Do Not Use Mirabegron (MYRBETRIQ) for Overactive Bladder

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]

Overactive bladder, which becomes more common as people get older, is caused by involuntary contractions of the bladder wall muscles, even when the amount of urine in the bladder is low.[3]

Mirabegron is the first member of a new family of medicines known as beta-3 adrenergic agonists.[4] 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.[5]

Public Citizen’s Health Research Group has designated mirabegron as Do Not Use for the treatment of overactive bladder because the drug’s significant risks far outweigh its minimal benefits.

Little benefit

The efficacy of mirabegron was evaluated in three 12-week randomized, placebo-controlled clinical trials that together enrolled more than 4,600 adults with overactive bladder symptoms.[6] The subjects had an average age of 59 years; nearly 40 percent were 65 or older. At baseline, they reported urinating an average of about 12 times every 24 hours. Among those subjects who had urinary incontinence at the start of the trial, the average number of urinary incontinence episodes was about 3 per day.

Subjects were randomly assigned to receive either mirabegron — at a dose of 25, 50 or 100 milligrams (mg) — or a placebo once daily for 12 weeks. At the end of the 12 weeks, subjects recorded the frequency of urinating and experiencing incontinence episodes in a three-day diary.

At the end of the 12-week study period, subjects receiving mirabegron at all three doses reported urinating, on average, about 10 times every 24 hours. Compared with a placebo, mirabegron resulted in an average of only one less urination every 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 very modest differences in urinary frequency and incontinence are unlikely to be clinically meaningful. At an advisory committee meeting convened by the FDA to consider whether mirabegron should be approved, one-third of committee members concluded that there was not substantial evidence that mirabegron was effective for treating overactive bladder.[7] One physician member correctly noted that the overall degree of benefit was “quite small and marginal.”[8]

Alongside these minimal benefits, the drug poses serious risks.

Adverse cardiovascular effects

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.[9]

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.[10] In the clinical trials involving patients with overactive bladder, smaller increases in heart rate and blood pressure also were seen with use of mirabegron.[11]

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.[12] The FDA approved the drug despite these concerns.

During the clinical trials, atrial fibrillation — a common abnormal heart rhythm characterized by an irregular and often rapid heartbeat — occurred in slightly more subjects receiving mirabegron than in those receiving a placebo (0.2 percent versus 0.1 percent, respectively).[13]

In 2015, researchers in England reported that among a group of 279 consecutive patients prescribed mirabegron at a dosage of 50 mg daily, eight (3 percent) developed palpitations (the sensation that the heart is beating too hard or too fast, skipping a beat or fluttering) within six weeks.[14] In seven of these patients, the palpitations resolved completely once the drug was stopped (the other patient continued taking the drug despite the symptoms).

In 2015, the Medicines and Healthcare products Regulatory Agency in the UK (an agency similar to the FDA) announced that a review of European drug safety data for mirabegron revealed cases of severe hypertension in patients using the drug.[15] Some of the cases involved hypertensive crisis (sudden severe rise in blood pressure) associated with adverse cardiovascular events (mainly transient ischemic attack and stroke) for which there was a clear temporal relationship to mirabegron use. The UK agency advised health care professionals to check patients’ blood pressure before prescribing the drug and to monitor it regularly during treatment, especially in patients with hypertension.

Finally, in May 2017, the independent French drug safety bulletin Prescrire International reported that a recent review of the European adverse drug event database identified 464 cases of cardiac disorders linked to mirabegron use, including 114 cases of atrial fibrillation.[16] The bulletin recommended against using the drug for urinary incontinence.

Other adverse effects

During clinical trials, urinary tract infections consistently occurred more frequently in subjects receiving mirabegron than in those receiving a placebo.[17] 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 taking anticholinergic drugs that are approved for treatment of overactive bladder (for example, tolterodine [DETROL] and oxybutynin [DITROPAN XL, GELNIQUE, OXYTROL, OXYTROL FOR WOMEN]).[18] Urinary retention increases the risk of urinary tract infection.

