Betmiga

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BEMIGA (BETMIGA)

Composition:

Active substance: mirabegron;

1 tablet contains 25 mg or 50 mg of mirabegron;

Excipients: macrogol 8000, macrogol 2000000, hydroxypropylcellulose, butylhydroxytoluene (E 321), magnesium stearate;

Film coating: for 25 mg tablets – Opadry 03F43159 (hypromellose, macrogol 8000, iron oxide yellow (E 172), iron oxide red (E 172)); for 50 mg tablets – Opadry 03F42192 (hypromellose, macrogol 8000, iron oxide yellow (E 172)).

Pharmaceutical form. Extended-release tablets.

Main physicochemical properties:

25 mg tablets – oval, biconvex tablet with a film coating, brown in color, with engraving «325» and a graphic representation of the company logo «Astellas» on one side;

50 mg tablets – oval, biconvex tablet with a film coating, yellow in color, with engraving «355» and a graphic representation of the company logo «Astellas» on one side.

Pharmacotherapeutic group.

Agents used in urology. Agents for the treatment of frequent micturition and urinary incontinence. ATC code G04BD12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Mirabegron is a potent selective beta-3 adrenoceptor agonist. Under the influence of mirabegron, relaxation of the detrusor smooth muscle of the bladder occurs in animals and in isolated human tissue, increased concentrations of cyclic adenosine monophosphate (cAMP) are observed in bladder tissues of animals, and a relaxant effect on the bladder is demonstrated in functional animal models of the bladder.

Mirabegron increases the average voided volume per micturition and reduces micturition frequency without inducing detrusor muscle contractions outside of micturition, without affecting pressure or residual urine volume within the bladder cavity, in animal models of overactive bladder. In animal bladder models, mirabegron demonstrated reduced micturition frequency. These results indicate that mirabegron enhances urine storage function by stimulating beta-3 adrenoceptors in the bladder detrusor muscle.

Sympathetic stimulation of nerve receptors predominates during the urine storage phase, when urine accumulates in the bladder. Norepinephrine is released from nerve endings, primarily stimulating beta-adrenoceptors in the bladder detrusor muscle, thereby relaxing the bladder's smooth muscle. During the urine storage phase, the bladder is primarily under parasympathetic nervous system control. Acetylcholine, released from pelvic nerve endings, stimulates cholinergic M2 and M3 receptors, causing bladder contraction. Activation of the M2 pathway also inhibits beta-3 adrenoceptors, reducing cAMP levels. Therefore, stimulation of beta-3 adrenoceptors does not interfere with the urine storage process. This has been confirmed in models with partial urethral obstruction, where mirabegron reduced bladder contraction frequency without inducing detrusor contractions outside micturition and without affecting intravesical pressure or residual urine volume.

Pharmacokinetics.

Absorption.

After oral administration in healthy volunteers, mirabegron is absorbed into the systemic circulation and reaches maximum plasma concentration (Cmax) within 3–4 hours post-dose. Absolute bioavailability increases from 29% to 35% when the dose is increased from 25 mg to 50 mg. In this dose range, mean Cmax and AUC values increased more than proportionally. In the general population of men and women, doubling the mirabegron dose from 50 mg to 100 mg resulted in approximately 2.9- and 2.6-fold increases in Cmax and AUCtau, respectively, whereas a 4-fold dose increase from 50 mg to 200 mg induced approximately 8.4- and 6.5-fold increases in Cmax and AUCtau, respectively. Steady-state concentrations are achieved within 7 days (with once-daily mirabegron administration). After repeated once-daily dosing, plasma concentrations of mirabegron at steady state are approximately twice those observed after a single dose.

Clinical characteristics.

Indications.

Symptomatic treatment of urgent need to urinate, increased frequency of urination and/or urinary incontinence that may occur in adult patients with overactive bladder syndrome (OAB).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients. Severe uncontrolled hypertension (systolic blood pressure ≥ 180 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg).

Interaction with other medicinal products and other forms of interaction.

In vitro data.

Mirabegron is transported and metabolized via multiple pathways. Mirabegron is a substrate for cytochrome P450 (CYP) 3A4, CYP2D6, butyrylcholinesterase, uridine diphosphate-glucuronosyltransferase (UGT), P-glycoprotein (P-gp) transporter, and 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 time-dependent moderate inhibitor of CYP2D6 and a weak inhibitor of CYP3A. At high concentrations, mirabegron inhibited drug transport mediated by P-glycoprotein.

In vivo data.

CYP2D6 polymorphism.

Genetic polymorphism of CYP2D6 shows minimal effect on mean plasma concentration of mirabegron (see section "Pharmacokinetic properties").

