Briviact (in Italy: Nubriveo) · 4.1 Therapeutic indications · 2

HOS-097309 · has-adverse-reaction-information · PDF-Seite 45

Summary of the safety profile The most frequently reported adverse reactions (>10%) with brivaracetam treatment were: somnolence (14.3 %) and dizziness (11.0 %). They were usually mild to moderate in intensity. Somnolence and fatigue were reported at a higher incidence with increasing dose. The discontinuation rate due to adverse reactions was 3.5 %, 3.4 % and 4.0 % for patients randomized to brivaracetam at respectively the dose of 50 mg/day, 100 mg/day and 200 mg/day and 1.7 % for patients randomized to placebo. The adverse reactions most frequently resulting in discontinuation of brivaracetam therapy were dizziness (0.8 %) and convulsion (0.8 %). Tabulated list of adverse reactions In the table below, adverse reactions, which were identified based on review of the three placebo- controlled, fixed-dose studies safety database in subjects ≥ 16 years of age and from post-marketing experience, are listed by System Organ Class and frequency. The frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and not known (frequency cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 45  System organ class Frequency Adverse reactions Infections and Common Influenza infestations Blood and lymphatic Uncommon Neutropenia system disorders Immune system disorders Uncommon Type I hypersensitivity Metabolism and nutrition Common Decreased appetite disorders Psychiatric disorders Common Depression, anxiety, insomnia, irritability Uncommon Suicidal ideation, psychotic disorder, aggression, agitation Nervous system disorders Very common Dizziness, somnolence Common Convulsion, vertigo Respiratory, thoracic and Common Upper respiratory tract infections, cough mediastinal disorders Gastrointestinal Common Nausea, vomiting, constipation disorders Skin and subcutaneous Not known Stevens-Johnson syndrome(1) tissue disorders General disorders and Common

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HOS-097297 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most frequently reported adverse reactions (>10 %) with brivaracetam treatment were: somnolence (14.3 %) and dizziness (11.0 %). They were usually mild to moderate in intensity. Somnolence and fatigue were reported at a higher incidence with increasing dose. The discontinuation rate due to adverse reactions was 3.5 %, 3.4 % and 4.0 % for patients randomized to brivaracetam at respectively the dose of 50 mg/day, 100 mg/day and 200 mg/day and 1.7 % for 9 patients randomized to placebo. The adverse reactions most frequently resulting in discontinuation of brivaracetam therapy were dizziness (0.8 %) and convulsion (0.8 %). Tabulated list of adverse reactions In the table below, adverse reactions, which were identified based on review of the three placebo- controlled, fixed-dose studies safety database in subjects ≥ 16 years of age and from post-marketing experience, are listed by System Organ Class and frequency. The frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and not known (frequency cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System organ class Frequency Adverse reactions Infections and Common Influenza infestations Blood and lymphatic Uncommon Neutropenia system disorders Immune system disorders Uncommon Type I hypersensitivity Metabolism and nutrition Common Decreased appetite disorders Psychiatric disorders Common Depression, anxiety, insomnia, irritability Uncommon Suicidal ideation, psychotic disorder, aggression, agitation Nervous system disorders Very common Dizziness, somnolence Common Convulsion, vertigo Respiratory, thoracic and Common Upper respiratory tract infections, cough mediastinal disorders Gastrointestinal Common Nausea, vomiting, constipation disorders Skin and subcutaneous Not known Stevens-Johnson syndrome(1) tissue disorders General disorders and Common

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HOS-097303 · has-adverse-reaction-information · PDF-Seite 29

