BETMIGA Prolonged-release tablet Ref.[7511] Active ingredients: Mirabegron

Renal impairment

Betmiga has not been studied in patients with ESRD (eGFR < 15 ml/min/1.73 m²) or patients requiring haemodialysis and, therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (eGFR 15 to 29 ml/min/1.73 m²); based on a pharmacokinetic study (see section 5.2) a dose of 25 mg once daily is recommended in this population. This medicinal product is not recommended for use in patients with severe renal impairment (eGFR 15 to 29 ml/min/1.73 m²) concomitantly receiving strong CYP3A inhibitors (see section 4.5).

Hepatic impairment

Betmiga has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. This medicinal product is not recommended for use in patients with moderate hepatic impairment (Child-Pugh B) concomitantly receiving strong CYP3A inhibitors (see section 4.5).

Hypertension

Overactive bladder in adults

Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with mirabegron, especially in hypertensive patients.

Data are limited in patients with stage 2 hypertension (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg).

Neurogenic detrusor overactivity in the paediatric population

Mirabegron can increase blood pressure in paediatric patients. Blood pressure increases may be larger in children (3 to less than 12 years of age) than in adolescents (12 to less than 18 years of age). Blood pressure should be measured at baseline and periodically during treatment with mirabegron.

Patients with congenital or acquired QT prolongation

Betmiga, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies (see section 5.1). However, since patients with a known history of QT prolongation or patients who are taking medicinal products known to prolong the QT interval were not included in these studies, the effects of mirabegron in these patients is unknown. Caution should be exercised when administering mirabegron in these patients.

Patients with bladder outlet obstruction and patients taking antimuscarinics medicinal products for OAB

Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medicinal products for the treatment of OAB has been reported in post-marketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with Betmiga; however, Betmiga should be administered with caution to patients with clinically significant BOO. Betmiga should also be administered with caution to patients taking antimuscarinic medicinal products for the treatment of OAB.

In vitro data

Mirabegron is transported and metabolised through multiple pathways. Mirabegron is a substrate for cytochrome P450 (CYP) 3A4, CYP2D6, butyrylcholinesterase, uridine diphospho-glucuronosyltransferases (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

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 100 mg mirabegron 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 Betmiga is combined with inhibitors of CYP3A and/or P-gp. However, in patients with mild to moderate renal impairment (eGFR 30 to 89 ml/min/1.73 m²) or mild hepatic impairment (Child-Pugh Class A) concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is 25 mg once daily (see section 4.2). Betmiga is not recommended in patients with severe renal impairment (eGFR 15 to 29 ml/min/1.73 m²) or patients with moderate hepatic impairment (Child-Pugh Class B) concomitantly receiving strong CYP3A inhibitors (see sections 4.2 and 4.4).

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 CYP2D6 polymorphism

CYP2D6 genetic polymorphism has minimal impact on the mean plasma exposure to mirabegron (see section 5.2). 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.

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 Betmiga 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.

Paediatric population

Interaction studies have only been performed in adults.

Woman of childbearing potential

Betmiga is not recommended in women of childbearing potential not using contraception.

Pregnancy

There are no or limited amount of data from the use of mirabegron in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Betmiga is not recommended during pregnancy.

Breast-feeding

Mirabegron is excreted in the milk of rodents and therefore is predicted to be present in human milk (see section 5.3). No studies have been conducted to assess the impact of mirabegron on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child.

Betmiga should not be used during breast-feeding.

Fertility

There were no treatment-related effects of mirabegron on fertility in animals (see section 5.3). The effect of mirabegron on human fertility has not been established.

Betmiga has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The safety of Betmiga was evaluated in 8 433 adult patients with OAB, of which 5 648 received at least one dose of mirabegron in the phase ⅔ clinical program, and 622 patients received Betmiga for at least 1 year (365 days). In the three 12-week phase 3 double blind, placebo-controlled studies, 88% of the patients completed treatment with this medicinal product, and 4% of the patients discontinued due to adverse events. Most adverse reactions were mild to moderate in severity.

The most common adverse reactions reported for adult patients treated with Betmiga 50 mg during the three 12-week phase 3 double blind, placebo-controlled studies are tachycardia and urinary tract infections. The frequency of tachycardia was 1.2% in patients receiving Betmiga 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving Betmiga 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Betmiga 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving Betmiga 50 mg. Serious adverse reactions included atrial fibrillation (0.2%).

Adverse reactions observed during the 1-year (long term) active controlled (muscarinic antagonist) study were similar in type and severity to those observed in the three 12-week phase 3 double blind, placebo-controlled studies.

Tabulated list of adverse reactions

The table below reflects the adverse reactions observed with mirabegron in adults with OAB in the three 12-week phase 3 double blind, placebo-controlled studies.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000) and not known (cannot be established from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

^* observed during post-marketing experience

Paediatric population

The safety of mirabegron tablets and oral suspension was evaluated in 86 paediatric patients aged 3 to less than 18 years with NDO in a 52-week, open-label, baseline-controlled, multicentre, dose titration study. The most commonly reported adverse reactions observed in the paediatric population were urinary tract infection, constipation, and nausea.

In the paediatric patients with NDO, no severe adverse reactions were reported.

Overall, the safety profile in children and adolescents is similar to that observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.