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  • CLASSES

    Beta-3 Adrenergic Agonists

    DEA CLASS

    Rx

    DESCRIPTION

    Oral beta-3 adrenergic agonist; relaxes detrusor smooth muscle and increases bladder capacity, reducing incontinence
    Used for overactive bladder (OAB) in adults as monotherapy and in combination with solifenacin, a muscarinic antagonist
    May increase blood pressure; and use is not recommended in patients with severe uncontrolled hypertension

    COMMON BRAND NAMES

    Myrbetriq

    HOW SUPPLIED

    Myrbetriq Oral Tab ER: 25mg, 50mg

    DOSAGE & INDICATIONS

    For the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.
    Oral dosage
    Adults

    25 mg PO once daily; this dose is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg PO once daily. USE WITH SOLIFENACIN: 25 mg PO once daily with solifenacin (5 mg/day PO). Based on individual efficacy and tolerability, may increase mirabegron to 50 mg PO once daily if needed after 4 to 8 weeks.

    MAXIMUM DOSAGE

    Adults

    50 mg/day PO.

    Geriatric

    50 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (Child Pugh Class A): No dose adjustment required.
    Moderate hepatic impairment (Child Pugh Class B): Do not exceed 25 mg once daily.
    Severe hepatic impairment (Child Pugh Class C): Not recommended.

    Renal Impairment

    CrCl 30 mL/minute or greater (eGFR 30 mL/minute/1.73 m2 or greater): No dose adjustment needed.
    CrCl 15 to 29 mL/minute (eGFR 15 to 29 mL/minute/1.73 m2): Do not exceed 25 mg once daily.
    CrCl less than 15 mL/minute (eGFR less than 15 mL/minute/1.73 m2): Not recommended.
     
    Intermittent hemodialysis
    Not recommended in patients with end-stage renal disease (ESRD) or patients on dialysis.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    May be administered with or without food.
    The extended-release tablets should be taken with water, swallowed whole, and should not be chewed, divided, or crushed.

    STORAGE

    Myrbetriq:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Hypertension

    Mirabegron can increase blood pressure. It is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mmHg and/or diastolic blood pressure greater than or equal to 110 mmHg). In a clinical evaluation with healthy volunteers, a dose of 50 mg/day was associated with a mean maximum increase in systolic/diastolic blood pressure of approximately 3.5/1.5 mmHg greater than placebo. In patients with overactive bladder, the mean increase in systolic and diastolic blood pressure was approximately 0.5 to 1 mmHg greater than placebo. Clinicians should monitor patients blood pressure periodically during therapy, especially in hypertensive patients.

    Anticholinergic medications, bladder obstruction, urinary retention, urinary tract obstruction

    Mirabegron should be administered with caution in patients with clinically significant bladder outlet obstruction (BOO), urinary tract obstruction, or with risk factors for bladder obstruction or urinary retention. In postmarketing experience, urinary retention in patients with BOO and in patients taking concomitant antimuscarinic medications for the treatment of over active bladder (OAB) has been reported. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients receiving mirabegron alone. The concomitant use of antimuscarinic medications or other anticholinergic medications with mirabegron in the treatment of OAB warrants caution due to the risk for urinary retention. Monitor these patients for signs and symptoms of urinary retention.

    Dialysis, renal failure, renal impairment

    Mirabegron has not been evaluated in patients with end stage renal disease (CrCl less than 15 mL/min), or in renal failure patients requiring dialysis; thus, it is not recommended for use in these populations. Use caution and adjust dosage in patients with severe renal impairment (CrCl 15 to 29 mL/minute). No dose adjustment is necessary in patients with mild or moderate renal impairment (CrCl 30 mL/minute or more).

    Hepatic disease

    Mirabegron has not been evaluated in patients with severe hepatic disease (Child-Pugh Class C) and is not recommended for use in this population. Cautious use and dosage reduction are recommended for patients with moderate hepatic impairment (Child-Pugh Class B). No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).

    History of angioedema

    Angioedema of the face, lips, tongue and/or larynx has been reported with mirabegron. Do not use mirabegron if the patient has a history of angioedema to the drug or if hypersensitivity reactions to mirabegron or tablet components have occurred.

