Orladeyo · 4.3 Contraindications · 2

HOS-099229 · has-adverse-reaction-information · PDF-Seite 19

Summary of the safety profile The most common adverse reactions in patients 12 years and older are abdominal pain (all locations) (reported by 21% of patients), diarrhoea (reported by 15% of patients), and headache (reported by 13% of patients). The gastrointestinal events were reported primarily in the first 1-3 months of berotralstat use (median day of onset was day 66 for abdominal pain and day 45 for diarrhoea) and resolved without medicinal product while berotralstat treatment was continued. Almost all events (99%) of abdominal pain were mild or moderate with a median duration of 3.5 days (95% CI 2- 8 days). Almost all events (98%) of diarrhoea were mild or moderate with a median duration of 3.2 days (95% CI 2-8 days). The safety profile in patients 2 to < 12 years of age was similar to that observed in adults. Tabulated list of adverse reactions The safety of berotralstat has been evaluated in long term clinical studies in patients with HAE (both uncontrolled, open-label and placebo-controlled, blinded) in 381 adult and adolescent patients and 19 29 paediatric patients aged 3 to < 12 years. Adverse reactions obtained from clinical studies and post- marketing surveillance are listed below by MedDRA system organ class and by frequency. Frequencies are 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 2: Adverse reactions observed in clinical studies and post-marketing surveillance System organ class Frequency Adverse reactions Nervous system disorders Very common Headachea Gastrointestinal disorders Very common Abdominal painb, Diarrhoeac Common Vomiting, Gastroesophageal reflux, Flatulence Not known Nausea Skin and subcutaneous tissue disorders Common Rash Hepatobiliary disorders Common ALT increased, AST increased a Includes the events of Headache, Sinus headache b Includes the events of Abdominal

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HOS-099223 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile The most common adverse reactions are abdominal pain (all locations) (reported by 21% of patients), diarrhoea (reported by 15% of patients), and headache (reported by 13% of patients). The gastrointestinal events were reported primarily in the first 1-3 months of berotralstat use (median day of onset was day 66 for abdominal pain and day 45 for diarrhoea) and resolved without medicinal product while berotralstat treatment was continued. Almost all events (99%) of abdominal pain were mild or moderate with a median duration of 3.5 days (95% CI 2-8 days). Almost all events (98%) of diarrhoea were mild or moderate with a median duration of 3.2 days (95% CI 2-8 days). Tabulated list of adverse reactions The safety of berotralstat has been evaluated in long term clinical studies in patients with HAE (both uncontrolled, open-label and placebo-controlled, blinded) in 381 adult and adolescent patients and 29 paediatric patients aged 3 to < 12 years. Adverse reactions obtained from clinical studies and post- marketing surveillance are listed below by MedDRA system organ class and by frequency. Frequencies are 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); not known (cannot be 5 estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1: Adverse reactions observed in clinical studies and post-marketing surveillance System organ class Frequency Adverse reactions Nervous system disorders Very common Headachea Gastrointestinal disorders Very common Abdominal painb, Diarrhoeac Common Vomiting, Gastroesophageal reflux, Flatulence Not known Nausea Skin and subcutaneous tissue disorders Common Rash Hepatobiliary disorders Common ALT increased, AST increased a Includes the events of Headache, Sinus headache b Includes the events of Abdominal pain, Abdominal discomfort, Abdominal pain upper, Abdominal pain lower, Epigastric discomfort, Abdominal tenderness c Inclu

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HOS-099225 · has-contraindication-information · PDF-Seite 17

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-099219 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-099218 · has-indication-information · PDF-Seite 2

Orladeyo is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) in adult and adolescent patients aged 12 years and older weighing at least 40 kg.

