Fesoterodine: A New Antimuscarinic for Overactive Bladder

Abstract

Anticholinergic drugs are the mainstay of therapy of overactive bladder. Overactive bladder is defined by the presence of urinary urgency, with or without incontinence, usually accompanied by urinary frequency and nocturia. Until recently, there were five agents available and widely-used in this regard: darifenacin, oxybutynin, solifenacin, tolterodine and trospium chloride. Recently, fesoterodine has been approved for the treatment of urgency and urge incontinence associated with detrusor overactivity. Fesoterodine acts as a prodrug, delivering the active moiety (5-hydroxymethyl tolterodine or 5-HMT) to the circulation after nonspecific plasma esterases rapidly cleave off the 5-HMT portion from fesoterodine. In this way, it is somewhat similar to tolterodine, which could also be considered a ‘prodrug’, delivering 5-HMT via hepatic metabolism. This moiety is subject to extensive metabolism to a variety of inactive metabolites as well as renal excretion of unchanged 5-HMT to a limited extent. Cytochrome P-450 (CYP450) isozymes 2D6 and 3A4 are involved in the major metabolic pathways of 5-HMT. The activity of CYP450 isozyme 2D6 is subject to genetic polymorphism (7% of Caucasians and 2% of Blacks are poor metabolizers [PMs]) and this increases the potential for variability in drug effects and the magnitude of drug–drug interactions. Fesoterodine therapy (4 and 8 mg once daily) significantly reduced the numbers of micturitions and urge incontinence episodes per 24 h and increased the volume voided per micturition as compared with placebo in three published randomized, controlled trials. It has been compared with tolterodine long-acting in one of these randomized, controlled trials, but the results of fesoterodine and tolterodine long-acting were not compared statistically. Fesoterodine produces the same well-known adverse events as other urinary anticholinergics. The initial recommended dosage regimen is 4 mg once daily, which can be titrated up to 8 mg once daily based upon response. However, the following patient populations should not receive over 4 mg daily: patients with severe renal impairment (creatinine clearance <30 ml/min) and those receiving concurrent therapy with potent CYP450 isozyme 3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir and nelfinavir). Caution is warranted when using the drug in patients with moderate hepatic impairment (Child–Pugh class B), and, owing to a lack of clinical/pharmacokinetic data, fesoterodine should not be used in patients with severe hepatic impairment (Child–Pugh class C). A statement regarding the role of this agent in the management of overactive bladder must await the results of further studies and clinical experience in the community setting.