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ASTELLAS PHARMA
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00469260130

brand myrbetriq er 25 mg tablet

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Uses

Overactive Bladder

Mirabegron is used in the management of overactive bladder for the relief of symptoms associated with voiding such as urge urinary incontinence, urgency, and frequency.

Safety and efficacy of mirabegron for this indication were established in three 12-week randomized, double-blind, placebo-controlled studies in patients with symptoms of urinary frequency, urgency, and/or urge incontinence that had persisted for at least 3 months. Patients (mean age of 59 years) were required to have at least 8 micturitions per day and at least 3 episodes of urgency with or without incontinence over a 3-day period; 52% of these patients had received prior treatment with antimuscarinic agents for overactive bladder symptoms. In all studies, the primary efficacy outcome was the change from baseline to end of treatment in the mean number of micturitions and also the mean number of incontinence episodes per 24 hours. In the first 2 studies, patients were randomized to receive mirabegron 50 or 100 mg once daily or placebo. In the first study, a group of patients also was randomized to an active control arm with an antimuscarinic agent (i.e., tolterodine 4 mg extended-release tablets once daily); however, the study design did not allow for a direct comparison between mirabegron and tolterodine. In the third study, patients were randomized to receive mirabegron 25 or 50 mg once daily or placebo. Although mirabegron dosages of 25, 50, and 100 mg were evaluated in clinical studies, only the 25- and 50-mg dosages were considered for Food and Drug Administration (FDA) approval for the management of overactive bladder.

In the first 2 studies, mirabegron 50 mg daily was more effective than placebo in reducing the number of micturitions and incontinence episodes per 24 hours; mirabegron 50 mg daily also was more effective than placebo in increasing the volume of urine voided per micturition. In these 2 studies, urinary frequency was decreased from baseline by 1.66-1.93 or 1.05-1.34 micturitions per 24 hours; urge incontinence episodes were decreased from baseline by 1.47-1.57 or 1.13-1.17 occurrences per 24 hours; and urine volume voided per micturition was increased by 18.2-24.2 or 7-12.3 mL per micturition in patients receiving mirabegron or placebo, respectively. In the third study, mirabegron 25 or 50 mg daily was more effective than placebo in reducing the number of micturitions and incontinence episodes per 24 hours; urinary frequency was decreased from baseline by 1.6-1.65 or 1.18, and urge incontinence episodes were decreased from baseline by 1.36-1.38 or 0.96 in patients receiving mirabegron or placebo, respectively. Efficacy in treating the symptoms of overactive bladder was observed within 4 or 8 weeks in patients receiving mirabegron at a daily dosage of 50 or 25 mg, respectively; efficacy of both dosages was maintained throughout the 12-week treatment period.

In another randomized, double-blind, active-controlled study, patients received mirabegron 50 or 100 mg or tolterodine 4 mg extended-release tablets once daily for 12 months. These patients were required to have at least 8 micturitions per day and at least 3 episodes of urgency over a 3-day period. Mirabegron and the active control tolterodine improved symptoms of overactive bladder from the first measured time point of 4 weeks; efficacy was maintained throughout the 12-month treatment period.

In addition to objective improvements, a beneficial effect on quality-of-life scores has been demonstrated with mirabegron. Clinical study data indicate that treatment with mirabegron was associated with improvements in quality-of-life aspects related to severity measures, symptom severity, coping, concern, sleep, and treatment satisfaction.

Antimuscarinic agents (e.g., darifenacin, fesoterodine, oxybutinin, solifenacin, tolterodine) are considered first-line drugs for the treatment of overactive bladder. Mirabegron may be an appropriate alternative in patients with overactive bladder in whom antimuscarinic agents are ineffective or cannot be tolerated because of adverse anticholinergic effects (e.g., dry mouth and constipation). Mirabegron also may be considered for the management of overactive bladder in geriatric patients or patients with Alzheimer's disease, who may be more sensitive to anticholinergic effects and potential effects on cognition associated with antimuscarinic agents.

