` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`MYRBETRIQ® safely and effectively. See full prescribing information
`
`
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`for MYRBETRIQ®.
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`MYRBETRIQ® (mirabegron) extended-release tablets, for oral use
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`Initial U.S. Approval: 2012
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`----------------------------INDICATIONS AND USAGE--------------------------­
`
` MYRBETRIQ® is a beta-3 adrenergic agonist indicated for the treatment of
`
`
`
` overactive bladder (OAB) with symptoms of urge urinary incontinence,
`
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` urgency, and urinary frequency (1).
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`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
` • Recommended starting dose is 25 mg once daily, with or without food
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` (2.1).
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` • 25 mg is effective within 8 weeks. Based on individual efficacy and
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` tolerability, may increase dose to 50 mg once daily (2.1, 14).
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` • Swallow whole with water, do not chew, divide or crush (2.1).
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`● Patients with Severe Renal Impairment or Patients with Moderate Hepatic
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`Impairment: Maximum dose is 25 mg once daily (2.2, 8.6, 8.7, 12.3).
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`• Patients with End Stage Renal Disease (ESRD) or Patients with Severe
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`Hepatic Impairment: Not recommended (2.2, 8.6, 8.7, 12.3).
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`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`Extended-release tablets: 25 mg and 50 mg (3).
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`------------------------------CONTRAINDICATIONS-----------------------------­
`Hypersensitivity reactions (4).
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`------------------------WARNINGS AND PRECAUTIONS----------------------­
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` • Increases in Blood Pressure: MYRBETRIQ® can increase blood pressure.
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` Periodic blood pressure determinations are recommended, especially in
`
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`
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` hypertensive patients. MYRBETRIQ® is not recommended for use in
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` severe uncontrolled hypertensive patients (5.1).
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` • Urinary Retention in Patients With Bladder Outlet Obstruction and in
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` Patients Taking Antimuscarinic Drugs for Overactive Bladder: Administer
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` with caution in these patients because of risk of urinary retention (5.2).
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` • Angioedema: Angioedema of the face, lips, tongue and/or larynx has been
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`reported with MYRBETRIQ® (5.3, 6.2).
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`• Patients Taking Drugs Metabolized by CYP2D6: MYRBETRIQ® is a
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`moderate inhibitor of CYP2D6. Appropriate monitoring is recommended
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`and dose adjustment may be necessary for narrow therapeutic index
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`CYP2D6 substrates (5.4, 7.1, 12.3).
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`------------------------------ADVERSE REACTIONS------------------------------­
`Most commonly reported adverse reactions (> 2% and > placebo) were
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`hypertension, nasopharyngitis, urinary tract infection and headache (6.1).
`
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`To report SUSPECTED ADVERSE REACTIONS, contact Astellas
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`Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or
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`
`
`www.fda.gov/medwatch.
`
`
`-------------------------------DRUG INTERACTIONS-----------------------------­
`
`• Drugs Metabolized by CYP2D6 (e.g., Metoprolol and Desipramine):
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`Mirabegron is CYP2D6 inhibitor and when used concomitantly with drugs
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`metabolized by CYP2D6, especially narrow therapeutic index drugs,
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`appropriate monitoring and possible dose adjustment of those drugs may
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`be necessary (5.4, 7.1, 12.3).
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`• Digoxin: When initiating a combination of MYRBETRIQ® and digoxin,
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`prescribe the lowest dose of digoxin; monitor serum digoxin
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`concentrations to titrate digoxin dose to desired clinical effect (7.2, 12.3).
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`------------------------USE IN SPECIFIC POPULATIONS----------------------­
`• Pregnancy: Use only if the benefit to the mother outweighs the potential
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`risk to the fetus (8.1).
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` • Nursing mothers: MYRBETRIQ® is predicted to be excreted in human
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` milk and is not recommended for use by nursing mothers (8.3).
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` • Pediatric use: The safety and effectiveness of MYRBETRIQ® in pediatric
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` patients have not been established (8.4).
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` • Geriatric use: No dose adjustment is recommended for elderly patients
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` (8.5).
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` See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling
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`Revised: 7/2017
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`1 INDICATIONS AND USAGE
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`2 DOSAGE AND ADMINISTRATION
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`2.1 Dosing Information
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`2.2 Dose Adjustments in Specific Populations
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`3 DOSAGE FORMS AND STRENGTHS
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`4 CONTRAINDICATIONS
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Increases in Blood Pressure
`5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in
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`Patients Taking Antimuscarinic Medications for OAB
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`5.3 Angioedema
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`5.4 Patients Taking Drugs Metabolized by CYP2D6
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`6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`6.2 Postmarketing Experience
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`7 DRUG INTERACTIONS
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`7.1 Drugs Metabolized by CYP2D6
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`7.2 Digoxin
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`7.3 Warfarin
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`8.3 Nursing Mothers
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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`8.6 Renal Impairment
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`8.7 Hepatic Impairment
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`8.8 Gender
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`10 OVERDOSAGE
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`14 CLINICAL STUDIES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information
`
`
`are not listed.
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`
`
`
`Reference ID: 4131687
`
`ASTELLAS 2001
`Sawai v. Astellas
`IPR2018-00079
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
` 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
`
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`
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` once daily [see Clinical Studies (14)].
