ONTOZRY 200mg tablets medication leaflet

Ontozry 12.5 mg tablets

Ontozry 25 mg film-coated tablets

Ontozry 50 mg film-coated tablets

Ontozry 100 mg film-coated tablets

Ontozry 150 mg film-coated tablets

Ontozry 200 mg film-coated tablets

Ontozry 12.5 mg tablets

Each tablet contains 12.5 mg cenobamate.

Ontozry 25 mg film-coated tablets

Each film-coated tablet contains 25 mg cenobamate.

Ontozry 50 mg film-coated tablets

Each film-coated tablet contains 50 mg cenobamate.

Ontozry 100 mg film-coated tablets

Each film-coated tablet contains 100 mg cenobamate.

Ontozry 150 mg film-coated tablets

Each film-coated tablet contains 150 mg cenobamate.

Ontozry 200 mg film-coated tablets

Each film-coated tablet contains 200 mg cenobamate.

Each 12.5 mg tablet contains 39.7 mg lactose monohydrate.

Each 25 mg film-coated tablet contains 79.3 mg lactose monohydrate.

Each 50 mg film-coated tablet contains 158.7 mg lactose monohydrate.

Each 100 mg film-coated tablet contains 108.7 mg lactose monohydrate.

Each 150 mg film-coated tablet contains 163 mg lactose monohydrate.

Each 200 mg film-coated tablet contains 217.4 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Ontozry 12.5 mg tablet

Tablet

Ontozry 25 mg, 50 mg, 100 mg, 150 mg and 200 mg film-coated tablet

Film-coated tablet

Ontozry 12.5 mg tablet

Uncoated round white to off-white tablet with AV on one side and ‘12’ on the other side

Ontozry 25 mg film-coated tablet

Film-coated round brown tablet with AV on one side and ‘25’ on the other side

Ontozry 50 mg film-coated tablet

Film-coated round yellow tablet with AV on one side and ‘50’ on the other side

Ontozry 100 mg film-coated tablet

Film-coated round brown tablet with AV on one side and ‘100’ on the other side

Ontozry 150 mg film-coated tablet

Film-coated light orange round tablet with AV on one side and ‘150’ on the other side

Ontozry 200 mg film-coated tablet

Film-coated oval, light orange tablet with AV on one side and ‘200’ on the other side

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

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

The recommended titration schedule is provided in table 1, which should not be exceeded because ofthe 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) Duration12.5 mg Weeks 1 and 2

Treatment initiation25 mg Weeks 3 and 450 mg Weeks 5 and 6

Titration 100 mg Weeks 7 and 8150 mg Weeks 9 and 10

Target dose 200 mg Weeks 11 and 12 andonwards

Some patients, who do not reach optimal seizure control, may

Dose optimisation benefit from doses above 200 mg (increased by increments of50 mg/day every two weeks) up to a maximum of 400 mgdaily.

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.

It is recommended that discontinuation be undertaken gradually to minimise the potential for reboundseizures (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, todetermine whether they responded differently from younger patients. It has been reported that elderlysubjects on antiepileptic medicinal products have higher incidence of adverse reactions such asfatigue, gait disturbance, fall, ataxia, balance disorder, dizziness and somnolence. In general, doseselection 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 aswell as the potential interactions in polymedicated patients (see section 4.4).

Cenobamate should be used with caution and reduction of the target dose may be considered inpatients 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, orsevere renal impairment is 300 mg/day. Cenobamate should not be used in patients with end-stagerenal disease or patients undergoing haemodialysis.

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

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

Oral use.

Cenobamate should typically be taken once daily as single oral dose at any time. However, it shouldpreferably 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 isno 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 andadministered 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 feedingtube (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 NGtube.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.

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

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicinalproducts, 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 suicidalideation and behaviours and appropriate treatment should be considered.

Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidalideation or behaviour emerge.

