Mirabegron

Mirabegron is a Beta-3 Adrenergic agonist belonging to Sympathomimetics/ Drug for overactive bladder.

Mirabegron is a beta-3 adrenergic agonist used to treat overactive bladder and neurogenic detrusor overactivity.

The bioavailability of mirabegron is 29-35%. Time taken to reach peak plasma concentration is approximately 3.5 hr. Following intravenous administration, mirabegron has an apparent steady-state volume of distribution (Vd) of 1670 L indicating extensive distribution.

Mirabegron is approximately 71% protein-bound in plasma, primarily to albumin and alpha-1-acid glycoprotein.Mirabegron is extensively metabolized via a few mechanisms, although unchanged parent drug is still the major circulating component following oral administration. Presumed metabolic pathways and their resultant metabolites include amide hydrolysis (M5, M16, M17), glucuronidation (mirabegron O-glucuronide, N-glucuronide, N-carbamoylglucuronide, M12), and secondary amine oxidation or dealkylation (M8, M9, M15), amongst others. The enzymes responsible for the oxidative metabolism of mirabegron are thought to be CYP3A4 and CYP2D6, while the UDP-glucuronosyltransferases responsible for conjugation reactions have been identified as UGT2B7, UGT1A3, and UGT1A8. Approximately 55% of the radioactivity was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in the urine while 0% was recovered in the feces.

Mirabegron shows side effects like Headache, dizziness, dry mouth, constipation, back pain, joint pain, difficulty emptying the bladder, or weak urine stream.

Mirabegron is available in the form of Oral tablet and oral suspension.

Mirabegron is available in India, US, UK, Singapore, Malaysia, Canada, France, Japan, China, and Australia.

Mirabegron belongs to the Sympathomimetics/ Drug for overactive bladder acts as a Beta-3 Adrenergic agonist.

Mirabegron, a beta-3 adrenergic receptor agonist, activates beta-3 adrenergic receptors in the bladder resulting in relaxation of the detrusor smooth muscle during the urine storage phase, thus increasing bladder capacity. At usual doses, mirabegron is believed to display selectivity for the beta-3 adrenergic receptor subtype compared to its affinity for the beta-1 and -2 adrenoceptor subtypes. Data have shown that beta-adrenoceptors, predominately the beta-3 subtype, mediate detrusor smooth muscle tone and promote the storage function of the human bladder.

The Data of Onset and duration of action of Mirabegron is not clinically established.

The Tmax of Mirabegron is approximately 3.5 hours.

Mirabegron is available in the form of Oral tablet and oral suspension.

Mirabegron tablet and suspension is taken orally, usually once daily.

Mirabegron is used alone or in combination with other medicines for the treatment of overactive bladder, a condition characterized by symptoms such as a frequent feeling of a need to urinate, sudden urge to urinate, inability to control urination, leaking of urine, etc. It is not recommended for use in children below 18 years of age.

Mirabegron is a Beta-3 Adrenergic agonistbelonging toSympathomimetics/Drug for overactive bladder.

Mirabegron is a potent and selective agonist of beta-3 adrenergic receptors. The activation of beta-3 receptors relaxes detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle, which increases the bladder's storage capacity thereby alleviating feelings of urgency and frequency.

Mirabegron is approved for use in the following clinical indications

• Overactive bladder

Mirabegron is a beta-3 adrenergic agonist used to treat overactive bladder and neurogenic detrusor overactivity.

• Overactive bladder

Oral: Initial: 25 mg once daily. May increase to 50 mg once daily after 4 to 8 weeks based on response and tolerability.

Mirabegron is available in various strengths as 25 mg; 50 mg; 8 mg/mL.

Mirabegron is available in the form ofOral tablet and oral suspension.

• Dosage Adjustment in Kidney Patient

eGFR ≥30 mL/minute/1.73 m²: Oral: No dosage adjustment necessary.

eGFR 15 to <30 mL/minute/1.73 m²: Oral: Do not exceed 25 mg once daily.

eGFR <15 mL/minute/1.73 m²: Oral: Not recommended (has not been studied).

• Dosage Adjustment in Hepatic impairment Patient

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).

Mirabegron is contraindicated in patients with

• Mirabegron is contraindicated in patients who have known hypersensitivity reactions to mirabegron or any component of the tablet.

• Increases in Blood Pressure

Mirabegron can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. Mirabegron is not recommended for use in patients with severe uncontrolled hypertension (defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg). In two, randomized, placebo-controlled, healthy volunteer studies, Mirabegron was associated with dose-related increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo. In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the maximum recommended dose of 50 mg was approximately 0.5 - 1 mm Hg greater than placebo. Worsening of preexisting hypertension was reported infrequently in Mirabegron patients.

• Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Medications for OAB

Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medications for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in Mirabegron patients; however, Mirabegron should be administered with caution to patients with clinically significant BOO. Mirabegron should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB.

• Angioedema

Angioedema of the face, lips, tongue, and/or larynx has been reported with Mirabegron. In some cases angioedema occurred after the first dose. Cases of angioedema have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, promptly discontinue Mirabegron and initiate appropriate therapy and/or measures necessary to ensure a patent airway.

• Patients Taking Drugs Metabolized by CYP2D6

Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary, especially with narrow therapeutic index drugs metabolized by CYP2D6, such as thioridazine, flecainide, and propafenone.