Summary of the safety profile The most frequently reported adverse reactions (>10 %) with brivaracetam treatment were: somnolence (14.3 %) and dizziness (11.0 %). They were usually mild to moderate in intensity. Somnolence and fatigue were reported at a higher incidence with increasing dose. The discontinuation rate due to adverse reactions was 3.5 %, 3.4 % and 4.0 % for patients randomized to brivaracetam at respectively the dose of 50 mg/day, 100 mg/day and 200 mg/day and 1.7% for patients randomized to placebo. The adverse reactions most frequently resulting in discontinuation of brivaracetam therapy were dizziness (0.8 %) and convulsion (0.8 %). Tabulated list of adverse reactions In the table below, adverse reactions, which were identified based on review of the three placebo- controlled, fixed-dose studies safety database in subjects ≥ 16 years of age and from post-marketing experience, are listed by System Organ Class and frequency. The frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and not known (frequency cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System organ class Frequency Adverse reactions Infections and Common Influenza infestations Blood and lymphatic Uncommon Neutropenia system disorders Immune system disorders Uncommon Type I hypersensitivity Metabolism and nutrition Common Decreased appetite disorders Psychiatric disorders Common Depression, anxiety, insomnia, irritability Uncommon Suicidal ideation, psychotic disorder, aggression, agitation Nervous system disorders Very common Dizziness, somnolence Common Convulsion, vertigo Respiratory, thoracic and Common Upper respiratory tract infections, cough mediastinal disorders Gastrointestinal Common Nausea, vomiting, constipation disorders 29  System organ class Frequency Adverse reactions Skin and subcutaneous Not known Stev

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HOS-097293 · has-contraindication-information · PDF-Seite 5

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

HOS-097305 · has-contraindication-information · PDF-Seite 41

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

HOS-097299 · has-contraindication-information · PDF-Seite 25

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

HOS-097304 · has-indication-information · PDF-Seite 39

Briviact is indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents and children from 2 years of age with epilepsy.

HOS-097292 · has-indication-information · PDF-Seite 3

Briviact is indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents and children from 2 years of age with epilepsy.

HOS-097298 · has-indication-information · PDF-Seite 21

Briviact is indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents and children from 2 years of age with epilepsy.

HOS-097307 · has-interaction-information · PDF-Seite 42

Formal interaction studies have only been performed in adults. Pharmacodynamic interactions Concomitant treatment with levetiracetam In the clinical studies, although the numbers were limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently. No additional safety or tolerability concern was observed (see section 5.1). Interaction with alcohol In a pharmacokinetic and pharmacodynamic interaction study between brivaracetam 200 mg single dose and ethanol 0.6 g/L continuous infusion in healthy subjects, there was no pharmacokinetic interaction, but brivaracetam approximately doubled the effect of alcohol on psychomotor function, attention and memory. Intake of brivaracetam with alcohol is not recommended. Pharmacokinetic interactions Effects of other medicinal products on the pharmacokinetics of brivaracetam In vitro data suggest that brivaracetam has a low interaction potential. The main disposition pathway of brivaracetam is by CYP-independent hydrolysis. A second disposition pathway involves hydroxylation mediated by CYP2C19 (see section 5.2). Brivaracetam plasma concentrations may increase when coadministered with CYP2C19 strong inhibitors (e.g. fluconazole, fluvoxamine), but the risk of a clinically relevant CYP2C19-mediated interaction is considered to be low. Limited clinical data are available implying that coadministration of cannabidiol may increase the plasma exposure of brivaracetam, possibly through CYP2C19 inhibition, but the clinical relevance is uncertain. Rifampicin In healthy subjects, coadministration with the strong enzyme inducer rifampicin (600 mg/day for 5 days), decreased brivaracetam area under the plasma concentration curve (AUC) by 45 %. Prescribers should consider adjusting the brivaracetam dose in patients starting or ending treatment with rifampicin. Strong enzyme inducing AEDs Brivaracetam plasma concentrations are decreased when coadministered with strong enzyme inducing AEDs (carbamazepine, phenobarbital, phenytoin) but no dose adjustment is required (see table 1). Other enzyme inducers Other strong enzyme inducers (such as St John´s wort (Hypericum perforatum)) may also decrease the systemic exposure of brivaracetam. Therefore, starting or ending treatment with St John’s wort should be done with caution. 42 Effects of brivaracetam on other medicinal products Brivaracetam given 50 or 150 mg/day did not affect t

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HOS-097301 · has-interaction-information · PDF-Seite 26

