Leitlinien & Arzneimittelsicherheit

HOS-096186 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile In all controlled and uncontrolled trials in patients with partial-onset seizures, 1,639 patients have received perampanel of whom 1,147 have been treated for 6 months and 703 for longer than 12 months. In the controlled and uncontrolled study in patients with primary generalised tonic-clonic seizures, 114 patients have received perampanel of whom 68 have been treated for 6 months and 36 for longer than 12 months. Adverse reactions leading to discontinuation: In the controlled Phase 3 partial-onset seizures clinical trials, the rate of discontinuation as a result of an adverse reaction was 1.7% (3/172), 4.2% (18/431) and 13.7% (35/255) in patients randomised to receive perampanel at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 1.4% (6/442) in patients randomised to receive placebo. The adverse reactions most commonly (≥ 1% 11 in the total perampanel group and greater than placebo) leading to discontinuation were dizziness and somnolence. In the controlled Phase 3 primary generalised tonic-clonic seizures clinical trial, the rate of discontinuation as a result of an adverse reaction was 4.9% (4/81) in patients randomised to receive perampanel 8 mg, and 1.2% (1/82) in patients randomised to receive placebo. The adverse reaction most commonly leading to discontinuation (≥ 2% in the perampanel group and greater than placebo) was dizziness. Post-marketing use Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with perampanel treatment (see section 4.4). Tabulated list of adverse reactions In the table below, adverse reactions, which were identified based on review of the full Fycompa clinical studies safety database, are listed by System Organ Class and frequency. The following convention has been used for the classification of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing seriousness. System Organ Class Very common Common Uncommon Not known Metabolism and Decreased appetite nutrition disorders Increased appetite Psychiatric Aggres

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HOS-096192 · has-adverse-reaction-information · PDF-Seite 32

Summary of the safety profile In all controlled and uncontrolled trials in patients with partial-onset seizures, 1,639 patients have received perampanel of whom 1,147 have been treated for 6 months and 703 for longer than 12 months. In the controlled and uncontrolled study in patients with primary generalised tonic-clonic seizures, 114 patients have received perampanel of whom 68 have been treated for 6 months and 36 for longer than 12 months. Adverse reactions leading to discontinuation: In the controlled Phase 3 partial-onset seizures clinical trials, the rate of discontinuation as a result of an adverse reaction was 1.7% (3/172), 4.2% (18/431) and 13.7% (35/255) in patients randomised to receive perampanel at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 1.4% (6/442) in patients randomised to receive placebo. The adverse reactions most commonly (≥ 1% in the total perampanel group and greater than placebo) leading to discontinuation were dizziness and somnolence. In the controlled Phase 3 primary generalised tonic-clonic seizures clinical trial, the rate of discontinuation as a result of an adverse reaction was 4.9% (4/81) in patients randomised to receive perampanel 8 mg, and 1.2% (1/82) in patients randomised to receive placebo. The adverse reaction most commonly leading to discontinuation (≥ 2% in the perampanel group and greater than placebo) was dizziness. Post-marketing use Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with perampanel treatment (see section 4.4). Tabulated list of adverse reactions In the table below, adverse reactions, which were identified based on review of the full Fycompa clinical studies safety database, are listed by System Organ Class and frequency. The following convention has been used for the classification of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing seriousness. System Organ Class Very common Common Uncommon Not known Metabolism and Decreased appetite nutrition disorders Increased appetite Psychiatric Aggression Suicidal disorders

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HOS-096182 · has-contraindication-information · PDF-Seite 7

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

HOS-096188 · has-contraindication-information · PDF-Seite 27

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

HOS-096181 · has-indication-information · PDF-Seite 3

Fycompa (perampanel) is indicated for the adjunctive treatment of: - partial-onset seizures (POS) with or without secondarily generalised seizures in patients from 4 years of age and older. - primary generalised tonic-clonic (PGTC) seizures in patients from 7 years of age and older with idiopathic generalised epilepsy (IGE).

HOS-096187 · has-indication-information · PDF-Seite 23

Fycompa (perampanel) is indicated for the adjunctive treatment of - partial-onset seizures (POS) with or without secondarily generalised seizures in patients from 4 years of age and older. - primary generalised tonic-clonic (PGTC) seizures in patients from 7 years of age and older with idiopathic generalised epilepsy (IGE).

