Myrbetriq

Dosage Forms And Strengths

MYRBETRIQ^® extended-release tablets are supplied in two different strengths as described below:

• 25 mg oval, brown, film coated tablet, debossed with the (Astellas logo) and “325”
• 50 mg oval, yellow, film coated tablet, debossed with the (Astellas logo) and “355”

Storage And Handling

MYRBETRIQ^® is supplied as oval, film coated extended-release tablets, available in bottles and blister units as follows:

Store at 25°C (77°F) with excursions permitted from 15°C to 30°C (59°F to 86°F) {see USP controlled Room Temperature}.

Distributed by: Astellas Pharma US, Inc. Northbrook, Illinois 60062. Revised: July 2017.

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.

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.

MYRBETRIQ^® should be taken with water, swallowed whole and should not be chewed, divided, or crushed.

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 (CL_cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m²).
• Patients with moderate hepatic impairment (Child-Pugh Class B).

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).

MYRBETRIQ^® is contraindicated in patients who have known hypersensitivity reactions to mirabegron or any component of the tablet.

WARNINGS

Included as part of the "PRECAUTIONS" Section

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 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, 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 preexisting hypertension was reported infrequently in MYRBETRIQ^® 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 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.

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.

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.

Patient Counseling Information

Advise the patient to read the 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^®.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Long-term carcinogenicity studies were conducted in rats and mice dosed orally with mirabegron for two years. Male rats were dosed at 0, 12.5, 25, or 50 mg/kg/day and female rats and both sexes of mice were dosed at 0, 25, 50, or 100 mg/kg/day. Mirabegron showed no carcinogenic potential at systemic exposures (AUC) 38 to 45-fold higher in rats and 21 to 38-fold higher in mice than the human systemic exposure at the 50 mg dose.

Mutagenesis

Mirabegron was not mutagenic in the Ames bacterial reverse mutation assay, did not induce chromosomal aberrations in human peripheral blood lymphocytes at concentrations that were not cytotoxic, and was not clastogenic in the rat micronucleus assay.

Impairment Of Fertility

Fertility studies in rats showed that mirabegron had no effect on either male or female fertility at non-lethal doses up to 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg in female rats was estimated to be 22 times the MRHD in women and 93 times the MRHD in men.

Use In Specific Populations

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 (7^th to 17^th 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 (6^th to 20^th 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.

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.

Pediatric Use

The safety and effectiveness of MYRBETRIQ^® in pediatric patients have not been established.

Geriatric Use

No dose adjustment is necessary for the elderly. The pharmacokinetics of MYRBETRIQ^® is not significantly influenced by age. 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.

Renal Impairment

MYRBETRIQ^® has not been studied in patients with end stage renal disease (CL_cr < 15 mL/min or eGFR < 15 mL/min/1.73 m² or patients requiring hemodialysis), and, therefore is not recommended for use in these patient populations.

In patients with severe renal impairment (CL_cr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m²), the daily dose of MYRBETRIQ^® should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal impairment (CL_cr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m²).

Hepatic Impairment

MYRBETRIQ^® has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore is not recommended for use in this patient population.

In patients with moderate hepatic impairment (Child-Pugh Class B), the daily dose of MYRBETRIQ^® should not exceed 25 mg. No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh Class A).

Gender

No dose adjustment is necessary based on gender. When corrected for differences in body weight, the MYRBETRIQ^® systemic exposure is 20% to 30% higher in females compared to males.

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), MYRBETRIQ^® was evaluated for safety in 2736 patients. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received MYRBETRIQ^® 25 mg, 1375 received MYRBETRIQ^® 50 mg, and 929 received MYRBETRIQ^® 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).

MYRBETRIQ^® was also evaluated for safety in 1632 patients who received MYRBETRIQ^® 50 mg once daily (n=812 patients) or MYRBETRIQ^® 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received MYRBETRIQ^® in a previous 12-week study. In Study 4, 1385 patients received MYRBETRIQ^® continuously for at least 6 months, 1311 patients received MYRBETRIQ^® for at least 9 months, and 564 patients received MYRBETRIQ^® for at least 1 year.

