Mirabegron: Action, Dosage and Notes on Overactive Bladder

Mirabegron is a prescription-only active ingredient from the class of beta-3 adrenoceptor agonists. It was developed to relieve the symptoms of overactive bladder (OAB) without causing the side effects typical of antimuscarinics, such as dry mouth or cognitive impairment. Under the brand name Myrbetriq (Betmiga in Europe), mirabegron has been approved in the European Union since 2013.

Overactive bladder is a widespread functional disorder. An estimated 10 to 17 percent of adults are affected. In addition to the physical burden caused by urgent urinary urge, frequent toilet visits and involuntary urine loss, the condition often leads to significant psychosocial limitations. Since its launch, mirabegron has been an important pharmacological option, particularly for patient groups in whom antimuscarinics are not an option.

Mechanism of Action

Mirabegron acts as a selective agonist at the beta-3 adrenoceptor (beta3-AR). These receptors are present in high density in the smooth muscle of the detrusor, i.e. the bladder wall. Activation of the beta3-AR triggers relaxation of the detrusor muscle via intracellular signalling cascades, in particular via the second messenger cyclic adenosine monophosphate (cAMP). The result is an improved storage function of the bladder: the organ can hold more urine before the micturition reflex is triggered.

Unlike antimuscarinics, which block muscarinic acetylcholine receptors and thereby inhibit contraction of the detrusor, mirabegron uses a completely different signalling pathway. Beta-3 adrenoceptors are also found in adipose tissue, the heart and skeletal muscle, but the clinical impact of systemic beta3 activation at therapeutic doses is generally manageable. Cardiac safety has been evaluated in extensive clinical studies.

Mirabegron is rapidly absorbed after oral intake, with absolute bioavailability ranging from 29 to 35 percent depending on dose. Protein binding is approximately 71 percent. The elimination half-life is approximately 50 hours, enabling once-daily administration. Metabolism occurs primarily via CYP3A4 and CYP2D6 as well as direct glucuronidation.

Indications

Mirabegron is approved for the symptomatic treatment of overactive bladder in adults. The approved indications include:

• Urgency urinary incontinence: sudden, difficult-to-control urge to urinate
• Increased urinary frequency: more than eight bladder voidings per day
• Urge incontinence: involuntary urine loss in connection with urgent urge
• Nocturia: disturbing nocturnal waking to urinate

Mirabegron is frequently used as an alternative to antimuscarinics when they are not tolerated or are contraindicated. Typical patient groups are older people with cognitive impairment, patients with narrow-angle glaucoma, dry mouth as a therapy-limiting side effect, and persons with a tendency to constipation. A combination of mirabegron with the antimuscarinic solifenacin is also approved for certain patient groups and is available as a fixed-dose combination.

Mirabegron is not effective in pure stress incontinence, as this mechanism is not caused by detrusor overactivity. Careful differential diagnostic evaluation before starting therapy is therefore essential.

Dosage and Administration

Mirabegron is prescription-only. Dosage and duration of therapy are determined individually by the treating physician.

The recommended starting dose is 25 mg once daily as a modified-release tablet that can be taken independently of meals. The tablet is swallowed whole and must not be divided or chewed. After a period of four to eight weeks, the physician may increase the dose to 50 mg once daily if the lower dose is not sufficiently effective.

In patients with severe renal insufficiency (GFR 15 to 29 ml/min) or moderate hepatic insufficiency (Child-Pugh B), the maximum daily dose is limited to 25 mg. In severe hepatic insufficiency (Child-Pugh C), mirabegron is contraindicated as no adequate data are available. Caution is also required in severe renal insufficiency in combination with strong CYP3A4 inhibitors.

Side Effects

The side effect profile of mirabegron is more favourable than that of antimuscarinics, particularly with respect to anticholinergic symptoms. The following adverse drug reactions were observed in clinical studies:

Common (1 to 10 in 100 patients): Tachycardia (increased heart rate) is the most common cardiovascular side effect. Nasopharyngitis, urinary tract infections and hypertension were also commonly reported. Constipation and headaches occur less frequently than with antimuscarinics but do occur.

