Brand Name: Toviaz™

Generic Name: Fesoterodine Fumarate

Manufacturer: Pfizer

Drug Class: Antimuscarinic

Uses:

Fesoterodine is FDA approved for the treatment of symptoms associated with overactive bladder, such as urgency and frequency, in patients with urge urinary incontinence.¹ There are no off-label indications for this drug.

Mechanism of Action:

Fesoterodine is a competitive muscarinic receptor antagonist.^{1, 2} The active metabolite, 5-hydroxymethyltolterodine (5-HMT)³, inhibits the muscarinic receptors in the bladder that are responsible for urinary bladder smooth muscle contraction and detrusor pressure.^1,2 Detrusor pressure correlates with the volume at which the first detrusor contraction takes place.² 5-HMT has been shown to decrease detrusor pressure as well as increase bladder capacity.²

Pharmacokinetics:

Absorption:

Bioavailability of the 5-HMT is approximately 52%.¹ Fesoterodine cannot be detected in plasma due to rapid and complete hydrolysis by esterases to 5-HMT.¹

Distribution: 5-HMT is approximately 50% plasma protein bound. It is bound primarily to albumin and alpha-1-acid glycoprotein.¹ The steady-state V_d following IV infusion of the active metabolite is 169L.¹

Metabolism: Fesoterodine is rapidly hydrolyzed to its active metabolite 5-hydroxymethyltolterodine, which is a substrate for CYP3A4 and CYP2D6.^{1, 2} Patients who are poor metabolizers of CYP2D6 (~7% of Caucasians, 2% of African Americans) may have AUC and Cmax levels that are 1.7 to 2 times that of extensive metabolizers.¹

Elimination: 5-HMT undergoes both hepatic metabolism and renal excretion.¹  Approximately 70% of the oral dose is recovered in the urine, including 16% as the active metabolite.¹ 7% is recovered in feces.¹

Efficacy:

Chapple C, Van Kerrebroeck P, Tubaro A, Haag-Molkenteller C, Forst HT, Massow U, Wang J, Brodsky M. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2008 Jun;53(6):1319.

Study design: A randomised, double-blind, placebo and active controlled trial compared the efficacy of fesoterodine 4mg and fesoterodine 8mg to placebo, with tolterodine ER 4mg serving as the active control.

Description of study: Primary endpoints for the study were change from baseline to week 12 in micturitions per 24 hours, urge urinary incontinence (UUI) episodes per 24 hours, and treatment response based on a four category treatment benefit scale. Secondary outcomes included mean volume voided per micturition, daytime micturitions per 24 hours, nocturnal micturitions per 24 hours, urgency episodes per 24 hours, and continent days per week. Active treatment with fesoterodine 4mg and 8mg resulted in statistically significant changes from baseline in all primary outcomes and all secondary outcomes except for nocturnal micturitions per 24 hours. In the tolterodine ER 4mg group statistically significant changes were observed for many outcomes, but statistical differences were not found for UUI per 24 hours, nocturnal micturitions per 24 hours, and continent days per week. Adverse effects between all active treatments were similar, but not statistically analyzed. The authors also found that treatment effects were greater in the fesoterodine 8mg group than the fesoterodine 4mg group, with only slight increases in adverse effects (dry mouth and constipation) in the higher dosage group.

Limitations: There were large numbers of dropouts in the study. Another limitation to the study is that statistical analysis between the active control and the study drug was not performed. In future studies it may be beneficial to statistically compare fesoterodine with other treatment options, especially if other treatment options offer a cost advantage. The authors described the conflicts of interest of the study which included that several authors are speakers for Pfizer or employees of Pfizer, the company that funded the study and the manufacturer of Toviaz™.

Conclusion: The benefits of fesoterodine appear to be both statistically and clinically significant when compared to placebo, but we cannot determine the efficacy compared to tolterodine. The authors offer suggestions to improve the extrapolation ability of future studies, such as studies in broader patient diversities, as well as performing a long term, open-label extension trial.

