Mirabegron

G04B - Urologicals ATC G04BD12 Small molecule approved 2012 Oral First-in-class Natural product

JFDA label: Betmiga Prolonged Release Tab

Mechanism of Action

Agonist of Beta-3 adrenergic receptor — Beta-3 adrenergic receptor agonist

Target	Action	Gene / class
Beta-3 adrenergic receptor efficacy	AGONIST	ADRB3

Indications

Approved

Overactive bladder

Contraindications

Source: Lexicomp

Additional contraindications (not in U.S. labeling): Severe uncontrolled hypertension (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg) Absolute
Hypersensitivity to mirabegron or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Common Tachycardia

Nervous system disorders (2)

Common dizziness · Headache

Renal and urinary disorders (2)

Common cystitis · Urinary tract infection

Gastrointestinal disorders (4)

Common abdominal pain · Constipation · diarrhea · xerostomia

Musculoskeletal and connective tissue disorders (2)

Common arthralgia · Back pain

Infections and infestations (1)

Common Influenza

Other (1)

Very Common Cardiovascular: Hypertension

Respiratory, thoracic and mediastinal disorders (2)

Common Nasopharyngitis · sinusitis

Dosing

Source: Lexicomp

Overactive bladder (OAB): Oral: Initial: 25 mg once daily; efficacy is observed within 8 weeks for 25 mg dose. May increase to 50 mg once daily based on individual patient efficacy and tolerability.

Refer to adult dosing.

CrCl 30 to 89 mL/minute or eGFR 30 to 89 mL/minute/1.73 m2: No dosage adjustment necessary. CrCl 15 to 29 mL/minute or eGFR 15 to 29 mL/minute/1.73 m2: Do not exceed 25 mg once daily. CrCl 2: Not recommended (has not been studied). Hemodialysis: Not recommended (has not been studied).

Mild impairment (Child-Pugh class A): No dosage adjustment necessary. Moderate impairment (Child-Pugh class B): Do not exceed 25 mg once daily. Severe impairment (Child-Pugh class C): Not recommended (has not been studied).

Warnings & Precautions

Source: Lexicomp

Angioedema

Angioedema of the face, lips, tongue, and/or larynx has been reported; some cases have occurred after the first dose. May be life-threatening. Immediately discontinue and institute supportive care if the tongue, hypopharynx, or larynx is involved.

Blood pressure effects

Dose-related increases in blood pressure have been reported; monitor blood pressure periodically during therapy. Not recommended in patients with severe uncontrolled hypertension (SBP ≥180 and/or DBP ≥110 mm Hg); if used in patients with controlled and less severe hypertension, use with caution and monitor blood pressure closely; exacerbation of preexisting hypertension has been reported. Disease-related concerns:

Bladder flow obstruction

Use with caution in patients with bladder outlet obstruction (BOO); the risk of urinary retention may be increased.

Hepatic impairment

Use with caution in patients with mild to moderate hepatic impairment; dosage adjustment is required in patients with moderate hepatic impairment. Use is not recommended in severe hepatic impairment.

QT prolongation

Use with caution in patients with a history of QT interval prolongation or those receiving medications known to prolong the QT interval. In one thorough QT study, supratherapeutic doses prolonged the QTc interval based on the individual subject-specific correction method (QTcI) in females but not in males (Malik 2012). In general, mirabegron at the recommended dose has a low risk of QT interval prolongation (Sanford 2013).

Renal impairment

Use with caution in patients with renal impairment; dosage adjustment is required in patients with severe renal impairment. Use is not recommended in ESRD. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse effects have been observed in some animal reproduction studies.

Lactation

Mirabegron is expected to be excreted in breast milk. Because of the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or the drug, taking into account the importance of treatment to the mother.

Monitoring

Clinical pearl	Monitor blood pressure at baseline and then periodically during therapy

Chemistry & Properties

Formula	C21H24N4O2S
Molecular weight	396.52 g/mol
IUPAC name	2-(2-amino-1,3-thiazol-4-yl)-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]acetamide
CAS	223673-61-8
PubChem CID	9865528
InChIKey	`PBAPPPCECJKMCM-IBGZPJMESA-N`
logP	2.77 (XLogP 2.1)
Polar surface area	100.27 Å²
H-bond acceptors / donors	6 / 4
Drug-likeness (QED)	0.42
Lipinski violations	0

SMILES

Nc1nc(CC(=O)Nc2ccc(CCNC[C@H](O)c3ccccc3)cc2)cs1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.364 h
Volume of distribution	22.201 L/kg
Protein binding	62.6%
BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP2C8	Inhibitor	—
CYP2D6	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
β2-adrenoceptor (ADRB2)	Agonist	pEC50 5.0

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT(unspecified) (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OATP1A2 (Substrate)OATP2B1 (Substrate)OCT(unspecified) (Substrate)OCT1 (Substrate)OCT2 (Substrate)OCT3 (Substrate)P-gp (Substrate)PEPT2 (Substrate)

Drug–drug interactions (67, DDInter)

Interacting drug	Severity	Management
Eliglustat	major
Tamoxifen	major
Venetoclax	major
Binimetinib	moderate
Chlorpheniramine	moderate
Codeine	moderate
Dexfenfluramine	moderate
Dextromethorphan	moderate
Diphenhydramine	moderate
Doxepin	moderate
Fenfluramine	moderate
Fostamatinib	moderate
Glasdegib	moderate
Glycerol phenylbutyrate	moderate
Lorcaserin	moderate
Lusutrombopag	moderate
Metoclopramide	moderate
Pirfenidone	moderate
Promethazine	moderate
Talazoparib	moderate
Trospium	moderate
Aminoglutethimide	minor
Apalutamide	minor
Aprepitant	minor
Bexarotene	minor
Bicalutamide	minor
Ceritinib	minor
Chloramphenicol	minor
Cimetidine	minor
Clarithromycin	minor
Clotrimazole	minor
Cobicistat	minor
Crizotinib	minor
Cyclosporine	minor
Dabrafenib	minor
Dasatinib	minor
Deferasirox	minor
Dexamethasone	minor
Elagolix	minor
Entrectinib	minor

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Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Betmiga Prolonged Release Tab	Tablet 25 mg	30 tab	Ibn Rushd Drug Store	32.630
Betmiga Prolonged Release Tab	Tablet 50 mg	30 tab	Ibn Rushd Drug Store	32.630