    Pregnancy

    There are no adequate and well-controlled studies of the use of mirabegron during human pregnancy to inform drug-associated risk for birth defects or miscarriage. Mirabegron 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. Women who become pregnant during mirabegron treatment are encouraged to contact their physician.

    Breast-feeding

    Use mirabegron with caution during breast-feeding. There is no information regarding the presence of mirabegron in human milk, the effects on the breast-fed 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 radiolabeled mirabegron to lactating rats. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants

    The safety and effectiveness of mirabegron in pediatric patients have not been established. Therefore, use of mirabegron is not recommended in adolescents, children or infants.

    Geriatric

    The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to the OBRA guidelines, assessment of the underlying causes and identification of the type/category of urinary incontinence needs to be documented prior to or soon after the time of initiating treatment with a urinary incontinence medication such as mirabegron. These medications have specific and limited indications based on the cause and categorization of incontinence. Patients should be assessed periodically for medication effects on urinary incontinence as well as lower urinary tract symptoms and treatment tolerability.

    ADVERSE REACTIONS

    Severe

    vasculitis / Delayed / 0-1.0
    stroke / Early / 0.4-0.4
    atrial fibrillation / Early / 0.2-0.2
    ocular hypertension / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    hypertension / Early / 7.5-11.3
    constipation / Delayed / 1.6-2.8
    cystitis / Delayed / 2.1-2.1
    sinus tachycardia / Rapid / 1.2-1.6
    palpitations / Early / 0-1.0
    gastritis / Delayed / 0-1.0
    vaginitis / Delayed / 0-1.0
    nephrolithiasis / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known
    blurred vision / Early / Incidence not known

