WASHINGTON -- Mirabegron, an investigational drug for overactive bladder, is effective at reducing symptoms of urinary incontinence but has worrisome cardiovascular side effects and may be harmful to the liver, according to FDA staff reviewers.
The agency's Reproductive Health Drugs Advisory Committee will meet Thursday to discuss whether mirabegron's benefits outweigh its risks as a treatment for overactive bladder (OAB) in patients with symptoms of urge urinary incontinence, urgency, and urinary frequency.
Mirabegron, made by Astellas, selectively binds and activates beta-3 adrenoreceptors on bladder detrusor muscle to facilitate filling and storage.
In the company's three, 12-week, randomized, placebo-controlled trials, treatment with 50 mg of mirabegron showed a reduction of incontinence episodes and urination over 24 hours as compared with placebo of (P<0.001 for both).
Patient-reported outcomes all improved significantly in the mirabegron groups compared with the placebo groups, including treatment satisfaction, bothersome symptoms, and OAB-specific health-related quality of life (P<0.05).
In briefing documents posted ahead of Thursday's meeting, FDA reviewers said the company's safety data don't appear to indicate serious risks with the drug.
However, they added, a number of adverse events -- including increases in blood pressure and heart rate, liver function test abnormalities, urinary tract infections, neoplasms, and hypersensitivity reactions -- do "raise concerns and these issues require further consideration."
Compared with the placebo group, patients taking a 50-mg dose of mirabegron once a day experienced an increase in blood pressure of about 1 mm Hg from baseline in systolic and diastolic blood pressures, and an increase of approximately 1 beat per minute in heart rate.
The increase in blood pressure coupled with an increase in heart rate "may pose a health risk to OAB patients," the FDA reviewers wrote, adding that clinical relevance of those side effects "require further careful consideration"
There were also three reports of severe hepatotoxicity in patients taking mirabegron, which "appear to reflect a rare potential for mirabegron to adversely affect liver function," the FDA reviewers wrote.
In addition, there were reports of hypersensitivity reactions (including one case of Stevens Johnson Syndrome), urinary tract-related adverse events (UTI and renal colic), a variety of neoplasms, and reports of glaucoma and increases in intraocular pressure reported in the mirabegron group of the clinical trails.
The incidence of serious adverse events was low and comparable between mirabegron and placebo, the reviewers noted.
There were 11 deaths in clinical trials, "none of which appear directly related to treatment with mirabegron," reviewers said.
"Although the safety results from the clinical trials database appear generally reasonable, the special safety concerns, especially the increases in blood pressure and pulse need additional consideration," they wrote.
In Astellas' briefing documents, the company said the drug addresses an unmet medical need for OAB patients, who often report that the condition causes a significant impact on their health-related quality of life.
Mirabegron is a particularly good option for patients who aren't candidates for the current standard treatment for OAB, antimuscarinics, which can cause dry mouth, the company said.
"The benefits of treatment exceed any risk associated with the use of the product," the company said.