It is not known whether Mirabegron is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Mirabegron is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

There are no adequate and well-controlled studies using Mirabegron in pregnant women. Mirabegron should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Mirabegron treatment are encouraged to contact their physician.

• Common

Hypertension, Tachycardia, Abdominal pain, constipation, diarrhea, xerostomia , Cystitis, urinary tract infection, Influenza, Dizziness, headache, Arthralgia, back pain Nasopharyngitis, sinusitis, Atrial fibrillation, cerebrovascular accident, hypersensitivity angiitis, palpitations, Genital pruritus, pruritus, skin rash, urticaria, Increased gamma-glutamyl transferase, increased lactate dehydrogenase, Abdominal distension, dyspepsia, gastritis, Bladder pain, vaginal infection, Malignant neoplasm of breast, malignant neoplasm of lung, malignant neoplasm of prostate, purpuric rash, Increased serum alanine aminotransferase, increased serum aspartate aminotransferase, Osteoarthritis, Glaucoma, Nephrolithiasis, Rhinitis.

• Rare

Blurred vision, dry eye syndrome, Serum sickness-like reaction, Nausea, Urinary retention, Angioedema, Anxiety, confusion, hallucination, insomnia.

• Drugs Metabolized by CYP2D6

Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure of drugs metabolized by CYP2D6 enzyme such as metoprolol and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary when Mirabegron is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone.

• Digoxin

When given in combination, mirabegron increased mean digoxin Cmax from 1.01 to 1.3 ng/mL (29%) and AUC from 16.7 to 19.3 ng.h/mL (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.

• Warfarin

The mean Cmax of S- and R-warfarin was increased by approximately 4% and AUC by approximately 9% when administered as a single dose of 25 mg after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (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.

The common side effects of Mirabegron include the following

• Common side effects

Headache, dizziness, dry mouth, constipation, back pain, joint pain, difficulty emptying the bladder, or weak urine stream.

• Rare side effects

swelling of face, lips, tongue or throat, difficulty breathing or swallowing, hives, rash, itching, difficult, painful, urgent, or frequent urination.

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies using Mirabegron in pregnant women. Mirabegron should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Mirabegron treatment are encouraged to contact their physician.

• Nursing Mothers

It is not known whether Mirabegron is excreted in human milk. Mirabegron was found in the milk of rats at concentrations twice the maternal plasma level. Mirabegron was found in the lungs, liver, and kidneys of nursing pups. No studies have been conducted to assess the impact of Mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because Mirabegron is predicted to be excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

The safety and effectiveness of Mirabegron in pediatric patients have not been established.

• Geriatric Use

No dose adjustment is necessary for the elderly. The pharmacokinetics of Mirabegron is not significantly influenced by age. Of 5648 patients who received Mirabegron in the phase 2 and 3 studies, 2029 (35.9%) were 65 years of age or older, and 557 (9.9%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients younger than 65 years of age and those 65 years of age or older in these studies.

Symptoms: Palpitations, increased pulse rate and systolic BP.

Management: Symptomatic and supportive treatment.

Pharmacodynamic

Mirabegron exerts its pharmacologic effects by forcing bladder smooth muscle to relax, thereby expanding its capacity and relieving urgency. Mirabegron does not appear to adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in patients with lower urinary tract symptoms and bladder outlet obstruction (BOO), but should be used with in patients with bladder outlet obstruction (BOO) due to reports of significant urinary retention. Furthermore, mirabegron increases both blood pressure and heart rate in a dose-dependent manner and should therefore be used with caution in patients with severely uncontrolled hypertension or others for whom these increases may prove dangerous.

Pharmacokinetics

• Absorption

The bioavailability of mirabegron is 29-35%. Time taken to reach peak plasma concentration isapproximately 3.5 hr.

• Distribution

Following intravenous administration, mirabegron has an apparent steady-state volume of distribution (Vd) of 1670 L indicating extensive distribution.

Mirabegron is approximately 71% protein-bound in plasma, primarily to albumin and alpha-1-acid glycoprotein.

• Metabolism and Excretion

Mirabegron is extensively metabolized via a few mechanisms, although unchanged parent drug is still the major circulating component following oral administration. Presumed metabolic pathways and their resultant metabolites include amide hydrolysis (M5, M16, M17), glucuronidation (mirabegron O-glucuronide, N-glucuronide, N-carbamoylglucuronide, M12), and secondary amine oxidation or dealkylation (M8, M9, M15), amongst others. The enzymes responsible for the oxidative metabolism of mirabegron are thought to be CYP3A4 and CYP2D6, while the UDP-glucuronosyltransferases responsible for conjugation reactions have been identified as UGT2B7, UGT1A3, and UGT1A8. Approximately 55% of the radioactivity was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in the urine while 0% was recovered in the feces.

• https://www.uptodate.com/contents/mirabegron-drug-information?search=mirabegron&source=panel_search_result&selectedTitle=1~16&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://www.mims.com/malaysia/drug/info/mirabegron?mtype=generic
• https://www.drugs.com/mtm/mirabegron.html
• https://go.drugbank.com/drugs/DB08893
• https://medlineplus.gov/druginfo/meds/a612038.html
• https://reference.medscape.com/drug/myrbetriq-mirabegron-999757
• https://www.practo.com/medicine-info/mirabegron-2459-api
• https://www.rxlist.com/myrbetriq-drug.htm#indications
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202611s006lbl.pdf