Betmiga (Tablets) Instructions for Use

Marketing Authorization Holder

Astellas Pharma Europe B.V. (Netherlands)

Manufactured By

Avara Pharmaceutical Technologies, Inc. (USA)

Packaging and Quality Control Release

ASTELLAS PHARMA EUROPE, B.V. (Netherlands)

ATC Code

G04BD12 (Mirabegron)

Active Substance

Mirabegron (Rec.INN registered by WHO)

Dosage Forms

	Betmiga	Extended-release film-coated tablets, 25 mg: 10 or 30 pcs.
		Extended-release film-coated tablets, 50 mg: 10 or 30 pcs.

Dosage Form, Packaging, and Composition

Extended-release film-coated tablets brown, oval, biconvex, engraved with “325” and a graphical representation of the “Astellas” logo on one side; core white or almost white.

Excipients: macrogol 2000000 – 70 mg, macrogol 8000 – 144.6 mg, hypromellose – 7.5 mg, butylated hydroxytoluene – 0.4 mg, magnesium stearate – 2.5 mg.

Film coating composition: opadry 03F43159 (hypromellose 2910 6 mPa·s – 69.536%, macrogol 8000 – 13.024%, yellow iron oxide – 14.44%, red iron oxide – 3%) – 7.5 mg.

10 pcs. – blisters (1) – cardboard packs with first opening control.
10 pcs. – blisters (3) – cardboard packs with first opening control.

Extended-release film-coated tablets yellow, oval, biconvex, engraved with “355” and a graphical representation of the “Astellas” logo on one side; core white or almost white.

Excipients: macrogol 2000000 – 70 mg, macrogol 8000 – 119.6 mg, hypromellose – 7.5 mg, butylated hydroxytoluene – 0.4 mg, magnesium stearate – 2.5 mg.

Film coating composition: opadry 03F42192 (hypromellose 2910 6 mPa·s – 69.536%, macrogol 8000 – 13.024%, yellow iron oxide – 17.44%) – 7.5 mg.

10 pcs. – blisters (1) – cardboard packs with first opening control.
10 pcs. – blisters (3) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Selective beta₃-adrenergic receptor agonist. A drug that reduces the tone of the smooth muscles of the urinary tract

Pharmacotherapeutic Group

Other drugs for the treatment of urological diseases

Pharmacological Action

Selective beta₃-adrenergic receptor agonist. Studies have demonstrated that mirabegron induces relaxation of the detrusor smooth muscle in rats and in isolated human tissue preparations, as well as increases cAMP concentrations in rat bladder tissue.

Thus, mirabegron improves bladder storage function by stimulating beta₃-adrenergic receptors located in the bladder wall.

Studies have demonstrated the efficacy of mirabegron both in patients previously treated with antimuscarinics for overactive bladder (OAB) and in patients without a history of prior antimuscarinic therapy.

Mirabegron was also effective in patients with OAB who discontinued antimuscarinic treatment due to lack of efficacy.

A 12-week study in men with lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) demonstrated the safety and good tolerability of mirabegron at doses of 50 mg and 100 mg once daily, as well as the absence of an effect of mirabegron on urodynamic parameters.

Changes in heart rate and blood pressure during treatment are reversible and resolve after discontinuation.

Pharmacokinetics

After oral administration, mirabegron is absorbed into the bloodstream and reaches C_max in plasma between three and four hours after administration. Studies have revealed an increase in absolute bioavailability from 29% to 35% after increasing the dose from 25 mg to 50 mg. Meanwhile, the mean C_max and AUC values increased more than proportionally to the dose. C_ss is achieved after 7 days of once-daily mirabegron administration. After multiple once-daily administrations, the C_ss of mirabegron in plasma is approximately 2 times higher than after a single dose.

Mirabegron is extensively distributed in the body. The V_d at steady state (V_ss) is approximately 1670 L. Mirabegron is bound (approximately 71%) to plasma proteins and also exhibits moderate affinity for albumin and alpha-1 acid glycoprotein. Mirabegron distributes into erythrocytes. Concentrations of ¹⁴C-mirabegron in erythrocytes were 2 times higher than in plasma (as shown by in vitro studies).

