4.1. Therapeutic indications

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 treatment with at least 2 anti-epileptic medicinal products.

4.2. Posology and method of administration

Posology

Adults

The recommended starting dose of cenobamate is 12.5 mg per day, titrated gradually to the recommended target dose of 200 mg per day. Based on clinical response, dose may be increased to a maximum of 400 mg per day.

The recommended titration schedule is provided in table 1, which should not be exceeded because of the potential for serious adverse reactions (see section 4.8).

Table 1: Recommended dosage in adults with focal-onset seizures in epilepsy

Treatment phase

Dose (per day, oral)

Duration

Treatment initiation

12.5 mg

Weeks 1 and 2

25 mg

Weeks 3 and 4

Titration

50 mg

Weeks 5 and 6

100 mg

Weeks 7 and 8

150 mg

Weeks 9 and 10

Target dose

200 mg

Weeks 11 and 12 and onwards

Dose optimisation

Some patients, who do not reach optimal seizure control, may benefit from doses above 200 mg (increased by increments of 50 mg/day every two weeks) up to a maximum of 400 mg daily.

Missed doses

If patients miss one dose, it is recommended that they take a single dose as soon as they remember, unless it is less than 12 hours until their next regularly scheduled dose.

Discontinuation

It is recommended that discontinuation be undertaken gradually to minimise the potential for rebound seizures (i.e. over at least 2 weeks), unless safety concerns require abrupt withdrawal.

Elderly (65 years of age and above)

Clinical studies of cenobamate did not include sufficient numbers of subjects aged 65 and over, to determine whether they responded differently from younger patients. It has been reported that elderly subjects on antiepileptic medicinal products have higher incidence of adverse reactions such as fatigue, gait disturbance, fall, ataxia, balance disorder, dizziness and somnolence. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or renal function and of concomitant disease as well as the potential interactions in polymedicated patients (see section 4.4).

Renal 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.

Hepatic impairment

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.

Paediatric population

The safety and efficacy of Ontozry in children aged 0 months to 18 years have not yet been established. No data are available.

Method of administration

Oral use.

Cenobamate should typically be taken once daily as single oral dose at any time. However, it should preferably be taken at the same time each day. It may be taken with or without food (see section 5.2). The tablet should be swallowed with a glass of water. The tablets cannot be split accurately as there is no break line and the accuracy of the dose cannot be ensured.

The tablet can be taken whole or can be crushed. The crushed tablet can be mixed with water and administered orally or via a nasogastric tube (see also section 6.6).

Administration of Crushed Tablets via Nasogastric (NG) tube

Ontozry crushed tablet can be mixed with water and administered also through a nasogastric feeding tube (NG tube) as follows:

1. Crush the appropriate number of tablet(s) for the prescribed dose.

2. In an appropriate container, combine the crushed tablet(s) and 25 mL of water.

3. Shake to suspend the crushed tablet(s).

4. Ensuring no particles are left in the container, instill the suspension with a syringe into the NG tube.

5. Refill the catheter-tip syringe again with 10 mL of water, swirl gently, and administer.

6. Visually confirm that no particles are left in the syringe. If particles remain, repeat step 5.

4.3. Contraindications

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

Familial Short-QT syndrome (see section 4.4).

4.4. Special warnings and precautions for use

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).

QT-shortening

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 QT-shortening.

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).

Contains lactose

Patients with rare hereditary problems such as galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

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 drugs

Drug type or substrate

Clinical recommendation

Effect on PK parameters

Anti-epileptic drug

phenytoin

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.

↑ phenytoin plasma concentrations

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%).

phenobarbital

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.

↑ phenobarbital plasma concentrations

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%).

clobazam

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.

↑ clobazam active metabolite plasma concentrations

Pharmacometric analyses of data from healthy subjects and patients predict that clobazam slightly increases cenobamate exposures (by 24%).

lamotrigine

Depending on individual response, the dose of cenobamate may need to be increased.

Based on subpopulation analyses of patients taking concomitant lamotrigine, in individual cases, higher doses (200 - 400 mg/day) of cenobamate may be required for efficacy.

↓ lamotrigine plasma concentrations

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).

carbamazepine

No clinically meaningful decreases in efficacy were observed in patients taking concomitant carbamazepine. No dose adjustments are required for both carbamazepine and cenobamate.

↓ carbamazepine plasma concentrations

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%).

Valproic acid

No dose adjustments of cenobamate or valproic acid are required.

No clinically relevant effect of valproic acid

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.

lacosamide, levetiracetam and oxcarbazepine

No dose adjustments are required for cenobamate, lacosamide, levetiracetam, or oxcarbazepine.

No clinically relevant effect of lacosamide, levetiracetam and oxcarbazepine

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.

Other medicinal products

Drug or Substrate Type

Clinical Recommendation

Effect on PK parameters

Oral contraceptives (CYP3A4)

Women of reproductive potential concomitantly using oral contraceptives should practice additional or alternative non-hormonal measures of birth control (see section 4.6).

↓ oral contraceptives plasma concentrations

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.

CYP3A4 substrates

An increase in the dose of medicines metabolized by CYP3A4 may be required when used concomitantly with cenobamate.

↓ CYP3A4 substrates plasma concentrations

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.

CYP2B6 Substrates

An increase in the dose of medicines metabolized by CYP2B6 may be required when used concomitantly with cenobamate.

↓ CYP2B6 substrates plasma concentrations

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%).

CYP2C19 Substrates

A dose reduction of medicines metabolized by CYP2C19 may be required when used concomitantly with cenobamate.

↑ CYP2C19 substrates plasma concentrations

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%).

OAT3 substrates

Concomitant administration of cenobamate and medicinal products transported by OAT3 may result in higher exposure of these medicinal products.

↑ OAT3 substrates plasma concentrations

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).

4.6. Fertility, pregnancy and lactation

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 (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).

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

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 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

Uncommon

Suicidal ideation

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.

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). 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.).

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 2/3 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 of suspected adverse reactions

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms of overdose are expected to be consistent with the known adverse reactions of Ontozry and include somnolence, fatigue, dizziness. There is no available specific antidote to the effects of cenobamate. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.