Myrbetriq 25 MG 24HR Extended Release Oral Tablet
Generic Name: MIRABEGRON
Brand Name: Myrbetriq
- Substance Name(s):
- MIRABEGRON
DRUG INTERACTIONS
7 Drug interaction studies were conducted to investigate the effect of co-administered drugs on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of co-administered drugs (e.g., ketoconazole, rifampin, solifenacin, tamsulosin, and oral contraceptives) [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended when these drugs are co-administered with mirabegron. The following are drug interactions for which monitoring is recommended: • Drugs Metabolized by CYP2D6 (e.g., Metoprolol and Desipramine): Mirabegron is CYP2D6 inhibitor and when used concomitantly with drugs metabolized by CYP2D6, especially narrow therapeutic index drugs, appropriate monitoring and possible dose adjustment of those drugs may be necessary (5.4, 7.1, 12.3). • Digoxin: When initiating a combination of MYRBETRIQ® and digoxin, prescribe the lowest dose of digoxin; monitor serum digoxin concentrations to titrate digoxin dose to desired clinical effect (7.2, 12.3). 7.1 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 MYRBETRIQ® is co-administered with these drugs, especially with narrow therapeutic index CYP2D6 substrates, such as thioridazine, flecainide, and propafenone [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. 7.2 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 [see Clinical Pharmacology (12.3)]. 7.3 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 [see Clinical Pharmacology (12.3)].
OVERDOSAGE
10 Mirabegron has been administered to healthy volunteers at single doses up to 400 mg. At this dose, adverse events reported included palpitations (1 of 6 subjects) and increased pulse rate exceeding 100 bpm (3 of 6 subjects). Multiple doses of mirabegron up to 300 mg daily for 10 days showed increases in pulse rate and systolic blood pressure when administered to healthy volunteers. Treatment for overdosage should be symptomatic and supportive. In the event of overdosage, pulse rate, blood pressure and ECG monitoring is recommended.
DESCRIPTION
11 Mirabegron is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is: Mirabegron is a white powder. It is practically insoluble in water (0.082 mg/mL). It is soluble in methanol and dimethyl sulfoxide. Each MYRBETRIQ® extended-release tablet, for oral administration contains either 25 mg or 50 mg of mirabegron and the following inactive ingredients: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, butylated hydroxytoluene, magnesium stearate, hypromellose, yellow ferric oxide, and red ferric oxide (25 mg tablet only). structural formula
CLINICAL STUDIES
14 MYRBETRIQ® was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3 day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 – 95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for overactive bladder (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%). In Study 1, patients were randomized to placebo, MYRBETRIQ® 50 mg, MYRBETRIQ® 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, MYRBETRIQ® 50 mg or MYRBETRIQ® 100 mg once daily. In Study 3, patients were randomized to placebo, MYRBETRIQ® 25 mg or MYRBETRIQ® 50 mg once daily. The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition. Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3. Table 3: Mean Baseline and Change from Baseline at Week 12‡ for Incontinence Episodes, Micturition Frequency, and Volume Voided per Micturition in Patients with Overactive Bladder in Studies 1, 2, and 3 ‡ Week 12 is last observation on treatment † Least squares mean adjusted for baseline, gender, and geographical region ^For incontinence episodes per 24 hours, the analysis population is restricted to patients with at least 1 episode of incontinence at baseline. #Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment Parameter Study 1 Study 2 Study 3 Placebo MYRBETRIQ® 50 mg Placebo MYRBETRIQ® 50 mg Placebo MYRBETRIQ® 25 mg MYRBETRIQ® 50 mg Number of Incontinence Episodes per 24 Hours^ n 291 293 325 312 262 254 257 Baseline (mean) 2.67 2.83 3.03 2.77 2.43 2.65 2.51 Change from baseline (adjusted mean†) -1.17 -1.57 -1.13 -1.47 -0.96 -1.36 -1.38 Difference from placebo (adjusted mean†) — -0.41 — -0.34 — -0.40 -0.42 95% Confidence Interval — (-0.72, -0.09) — (-0.66, -0.03) — (-0.74, -0.06) (-0.76, -0.08) p-value 0.003# 0.026# 0.005# 0.001# Number of Micturitions per 24 Hours n 480 473 433 425 415 410 426 Baseline (mean) 11.71 11.65 11.51 11.80 11.48 11.68 11.66 Change from baseline (adjusted mean†) -1.34 -1.93 -1.05 -1.66 -1.18 -1.65 -1.60 Difference from placebo (adjusted mean†) — -0.60 — -0.61 — -0.47 -0.42 95% Confidence Interval — (-0.90, -0.29) — (-0.98, -0.24) — (-0.82, -0.13) (-0.76, -0.08) p-value < 0.001# 0.001# 0.007# 0.015# Volume Voided (mL) per Micturition n 480 472 433 424 415 410 426 Baseline (mean) 156.7 161.1 157.5 156.3 164.0 165.2 159.3 Change from baseline (adjusted mean†) 12.3 24.2 7.0 18.2 8.3 12.8 20.7 Difference from placebo (adjusted mean†) — 11.9 — 11.1 — 4.6 12.4 95% Confidence Interval — (6.3, 17.4) — (4.4, 17.9) — (-1.6, 10.8) (6.3, 18.6) p-value < 0.001# 0.001# 0.15 < 0.001# MYRBETRIQ® 25 mg was effective in treating the symptoms of OAB within 8 weeks, and MYRBETRIQ® 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of MYRBETRIQ® was maintained through the 12-week treatment period. Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3. Figure 3: Mean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours – Study 1 Figure 4: Mean (SE) Change from Baseline in Mean Number of Micturitions per 24 Hours – Study 1 Figure 5: Mean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours – Study 2 Figure 6: Mean (SE) Change from Baseline in Mean Number of Micturitions per 24 Hours – Study 2 Figure 7: Mean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours – Study 3 Figure 8: Mean (SE) Change from Baseline in Mean Number of Micturitions per 24 Hours – Study 3 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8
HOW SUPPLIED
16 /STORAGE AND HANDLING MYRBETRIQ® is supplied as oval, film coated extended-release tablets, available in bottles and blister units as follows: Strength 25 mg Color brown Bottle of 30 NDC 0469-2601-30 Bottle of 90 NDC 0469-2601-90 Unit dose pack of 100 NDC 0469-2601-71 NDC 69189-2601-1 single dose pack with 1 tablet as repackaged by Avera McKennan Hospital Store at 25oC (77oF) with excursions permitted from 15oC to 30oC (59oF to 86oF) {see USP controlled Room Temperature}.
RECENT MAJOR CHANGES
•Contraindications (4) 07/2015 •Warnings and Precautions (5.3) 07/2015
GERIATRIC USE
8.5 Geriatric Use No dose adjustment is necessary for the elderly. The pharmacokinetics of MYRBETRIQ® is not significantly influenced by age [see Clinical Pharmacology (12.3)]. Of 5648 patients who received MYRBETRIQ® 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.
DOSAGE FORMS AND STRENGTHS
3 MYRBETRIQ® extended-release tablets are supplied in two different strengths as described below: • 25 mg oval, brown, film coated tablet, • 50 mg oval, yellow, film coated tablet, Extended-release tablets: 25 mg and 50 mg (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although mirabegron showed very low intrinsic activity for cloned human beta-1 AR and beta-2 AR, results in humans indicate that beta-1 AR stimulation occurred at a mirabegron dose of 200 mg.
INDICATIONS AND USAGE
1 MYRBETRIQ® is a beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. MYRBETRIQ® is a beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency (1).
