Use Caution/Monitor.captoprilMonitor Closely (1)mirabegron will increase the level or effect of captopril by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.carvedilolMonitor Closely (1)mirabegron will increase the level or effect of carvedilol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.chloroquineMonitor Closely (1)mirabegron will increase the level or effect of chloroquine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.chlorpromazineMonitor Closely (1)mirabegron will increase the level or effect of chlorpromazine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.cinacalcetMonitor Closely (1)mirabegron will increase the level or effect of cinacalcet by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.citalopramMonitor Closely (1)mirabegron will increase the level or effect of citalopram by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.clomipramineMonitor Closely (1)mirabegron will increase the level or effect of clomipramine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.codeineMonitor Closely (1)mirabegron will increase the level or effect of codeine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.desipramineMonitor Closely (1)mirabegron will increase the level or effect of desipramine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.deutetrabenazineMonitor Closely (1)mirabegron will increase the level or effect of deutetrabenazine by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Strong CYP2D6 inhibitors increase the systemic exposure to the active dihydro-metabolites of deutetrabenazine by approximately 3-fold. Do not exceed 18 mg/dose and 36 mg/day of deutetrabenazine if coadministered with strong CYP2D6 inhibitors.dextroamphetamine transdermalMonitor Closely (1)mirabegron will increase the level or effect of dextroamphetamine transdermal by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during dextroamphetamine initiation and after a dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine transdermal and CYP2D6 inhibitor.digoxinMonitor Closely (1)mirabegron will increase the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.doxepinMonitor Closely (1)mirabegron will increase the level or effect of doxepin by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.doxepin creamMonitor Closely (1)mirabegron will increase the level or effect of doxepin cream by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.doxorubicinMonitor Closely (1)mirabegron will increase the level or effect of doxorubicin by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.doxorubicin liposomalMonitor Closely (1)mirabegron will increase the level or effect of doxorubicin liposomal by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.duloxetineMonitor Closely (1)mirabegron will increase the level or effect of duloxetine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.flecainideMonitor Closely (1)mirabegron will increase the level or effect of flecainide by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.fluoxetineMonitor Closely (1)mirabegron will increase the level or effect of fluoxetine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.fluphenazineMonitor Closely (1)mirabegron will increase the level or effect of fluphenazine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.fluvoxamineMonitor Closely (1)mirabegron will increase the level or effect of fluvoxamine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.haloperidolMonitor Closely (1)mirabegron will increase the level or effect of haloperidol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.iloperidoneMonitor Closely (1)mirabegron will increase the level or effect of iloperidone by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.imipramineMonitor Closely (1)mirabegron will increase the level or effect of imipramine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.lofexidineMonitor Closely (1)mirabegron will increase the level or effect of lofexidine by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Concomitant use of lofexidine with strong CYP2D6 inhibitors may increase lofexidine plasma levels. Monitor for symptoms of orthostasis and bradycardia if coadministered with a CYP2D6 inhibitor. Consider lofexidine dose reduction.maprotilineMonitor Closely (1)mirabegron will increase the level or effect of maprotiline by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.metaxaloneMonitor Closely (1)mirabegron will increase the level or effect of metaxalone by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.methamphetamineMonitor Closely (1)mirabegron will increase the level or effect of methamphetamine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.metoclopramide intranasalSerious - Use Alternative (1)mirabegron will increase the level or effect of metoclopramide intranasal by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Concurrent use of metoclopramide intranasal and strong CYP2D6 inhibitors is not recommended since the metoclopramide intranasal dose cannot be adjusted.metoprololMonitor Closely (1)mirabegron will increase the level or effect of metoprolol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.mirtazapineMonitor Closely (1)mirabegron will increase the level or effect of mirtazapine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.nebivololMonitor Closely (1)mirabegron will increase the level or effect of nebivolol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.nefazodoneMonitor Closely (1)mirabegron will increase the level or effect of nefazodone by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.nortriptylineMonitor Closely (1)mirabegron will increase the level or effect of nortriptyline by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.oliceridineMonitor Closely (1)mirabegron will increase the level or effect of oliceridine by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. If concomitant use is necessary, may require less frequent oliceridine dosing. Closely monitor for respiratory depression and sedation and titrate subsequent doses accordingly. If inhibitor is discontinued, consider increase oliceridine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. ozanimodSerious - Use Alternative (1)ozanimod increases toxicity of mirabegron by sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Because the active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, coadministration of ozanimod with drugs that can increase norepinephrine or serotonin is not recommended. Monitor for hypertension with concomitant use.paroxetineMonitor Closely (1)mirabegron will increase the level or effect of paroxetine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.perphenazineMonitor Closely (1)mirabegron will increase the level or effect of perphenazine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.pindololMonitor Closely (1)mirabegron will increase the level or effect of pindolol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.pitolisantMonitor Closely (1)mirabegron will increase the level or effect of pitolisant by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. If coadministered with strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg/day and increase after 7 days to maximum of 17.8 mg/day. For patients currently taking pitolisant, reduce pitolisant dose by half upon initiating strong CYP2D6 inhibitors.procainamideMonitor Closely (1)mirabegron will increase the level or effect of procainamide by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.promethazineMonitor Closely (1)mirabegron will increase the level or effect of promethazine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.propafenoneMonitor Closely (1)mirabegron will increase the level or effect of propafenone by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.propranololMonitor Closely (1)mirabegron will increase the level or effect of propranolol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.protriptylineMonitor Closely (1)mirabegron will increase the level or effect of protriptyline by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.risperidoneMonitor Closely (1)mirabegron will increase the level or effect of risperidone by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.ritonavirMonitor Closely (1)mirabegron will increase the level or effect of ritonavir by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.sertralineMonitor Closely (1)mirabegron will increase the level or effect of sertraline by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.solifenacinMonitor Closely (1)mirabegron increases toxicity of solifenacin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor patients for signs/symptoms of urinary retention.tamoxifenMonitor Closely (1)mirabegron will decrease the level or effect of tamoxifen by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.thioridazineMonitor Closely (1)mirabegron will increase the level or effect of thioridazine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.timololMonitor Closely (1)mirabegron will increase the level or effect of timolol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.timolol ophthalmicMonitor Closely (1)mirabegron will increase the level or effect of timolol ophthalmic by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.tolterodineMonitor Closely (1)mirabegron will increase the level or effect of tolterodine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.tramadolMonitor Closely (1)mirabegron will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.trimipramineMonitor Closely (1)mirabegron will increase the level or effect of trimipramine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.venlafaxineMonitor Closely (1)mirabegron will increase the level or effect of venlafaxine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. >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 ratsPregnancy 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