Dosage and Administration

Administration

Mirabegron is administered orally once daily without regard to meals. Mirabegron extended-release tablets should be administered with water and swallowed whole; the tablets should not be chewed, divided, or crushed.

Dosage

Overactive Bladder

For the management of overactive bladder, the recommended initial dosage of mirabegron in adults is 25 mg once daily. A dosage of 25 mg once daily has been shown to be effective for symptomatic relief of overactive bladder within 8 weeks. Depending on individual response and tolerance, dosage may be increased to 50 mg once daily.

Special Populations

Dosage of mirabegron should not exceed 25 mg daily in patients with moderate hepatic impairment (Child-Pugh class B). Mirabegron is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C). Dosage adjustment is not necessary in patients with mild hepatic impairment (Child-Pugh class A).(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage of mirabegron should not exceed 25 mg daily in patients with severe renal impairment (creatinine clearance 15-29 mL/minute). Mirabegron is not recommended for use in patients with end-stage renal disease (ESRD) (creatinine clearance below 15 mL/minute or when hemodialysis is required). Dosage adjustment is not necessary in patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute).(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The manufacturer makes no specific dosage recommendations for geriatric patients.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.) Dosage adjustment of mirabegron based on gender is not necessary.

Cautions

Contraindications

Manufacturer states none known.

Warnings/Precautions

Cardiovascular Effects

Increased blood pressure has been reported in patients receiving mirabegron. In clinical studies in patients with overactive bladder, hypertension occurred in 7.5-11.3% of patients receiving mirabegron 25 or 50 mg once daily compared with 7.6% of patients receiving placebo. Reports of hypertension included cases of blood pressure above the normal range as well as blood pressure levels above baseline mainly in individuals with preexisting hypertension. Worsening of preexisting hypertension has been reported infrequently in patients receiving mirabegron. Mean increases in supine systolic and diastolic blood pressure from baseline of 0.5-1 mm Hg greater than those observed with placebo were reported in patients with overactive bladder receiving mirabegron in clinical trials. Increases in morning systolic blood pressure of at least 15 mm Hg from baseline were observed in 5.1, 6.7, or 5.3% of patients with overactive bladder receiving mirabegron or placebo, respectively. Increases in morning diastolic blood pressure of at least 10 mm Hg from baseline were observed in 4.1, 6.6, or 4.6% of patients receiving mirabegron 25 mg, 50 mg, or placebo, respectively. These increases in systolic and diastolic blood pressure appeared to be dose related and reversible following discontinuance of the drug.

In addition, mirabegron was associated with dose-related increases in supine blood pressure in healthy individuals. Mean maximum increases in supine systolic and diastolic blood pressure of 3.5 and 1.5 mm Hg, respectively, greater than those observed with placebo were reported in healthy individuals receiving the maximum dosage of mirabegron 50 mg once daily.

Blood pressure should be measured periodically in patients receiving mirabegron, especially in those with preexisting hypertension. The manufacturer states that mirabegron is not recommended for use in patients with severe uncontrolled hypertension (i.e., systolic blood pressure of 180 mm Hg or greater and/or diastolic blood pressure of 110 mm Hg or greater).

In a placebo- and active-controlled study in healthy individuals, the mean difference from placebo in baseline-corrected QT interval (QTc) based on individual correction method (QTcI) at 4-5 hours following a 50-mg dose of mirabegron was 3.7 msec. In this thorough QT study, mirabegron produced a dose-dependent increase in heart rate with a maximum mean increase of 6.7 beats per minute in patients receiving mirabegron 50 mg compared with those receiving placebo. In clinical trials, an increase in mean heart rate from baseline of approximately 1 beat per minute was observed in patients receiving mirabegron 50 mg.