HOS-096190 · has-interaction-information · PDF-Seite 29

Fycompa is not considered a strong inducer or inhibitor of cytochrome P450 or UGT enzymes (see section 5.2). Hormonal contraceptives In healthy women receiving 12 mg (but not 4 or 8 mg/day) for 21 days concomitantly with a combined oral contraceptive, Fycompa was shown to decrease the levonorgestrel exposure (mean Cmax and AUC values were each decreased by 40%). Ethinylestradiol AUC was not affected by Fycompa 12 mg whereas Cmax was decreased by 18%. Therefore, the possibility of decreased efficacy of hormonal progestative-containing contraceptives should be considered for women needing Fycompa 12 mg/day and an additional reliable method (intra-uterine device (IUD), condom) is to be used (see section 4.4). Interactions between Fycompa and other anti-epileptic medicinal products Potential interactions between Fycompa and other anti-epileptic drugs (AEDs) were assessed in clinical studies. A population PK analysis of three pooled Phase 3 studies in adolescent and adult patients with partial-onset seizures evaluated the effect of Fycompa (up to 12 mg once daily) on the PK of other AEDs. In another population PK analysis of pooled data from twenty Phase 1 studies in healthy subjects, with Fycompa up to 36 mg, and one Phase 2 and six Phase 3 studies in paediatric, adolescent and adult patients with partial-onset seizures or primary generalised tonic-clonic seizures, with Fycompa up to 16 mg once daily, evaluated the effect of concomitant AEDs of perampanel clearance. The effect of these interactions on average steady state concentration is summarised in the following table. 29  AED Influence of AED on Fycompa Influence of Fycompa on AED coadministered concentration concentration Carbamazepine 3 fold decrease <10% decrease Clobazam No influence <10% decrease Clonazepam No influence No influence Lamotrigine No influence <10% decrease Levetiracetam No influence No influence Oxcarbazepine 2 fold decrease 35% increase 1) Phenobarbital 20% decrease No influence Phenytoin 2 fold decrease No influence Topiramate 20% decrease

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HOS-096184 · has-interaction-information · PDF-Seite 9

Fycompa is not considered a strong inducer or inhibitor of cytochrome P450 or UGT enzymes (see section 5.2). Hormonal contraceptives In healthy women receiving 12 mg (but not 4 or 8 mg/day) for 21 days concomitantly with a combined oral contraceptive, Fycompa was shown to decrease the levonorgestrel exposure (mean Cmax and AUC values were each decreased by 40%). Ethinylestradiol AUC was not affected by Fycompa 12 mg whereas Cmax was decreased by 18%. Therefore, the possibility of decreased efficacy of hormonal progestative-containing contraceptives should be considered for women needing Fycompa 12 mg/day and an additional reliable method (intra-uterine device (IUD), condom) is to be used (see section 4.4). Interactions between Fycompa and other anti-epileptic medicinal products Potential interactions between Fycompa and other anti-epileptic drugs (AEDs) were assessed in clinical studies. A population PK analysis of three pooled Phase 3 studies in adolescent and adult patients with partial-onset seizures evaluated the effect of Fycompa (up to 12 mg once daily) on the PK of other AEDs. In another population PK analysis of pooled data from twenty Phase 1 studies in healthy subjects, with Fycompa up to 36 mg, and one Phase 2 and six Phase 3 studies in paediatric, adolescent, and adult patients with partial-onset seizures or primary generalised tonic-clonic seizures, with Fycompa up to 16 mg once daily, evaluated the effect of concomitant AEDs of perampanel clearance. The effect of these interactions on average steady state concentration is summarised in the following table. AED Influence of AED on Fycompa Influence of Fycompa on AED coadministered concentration concentration Carbamazepine 3 fold decrease <10% decrease Clobazam No influence <10% decrease Clonazepam No influence No influence Lamotrigine No influence <10% decrease Levetiracetam No influence No influence Oxcarbazepine 2 fold decrease 35% increase 1) Phenobarbital 20% decrease No influence Phenytoin 2 fold decrease No influence Topiramate 20% decrease No influence Valproic Acid No influence

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HOS-096185 · has-pregnancy-information · PDF-Seite 11