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`MYRBETRIQ® should be taken with water, swallowed whole and should not be chewed, divided, or crushed.
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` 2.2 Dose Adjustments in Specific Populations
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` The daily dose of MYRBETRIQ® should not exceed 25 mg once daily in the following populations:
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`• Patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2) [see Use in
`
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`Specific Populations (8.6) and Clinical Pharmacology (12.3)].
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`• Patients with moderate hepatic impairment (Child-Pugh Class B) [see Use in Specific Populations (8.7) and
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`
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`Clinical Pharmacology (12.3)].
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`MYRBETRIQ® is not recommended for use in patients with end stage renal disease (ESRD), or in patients with
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`
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`severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6, 8.7) and Clinical
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`Pharmacology (12.3)].
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` 3 DOSAGE FORMS AND STRENGTHS
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` MYRBETRIQ® extended-release tablets are supplied in two different strengths as described below:
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` • 25 mg oval, brown, film coated tablet, debossed with the
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`(Astellas logo) and “325”
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`• 50 mg oval, yellow, film coated tablet, debossed with the
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`(Astellas logo) and “355”
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` 4 CONTRAINDICATIONS
`
`
` MYRBETRIQ® is contraindicated in patients who have known hypersensitivity reactions to mirabegron or any
` component of the tablet [see Adverse Reactions (6.1, 6.2)].
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` 5 WARNINGS AND PRECAUTIONS
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` 5.1 Increases in Blood Pressure
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` 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
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`(defined as systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or
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`equal to 110 mm Hg) [see Clinical Pharmacology (12.2)].
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`Reference ID: 4131687
`
`Page 2 of 24
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`In two, randomized, placebo-controlled, healthy volunteer studies, MYRBETRIQ® was associated with dose-related
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`increases in supine blood pressure. In these studies, at the maximum recommended dose of 50 mg, the mean
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`maximum increase in systolic/diastolic blood pressure was approximately 3.5/1.5 mm Hg greater than placebo.
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`In contrast, in OAB patients in clinical trials, the mean increase in systolic and diastolic blood pressure at the
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`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.
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` 5.2 Urinary Retention in Patients with Bladder Outlet Obstruction and in Patients Taking
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` Antimuscarinic Medications for OAB
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` 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
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` clinical safety study in patients with BOO did not demonstrate increased urinary retention in MYRBETRIQ®
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`patients; however, MYRBETRIQ® should be administered with caution to patients with clinically significant BOO.
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`MYRBETRIQ® should also be administered with caution to patients taking antimuscarinic medications for the
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`treatment of OAB [see Clinical Pharmacology (12.2)].
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` 5.3 Angioedema
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` Angioedema of the face, lips, tongue, and/or larynx has been reported with MYRBETRIQ®. In some cases
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` 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
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`
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`of the tongue, hypopharynx, or larynx occurs, promptly discontinue MYRBETRIQ® and initiate appropriate therapy
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`and/or measures necessary to ensure a patent airway [see Adverse Reactions (6.2)].
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` 5.4 Patients Taking Drugs Metabolized by CYP2D6
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` Since mirabegron is a moderate CYP2D6 inhibitor, the systemic exposure to CYP2D6 substrates such as metoprolol
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` and desipramine is increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose
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`
`
` 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)].
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` 6 ADVERSE REACTIONS
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` 6.1 Clinical Trials Experience
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` 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
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` observed in clinical practice.
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` In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies in patients with overactive bladder
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`(Studies 1, 2, and 3), MYRBETRIQ® was evaluated for safety in 2736 patients [see Clinical Studies (14)]. Study 1
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`also included an active control. For the combined Studies 1, 2, and 3, 432 patients received MYRBETRIQ® 25 mg,
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`1375 received MYRBETRIQ® 50 mg, and 929 received MYRBETRIQ® 100 mg once daily. In these studies, the
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`majority of the patients were Caucasian (94%), and female (72%) with a mean age of 59 years (range 18 to 95 years).
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`MYRBETRIQ® was also evaluated for safety in 1632 patients who received MYRBETRIQ® 50 mg once daily
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`(n=812 patients) or MYRBETRIQ® 100 mg (n=820 patients) in a 1 year, randomized, fixed dose, double-blind,
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`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
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`least 6 months, 1311 patients received MYRBETRIQ® for at least 9 months, and 564 patients received
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`MYRBETRIQ® for at least 1 year.
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`Reference ID: 4131687
`
`Page 3 of 24
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`The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2 and 3 for the 25 mg or 50 mg
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`dose were nausea, headache, hypertension, diarrhea, constipation, dizziness and tachycardia.
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`Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient
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`and at a rate greater than placebo.
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`Table 1 lists adverse reactions, derived from all adverse events, that were reported in Studies 1, 2 and 3 at an
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`incidence greater than placebo and in 1% or more of patients treated with MYRBETRIQ® 25 mg or 50 mg once daily
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`for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of MYRBETRIQ® patients and
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`greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.
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`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
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`in Studies 1, 2, and 3
