Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Angelini Pharma S.p.A, Viale Amelia 70, 00181, Rome – Italy
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Familial Short-QT syndrome (see section 4.4).
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 antiepileptic 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 cenobamate. 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), 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 If signs and symptoms suggestive of these reactions appear, cenobamate should be withdrawn immediately and an alternative treatment considered (as appropriate).
A dose-dependent shortening of the QTcF interval has been observed with cenobamate. Reductions of the QTcF interval below 340 msec were not observed (see section 5.1). In clinical trials there was no evidence that the combination of cenobamate with other antiepileptic medicines led to further QTshortening. Clinicians should use caution when prescribing cenobamate in combination with other medicinal products that are known to shorten the QT.
Familial Short QT syndrome is a rare genetic syndrome, which is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Cenobamate must not be used in patients with Familial Short-QT syndrome (see section 4.3).
Patients with rare hereditary problems such as galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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.
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.
In a study in healthy subjects, concomitant administration of cenobamate 200 mg/day and phenytoin 300 mg/day slightly reduced cenobamate exposures (Cmax by -27%, AUC by -28%), and increased phenytoin exposures (Cmax by 67%, AUC by 84%). No dose adjustment of cenobamate is required. Phenytoin concentrations should be monitored during titration of cenobamate, and based on individual response, the dose of phenytoin may need to be reduced.
In a study in healthy subjects, concomitant administration of cenobamate 200 mg/day and phenobarbital 90 mg/day did not cause clinically meaningful changes in cenobamate exposure but led to increased phenobarbital exposures (Cmax by 34% and AUC by 37%). No dose adjustment of cenobamate is required. Concentrations of phenobarbital should be monitored during cenobamate titration, and based on individual response, the dose of phenobarbital may need to be reduced.
Pharmacometric analyses of data from healthy subjects and patients predict that clobazam slightly increases cenobamate exposures (by 24%). No dose adjustment of cenobamate is required. Due to a possible increase in exposure of the active metabolite of clobazam (N-desmethylclobazam), related to the induction of CYP3A4 (formation) and the inhibition of CYP2C19 (elimination), the dose of clobazam may need to be reduced.
Pharmacometric analyses of data from healthy subjects and patients showed that concomitant administration of cenobamate with lamotrigine had no effect on cenobamate exposures, but resulted in dose-dependent decreases in lamotrigine concentrations (by -21%, -35%, and -52% for cenobamate 100, 200, and 400 mg/day). Based on subpopulation analyses of patients taking concomitant lamotrigine, higher doses (200-400 mg/day) of cenobamate may be required for efficacy when coadministered with lamotrigine. Depending on individual response, the dose of cenobamate may need to be increased.
In a study in healthy subjects, concomitant administration of cenobamate 200 mg once daily and carbamazepine 200 mg twice daily showed no significant change in exposure of cenobamate, but carbamazepine exposures were slightly reduced (Cmax reduced by 23%, AUC reduced by 24%). No clinically meaningful decreases in efficacy were observed in subpopulation analyses of patients taking concomitant carbamazepine. Therefore, no dose adjustments are required.
In a study in healthy subjects, concomitant administration of cenobamate 150 mg once daily and valproic acid 1,000 mg once daily showed no significant changes in exposures of either medicinal product. Pharmacometric analyses of data from healthy subjects and patients indicated that concomitant administration of cenobamate with valproic acid did not affect cenobamate exposures and had no clinically relevant reductions in valproic acid concentration. No dose adjustments are required.
Pharmacometric analyses of data from healthy subjects and patients indicated that concomitant administration with lacosamide, levetiracetam, or oxcarbazepine did not affect the exposure of cenobamate, and cenobamate did not have a clinically relevant effect on exposures of lacosamide, levetiracetam, or oxcarbazepine. No dose adjustments are required for cenobamate, lacosamide, levetiracetam, or oxcarbazepine.
Cenobamate showed a dose-dependent induction of CYP3A4, reducing exposures (AUC) of the CYP3A4 substrate, midazolam 2 mg by 72% with cenobamate 200 mg/day in healthy subjects. Since hormonal contraceptives may also be metabolized by CYP3A4, their efficacy may be reduced by concomitant use with cenobamate. Therefore, women of reproductive potential concomitantly using oral contraceptives should practice additional or alternative non-hormonal measures of birth control (see section 4.6).