Interaction between mirabegron and known CYP2D6 inhibitors is neither expected nor studied. Dose adjustment of mirabegron is not required in patients taking CYP2D6 inhibitors or in patients with reduced CYP2D6 metabolism.

Interactions with medicinal products.

The effect of concomitant administration of medicinal products on the pharmacokinetics of mirabegron and the effect of mirabegron on the pharmacokinetics of other drugs were studied after single and multiple dosing. Most drug interactions were studied with mirabegron administered at a dose of 100 mg as an oral controlled-release tablet (OCAS). In interaction studies of mirabegron with metoprolol and metformin, mirabegron immediate-release (IR) formulation at a dose of 160 mg was used. Clinically significant drug interaction between mirabegron and medicinal products that inhibit, induce, or are substrates or transporters of any of the CYP enzymes is not expected, except for the inhibitory effect of mirabegron on the metabolism of CYP2D6 substrates.

Effect of enzyme inhibitors.

In healthy volunteers, co-administration with ketoconazole, a strong inhibitor of CYP3A/P-glycoprotein, increased mirabegron exposure (AUC) by 1.8-fold. Dose adjustment of the medicinal product Betmiga is not required when used concomitantly with CYP3A and/or P-glycoprotein inhibitors. However, for patients with mild to moderate renal impairment (eGFR from 30 to 89 mL/min/1.73 m²) or mild hepatic impairment (Child-Pugh class A), the recommended dose when co-administered with strong CYP3A inhibitors such as itraconazole, ketoconazole, ritonavir, and clarithromycin is 25 mg once daily, regardless of food intake (see section "Dosage and administration"). Concomitant use of Betmiga is not recommended in patients with severe renal impairment (eGFR from 15 to 29 mL/min/1.73 m²) or moderate hepatic impairment (Child-Pugh class B) when used with strong CYP3A inhibitors (see sections "Dosage and administration" and "Special precautions").

Effect of enzyme inducers.

Substances that are inducers of CYP3A or P-glycoprotein reduce mirabegron plasma concentrations. No dose adjustment of mirabegron is required when used concomitantly with rifampicin or other therapeutic doses of CYP3A inducers or P-glycoprotein inducers.

Effect of mirabegron on CYP2D6 substrates.

In healthy volunteers, mirabegron moderately inhibits CYP2D6, with enzyme activity recovering within 15 days after discontinuation of mirabegron. Daily single-dose administration of mirabegron in an immediate-release formulation increased Cmax and AUC of a single dose of metoprolol by 90% and 229%, respectively. Daily single-dose administration of mirabegron increased Cmax by 79% and AUC of desipramine by 241% after single-dose administration.

Caution should be exercised when co-administering mirabegron with medicinal products having a narrow therapeutic index and strong dependence on CYP2D6 metabolism, such as thioridazine, class 1C antiarrhythmics (e.g., flecainide, propafenone), and tricyclic antidepressants (e.g., imipramine, desipramine). Mirabegron should also be used cautiously with CYP2D6 substrates requiring individual dose titration.

Effect of mirabegron on enzyme transporters.

Mirabegron is a weak inhibitor of P-glycoprotein (P-gp). In healthy volunteers, co-administration of mirabegron with digoxin may increase digoxin Cmax and AUC by 29% and 27%, respectively. For patients initiating Betmiga concomitantly with digoxin, the lowest possible dose of digoxin should be prescribed. Digoxin blood levels should be monitored and the digoxin dose titrated to achieve the desired clinical effect. The potential for P-glycoprotein inhibition by mirabegron should be considered when administering Betmiga concomitantly with P-gp substrate drugs, such as dabigatran.

Other interactions. No clinically significant interactions were observed between mirabegron and solifenacin, tamsulosin, warfarin, metformin, or combined oral contraceptives containing ethinylestradiol and levonorgestrel when administered concomitantly at therapeutic doses. Dose adjustment is not required.

Enhanced effects of mirabegron when used concomitantly with other medicinal products may manifest as increased heart rate.

Special precautions for use.

Renal impairment.

The use of Betmiga has not been studied in patients with end-stage renal disease (eGFR <15 mL/min/1.73 m² or patients requiring hemodialysis); therefore, this medicinal product is not recommended for use in such patients. Limited data are available on the use of Betmiga in patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m²); based on pharmacokinetic studies (see section "Pharmacokinetic properties"), a dose reduction to 25 mg is recommended for these patients. Betmiga is not recommended for use in patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m²) when co-administered with strong CYP3A inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment.

The use of Betmiga has not been studied in patients with severe hepatic impairment (Child-Pugh class C); therefore, the drug is not recommended for use in this patient population. Betmiga is not recommended for use in patients with moderate hepatic impairment (Child-Pugh class B) when co-administered with strong CYP3A inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

Arterial hypertension.

