Mirabegron (Betmiga®) for Overactive Bladder

An overactive bladder is a condition characterised by urinary urgency, frequency, urge incontinence, and nocturia resulting from sudden involuntary bladder (detrusor) muscle contractions.

The prevalence of urinary incontinence increases with age and affects approximately 16% of adults over 40 years of age. Of these, 30% are affected by urge incontinence. Although incontinence is not life threatening, it has significant impacts on patients’ quality of life.

Both non-pharmacological and pharmacological therapies are used in treatment. Lifestyle modifications such as bladder training, pelvic floor muscle exercises, and fluid scheduling are used alone or in conjunction with antimuscarinic agents.

Muscarinic receptors are thought to be the most important contributors to regulating detrusor contractions. Antimuscarinic agents competitively inhibit the effect of acetylcholine at muscarinic receptors, thus inhibiting spontaneous muscle contractions. Anticholinergic (antimuscarinic) agents such as oxybutynin, tolterodine, solifenacin, and darifenacin are the mainstay of pharmacological treatments. Most current medicines however, also produce varying degrees of antimuscarinic adverse effects such as dry mouth, blurred vision, confusion, constipation and (rarely) tachycardia.

Beta-adrenoreceptors also play a central role in control of the micturition cycle. Adrenaline activates beta-3 adrenoreceptors in the bladder, which relaxes bladder smooth muscle, decreasing the frequency of rhythmic bladder contractions during the filling phase and thereby increasing bladder capacity. Mirabegron is a selective beta-3 adrenoceptor agonist recently approved to be used for overactive bladder.

The safety and efficacy of mirabegron has been evaluated in three phase III randomised, placebo-controlled, 12 week studies in patients with symptoms of overactive bladder for more than three months, more than eight micturitions per day, or more than three episodes of urge incontinence over a three day period. A pooled analysis of the trials showed that mirabegron 50mg or 100mg once daily statistically reduces the frequency of incontinence and micturition. The mean number of incontinent episodes per day was reduced with mirabegron by 1.48 for 50mg and 1.54 for 100mg doses compared with a reduction of 1.09 with placebo. The number of urinations was reduced by 1.77 with mirabegron 50mg compared with a reduction of 1.19 with placebo.

The recommended dose for mirabegron is 25mg once daily, without regard to meals. The dose may be increased to 50mg once daily depending on individual patient efficacy and tolerability. Increasing to 100mg was not found to offer an improved dose-response effect in the clinical studies. The maximum recommended dose for patients with renal impairment or patients with hepatic impairment is 25mg once daily. Mirabegron is not recommended for patients with severe renal impairment (eGFR > 29 mL/min/1.73m2) or patients with severe hepatic impairment (Child-Pugh class C). It is also not recommended in pregnancy or lactation as it has shown reproductive toxicity and is excreted in milk.

The bioavailability of mirabegron is 29% for the 25mg dose and 35% for 50mg. It reaches peak plasma concentrations three to four hours after an oral administration. Steady-state concentrations are achieved within seven days. Mirabegron is extensively distributed with 71% protein bound. It is eliminated in the urine (55%) and faeces (34%) with elimination half-life of approximately 50 hours. It is metabolised by multiple pathways including dealkylation, (direct) glucuronidation, amide hydrolysis and minimal oxidative metabolism. Monitoring and dose adjustment may be required when used concomitantly with medicines with narrow therapeutic indices such as imipramine and flecainide. Mirabegron also increases the plasma concentration of digoxin when given in combination; thus the dose of digoxin should be monitored and titrated based on serum concentration.

Common adverse reactions associated with mirabegron are hypertension, nasopharyngitis, urinary tract infections, headache, dyspepsia and constipation. Tachycardia, palpitations and atrial fibrillation have also been reported. Regular blood pressure monitoring is recommended and mirabegron is not recommended for patients with uncontrolled hypertension. Caution should be exercised when mirabegron is used in patients with a history of QT interval prolongation or in patients who are taking medicines known to prolong the QT interval.

Urinary retention has been reported post-marketing in patients with bladder outlet obstruction taking mirabegron, and in patients also taking antimuscarinic medicines. It is recommended that mirabegron should be administered with caution in these patients.

The place of mirabegron in the treatment of overactive bladder has yet to be established due to limited studies being available. The only guideline available is in the United Kingdom, where mirabegron is only recommended when antimuscarinic agents are contraindicated, ineffective, or not tolerated.