Relasur

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RELASUR (RELASUR)

Composition:

Active substance: mirabegron;

One tablet contains 50 mg of mirabegron;

Excipients: macrogol 2,000,000, microcrystalline cellulose, hypromellose, hydroxypropylcellulose, butylhydroxytoluene, magnesium stearate, colloidal anhydrous silicon dioxide;

Film coating: Opadry II 85F220232 Orange: polyvinyl alcohol, titanium dioxide (E 171), macrogol (polyethylene glycol), talc, yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Extended-release tablets.

Main physicochemical properties: oval, biconvex, film-coated tablets of light yellow color.

Pharmacotherapeutic group

Medicinal products used in urology. Medicinal products for the treatment of frequent urination and urinary incontinence. ATC code G04BD12.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Mirabegron is a potent selective beta-3 adrenergic receptor agonist. Under the influence of mirabegron, relaxation of the detrusor smooth muscle of the urinary 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 urinary bladder is noted in functioning animal bladder models.

Mirabegron increases the average voided volume and reduces micturition frequency without contractions of the bladder muscle outside micturition, without affecting pressure or residual urine in the bladder cavity, in animal models of overactive bladder. In animal bladder models, mirabegron demonstrated a reduction in micturition frequency. These results indicate that mirabegron enhances urine storage function by stimulating beta-3 adrenergic receptors in the bladder muscle. Sympathetic receptor stimulation predominates during the urine storage phase, when urine accumulates in the bladder. Norepinephrine is released from nerve endings, predominantly stimulating beta-adrenergic receptors in the bladder muscle tissue, thereby relaxing the detrusor smooth muscle. During the filling 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 suppresses beta-3 adrenergic receptors, reducing cAMP. Therefore, stimulation of beta-3 adrenergic receptors does not interfere with the urine filling process. This has been confirmed in models with partial urethral obstruction, where mirabegron reduced the frequency of bladder contractions without affecting detrusor muscle contractions outside micturition, and without influencing pressure or residual urine volume in the bladder cavity.

Pharmacokinetics

Absorption

After oral administration in healthy volunteers, mirabegron is absorbed into the systemic circulation and reaches maximum plasma concentration (C_max) within 3–4 hours after dosing. Absolute bioavailability increases from 29% to 35% when the dose is increased from 25 mg to 50 mg. In this case, mean C_max and AUC values increased more than proportionally within this dose range. In the general population of men and women, doubling the dose of mirabegron from 50 mg to 100 mg resulted in approximately 2.9- and 2.6-fold increases in C_max and AUC_tau, respectively, whereas a 4-fold increase in dose from 50 mg to 200 mg induced approximately 8.4- and 6.5-fold increases in C_max and AUC_tau, 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 urination, 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 interactions

In vitro data.

Mirabegron is transported and metabolized via multiple pathways. Mirabegron is a substrate of 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.

Polymorphism of CYP2D6

Genetic polymorphism of CYP2D6 has minimal impact on the average 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 slow 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 medicinal products were studied after single and multiple doses. Most drug interactions were investigated with mirabegron administered at a dose of 100 mg as orally administered controlled-release tablets (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 on enzyme inhibitors

In healthy volunteers, in the presence of ketoconazole, a strong CYP3A/P-glycoprotein inhibitor, mirabegron exposure (AUC) increased by 1.8-fold. Dose adjustment of mirabegron is not required when co-administered 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 is 25 mg once daily, regardless of food intake (see section "Dosage and administration"). Concomitant use of mirabegron with strong CYP3A inhibitors such as itraconazole, ketoconazole, ritonavir, and clarithromycin 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) (see sections "Dosage and administration" and "Special precautions").