The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.

Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.

Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with MYRBETRIQ^® 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of MYRBETRIQ^® patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.

Table 1: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo Rate and Reported by 1% or More Patients Treated with MYRBETRIQ^® 25 mg or 50 mg Once Daily in Studies 1, 2, and 3

Other adverse reactions reported by less than 1% of patients treated with MYRBETRIQ^® in Studies 1, 2, or 3 included:

Cardiac disorders: palpitations, blood pressure increased

Eye disorders: glaucoma

Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension

Infections and Infestations: sinusitis, rhinitis

Investigations: GGT increased, AST increased, ALT increased, LDH increased

Renal and urinary disorders: nephrolithiasis, bladder pain

Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection

Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema

Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with MYRBETRIQ^® 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (> 3% of MYRBETRIQ^® patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.

Table 2: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Reported by Greater Than 2% of Patients Treated with MYRBETRIQ^® 50 mg Once Daily in Study 4

In Study 4, in patients treated with MYRBETRIQ^® 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking MYRBETRIQ^® 50 mg, and these markers subsequently returned to baseline while both patients continued MYRBETRIQ^®.

In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with MYRBETRIQ^® 50 mg, MYRBETRIQ^® 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with MYRBETRIQ^® 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.

In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST and bilirubin in a patient taking MYRBETRIQ^® 100 mg as well as an herbal medication (Kyufu Gold).

Postmarketing Experience

Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.

The following events have been reported in association with mirabegron use in worldwide postmarketing experience:

Gastrointestinal disorders: nausea, constipation, diarrhea

Nervous system disorders: dizziness, headache

There have been postmarketing reports of confusion, hallucinations, insomnia and anxiety in patients taking mirabegron. The majority of these patients had pre-existing medical conditions or concomitant medications that may cause confusion, hallucinations, insomnia and anxiety. A causal relationship between mirabegron and these disorders has not been established.

Skin and subcutaneous tissue: angioedema of the face, lips, tongue, and larynx, with or without respiratory symptoms ; pruritus

Urologic: urinary retention

DRUG INTERACTIONS

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). 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

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.

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.

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 (7^th to 17^th 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 (6^th to 20^th 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder (Studies 1, 2, and 3), MYRBETRIQ^® was evaluated for safety in 2736 patients. Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received MYRBETRIQ^® 25 mg, 1375 received MYRBETRIQ^® 50 mg, and 929 received MYRBETRIQ^® 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).

MYRBETRIQ^® was also evaluated for safety in 1632 patients who received MYRBETRIQ^® 50 mg once daily (n=812 patients) or MYRBETRIQ^® 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind, active controlled, safety study in patients with overactive bladder (Study 4). Of these patients, 731 received MYRBETRIQ^® in a previous 12-week study. In Study 4, 1385 patients received MYRBETRIQ^® continuously for at least 6 months, 1311 patients received MYRBETRIQ^® for at least 9 months, and 564 patients received MYRBETRIQ^® for at least 1 year.

The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.

Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo.

Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an incidence greater than placebo and in 1% or more of patients treated with MYRBETRIQ^® 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of MYRBETRIQ^® patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.

Table 1: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo Rate and Reported by 1% or More Patients Treated with MYRBETRIQ^® 25 mg or 50 mg Once Daily in Studies 1, 2, and 3

Other adverse reactions reported by less than 1% of patients treated with MYRBETRIQ^® in Studies 1, 2, or 3 included:

Cardiac disorders: palpitations, blood pressure increased

Eye disorders: glaucoma

Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension

Infections and Infestations: sinusitis, rhinitis

Investigations: GGT increased, AST increased, ALT increased, LDH increased

Renal and urinary disorders: nephrolithiasis, bladder pain

Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection

Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema

Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with MYRBETRIQ^® 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (> 3% of MYRBETRIQ^® patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.