    Mild

    headache / Early / 2.1-4.1
    pharyngitis / Delayed / 3.5-3.9
    xerostomia / Early / 2.8-2.8
    back pain / Delayed / 2.8-2.8
    dizziness / Early / 2.7-2.7
    sinusitis / Delayed / 0-2.7
    influenza / Delayed / 2.6-2.6
    arthralgia / Delayed / 1.3-2.1
    diarrhea / Early / 1.2-1.5
    abdominal pain / Early / 0.6-1.4
    fatigue / Early / 1.2-1.4
    dyspepsia / Early / 0-1.0
    bladder discomfort / Early / 0-1.0
    vaginal irritation / Early / 0-1.0
    rhinitis / Early / 0-1.0
    purpura / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    urticaria / Rapid / 0-1.0
    rash / Early / 0-1.0
    nausea / Early / 0.4-0.4
    infection / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    xerophthalmia / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with mirabegron may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of mirabegron could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If mirabegron is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mirabegron is a moderate inhibitor of CYP2D6.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as dihydrocodeine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome, (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome, (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with mirabegron may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of mirabegron could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If mirabegron is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mirabegron is a moderate inhibitor of CYP2D6.
    Acetaminophen; Dextromethorphan: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Acetaminophen; Diphenhydramine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as diphenhydramine may be increased when co-administered with mirabegron. Diphenhydramine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Acetaminophen; Oxycodone: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6, such as oxycodone, may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Acetaminophen; Tramadol: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as tramadol may be increased when co-administered with mirabegron. Tramadol is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Almotriptan: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as almotriptan may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Amitriptyline: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Amitriptyline; Chlordiazepoxide: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Amoxapine: (Major) Concomitant use of amoxapine with drugs that can inhibit cytochrome P450 2D6, such as mirabegron, may require lower doses than usually prescribed for either amoxapine or mirabegron. Furthermore, whenever mirabegron is withdrawn from co-therapy, an increased dose of the amoxapine may be required. It is desirable to monitor amoxapine plasma levels whenever amoxapine is going to be co-administered with another drug known to be an inhibitor of P450 2D6.
    Aripiprazole: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as aripiprazole may be increased when administered with mirabegron. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.
    Asenapine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as asenapine may be increased when co-administered with mirabegron. Asenapine has been shown to be a CYP2D6 substrate in vitro. Appropriate monitoring and dose adjustment may be necessary.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with mirabegron may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of mirabegron could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If mirabegron is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mirabegron is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as dihydrocodeine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with mirabegron may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of mirabegron could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If mirabegron is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mirabegron is a moderate inhibitor of CYP2D6.
    Aspirin, ASA; Oxycodone: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6, such as oxycodone, may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with mirabegron as there is a potential for elevated cobicistat concentrations. Mirabegron is a moderate CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6 and CYP3A4.
    Atomoxetine: (Moderate) Because atomoxetine is primarily metabolized by CYP2D6, concurrent use of CYP2D6 inhibitors such as mirabegron may theoretically increase the risk of atomoxetine-induced adverse effects. Monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, QT prolongation).
    Brimonidine; Timolol: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as timolol may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Carbetapentane; Chlorpheniramine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as diphenhydramine may be increased when co-administered with mirabegron. Diphenhydramine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Carvedilol: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as carvedilol may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Cevimeline: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as cevimeline may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with mirabegron may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of mirabegron could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If mirabegron is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mirabegron is a moderate inhibitor of CYP2D6. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Dextromethorphan: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome, (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome, (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as dihydrocodeine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as dihydrocodeine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpheniramine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Chlorpromazine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as chlorpromazine may be increased when co-administered with mirabegron. Chlorpromazine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Cinacalcet: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as cinacalcet may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Clomipramine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Clozapine: (Moderate) Patients receiving clozapine in combination with a CYP2D6 inhibitor such as mirabegron should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. Mirabegron is a moderate inhibitor of CYP2D6, and clozapine is a CYP2D6 substrate. Elevated plasma concentrations of clozapine may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with mirabegron as there is a potential for elevated cobicistat concentrations. Mirabegron is a moderate CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6 and CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with mirabegron as there is a potential for elevated cobicistat concentrations. Mirabegron is a moderate CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6 and CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with mirabegron as there is a potential for elevated cobicistat concentrations. Mirabegron is a moderate CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6 and CYP3A4.