In a study in healthy subjects, concomitant administration of cenobamate 100 and 200 mg once daily reduced exposures (AUC) of the CYP3A4 substrate, midazolam 2 mg by 27% and 72%, respectively. An increase in the dose of medicines metabolized by CYP3A4 may be required when used concomitantly with cenobamate.
In a study in healthy subjects, concomitant administration of cenobamate 200 mg once daily reduced exposures of the CYP2B6 substrate, bupropion 150 mg (Cmax reduced by 23%, AUC reduced by 39%). An increase in the dose of medicines metabolized by CYP2B6 may be required when used concomitantly with cenobamate.
In a study in healthy subjects, concomitant administration of cenobamate 200 mg once daily increased exposures of the CYP2C19 substrate, omeprazole 20 mg (Cmax increase by 83%, AUC increased by 107%). A dose reduction of medicines metabolized by CYP2C19 may be required when used concomitantly with cenobamate.
In vitro studies have shown that cenobamate inhibits OAT3, a transporter predominantly involved in the elimination of certain medicines (e.g. baricitinib, cefaclor, empagliflozin, penicillin G, ritobegron, and sitagliptin). Therefore, concomitant administration of cenobamate and medicinal products transported by OAT3 may result in higher exposure of these medicinal products.
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).
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.
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).
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.
The effects of cenobamate on human fertility are unknown. Animal data are insufficient due to exposure below clinical levels (see section 5.3).
Ontozry has moderate influence on the ability to drive and use machines.
Cenobamate may cause somnolence, dizziness, fatigue, impaired vision and other CNS-related symptoms, which may influence the ability to drive or use machines. Patients are advised not to drive a vehicle, operate complex machinery or engage in other potentially hazardous activities until it is known whether cenobamate affects their ability to perform these tasks (see section 4.5).
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% placebo). These adverse reactions are dose dependent and the titration scheme should be strictly followed).
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 disorders | Uncommon | Hypersensitivity* |
| Psychiatric disorders | Common | Confusional state, Irritability |
| Nervous system disorders | Very common | Somnolence*, Coordination and Gait abnormalities*, Headache |
| Common | Dysarthria, Nystagmus, Aphasia, Memory impairment | |
| Eye disorders | Common | Diplopia, Vision blurred |
| Gastrointestinal disorders | Common | Constipation, Diarrhoea, Nausea, Vomiting, Dry mouth |
| Skin and subcutaneous tissue disorder | Common | Rash* |
| Rare | Drug reaction with eosinophilia and systemic symptoms (DRESS) | |
| Investigations | Common | Hepatic enzyme increased* |
* Grouped terms:
Somnolence: Somnolence, Fatigue, Sedation and Hypersomnia
Coordination and Gait abnormalities: Dizziness, Vertigo, Balance disorder, Ataxia, Gait disturbance and abnormal coordination
Hypersensitivity: Hypersensitivity, Drug hypersensitivity, Eyelid oedema; Rash: Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash morbilliform, Rash papular, Rash pruritic
Hepatic enzyme increased: Alanine aminotransferase increased, Aspartate aminotransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Transaminases increased.
Three cases of DRESS were reported within 2 to 4 weeks of starting cenobamate in studies with high starting doses (50 mg or 100 mg once daily) and weekly or faster titration. 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). Ontozry should always be initiated at 12.5 mg once daily and titrated not faster than once every two weeks (see sections 4.2 and 4.4.).
Four (0.9%) Cenobamate treated patients and one (0.5%) placebo patient experienced an event of hypersensitivity. Two patients in the cenobamate dose group experienced events of drug hypersensitivity. One cenobamate treated patient experienced an event of hypersensitivity and 1 cenobamate treated patient experienced an event on eyelid oedema. The placebo patient experienced an event of hypersensitivity. All events were classified as mild or moderate.
Safety data from the Pooled Double-Blind and All Phase ⅔ datasets along with PK data from a Phase 1 study showed no additional safety risks in elderly subjects ≥65 years of age at study entry. Additional subgrouping by age for subjects who were ≥65 years of age during study participation showed similar results for adverse reactions in these 87 subjects as compared with the 51 subjects who were ≥65 years of age at study entry (see section 4.2).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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