Table 2: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Reported by Greater Than 2% of Patients Treated with MYRBETRIQ^® 50 mg Once Daily in Study 4

In Study 4, in patients treated with MYRBETRIQ^® 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking MYRBETRIQ^® 50 mg, and these markers subsequently returned to baseline while both patients continued MYRBETRIQ^®.

In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with MYRBETRIQ^® 50 mg, MYRBETRIQ^® 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with MYRBETRIQ^® 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.

In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST and bilirubin in a patient taking MYRBETRIQ^® 100 mg as well as an herbal medication (Kyufu Gold).

Postmarketing Experience

Because these spontaneously reported events are from the worldwide postmarketing experience, from a population of uncertain size, the frequency of events and the role of mirabegron in their causation cannot be reliably determined.

The following events have been reported in association with mirabegron use in worldwide postmarketing experience:

Gastrointestinal disorders: nausea, constipation, diarrhea

Nervous system disorders: dizziness, headache

There have been postmarketing reports of confusion, hallucinations, insomnia and anxiety in patients taking mirabegron. The majority of these patients had pre-existing medical conditions or concomitant medications that may cause confusion, hallucinations, insomnia and anxiety. A causal relationship between mirabegron and these disorders has not been established.

Skin and subcutaneous tissue: angioedema of the face, lips, tongue, and larynx, with or without respiratory symptoms ; pruritus

Urologic: urinary retention

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.

Urodynamics

The effects of MYRBETRIQ^® on maximum urinary flow rate and detrusor pressure at maximum flow rate were assessed in a urodynamic study consisting of 200 male patients with lower urinary tract symptoms (LUTS) and BOO. Administration of MYRBETRIQ^® once daily for 12 weeks did not adversely affect the mean maximum flow rate or mean detrusor pressure at maximum flow rate in this study. Nonetheless, MYRBETRIQ^® should be administered with caution to patients with clinically significant BOO.

Cardiac Electrophysiology

The effect of multiple doses of MYRBETRIQ^® 50 mg, 100 mg and 200 mg once daily on QTc interval was evaluated in a randomized, placebo-and active-controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study in 352 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 msec. For the 50 mg MYRBETRIQ^® dose group (the maximum approved dosage), the mean difference from placebo on QTcI interval at 4-5 hours post-dose was 3.7 msec (upper bound of the 95% CI 5.1 msec).

For the MYRBETRIQ^® 100 mg and 200 mg doses groups (dosages greater than the maximum approved dose and resulting in substantial multiples of the anticipated maximum blood levels at 50 mg), the mean differences from placebo in QTcI interval at 4-5 hours post-dose were 6.1 msec (upper bound of the 95% CI 7.6 msec) and 8.1 msec (upper bound of the 95% CI 9.8 msec), respectively. At the MYRBETRIQ^® 200 mg dose, in females, the mean effect was 10.4 msec (upper bound of the 95% CI 13.4 msec).

In this thorough QT study, MYRBETRIQ^® increased heart rate on ECG in a dose dependent manner. Maximum mean increases from baseline in heart rate for the 50 mg, 100 mg, and 200 mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm, respectively. In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for MYRBETRIQ^® 50 mg was approximately 1 bpm. In this thorough QT study, MYRBETRIQ^® also increased blood pressure in a dose dependent manner (see Effects On Blood Pressure).

Effects On Blood Pressure

In a study of 352 healthy subjects assessing the effect of multiple daily doses of 50 mg, 100 mg, and 200 mg of MYRBETRIQ^® for 10 days on the QTc interval, the maximum mean increase in supine SBP/DBP at the maximum recommended dose of 50 mg was approximately 4.0/1.6 mm Hg greater than placebo. The 24-hour average increases in SBP compared to placebo were 3.0, 5.5, and 9.7 mm Hg at MYRBETRIQ^® doses of 50 mg, 100 mg and 200 mg, respectively. Increases in DBP were also dose-dependent, but were smaller than SBP.

