Mirabegron

Each tablet contains 25 mg and 50 mg of Mirabegron.

Excipients/Inactive Ingredients: Core Tablet: Macrogols, hydroxypropylcellulose, butylhydroxytoluene and magnesium stearate.

Film-Coating (25 mg):

Film-Coating (50 mg): Hypromellose, macrogol, iron oxide yellow.

Mirabegron is a beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. (Overactive bladder;)

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

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

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

Dosing Information

The recommended starting dose of Mirabegron® is 25 mg once daily with or without food. Mirabegron® 25 mg is effective within 8 weeks. Based on individual patient efficacy and tolerability the dose may be increased to 50 mg once daily.

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

Dose Adjustments In Specific Populations

The daily dose of Mirabegron® should not exceed 25 mg once daily in the following populations:

• Patients with serate vere renal impairment (CLcr 15 to 29 mL/min or eGFR 15 to 29 mL/min/1.73 m²).
• Patients with mode

hepatic impairment (Child-Pugh Class B).

Mirabegron® is not recommended for use in patients with end stage renal disease (ESRD), or in patients with severe hepatic impairment (Child-Pugh Class C).

How supplied

Dosage Forms And Strengths

Mirabegron® 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

Mirabegron® 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}.

Marketed and Distributed by: Astellas Pharma US, Inc., Northbrook, Illinois 60062. Revised: Dec 2015

See also:
What is the most important information I should know about Mirabegron?

You should not use Mirabegron if you are allergic to it, or if you have severe kidney disease, severe liver disease, or untreated or uncontrolled hypertension (high blood pressure).

Before you take Mirabegron, tell your doctor if you have kidney or liver disease, high blood pressure, glaucoma, an enlarged prostate or trouble urinating, or a blockage in your digestive tract (stomach or intestines).

Your blood pressure will need to be checked often. Visit your doctor regularly.

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 after 8 weeks of treatment.

Serious side effects may include fast or pounding heartbeats, pain or burning when you urinate, or increased blood pressure (severe headache, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath, uneven heartbeats, seizure).

Tell your doctor about all other medicines you use, especially blood pressure medication, an antidepressant or medicine to treat a psychiatric disorder, cancer medicine, cough medicine, heart rhythm medication, prescription pain medicine, or other drugs to treat overactive bladder.

Use Mirabegron as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Mirabegron. Talk to your pharmacist if you have questions about this information.
• Take Mirabegron by mouth with or without food.
• Swallow Mirabegron whole with water. Do not break, crush, or chew before swallowing.
• If you miss a dose of Mirabegron, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses on the same day.

Ask your health care provider any questions you may have about how to use Mirabegron.

Use: Labeled Indications

Overactive bladder: Treatment of overactive bladder (OAB) with symptoms of urinary frequency, urgency, or urge urinary incontinence as monotherapy or in combination with solifenacin

See also:
What other drugs will affect Mirabegron?

In vitro Data: Mirabegron is transported and metabolised through multiple pathways. Mirabegron is a substrate for cytochrome P450 (CYP) 3A4, CYP2D6, butyrylcholinesterase, uridine diphospho-glucuronosyl transferases (UGT), the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2 and OCT3. Studies of Mirabegron using human liver microsomes and recombinant human CYP enzymes showed that Mirabegron is a moderate and time-dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A. Mirabegron inhibited P-gp-mediated drug transport at high concentrations.

In vivo Data: CYP2D6 Polymorphism: CYP2D6 genetic polymorphism has minimal impact on the mean plasma exposure to Mirabegron. Interaction of Mirabegron with a known CYP2D6 inhibitor is not expected and was not studied. No dose adjustment is needed for Mirabegron when administered with CYP2D6 inhibitors or in patients who are CYP2D6 poor metabolisers.

Drug-Drug Interactions: The effect of co-administered medicinal products on the pharmacokinetics of Mirabegron and the effect of Mirabegron on the pharmacokinetics of other medicinal products was studied in single- and multiple-dose studies. Most drug-drug interactions were studied using a dose of Mirabegron 100 mg given as oral controlled absorption system (OCAS) tablets. Interaction studies of Mirabegron with metoprolol and with metformin used Mirabegron immediate-release (IR) 160 mg.

