Leitlinien & Arzneimittelsicherheit

HOS-155225 · has-adverse-reaction-information · PDF-Seite 28

Summary of the safety profile The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The adverse reaction profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label 28 extension studies, as well as post-marketing experience. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications. Tabulated list of adverse reactions Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. Adverse reactions are presented in the order of decreasing seriousness and their frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000) and very rare (< 1/10000). Frequency category MedDRA Very Common Uncommon Rare Very rare SOC common Infections and Nasopharyngi Infection infestations tis Blood and Thrombocytope Pancytopenia, lymphatic nia, leukopenia neutropenia, system agranulocytosis disorders Immune Drug reaction system with eosinophilia disorders and systemic symptoms (DRESS)(1), Hypersensitivity (including angioedema and

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HOS-155219 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The adverse reaction profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications. Tabulated list of adverse reactions Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. Adverse reactions are presented in the order of decreasing seriousness and their frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000) and very rare (< 1/10000). 9  Frequency category MedDRA SOC Very Common Uncommon Rare Very rare common Infections and Nasopharyngi Infection infestations tis Blood and Thrombocytope Pancytopenia, lymphatic nia, leukopenia neutropenia, system agranulocytosis disorders Immune system Drug reaction disorders with eosinophilia and systemic symptoms (DRESS)(1), Hypersensitivity (including angioedema and anaphylaxis) Metabolism and Anorexia

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HOS-155215 · has-contraindication-information · PDF-Seite 6

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

HOS-155221 · 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-155220 · has-indication-information · PDF-Seite 21

Levetiracetam ratiopharm is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy. Levetiracetam ratiopharm is indicated as adjunctive therapy • in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy. • in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy. • in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

HOS-155214 · has-indication-information · PDF-Seite 2

Levetiracetam ratiopharm is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy. Levetiracetam ratiopharm is indicated as adjunctive therapy • in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy. • in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy. 2  • in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

HOS-155217 · has-interaction-information · PDF-Seite 7

Antiepileptic medicinal products Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam. As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam. A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme- inducing antiepileptic medicinal products. Dose adjustment is not required. Probenecid Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. Methotrexate Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs. 7 Oral contraceptives and other pharmacokinetics interactions Levetiracetam 1000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl- estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam. Laxatives There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking

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HOS-155223 · has-interaction-information · PDF-Seite 27

Antiepileptic medicinal products Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam. As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam. A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme- inducing antiepileptic medicinal products. Dose adjustment is not required. Probenecid Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. Methotrexate Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs. Oral contraceptives and other pharmacokinetics interactions Levetiracetam 1000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl- estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam. Laxatives There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam. Food and alcohol The extent of absor

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HOS-155218 · has-pregnancy-information · PDF-Seite 8

Women of child bearing potential Specialist advice should be given to women who are of childbearing potential. Treatment with levetiracetam should be reviewed when a woman is planning to become pregnant. As with all antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic medicines AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics. Pregnancy A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy (more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not suggest an increase in the risk for major congenital malformations. Limited evidence is available on the neurodevelopment of children exposed to levetiracetam monotherapy in utero. Data from two observational population-based registry studies undertaken in largely the same dataset from the Nordic countries and including more than 1000 children born to women with epilepsy prenatally exposed to levetiracetam monotherapy do not suggest an increased risk of autism spectrum disorders or intellectual disability compared to children born to women with epilepsy not exposed to an antiepileptic drug in utero. The mean follow-up time of children in the levetiracetam group was shorter than for the group of children non exposed to any antiepileptic drug (e.g. 4.4 years vs 6.8 years in one of the studies). Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically needed. In such case, the lowest effective dose is recommended. Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60 % of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. Breast-feeding Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended. 8 However, if levetiracetam treatment is needed during breast-feeding, the benefit/risk of the treatment should be weighed considering th

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HOS-155224 · has-pregnancy-information · PDF-Seite 27

Women of child bearing potential 27 Specialist advice should be given to women who are of childbearing potential. Treatment with levetiracetam should be reviewed when a woman is planning to become pregnant. As with all antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic medicines AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics. Pregnancy A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy (more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not suggest an increase in the risk for major congenital malformations. Limited evidence is available on the neurodevelopment of children exposed to levetiracetam monotherapy in utero. Data from two observational population-based registry studies undertaken in largely the same dataset from the Nordic countries and including more than 1000 children born to women with epilepsy prenatally exposed to levetiracetam monotherapy do not suggest an increased risk of autism spectrum disorders or intellectual disability compared to children born to women with epilepsy not exposed to an antiepileptic drug in utero. The mean follow-up time of children in the levetiracetam group was shorter than for the group of children non exposed to any antiepileptic drug (e.g. 4.4 years vs 6.8 years in one of the studies). Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically needed. In such case, the lowest effective dose is recommended. Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60 % of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. Breast-feeding Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended. However, if levetiracetam treatment is needed during breast-feeding, the benefit/risk of the treatment should be weighed considering t

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HOS-155222 · has-warning-information · PDF-Seite 25

Renal impairment The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see section 4.2). Acute kidney injury The use of levetiracetam has been very rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months. Blood cell counts Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam 25 administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders (section 4.8). Suicide Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore, patients should be monitored for signs of depression and/or 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 depression and/or suicidal ideation or behaviour emerge. Abnormal and aggressive behaviours Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment adaptation or gradual discontinuation should be considered. If discontinuation is considered, please refer to section 4.2. Worsening of seizures As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or severity. This paradoxical effect was mostly reported within the first month after levetiracetam initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. Patients should be advised to consult their physician immediately in case of aggravation of epilepsy. Lack of efficacy or seizure worsening has for example been

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HOS-155216 · has-warning-information · PDF-Seite 6

Renal impairment The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see section 4.2). Acute kidney injury The use of levetiracetam has been very rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months. Blood cell counts Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders (section 4.8). Suicide Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore, patients should be monitored for signs of depression and/or 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 depression and/or suicidal ideation or behaviour emerge. Abnormal and aggressive behaviours Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric 6 signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment adaptation or gradual discontinuation should be considered. If discontinuation is considered, please refer to section 4.2. Worsening of seizures As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or severity. This paradoxical effect was mostly reported within the first month after levetiracetam initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. Patients should be advised to consult their physician immediately in case of aggravation of epilepsy. Lack of efficacy or seizure worsening has for example b

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