Myrbetriq

MYRBETRIQ- mirabegron tablet, film coated, extended release
Cardinal Health

1 INDICATIONS AND USAGE

1.1 Monotherapy

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.

1.2 Combination with Muscarinic Antagonist

MYRBETRIQ in combination with the muscarinic antagonist solifenacin succinate is indicated for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

Monotherapy
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 (14.1)].

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

Combination with Muscarinic Antagonist Solifenacin Succinate The recommended starting doses for combination treatment are MYRBETRIQ 25 mg once daily and solifenacin succinate 5 mg once daily. Based on individual patient efficacy and tolerability, the MYRBETRIQ dose may be increased to 50 mg once daily after 4 to 8 weeks [see Clinical Studies ( 14.2 )].

MYRBETRIQ and solifenacin succinate can be taken together with or without food.

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)].

3 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 (Astellas logo) and “325”

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

4 CONTRAINDICATIONS

Do not use MYRBETRIQ in patients who have known hypersensitivity reactions to mirabegron or any component of the tablet [see Adverse Reactions (6.1, 6.2)].

5 WARNINGS AND PRECAUTIONS

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, MYRBETRIQ taken as monotherapy or in combination with solifenacin succinate 5 mg, the mean increase in systolic and diastolic blood pressure at the maximum recommended MYRBETRIQ dose of 50 mg was approximately 0.5 to 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 Muscarinic Antagonist Medications for OAB

In patients taking MYRBETRIQ, urinary retention has been reported to occur in patients with bladder outlet obstruction (BOO) and in patients taking muscarinic antagonist medications for the treatment of OAB. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in MYRBETRIQ patients; however, MYRBETRIQ should still be administered with caution to patients with clinically significant BOO. For example, monitor these patients for signs and symptoms of urinary retention. MYRBETRIQ should also be administered with caution to patients taking muscarinic antagonist medications for the treatment of OAB, including solifenacin succinate [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)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling.

Hypertension [see Warnings and Precautions (5.1)]
Urinary retention [see Warnings and Precautions (5.2)]
Angioedema [see Warnings and Precautions (5.3)]

6.1 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.

Monotherapy

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 [see Clinical Studies (14)]. 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 of Patients Treated with MYRBETRIQ 25 mg or 50 mg Once Daily in Studies 1, 2, and 3
*
Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline hypertension.

Placebo

(%)

MYRBETRIQ 25 mg

(%)

MYRBETRIQ 50 mg

(%)

Number of Patients

1380

432

1375

Hypertension *

7.6

11.3

7.5

Nasopharyngitis

2.5

3.5

3.9

Urinary Tract Infection

1.8

4.2

2.9

Headache

3.0

2.1

3.2

Constipation

1.4

1.6

1.6

Upper Respiratory Tract Infection

1.7

2.1

1.5

Arthralgia

1.1

1.6

1.3

Diarrhea

1.3

1.2

1.5

Tachycardia

0.6

1.6

1.2

Abdominal Pain

0.7

1.4

0.6

Fatigue

1.0

1.4

1.2

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 [see Clinical Pharmacology (12.2)]
Eye disorders: glaucoma [see Clinical Pharmacology (12.2)]
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 infectionSkin 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

MYRBETRIQ 50 mg

(%)

Active Control

(%)

Number of Patients

812

812

Hypertension

9.2

9.6

Urinary Tract Infection

5.9

6.4

Headache

4.1

2.5

Nasopharyngitis

3.9

3.1

Back Pain

2.8

1.6

Constipation

2.8

2.7

Dry Mouth

2.8

8.6

Dizziness

2.7

2.6

Sinusitis

2.7

1.5

Influenza

2.6

3.4

Arthralgia

2.1

2.0

Cystitis

2.1

2.3

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. A causal relationship between mirabegron and these reported neoplasms has not been established.

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).

Combination Therapy of MYRBETRIQ with Solifenacin Succinate

In three, 12-week, double-blind, randomized, active-controlled safety and efficacy studies in patients with overactive bladder (Studies 5, 6, and 7), combination treatment of MYRBETRIQ and solifenacin succinate was evaluated for safety in 6818 patients. Studies 5 and 6 also included a placebo control. For the combined Studies 5, 6, and 7, 997 patients received combination treatment with MYRBETRIQ 25 mg and solifenacin succinate 5 mg, and 1706 patients received combination treatment with MYRBETRIQ 50 mg and solifenacin succinate 5 mg. In these studies, the majority of the patients were Caucasian (88%), and female (77%) with a mean age of 57 years (range 18 to 89 years).