Genitourinary Effects

Urinary retention has been reported in patients with bladder outflow obstruction and in those receiving antimuscarinic agents for the treatment of overactive bladder during postmarketing experience with mirabegron.

Although a clinical study in patients with bladder outflow obstruction did not show increased urinary retention in those receiving mirabegron, the manufacturer states that the drug should be used with caution in patients with clinically important bladder outflow obstruction and in those receiving antimuscarinic agents for the treatment of overactive bladder. Administration of mirabegron once daily for 12 weeks in male patients with lower urinary tract symptoms and bladder outflow obstruction was not shown to have adverse effects on mean maximum flow rate or mean detrusor pressure at maximum flow rate.

Interactions with Drugs Metabolized by Hepatic Microsomal Enzymes

Systemic exposure to substrates of cytochrome P-450 (CYP) isoenzyme 2D6 may be increased when these drugs are used concomitantly with mirabegron.(See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.) When mirabegron is used concomitantly with CYP2D6 substrates, patients should be monitored and dosage adjusted if necessary, especially in those receiving CYP2D6 substrates with a narrow therapeutic index (e.g., flecainide, propafenone, and thioridazine).

Specific Populations

Pregnancy

Category C.

Lactation

Mirabegron is distributed into milk in rats and has been detected in lungs, liver, and kidneys of nursing pups. It is not known whether mirabegron is distributed into human milk. Because it is predicted that mirabegron will be excreted in human milk and because of the potential for serious adverse reactions to the drug in nursing infants, a decision should be made whether to discontinue nursing or to discontinue mirabegron, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy of mirabegron have not been established in pediatric patients.

Geriatric Use

Pharmacokinetics of mirabegron are not substantially affected by patient age, and no substantial differences in safety and efficacy in geriatric patients relative to younger adults have been observed. Therefore, no dosage adjustment is necessary in geriatric patients.

Hepatic Impairment

Increased plasma concentrations of mirabegron have been reported in patients with moderate hepatic impairment (Child-Pugh class B).(See Dosage and Administration: Special Populations.) Use of mirabegron has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) and, therefore, is not recommended in such patients.

Renal Impairment

Increased plasma concentrations of mirabegron have been reported in patients with severe renal impairment (creatinine clearance 15-29 mL/minute).(See Dosage and Administration: Special Populations.) Use of mirabegron has not been evaluated in patients with end-stage renal disease (ESRD) (i.e., creatinine clearance below 15 mL/minute or when hemodialysis is required) and, therefore, is not recommended in such patients.

Common Adverse Effects

Adverse effects reported in more than 2% of patients receiving mirabegron and at an incidence higher than that reported with placebo include hypertension, nasopharyngitis, urinary tract infection, and headache.

Drug Interactions

Mirabegron is a substrate of cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6, butyrylcholinesterase, uridine 5'-diphospho-glucuronosyltransferase (UGT), the efflux transporter P-glycoprotein (P-gp), and the influx organic cation transporters (OCT) 1, 2, and 3.

Mirabegron is a moderate, time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron is not likely to inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2E1 because in vitro studies showed that the drug did not inhibit the activity of these enzymes at clinically relevant concentrations. In addition, mirabegron does not induce CYP1A2 or 3A. At high concentrations, mirabegron inhibits P-gp-mediated drug transport. Mirabegron is not expected to cause clinically important inhibition of OCT-mediated drug transport.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Pharmacokinetic interaction observed during concomitant use of mirabegron with desipramine or metoprolol (increased plasma desipramine or metoprolol concentrations). Caution is advised with concomitant use. Appropriate monitoring and dosage adjustment may be necessary in patients receiving concomitant therapy with mirabegron and drugs metabolized by CYP2D6, especially such drugs with a narrow therapeutic index (e.g., flecainide, propafenone, and thioridazine).

Substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2E1: Pharmacokinetic interaction unlikely.

