Safety and tolerability of the β ₃ ‐adrenoceptor agonist mirabegron, for the treatment of overactive bladder: results of a prospective pooled analysis of three 12‐week randomised Phase III trials and of a 1‐year randomised Phase III trial

Abstract

SUMMA RYAims: To evaluate the safety and tolerability of the b 3 -adrenoceptor agonist, mirabegron, in patients with overactive bladder (OAB). Methods: Tolerability and safety data from three 12-week, randomised, placebo-controlled, double-blind, Phase III trials (Studies 046, 047 and 074) were pooled by treatment group. The three studies were of a similar design, although the assessed doses of mirabegron [25, 50 or 100 mg once daily (qd)] varied, and tolterodine extended release (ER) 4 mg was included as an active-control arm in Study 046 only. Tolerability and safety data from a 1-year, randomised, double-blind, Phase III trial (Study 049) are also presented. Safety variables included the incidence and severity of treatmentemergent adverse events (TEAEs), vital signs and electrocardiogram data. Results: Mirabegron (25, 50 or 100 mg qd) was safe and well-tolerated in patients with OAB over 12-week (n = 2736) and 1-year (n = 1632) periods. The incidence of TEAEs and treatment discontinuations as a result of TEAEs was low; the majority were mild in severity and few were serious. Hypertension, nasopharyngitis and urinary tract infection were the most common TEAEs with mirabegron. The mirabegron tolerability profile was similar to that seen with placebo and tolterodine ER 4 mg, except for dry mouth, which occurred, on average, five times less frequently with mirabegron than tolterodine ER 4 mg. In the pooled 12-week analysis, mirabegron 50 mg was associated with placebo-adjusted mean increases of 0.4-0.6 mmHg in blood pressure and approximately one beat per minute in pulse rate, both reversible upon treatment discontinuation. The incidence of Major Adverse Cardiovascular Events as adjudicated by an independent cardiovascular committee was low and similar across treatment groups. Conclusion: The favourable tolerability profile of mirabegron in patients with OAB may allow improved treatment compliance compared with antimuscarinics, with important implications for patient outcomes. What's knownOral antimuscarinic agents are currently the standard pharmacological treatment for the symptoms of overactive bladder (OAB), but can be associated with suboptimal efficacy and adverse events (AEs) including dry mouth, constipation and blurred vision that limit patient compliance. The b 3 -adrenoceptor agonist, mirabegron, has a different mechanism of action to that of antimuscarinic agents and is the first in this new class of compounds to be approved for the treatment of OAB. What's newA randomised, 1-year, Phase III trial and a pooled analysis of three randomised, 12-week, Phase III trials demonstrate that mirabegron has a favourable tolerability profile in patients with OAB. Hypertension, nasopharyngitis and urinary tract infection were the most common AEs with mirabegron. Except for dry mouth (up to fivefold more frequent with tolterodine extended release (ER) 4 mg than mirabegron), the incidence of AEs was similar for mirabegron, placebo and tolterodine ER 4 mg.

Mirabegron: a guide to its use in overactive bladder syndrome in the EU

“…Treatment with mirabegron was not associated with an increased risk of hepatic or other laboratory disturbances, or an increased rate of cardiovascular adverse events relative to placebo or tolterodine ER [19]. Tachycardia TEAEs were experienced by a small (1.2 %) proportion of patients receiving mirabegron 50 mg/day in the 12-month study [19].…”

“…Mirabegron 50 mg once daily was generally well tolerated, with most treatment-emergent adverse events (TEAEs) being of mild or moderate severity [19].…”

“…In a pooled analysis of the 12-week, placebo-controlled trials [19], TEAEs considered to be related to study drug were reported in 18.6 % of mirabegron 50 mg/day recipients compared with 26.5 % of tolterodine ER 4 mg/day recipients and 16.8 % of placebo recipients. In the Carefully monitor digoxin therapy Consider possibility of interactions with concomitant use of other sensitive P-gp substrates (e.g.…”

“…dabigatran) BP blood pressure, CYP cytochrome P450, P-gp P-glycoprotein corresponding groups, 0.5, 1.2 and 0.4 % had serious drugrelated TEAEs, and 2.5, 2.6 and 2.0 % had drug-related TEAEs leading to permanent drug discontinuation. The most common drug-related TEAEs were hypertension (4.7 % of mirabegron 50 mg/day recipients vs. 6.1 % of tolterodine ER 4 mg/day and 4.6 % of placebo recipients), headache (2.0 vs. 2.2 and 1.3 %), dry mouth (0.9 vs. 9.5 and 1.6 %), and constipation (0.8 vs. 1.4 and 1.2 %) [19]. Acute urinary retention occurred in 0.1, 0.6 and 0.2 % of mirabegron 50 mg/day, tolterodine ER 4 mg/day and placebo recipients, respectively [19].…”

Cost-effectiveness of mirabegron compared to tolterodine ER 4 mg for overactive bladder in Canada

“…31 The pooled analysis also demonstrated that the tolerability profile of mirabegron was similar to that of placebo and tolterodine ER 4 mg, with the exception of dry mouth, where the incidence was five times higher with tolterodine ER 4 mg than with mirabegron. 32 In a review of clinical trials of up to 12 months, the most common adverse events (AEs) observed with mirabegron were hypertension, nasopharyngitis, and urinary tract infection. 33 Real-world experience (based on data from >19 000 patients treated for OAB in Canada) indicates that mirabegron provides greater persistence and adherence than antimuscarinic agents.…”