HOS-099224 · has-indication-information · PDF-Seite 15

Orladeyo is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) in: • children aged 2 to less than 12 years weighing at least 15 kg • adolescents aged 12 and older weighing less than 40 kg

HOS-099227 · has-interaction-information · PDF-Seite 18

Berotralstat is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate. Effects of other medicinal products on berotralstat P-gp and BCRP inhibitors Ciclosporine, a P-gp and BCRP inhibitor, decreased the maximum concentration (Cmax) of a single 150 mg dose of berotralstat by 7% and increased the area under the concentration versus time curve (AUC) by 27%. No dose adjustment of berotralstat is recommended for concomitant use with P-gp and BCRP inhibitors. P-gp and BCRP inducers Berotralstat is a substrate of P-gp and BCRP. P-gp and BCRP inducers (e.g. rifampicin, St. John’s wort) may decrease berotralstat plasma concentration, leading to reduced efficacy of berotralstat. The use of P-gp inducers is not recommended with berotralstat. Effects of berotralstat on other medicinal products CYP3A4 substrates Berotralstat is a moderate inhibitor of CYP3A4, increasing the Cmax and AUC of oral midazolam by 45% and 124%, respectively, and the Cmax and AUC of amlodipine by 45% and 77%, respectively. Concomitant administration may increase concentrations of other medicinal products that are CYP3A4 substrates. Refer to the SmPC for concomitant medicinal products that are predominantly metabolised by CYP3A4, particularly those with a narrow therapeutic index (e.g. ciclosporine, fentanyl). Dose adjustments of these medicinal products may be required (see section 5.2). CYP2D6 substrates Berotralstat is a moderate inhibitor of CYP2D6, increasing the Cmax and AUC of dextromethorphan by 196% and 177%, respectively, and the Cmax and AUC of desipramine by 64% and 87%, respectively. Concomitant administration may increase exposure of other medicinal products that are CYP2D6 substrates. Refer to the SmPC for concomitant medicinal products that are predominantly metabolised by CYP2D6, particularly those with a narrow therapeutic index (e.g. thioridazine, pimozide) or whose prescribing information recommends therapeutic monitoring (e.g. tricyclic antidepressants). Dose adjustments of these medicinal products may be required (see section 5.2). CYP2C9 substrates Berotralstat is a weak inhibitor of CYP2C9 increasing the Cmax and AUC of tolbutamide by 19% and 73%, respectively. No dose adjustment is recommended for concomitant use of medicinal products that are predominantly metabolised by CYP2C9 (e.g. tolbutamide) (see section 5.2). The effect of berotralstat on the CYP2C9 conversion of desogestrel to etonogestrel (active metabolite) was negligible. No do

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HOS-099221 · has-interaction-information · PDF-Seite 4

Berotralstat is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate. Effects of other medicinal products on berotralstat P-gp and BCRP inhibitors Ciclosporine, a P-gp and BCRP inhibitor, decreased the maximum concentration (Cmax) of a single 150 mg dose of berotralstat by 7% and increased the area under the concentration versus time curve (AUC) by 27%. No dose adjustment of berotralstat is recommended for concomitant use with P-gp and BCRP inhibitors. P-gp and BCRP inducers Berotralstat is a substrate of P-gp and BCRP. P-gp and BCRP inducers (e.g. rifampicin, St. John’s wort) may decrease berotralstat plasma concentration, leading to reduced efficacy of berotralstat. The use of P-gp inducers is not recommended with berotralstat. Effects of berotralstat on other medicinal products CYP3A4 substrates Berotralstat is a moderate inhibitor of CYP3A4, increasing the Cmax and AUC of oral midazolam by 45% and 124%, respectively, and the Cmax and AUC of amlodipine by 45% and 77%, respectively. Concomitant administration may increase concentrations of other medicinal products that are CYP3A4 substrates. Refer to the SmPC for concomitant medicinal products that are predominantly metabolised by CYP3A4, particularly those with a narrow therapeutic index (e.g. ciclosporine, fentanyl). Dose adjustments of these medicinal products may be required (see section 5.2). CYP2D6 substrates Berotralstat is a moderate inhibitor of CYP2D6, increasing the Cmax and AUC of dextromethorphan by 196% and 177%, respectively, and the Cmax and AUC of desipramine by 64% and 87%, respectively. Concomitant administration may increase exposure of other medicinal products that are CYP2D6 substrates. Refer to the SmPC for concomitant medicinal products that are predominantly metabolised by CYP2D6, particularly those with a narrow therapeutic index (e.g. thioridazine, pimozide) or whose prescribing information recommends therapeutic monitoring (e.g. tricyclic antidepressants). Dose adjustments of these medicinal products may be required (see section 5.2). CYP2C9 substrates Berotralstat is a weak inhibitor of CYP2C9 increasing the Cmax and AUC of tolbutamide by 19% and 73%, respectively. No dose adjustment is recommended for concomitant use of medicinal products that are predominantly metabolised by CYP2C9 (e.g. tolbutamide) (see section 5.2). The effect of berotralstat on the CYP2C9 conversion of desogestrel to etonogestrel (active metabolite) was negligible. No do