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening orfatal, has been reported in association with cenobamate when started at higher doses and titratedrapidly (weekly or faster titration) (see section 4.8). When cenobamate was initiated at 12.5 mg/dayand 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 andmonitored closely for skin reactions. Symptoms of DRESS include typically, although not exclusively,fever, rash associated with other organ system involvement, lymphadenopathy, liver function testsabnormalities 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 andsymptoms suggestive of these reactions appear, cenobamate should be withdrawn immediately and analternative treatment considered (as appropriate).

QT-shortening

A dose-dependent shortening of the QTcF interval has been observed with cenobamate. Reductions ofthe QTcF interval below 340 msec were not observed (see section 5.1). In clinical trials there was noevidence that the combination of cenobamate with other antiepileptic medicines led to further QT-shortening. Clinicians should use caution when prescribing cenobamate in combination with othermedicinal products that are known to shorten the QT.

Familial Short QT syndrome is a rare genetic syndrome, which is associated with an increased risk ofsudden death and ventricular arrhythmias, particularly ventricular fibrillation. Cenobamate must not beused 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 orglucose-galactose malabsorption should not take this medicine.

Cenobamate is extensively metabolized, primarily by glucuronidation, with oxidation contributing to alesser degree.

Cenobamate may reduce exposures of products primarily metabolized by CYP3A4 and 2B6.

Cenobamate may increase exposures of products primarily metabolized by CYP2C19. When initiatingor discontinuing treatment with cenobamate or changing the dose, it may take 2 weeks to reach thenew level of enzyme activity.

CNS depressants

Concomitant use of cenobamate with other CNS depressants, including alcohol, barbiturates, andbenzodiazepines may increase the risk of neurological adverse reactions. Therefore, based onindividual response, doses of barbiturates and benzodiazepines may need to be reduced, as clinicallyappropriate, when used concomitantly with cenobamate.

Interactions with other anti-epileptic drug

Drug type or substrate Clinical recommendation Effect on PK parameters

Anti-epileptic drugphenytoin No dose adjustment of ↑ phenytoin plasmacenobamate is required. concentrations

Phenytoin concentrations In a study in healthy subjects,should be monitored during concomitant administration oftitration of cenobamate, and cenobamate 200 mg/day andbased on individual response, phenytoin 300 mg/day slightlythe dose of phenytoin may reduced cenobamate exposuresneed to be reduced. (Cmax by -27%, AUC by -28%),and increased phenytoinexposures (Cmax by 67%, AUCby 84%).

phenobarbital No dose adjustment of ↑ phenobarbital plasmacenobamate is required. concentrations

Concentrations ofphenobarbital should be In a study in healthy subjects,monitored during cenobamate concomitant administration oftitration, and based on cenobamate 200 mg/day andindividual response, the dose of phenobarbital 90 mg/day didphenobarbital may need to be not cause clinically meaningfulreduced. changes in cenobamateexposure but led to increasedphenobarbital exposures (Cmaxby 34% and AUC by 37%).

clobazam No dose adjustment of ↑ clobazam active metabolitecenobamate is required. plasma concentrations

Due to a possible increase in Pharmacometric analyses ofexposure of the active data from healthy subjects andmetabolite of clobazam (N- patients predict that clobazamdesmethylclobazam), related to slightly increases cenobamatethe induction of CYP3A4 exposures (by 24%).(formation) and the inhibitionof CYP2C19 (elimination), thedose of clobazam may need tobe reduced.

lamotrigine Depending on individual ↓ lamotrigine plasmaresponse, the dose of concentrationscenobamate may need to beincreased. Pharmacometric analyses ofdata from healthy subjects and

Based on subpopulation patients showed thatanalyses of patients taking concomitant administration ofconcomitant lamotrigine, in cenobamate with lamotrigineindividual cases, higher doses had no effect on cenobamate(200 - 400 mg/day) of exposures, but resulted in dose-cenobamate may be required dependent decreases infor efficacy. lamotrigine concentrations (by

- 21%, -35%, and -52% forcenobamate 100, 200, and400 mg/day).

carbamazepine No clinically meaningful ↓ carbamazepine plasmadecreases in efficacy were concentrationsobserved in patients takingconcomitant carbamazepine. In a study in healthy subjects,

No dose adjustments are concomitant administration ofrequired for both cenobamate 200 mg once dailycarbamazepine and and carbamazepine 200 mgcenobamate. twice daily showed nosignificant change in exposureof cenobamate, butcarbamazepine exposures wereslightly reduced (Cmax reducedby 23%, AUC reduced by24%).