The product labeling for mirabegron 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 occurred much more frequently in subjects receiving mirabegron than in those receiving a placebo.[19]

Finally, although there was some evidence from clinical trial data suggesting that mirabegron rarely may cause liver damage, there is no mention of this in the product labeling.[20]

What You Can Do

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 underlying conditions and other factors that may be contributing to symptoms of overactive bladder (see text box, above). See the article “Nonsurgical Treatments for Urinary Incontinence” in the May 2017 issue of Worst Pills, Best Pills News for additional advice.

References

[1] Food and Drug Administration. Approval letter to Astellas Pharma Global Development for NDA 202611, Myrbetriq (mirabegron). June 28, 2012. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/202611Orig1s000ltr.pdf. Accessed November 1, 2017.

[2] Astellas Pharma US. Label: mirabegron (MYRBETRIQ). July 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202611s012lbl.pdf. Accessed November 1, 2017.

[3] Mayo Clinic. Overactive bladder. August 12, 2017. http://www.mayoclinic.org/diseases-conditions/overactive-bladder/symptoms-causes/dxc-20311824. Accessed November 1, 2017.

[4] Food and Drug Administration. Medical reviews for NDA 202611, Myrbetriq (mirabegron). June 1, 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202611Orig1s000MedR.pdf. Accessed November 1, 2017.

[5] Astellas Pharma US. Label: mirabegron (MYRBETRIQ). July 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202611s012lbl.pdf. Accessed November 1, 2017.

[6] Food and Drug Administration. Medical reviews for NDA 202611, Myrbetriq (mirabegron). June 1, 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202611Orig1s000MedR.pdf. Accessed November 1, 2017.

[7] Food and Drug Administration. Summary minutes for the meeting of the Advisory Committee for Reproductive Health Drugs. April 5, 2012. https://wayback.archive-it.org/7993/20170404150020/https:/www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM303955.pdf. Accessed November 1.

[8] Food and Drug Administration. Transcript of the meeting of the Advisory Committee for Reproductive Health Drugs. April 5, 2012. https://wayback.archive-it.org/7993/20170404150021/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM303956.pdf. Accessed November 1, 2017.

[9] Food and Drug Administration. Office director memo for NDA 202611, mirabegron. June 30, 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202611Orig1s000ODMemo.pdf. Accessed November 1, 2017.

[10] Food and Drug Administration. Background materials for meeting of the Advisory Committee for Reproductive Health Drugs. April 5, 2012. https://wayback.archive-it.org/7993/20170405210832/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM298641.pdf. Accessed November 1, 2017.

[11] Ibid.

[12] Ibid.

[13] Ibid.

[14] Balachandran AA, Duckett JR. The risk and severity of developing symptomatic palpitations when prescribed mirabegron for overactive bladder. Eur J Obstet Gynecol Reprod Biol. 2015 Apr;187:60-63.

[15] GOV.UK. Mirabegron (Betmiga): risk of severe hypertension and associated cerebrovascular and cardiac events. October 14, 2015. https://www.gov.uk/drug-safety-update/mirabegron-betmiga-risk-of-severe-hypertension-and-associated-cerebrovascular-and-cardiac-events. Accessed November 1, 2017.

[16] Mirabegron: atrial fibrillation. Prescrire Int. 2017;26(182):125.

[17] Food and Drug Administration. Background materials for meeting of the Advisory Committee for Reproductive Health Drugs. April 5, 2012. https://wayback.archive-it.org/7993/20170405210832/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM298641.pdf. Accessed November 1, 2017.

[18] Astellas Pharma US. Label: mirabegron (MYRBETRIQ). July 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202611s012lbl.pdf. Accessed November 1, 2017.

[19] Food and Drug Administration. Background materials for meeting of the Advisory Committee for Reproductive Health Drugs. April 5, 2012. https://wayback.archive-it.org/7993/20170405210832/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM298641.pdf. Accessed November 1, 2017.

[20] Ibid.

[21] Mayo Clinic. Overactive bladder. August 12, 2017. http://www.mayoclinic.org/diseases-conditions/overactive-bladder/symptoms-causes/dxc-20311824. Accessed November 1, 2017.