Ontozry · 4.8 Undesirable effects · 1

HOS-099593 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most commonly reported adverse reactions were somnolence, dizziness, fatigue and headache. The discontinuation rates because of adverse reactions in clinical trials were 5%, 6% and 19% for patients randomised to receive cenobamate at doses of 100 mg/day, 200 mg/day and 400 mg/day respectively, compared to 3% in patients randomised to receive placebo. The 400 mg dose was more associated with adverse reactions especially when taken concomitantly with clobazam. The adverse reactions most commonly leading to discontinuation, in descending order of frequency, were: ataxia (1.6% vs 0.5% placebo), dizziness (1.6% vs 0.5% placebo), somnolence (1.4% vs 0.5% placebo), nystagmus (0.7% vs 0 % placebo), vertigo (0.7% vs 0 % placebo) and diplopia (0.5% vs 0 % 10 placebo). These adverse reactions are dose dependent and the titration scheme should be strictly followed). Tabulated list of adverse reactions Adverse reactions reported in clinical studies are listed in table 2 per system organ class (SOC) and per frequency. Within each frequency group, undesirable effects are ranked in decreasing order of severity: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000). Table 2: Tabulated list of adverse reactions System organ class Frequency Adverse reactions from clinical trials Immune system Uncommon Hypersensitivity* disorders Psychiatric Common Confusional state, Irritability disorders Uncommon Suicidal ideation Nervous system Very common Somnolence*, Coordination and Gait abnormalities*, disorders Headache Common Dysarthria, Nystagmus, Aphasia, Memory impairment Eye disorders Common Diplopia, Vision blurred Gastrointestinal Common Constipation, Diarrhoea, Nausea, Vomiting, Dry disorders mouth Skin and Common Rash* subcutaneous tissue disorder Rare Drug reaction with eosinophilia and systemic symptoms (DRESS) Hepatobiliary Rare Liver injury disorders Common Hepatic enzyme incre

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HOS-099589 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Familial Short-QT syndrome (see section 4.4).

HOS-099588 · has-indication-information · PDF-Seite 3

Ontozry is indicated for the adjunctive treatment of focal-onset seizures with or without secondary generalisation in adult patients with epilepsy who have not been adequately controlled despite a history of treatment with at least 2 anti-epileptic medicinal products.

HOS-099591 · has-interaction-information · PDF-Seite 6

Cenobamate is extensively metabolized, primarily by glucuronidation, with oxidation contributing to a lesser degree. Cenobamate may reduce exposures of products primarily metabolized by CYP3A4 and 2B6. Cenobamate may increase exposures of products primarily metabolized by CYP2C19. When initiating or discontinuing treatment with cenobamate or changing the dose, it may take 2 weeks to reach the new level of enzyme activity. Pharmacodynamic interactions CNS depressants Concomitant use of cenobamate with other CNS depressants, including alcohol, barbiturates, and benzodiazepines may increase the risk of neurological adverse reactions. Therefore, based on individual response, doses of barbiturates and benzodiazepines may need to be reduced, as clinically appropriate, when used concomitantly with cenobamate. Interactions with other anti-epileptic drug Drug type or substrate Clinical recommendation Effect on PK parameters Anti-epileptic drug phenytoin No dose adjustment of ↑ phenytoin plasma cenobamate is required. concentrations Phenytoin concentrations In a study in healthy subjects, should be monitored during concomitant administration of titration of cenobamate, and cenobamate 200 mg/day and 6  based on individual response, phenytoin 300 mg/day slightly the dose of phenytoin may reduced cenobamate exposures need to be reduced. (Cmax by -27%, AUC by -28%), and increased phenytoin exposures (Cmax by 67%, AUC by 84%). phenobarbital No dose adjustment of ↑ phenobarbital plasma cenobamate is required. concentrations Concentrations of phenobarbital should be In a study in healthy subjects, monitored during cenobamate concomitant administration of titration, and based on cenobamate 200 mg/day and individual response, the dose of phenobarbital 90 mg/day did phenobarbital may nee

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HOS-099592 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential and contraception in males and females 9 Cenobamate is not recommended in women of childbearing potential not using contraception. Women of reproductive potential concomitantly using oral contraceptives should practice additional or alternative non-hormonal measures of birth control during treatment with cenobamate and until 4 weeks after treatment discontinuation (see section 4.5). Pregnancy Risk related to epilepsy and antiepileptic medicinal products in general 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 cenobamate There are no adequate data from the use of Ontozry in pregnant women. Animal studies have shown that cenobamate crosses the placenta of rats. Studies in animals have shown reproductive toxicity at levels below clinical exposure (see section 5.3). Ontozry should not be used during pregnancy unless the clinical condition of the woman requires treatment with cenobamate. Women of childbearing potential must use effective contraception during use of cenobamate and until 4 weeks after treatment discontinuation (see section 4.5). Breast-feeding It is unknown whether cenobamate or its metabolites are excreted in human milk. Studies in rats showed excretion of cenobamate in the maternal milk (see section 5.3). A risk to the suckling child cannot be excluded. As a precautionary measure, breast-feeding should be discontinued during treatment with Ontozry. Fertility The effects of cenobamate on human fertility are unknown. Animal data are insufficient due to exposure below clinical levels (see section 5.3).

HOS-099590 · has-warning-information · PDF-Seite 5

Suicidal ideation Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicinal products, including cenobamate. 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. Therefore, 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 signs of suicidal ideation or behaviour emerge. Drug reaction with eosinophilia and systemic symptoms (DRESS) Drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, has been reported in association with cenobamate when started at higher doses and titrated rapidly (weekly or faster titration) (see section 4.8). When cenobamate was initiated at 12.5 mg/day and titrated every two weeks, in an open-label safety study of 1,340 epilepsy patients, no cases of DRESS were reported. At the time of prescription, patients should be advised of the signs and symptoms of DRESS 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. If signs and symptoms suggestive of these reactions appear, cenobamate should be withdrawn immediately and an alternative treatment considered (as appropriate). 5 Liver injury Increased levels of hepatic enzymes and rare cases of severe liver injury with hepatic failure have been reported in patients treated with cenobamate. Many cases occurred in the context of a polytherapy with other antiseizure medications (see section 4.8). Serum transaminases (ALT and AST), gamma-glutamyl transferase (GGT), alkaline phosphatase and total bilirubin should be evaluated before initiation of cenobamate and monitored during treatment. If liver injury is suspected or detected, dose reduction or discontinuation of cenobamate should be considered. QT-shortening A dose-dependent shortening of the QTcF interval has been observed with cenobamate. Reductions of

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