Effect on enzyme inducers

Substances that are inducers of CYP3A or P-glycoprotein reduce mirabegron plasma concentrations. No dose adjustment of mirabegron is required when co-administered with rifampicin or other therapeutic doses of CYP3A inducers or P-glycoproteins. 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 administration of mirabegron in an immediate-release formulation increased Cmax and AUC of a single dose of metoprolol by 90% and 229%, respectively. Daily administration of mirabegron increased Cmax by 79% and AUC of desipramine by 241% following a single dose of desipramine.

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 receiving digoxin, mirabegron may increase its Cmax and AUC by 29% and 27%, respectively. For patients initiating mirabegron and digoxin simultaneously, the lowest dose of digoxin should be prescribed. Monitoring of digoxin blood levels and dose titration are required to achieve the desired clinical effect. The potential for mirabegron to inhibit P-glycoprotein should be considered when administering the drug concomitantly with P-gp sensitive substrates, such as dabigatran.

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

Enhanced effects of mirabegron when co-administered with other medicinal products may manifest as increased pulse rate.

Special precautions for use

Renal impairment

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

Hepatic impairment

The use of mirabegron has not been studied in patients with severe hepatic impairment (Child-Pugh class C); therefore, the drug is not recommended for use in these patients. The drug is not recommended for patients with moderate hepatic impairment (Child-Pugh class B) when used concomitantly 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 starting treatment and periodically during the course of treatment, 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 administered at therapeutic doses did not result in clinically significant QT interval prolongation on electrocardiogram. 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 prolonged QT interval, the effect of mirabegron in such patients is unknown. Caution should be exercised when using mirabegron in these patient populations.

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

Post-marketing reports have described urinary retention 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 receiving the drug; however, mirabegron should be used with caution in patients with clinically significant bladder outlet obstruction. The drug 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. The drug is not recommended during pregnancy and in women of reproductive potential who are not using contraception.

In rodents, mirabegron passes into breast milk, and therefore there is a risk that mirabegron may pass into human breast milk. The effect of mirabegron on human breast milk production or on breastfeeding infants has not been studied. Mirabegron should not be administered to women who are 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

Mirabegron has no effect or has a negligible effect on the ability to drive or operate machinery.

Dosage and Administration

Adults, including elderly patients

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

Renal and hepatic impairment

The use of mirabegron has not been studied in patients with end-stage renal disease (eGFR < 15 mL/min/1.73 m²) or in patients requiring hemodialysis, or in patients with severe hepatic impairment (Child–Pugh class C). Therefore, mirabegron is not recommended for use in these patient populations (see sections «Special precautions», «Pharmacokinetic properties»). Table 1 provides recommendations for daily dosing of mirabegron in patients with renal or hepatic impairment, with or without concomitant use of strong CYP3A inhibitors (see sections «Special precautions», «Interaction with other medicinal products and other forms of interactions», «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 interactions".

The tablets should be taken once daily with liquid; the tablet should be swallowed whole; do not chew, divide, or crush the tablet.

Sex

Dose adjustment is not required based on sex.

Children

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

Overdose

Symptoms. Following a single 400 mg dose of mirabegron in 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). Daily administration of mirabegron at a dose of 300 mg per day for 10 days in healthy volunteers resulted in increased pulse rate and systolic blood pressure.

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

Adverse reactions

Most adverse reactions were of mild or moderate severity.

The most common adverse reactions were tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% and led to discontinuation of treatment in 0.1% of patients. The frequency of urinary tract infections was 2.9%. Urinary tract infections did not lead to discontinuation of treatment in any of the 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 (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated due to insufficient data). Within each group, adverse reactions are listed in order of decreasing severity.

Table 2

*Reported 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 enables continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions

No special storage conditions required. Keep out of reach and sight of children.

Packaging

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer

Pharmadox Health Care Limited

or

ADALVO LIMITED.

Manufacturer's address and site of operations

Kw20a Cordier Industrial Park, Paola, PLA 3000, Malta

or

Malta Life Sciences Park, Building 1, Level 4, Sir Temi Zammit Buildings, San Gwann Industrial Estate, San Gwann, SGN 3000, Malta.