Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Pharmacotherapeutic group: Urologicals, Urinary antispasmodics
ATC code: G04BD11
Fesoterodine is a competitive, specific muscarinic receptor antagonist. It is rapidly and extensively hydrolysed by non-specific plasma esterases to the 5-hydroxymethyl derivative, its primary active metabolite, which is the main active pharmacological principle of fesoterodine.
The efficacy of fixed doses of fesoterodine 4 mg and 8 mg was evaluated in two Phase 3 randomised, 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.
Fesoterodine 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 to placebo. 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 fesoterodine compared to placebo. Furthermore, fesoterodine 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 below).
Table 1. Mean changes from Baseline to end of treatment for primary and selected secondary endpoints:
| Study 1 | Study 2 | ||||||
|---|---|---|---|---|---|---|---|
| Parameter | Placebo | Fesoterodine 4 mg | Fesoterodine 8 mg | Active comparator | Placebo | Fesoterodine 4 mg | Fesoterodine 8 mg |
| Number of micturitions per 24 hours# | |||||||
| N=279 | N=265 | N=276 | N=283 | N=266 | N=267 | N=267 | |
| Baseline | 12.0 | 11.6 | 11.9 | 11.5 | 12.2 | 12.9 | 12.0 |
| Change from baseline | -1.02 | -1.74 | -1.94 | -1.69 | -1.02 | -1.86 | -1.94 |
| p-value | <0.001 | <0.001 | 0.032 | <0.001 | |||
| Responder rate (treatment response)# | |||||||
| N=279 | N=265 | N=276 | N=283 | N=266 | N=267 | N=267 | |
| Responder rate | 53.4% | 74.7% | 79.0% | 72.4% | 45.1% | 63.7% | 74.2% |
| p-value | <0.001 | <0.001 | <0.001 | <0.001 | |||
| Number of urge incontinence episodes per 24 hours | |||||||
| N=211 | N=199 | N=223 | N=223 | N=205 | N=228 | N=218 | |
| Baseline | 3.7 | 3.8 | 3.7 | 3.8 | 3.7 | 3.9 | 3.9 |
| Change from baseline | -1.20 | -2.06 | -2.27 | -1.83 | -1.00 | -1.77 | -2.42 |
| p-value | 0.001 | <0.001 | 0.003 | <0.001 | |||
| Number of continent days per week | |||||||
| N=211 | N=199 | N=223 | N=223 | N=205 | N=228 | N=218 | |
| Baseline | 0.8 | 0.8 | 0.6 | 0.6 | 0.6 | 0.7 | 0.7 |
| Change from baseline | 2.1 | 2.8 | 3.4 | 2.5 | 1.4 | 2.4 | 2.8 |
| p-value | 0.007 | <0.001 | <0.001 | <0.001 | |||
| Voided volume per micturition (ml) | |||||||
| N=279 | N=265 | N=276 | N=283 | N=266 | N=267 | N=267 | |
| Baseline | 150 | 160 | 154 | 154 | 159 | 152 | 156 |
| Change from baseline | 10 | 27 | 33 | 24 | 8 | 17 | 33 |
| p-value | <0.001 | <0.001 | 0.150 | <0.001 | |||
# primary end points
The effect of fesoterodine 4 mg and 28 mg on the QT interval was thoroughly evaluated in a double-blind, randomised, 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 the active treatment and placebo group.
After oral administration, due to rapid and extensive hydrolysis by non-specific plasma esterases, fesoterodine was not detected in plasma.
Bioavailability of the active metabolite is 52%. After single or multiple-dose oral administration of fesoterodine 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 fesoterodine. 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, fesoterodine is rapidly and extensively hydrolysed to its active metabolite. The active metabolite is further metabolised 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 fesoterodine. Mean Cmax and AUC of the active metabolite are 1.7 and 2-fold higher, respectively, in CYP2D6 poor metabolisers as compared to extensive metabolisers.
Hepatic metabolism and renal excretion contribute significantly to the elimination of the active metabolite. After oral administration of fesoterodine, 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 faeces. The terminal half-life of the active metabolite following oral administration is approximately 7 hours and is absorption rate-limited.
No dose adjustment is recommended in these subpopulations. The pharmacokinetics of fesoterodine are not significantly influenced by age and gender.
The pharmacokinetics of fesoterodine have not been evaluated in paediatric patients.
In patients with mild or moderate renal impairment (GFR 30–80 ml/min), Cmax and AUC of the active metabolite increased up to 1.5 and 1.8-fold, respectively, as compared to healthy subjects. In patients with severe renal impairment (GFR<30 ml/min), Cmax and AUC are increased 2.0 and 2.3-fold, respectively.
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 to healthy subjects. Pharmacokinetics of fesoterodine in patients with severe hepatic impairment have not been studied.
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.
Reproduction studies have shown minor embryotoxicity at doses close to maternally toxic ones (increased number of resorptions, pre-implantation and post-implantation losses).
Supratherapeutic concentrations of the active metabolite of fesoterodine, have been shown to inhibit K+ current in cloned human ether-à-go-go-related gene (hERG) channels and prolong action potential duration (70% and 90% repolarisation) in canine isolated Purkinje fibres. However in conscious dogs, the active metabolite had no effect on the QT interval and QTc interval at plas ma exposures at least 33-fold higher than mean peak free plasma concentration in human subjects who are extensive metabolisers and 21-fold higher than measured in subjects who are poor CYP2D6 metabolisers after fesoterodine 8 mg once daily.
In a study of fertility and early embryonic development in mice, fesoterodine had no effect on male reproductive function or fertility at doses up to 45 mg/kg/day. At 45 mg/kg/day, a lower number of corpora lutea, implantation sites and viable foetuses was observed in female mice administered fesoterodine for 2 weeks prior to mating and continuing through day 7 of gestation. The maternal No-Observed-Effect Level (NOEL) and the NOEL for effects on reproduction and early embryonic development were both 15 mg/kg/day. Based on AUC, the systemic exposure was 0.6 to 1.5 times higher in mice than in humans at the MRHD, whereas based on peak plasma concentrations, the exposure in mice was 5 to 9 times higher.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
