Mirabegron - Drug Monograph

Introduction

Mirabegron is a beta-3 adrenergic receptor agonist medication used primarily for the treatment of overactive bladder (OAB) syndrome. Approved by the FDA in 2012, it represents a novel therapeutic class distinct from traditional antimuscarinic agents used for OAB. Mirabegron offers an alternative mechanism of action that has demonstrated efficacy in reducing urinary urgency, frequency, and urge incontinence episodes.

Mechanism of Action

Mirabegron selectively activates beta-3 adrenergic receptors in the detrusor smooth muscle of the bladder. This activation stimulates adenylate cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP) levels. The elevated cAMP promotes bladder relaxation during the storage phase, thereby increasing bladder capacity without affecting voiding contractions. Unlike antimuscarinic agents, mirabegron does not inhibit muscarinic receptors and therefore avoids anticholinergic side effects.

Indications

Mirabegron is FDA-approved for:

• Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency

It may be used as:

• First-line therapy for OAB
• Alternative for patients intolerant to antimuscarinic agents
• Adjunctive therapy in combination with antimuscarinics (off-label)

Dosage and Administration

• Initial dose: 25 mg once daily
• May be increased to 50 mg once daily after 8 weeks based on efficacy and tolerability

• Oral administration with water
• Should be swallowed whole; tablets should not be chewed, divided, or crushed
• Can be taken with or without food

• Renal impairment: No dosage adjustment needed for mild to moderate impairment (CrCl 30-89 mL/min). Use with caution in severe renal impairment (CrCl 15-29 mL/min); maximum dose 25 mg daily. Not recommended in end-stage renal disease (CrCl <15 mL/min)
• Hepatic impairment: No dosage adjustment needed for mild impairment (Child-Pugh A). Maximum dose 25 mg daily for moderate impairment (Child-Pugh B). Not recommended for severe hepatic impairment (Child-Pugh C)
• Geriatric patients: No dosage adjustment required based on age alone
• Pediatric patients: Safety and effectiveness not established

Pharmacokinetics

• Oral bioavailability: Approximately 29-35%
• Tmax: 3-4 hours post-administration
• Food does not significantly affect absorption

• Protein binding: Approximately 71%
• Steady-state volume of distribution: Approximately 1670 L
• Crosses placenta and enters breast milk

• Primarily metabolized via multiple pathways including hydrolysis, oxidation, and glucuronidation
• CYP3A4 and CYP2D6 play minor roles in metabolism
• Multiple metabolites, none considered pharmacologically active

• Elimination half-life: Approximately 50 hours
• Excretion: Approximately 55% in urine (primarily as unchanged drug), 34% in feces
• Total clearance: Approximately 57 L/h

Contraindications

• Known hypersensitivity to mirabegron or any component of the formulation
• Severe uncontrolled hypertension (due to potential for blood pressure elevation)
• Use with strong CYP2D6 inhibitors in patients with specific CYP2D6 genotypes who are taking other CYP2D6 substrates with narrow therapeutic indices

Warnings and Precautions

• May increase blood pressure; monitor regularly, especially in hypertensive patients
• Use with caution in patients with controlled hypertension

• May increase risk of urinary retention in patients with bladder outlet obstruction
• Monitor patients for signs and symptoms of urinary retention

• Rare cases of angioedema of the face, lips, tongue, and/or larynx have been reported

• Use with caution and dose adjustment in moderate to severe impairment

• Theoretical risk of interference with medical devices due to potential effects on heart rate

• Pregnancy Category C: Use only if potential benefit justifies potential risk to fetus
• Excreted in breast milk; decision should be made to discontinue nursing or discontinue drug

Drug Interactions

• Drugs like paroxetine, bupropion, fluoxetine, quinidine may increase mirabegron exposure
• Consider dose reduction of mirabegron to 25 mg when used concomitantly

• Mirabegron may increase digoxin concentrations; monitor digoxin levels

• May increase metoprolol exposure; monitor for increased beta-blocker effects

• Potential to increase international normalized ratio (INR); monitor coagulation parameters

• May increase exposure to drugs metabolized by CYP2D6 (e.g., desipramine, flecainide, thioridazine)

Adverse Effects

• Hypertension (11.3%)
• Nasopharyngitis (4.2%)
• Urinary tract infection (3.0%)
• Headache (3.0%)
• Constipation (2.3%)

• Tachycardia (heart rate increase of ≥15 bpm reported in some patients)
• Angioedema
• Urinary retention
• Atrial fibrillation (rare)
• Liver enzyme elevations

Monitoring Parameters

• Blood pressure at baseline and regularly during treatment
• Heart rate assessment
• Renal and hepatic function in patients with impairment
• Symptoms of urinary retention, especially in patients with bladder outlet obstruction
• Signs of angioedema or hypersensitivity reactions
• Efficacy assessment: reduction in incontinence episodes, urgency, and frequency

Patient Education

• Take medication exactly as prescribed at the same time each day
• Swallow tablet whole with water; do not chew, crush, or split
• Report any signs of allergic reaction (swelling of face, lips, tongue, or throat)
• Monitor blood pressure regularly if advised by healthcare provider
• Report rapid heartbeat, dizziness, or difficulty urinating
• Inform all healthcare providers about mirabegron use, especially before starting new medications
• Be aware that improvement in bladder symptoms may take several weeks
• Do not stop medication without consulting healthcare provider

References

1. FDA Prescribing Information: Myrbetriq (mirabegron) [2023] 2. Chapple CR, et al. Mirabegron in overactive bladder: a review of efficacy, safety, and tolerability. Neurourol Urodyn. 2014;33(1):17-30 3. Nitti VW, et al. Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract. 2013;67(7):619-631 4. Rosa GM, et al. Cardiovascular safety of β3-adrenoceptor agonists for the treatment of patients with overactive bladder syndrome. Eur Urol. 2016;69(2):311-323 5. Krauwinkel W, et al. Pharmacokinetic properties of mirabegron, a β3-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women. Clin Ther. 2012;34(10):2144-2160 6. American Urological Association Guidelines on Pharmacologic Management of Overactive Bladder [2019]