Clinically relevant drug interactions between Mirabegron and medicinal products that inhibit, induce or are a substrate for one of the CYP isozymes or transporters are not expected, except for the inhibitory effect of Mirabegron on the metabolism of CYP2D6 substrates.

Effect of Enzyme Inhibitors: Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole in healthy volunteers. No dose adjustment is needed when Mirabegron is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment (GFR 30 to 89 mL/min/1.73 m²) or mild hepatic impairment (Child-Pugh Class A), concomitantly receiving strong CYP3A inhibitors eg, itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily with or without food. Mirabegron is not recommended in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m²) or patients with moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors.

Effect of Enzyme Inducers: Substances that are inducers of CYP3A or P-gp decrease the plasma concentrations of Mirabegron. No dose adjustment is needed for Mirabegron when administered with therapeutic doses of rifampicin, or other CYP3A or P-gp inducers.

Effect of Mirabegron on CYP2D6 Substrates: In healthy volunteers, the inhibitory potency of Mirabegron towards CYP2D6 is moderate and the CYP2D6 activity recovers within 15 days after discontinuation of Mirabegron. Multiple once daily dosing of Mirabegron IR resulted in a 90% increase in C_max and a 229% increase in AUC of a single dose of metoprolol. Multiple once daily dosing of Mirabegron resulted in a 79% increase in C_max and a 241% increase in AUC of a single dose of desipramine. Caution is advised if Mirabegron is co-administered with medicinal products with a narrow therapeutic index and significantly metabolised by CYP2D6 such as thioridazine, type 1C antiarrhythmics (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if Mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated.

Effect of Mirabegron on Transporters: Mirabegron is a weak inhibitor of P-gp. Mirabegron increased C_max and AUC by 29% and 27%, respectively, of the P-gp substrate digoxin in healthy volunteers. For patients who are initiating a combination of Mirabegron and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. The potential for inhibition of P-gp by Mirabegron should be considered when Mirabegron is combined with sensitive P-gp substrates e.g. dabigatran.

Other Interactions: No clinically relevant interactions have been observed when Mirabegron was co-administered with therapeutic doses of solifenacin, tamsulosin, warfarin, metformin or a combined oral contraceptive medicinal product containing ethinylestradiol and levonorgestrel. Dose-adjustment is not recommended.

Increases in Mirabegron exposure due to drug-drug interactions may be associated with increases in pulse rate.

See also:
What are the possible side effects of Mirabegron?

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), Mirabegron® 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 Mirabegron® 25 mg, 1375 received Mirabegron® 50 mg, and 929 received Mirabegron® 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).

Mirabegron® was also evaluated for safety in 1632 patients who received Mirabegron® 50 mg once daily (n=812 patients) or Mirabegron® 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 Mirabegron® in a previous 12-week study. In Study 4, 1385 patients received Mirabegron® continuously for at least 6 months, 1311 patients received Mirabegron® for at least 9 months, and 564 patients received Mirabegron® 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 Mirabegron® 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of Mirabegron® patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection and headache.

Table 1: Percentages of Patients with Advers e Reactions, Derived from All Advers e Events, Exceeding Placebo Rate and Reported by 1% or More Patients Treated with Mirabegron® 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 Mirabegron® 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, lipedema

Table 2 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with Mirabegron® 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions ( > 3% of Mirabegron® 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 Mirabegron® 50 mg Once Daily in Study 4

In Study 4, in patients treated with Mirabegron® 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 Mirabegron® 50 mg, and these markers subsequently returned to baseline while both patients continued Mirabegron®.

In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with Mirabegron® 50 mg, Mirabegron® 100 mg and active control once daily, respectively. Neoplasms reported by 2 patients treated with Mirabegron® 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 Mirabegron® 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

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

Urologic: urinary retention