Drug Profile

In 2012, the Food and Drug Administration (FDA) approved mirabegron (MYRBETRIQ) for the treatment of overactive bladder in adults who have the following symptoms: urgency (sudden urge to urinate), urge urinary incontinence (involuntary leakage of urine from the bladder) and urinary frequency (the need to urinate frequently).[1],[2] This drug is the first member of a new family of medicines known as beta-3 adrenergic agonists.[3] The drug works by activating beta-3 adrenergic receptors in the muscles of the bladder wall, which is supposed to relax the muscles and increase bladder capacity.[2]

The drug also is now approved for children aged three and older who have neurogenic detrusor overactivity, a type of bladder muscle disorder often seen in patients with multiple sclerosis and spinal cord injury; we have not evaluated the drug for this condition.[2]

We have designated mirabegron as Do Not Use for the treatment of overactive bladder because the drug’s significant risks far outweigh its minimal benefits.

The efficacy of mirabegron for treatment of adults with overactive bladder was evaluated in three 12-week randomized, placebo-controlled clinical trials that together enrolled more than 4,600 adults with overactive bladder symptoms.[3] At baseline, the subjects reported urinating an average of about 12 times every 24 hours. Among those subjects who also had urinary incontinence at the start of the trial, the average number of urinary incontinence episodes was about three per day. At the end of the 12-week study period, subjects receiving mirabegron reported urinating, on average, about 10 times every 24 hours. Compared with a placebo, mirabegron resulted in an average of only one fewer episode of urination every two days out of the average 20 times in the two days. In addition, subjects with incontinence who received mirabegron experienced only one fewer episode of incontinence every two to three days compared with those given a placebo. These minimal differences in urinary frequency and incontinence are unlikely to be clinically meaningful.

In addition to these minimal benefits, the drug poses serious risks. Although mirabegron was designed to specifically target beta-3 adrenergic receptors in the muscles of the bladder wall, it also is able to activate, to a lesser degree, beta-1 adrenergic receptors in the heart, which can increase heart rate and blood pressure.[4] Therefore, not surprisingly, early clinical trials testing mirabegron in healthy adults demonstrated that the drug caused significant, dose-dependent increases in heart rate and blood pressure. In the clinical trials involving patients with overactive bladder, smaller increases in heart rate and blood pressure also were seen with use of mirabegron.[5] FDA scientists with expertise in cardiovascular disease concluded that the small increases in blood pressure seen in the mirabegron clinical trials likely would be associated with small increases in the risk of adverse cardiovascular events, including stroke and heart attack.[5] The FDA approved the drug despite these concerns.

There is also evidence linking use of mirabegron to atrial fibrillation[5],[6] — a common abnormal heart rhythm characterized by an irregular and often rapid heartbeat — as well as palpitations (the sensation that the heart is beating too hard or too fast, skipping a beat or fluttering)[7] and hypertensive crisis (sudden severe rise in blood pressure), which can lead to adverse cardiovascular events.[8]

During clinical trials, urinary tract infections consistently occurred more frequently in subjects receiving mirabegron than in those receiving a placebo.[5] The product labeling for mirabegron warns that the drug has been linked to urinary retention (inability to empty the bladder) in patients who have conditions that block urine flow out of the bladder, such as an enlarged prostate, or who are simultaneously taking anticholinergic drugs that are approved for treatment of overactive bladder (for example, tolterodine [DETROL, DETROL LA] and oxybutynin [DITROPAN XL, GELNIQUE, OXYTROL, OXYTROL FOR WOMEN]).[2] Urinary retention increases the risk of urinary tract infection.

The product labeling for mirabegron also warns that angioedema — a life-threatening allergic reaction that can cause swelling of the face, lips, tongue or throat and difficulty breathing — has been reported in patients using mirabegron. In some cases, angioedema occurred after the first dose of the drug. Other types of allergic reactions also may occur with use of mirabegron.[5]

You should avoid starting mirabegron if you are not currently taking it. If you are already taking it, consult with your doctor before discontinuing the drug. Work with your doctor to optimize the treatment of any of the following underlying conditions and other factors that may contribute to symptoms of overactive bladder:

• Diabetes
• Medications that increase urine production, such as diuretics
• Neurological disorders, such as stroke and multiple sclerosis
• Urinary tract infections
• Abnormalities in the bladder, such as tumors or bladder stones
• Conditions that obstruct urine flow out of the bladder, such as an enlarged prostate, previous surgery to treat other forms of incontinence, and constipation
• Excessive consumption of caffeine, alcohol or water, which increases urine production
• Declining cognitive function due to aging or dementia
• Difficulty walking, which can lead to bladder urgency if patients are unable to get to the bathroom quickly

For patients under 65, treatment with one of the anticholinergic drugs approved for treatment of overactive bladder may be appropriate. Older patients should avoid such drugs unless absolutely necessary.