Valproic acid No dose adjustments of No clinically relevant effect ofcenobamate or valproic acid valproic acidare required.

In a study in healthy subjects,concomitant administration ofcenobamate 150 mg once dailyand valproic acid 1,000 mgonce daily showed nosignificant changes inexposures of either medicinalproduct.

Pharmacometric analyses ofdata from healthy subjects andpatients indicated thatconcomitant administration ofcenobamate with valproic aciddid not affect cenobamateexposures and had no clinicallyrelevant reductions in valproicacid concentration.

lacosamide, levetiracetam No dose adjustments are No clinically relevant effect ofand oxcarbazepine required for cenobamate, lacosamide, levetiracetam andlacosamide, levetiracetam, or oxcarbazepineoxcarbazepine.

Pharmacometric analyses ofdata from healthy subjects andpatients indicated thatconcomitant administrationwith lacosamide, levetiracetam,or oxcarbazepine did not affectthe exposure of cenobamate,and cenobamate did not have aclinically relevant effect onexposures of lacosamide,levetiracetam, oroxcarbazepine.

Other medicinal products

Drug or Substrate Type Clinical Recommendation Effect on PK parameters

Oral contraceptives Women of reproductive ↓ oral contraceptives plasma(CYP3A4) potential concomitantly using concentrationsoral contraceptives shouldpractice additional or Cenobamate showed a dose-alternative non-hormonal dependent induction ofmeasures of birth control (see CYP3A4, reducing exposuressection 4.6). (AUC) of the CYP3A4substrate, midazolam 2 mg by72% with cenobamate200 mg/day in healthy subjects.

Since hormonal contraceptivesmay also be metabolized by

CYP3A4, their efficacy may bereduced by concomitant usewith cenobamate.

CYP3A4 substrates An increase in the dose of ↓ CYP3A4 substrates plasmamedicines metabolized by concentrations

CYP3A4 may be requiredwhen used concomitantly with In a study in healthy subjects,cenobamate. concomitant administration ofcenobamate 100 and 200 mgonce daily reduced exposures(AUC) of the CYP3A4substrate, midazolam 2 mg by27% and 72%, respectively.

CYP2B6 Substrates ↓ CYP2B6 substrates plasma

An increase in the dose of concentrationsmedicines metabolized by

CYP2B6 may be required In a study in healthy subjects,when used concomitantly with concomitant administration ofcenobamate. cenobamate 200 mg once dailyreduced exposures of the

CYP2B6 substrate, bupropion150 mg (Cmax reduced by 23%,

AUC reduced by 39%).

CYP2C19 Substrates ↑ CYP2C19 substrates plasma

A dose reduction of medicines concentrationsmetabolized by CYP2C19 may In a study in healthy subjects,be required when used concomitant administration ofconcomitantly with cenobamate 200 mg once dailycenobamate. increased exposures of the

CYP2C19 substrate,omeprazole 20 mg (Cmaxincrease by 83%, AUCincreased by 107%).

OAT3 substrates Concomitant administration of ↑ OAT3 substrates plasmacenobamate and medicinal concentrationsproducts transported by OAT3may result in higher exposure In vitro studies have shownof these medicinal products. that cenobamate inhibits

OAT3, a transporterpredominantly involved in theelimination of certainmedicines (e.g. baricitinib,cefaclor, empagliflozin,penicillin G, ritobegron, andsitagliptin).

Cenobamate is not recommended in women of childbearing potential not using contraception. Womenof reproductive potential concomitantly using oral contraceptives should practice additional oralternative non-hormonal measures of birth control during treatment with cenobamate and until 4weeks after treatment discontinuation (see section 4.5).