    Codeine: (Moderate) Concomitant use of codeine with mirabegron may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of mirabegron could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If mirabegron is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mirabegron is a moderate inhibitor of CYP2D6.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with mirabegron may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of mirabegron could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If mirabegron is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mirabegron is a moderate inhibitor of CYP2D6.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with mirabegron may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of mirabegron could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If mirabegron is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mirabegron is a moderate inhibitor of CYP2D6. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as promethazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with mirabegron may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of mirabegron could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If mirabegron is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Mirabegron is a moderate inhibitor of CYP2D6. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as promethazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Darifenacin: (Moderate) Mirabegron should be administered with caution in patients taking antimuscarinic medications for the treatment of overactive bladder, such as darifenacin, because of the risk of urinary retention. In addition, mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as darifenacin may be increased when administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with mirabegron as there is a potential for elevated cobicistat concentrations. Mirabegron is a moderate CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6 and CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with mirabegron as there is a potential for elevated cobicistat concentrations. Mirabegron is a moderate CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6 and CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of mirabegron with ritonavir may result in elevated plasma concentrations of ritonavir. Mirabegron is a moderate inhibitor of CYP2D6. Ritonavir is a CYP2D6 substrate. Caution and close monitoring are advised if these drugs are administered together.
    Delavirdine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as delavirdine may be increased when administered with mirabegron. Delavirdine has been shown to be a CYP2D6 substrate invitro. Appropriate monitoring and dose adjustment may be necessary.
    Desipramine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Dextromethorphan: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome, (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as diphenhydramine may be increased when co-administered with mirabegron. Diphenhydramine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Dextromethorphan; Guaifenesin: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Dextromethorphan; Promethazine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome, (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as promethazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Dextromethorphan; Quinidine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of dextromethorphan may be increased when administered with mirabegron. Dextromethorphan is primarily metabolized by CYP2D6. Appropriate monitoring and dose adjustment of dextromethorphan may be necessary. Adverse effects of excessive dextromethorphan dosage include nausea, vomiting, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects may include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause also serotonin syndrome,
    Digoxin: (Major) When given in combination, mirabegron increased the mean digoxin Cmax by 29% and the AUC by 27%. Therefore, for patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should initially be considered. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. Monitor heart rate and other clinical parameters to ensure appropriate clinical endpoints.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as dihydrocodeine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Diphenhydramine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as diphenhydramine may be increased when co-administered with mirabegron. Diphenhydramine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as diphenhydramine may be increased when co-administered with mirabegron. Diphenhydramine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Diphenhydramine; Ibuprofen: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as diphenhydramine may be increased when co-administered with mirabegron. Diphenhydramine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Diphenhydramine; Naproxen: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as diphenhydramine may be increased when co-administered with mirabegron. Diphenhydramine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Diphenhydramine; Phenylephrine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as diphenhydramine may be increased when co-administered with mirabegron. Diphenhydramine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Dolasetron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as dolasetron may be increased when co-administered with mirabegron. Dolasetron is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Donepezil: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as donepezil may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Donepezil; Memantine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as donepezil may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Dorzolamide; Timolol: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as timolol may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Doxepin: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Doxorubicin: (Major) Mirabegron is a moderate CYP2D6 inhibitor; doxorubicin is a substrate of both CYP2D6 and CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of mirabegron and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Duloxetine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as duloxetine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Dutasteride; Tamsulosin: (Moderate) The effect of mirabegron on tamsulosin pharmacokinetics was determined in drug interaction studies, there was a lack of pharmacokinetic interaction. However, it is recommended that mirabegron be administered with caution in patients taking other medications in the setting of risks for urinary obstruction because of the risk of urinary retention. This includes caution when used with tamsulosin. In addition, mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as tamsulosin may be increased when co-administered with mirabegron.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of mirabegron and eliglustat is not recommended. In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both mirabegron and a moderate or strong CYP3A inhibitor is contraindicated in all patients. Mirabegron is a moderate CYP2D6 inhibitor; eliglustat is a CYP2D6 and CYP3A substrate. Coadministration of eliglustat with CYP2D6 inhibitors, such as mirabegron, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Encainide: (Major) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as encainide may be increased when administered with mirabegron. Encainide is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Fesoterodine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor and may increase the exposure of drugs metabolized by CYP2D6 such as fesoterodine. Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via CYP2D6 and CYP3A4. Mirabegron should also be administered with caution in patients taking antimuscarinic medications for the treatment of overactive bladder because of the risk of urinary retention. Appropriate monitoring and dose adjustment may be necessary. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
