adult patients requiring dialysis.