Khullar V, Rovner ES, Dmochowski R, Nitti V, Wang J, Guan Z. Fesoterodine dose response in subjects with overactive bladder syndrome. Urology. 2008 May;71(5):839-43. Epub 2008 Mar 17.

Study design: Pooled data from two randomized placebo-controlled double-blind phase III clinical trials demonstrated effectiveness of fesoterodine in improving the symptoms of overactive bladder (analyzed data from Chapple et al. discussed above, and a separate published study). Furthermore, the pooled analysis showed that fesoterodine 8mg was more effective than fesoterodine 4mg in reducing symptoms without a significant decrease in tolerability.

Description of study: The primary outcome measure for both studies was change from baseline in the number of micturitions per 24 hours. Other primary endpoints were change in number of urge urinary incontinence (UUI) episodes per 24 hours and treatment response. Secondary outcome measures were change in mean volume voided (MVV), mean number of daytime micturitions, mean number of nocturnal micturitions, continent days per week, and mean number of urgency episodes per 24 hours. Outcome measures were evaluated at week two and at week 12. Improvement in symptoms was seen at week two, and statistically significant improvements in both treatment groups were evident at week 12. Statistical significance was observed in change from baseline for micturition frequency per 24 hours, UUI episodes per 24 hours, treatment response, MVV per micturition, urgency episodes per 24 hours, and continent days per week (P<0.01 versus placebo). Additionally, fesoterodine 8mg was statistically superior to fesoterodine 4mg (P<0.05) in all variables except for micturition frequency.

Limitations: One of the authors, Dr. Vik Kulllar is a consultant and investigator for Pfizer, and the study was sponsored by Pfizer, the manufacturer of Toviaz™. The authors did not adequately describe methods of enrollment, methods and effectiveness of blinding, compliance, and measures of variability. Individual analysis of each phase III trial in depth should decrease the number of these limitations. Pooling data from different trials is not as powerful as examining data from a single trial due to variations that may exist between the different studies.

Conclusion: The authors concluded that fesoterodine use led to a statistically significant improvement in the symptoms associated with overactive bladder, as well as demonstrated a dose-dependent increase in effectiveness. By discussing fesoterodine as compared to other antimuscarinic agents used in the treatment of overactive bladder, both in dose-responsiveness and differences in some adverse effects, the authors were able to further support the clinical significance of fesoterodine.

Chapple CR, Van Kerrebroeck PE, Jünemann KP, Wang JT, Brodsky M. Comparison of fesoterodine and tolterodine in patients with overactive bladder. BJU Int. 2008 Nov;102(9):1128-32. Epub 2008 Jul 21.

Study design: A post hoc analysis of a phase III trial compared the effectiveness of the maximum dose of fesoterodine (8mg) and tolterodine (4mg) in reducing the symptoms associated with overactive bladder and improving health-related quality of life (HRQoL). This analysis is based on data from collected from the clinical trial previously discussed (Chapple C et al.). The clinical trial also included fesoterodine 4mg, but the authors did not publish that data in this article.

Description of study: The primary endpoints were voids per 24 hours, urge urinary incontinence (UUI) episodes per 24 hours, and treatment response. The secondary outcome measures were severe urgency plus UUI per 24 hours, mean void volume, and continent days per week. A post hoc analysis was conducted on these endpoints as well as on HRQoL using the King’s Health Questionnaire (KHQ), the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and self-reported bladder-related problems using the six-point Likert scale. A subanalysis was performed on all patients who were incontinent at baseline. At the end of the study, fesoterodine 8mg had greater statistical significance than tolterodine ER 4mg for improving UUI episodes per 24 hours (p < 0.001), mean voided volume (p<0.05), continent days per week (p<0.05), and severe urgency plus UUI (p<0.001 versus placebo). Statistically significant improvements over placebo were observed in eight of the nine domains of the KHQ in the fesoterodine 8mg group versus six of nine KHQ domains in the tolterodine ER 4mg group. Both groups had significant improvement in bladder-related problems from baseline to end of treatment (p<0.01). The most commonly reported adverse effects were dry mouth and constipation, which occurred slightly more in the fesoterodine 8mg group. Dropouts due to adverse effects, however, were similar between the groups (2% placebo, 3% tolterodine, 5% fesoterodine). The subanalysis of patients with incontinence at baseline showed that UUI does not significantly decrease HRQoL in suffers versus non-suffers, meaning that the other symptoms of overactive bladder are equally as detrimental to HRQoL.