    Flecainide: (Major) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as flecainide may be increased when administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Fluoxetine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as fluoxetine may be increased when co-administered with mirabegron. Fluoxetine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Fluoxetine; Olanzapine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as fluoxetine may be increased when co-administered with mirabegron. Fluoxetine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as olanzapine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Fluphenazine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as fluphenazine may be increased when co-administered with mirabegron. Fluphenazine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as umeclidinium may be increased when co-administered with mirabegron. Umeclidinium is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary. Monitor for dry mouth, constipation, blurred vision or urinary retention.
    Fluvoxamine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as fluvoxamine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Fosamprenavir: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as fosamprenavir may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Gefitinib: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and mirabegron are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. In patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Haloperidol: (Moderate) Mirabegron is a substrate and a moderate inhibitor of CYP2D6. Exposure of drugs metabolized by CYP2D6 such as haloperidol may be increased when co-administered with mirabegron. Haloperidol is primarily metabolized by CYP2D6. In addition, in vitro data suggest that haloperidol has CYP2D6 inhibitory effects and has the potential to decrease the metabolism of CYP2D6 substrates such as mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; mirabegron is a moderate CYP2D6 inhibitor. In drug interaction studies, mirabegron increased the Cmax and AUC of metoprolol by 90% and 229%, respectively, after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet administered before and concomitantly with mirabegron.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as propranolol may be increased when co-administered with mirabegron. Propranolol is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with mirabegron may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of mirabegron could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6.
    Ibuprofen; Oxycodone: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6, such as oxycodone, may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Iloperidone: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as iloperidone may be increased whenadministered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Imipramine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Indacaterol: (Minor) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as indacaterol may be increased when administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Indacaterol; Glycopyrrolate: (Minor) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as indacaterol may be increased when administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Isocarboxazid: (Moderate) It is unclear if it is safe to use of mirabegron with non-selective MAOI therapy. It may be best to use caution and avoid use together if possible. Use of mirabegron (a selective beta-3 adrenergic agonist) with non-selective MAOIs may theoretically result in an increased risk for high blood pressure. Mirabegron has increased blood pressure at clinically used doses (e.g., 50 mg/day). In these studies, at the maximum recommended dose of 50 mg/day, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mmHg greater than placebo. Beta-3 selectivity is usually lost at doses above those used clinically for overactive bladder (e.g, 200 mg/day PO). Sympathomimetic adrenergic agonists are typically contraindicated in patients receiving MAOIs. When administering a MAOI in close proximity to such a drug, at least 2 weeks should usually elapse between discontinuation of 1 agent and initiation of therapy with the other; consult the specific product literature for precise recommendations.
    Ivermectin: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as ivermectin may be increased when co-administered with mirabegron. Ivermectin has been shown to be a CYP2D6 substrate in vitro. Appropriate monitoring and dose adjustment may be necessary.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP2D6 and CYP3A4 substrate, may be increased when administered with mirabegron, a moderate inhibitor of CYP2D6. If these drugs are used together, do not exceed recommended loperamide doses and monitor for loperamide-associated adverse reactions, such as CNS effects (drowsiness, confusion) and cardiac toxicities (i.e., syncope, tachycardia, QT prolongation).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP2D6 and CYP3A4 substrate, may be increased when administered with mirabegron, a moderate inhibitor of CYP2D6. If these drugs are used together, do not exceed recommended loperamide doses and monitor for loperamide-associated adverse reactions, such as CNS effects (drowsiness, confusion) and cardiac toxicities (i.e., syncope, tachycardia, QT prolongation).
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of mirabegron with ritonavir may result in elevated plasma concentrations of ritonavir. Mirabegron is a moderate inhibitor of CYP2D6. Ritonavir is a CYP2D6 substrate. Caution and close monitoring are advised if these drugs are administered together.
    Maprotiline: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as maprotiline may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Meclizine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as meclizine may be increased when co-administered with mirabegron. Meclizine has been shown to be a CYP2D6 substrate in vitro. Appropriate monitoring and dose adjustment may be necessary.
    Meperidine; Promethazine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as promethazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Methadone: (Moderate) Concurrent use of methadone with mirabegron may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Monitor closely until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Methadone is a substrate for CYP3A4 and CYP2D6. Mirabegron is a moderate inhibitor of CYP2D6. Discontinuation of mirabegron in a patient taking methadone chronically may decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If mirabegron is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate.
    Methamphetamine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as methamphetamine may be increased when co-administered with mirabegron. Methamphetamine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Metoclopramide: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as metoclopramide may be increased when administered with mirabegron. Metoclopramide has been shown to be a CYP2D6 substrate. Use of potent CYP2D6 inhibitors with metoclopramide is known to increase metoclopramide exposure and the risk of exacerbation of extrapyramidal symptoms. Consider if an alternative treatment might be appropriate. Appropriate monitoring and metoclopramide dose adjustment may be necessary if mirabegron is used concomitantly.
    Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; mirabegron is a moderate CYP2D6 inhibitor. In drug interaction studies, mirabegron increased the Cmax and AUC of metoprolol by 90% and 229%, respectively, after multiple doses of 160 mg mirabegron IR tablets once daily for 5 days and a single dose of 100 mg metoprolol tablet administered before and concomitantly with mirabegron.
    Mexiletine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as mexiletine may be increased when co-administered with mirabegron. Mexiletine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6 such as mirtazapine may be increased when co-administered with mirabegron. Mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4 in vitro. Appropriate monitoring and dose adjustment may be necessary.
    Monoamine oxidase inhibitors: (Moderate) It is unclear if it is safe to use of mirabegron with non-selective MAOI therapy. It may be best to use caution and avoid use together if possible. Use of mirabegron (a selective beta-3 adrenergic agonist) with non-selective MAOIs may theoretically result in an increased risk for high blood pressure. Mirabegron has increased blood pressure at clinically used doses (e.g., 50 mg/day). In these studies, at the maximum recommended dose of 50 mg/day, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mmHg greater than placebo. Beta-3 selectivity is usually lost at doses above those used clinically for overactive bladder (e.g, 200 mg/day PO). Sympathomimetic adrenergic agonists are typically contraindicated in patients receiving MAOIs. When administering a MAOI in close proximity to such a drug, at least 2 weeks should usually elapse between discontinuation of 1 agent and initiation of therapy with the other; consult the specific product literature for precise recommendations.
    Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with mirabegron. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as mirabegron, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. Dose adjustment may be necessary.
    Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with mirabegron. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as mirabegron, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. Dose adjustment may be necessary.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as palonosetron may be increased when co-administered with mirabegron. Palonosetron is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Nortriptyline: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Olanzapine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as olanzapine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of mirabegron with ritonavir may result in elevated plasma concentrations of ritonavir. Mirabegron is a moderate inhibitor of CYP2D6. Ritonavir is a CYP2D6 substrate. Caution and close monitoring are advised if these drugs are administered together.
    Ondansetron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6, such as ondansetron may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Oxybutynin: (Moderate) Mirabegron should be administered with caution in patients taking antimuscarinic medications for the treatment of overactive bladder, such as oxybutynin, because of the risk of urinary retention. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
    Oxycodone: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6, such as oxycodone, may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Palonosetron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as palonosetron may be increased when co-administered with mirabegron. Palonosetron is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Paroxetine: (Moderate) Mirabegron is a moderate CYP2D6 substrate and inhibitor. Exposure of drugs metabolized by CYP2D6 such as paroxetine may be increased when co-administered with mirabegron. Paroxetine is a substrate and inhibitor of CYP2D6. Mirabegron exposure may also increase. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Pentamidine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as systemic pentamidine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Perphenazine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as perphenazine may be increased when co-administered with mirabegron. Perphenazine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Perphenazine; Amitriptyline: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as perphenazine may be increased when co-administered with mirabegron. Perphenazine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Phenelzine: (Moderate) It is unclear if it is safe to use of mirabegron with non-selective MAOI therapy. It may be best to use caution and avoid use together if possible. Use of mirabegron (a selective beta-3 adrenergic agonist) with non-selective MAOIs may theoretically result in an increased risk for high blood pressure. Mirabegron has increased blood pressure at clinically used doses (e.g., 50 mg/day). In these studies, at the maximum recommended dose of 50 mg/day, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mmHg greater than placebo. Beta-3 selectivity is usually lost at doses above those used clinically for overactive bladder (e.g, 200 mg/day PO). Sympathomimetic adrenergic agonists are typically contraindicated in patients receiving MAOIs. When administering a MAOI in close proximity to such a drug, at least 2 weeks should usually elapse between discontinuation of 1 agent and initiation of therapy with the other; consult the specific product literature for precise recommendations.
    Phenylephrine; Promethazine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as promethazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Pimozide: (Major) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as pimozide may be increased when administered with mirabegron. Caution is advisable during concurrent use of pimozide. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP2D6 and CYP1A2. While the manufacturer has provided no guidance regarding pimozide use with mild or moderate CYP2D6 inhibitors, concurrent use of pimozide with more potent inhibitors of CYP2D6 is contraindicated. Elevated concentrations of pimozide can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Pirfenidone: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as pirfenidone may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Promethazine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as promethazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Propafenone: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as propafenone may be increased when administered with mirabegron. This is especially true for patients who are also CYP2D6 poor metabolizers (PMs). Therefore, appropriate monitoring and dose adjustment may be necessary.
    Propranolol: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as propranolol may be increased when co-administered with mirabegron. Propranolol is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Protriptyline: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Quinine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as quinine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Ranolazine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as ranolazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Ritonavir: (Moderate) Concurrent administration of mirabegron with ritonavir may result in elevated plasma concentrations of ritonavir. Mirabegron is a moderate inhibitor of CYP2D6. Ritonavir is a CYP2D6 substrate. Caution and close monitoring are advised if these drugs are administered together.