Formal interaction studies have only been performed in adults. Pharmacodynamic interactions Concomitant treatment with levetiracetam In the clinical studies, although the numbers were limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently. No additional safety or tolerability concern was observed (see section 5.1). Interaction with alcohol In a pharmacokinetic and pharmacodynamic interaction study between brivaracetam 200 mg single dose and ethanol 0.6 g/L continuous infusion in healthy subjects, there was no pharmacokinetic interaction, but brivaracetam approximately doubled the effect of alcohol on psychomotor function, attention and memory. Intake of brivaracetam with alcohol is not recommended. Pharmacokinetic interactions Effects of other medicinal products on the pharmacokinetics of brivaracetam In vitro data suggest that brivaracetam has a low interaction potential. The main disposition pathway of brivaracetam is by CYP-independent hydrolysis. A second disposition pathway involves hydroxylation mediated by CYP2C19 (see section 5.2). Brivaracetam plasma concentrations may increase when coadministered with CYP2C19 strong inhibitors (e.g. fluconazole, fluvoxamine), but the risk of a clinically relevant CYP2C19-mediated interaction is considered to be low. Limited clinical data are available implying that coadministration of cannabidiol may increase the plasma exposure of brivaracetam, possibly through CYP2C19 inhibition, but the clinical relevance is uncertain. Rifampicin In healthy subjects, coadministration with the strong enzyme inducer rifampicin (600 mg/day for 5 days), decreased brivaracetam area under the plasma concentration curve (AUC) by 45 %. Prescribers should consider adjusting the brivaracetam dose in patients starting or ending treatment with rifampicin. Strong enzyme inducing AEDs Brivaracetam plasma concentrations are decreased when coadministered with strong enzyme inducing AEDs (carbamazepine, phenobarbital, phenytoin) but no dose adjustment is required (see table 1). 26 Other enzyme inducers Other strong enzyme inducers (such as St John´s wort (Hypericum perforatum)) may also decrease the systemic exposure of brivaracetam. Therefore, starting or ending treatment with St John’s wort should be done with caution. Effects of brivaracetam on other medicinal products Brivaracetam given 50 or 150 mg/day did not affec

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HOS-097295 · has-interaction-information · PDF-Seite 6

Formal interaction studies have only been performed in adults. Pharmacodynamic interactions Concomitant treatment with levetiracetam In the clinical studies, although the numbers were limited, there was no observed benefit of brivaracetam versus placebo in patients taking levetiracetam concurrently. No additional safety or tolerability concern was observed (see section 5.1). Interaction with alcohol In a pharmacokinetic and pharmacodynamic interaction study between brivaracetam 200 mg single dose and ethanol 0.6 g/L continuous infusion in healthy subjects, there was no pharmacokinetic interaction, but brivaracetam approximately doubled the effect of alcohol on psychomotor function, attention and memory. Intake of brivaracetam with alcohol is not recommended. Pharmacokinetic interactions Effects of other medicinal products on the pharmacokinetics of brivaracetam In vitro data suggest that brivaracetam has a low interaction potential. The main disposition pathway of brivaracetam is by CYP-independent hydrolysis. A second disposition pathway involves hydroxylation mediated by CYP2C19 (see section 5.2). Brivaracetam plasma concentrations may increase when coadministered with CYP2C19 strong inhibitors (e.g. fluconazole, fluvoxamine), but the risk of a clinically relevant CYP2C19-mediated interaction is considered to be low. Limited clinical data are available implying that coadministration of cannabidiol may increase the plasma exposure of brivaracetam, possibly through CYP2C19 inhibition, but the clinical relevance is uncertain. 6 Rifampicin In healthy subjects, coadministration with the strong enzyme inducer rifampicin (600 mg/day for 5 days), decreased brivaracetam area under the plasma concentration curve (AUC) by 45 %. Prescribers should consider adjusting the brivaracetam dose in patients starting or ending treatment with rifampicin. Strong enzyme inducing AEDs Brivaracetam plasma concentrations are decreased when coadministered with strong enzyme inducing AEDs (carbamazepine, phenobarbital, phenytoin) but no dose adjustment is required (see table 1). Other enzyme inducers Other strong enzyme inducers (such as St John´s wort (Hypericum perforatum)) may also decrease the systemic exposure of brivaracetam. Therefore, starting or ending treatment with St John’s wort should be done with caution. Effects of brivaracetam on other medicinal products Brivaracetam given 50 or 150 mg/day did not affec