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` Placebo
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` (%)
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` 1380
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` 7.6
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` 2.5
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` 1.8
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` 3.0
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` 1.4
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` 1.7
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`
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`
`
` MYRBETRIQ® 25 mg
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` (%)
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` 432
`
` 11.3
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` 3.5
`
` 4.2
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` 2.1
`
` 1.6
`
` 2.1
`
` MYRBETRIQ® 50 mg
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` (%)
` 1375
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`
` 7.5
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` 3.9
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` 2.9
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` 3.2
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` 1.6
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` 1.5
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` Number of Patients
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`
` Hypertension*
` Nasopharyngitis
`
` Urinary Tract Infection
`
`
` Headache
` Constipation
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` Upper Respiratory Tract
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`
` Infection
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` Arthralgia
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` 1.3
`
` 1.6
`
` 1.1
`
` Diarrhea
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` 1.5
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` 1.2
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` 1.3
` Tachycardia
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` 1.2
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` 1.6
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` 0.6
`
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` 0.6
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` 1.4
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` 0.7
` Abdominal Pain
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` 1.2
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` 1.4
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` 1.0
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` Fatigue
` * Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in
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` subjects with baseline hypertension.
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` Other adverse reactions reported by less than 1% of patients treated with MYRBETRIQ® in Studies 1, 2, or 3
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` included:
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` Cardiac disorders: palpitations, blood pressure increased [see Clinical Pharmacology (12.2)]
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` Eye disorders: glaucoma [see Clinical Pharmacology (12.2)]
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` Gastrointestinal disorders: dyspepsia, gastritis, abdominal distension
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` Infections and Infestations: sinusitis, rhinitis
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` Investigations: GGT increased, AST increased, ALT increased, LDH increased
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` Renal and urinary disorders: nephrolithiasis, bladder pain
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` Reproductive system and breast disorders: vulvovaginal pruritus, vaginal infection
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` Skin and subcutaneous tissue disorders: urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema
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` Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients
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`treated with MYRBETRIQ® 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions
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`(> 3% of MYRBETRIQ® patients) were hypertension, urinary tract infection, headache, and nasopharyngitis.
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`Reference ID: 4131687
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`Page 4 of 24
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`Table 2: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Reported by
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`Greater Than 2% of Patients Treated with MYRBETRIQ® 50 mg Once Daily in Study 4
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` Number of Patients
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` Hypertension
` Urinary Tract Infection
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` Headache
` Nasopharyngitis
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` Back Pain
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` Constipation
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` Dry Mouth
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` Dizziness
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` Sinusitis
` Influenza
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` Arthralgia
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` Cystitis
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` MYRBETRIQ® 50 mg
`
` (%)
`
` 812
`
` 9.2
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` 5.9
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` 4.1
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` 3.9
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` 2.8
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` 2.8
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` 2.8
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` 2.7
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` 2.7
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` 2.6
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` 2.1
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` 2.1
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`
` Active Control
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` (%)
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` 812
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` 9.6
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` 6.4
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` 2.5
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` 3.1
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` 1.6
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` 2.7
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` 8.6
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` 2.6
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` 1.5
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` 3.4
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` 2.0
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` 2.3
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` In Study 4, in patients treated with MYRBETRIQ® 50 mg once daily, adverse reactions leading to discontinuation
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` 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
`
`
`
`
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` cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than
`
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`10-fold in 2 patients (0.3%) taking MYRBETRIQ® 50 mg, and these markers subsequently returned to baseline while
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`both patients continued MYRBETRIQ®.
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`
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`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
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`2 patients treated with MYRBETRIQ® 100 mg included breast cancer, lung neoplasm malignant and prostate cancer.
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`
`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).
`
`
`
`
`
`
`
`
`
`
` 6.2 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 [see Warnings and Precautions (5.3)]; pruritus
`
`
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`
`
`
`
`
`
` Urologic: urinary retention [see Warnings and Precautions (5.2)]
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`
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`
`
`Reference ID: 4131687
`
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`
`Page 5 of 24
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`

