Inovelon · 4.6 Fertility, pregnancy and lactation · 1

HOS-094266 · has-adverse-reaction-information · PDF-Seite 22

Summary of the safety profile The clinical development program has included over 1,900 patients, with different types of epilepsy, exposed to rufinamide. The most commonly reported adverse reactions overall were headache, dizziness, fatigue, and somnolence. The most common adverse reactions observed at a higher incidence than placebo in patients with Lennox-Gastaut syndrome were somnolence and vomiting. Adverse reactions were usually mild to moderate in severity. The discontinuation rate in Lennox-Gastaut syndrome due to adverse reactions was 8.2% for patients receiving rufinamide and 0% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from the rufinamide treatment group were rash and vomiting. Tabulated list of adverse reactions Adverse reactions reported with an incidence greater than placebo, during the Lennox-Gastaut syndrome double-blind studies or in the overall rufinamide-exposed population, are listed in the table below by MedDRA preferred term, system organ class and by frequency. Frequencies are defined as: 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). 22 System Organ Class Very Common Common Uncommon Rare Infections and Pneumonia infestations Influenza Nasopharyngitis Ear infection Sinusitis Rhinitis Immune system disorders Hypersensitivity* Metabolism and Anorexia nutrition Eating disorder disorders Decreased appetite Psychiatric Anxiety disorders Insomnia Nervous system Somnolence* Status epilepticus* disorders Headache Convulsion Dizziness* Coordination Abnormal* Nystagmus Psychomotor hyperactivity Tremor Eye Disorders Diplopia Vision blurred Ear and Vertigo Labyrinth disorders Respiratory, Epistaxis thoracic and

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HOS-094260 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The clinical development program has included over 1,900 patients, with different types of epilepsy, exposed to rufinamide. The most commonly reported adverse reactions overall were headache, dizziness, fatigue, and somnolence. The most common adverse reactions observed at a higher incidence than placebo in patients with Lennox-Gastaut syndrome were somnolence and vomiting. Adverse reactions were usually mild to moderate in severity. The discontinuation rate in Lennox-Gastaut syndrome due to adverse reactions was 8.2% for patients receiving rufinamide and 0% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from the rufinamide treatment group were rash and vomiting. Tabulated list of adverse reactions Adverse reactions reported with an incidence greater than placebo, during the Lennox-Gastaut syndrome double-blind studies or in the overall rufinamide-exposed population, are listed in the table below by MedDRA preferred term, system organ class and by frequency. Frequencies are defined as: 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). 8 System Organ Class Very Common Common Uncommon Rare Infections and Pneumonia infestations Influenza Nasopharyngitis Ear infection Sinusitis Rhinitis Immune system disorders Hypersensitivity* Metabolism and Anorexia nutrition Eating disorder disorders Decreased appetite Psychiatric Anxiety disorders Insomnia Nervous system Somnolence* Status epilepticus* disorders Headache Convulsion Dizziness* Coordination Abnormal* Nystagmus Psychomotor hyperactivity Tremor Eye Disorders Diplopia Vision blurred Ear and Vertigo Labyrinth disorders Respiratory, Epistaxis thoracic and

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HOS-094256 · has-contraindication-information · PDF-Seite 5

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

HOS-094262 · has-contraindication-information · PDF-Seite 18

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

HOS-094255 · has-indication-information · PDF-Seite 2

Inovelon is indicated as adjunctive therapy in the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 1 year of age and older.

HOS-094261 · has-indication-information · PDF-Seite 16

Inovelon is indicated as adjunctive therapy in the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 1 year of age and older.

HOS-094258 · has-interaction-information · PDF-Seite 6

Potential for other medicinal products to affect rufinamide Other antiepileptic medicinal products Rufinamide concentrations are not subject to clinically relevant changes on co-administration with known enzyme inducing antiepileptic medicinal products. For patients on Inovelon treatment who have administration of valproate initiated, significant increases in rufinamide plasma concentrations may occur. Therefore, consideration should be given to a dose reduction of Inovelon in patients who are initiated on valproate therapy (see section 4.2). The addition or withdrawal of these medicinal products or adjusting of the dose of these medicinal products during rufinamide therapy may require an adjustment in dosage of rufinamide (see section 4.2). No significant changes in rufinamide concentration are observed following co-administration with lamotrigine, topiramate or benzodiazepines. Potential for rufinamide to affect other medicinal products Other antiepileptic medicinal products The pharmacokinetic interactions between rufinamide and other antiepileptic medicinal products have been evaluated in patients with epilepsy, using population pharmacokinetic modelling. Rufinamide appears not to have a clinically relevant effect on carbamazepine, lamotrigine, phenobarbital, topiramate, phenytoin or valproate steady state concentrations. Oral contraceptives Co-administration of rufinamide 800 mg twice daily and a combined oral contraceptive (ethinyloestradiol 35 μg and norethindrone 1 mg) for 14 days resulted in a mean decrease in the ethinyl estradiol AUC0-24 of 22% and in norethindrone AUC0-24 of 14%. Studies with other oral or implant contraceptives have not been conducted. Women of child-bearing potential using hormonal contraceptives are advised to use an additional safe and effective contraceptive method (see sections 4.4 and 4.6). 6 Cytochrome P450 enzymes Rufinamide is metabolised by hydrolysis, and is not metabolised to any notable degree by cytochrome P450 enzymes. Furthermore, rufinamide does not inhibit the activity of cytochrome P450 enzymes (see section 5.2). Thus, clinically significant interactions mediated through inhibition of cytochrome P450 system by rufinamide are unlikely to occur. Rufinamide has been shown to induce the cytochrome P450 enzyme CYP3A4 and may therefore reduce the plasma concentrations of substances which are metabolised by this enzyme. The effect was modest to moderate.