Women of childbearing potential and contraception in males and females Fycompa is not recommended in women of childbearing potential not using contraception unless clearly necessary. Fycompa may decrease the effectiveness of progestative-containing hormonal contraceptives. An additional non-hormonal form of contraception is, therefore recommended (see sections 4.4 and 4.5). Pregnancy There are limited amounts of data (less than 300 pregnancy outcomes) from the use of perampanel in pregnant women. Studies in animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats at maternally toxic doses (see section 5.3). Fycompa is not recommended during pregnancy. Breast-feeding Studies in lactating rats have shown excretion of perampanel and/or its metabolites in milk (for details see section 5.3). It is not known whether perampanel is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fycompa therapy taking into account the benefit of breast--feeding for the child and the benefit of therapy for the woman. Fertility In the fertility study in rats, prolonged and irregular oestrous cycles were observed at high-dose (30 mg/kg) in females; however, these changes did not affect the fertility and early embryonic development. There were no effects on male fertility (see section 5.3). The effect of perampanel on human fertility has not been established.

HOS-096191 · has-pregnancy-information · PDF-Seite 31

Women of childbearing potential and contraception in males and females Fycompa is not recommended in women of childbearing potential not using contraception unless clearly necessary. Fycompa may decrease the effectiveness of progestative-containing hormonal contraceptives. An additional non-hormonal form of contraception is, therefore recommended (see sections 4.4 and 4.5). Pregnancy There are limited amounts of data (less than 300 pregnancy outcomes) from the use of perampanel in pregnant women. Studies in animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats at maternally toxic doses (see section 5.3). Fycompa is not recommended during pregnancy. Breast-feeding Studies in lactating rats have shown excretion of perampanel and/or its metabolites in milk (for details see section 5.3). It is not known whether perampanel is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fycompa therapy taking into account the benefit of breast--feeding for the child and the benefit of therapy for the woman. Fertility In the fertility study in rats, prolonged and irregular oestrous cycles were observed at high-dose (30 mg/kg) in females; however, these changes did not affect the fertility and early embryonic development. There were no effects on male fertility (see section 5.3). The effect of perampanel on human fertility has not been established.

HOS-096189 · has-warning-information · PDF-Seite 27

Suicidal ideation Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicinal products in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicinal products 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 perampanel. Therefore, patients (children, adolescents, and adults) 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 signs of suicidal ideation or behaviour emerge. Severe cutaneous adverse reactions (SCARs) Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens - Johnson Syndrome (SJS), which can be life-threatening or fatal, have been reported (frequency unknown; see section 4.8) in association with perampanel treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Symptoms of SJS include typically although not exclusively, skin detachment (epidermal necrosis/blister) < 10%, erythematous skin (confluent), rapid progression, painful atypical target-like 27 lesions and/or purpuric macules in wide dissemination or large erythema (confluent), bullous/erosive involvement of more than 2 mucous membranes. If signs and symptoms suggestive of these reactions appear, perampanel should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or DRESS with the use of perampanel, treatment with perampanel must not be restarted in this patient at any time. Absence and myoclonic seizures Absence and myoclonic seizures are two common generalised seizure types that frequently occur in IGE patients. Other AEDs are known to induce or aggravate these seizure typ

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HOS-096183 · has-warning-information · PDF-Seite 7

Suicidal ideation Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicinal products in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicinal products 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 perampanel. Therefore, patients (children, adolescents, and adults) 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 signs of suicidal ideation or behaviour emerge. Severe cutaneous adverse reactions (SCARs) Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens - Johnson Syndrome (SJS), which can be life-threatening or fatal, have been reported (frequency unknown; see section 4.8) in association with perampanel treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Symptoms of SJS include typically although not exclusively, skin detachment (epidermal necrosis/blister) < 10%, erythematous skin (confluent), rapid progression, painful atypical target-like lesions and/or purpuric macules in wide dissemination or large erythema (confluent), bullous/erosive involvement of more than 2 mucous membranes. If signs and symptoms suggestive of these reactions appear, perampanel should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or DRESS with the use of perampanel, treatment with perampanel must not be restarted in this patient at any time. 7 Absence and myoclonic seizures Absence and myoclonic seizures are two common generalised seizure types that frequently occur in IGE patients. Other AEDs are known to induce or aggravate these seizure ty

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