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 ofmalformations is two to three times greater than the rate of approximately 3% in the generalpopulation. 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 beenelucidated. Discontinuation of anti-epileptic treatments may result in exacerbation of the diseasewhich 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 haveshown reproductive toxicity at levels below clinical exposure (see section 5.3). Ontozry should not beused 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 until4 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 thesuckling child cannot be excluded. As a precautionary measure, breast-feeding should be discontinuedduring treatment with Ontozry.

The effects of cenobamate on human fertility are unknown. Animal data are insufficient due toexposure 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-relatedsymptoms, which may influence the ability to drive or use machines. Patients are advised not to drivea vehicle, operate complex machinery or engage in other potentially hazardous activities until it isknown 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% forpatients randomised to receive cenobamate at doses of 100 mg/day, 200 mg/day and 400 mg/dayrespectively, compared to 3% in patients randomised to receive placebo. The 400 mg dose was moreassociated 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 strictlyfollowed).

Adverse reactions reported in clinical studies are listed in table 2 per system organ class (SOC) andper frequency. Within each frequency group, undesirable effects are ranked in decreasing order ofseverity: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100) andrare (≥ 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, Irritabilitydisorders 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, Drydisorders mouth

Skin and Common Rash*subcutaneous tissuedisorder Rare Drug reaction with eosinophilia and systemicsymptoms (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 abnormalcoordination; Hypersensitivity: Hypersensitivity, Drug hypersensitivity, Eyelid oedema; Rash: Rash,

Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash morbilliform, Rashpapular, Rash pruritic; Hepatic enzyme increased: Alanine aminotransferase increased, Aspartateaminotransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Transaminasesincreased.

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 highstarting doses (50 mg or 100 mg once daily) and weekly or faster titration. When cenobamate wasinitiated at 12.5 mg/day and titrated every two weeks, in an open-label safety study of 1,340 epilepsypatients, no cases of DRESS were reported.

At the time of prescription, patients should be advised of the signs and symptoms of DRESS andmonitored closely for skin reactions. Symptoms of DRESS include typically, although not exclusively,fever, rash associated with other organ system involvement, lymphadenopathy, liver function testsabnormalities 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 andsymptoms suggestive of these reactions appear, cenobamate should be withdrawn immediately and analternative treatment considered (as appropriate). Ontozry should always be initiated at 12.5 mg oncedaily 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 ofhypersensitivity. Two patients in the cenobamate dose group experienced events of drughypersensitivity. One cenobamate treated patient experienced an event of hypersensitivity and 1cenobamate treated patient experienced an event on eyelid oedema. The placebo patient experiencedan event of hypersensitivity. All events were classified as mild or moderate.

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 participationshowed similar results for adverse reactions in these 87 subjects as compared with the 51 subjects whowere >65 years of age at study entry (see section 4.2).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX25.

Cenobamate is a small molecule with a dual mechanism of action. It is a positive allosteric modulatorof subtypes of the γ-aminobutyric acid (GABAA) ion channel, that does not bind to the benzodiazepinebinding site. Cenobamate has also been shown to reduce repetitive neuronal firing by enhancing theinactivation of sodium channels and by inhibiting the persistent component of the sodium current. Theprecise mechanism of action by which cenobamate exercises its therapeutic effects in patients with focal-onset seizures is unknown.

In a placebo-controlled QT study in healthy volunteers, dose-dependent shortening of the QTcF intervalhas been observed with cenobamate. The mean ΔΔQTcF is -10.8 [CI: -13.4, -8.2] msec for 200 mg oncedaily and -18.4 [CI: -21.5, -15.2] msec for 500 mg once daily (1.25 times the maximum recommendeddosage). Reductions of the QTc interval below 340 msec were not observed (see section 4.4).

The efficacy of cenobamate as adjunctive therapy in focal-onset seizures was studied in a multi-centre,randomised, double-blind, placebo-controlled study in adult patients with focal-onset epilepsy whohave not been adequately controlled despite a history of treatment with anti-epileptic products.