There are multiple pathways for the metabolism of mirabegron in the body, including dealkylation, oxidation, (direct) glucuronidation, and amide hydrolysis. After a single administration of ¹⁴C-mirabegron, the main circulating component is mirabegron. Two major metabolites of mirabegron have been identified in human plasma: both are glucuronides (Phase II metabolites) and account for 16% and 11% of the total drug-related exposure, respectively. These metabolites do not possess pharmacological activity.

Although CYP2D6 and CYP3A4 isoenzymes are involved in the oxidative pathway of mirabegron metabolism in vitro, their role in overall elimination in vivo is minor.

Total plasma clearance is approximately 57 L/h. The terminal T_1/2 is approximately 50 h. Renal clearance is approximately 13 L/h, which corresponds to nearly 25% of the total clearance. The main mechanisms of renal excretion are active tubular secretion and glomerular filtration. The amount of unchanged mirabegron excreted in urine is dose-dependent and ranges from 6.0% after a daily dose of 25 mg to 12.2% after a daily dose of 100 mg. After administration of 160 mg of ¹⁴C-mirabegron to healthy volunteers, approximately 55% of the radioactivity was recovered in urine and 34% in feces. The fraction of unchanged mirabegron accounted for approximately 45% of the total radiolabeled drug in urine, indicating the presence of metabolites. The majority of the radiolabeled drug in feces was unchanged mirabegron.

Indications

Overactive bladder (OAB) with symptoms of urinary incontinence, frequent urination, and urinary urgency.

ICD codes

Dosage Regimen

For oral administration.

A single dose is 25-50 mg, depending on renal function and concomitant therapy. Frequency of administration is once daily.

Patients with renal and hepatic impairment

The following table shows the recommended daily doses for patients suffering from renal or hepatic impairment, with or without CYP3A isoenzyme inhibitors.

*Mild stage: eGFR 60 – 89 ml/min/1.73 m²; Moderate stage: eGFR 30 – 59 ml/min/1.73 m²; Severe stage: eGFR 15 – 29 ml/min/1.73 m²

** Mild stage: Child-Pugh class A; Moderate stage: Child-Pugh class B

Adverse Reactions

Infections and infestations: common – urinary tract infection; uncommon – vaginal infection, cystitis.

Eye disorders rare – eyelid edema.

Cardiac disorders: common – tachycardia; uncommon – palpitations, atrial fibrillation, increased blood pressure

Gastrointestinal disorders: common – nausea; uncommon – dyspepsia, gastritis, increased GGT, AST, ALT; rare – lip edema.

Skin and subcutaneous tissue disorders: uncommon – urticaria, rash, maculopapular rash, papular rash, pruritus; rare – leukocytoclastic vasculitis, purpura, angioedema.

Musculoskeletal and connective tissue disorders: uncommon – joint swelling.

Reproductive system and breast disorders: uncommon – vulvovaginal pruritus

*Identified during post-marketing use

Contraindications

End-stage renal disease (eGFR<15 ml/min/1.73 m² or patients requiring hemodialysis); severe renal impairment (eGFR 15-29 ml/min/1.73 m²) with concomitant use of strong CYP3A isoenzyme inhibitors; severe hepatic impairment (Child-Pugh class C); severe uncontrolled hypertension, defined as systolic BP ≥180 mmHg and/or diastolic BP ≥110 mmHg; moderate hepatic impairment (Child-Pugh class B) with concomitant use of strong CYP3A isoenzyme inhibitors; pediatric age (lack of efficacy and safety data); pregnancy and breastfeeding; hypersensitivity to the active substance.

Use in Pregnancy and Lactation

Pregnancy

The amount of data on the use of mirabegron in pregnant women is limited. Animal studies have shown reproductive toxicity. Mirabegron is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breastfeeding period

In rodents, mirabegron is excreted in breast milk, therefore, there is a risk of the drug passing into breast milk in humans. There are no studies on the effects of mirabegron on breast milk production, excretion of mirabegron in breast milk, or effects on the infant. Mirabegron should not be used by women during breastfeeding.