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of MYRBETRIQ® in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies using MYRBETRIQ® in pregnant women. MYRBETRIQ® 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 MYRBETRIQ® treatment are encouraged to contact their physician. Risk Summary Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximum recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits. Animal Data In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible. In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported. The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MRHD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether MYRBETRIQ® 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 MYRBETRIQ® on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because MYRBETRIQ® 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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Increases in Blood Pressure: MYRBETRIQ® can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. MYRBETRIQ® is not recommended for use in severe uncontrolled hypertensive patients (5.1). • Urinary Retention in Patients With Bladder Outlet Obstruction and in Patients Taking Antimuscarinic Drugs for Overactive Bladder: Administer with caution in these patients because of risk of urinary retention (5.2). • Angioedema: Angioedema of the face, lips, tongue and/or larynx has been reported with MYRBETRIQ® (5.3, 6.2). • Patients Taking Drugs Metabolized by CYP2D6: MYRBETRIQ® is a moderate inhibitor of CYP2D6. Appropriate monitoring is recommended and dose adjustment may be necessary for narrow therapeutic index CYP2D6 substrates (5.4, 7.1, 12.3). 5.1 Increases in Blood Pressure MYRBETRIQ® can increase blood pressure. Periodic blood pressure determinations are recommended, especially in hypertensive patients. MYRBETRIQ® 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) [see Clinical Pharmacology (12.2)]. In two, randomized, placebo-controlled, healthy volunteer studies, MYRBETRIQ® 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 pre-existing hypertension was reported infrequently in MYRBETRIQ® patients. 5.2 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 MYRBETRIQ® patients; however, MYRBETRIQ® should be administered with caution to patients with clinically significant BOO. MYRBETRIQ® should also be administered with caution to patients taking antimuscarinic medications for the treatment of OAB [see Clinical Pharmacology (12.2)]. 5.3 Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with MYRBETRIQ®. 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 MYRBETRIQ® and initiate appropriate therapy and/or measures necessary to ensure a patent airway [see Adverse Reactions (6.2)]. 5.4 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 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Inform patients that MYRBETRIQ® may increase blood pressure. Periodic blood pressure determinations are recommended, especially in patients with hypertension. MYRBETRIQ® has also been associated with infrequent urinary tract infections, rapid heartbeat, rash, and pruritus. Inform patients that urinary retention has been reported when taking mirabegron in combination with antimuscarinic drugs used in the treatment of overactive bladder. Instruct patients to contact their physician if they experience these effects while taking MYRBETRIQ®. Patients should read the patient leaflet entitled “Patient Information” before starting therapy with MYRBETRIQ®. Rx Only PRODUCT OF JAPAN OR IRELAND – See bottle label or blister package for origin Manufactured by: Astellas Pharma Technologies, Inc. Norman, Oklahoma 73072 Marketed and Distributed by: Astellas Pharma US, Inc. Northbrook, Illinois 60062 MYRBETRIQ® is a registered trademark of Astellas Pharma Inc. All other trademarks or registered trademarks are the property of their respective owners. © 2015 Astellas Pharma US, Inc. Revised: November 2015 15C024-MIR
DOSAGE AND ADMINISTRATION
2 •Recommended starting dose is 25 mg once daily, with or without food (2.1). •25 mg is effective within 8 weeks. Based on individual efficacy and tolerability, may increase dose to 50 mg once daily (2.1, 14). •Swallow whole with water, do not chew, divide or crush (2.1). • Patients with Severe Renal Impairment or Patients with Moderate Hepatic Impairment: Maximum dose is 25 mg once daily (2.2, 8.6, 8.7, 12.3). • Patients with End Stage Renal Disease (ESRD) or Patients with Severe Hepatic Impairment: Not recommended (2.2, 8.6, 8.7, 12.3). 2.1 Dosing Information The recommended starting dose of MYRBETRIQ® is 25 mg once daily with or without food. MYRBETRIQ® 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily [see Clinical Studies (14)]. MYRBETRIQ® should be taken with water, swallowed whole and should not be chewed, divided, or crushed. 2.2 Dose Adjustments in Specific Populations The daily dose of MYRBETRIQ® should not exceed 25 mg once daily in the following populations: •Patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. •Patients with moderate hepatic impairment (Child-Pugh Class B) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. MYRBETRIQ® is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].