Limitations: There was a lack of power for comparison between active treatments, as well as HRQoL. Many statistically significant results had questionable clinical significance when comparing fesoterodine with tolterodine. The other limitation of the study was ambiguity of the urgency classification. The authors propose that a consensus on the definition is necessary to appropriately gather and analyze data regarding urgency.

Conclusion: The authors concluded that both active treatments resulted in statistically significant improvements in OAB symptoms and HRQoL. The study also showed that fesoterodine 8mg was superior to tolterodine ER 4mg in reducing UUI episodes and increasing mean voided volume as well as improving a greater number of KHQ domains.

Contraindications:

 Fesoterodine is contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. Fesoterodine is also contraindicated in patients with a known hypersensitivity to fesoterodine or one of its ingredients.¹

Precautions:

Fesoterodine should be used with caution in patients with urinary obstruction, delayed gastric motility, controlled narrow angle glaucoma, hepatic impairment, renal impairment, myasthenia gravis, and coadministration with CYP3A4 inhibitors.¹

Adverse Effects:

• The most common adverse effects reported from two 12 week phase III clinical trials were dry mouth (8mg/35%, 4mg/19%, placebo/7%) and constipation (8mg/6%, 4mg/4%, placebo/2%).¹
• Other adverse effects that had ≥1 incidence included dyspepsia, nausea, upper abdominal pain, urinary tract infection, upper respiratory tract infection, dry eyes, dysuria, urinary retention, cough, dry throat, peripheral edema, back pain, insomnia, increased ALT and GGT, and rash.¹
• Serious adverse effects reported during the 3 year open-label extension period  of phase II and phase III clinical trials included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).¹

Drug Interactions:

• CYP3A4 inhibitors: Coadministration of CYP3A4 inhibitors may increase plasma concentrations of 5-hydroxymethyltolterodine. Patients taking CYP3A4 inhibitors such as ketoconazole, irtaconazole, and clarithromycin should not take more than 4mg/day of fesoterodine.¹ Other CYP3A4 inhibitors include anti-retroviral protease inhibitors, conivaptan, delavirdine, diltiazem, efavirenz, erythromycin, fluconazole, fluvoxamine, imatinib, nefazodone, quinine, ranolazine, troleandomycin, verapamil, voriconazole, zafirlukast, and grapefruit juice.²
• CYP3A4 inducers: Coadministration of CYP3A4 inducers such as rifampin 600mg with Toviaz 8mg, may decrease plasma AUC of 5-hydroxymethyltolterodine by 75%.¹ Currently no changes in dosage are recommended.¹
• CYP2D6 inhibitors: Although poor metabolizers of CYP2D6 may have increased levels of the active metabolite, there is no dosage adjustment recommended for coadministration with CYP2D6 inhibitors.¹
• Anticholinergic agents: Coadministration of fesoterodine with drugs that cause moderate to severe anticholinergic effects may lead to additive side effects.² These adverse effects include blurred vision, constipation, xerostomia, and urinary retention.² Drugs that may worsen anticholinergic side effects include amantadine, amoxapine, clozapine, cyclobenzaprine, disopyramide, maprotiline, olanzapine, orphenadrine, sedating H₁ blockers, phenothiazines, and tricyclic antidepressants.²
• Foods: Some foods can decrease the effectiveness of fesoterodine by worsening bladder symptoms.² These foods include caffeinated beverages, alcohol, and guarana.²

Dosage/Administration:

Fesoterodine should be taken with liquid and must be swallowed whole.¹ Fesoterodine may be taken without regard to food.¹