Patients were treated with one to three concomitant antiepileptic medicinal products that remainedstable over the course of double-blind study treatment. The daily dose of cenobamate ranged from100 to 400 mg/day.

The study had an 8-week prospective baseline period, during which patients were required to have atleast 3 or 4 partial-onset seizures per 28 days with no seizure-free period exceeding 3 to 4 weeks,followed by an 18-week treatment period including 12 weeks at fixed. The most commonly takenantiepileptic medicinal products at the time of study entry were levetiracetam, lamotrigine,carbamazepine and lacosamide. All subjects who entered the study continued to have seizures, despitea majority having had a history of treatment with 2 or more antiepileptic medicinal products. Morethan 80% of patients were taking two or more concomitant antiepileptic medicinal products at the timeof study enrolment. The efficacy outcomes are summarised in table 3.

The study compared doses of cenobamate 100 mg/day, 200 mg/day and 400 mg/day with placebo, ontop of standard of care. Subjects continued stable treatment on one to three background antiepilepticmedicinal products. Patients were started on a daily dose of 50 mg and subsequently increased by50 mg/day every week until 200 mg/day was reached and then increased by 100 mg/day every week insubjects randomised to 400 mg/day.

Table 3 shows the proportion of patients who exhibited a 50% or greater reduction in seizurefrequency from baseline.

Table 3: Proportion of patients exhibiting 50% or greater response in Study C017

Study Standard of care Standard of care and cenobamateand placebo 100 mg/day 200 mg/day 400 mg/day

Study C017n=102 n=102 n=98 n=9550% Responder 26 (25.5%) 41 (40.2%) 55 (56.1%) 61 (64.2%)rate1

Cenobamate 14.7% 30.6% 38.7%placebo (p=0.036) (p < 0.001) (p < 0.001)difference1Over 12 weeks of fixed-dose double-blind treatment

Figure 1 shows the percentage of patients by category of seizure response during the maintenancephase with increasingly stringent criteria for response.

Figure 1: Cumulative distribution of percent reduction in seizures from baseline by treatmentgroup in the 12-week fixed-dose period in the Study

In the study, 4 of 102 (3.9%) patients in the cenobamate 100 mg/day group, 11 of 98 (11.2%) patientsin the cenobamate 200 mg/day group, 20 of 95 (21.1%) patients in the cenobamate 400 mg/day groupand 1 of 102 (1%) of patients in the placebo group obtained seizure freedom (100% reduction inseizures) during the 12-week fixed-dose phase. Similar responses were seen across subpopulationsgreater than or less than median seizure frequency, and greater than or less than median diseaseduration.

Long term open label study

The majority of subjects chose to enter the open-label extension from Study 1 (98.9%). 80% ofsubjects remained in the study for at least 12 months, and 58% for at least 60 months. Additionalseizure frequency data were collected and were consistent with the results from the double-blindportion of the study.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Ontozry in one or more subsets of the paediatric population in epilepsy (see section 4.2 forinformation on paediatric use).

Cenobamate is well absorbed (at least 88% based on urine recovery) after oral administration, withmedian Tmax ranging from 1 to 4 hours after single- or multiple-dose administration under fastedcondition over the range of 10 to 400 mg.

Co-administration with a high-fat meal (800-1,000 kcal with 50% fat) showed no significant effect onthe rate and the extent of absorption of cenobamate.

Plasma exposures for cenobamate crushed tablets mixed in water, administered either orally orthrough a nasogastric tube, were comparable to whole tablets (confidence intervals for AUCand Cmax within 80-125%). The median Tmax for crushed tablets is 0.5 hours.

The apparent volume of distribution (Vd/F) of cenobamate after oral administration is approximately40-50 L. Plasma protein binding of cenobamate is 60% and independent of concentration in vitro.

Cenobamate primarily binds with human albumin protein.

Cenobamate is extensively metabolised. The primary metabolic pathway is glucuronidation via

UGT2B7 and to a lesser extent by UGT2B4. Minor pathways for metabolism of cenobamate includeoxidation via CYP2E1, CYP2A6, CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5.

