Toviaz is a competitive, specific muscarinic receptor antagonist. It is rapidly and extensively hydrolyzed by non-specific esterases to the 5-hydroxymethyl derivative, its primary active metabolite, which is the active pharmacological principle of Toviaz.
The efficacy of fixed doses of Toviaz 4 mg and 8 mg was evaluated in two Phase 3 randomized, double-blind, placebo-controlled, 12-week studies. Female (79%) and male (21%) patients with a mean age of 58 years (range 19-91 years) were included. A total of 33% of patients were ≥65 years of age and 11% were ≥75 years of age.
Toviaz treated patients had statistically significant mean reductions in the number of micturitions per 24 hours and in the number of urge incontinence episodes per 24 hours at the end of treatment compared with placebo treated patients. Likewise, the response rate (% of patients reporting that their condition has been "greatly improved" or "improved" using a 4-point Treatment Benefit Scale) was significantly greater with Toviaz compared with placebo. Furthermore, Toviaz improved the mean change in the voided volume per micturition, and the mean change in the number of continent days per week (see Table 1).
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The effect of Toviaz 4 mg and 28 mg on the QT interval was thoroughly evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg) parallel group study with once-daily treatment over a period of 3 days in 261 male and female subjects aged 45 to 65 years. Change from baseline in QTc based on the Fridericia correction method did not show any differences between Toviaz 4 mg and 28 mg treatment and the placebo group.
After oral administration, Toviaz was well-absorbed and was not detected in plasma due to rapid and extensive hydrolysis by non-specific esterases. Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of Toviaz in doses from 4 mg to 28 mg, plasma concentrations of the active metabolite are proportional to the dose. Maximum plasma levels are reached after approximately 5 hours. Therapeutic plasma levels are achieved after the first administration of Toviaz. No accumulation occurs after multiple-dose administration.
Plasma protein binding of the active metabolite is low with approximately 50% bound to albumin and alpha-1-acid glycoprotein. The mean steady-state volume of distribution following intravenous infusion of the active metabolite is 169 l.
After oral administration, Toviaz is rapidly and extensively hydrolysed to its active metabolite. The active metabolite is further metabolized in the liver to its carboxy, carboxy-N-desisopropyl, and N-desisopropyl metabolite with involvement of CYP2D6 and CYP3A4. None of these metabolites contribute significantly to the antimuscarinic activity of Toviaz. Mean Cmax
and AUC of the active metabolite are 1.7 and 2-fold higher, respectively, in CYP2D6 poor metabolizers as compared with extensive metabolizers.
Hepatic metabolism and renal excretion contribute significantly to the elimination of the active metabolite. After oral administration of Toviaz, approximately 70% of the administered dose was recovered in urine as the active metabolite (16%), carboxy metabolite (34%), carboxy-N-desisopropyl metabolite (18%), or N-desisopropyl metabolite (1%), and a smaller amount (7%) was recovered in feces. The terminal half-life of the active metabolite following oral administration is approximately 7 hours.
Pharmacokinetics in special patient groups:
Age and Gender: The pharmacokinetics of Toviaz is not significantly influenced by age and gender. No dose adjustment is recommended for the elderly.
Pediatric Patients: The pharmacokinetics of Toviaz has not been evaluated in pediatric patients.
Renal Impairment: In patients with mild or moderate renal impairment (CrCl 30-80 mL/min), Cmax
and AUC of the active metabolite increased up to 1.5 and 1.8-fold, respectively, as compared with healthy subjects. In patients with severe renal impairment (CrCl <30 mL/min), Cmax
and AUC are increased 2.0 and 2.3-fold, respectively, as compared with healthy subjects (see Dosage & Administration and Precautions).
Hepatic Impairment: In patients with moderate hepatic impairment (Child Pugh B), Cmax
and AUC of the active metabolite increased 1.4 and 2.1-fold, respectively, as compared with healthy subjects. Pharmacokinetics of Toviaz in patients with severe hepatic impairment have not been studied (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data:
In non-clinical safety pharmacology, general toxicity, genotoxicity and carcinogenicity studies no clinically relevant effects have been observed, except those related to the pharmacological effect of the active substance. Fesoterodine had no effect on male reproductive function or fertility in mice at doses up to 45 mg/kg/day. At doses of 45 mg/kg/day, resulting in exposures approximately 5 to 19 times those at the MRHD, a lower number of corpora lutea, implantation sites and viable fetuses was observed in female mice administered fesoterodine for 2 weeks prior to mating and continuing through day 7 of gestation. Reproduction studies have shown minor embryotoxicity (increased number of resorptions, pre-implantation and post-implantation losses). The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day.