Vol. VIII, No. 2
  March/April 2005

  Abigail Bridger,
  Pharm.D.

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 Pharmacotherapy
 Update Index

New Therapies for the Treatment of Overactive Bladder

Overactive bladder (OAB) is a form of urinary incontinence affecting both male and female patients of all ages. An estimated 34 million American men and women over 18 years of age report symptoms of OAB. Signs and symptoms of OAB include 1) urgency (defined as a sudden need to urinate), 2) frequency (defined as emptying the bladder more than eight times per day), and 3) nocturia with or without incontinence.¹ The International Continence Society defines OAB as urgency, with or without urge urinary incontinence, usually with frequency and nocturia.² The prevalence of OAB increases with age, and patients with a history of pelvic surgery, dementia, or diabetes may be at an increased risk of developing this condition.³

Bladder contraction is primarily under control of the parasympathetic nervous system and anticholinergics are considered to be the pharmacologic treatment of choice for OAB. Currently available anticholinergics for OAB include oxybutynin, (Ditropan®, Aventis; Ditropan® XL, ALZA Corporation; Oxytrol®, Watson Pharma), tolterodine (Detrol®, Pfizer; Detrol® LA, Pfizer), and trospium (Sanctura®, Odyssey Pharmaceuticals/Indevus Pharmaceuticals).⁴ These agents work through the non-selective inhibition of acetylcholine on muscarinic receptors in smooth muscle throughout the body. Research suggests that the muscarinic₃ (M₃) receptor, located on bladder smooth muscle, is the predominate factor responsible for bladder contraction (i.e., these anticholinergics prevent unintentional bladder contraction). In addition, the M₃ receptor mediates saliva production, gastrointestinal smooth muscle, and iris sphincter function; therefore, expected side effects of anticholinergics include dry mouth, constipation, and miosis.⁵ Solifenacin and darifenacin, two new agents for OAB, have a stronger affinity for the M₃ receptor compared to other anticholinergic agents and therefore have comparable efficacy but a proposed lower side effect profile.

Solifenacin (Vesicare®, Yamanouchi/GlaxoSmithKline) and darifenacin (Enablex®, Pfizer) were approved by the Food and Drug Administration (FDA) in the fourth quarter of 2004. Both products are indicated for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency.^6,7 Solifenacin and darifenacin are competitive M₃ selective receptor antagonists providing a significant reduction in the frequency of micturation and incidence of incontinence episodes along with an increased volume of urine voided per micturation when compared to placebo.^6,7

The most frequently reported adverse events associated with solifenacin are dry mouth, constipation, and blurred vision. While the most commonly reported adverse events from use of darifenacin are dry mouth, constipation, and urinary tract infection. Dry mouth was the most frequent reason for discontinuation of therapy reported for both solifenacin and darifenacin.^6,7 Higher doses of each are associated with an increased risk of developing anticholinergic side effects compared to the starting doses. However, patients on initial doses of solifenacin and darifenacin reported lower incidences of dry mouth compared to oxybutynin XL, tolterodine LA, and trospium (See Table 1).^6-10

Both solifenacin and darifenacin are contraindicated in patients with urinary or gastric retention, uncontrolled narrow-angle glaucoma, or a known hypersensitivity to either drug compound. These medications should be used with caution in patients at risk for bladder outflow obstruction, decreased gastric motility, and controlled narrow-angle glaucoma.^6,7 Solifenacin and darifenacin are rated as a pregnancy-risk category C, indicating that studies in animals have revealed adverse effects on the fetus and there are no controlled studies in women, or that studies in women and animals are not available. These drugs should only be administered during pregnancy if the potential benefit justifies the potential risk to the fetus.¹¹

Solifenacin is primarily metabolized hepatically through the cytochrome P450 (CYP) 3A4 enzyme, while darifenacin is metabolized through both the CYP 3A4 and 2D6 pathways. Potential drug interactions exist between solifenacin, darifenacin, and medications metabolized via the CYP 3A4 enzyme. Known CYP 3A4 enzyme inducers, including carbamazepine (Tegretol®), phenytoin (Dilantin®), and phenobarbital as well as CYP 3A4 enzyme inhibitors such as azole antifungals (ketoconazole [Nizoral®]), clarithromycin (Biaxin®), and verapamil (Calan®), may alter the pharmacokinetic profiles of solifenacin and darifenacin. In addition, darifenacin should be used with caution in patients concomitantly on medications metabolized through the CYP 2D6 pathway with narrow therapeutic indexes such as flecainide (Tambocor®) and tricyclic antidepressants (e.g., imipramine [Tofranil®] and amitriptyline [Elavil®]).^6,7

