Cenobamate

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 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.

In a study in healthy subjects, concomitant administration of cenobamate 200 mg once daily increased exposures of the CYP2C19 substrate, omeprazole 20 mg (C_max increase by 83%, AUC increased by 107%). A dose reduction of medicines metabolized by CYP2C19 may be required when used concomitantly with cenobamate.

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.

Exposure to cenobamate was increased in patients with chronic hepatic disease. A change in the starting dose is not required; however, a decrease in target doses of up to 50% may need to be considered. The maximum recommended dose in patients with mild and moderate hepatic impairment is 200 mg/day. Cenobamate should not be used in patients with severe hepatic impairment.

Cenobamate should be used with caution and reduction of the target dose may be considered in patients with mild to moderate (creatinine clearance 30 to <90 ml/min) or severe (creatinine clearance <30 ml/min) renal impairment. The maximum recommended dose for patients with mild, moderate, or severe renal impairment is 300 mg/day. Cenobamate should not be used in patients with end-stage renal disease or patients undergoing haemodialysis.

In a study in healthy subjects, concomitant administration of cenobamate 200 mg once daily reduced exposures of the CYP2B6 substrate, bupropion 150 mg (C_max 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.

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.

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.

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 cenobamate 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. Cenobamate 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.

It is unknown whether cenobamate or its metabolites are excreted in human milk. Studies in rats showed excretion of cenobamate in the maternal milk. A risk to the suckling child cannot be excluded. As a precautionary measure, breast-feeding should be discontinued during treatment with cenobamate.

Carcinogenesis

Oral administration of cenobamate (0, 5, 15, or 35 mg/kg/day) to Tg.rasH2 mice for up to 26 weeks did not result in an increase in tumors. Oral administration of cenobamate (0, 4, 8, or 20 mg/kg/day) to male and female rats for up to 87 or 90 weeks, respectively, did not result in an increase in tumors. Plasma exposure at the highest dose tested in rats was less than that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

Mutagenesis

Cenobamate was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays.

Impairment of fertility

The effects of cenobamate on human fertility are unknown. Animal data are insufficient due to exposure below clinical levels.

Oral administration of cenobamate (0, 11, 22, or 44 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females to Gestation Day 6 did not produce adverse effects on fertility, general reproductive performance, or early embryonic development. Plasma exposure (AUC) at the highest dose tested in rats was less than that in humans at the MRHD.

Women of childbearing potential and contraception in males and females

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.

Cenobamate 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.

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% 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 the following table 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).

^* 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.

Description of selected adverse reactions

Drug reaction with eosinophilia and systemic symptoms (DRESS)

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). Cenobamate should always be initiated at 12.5 mg once daily and titrated not faster than once every two weeks.

Hypersensitivity

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.

Elderly

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.