Myrbetriq

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Oral extended release tablets: 25 mg and 50 mg

Tablets should be stored at room temperature between 15 C to 30 C (59 F to 86 F).

Instructions

May take with or without food

Swallow whole with water, do not chew, divide, or crush tablet

Myrbetriq is a prescription medication used to treat adults with the symptoms of overactive bladder.

Symptoms of overactive bladder include:

• urinary frequency (urinating often)
• urinary urgency (a strong need to urinate right away)
• urinary incontinence (leakage)

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Myrbetriq may cause serious side effects including:

• increased blood pressure. Myrbetriq may cause your blood pressure to increase or make your blood pressure worse if you have a history of high blood pressure. It is recommended that your doctor check your blood pressure while you are taking Myrbetriq.
• inability to empty your bladder (urinary retention). Myrbetriq may increase your chances of not being able to empty your bladder if you have bladder outlet obstruction or if you are taking other medicines to treat overactive bladder. Tell your doctor right away if you are unable to empty your bladder.

The most common side effects of Myrbetriq include:

• increased blood pressure
• common cold symptoms (nasopharyngitis)
• urinary tract infection
• headache

Tell your doctor if you have any side effect that bothers you or that does not go away or if you have hives, skin rash or itching while taking Myrbetriq.

These are not all the possible side effects of Myrbetriq. For more information, ask your doctor or pharmacist.

Tell your doctor if you are breastfeeding or plan to breastfeed. 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, talk to your doctor about whether you should discontinue nursing or discontinue taking this medicine.

• Store Myrbetriq at room temperature, between 59˚F to 86˚F (15˚C to 30˚C). Keep the bottle closed.
• Safely throw away medicine that is out of date or no longer needed.
• Keep Myrbetriq and all medicines out of the reach of children.

You should not use mirabegron if you are allergic to it, or if you have:

• severe kidney disease;

• severe liver disease; or

• severe uncontrolled hypertension (high blood pressure).

To make sure mirabegron is safe for you, tell your doctor if you have:

• kidney disease;

• liver disease;

• high blood pressure;

• urination problems; or

• trouble emptying your bladder (very little urine or a weak stream of urine).

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether mirabegron passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Mirabegron is not approved for use by anyone younger than 18 years old.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Nose and throat irritation.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Pregnancy

Pregnancy Category C
There are no adequate and well-controlled studies using Myrbetriq® in pregnant women. Myrbetriq® should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during Myrbetriq® treatment are encouraged to contact their physician.

Risk Summary
Based on animal data, mirabegron is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background risk. Reversible adverse developmental findings consisting of delayed ossification and wavy ribs in rats and decreased fetal body weights in rabbits occurred at exposures greater than or equal to 22 and 14 times, respectively, the maximum recommended human dose (MRHD). At maternally toxic exposures decreased fetal weights were observed in rats and rabbits, and fetal death, dilated aorta, and cardiomegaly were reported in rabbits.

Animal Data
In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of mirabegron at 0, 10, 30, 100, or 300 mg/kg from implantation to closure of the fetal hard palate (7th to 17th day of gestation). Maternal systemic exposures were approximately 0, 1, 6, 22, or 96 times greater than exposures in women treated at the MRHD of 50 mg based on AUC. No embryo/fetal toxicities were observed in rats exposed up to 6 times the human systemic exposure at the MRHD of 50 mg. At systemic exposures equal to or greater than 22 times the human systemic exposure at the MRHD, delayed ossification and wavy ribs were observed in fetuses at an increased incidence. These findings were reversible.

In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of mirabegron at 0, 3, 10, or 30 mg/kg from implantation to closure of the fetal hard palate (6th to 20th day of gestation). Maternal systemic exposures were 0, 1, 14, or 36 times that in women treated at the MRHD of 50 mg based on AUC. The embryo/fetal No Adverse Effect Level (NOAEL) was similar to the exposure in women at the MRHD and was established in this species based on reduced fetal body weight observed at systemic exposures that were 14-fold higher than the human systemic exposure at MRHD. At higher doses, where systemic exposures were 36-fold higher than the human exposure at MRHD, maternal body weight gain and food consumption were reduced, one of 17 pregnant rabbits died, the incidence of fetal death increased, and fetal findings of dilated aorta and cardiomegaly were reported.