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HOS-097302 · has-pregnancy-information · PDF-Seite 28

Women of childbearing potential Physicians should discuss family planning and contraception with women of childbearing potential taking brivaracetam (see Pregnancy). If a woman decides to become pregnant, the use of brivaracetam should be carefully re-evaluated. Pregnancy Risk related to epilepsy and antiepileptic medicinal products in general For all anti-epileptic drugs, it has been shown that in the offspring of treated women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3 % in the general population. In the treated population, an increase in malformations has been noted with polytherapy; however, the extent to which the treatment and/or the underlying condition is responsible has not been elucidated. Discontinuation of anti-epileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus. Risk related to brivaracetam There is a limited amount of data from the use of brivaracetam in pregnant women. There is no data on placental transfer in humans, but brivaracetam was shown to readily cross the placenta in rats (see section 5.3). The potential risk for humans is unknown. Animal studies did not detect any teratogenic potential of brivaracetam (see section 5.3). In clinical studies, brivaracetam was used as adjunctive therapy and when it was used with carbamazepine, it induced a dose-related increase in the concentration of the active metabolite, carbamazepine-epoxide (see section 4.5). There is insufficient data to determine the clinical significance of this effect in pregnancy. As a precautionary measure, brivaracetam should not be used during pregnancy unless clinically necessary i.e. (if the benefit to the mother clearly outweighs the potential risk to the foetus). Breast-feeding Brivaracetam is excreted in human breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue brivaracetam, taking into account the benefit of the medicinal product to the mother. In case of co-administration of brivaracetam and carbamazepine, the amount of 28 carbamazepine-epoxide excreted in breast milk could increase. There is insufficient data to determine the clinical significance. Fertility No human data on the effect of brivaracetam on fertility are available. In rats, there was no effect on fertility with brivaracetam (see section 5.3).

HOS-097296 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential Physicians should discuss family planning and contraception with women of childbearing potential taking brivaracetam (see Pregnancy). If a woman decides to become pregnant, the use of brivaracetam should be carefully re-evaluated. 8 Pregnancy Risk related to epilepsy and antiepileptic medicinal products in general For all anti-epileptic drugs, it has been shown that in the offspring of treated women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3 % in the general population. In the treated population, an increase in malformations has been noted with polytherapy; however, the extent to which the treatment and/or the underlying condition is responsible has not been elucidated. Discontinuation of anti-epileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus. Risk related to brivaracetam There is a limited amount of data from the use of brivaracetam in pregnant women. There is no data on placental transfer in humans, but brivaracetam was shown to readily cross the placenta in rats (see section 5.3). The potential risk for humans is unknown. Animal studies did not detect any teratogenic potential of brivaracetam (see section 5.3). In clinical studies, brivaracetam was used as adjunctive therapy and when it was used with carbamazepine, it induced a dose-related increase in the concentration of the active metabolite, carbamazepine-epoxide (see section 4.5). There is insufficient data to determine the clinical significance of this effect in pregnancy. As a precautionary measure, brivaracetam should not be used during pregnancy unless clinically necessary i.e. (if the benefit to the mother clearly outweighs the potential risk to the foetus). Breast-feeding Brivaracetam is excreted in human breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue brivaracetam, taking into account the benefit of the medicinal product to the mother. In case of co-administration of brivaracetam and carbamazepine, the amount of carbamazepine-epoxide excreted in breast milk could increase. There is insufficient data to determine the clinical significance. Fertility No human data on the effect of brivaracetam on fertility are available. In rats, there was no effect on fertility with brivaracetam (see section 5.3).

