Pharmacology Update

Mirabegron Extended-Release Tablets (Myrbetriq™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

A BETA-3 ADRENERGIC AGONIST HAS BEEN APPROVED FOR the treatment of overactive bladder in adults. Mirabegron differs from other agents approved for this same indication, such as oxybutynin, tolterodine, solifenacin, darifenacin, etc., which are anticholinergic/antimuscarinic agents. Mirabegron is marketed by Astellas Pharma as Myrbetriq.

Indications

Mirabegron is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.1

Dosage

The recommended dose is one 25 mg tablet, swallowed whole, once daily without regard to meals.1 Effectiveness should be achieved within 8 weeks. The dose may be increased to 50 mg based on effectiveness and tolerance. The dose should not be increased in patients with severe renal dysfunction or moderate hepatic dysfunction.1

Mirabegron is available as 25 mg and 50 mg tablets.

Potential Advantages

Mirabegron is the first in the class of beta-3 adrenergic agonists. It offers a different adverse event profile compared to the antimuscarinic agents (e.g., dry mouth, constipation).

Potential Disadvantages

Mirabegron may increase blood pressure, particularly in those with baseline hypertension.1 It is also a moderate inhibitor of CYP2D6; therefore monitoring or dose adjustments may be needed if coadministered with drugs with a narrow therapeutic index which are substrates of this isoenzyme (e.g., propafenone, flecainide, thioridazine).1 Mirabegron may not be effective in males with BPH.3

Comments

The involuntary contraction of the detrusor muscle in the bladder results in overactive bladder. The antimuscarinic agents inhibit the contraction of this muscle. Mirabegron’s action on the beta-3 adrenergic receptor relaxes the detrusor smooth muscle, which results in improved bladder compliance on filling and increases bladder capacity.1,2 In general terms, antimuscarinics act on the voiding phase of the micturition while beta-3 adrenergic agonists work on the filling/storage phase of micturition. The safety and efficacy of mirabegron was studied in three, randomized, double-blind, placebo-controlled, 12-week trials (SCORPIO, ARIES, CAPRICORN).1,3 Overactive bladder was defined as at least eight micturitions/day and at least three episodes of urgency with or without incontinence over a 3-day period for at least a 3-month duration. Adult subjects were randomized to mirabegron 50 mg, 100 mg, and tolterodine ER 4 mg in study 1; 50 mg, 100 mg, and placebo in study 2; and 25 mg, 50 mg, or placebo in study 3. The co-primary endpoints were change from baseline to week 12 in mean number of incontinence episodes/day and change in mean number of micturitions/day. A secondary endpoint was the change from baseline in mean volume voided/micturition.1 The pooled results for the 50 mg dose (n = 1324) compared to placebo (n = 1328) were a mean reduction of 0.55 micturitions/24 hours from a baseline of 11.7 and 11.6, respectively (P < 0.001).3 Incontinence episodes compared to placebo (n = 862 and 878, respectively) were reduced by a mean of 0.40 incontinence episodes/24 hours from a baseline of 2.7 (P < 0.001). Mean volume voided compared to placebo (n = 1324 and 1328, respectively) increased by 11.9 mL from a baseline of 159 mL (P < 0.001). The improvements with the 25 mg dose (n = 254) compared to placebo (n = 262) were mean reductions of 0.47 (P = 0.005), 0.40 (P = 0.007), and 4.6 (P = 0.15), respectively. Symptomatic effectiveness was seen within 8 weeks for the 25 mg dose and 4 weeks for the 50 mg dose. The 100 mg dose was not considered for marketing and comparison to tolterodine was not a primary objective.4 Overall, the 50 mg dose appears to be more effective but the effects are quite modest. Only 4% of study participants achieved a minimally important improvement in the level of urgency with the 25 mg dose and 8.3% with the 50 mg dose, and only the 50 mg dose was statistically different from placebo.4

Clinical Implications

Mirabegron offers an agent with a different mechanism of action and adverse reaction profile compared to the antimuscarinic drugs for the treatment of overactive bladder in adults. Overall these agents are modestly effective.5 Mirabegron appears to no different albeit with a difference adverse reaction profile.

References

1. Myrbetriq Prescribing Information. Northbrook, Ill: Astellas Pharma US, Inc.; June 2012.

2. Bhide AA, et al. Use of mirabegron in treating overactive bladder. Int Urogynecol J 2012; Mar 13. [Epub ahead of print.]

3. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM300108.pdf. Accessed July 12, 2012.

4. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM298641.pdf. Accessed July 12, 2012.

5. Chapple CR, et al. The effects of antimuscarinic treatments in overactive bladder: An update of a systematic review and meta-analysis. Eur Urol 2008;54:543-562.