Occasionally: Cardiac arrhythmias, palpitations, insomnia, dizziness and nausea were reported in individual patients. A rise in blood pressure is possible and should be particularly noted in pre-existing arterial hypertension.

Rare or very rare: Angioedema (sudden swelling of the face, lips, tongue or throat) has been reported in individual cases. If angioedema is suspected, mirabegron should be immediately discontinued and medical help sought. Urinary retention may occur, particularly in men with bladder outlet obstruction.

Compared to antimuscarinics, dry mouth under mirabegron is significantly rarer and occurs barely more often than under placebo. Cognitive side effects are also not a relevant concern with mirabegron, which facilitates its use in older patients.

Drug Interactions

Mirabegron is a moderate inhibitor of the enzyme CYP2D6 and also inhibits transporter proteins such as P-glycoprotein. This has clinically relevant consequences for concomitant medication:

CYP2D6 substrates: The plasma levels of medicinal products metabolised by CYP2D6 (e.g. metoprolol, desipramine, flecainide) can increase under mirabegron. Special caution and therapeutic drug monitoring are recommended when using antiarrhythmics with a narrow therapeutic window (e.g. flecainide, propafenone, digoxin) concurrently.

CYP3A4 inhibitors: Strong inhibitors of this enzyme (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin) can increase mirabegron exposure. In patients with impaired renal or hepatic function, the dose should remain limited to 25 mg daily.

Combination with other OAB therapeutics: Combination with antimuscarinics may be therapeutically appropriate in selected cases (approved fixed-dose combination), but increases the risk of urinary retention. Medical monitoring is required.

Patients should discuss all medications they are taking, including herbal preparations and over-the-counter products, with the treating physician or pharmacist.

Special Notes

High blood pressure: Mirabegron increases blood pressure and heart rate. Patients with pre-existing uncontrolled high blood pressure should only receive mirabegron after adequate blood pressure control. Regular monitoring is recommended during treatment.

Heart disease: In patients with severe cardiac arrhythmias or QT prolongation on the ECG, mirabegron must be used with special caution. Concurrent use of QT-prolonging medicinal products increases the risk of ventricular tachyarrhythmias.

Urinary retention: Men with benign prostatic hyperplasia or other forms of bladder outlet obstruction have an increased risk of urinary retention. This factor should be discussed with the physician before starting therapy.

Pregnancy and breastfeeding: Animal studies have shown harmful effects on reproduction. Mirabegron should not be used during pregnancy. Since excretion into breast milk cannot be excluded, use during breastfeeding is not advisable.

Children and adolescents: Mirabegron is not approved for persons under 18 years of age. Paediatric studies have shown an increased heart rate as a safety signal, which is why use in this age group was rejected.

Frequently Asked Questions

How long does it take for mirabegron to work?

A noticeable improvement in bladder control is seen in most patients after two to four weeks. Full therapeutic efficacy is often only achieved after eight to twelve weeks. Premature interruption of therapy should be coordinated with the physician.

Can mirabegron be taken together with solifenacin?

Yes, in certain cases the combination of both active ingredients is medically appropriate and is also available as a finished medicinal product. The decision is made by the treating physician on the basis of the individual symptom profile and side effect profile.

Is mirabegron also suitable for older patients?

Mirabegron is considered better tolerated than antimuscarinics for older people, as anticholinergic side effects such as cognitive impairment and dry mouth occur less frequently. The treating physician assesses use in the individual case, particularly with regard to cardiovascular pre-existing conditions.

What happens if a dose is forgotten?

The forgotten dose should be taken as soon as possible, unless it is almost time for the next intake. In that case, the forgotten dose is skipped. Two doses should never be taken at the same time.

References

• European Medicines Agency (EMA): Betmiga Summary of Product Characteristics (current version)
• German Institute for Medical Documentation and Information (DIMDI): Drug information mirabegron
• Guideline of the German Society of Urology: Overactive Bladder (S3 guideline)
• Chapple CR et al.: Mirabegron in overactive bladder. Eur Urol. 2013;63(2):296-305
• Herschorn S et al.: A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the beta-3 adrenoceptor agonist, mirabegron. Urology. 2013;82(2):313-320