HOS-097308 · has-pregnancy-information · PDF-Seite 44

Women of childbearing potential Physicians should discuss family planning and contraception with women of childbearing potential taking brivaracetam (see Pregnancy). If a woman decides to become pregnant, the use of brivaracetam should be carefully re-evaluated. Pregnancy Risk related to epilepsy and antiepileptic medicinal products in general For all anti-epileptic drugs, it has been shown that in the offspring of treated women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3 % in the general population. In the treated population, an increase in malformations has been noted with polytherapy; however, the extent to which the treatment and/or the underlying condition is responsible has not been elucidated. Discontinuation of anti-epileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus. Risk related to brivaracetam There is a limited amount of data from the use of brivaracetam in pregnant women. There is no data on placental transfer in humans, but brivaracetam was shown to readily cross the placenta in rats (see section 5.3). The potential risk for humans is unknown. Animal studies did not detect any teratogenic potential of brivaracetam (see section 5.3). In clinical studies, brivaracetam was used as adjunctive therapy and when it was used with carbamazepine, it induced a dose-related increase in the concentration of the active metabolite, carbamazepine-epoxide (see section 4.5). There is insufficient data to determine the clinical significance of this effect in pregnancy. As a precautionary measure, brivaracetam should not be used during pregnancy unless clinically necessary i.e. (if the benefit to the mother clearly outweighs the potential risk to the foetus). Breast-feeding Brivaracetam is excreted in human breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue brivaracetam, taking into account the benefit of the medicinal product to the mother. In case of co-administration of brivaracetam and carbamazepine, the amount of carbamazepine-epoxide excreted in breast milk could increase. There is insufficient data to determine the clinical significance. 44 Fertility No human data on the effect of brivaracetam on fertility are available. In rats, there was no effect on fertility with brivaracetam (see section 5.3).

HOS-097294 · has-warning-information · PDF-Seite 5

Suicidal ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic drugs (AEDs), including brivaracetam, in several indications. A meta-analysis of randomized placebo- controlled clinical studies of AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for brivaracetam. Patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should any signs of suicidal ideation or behaviour emerge. See also section 4.8, paediatric data. 5 Hepatic impairment There are limited clinical data on the use of brivaracetam in patients with pre-existing hepatic impairment. Dose adjustments are recommended for patients with hepatic impairment (see section 4.2). Severe cutaneous adverse reactions (SCARs) Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, have been reported in association with brivaracetam treatment. At the time of the prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, brivaracetam should be withdrawn immediately and an alternative treatment should be considered. Excipients Lactose intolerance Brivaracetam film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Sodium content Brivaracetam film-coated tablets contain less than 1 mmol sodium (23mg) per tablet, that is to say essentially ‘sodium free’.

HOS-097300 · has-warning-information · PDF-Seite 25

Suicidal ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic drugs (AEDs), including brivaracetam, in several indications. A meta-analysis of randomized placebo- controlled clinical studies of AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for brivaracetam. Patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should any signs of suicidal ideation or behaviour emerge. See also section 4.8, paediatric data. Hepatic impairment There are limited clinical data on the use of brivaracetam in patients with pre-existing hepatic impairment. Dose adjustments are recommended for patients with hepatic impairment (see section 4.2). Severe cutaneous adverse reactions (SCARs) Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, have been reported in association with brivaracetam treatment. At the time of the prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, brivaracetam should be withdrawn immediately and an alternative treatment should be considered. 25 Excipients Sodium content Brivaracetam oral solution contains less than 1 mmol sodium (23mg) per ml, that is to say essentially ‘sodium free’. Fructose intolerance This medicine contains 168 mg sorbitol (E420) in each ml. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product. Excipients which may cause intolerance The oral solution contains methyl parahydroxybenzoate (E218), which may cause allergic reactions (possibly delayed). Brivaracetam oral solution contains propylene glycol (E1520).

HOS-097306 · has-warning-information · PDF-Seite 41

Suicidal ideation and behaviour Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic drugs (AEDs), including brivaracetam, in several indications. A meta-analysis of randomized placebo- controlled clinical studiesof AEDs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for brivaracetam. Patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should any signs of suicidal ideation or behaviour emerge. See also section 4.8, paediatric data. Hepatic impairment There are limited clinical data on the use of brivaracetam in patients with pre-existing hepatic impairment. Dose adjustments are recommended for patients with hepatic impairment (see section 4.2). 41 Severe cutaneous adverse reactions (SCARs) Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, have been reported in association with brivaracetam treatment. At the time of the prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, brivaracetam should be withdrawn immediately and an alternative treatment should be considered. Excipients This medicinal product contains 19.1 mg sodium per vial, equivalent to 1 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.