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` 7 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) [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:
`
`
`
` 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)].
`
`
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`
`
` 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)].
`
`
`
`
`
`
`
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`
`
` 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)].
`
`
`
`
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
`
` 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
`
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`
`
`
`MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human
`
`
`
`Page 6 of 24
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`Reference ID: 4131687
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`

`

`
`
`
`
`
`
` 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.
`
`
`
` 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.
`
`
`
`
`
` 8.4 Pediatric Use
`
`
`
` The safety and effectiveness of MYRBETRIQ® in pediatric patients have not been established.
`
`
`
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`
`
`
`
`
` 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.
`
`
`
` 8.6 Renal Impairment
`
`
`
`MYRBETRIQ® has not been studied in patients with end stage renal disease (CLcr < 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
`
`
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`
`
`
` populations.
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`
`Reference ID: 4131687
`
`
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`Page 7 of 24
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`

`

`
`In patients with severe renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m2), the daily dose
`
`
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`
`
`
`
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`
`
`of MYRBETRIQ® should not exceed 25 mg. No dose adjustment is necessary in patients with mild or moderate renal
`
`
`
`
`
`
`
`
`
`impairment (CLcr 30 to 89 mL/min or eGFR 30 to 89 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)].
`
`
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`
`
`
` 8.7 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) [see
`
`
`
`
`
`Clinical Pharmacology (12.3)].
`
`
`
`
` 8.8 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.
`
`
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`
`
`
`
`
`
`
` 10 OVERDOSAGE
`
`
`
` 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).
`
`
`
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`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
` 11 DESCRIPTION
`
` 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:
`
`O
`
`N
`H
`
`S
`
`N
`
`NH2
`
`
`
`NH
`
`
`
`H
`
`OH
`
`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).
`
`
`
` 12 CLINICAL PHARMACOLOGY
`
`
`
` 12.1 Mechanism of Action
`
`
`
`
` Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory
`
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`
`
`
`
` experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage
`
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`
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`
`
` phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Although
`
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`Page 8 of 24
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`Reference ID: 4131687
`
`

`

`
`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.
`
`
`
`
`
`
`
` 12.2 Pharmacodynamics
`
`
` 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 [see Warnings and Precautions (5.2)].
`
`
`
`
`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
`
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`
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`
`
`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
`
`
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`
`
`
`
`
`
`
`(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).
`
`
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`
`
`In this thorough QT study, MYRBETRIQ® increased heart rate on ECG in a dose d