MYRBETRIQ 50 mg and solifenacin succinate 5 mg co-administration was also evaluated for safety in 1814 patients in a 52-week, double-blind, randomized, active-controlled study in patients with overactive bladder (Study 8).

In Studies 5, 6, and 7, the most commonly reported adverse reactions (greater than 2% of patients treated with combination therapy of MYRBETRIQ and solifenacin succinate 5 mg, and greater than placebo and/or MYRBETRIQ or solifenacin succinate comparator at the same dose as in the combination treatment) were dry mouth, urinary tract infection, constipation, and tachycardia. The most frequent adverse reactions (≥ 0.2%) leading to discontinuation in the co-administration trials were dry mouth and urinary retention. No serious adverse reactions were reported by more than 2 patients.

Table 3 lists adverse reactions, derived from all adverse events that were reported in Studies 5, 6, and 7 in 1% or more of patients treated with MYRBETRIQ 25 mg or 50 mg co-administered with solifenacin succinate 5 mg and at an incidence greater than placebo and mirabegron or solifenacin succinate comparator at the same dose as in the combination treatment when administered once daily for up to 12 weeks.

Table 3: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo and Comparator (at same dose level) Rate and Reported by 1% or More of Patients Treated With Combination Therapy in Studies 5, 6, and 7*
*
Adverse reactions occurring in patients treated with co-administration of MYRBETRIQ and solifenacin succinate in Study 7, that included a 4-week initial treatment period with MYRBETRIQ 25 mg + solifenacin succinate 5 mg, are included in the MYRBETRIQ 50 mg + solifenacin succinate 5 mg group.
Includes any recorded treatment-emergent UTI.

Placebo

(%)

MYRBETRIQ

25 mg

(%)

MYRBETRIQ

50 mg

(%)

Solifenacin succinate

5 mg

(%)

MYRBETRIQ

25 mg + Solifenacin succinate 5 mg

(%)

MYRBETRIQ

50 mg + Solifenacin succinate 5 mg *

(%)

Number of Patients

510

500

500

1288

997

1706

Dry Mouth

2.2

3.8

3.6

6.5

9.3

7.2

Urinary Tract Infections

5.3

4.0

4.2

3.6

7.0

4.0

Constipation

1.2

1.2

2.8

2.4

4.2

3.9

Tachycardia

0.8

1.6

1.6

0.7

2.2

0.9

Dyspepsia

0.6

0.4

0.2

0.7

1.1

1.3

Dizziness

0.4

0.8

1.2

1.2

1.3

0.4

Vision Blurred

0.4

0.2

0.2

0.9

0.7

1.1

Arthralgia

0.8

0.8

0.8

0.8

0.5

1.1

In Study 8, the most common adverse reactions (more than 2% of patients treated with co-administration of MYRBETRIQ and solifenacin succinate and exceeding comparator rate) were UTI, dry mouth, constipation, and headache. The most frequent adverse reactions leading to discontinuation in the trial were constipation (0.2%), urinary retention (0.2%), urinary hesitation (0.2%), and vision blurred (0.2%).

In Study 8, serious adverse events of neoplasm were reported by 0.7%, 0.3%, and 0% of patients who received co-administration of MYRBETRIQ 50 mg and solifenacin succinate 5 mg, MYRBETRIQ 50 mg monotherapy, and solifenacin succinate 5 mg monotherapy, respectively. Neoplasms reported by more than 1 patient who received co-administration with MYRBETRIQ 50 mg and solifenacin succinate 5 mg included basal cell carcinoma (n=3), breast cancer (n=2), melanoma (n=2), and squamous cell carcinoma (n=2). A causal relationship between the co-administration of mirabegron and solifenacin succinate and these reported neoplasms has not been established.

Table 4 lists adverse reactions, derived from all adverse events that were reported at an incidence greater than comparator and in 2% or more of patients treated with MYRBETRIQ 50 mg co-administered with solifenacin succinate 5 mg once daily for up to 52 weeks in Study 8.

Table 4: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Comparator Rate and Reported by 2% or More of Patients Treated With Combination Therapy in Study 8
*
Includes any recorded treatment-emergent UTI.

MYRBETRIQ

50 mg

(%)

Solifenacin succinate

5 mg

(%)

MYRBETRIQ

50 mg + Solifenacin succinate

5 mg

(%)

Number of Patients

305

303

1206

Urinary Tract Infections *

6.2

5.9

8.4

Dry Mouth

3.9

5.9

6.1

Constipation

1.0

2.3

3.3

Headache

1.6

1.7

2.9

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