mirabegron (Rx)

>10%

Adults

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

Children aged 3-17 years

• Urinary tract infection (24.4%)

1-10%

Adults

• 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%)

Children aged 3-17 years

• Nasopharyngitis (5.8%)
• Constipation (4.7%)
• Headache (3.5%)
• Nausea (2.3%)
• Gastroenteritis (2.3%)
• Rhinitis (2.3%)
• Cough (2.3%)

<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

Cardiac disorders: Atrial fibrillation

Gastrointestinal disorders: Nausea, constipation, diarrhea

Nervous system disorders: Dizziness, headache

Skin and subcutaneous tissue disorders: Angioedema of the face, lips, tongue, and larynx, with or without respiratory symptoms; pruritus

Renal and urinary disorders: Urinary retention

Contraindications

Hypersensitivity

Cautions

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

Increased blood pressure

• May increase blood pressure (BP); monitor BP periodically, especially in hypertensive patients
• Not recommended for use in severe uncontrolled hypertensive patients (ie, systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg for adults; systolic and/or diastolic BP >99th percentile plus 5 mm Hg for age, sex, and stature for children)
• BP increases may be larger in children aged 3 to <12 years compared with adolescents

Drug interactions overview

Moderate CYP2D6 inhibitor

• Sensitive CYP2D6 substrates

  • Appropriate monitoring is recommended and dose adjustment may be necessary for narrow therapeutic index CYP2D6 substrates

• Digoxin

  • Modify dose
  • 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
  • Consider initiating lowest dose for digoxin; monitor serum digoxin concentrations and titrate digoxin dose to obtain desired clinical effect

• Concomitant antimuscarinic drugs

  • Use with caution
  • Urinary retention may occur with bladder outlet obstruction or with concomitant antimuscarinic therapy

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

Adults (tablets)

• 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
• Effect of food: No clinically significant differences in adults

Pediatrics (tablets or oral suspension)

• Peak plasma time: 4-5 hr (single dose); 3-4 hr (steady-state)

• Effect of food

  • Tablets: AUC increased by 120% in fasted stated compared to the fed state
  • Oral suspension: Peak plasma concentration and AUC increased by 170% and 80%, respectively, in fasted stated compared to the fed state

Distribution

Adults (tablets)

• Protein Bound: 71%
• Vd, steady state: 1670 L

Pediatrics (tablets or oral suspension)

• Vd: 4895-13,726 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

Adults (tablets)

• Half-Life: 50 hr
• Total body clearance: 57 L/hr (following IV administration)
• Excretion: Urine (55%); feces (34%)
• Excretion, unchanged: Urine (~25%); feces (0%)

Pediatrics (tablets or oral suspension)

• Half-life: ~26-31 hr

Oral Suspension Preparation

Prepare oral suspension at time of dispensing

Keep bottle in pouch until time of reconstitution

Reconstitution

• Discard pouch and desiccant before reconstitution; do not dispense
• Tap closed bottle several times to loosen granules
• Add 100 mL of water to bottle, and immediately shake vigorously for 1 minute, then let it stand for 10-30 minutes; shake vigorously again for 1 minute
• If granules have not dispersed, shake vigorously for another 1 minute
• Record 28-day expiration date on container and carton based on reconstitution date
• Dispense with an appropriate dosing measuring device
• Reconstituted suspension contains 8 mg/mL

Oral Administration

Tablets

• Adults: May take with or without food
• Children: Take with food to reduce potential exposure-related risks (eg, increased heart rate)
• Swallow tablet whole with water, do not chew, divide, or crush

Oral suspension

• For pediatric use only; dosage for adults not determined
• Take with food to reduce potential exposure-related risks (eg, increased heart rate)

Missed dose

• <12 hours since missed dose: Take as soon as remembered
• >12 hours since missed dose: Skip dose and take next dose at usual time

Storage

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

Reconstituted oral granules for suspension

• Store at 20-25ºC (68-77ºF) for up to 28 days
• Discard unused portion after 28 days