In another study in 96 healthy subjects to assess the impact of age on pharmacokinetics of multiple daily doses of 50 mg, 100 mg, 200 mg, and 300 mg of MYRBETRIQ^® for 10 days, SBP also increased in a dose-dependent manner. The mean maximum increases in SBP were approximately 2.5, 4.5, 5.5 and 6.5 mm Hg for MYRBETRIQ^® exposures associated with doses of 50 mg, 100 mg, 200 mg and 300 mg, respectively.

In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies (Studies 1, 2 and 3) in OAB patients receiving MYRBETRIQ^® 25 mg, 50 mg, or 100 mg once daily, mean increases in SBP/DBP compared to placebo of approximately 0.5 – 1 mm Hg were observed. Morning SBP increased by at least 15 mm Hg from baseline in 5.3%, 5.1%, and 6.7% of placebo, MYRBETRIQ^® 25 mg and MYRBETRIQ^® 50 mg patients, respectively. Morning DBP increased by at least 10 mm Hg in 4.6%, 4.1% and 6.6% of placebo, MYRBETRIQ^® 25 mg, and MYRBETRIQ^® 50 mg patients, respectively. Both SBP and DBP increases were reversible upon discontinuation of treatment.

Effect On Intraocular Pressure (IOP)

MYRBETRIQ^® 100 mg once daily did not increase IOP in healthy subjects after 56 days of treatment. In a phase 1 study assessing the effect of MYRBETRIQ^® on IOP using Goldmann applanation tonometry in 310 healthy subjects, a dose of MYRBETRIQ^® 100 mg was non-inferior to placebo for the primary endpoint of the treatment difference in mean change from baseline to day 56 in subject-average IOP; upper bound of the two-sided 95% CI of the treatment difference between MYRBETRIQ^® 100 mg and placebo was 0.3 mm Hg.

Absorption

After oral administration of mirabegron in healthy volunteers, mirabegron is absorbed to reach maximum plasma concentrations (Cmax) at approximately 3.5 hours. The absolute bioavailability increases from 29% at a dose of 25 mg to 35% at a dose of 50 mg. Mean Cmax and AUC increase more than dose proportionally. This relationship is more apparent at doses above 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 AUCtau 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 AUCtau by approximately 8.4-and 6.5-fold. Steady state concentrations are achieved within 7 days of once daily dosing with mirabegron. After once daily administration, plasma exposure of mirabegron at steady state is approximately double that seen after a single dose.

Effect Of Food

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. In the phase 3 studies, mirabegron was administered irrespective of food contents and intake (i.e., with or without food) and demonstrated both safety and efficacy. Therefore, mirabegron can be taken with or without food at the recommended dose.

Distribution

Mirabegron is extensively distributed in the body. The volume of distribution at steady state (Vss) is approximately 1670 L following intravenous administration. Mirabegron is bound (approximately 71%) to human plasma proteins, and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes to erythrocytes. Based on in vitro study erythrocyte concentrations of ¹⁴C-mirabegron were about 2-fold higher than in plasma.

Metabolism

Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. Mirabegron is the major circulating component following a single dose of ¹⁴C-mirabegron. Two major metabolites were observed in human plasma and are phase 2 glucuronides representing 16% and 11% of total exposure, respectively. These metabolites are not pharmacologically active toward beta-3 adrenergic receptor. 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. In healthy subjects who are genotypically poor metabolizers of CYP2D6, mean Cmax and AUCtau were approximately 16% and 17% higher than in extensive metabolizers of CYP2D6, respectively. In vitro and ex vivo studies have shown the involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase in the metabolism of mirabegron, in addition to CYP3A4 and CYP2D6.

Excretion

Total body clearance (CL_tot) from plasma is approximately 57 L/h following intravenous administration. The terminal elimination half-life (t_1/2) is approximately 50 hours. Renal clearance (CL_R) is approximately 13 L/h, which corresponds to nearly 25% of CL_tot. Renal elimination of mirabegron is primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from approximately 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. Following the administration of 160 mg ¹⁴C-mirabegron solution to healthy volunteers, approximately 55% of the radioactivity dose was recovered in the urine and 34% in the feces. Approximately 25% of unchanged mirabegron was recovered in urine and 0% in feces.