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HOS-094264 · has-interaction-information · PDF-Seite 20

Potential for other medicinal products to affect rufinamide Other antiepileptic medicinal products Rufinamide concentrations are not subject to clinically relevant changes on co-administration with known enzyme inducing antiepileptic medicinal products. For patients on Inovelon treatment who have administration of valproate initiated, significant increases in rufinamide plasma concentrations may occur. Therefore, consideration should be given to a dose reduction of Inovelon in patients who are initiated on valproate therapy (see section 4.2). The addition or withdrawal of these medicinal products or adjusting of the dose of these medicinal products during rufinamide therapy may require an adjustment in dosage of rufinamide (see section 4.2). No significant changes in rufinamide concentration are observed following co-administration with lamotrigine, topiramate or benzodiazepines. 20 Potential for rufinamide to affect other medicinal products Other antiepileptic medicinal products The pharmacokinetic interactions between rufinamide and other antiepileptic medicinal products have been evaluated in patients with epilepsy, using population pharmacokinetic modelling. Rufinamide appears not to have a clinically relevant effect on carbamazepine, lamotrigine, phenobarbital, topiramate, phenytoin or valproate steady state concentrations. Oral contraceptives Co-administration of rufinamide 800 mg twice daily and a combined oral contraceptive (ethinyloestradiol 35 μg and norethindrone 1 mg) for 14 days resulted in a mean decrease in the ethinyl estradiol AUC0-24 of 22% and in norethindrone AUC0-24 of 14%. Studies with other oral or implant contraceptives have not been conducted. Women of child-bearing potential using hormonal contraceptives are advised to use an additional safe and effective contraceptive method (see sections 4.4 and 4.6). Cytochrome P450 enzymes Rufinamide is metabolised by hydrolysis, and is not metabolised to any notable degree by cytochrome P450 enzymes. Furthermore, rufinamide does not inhibit the activity of cytochrome P450 enzymes (see section 5.2). Thus, clinically significant interactions mediated through inhibition of cytochrome P450 system by rufinamide are unlikely to occur. Rufinamide has been shown to induce the cytochrome P450 enzyme CYP3A4 and may therefore reduce the plasma concentrations of substances which are metabolised by this enzyme. The effect was modest to moderate

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HOS-094259 · has-pregnancy-information · PDF-Seite 7

Pregnancy Risk related to epilepsy and antiepileptic medicinal products in general: It has been shown that in the offspring of 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 illness is responsible has not been elucidated. Moreover, effective antiepileptic therapy should not be interrupted abruptly, since the aggravation of the illness is detrimental to both the mother and the foetus. AED treatment during pregnancy should be carefully discussed with the treating physician. Risk related to rufinamide: Studies in animals revealed no teratogenic effect, but foetotoxicity in the presence of maternal toxicity was observed (see section 5.3). The potential risk for humans is unknown. For rufinamide, no clinical data on exposed pregnancies are available. Taking these data into consideration, rufinamide should not be used during pregnancy, or in women of childbearing age not using contraceptive measures, unless clearly necessary. Women of childbearing potential must use contraceptive measures during treatment with rufinamide. Physicians should try to ensure that appropriate contraception is used, and should use clinical judgement when assessing whether oral contraceptives, or the doses of the oral contraceptive components, are adequate based on the individual patients clinical situation (see sections 4.4 and 4.5). If women treated with rufinamide plan to become pregnant, the continued use of this product should be carefully weighed. During pregnancy, interruption of an effective antiepileptic can be detrimental to both the mother and the foetus if it results in aggravation of the illness. 7 Breast-feeding It is not known if rufinamide is excreted in human breast milk. Due to the potential harmful effects for the breast-fed infant, breast-feeding should be avoided during maternal treatment with rufinamide. Fertility No data are available on the effects on fertility following treatment with rufinamide.

