Pharmacology Update
Fesoterodine Fumarate Extended Release Tablets (Toviaz™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.
The FDA has approved a new muscarinic receptor antagonist for the treatment of overactive bladder. Fesoterodine is the prodrug of 5-hydroxymethyltolterodine. It is manufactured by Schwarz Pharma in Germany and distributed by Pfizer Labs as Toviaz™.
Indication
Fesoterodine is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.
Dosage
The recommended initial dose is 4 mg once daily. The dose may be increased to 8 mg once daily depending on response and tolerability. The tablets should be swallowed whole and may be taken without regard to meals.1 No dosage adjustment is recommended for patients with mild-to-moderate renal or hepatic insufficiency.1
Potential Advantages
Fesoterodine has low lipophilicity and therefore low CNS penetration. It also has low interpatient variability, which may result in more consistent and predictable clinical response.2
Potential Disadvantages
Similar to other drugs in the class, dry mouth is the most common adverse event. Other side effects include constipation, dry eyes, and difficulty urinating. Fesoterodine should not be used concomitantly with potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole).1
Commentary
Fesoterodine is completely absorbed and is rapidly metabolized by nonspecific esterases to an active metabolite, 5-hydroxymethyltolterodine (5MHT). The active metabolite has high affinity for muscarinic receptors in the bladder compared to the salivary gland.2 It also has lower lipophilicity compared to other available agents with the exception of trospium.2 Its efficacy and safety were shown in two Phase III, randomized, double-blind, placebo-controlled, 12-week studies involving a total of 1903 subjects.1,3,4 Subjects had symptoms of overactive bladder for 6 months or longer, at least 8 micturitions per day, at least 6 urinary urgency episodes, or 3 urge incontinences per 3-day diary period. The mean age of the subjects was 58 years and they were composed mainly of Caucasian (91%) women (79%). Subjects were randomized to fesoterodine 4 mg, 8 mg, or placebo. One study had an active control (tolterodine ER 4 mg).4 The primary endpoints were the mean change in the number or urge urinary incontinence (UUI) episodes and the number of micturitions per 24 hours. Baseline UUIs were 3.7 for placebo, 3.8 and 3.9 for 4 mg, and 3.7 and 3.9 for 8 mg. Overall the mean reductions from baseline in the number of UUIs were 1.0 and 1.2, 1.77 and 2.06, and 2.27 and 2.42, respectively.1 Baseline micturitions per 24 hours were 12.0 and 12.2 for placebo, 11.6 and 12.9 for 4 mg, and 11.9 and 12.0 for 8 mg. Mean reductions from baseline were 1.02, 1.74 and 1.86, and 1.94, respectively. Fesoterodine also improved health-related quality of life.5 The most common adverse event was mild-to-moderate dry mouth. The frequencies were 7% for placebo, 16% for 4 mg, and 34% and 36% for 8 mg. Fesoterodine 8 mg was more effective than tolterodine ER 4 mg daily in terms of UUIs per 24 hours but had a higher frequency of dry mouth (34% vs 17%).4
Clinical Implications
Fesoterodine is the newest antimuscarinic agent approved for overactive bladder. It is not certain if this new agent offers any real clinical advantages over existing agents. In general, all these agents have shown moderate efficacy and improved health-related quality of life compared to placebo. However, relative efficacy among agents is not clear.6 The adverse effects profile may differ, although the incidence of dry mouth appeared similar for extended release products.
References
1. Toviaz Product Information. New York, NY: Pfizer Labs; April 2008.
2. Michel MC. Fesoterodine: A novel muscarinic receptor antagonist for the treatment of overactive bladder syndrome. Expert Opin Pharmacother 2008;9:1787-1796.
3. Nitti VW, et al. Efficacy, safety and tolerability of fesoterodine for overactive bladder syndrome. J Urol 2007;178:2488-494.
4. Chapple CR, et al. Comparison of fesoterodine and tolterodine in patients with overactive bladder. BJU Int 2008;102:1128-1132.
5. Kelleher CJ, et al. Impact of fesoterodine on quality of life: Pooled data from two randomized trials. BJU Int 2008;102:56-61.
6. Chapple CR, et al. The effects of antimuscarinic treatments in overactive bladder: An update of a systematic review and meta-analysis. Eur Urol 2008;54:543-562.
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