Antimuscarinic Agents

Potential for additive pharmacologic effects (e.g., urinary retention) with concomitant administration of mirabegron and antimuscarinic agents (e.g., darifenacin, solifenacin). Because of the increased risk of urinary retention, mirabegron should be used with caution in patients receiving antimuscarinic agents.

Pharmacokinetic interaction unlikely (no substantial effect on pharmacokinetics of mirabegron or solifenacin). Dosage adjustment of mirabegron or solifenacin is not recommended with concomitant use.

Antidiabetic Agents

Concomitant administration of mirabegron with sulfonylurea antidiabetic agents (e.g., glibenclamide [not commercially available in the US], gliclazide [not commercially available in the US], and tolbutamide) did not affect the in vitro metabolism of mirabegron. In addition, mirabegron did not affect the metabolism of glibenclamide or tolbutamide.

Desipramine

Pharmacokinetic interaction (increased desipramine exposure). Peak plasma concentrations and area under the serum concentration-time curve (AUC) of desipramine were increased by 79 and 241%, respectively, in healthy individuals following multiple-dose administration of extended-release mirabegron 100 mg once daily for 18 days with a single 50-mg dose of desipramine administered before and concurrently with mirabegron. Caution is advised with concomitant use. Appropriate monitoring is recommended and dosage adjustment of desipramine may be necessary.

Digoxin

Pharmacokinetic interaction (increased digoxin exposure). Increases in digoxin peak plasma concentrations and AUC of 29 and 27%, respectively, were observed in patients receiving concomitant therapy with mirabegron and digoxin. Initiation of digoxin at the lowest recommended dosage should be considered in patients receiving concomitant therapy. Serum digoxin concentrations should be monitored and dosage carefully titrated to the desired clinical effect.

Ketoconazole

Pharmacokinetic interaction (increased mirabegron exposure). Increases in mirabegron peak plasma concentrations and AUC of 45 and 80%, respectively, were observed in healthy individuals following multiple-dose administration of ketoconazole 400 mg for 9 days prior to a single 100-mg dose of extended-release mirabegron. Dosage adjustment of mirabegron is not recommended with concomitant use.

Metformin

Pharmacokinetic interaction unlikely (no substantial effect on pharmacokinetics of metformin or mirabegron). Dosage adjustment of metformin or mirabegron is not recommended with concomitant use.

Metoprolol

Pharmacokinetic interaction (increased metoprolol exposure). Increases in metoprolol peak plasma concentrations and AUC of 90 and 229%, respectively, were observed in healthy individuals following multiple-dose administration of mirabegron immediate-release 160 mg once daily for 5 days with a single 100-mg dose of metoprolol administered before and concurrently with mirabegron. Caution is advised with concomitant use. Appropriate monitoring is recommended and dosage adjustment of metoprolol may be necessary.

Oral Contraceptives

Pharmacokinetic interaction unlikely (no substantial changes in plasma concentrations of ethinyl estradiol or levonorgestrel). Dosage adjustment of oral contraceptives is not recommended with concomitant use.

Rifampin

Pharmacokinetic interaction unlikely (no substantial effect on pharmacokinetics of mirabegron). Dosage adjustment of mirabegron is not recommended with concomitant use.

Tamsulosin

Pharmacokinetic interaction unlikely (no substantial effect on pharmacokinetics of tamsulosin or mirabegron). Dosage adjustment of tamsulosin or mirabegron is not recommended with concomitant use.

Warfarin

Pharmacokinetic interaction (increased warfarin exposure). Mean peak plasma concentrations and AUC of S- and R-warfarin were increased by approximately 4 and 9%, respectively, in individuals receiving a single dose of warfarin 25 mg following multiple 100-mg doses of extended-release mirabegron. However, no effects on International Normalized Ratio (INR) or prothrombin time (PT) were observed. The effects of mirabegron on warfarin pharmacokinetics and pharmacodynamics in patients receiving multiple doses of warfarin have not been fully investigated.

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