Mirabegron may increase blood pressure. Blood pressure should be measured before initiating treatment and monitored periodically during therapy, especially in patients with arterial hypertension. Data on the use of the drug in patients with stage 2 arterial hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg) are limited.

Patients with congenital or acquired QT interval prolongation.

During clinical trials, mirabegron at therapeutic doses did not result in clinically significant QT interval prolongation on electrocardiograms. Since the use of mirabegron has not been studied in patients taking medicinal products that may prolong the QT interval or in patients with a history of QT prolongation, the effect of mirabegron in such patients is unknown. Caution should be exercised when administering mirabegron to these patients.

Patients with urinary retention and patients taking antimuscarinic medicinal products for the treatment of overactive bladder syndrome.

Urinary retention has been reported in the post-marketing period in patients with bladder outlet obstruction and in patients taking antimuscarinic medicinal products for the treatment of overactive bladder syndrome during mirabegron therapy. Controlled clinical safety studies in patients with bladder outlet obstruction did not show an increased incidence of urinary retention in patients taking Betmiga; however, Betmiga should be used with caution in patients with clinically significant bladder outlet obstruction. Betmiga should be used with caution in patients taking antimuscarinic medicinal products for the treatment of overactive bladder syndrome.

Use during pregnancy or breastfeeding.

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

In rodents, mirabegron is excreted in milk; therefore, there is a risk of the drug being present in human breast milk. The effect of mirabegron on human milk production or its impact on breastfeeding infants has not been studied. Mirabegron should not be administered to women during breastfeeding.

Fertility.

Animal studies did not reveal any effect of mirabegron when administered at non-therapeutic doses. The effect of mirabegron on human fertility has not been evaluated.

Ability to affect reaction speed when driving or operating machinery.

Betmiga has no or negligible influence on the ability to drive or operate machinery.

Method of administration and doses.

Adults, including elderly patients.

The recommended dose is 50 mg once daily, regardless of food intake.

Renal and hepatic impairment

The use of the medicinal product Betmiga in patients with end-stage renal disease (eGFR <15 mL/min/1.73 m² or patients requiring hemodialysis) or in patients with severe hepatic impairment (Child-Pugh class C) has not been studied; therefore, Betmiga is not recommended for use in these patient populations (see sections «Special precautions», «Pharmacokinetic properties»).

Table 1 provides dosage recommendations for daily administration of the drug in patients with renal or hepatic impairment, with or without strong CYP3A inhibitors (see sections «Special precautions», «Interaction with other medicinal products and other forms of interaction», «Pharmacokinetic properties»).

Table 1

1 Mild: eGFR 60–89 mL/min/1.73 m²; moderate: eGFR 30–59 mL/min/1.73 m²; severe: eGFR 15–29 mL/min/1.73 m².

2 Mild: Child-Pugh class A; moderate: Child-Pugh class B.

3 Strong CYP3A inhibitors, see section "Interaction with other medicinal products and other forms of interaction".

The tablets should be taken once daily with liquid; the tablet should be swallowed whole; the tablet must not be chewed, divided, or crushed.

Sex

No dosage adjustment is required based on sex.

Children

Safety and efficacy of mirabegron in children (under 18 years of age) have not been established.

Overdose

Mirabegron was administered as a single 400 mg dose to healthy volunteers, palpitations were observed (in 1 out of 6 volunteers) and increased pulse rate exceeding 100 beats per minute (in 3 out of 6 volunteers). With daily administration of mirabegron at a dose of 300 mg per day for 10 days in healthy volunteers, increased pulse rate and systolic blood pressure were observed.

Treatment of overdose is symptomatic and supportive. In case of overdose, pulse rate, blood pressure, and ECG monitoring are recommended.

Adverse reactions

Most adverse reactions were of mild or moderate severity.

The most commonly reported adverse reactions were tachycardia and urinary tract infections. The incidence of tachycardia was 1.2%, leading to discontinuation of treatment in 0.1% of patients. The incidence of urinary tract infections was 2.9%. Urinary tract infections did not lead to discontinuation of treatment in any patients. Serious adverse reactions included atrial fibrillation (0.2%).

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥ 1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated due to insufficient data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 2

*Occurred during the post-marketing period.

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization of a medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister pack. 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Delpharm Meppel B.V., the Netherlands / Delpharm Meppel B.V., the Netherlands.

Manufacturer's address.

Hogemaat 2, 7942 JG Meppel, the Netherlands / Hogemaat 2, 7942 JG Meppel, the Netherlands.

Marketing Authorization Holder. Astellas Pharma Europe B.V. / Astellas Pharma Europe B.V.

Address of the Marketing Authorization Holder. Sylviusweg, 62, 2333 BE Leiden, the Netherlands / Sylviusweg, 62, 2333 BE Leiden, the Netherlands.