    Selegiline: (Moderate) It is unclear if it is safe to use of mirabegron with non-selective MAOI therapy. It may be best to use caution and avoid use together if possible. Use of mirabegron (a selective beta-3 adrenergic agonist) with non-selective MAOIs may theoretically result in an increased risk for high blood pressure. Mirabegron has increased blood pressure at clinically used doses (e.g., 50 mg/day). In these studies, at the maximum recommended dose of 50 mg/day, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mmHg greater than placebo. Beta-3 selectivity is usually lost at doses above those used clinically for overactive bladder (e.g, 200 mg/day PO). Sympathomimetic adrenergic agonists are typically contraindicated in patients receiving MAOIs. When administering a MAOI in close proximity to such a drug, at least 2 weeks should usually elapse between discontinuation of 1 agent and initiation of therapy with the other; consult the specific product literature for precise recommendations.
    Sertraline: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as sertraline may be increased when co-administered with mirabegron. Sertraline has been shown to be a CYP2D6 substrate and a mild to moderate inhibitor of CYP2D6 in vitro. Mirabegron exposure may also increase. Appropriate monitoring and dose adjustment may be necessary.
    Solifenacin: (Minor) There is no pharmacokinetic interaction with solifenacin and mirabegron, and the two drugs have been proven effective in combination treatment for overactive bladder. However, monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
    Tamoxifen: (Major) Concomitant use of mirabegron with tamoxifen may decrease concentrations of the active metabolites of tamoxifen, which may compromise tamoxifen efficacy. Consider alternatives to mirabegron. If it is not possible to avoid concomitant use, monitor patients for appropriate response to tamoxifen. Mirabegron may inhibit the CYP2D6-mediated metabolism of tamoxifen to its active metabolites. Mirabegron is a moderate inhibitor of CYP2D6. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33- times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Some data suggest that tamoxifen efficacy is reduced when used with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p less than 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed vs. those not receiving a CYP2D6 inhibitor.
    Tamsulosin: (Moderate) The effect of mirabegron on tamsulosin pharmacokinetics was determined in drug interaction studies, there was a lack of pharmacokinetic interaction. However, it is recommended that mirabegron be administered with caution in patients taking other medications in the setting of risks for urinary obstruction because of the risk of urinary retention. This includes caution when used with tamsulosin. In addition, mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as tamsulosin may be increased when co-administered with mirabegron.
    Tetrabenazine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as tetrabenazine may be increased when administered with mirabegron. Two of the primary metabolites of tetrabenazine, alpha-dihydrotetrabenzaine (alpha-HTBZ) and beta-dihydrotetrabenazine (beta-HTBZ), are substrates for CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Thioridazine: (Major) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6, such as thioridazine, may be increased when co-administered with mirabegron. Thioridazine has been established to have a causal association with QT prolongation and torsade de pointes (TdP); the risk increases with increased drug concentrations. Therefore, alternative treatment may be considered, and appropriate monitoring and dose adjustment may be necessary if the drugs are used together.
    Timolol: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as timolol may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Tolterodine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as tolterodine may be increased when administered with mirabegron. Tolterodine is primarily metabolized by CYP2D6. Mirabegron should also be used with caution in patients taking antimuscarinic medications for the treatment of overactive bladder because of the risk of urinary retention. Appropriate monitoring and dose adjustment may be necessary. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
    Tramadol: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as tramadol may be increased when co-administered with mirabegron. Tramadol is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Tranylcypromine: (Moderate) It is unclear if it is safe to use of mirabegron with non-selective MAOI therapy. It may be best to use caution and avoid use together if possible. Use of mirabegron (a selective beta-3 adrenergic agonist) with non-selective MAOIs may theoretically result in an increased risk for high blood pressure. Mirabegron has increased blood pressure at clinically used doses (e.g., 50 mg/day). In these studies, at the maximum recommended dose of 50 mg/day, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mmHg greater than placebo. Beta-3 selectivity is usually lost at doses above those used clinically for overactive bladder (e.g, 200 mg/day PO). Sympathomimetic adrenergic agonists are typically contraindicated in patients receiving MAOIs. When administering a MAOI in close proximity to such a drug, at least 2 weeks should usually elapse between discontinuation of 1 agent and initiation of therapy with the other; consult the specific product literature for precise recommendations.
    Tricyclic antidepressants: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Trimipramine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Umeclidinium: (Minor) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as umeclidinium may be increased when co-administered with mirabegron. Umeclidinium is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary. Monitor for dry mouth, constipation, blurred vision or urinary retention.
    Umeclidinium; Vilanterol: (Minor) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as umeclidinium may be increased when co-administered with mirabegron. Umeclidinium is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary. Monitor for dry mouth, constipation, blurred vision or urinary retention.
    Venlafaxine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as venlafaxine may be increased when co-administered with mirabegron. Venlafaxine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Vilazodone: (Minor) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as vilazodone may be increased when co-administered with mirabegron. However, CYP2D6 is a minor metabolic pathway for vilazodone. Appropriate monitoring may be necessary.
    Warfarin: (Moderate) When given in combination, mirabegron increased the mean warfarin (S- and R-warfarin) Cmax by approximately 4% and the AUC by approximately 9% when administered as a single dose of 25 mg warfarin after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated. Therefore, careful monitoring and dose adjustment may be necessary.
    Yohimbine: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6 isoenzymes such as yohimbine, may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of the use of mirabegron during human pregnancy to inform drug-associated risk for birth defects or miscarriage. Mirabegron 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. Women who become pregnant during mirabegron treatment are encouraged to contact their physician.

