Betmiga · 4.4 Special warnings and precautions for use · 2

HOS-096110 · has-adverse-reaction-information · PDF-Seite 32

Summary of the safety profile The safety of mirabegron tablets was evaluated in 8 433 adult patients with OAB, of which 5 648 received at least one dose of mirabegron in the phase 2/3 clinical program, and 622 patients received mirabegron 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 mirabegron 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 mirabegron 50 mg. Tachycardia led to discontinuation in 0.1% patients receiving mirabegron 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving mirabegron 50 mg. Urinary tract infections led to discontinuation in none of the patients receiving mirabegron 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. 32 MedDRA Common Uncommon Rare Very rare Not known System organ (cannot be class estimated from the

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HOS-096104 · has-adverse-reaction-information · PDF-Seite 8

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 2/3 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. 8 MedDRA Common Uncommon Rare Very rare Not known System organ (cannot be class estimated from the available

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HOS-096100 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. - Severe uncontrolled hypertension defined as systolic blood pressure ≥ 180 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg. 4

HOS-096106 · has-contraindication-information · PDF-Seite 29

- Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. - Severe uncontrolled hypertension defined as systolic blood pressure ≥ 180 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg.

HOS-096099 · has-indication-information · PDF-Seite 2

Overactive bladder in adults Betmiga prolonged-release tablets are indicated for symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome. Neurogenic detrusor overactivity in the paediatric population Betmiga prolonged-release tablets are indicated for treatment of neurogenic detrusor overactivity (NDO) in paediatric patients aged 3 to less than 18 years.

HOS-096105 · has-indication-information · PDF-Seite 27

Betmiga granules for prolonged-release oral suspension is indicated for treatment of neurogenic detrusor overactivity (NDO) in paediatric patients aged 3 to less than 18 years.

HOS-096102 · has-interaction-information · PDF-Seite 6

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 polymo

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HOS-096108 · has-interaction-information · PDF-Seite 30

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 mirabegron 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) 30 concomitantly receiving strong CYP3A inhibitors, such as itraconazole, ketoconazole, ritonavir and clarithromycin, the recommended dose is no more than the starting dose (see section 4.2). Mirabegron 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 C

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HOS-096103 · has-pregnancy-information · PDF-Seite 7

Women 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.

HOS-096109 · has-pregnancy-information · PDF-Seite 31

Women of childbearing potential Betmiga granules for prolonged-release oral suspension is not recommended in women of childbearing potential not using contraception. 31 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 granules for prolonged-release oral suspension 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 granules for prolonged-release oral suspension 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.

HOS-096107 · has-warning-information · PDF-Seite 29

Renal impairment Mirabegron 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 no more than the starting dose 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 Mirabegron 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 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. 29 Patients with congenital or acquired QT prolongation Mirabegron, 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 overactive bladder (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 mirabegron; however, mirabegron should be administered with caution to patients with clinically significant BOO. Mirabegron should also be administered with caution t

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HOS-096101 · has-warning-information · PDF-Seite 5

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 mirabe

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