• Adult dose: The initial dose is 4mg/day. The dose may be increased to 8mg/day based on individual response.^1,2
• Geriatric dose: See adult dose.² The incidence of anticholinergic side effects, such as dry mouth, constipation, and urinary retention, and urinary tract infection were higher in patients >75 years old taking 8mg/day.¹
• Pediatric dose: Not established¹
• Renal impairment: No dosage adjustments needed in patients with mild to moderate renal insufficiency.^1,2 Doses >4mg/day are not recommended in patients with severe renal impairment.¹ Dosage guidelines are not available for patients with renal failure or who are receiving dialysis.²
• Hepatic impairment: No dosage adjustments are needed in patients with mild to moderate hepatic insufficiency.^1,2 Fesoterodine has not been evaluated in patients with severe hepatic insufficiency and cannot be recommended.¹

Use in Special Circumstances:

• Patients taking CYP3A4 inhibitors: The maximum daily dose is 4mg.^1,2
• Pregnancy: Pregnancy Category C- Fesoterodine should only be used when potential benefit outweighs potential risk.^1,2
• Lactation: It is not known whether Fesoterodine is excreted in breast milk. Fesoterodine should only be used when potential benefit outweighs potential risk.^1,2

Conclusion:

Toviaz™ has been proven to be safe and effective in treating the symptoms associated with overactive bladder. In clinical studies, fesoterodine treatment resulted in statistically significant changes from baseline in almost all primary and secondary outcomes compared to placebo.³ An additional study comparing fesoterodine 8mg to fesoterodine 4mg was able to determine that there is a dose response with fesoterodine treatment without a significant increase in adverse effects.⁴ A post hoc analysis of one of the phase III trial data showed that fesoterodine 8mg was statistically superior to tolterodine ER 4mg, the active control for the original study,⁵ even though both drugs have the same active metabolite, 5-HMT. As opposed to fesoterodine, tolterodine must be metabolized by CYP2D6 to 5-HMT, which could be a problem for patients that are poor metabolizers of CYP2D6 (7% of Caucasians, 2& of African Americans¹).³ The clinical studies showed that fesoterodine results in both statistically and clinically significant improvements in the symptoms of overactive bladder when compared to placebo. Furthermore, fesoterodine may have advantages over other drugs used to treat overactive bladder including increased efficacy in the treatment of some symptoms of OAB and lower incidences of some side effects. Dry mouth and constipation were the most commonly reported adverse effects associated with fesoterodine use in clinical trials, however, the incidences were mostly mild to moderate in severity and few led to dropouts.³ In fact, fesoterodine is reported to have a lower incidence of constipation than immediate-release oxybutynin,  sollifenacin, and darifenacin.^6,7,8 In order to improve the extrapolation ability of the study data, future studies should include broader patient diversities, and analysis of data from a long term, open-label extension trial would also be beneficial.

Recommended References:

1. FDA Toviaz™ package insert
2. Fesoteridine. Clinical Pharmacology [Internet database]. Gold Standard, Inc., 2009. Available at: http://www.clinicalpharmacology.com. Accessed January 09, 2009.
3. Chapple C, Van Kerrebroeck P, Tubaro A, Haag-Molkenteller C, Forst HT, Massow U, Wang J, Brodsky M. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2008 Jun;53(6):1319.
4. Khullar V, Rovner ES, Dmochowski R, Nitti V, Wang J, Guan Z. Fesoterodine dose response in subjects with overactive bladder syndrome. Urology. 2008 May;71(5):839-43. Epub 2008 Mar 17.
5. Chapple CR, Van Kerrebroeck PE, Jünemann KP, Wang JT, Brodsky M. Comparison of fesoterodine and tolterodine in patients with overactive bladder. BJU Int. 2008 Nov;102(9):1128-32. Epub 2008 Jul 21.
6. Ditropan® (oxybutynin chloride). Full prescribing information. Mountain View (CA): ALZA Corporation; 1998.
7. VESIcare® (Solifenacin succinate). Full prescribing information. Norman (OK): Yamanouchi Pharma America, Inc, and GlaxoSmithKline; 2004.
8. Enablex® (Darifenacin). Full prescribing information. East Hanover (NJ):  Novartis Pharmaceuticals Corporation; 2004. 

Prepared by: Monica Pipes, Doctor of Pharmacy Candidate