HOS-094265 · has-pregnancy-information · PDF-Seite 21

Pregnancy Risk related to epilepsy and antiepileptic medicinal products in general: It has been shown that in the offspring of 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 illness is responsible has not been elucidated. Moreover, effective antiepileptic therapy should not be interrupted abruptly, since the aggravation of the illness is detrimental to both the mother and the foetus. AED treatment during pregnancy should be carefully discussed with the treating physician. 21 Risk related to rufinamide: Studies in animals revealed no teratogenic effect, but foetotoxicity in the presence of maternal toxicity was observed (see section 5.3). The potential risk for humans is unknown. For rufinamide, no clinical data on exposed pregnancies are available. Taking these data into consideration, rufinamide should not be used during pregnancy, or in women of childbearing age not using contraceptive measures, unless clearly necessary. Women of childbearing potential must use contraceptive measures during treatment with rufinamide. Physicians should try to ensure that appropriate contraception is used, and should use clinical judgement when assessing whether oral contraceptives, or the doses of the oral contraceptive components, are adequate based on the individual patients clinical situation (see sections 4.4 and 4.5). If women treated with rufinamide plan to become pregnant, the continued use of this product should be carefully weighed. During pregnancy, interruption of an effective antiepileptic can be detrimental to both the mother and the foetus if it results in aggravation of the illness. Breast-feeding It is not known if rufinamide is excreted in human breast milk. Due to the potential harmful effects for the breast-fed infant, breast-feeding should be avoided during maternal treatment with rufinamide. Fertility No data are available on the effects on fertility following treatment with rufinamide.

HOS-094257 · has-warning-information · PDF-Seite 5

Status epilepticus Status epilepticus cases have been observed during treatment with rufinamide in clinical development studies, whereas no such cases were observed with placebo. These events led to rufinamide discontinuation in 20% of the cases. If patients develop new seizure types and/or experience an increased frequency of status epilepticus that is different from the patient’s baseline condition, then the benefit-risk ratio of the therapy should be reassessed. Withdrawal of rufinamide Rufinamide should be withdrawn gradually to reduce the possibility of seizures on withdrawal. In clinical studies discontinuation was achieved by reducing the dose by approximately 25% every two days. There are insufficient data on the withdrawal of concomitant antiepileptic medicinal products once seizure control has been achieved with the addition of rufinamide. Central Nervous System reactions Rufinamide treatment has been associated with dizziness, somnolence, ataxia and gait disturbances, which could increase the occurrence of accidental falls in this population (see section 4.8). Patients and carers should exercise caution until they are familiar with the potential effects of this medicinal product. Hypersensitivity reactions Serious antiepileptic medicinal product hypersensitivity syndrome including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome have occurred in association with rufinamide therapy. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included lymphadenopathy, liver function tests abnormalities, and haematuria. As the disorder is variable in its expression, other organ system signs and symptoms not noted here may occur. The antiepileptic drug (AED) hypersensitivity syndrome occurred in close temporal association to the initiation of rufinamide therapy and in the paediatric population. If this reaction is suspected, rufinamide should be discontinued and alternative treatment started. All patients who develop a rash while taking rufinamide must be closely monitored. QT shortening In a thorough QT study, rufinamide produced a decrease in QTc interval proportional to concentration. Although the underlying mechanism and safety relevance of this finding is not known, clinicians should use clinical judgment when assessing whether to prescribe r

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HOS-094263 · has-warning-information · PDF-Seite 18

Status epilepticus Status epilepticus cases have been observed during treatment with rufinamide in clinical development studies, whereas no such cases were observed with placebo. These events led to rufinamide 18 discontinuation in 20% of the cases. If patients develop new seizure types and/or experience an increased frequency of status epilepticus that is different from the patient’s baseline condition, then the benefit-risk ratio of the therapy should be reassessed. Withdrawal of rufinamide Rufinamide should be withdrawn gradually to reduce the possibility of seizures on withdrawal. In clinical studies discontinuation was achieved by reducing the dose by approximately 25% every two days. There are insufficient data on the withdrawal of concomitant antiepileptic medicinal products once seizure control has been achieved with the addition of rufinamide. Central Nervous System reactions Rufinamide treatment has been associated with dizziness, somnolence, ataxia and gait disturbances, which could increase the occurrence of accidental falls in this population (see section 4.8). Patients and carers should exercise caution until they are familiar with the potential effects of this medicinal product. Hypersensitivity reactions Serious antiepileptic medicinal product hypersensitivity syndrome including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome have occurred in association with rufinamide therapy. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included lymphadenopathy, liver function tests abnormalities, and haematuria. As the disorder is variable in its expression, other organ system signs and symptoms not noted here may occur. The antiepileptic drug (AED) hypersensitivity syndrome occurred in close temporal association to the initiation of rufinamide therapy and in the paediatric population. If this reaction is suspected, rufinamide should be discontinued and alternative treatment started. All patients who develop a rash while taking rufinamide must be closely monitored. QT shortening In a thorough QT study, rufinamide produced a decrease in QTc interval proportional to concentration. Although the underlying mechanism and safety relevance of this finding is not known, clinicians should us

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