Both medications are oral tablets that should be swallowed whole, are dosed once daily, and can be taken with or without food. Solifenacin dosing should be initiated at 5 mg once daily and may be increased to 10 mg (no time frame specified) if the desired effect is not achieved and the patient has tolerated therapy. The recommended starting dose of darifenacin is 7.5 mg once daily which may be increased to 15 mg once daily 2 weeks after initial therapy has begun if the desired effect is not achieved.^6,7 For both solifenacin and darifenacin, dosage adjustments are not necessary for patients with mild hepatic impairment. However, patients with moderate hepatic impairment should not receive greater than 5 mg of solifenacin daily or 7.5 mg of darifenacin daily. In addition, neither solifenacin nor darifenacin are recommended for use in patients with severe hepatic impairment. Patients with impaired renal function (CrCl < 30 mL/min) should not receive doses of solifenacin exceeding 5 mg daily. In contrast, dose adjustments are not necessary with darifenacin in patients with renal dysfunction.⁴

The average wholesale price for a 30-day supply of both the solifenacin 5 mg tablets and 10 mg tablets is $101.16. While the average wholesale price for a 30-day supply of darifenacin 7.5- and 15-mg extended-release tablets is $95.76 (See Table 2).^12,13

Solifenacin and darifenacin represent a new class of selective M3 receptor anticholinergics that may help patients with OAB gain control over the symptoms of urgency, urge incontinence, and frequency. Solifenacin 5 mg is associated with the lowest incidence of anticholinergic side effects including dry mouth and constipation in comparison to darifenacin and the non-selective muscarinic anticholinergics used to treat OAB. All of the currently available anticholinergics used for OAB, including solifenacin and darifenacin, require dose adjustment for varying degrees of hepatic impairment. Solifenacin requires dose adjustment in patients with renal insufficiency, while darifenacin does not. The new treatments for OAB offer comparable efficacy, lower incidence of select anticholinergic side effects at lower doses, and competitive pricing compared to branded long-acting, non-selective muscarinic anticholinergics for OAB. Solifenacin and darifenacin have not been requested for formulary review (i.e., both medications are currently non-formulary).

At the time of writing, Abigail was a student in the Drug Information Center. She is currently a Clinical Pharmacist working for the Indian Health Service at the Tsaile Health Center in Tsaile, Arizona.

References

1. Rovner R, Wyman J, Lackner T, Guay D. Urinary incontinence. In: Dipiro J, Talbert R, Yee G, Matzke Wells B, Posey L, editors. Pharmacotherapy: a pathophysiologic approach. 5th ed. New York: McGraw-Hill Medical Publishing Division; 2002. p. 1543-56.
2. Wood AJ. Management of overactive bladder. N Engl J Med 2004;350:786-96.
3. Hashim H, Abrams P. Drug treatment of overactive bladder: efficacy, cost and quality-of-life considerations. Drugs 2004;64:1643-56.
4. Lexi-Comp Online. www.crlonline.com. Accessed 3/14/05.
5. Chapple C, Yamanishi T, Chess-Williams R. Muscarinic receptor subtypes and management of the overactive bladder. Urology 2002;60 (Suppl 5A):82-9.
6. Vesicare® Package Insert: Research Triangle Park, NC: GlaxoSmithKline; 2004 Nov.
7. Enablex® Package Insert: East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004 Dec.
8. Detrol® LA Package Insert: Kalamazoo, MI: Pharmacia & Upjohn; 2004 April.
9. Ditropan® XL Package Insert: Palo Alto, CA: ALZA Corporation; 1998 Dec.
10. Sanctura® Package Insert: East Hanover, NJ: Odyssey Pharmaceuticals; 2004 July.
11. Briggs GG, Freeman RK, Gaffe SJ. Drugs in pregnancy and lactation. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002.
12. Redbook Update: Thomson 2005 March; 24. p. 37, 73.
13. Redbook: Thomson 2004; 23. p. 303, 321, 486-7.