The effects of mirabegron on prenatal and postnatal development was assessed in pregnant rats dosed at 0, 10, 30, or 100 mg/kg/day from the seventh day of gestation until 20 days after birth. Maternal systemic exposures were 0, 1, 6, and 22 times the exposure in women at the MRHD based on AUC. Rat pups exposed to mirabegron in utero and through 21 days of lactation had no discernable adverse effects at maternal systemic exposures 6 times the MRHD. A slight but statistically significant decrease in the survival of pups was observed 4 days after birth at exposures 22 times the MRHD (92.7% survival) compared to the control group (98.8%), however, there was no effect on survival of pups 21 days after birth. Absolute body weight of pups was not affected on the day of birth. However, at the 30 mg/kg dose (22-fold higher systemic exposure than humans at MRHD) body weight gain of pups was reduced 5% to 13% from postnatal day 4 to 7 but not throughout the remainder of the lactation period. In utero and lactational exposure did not affect behavior or fertility of offspring at exposures up to 22 times the MRHD.

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 [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.

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 populations.

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 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)].

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)].

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.

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.

Myrbetriq® was evaluated in three, 12-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials in patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (Studies 1, 2, and 3). Entry criteria required that patients had symptoms of overactive bladder for at least 3 months duration, at least 8 micturitions per day, and at least 3 episodes of urgency with or without incontinence over a 3 day period. The majority of patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 – 95 years). The population included both naïve patients who had not received prior antimuscarinic pharmacotherapy for overactive bladder (48%) and those who had received prior antimuscarinic pharmacotherapy for OAB (52%).

In Study 1, patients were randomized to placebo, Myrbetriq® 50 mg, Myrbetriq® 100 mg, or an active control once daily. In Study 2, patients were randomized to placebo, Myrbetriq® 50 mg or Myrbetriq® 100 mg once daily. In Study 3, patients were randomized to placebo, Myrbetriq® 25 mg or Myrbetriq® 50 mg once daily.

The co-primary efficacy endpoints in all 3 trials were (1) change from baseline to end of treatment (Week 12) in mean number of incontinence episodes per 24 hours and (2) change from baseline to end of treatment (Week 12) in mean number of micturitions per 24 hours, based on a 3-day micturition diary. An important secondary endpoint was the change from baseline to end of treatment (Week 12) in mean volume voided per micturition.

Results for the co-primary endpoints and mean volume voided per micturition from Studies 1, 2, and 3 are shown in Table 3.

Myrbetriq® 25 mg was effective in treating the symptoms of OAB within 8 weeks, and Myrbetriq® 50 mg was effective in treating the symptoms of OAB within 4 weeks. Efficacy of both 25 mg and 50 mg doses of Myrbetriq® was maintained through the 12-week treatment period.

Figures 3 through 8 show the co-primary endpoints, mean change from baseline (BL) over time in number of incontinence episodes per 24 hours and mean change from baseline over time in number of micturitions per 24 hours, in Studies 1, 2 and 3.

Figure 3: Mean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours – Study 1

Figure 4: Mean (SE) Change from Baseline in Mean Number of Micturitions per 24 Hours – Study 1

Figure 5: Mean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours – Study 2

Figure 6: Mean (SE) Change from Baseline in Mean Number of Micturitions per 24 Hours – Study 2

Figure 7: Mean (SE) Change from Baseline in Mean Number of Incontinence Episodes per 24 Hours – Study 3

Figure 8: Mean (SE) Change from Baseline in Mean Number of Micturitions per 24 Hours – Study 3

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®.

Rx Only

PRODUCT OF JAPAN OR IRELAND – See bottle label or blister package for origin

Marketed and Distributed by:
Astellas Pharma US, Inc.
Northbrook, Illinois 60062

Myrbetriq® is a registered trademark of Astellas Pharma Inc. All other trademarks or registered trademarks are the property of their respective owners.

© 2012 – 2017 Astellas Pharma US, Inc.

Revised: July 2017

17A004-MIR

Myrbetriq (mirabegron) reduces muscle spasms of the bladder and urinary tract.

Myrbetriq is used to treat overactive bladder with symptoms of frequent or urgent urination and urinary incontinence.

Myrbetriq may also be used for purposes not listed in this medication guide.

You should not use Myrbetriq if you are allergic to mirabegron, or if you have:

• severe kidney disease;

• severe liver disease; or

• severe uncontrolled hypertension (high blood pressure).

To make sure this medicine is safe for you, tell your doctor if you have:

• kidney disease;

• liver disease;

• high blood pressure;

• urination problems; or

• trouble emptying your bladder (very little urine or a weak stream of urine).

It is not known whether Myrbetriq will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether mirabegron passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Myrbetriq is not approved for use by anyone younger than 18 years old.

Myrbetriq is usually taken once per day. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take Myrbetriq with or without food.

Take this medicine with a full glass of water.

Do not crush, chew, or break an extended-release tablet. Swallow it whole.

Your blood pressure will need to be checked often.

It may take up to 8 weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve.

Store at room temperature away from moisture and heat.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.