    Use mirabegron with caution during breast-feeding. There is no information regarding the presence of mirabegron in human milk, the effects on the breast-fed 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 radiolabeled mirabegron to lactating rats. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    In vitro, mirabegron has demonstrated agonist activity at the human beta-3 adrenergic receptor (AR); with very low intrinsic activity for human beta-1 AR and beta-2 AR at doses used clinically for overactive bladder. By activation of beta-3 AR, mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle which increases bladder capacity. At high doses (i.e., 200 mg/day) beta-1 AR stimulation occurs.

    PHARMACOKINETICS

    Mirabegron is administered orally. It is extensively distributed throughout the body. Approximately 71% is bound to human plasma proteins with a moderate affinity for albumin and alpha-1 acid glycoprotein. In vitro, it distributes to erythrocytes with concentrations about 2-fold higher than in plasma. Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component. Two non-active metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 in the oxidative metabolism of mirabegron, in vivo results indicate that these isozymes play a limited role in the overall elimination of the drug. Approximately 25% of unchanged mirabegron is recovered in urine and 0% in feces. Urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. In studies, 55% of radiolabeled mirabegron is recovered in the urine and 34% in the feces. The terminal elimination half-life is approximately 50 hours.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, possibly P-glycoprotein (P-gp)
    Mirabegron is a moderate CYP2D6 inhibitor and may reduce the elimination of other drugs dependent on this isozyme for metabolism. Because of the limited role of CYP3A4 and CYP2D6 in the overall elimination of mirabegron in vivo, drug-drug interactions with inducers or inhibitors of these 2 enzymes do not have a significant effect on mirabegron disposition and no dosage adjustments of mirabegron are needed.
     
    Involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase metabolism has been demonstrated for mirabegron. Mirabegron is also a substrate for butyrylcholinesterase, UGT, the efflux transporter P-glycoprotein (P-gp), and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3; however, clinically significant drug-drug interactions related to these drug transporters are unclear. A small effect of mirabegron on digoxin, a P-gp substrate with a narrow therapeutic index, has been noted and requires caution with concurrent use.

    Oral Route

    Following oral administration, mirabegron attains maximum plasma concentrations (Cmax) at approximately 3.5 hours. Absolute bioavailability is dose-proportional, increasing from 29% to 35% as dose increases from 25 to 50 mg; mean Cmax and AUC increase more than dose-proportionally, especially for doses greater than 50 mg. In the overall population of males and females, a 2-fold increase in dose from 50 mg to 100 mg mirabegron increased Cmax and AUC by approximately 2.9- and 2.6-fold, respectively, whereas a 4-fold increase in dose from 50 to 200 mg mirabegron increased Cmax and AUC by approximately 8.4- and 6.5-fold. Co-administration of a 50 mg tablet with a high-fat meal reduced mirabegron Cmax and AUC by 45% and 17%, respectively. A low-fat meal decreased mirabegron Cmax and AUC by 75% and 51%, respectively. However, clinical safety and efficacy were demonstrated in clinical evaluation under fed and fasting conditions; thus, mirabegron may be administered without regard to food. Steady state concentrations are achieved within 7 days. Plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.