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HOS-099222 · has-pregnancy-information · PDF-Seite 5

Women of childbearing potential Women of childbearing potential must use effective contraception during treatment with berotralstat and for at least 1 month following the last dose. Berotralstat is not recommended in women of childbearing potential not using contraception. Pregnancy There are no or limited amount of data from the use of berotralstat in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Berotralstat is not recommended during pregnancy. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of berotralstat in milk (see section 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from berotralstat therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility No effect on fertility was observed in animal studies (see section 5.3).

HOS-099228 · has-pregnancy-information · PDF-Seite 19

Women of childbearing potential Women of childbearing potential must use effective contraception during treatment with berotralstat and for at least 1 month following the last dose. Berotralstat is not recommended in women of childbearing potential not using contraception. Pregnancy There are no or limited amount of data from the use of berotralstat in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Berotralstat is not recommended during pregnancy. Breast-feeding Available pharmacodynamic/toxicological data in animals have shown excretion of berotralstat in milk (see section 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from berotralstat therapy taking into account the benefit of breast-feeding for the newborn/infant and the benefit of therapy for the woman. Fertility No effect on fertility was observed in animal studies (see section 5.3).

HOS-099226 · has-warning-information · PDF-Seite 17

General Berotralstat is not intended for treatment of acute HAE attacks, individualised treatment should be initiated with an approved rescue medicinal product. There are limited clinical data on the use of berotralstat in HAE patients with nC1-INH activity. Some categories of nC1-INH HAE may not respond to treatment due to alternative pathways that do not include plasma kallikrein activation. In this population, it is recommended to perform genetic testing, if available, according to the current HAE guidelines and to discontinue the treatment if clinical response is not observed (see sections 4.2 and 5.1). QT prolongation An increased risk of QT prolongation may be observed with higher concentrations of berotralstat (see section 5.1). Children should not take doses of berotralstat higher than indicated for their weight. Patients with moderate or severe hepatic impairment may develop increased serum berotralstat concentrations that are associated with a risk of prolonged QT. Use of berotralstat in these patients should be avoided. Patients with severe renal impairment may be at risk of prolonged QT. It is preferable to avoid the use of berotralstat in these patients. If treatment is required, appropriate monitoring (e.g. ECGs) should be considered. There are no data available for the use of berotralstat in patients with independent risk factors for QT prolongation such as electrolyte disturbances, known pre-existing QT prolongation (either acquired or familial), advancing age, or concomitant use of other medicinal products known to prolong the QT. It is preferrable to avoid the use of berotralstat in these patients. If treatment is required, appropriate monitoring (e.g. ECGs) should be considered. Excipients This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially ‘sodium-free’. 17

HOS-099220 · has-warning-information · PDF-Seite 3

General Berotralstat is not intended for treatment of acute HAE attacks, individualised treatment should be initiated with an approved rescue medicinal product. There are limited clinical data on the use of berotralstat in HAE patients with nC1-INH activity. Some categories of nC1-INH HAE may not respond to treatment due to alternative pathways that do not include plasma kallikrein activation. In this population, it is recommended to perform genetic testing, if available, according to the current HAE guidelines and to discontinue the treatment if clinical response is not observed (see sections 4.2 and 5.1). QT prolongation An increased risk of QT prolongation may be observed with higher concentrations of berotralstat (see section 5.1). Patients with moderate or severe hepatic impairment may develop increased serum berotralstat concentrations that are associated with a risk of prolonged QT. Use of berotralstat in these patients should be avoided. Patients with severe renal impairment may be at risk of prolonged QT. It is preferable to avoid the use of berotralstat in these patients. If treatment is required, appropriate monitoring (e.g. ECGs) should be considered. There are no data available for the use of berotralstat in patients with independent risk factors for QT prolongation such as electrolyte disturbances, known pre-existing QT prolongation (either acquired or familial), advancing age (see section 4.2), or concomitant use of other medicinal products known to prolong the QT. It is preferable to avoid the use of berotralstat in these patients. If treatment is required, appropriate monitoring (e.g. ECGs) should be considered. 3