Detrol

The U.S. Food and Drug Administration has approved a muscarinic receptor antagonist for treating overactive bladder that is more selective to the muscarinic receptors in the bladder than some older drugs in this class.

Approved in November, solifenacin succinate was developed with the aim of reducing dry mouth and other bothersome anticholinergic side effects that can limit treatment with less specific drugs.

Solifenacin was approved for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. The agent is manufactured by Yamanouchi Pharmaceutical Co., Ltd., and will be marketed under the trade name Vesicare.

Compared with older anticholinergics approved for OAB, solifenacin is a more selective muscarinic receptor blocker, as is trospium chloride, Richard Bercik, M.D., director of the division of urogynecology and reconstructive surgery at Yale University, New Haven, said in an interview. Trospium chloride, marketed as Sanctura, was approved for the treatment of OAB last May.

None of the newer agents has proved to be more effective than oxybutynin, the first anticholinergic approved for OAB, in the 1970s, but the newer agents have fewer side effects, observed Dr. Bercik, who said he is not affiliated with Yamanouchi or manufacturers of other OAB drugs, nor an investigator in any solifenacin studies.

Approval of solifenacin was based on four 12-week trials of 3,027 patients, who were predominantly white and female (mean age 58 years) and who had OAB symptoms for at least 3 years, with 11.5-12.2 micturitions over 24 hours at baseline. At 12 weeks, the number of micturitions per 24 hours had dropped by a mean of 2.3 in patients on the 5-mg dosage and 2.7 in those on 10 mg. vs. 1.4 with placebo--statistically significant differences. Efficacy was similar among different age groups and among men and women.

Secondary end points--the number of incontinence episodes over 24 hours and the mean volume voided per micturition--also were significantly improved with both solifenacin doses.

The most common side effects were typical antimuscarinic effects: dry mouth in 11% and 28% in those on 5 mg and 10 mg, respectively, vs. 4% on placebo; and constipation in 5% (5 mg) and 13% (10 mg), vs. 3% (placebo). Dry mouth was the most common reason (1.5%) for discontinuing participation in the study.

The recommended dosage is 5 mg once a day; if this is well tolerated, it can be increased to 10 mg once a day, according to the drug's label. (No more than 5 mg daily is recommended for patients with renal or moderate hepatic impairment and for those taking CYP3A4 inhibitors, such as ketoconazole; the drug is not recommended for patients with severe hepatic impairment.)

Solifenacin, which is taken once a day, does not need to be taken on an empty stomach. It's longer acting than trospium, which must be taken on an empty stomach twice a day. These two features of solifenacin can be considered advantages, although two or more doses of another anticholinergic can be helpful in some cases, said Dr. Bercik. For example, for a patient with more frequency and urgency symptoms at night, he might prescribe a long-acting anticholinergic in the morning and a short-acting anticholinergic at bedtime.

Older OAB drugs don't have to be taken on an empty stomach but are not as selective as the two newer drugs and have a few more side effects. Still, "there is a place for all these medications," he added, noting that sometimes patients have side effects with one of these drugs but not with another; one drug may not work on everybody, and sometimes multiple medications may be necessary. And as older drugs go off patent, they will become cheaper than the newer ones.

In addition to Sanctura and oxybutynin--available as Ditropan and in generic formulations and as extended release oxybutynin (Ditropan XL)--the other anticholinergics approved for OAB are regular and long-acting tolterodine (Detrol and Detrol LA) and the oxybutynin transdermal patch (Oxytrol).

In an interview, Christopher Klingele, M.D., a urogynecologist at the Mayo Clinic, Rochester, Minn., agreed that having another anticholinergic "gives us more options to offer patients who may not have tolerated one of the other anticholinergics" or did not have a satisfactory response to the other drugs.

An advantage of generic oxybutynin, he said, is its low cost. "It is not infrequent that my choice of drug is made" because a patient cannot afford to pay out of pocket for another drug, Dr. Klingele said.

Yamanouchi is copromoting solifenacin with GlaxoSmithKline. The cost of the drug was not available at press time.

BY ELIZABETH MECHCATIE

Senior Writer

COPYRIGHT 2005 International Medical News Group
COPYRIGHT 2005 Gale Group