mirabegron (Rx)

>10%

Elevated BP occurring predominantly in patients with preexisting hypertension (7.5-11.5%)

1-10%

Monotherapy

• Dry mouth (3-9%)
• Urinary tract infection (UTI) (2.9-4.2%)
• Nasopharyngitis (3.5-3.9%)
• Headache (2.1-3.2%)
• Back pain (2.8%)
• Sinusitis (2.7%)
• Arthralgia (1.3-2.1%)
• Cystitis (2.1%)
• Dizziness (2%)
• Constipation (1.6%)
• Tachycardia (1.2-1.6%)
• Diarrhea (1.2-1.5%)
• Fatigue (1.2-1.4%)
• Reports of neoplasms (0-1%)

Combination with solifenacin

• Dry mouth (7.2-9.3%)
• UTI (4-8.4%)
• Constipation (3.9-4.2%)
• Tachycardia (0.9-2.2%)
• Dyspepsia (1.1-1.3%)
• Dizziness (0.4-1.3%)
• Blurred vision (0.7-1.1%)
• Arthralgia (0.5-1.1%)

<1%

Cardiac disorders (eg, palpitations, elevated BP)

Eye Disorders (eg, glaucoma, blurry vision)

GI disorders (eg, dyspepsia, gastritis, abdominal distension)

Rhinitis

Elevations in GGT, AST, ALT, LDH

Renal and urinary disorders (eg, nephrolithiasis, bladder pain)

Reproductive system disorders (eg, vulvovaginal pruritis, vaginal infection)

Skin and subcutaneous tissue disorders (eg, urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema)

Stevens-Johnson syndrome associated with increased serum ALT, AST and bilirubin

Postmarketing Reports

Urinary retention

Angioedema of the face, lips, tongue, and larynx, with or without respiratory symptoms

Nausea, constipation, diarrhea

Pruritus

Atrial fibrillation

Dizziness, headache

Contraindications

Hypersensitivity

Cautions

May increase blood pressure; monitor blood pressure periodically, especially in hypertensive patients; not recommended for use in severe uncontrolled hypertensive patients (defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg)

Urinary retention may occur with bladder outlet obstruction or with concomitant antimuscarinic therapy; administer with caution in these patients

Angioedema of the face, lips, tongue, and/or larynx reported; may occur after the first dose or following multiple doses; promptly discontinue and initiate appropriate therapy to ensure a patent airway

Drug interactions overview

• Appropriate monitoring is recommended and dose adjustment may be necessary for narrow therapeutic index CYP2D6 substrates
• Coadministration of digoxin 0.25 mg with a combination of solifenacin 5 mg and mirabegron 50 mg increased digoxin AUC and peak plasma concentration by ~10% and 14%, respectively; for patients who are initiating a combination of mirabegron and digoxin, consider initiating lowest dose for digoxin; monitor serum digoxin concentrations and titrate digoxin dose to obtain the desired clinical effect
• In studies, ketoconazole increased mirabegron peak plasma concentration by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron in 23 male and female healthy subjects

Pregnancy

There are no studies with the use in pregnant women to inform drug-associated risk for birth defects or miscarriage

Animal data

• Administration to pregnant animals during organogenesis resulted in reversible skeletal variations (in rats) at 22-fold (via AUC) the maximum recommended human dose (MRHD) of 50 mg/day and decreased fetal body weights (in rabbits) at 14-fold the MRHD
• At maternally toxic exposures in rats (96-fold), decreased fetal weight and increased fetal mortality were observed and, in rabbits (36-fold), cardiac findings (fetal cardiomegaly and fetal dilated aortae) were observed

Lactation

There is no information on the presence of mirabegron in human milk, the effects on the breastfed child, or the effects on milk production

Mirabegron-related material was present in rat milk and in the stomach of nursing pups following administrations of a single 10 mg/kg oral dose of 14C-labeled mirabegron to lactating rats

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Beta-3 adrenergic receptor agonist which causes relaxation of the detrusor smooth muscle of the urinary bladder and increases bladder capacity

Absorption

Bioavailability: 29% (25-mg), 35% (50-mg)

Peak Plasma Time: 3.5 hr

Peak Plasma Concentration: ~3-fold increase from 50 mg dose to 100 mg dose

AUC: ~2.5-fold increase from 50 mg dose to 100 mg dose

Steady state: 7 days

Distribution

Protein Bound: 71%

Vd, steady state: 1670 L

Metabolism

Via multiple pathways including dealkylation, (direct) glucuronidation, amide hydrolysis, and minimal oxidative metabolism in vivo by CYP2D6 and CYP3A4

Possible involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and alcohol dehydrogenase

Moderate CYP2D6 inhibitor

Elimination

Half-Life: 50 hr

Total body clearance: 57 L/hr (following IV administration)

Excretion: Urine (55%); feces (34%)

Excretion, unchanged: Urine (~25%); feces (0%)

Oral Administration

May take with or without food

Swallow whole with water, do not chew, divide, or crush tablet

Storage

Extended-release tablets: Store at 25°C (77°F) with excursions permitted from 15-30°C (59-86°F)