Fertility

Animal studies did not reveal any effect of mirabegron on fertility at non-lethal doses.

It is not established whether mirabegron affects human fertility.

Pediatric Use

The use of the drug in children is prohibited due to lack of efficacy and safety data.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Mirabegron at therapeutic doses did not demonstrate clinically significant QT interval prolongation in conducted studies. However, since patients taking drugs that may provoke QT interval prolongation did not participate in these mirabegron studies, the effect on such categories of patients is unknown. This category of patients should take mirabegron with caution.

Mirabegron should be prescribed with caution in combination with drugs that have a narrow therapeutic index and drugs that are extensively metabolized by the CYP2D6 isoenzyme, for example, thioridazine, Class 1C antiarrhythmic drugs (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Mirabegron should also be taken with caution when co-administered with drugs that are metabolized by the CYP2D6 isoenzyme and whose dose requires individual determination.

During post-marketing surveillance of mirabegron use, cases of urinary retention have been noted in patients with bladder outlet obstruction (BOO) and in patients already taking anticholinergics for OAB. A controlled clinical safety study in patients with BOO did not find an increase in urinary retention in patients receiving mirabegron; nevertheless, mirabegron should be prescribed with caution for patients with clinically significant BOO.

Mirabegron should also be used with caution in patients already taking anticholinergics for OAB.

Mirabegron may increase blood pressure. It is recommended to measure blood pressure before starting treatment and periodically during treatment with mirabegron, especially in patients suffering from hypertension.

Drug Interactions

Mirabegron is a moderate, time-dependent inhibitor of the CYP2D6 isoenzyme and a weak inhibitor of the CYP3A isoenzyme. At high concentrations, mirabegron inhibited drug transport mediated by P-glycoprotein.

Clinically significant interactions between mirabegron and drugs that inhibit, induce, or are substrates of one of the CYP isoenzymes or transporters are not expected, except for the inhibitory effect of mirabegron on the metabolism of CYP2D6 isoenzyme substrates.

The concentration (AUC) of mirabegron increased 1.8-fold under the influence of the strong CYP3A/P-gp inhibitor ketoconazole in healthy volunteers. Dose adjustment of mirabegron is not required when co-administered with CYP3A isoenzyme or P-gp inhibitors. However, in patients with mild or moderate renal impairment (eGFR 30-89 ml/min/1.73 m²) or mild hepatic impairment (Child-Pugh class A) taking such strong CYP3A inhibitors as itraconazole, ketoconazole, ritonavir, and clarithromycin, the recommended daily dose of mirabegron is 25 mg regardless of food intake.

Substances that induce CYP3A isoenzymes or P-gp reduce the plasma concentration of mirabegron.

In healthy volunteers, mirabegron moderately inhibits the CYP2D6 isoenzyme, the activity of which recovers within 15 days after discontinuation of mirabegron. Daily administration of mirabegron led to an increase in C_max by 90% and AUC by 229% for a single dose of metoprolol. Daily administration of mirabegron led to an increase in C_max by 79% and AUC by 241% for a single dose of desipramine. Mirabegron should be used with caution in combination with drugs that have a narrow therapeutic index and drugs that are extensively metabolized by the CYP2D6 isoenzyme, for example, thioridazine, Class 1C antiarrhythmic drugs (e.g., flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Mirabegron should also be taken with caution when co-administered with drugs that are metabolized by the CYP2D6 isoenzyme and whose dose requires individual determination.

Mirabegron is a weak inhibitor of P-gp protein. Mirabegron led to an increase in C_max and AUC by 29% and 27%, respectively, when co-administered with digoxin in healthy volunteers. For patients starting mirabegron and digoxin simultaneously, digoxin should be administered at the lowest dose. Monitoring of digoxin plasma concentrations and subsequent adjustment of the effective digoxin dose based on control tests is necessary. The potential for P-gp inhibition by mirabegron should be taken into account when prescribing mirabegron concomitantly with drugs transported by P-gp, for example, dabigatran.

The enhanced effect of mirabegron when taken concomitantly with other drugs is expressed as an increase in heart rate.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.