Cenobamate and its metabolites are eliminated primarily via urine. Excretion via faeces accounted foronly 5.2% of the dose. More than 50% of the dose was excreted within 72 hours. The apparentterminal half-life of cenobamate in plasma was 50-60 hours within the therapeutic range of100 mg/day to 400 mg/day. Steady state is reached by 14 days.

The Cmax of cenobamate increased proportionally with increasing doses following single oral dosesfrom 5 to 750 mg and multiple oral doses from 50 to 500 mg/day. Steady-state exposures (Cmax and

AUC) increased proportionally with increasing doses in the therapeutic range (100 to 400 mg), butdoses less than 100 mg/day may be cleared faster.

Cenobamate plasma AUC was 1.4-fold to 1.5-fold higher in subjects with mild (CLcr60 to < 90 mL/min) and moderate (CLcr 30 to < 60 mL/min) renal impairment following a single oral200 mg dose of cenobamate compared to healthy controls. In subjects with severe (CLcr < 30 mL/min)renal impairment, cenobamate plasma AUC did not change significantly compared to healthy controlsfollowing single oral 100 mg dose of cenobamate (see section 4.2), The effect of haemodialysis oncenobamate pharmacokinetics has not been studied.

Cenobamate plasma AUC was 1.9-fold and 2.3-fold higher in subjects with mild and moderate hepaticimpairment, respectively, following a single oral 200 mg dose of cenobamate compared to matchedhealthy controls (see section 4.2). The effect of severe hepatic impairment on cenobamatepharmacokinetics has not been studied.

There was no difference observed in the pharmacokinetics of cenobamate between male and femalepatients.

No clinically significant effect of ethnicity on the pharmacokinetics of cenobamate was noted in apopulation PK analysis of pooled data from clinical studies from subjects categorised as Asian, Black,

Caucasian, Hispanic or other.

A 45% decrease in exposure has been estimated across a body weight range from 54 kg to 112 kg.

This variability is not considered to be clinically relevant when establishing a dose of cenobamate.

However, cenobamate dose adjustments may need to be considered in patients who experience weightchanges of ≥30% of their initial body weight, or more.

Elderly (65 years and above)

No clinically significant differences in the pharmacokinetics of cenobamate were observed based onage based on data from subjects aged 18 years to 77 years.

Safety and effectiveness of Ontozry in patients less than 18 years of age has not been established.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity, and carcinogenic potential. However, maximum systemic exposureachieved in the carcinogenicity study in rats was less than that in humans at the maximumrecommended human dose (MRHD) of 400 mg/day.

Maximum doses in repeat dose toxicity studies were limited by the exaggerated CNS effects ofcenobamate (including hypoactivity, uncoordinated gait, hypothermia, and tremor). Systemicexposures at NOAEL (no observed adverse effect levels) were identified or below exposures reachedin humans at the MRHD.

Toxicity to reproduction and development

Reproductive toxicity studies with once daily oral administration showed adverse effects on embryo-foetal and postnatal development. No adverse effects were observed on fertility in a dedicated study inrats. However, systemic exposures at the respective NOAELs for the fertility, embryo-foetaldevelopment, pre- and postnatal development studies were below human exposure at the MRHD.

Cenobamate did not show any teratogenic effects when orally administered twice daily to female ratsand once daily to female rabbits, during the period of organogenesis. However, administration ofcenobamate to pregnant rabbits resulted in increased embryo-foetal mortality, at a dose level associatedwith maternal toxicity. The systemic exposure at the respective NOELs (no observed effect levels) wasbelow human exposure at the MRHD.

When cenobamate was administered to female rats throughout pregnancy and lactation,neurobehavioural impairment (increased auditory startle response) was observed in the offspring at alldoses and decreased preweaning body weight gain and adverse reactions on female reproductivefunction (decreased numbers of corpora lutea, implantations and live foetuses) were seen in theoffspring

Placental and lacteal transfer of cenobamate was confirmed by the presence of cenobamate in bothamniotic fluid and foetal blood from pregnant rats and in the milk of lactating rats.

The environmental risk assessment demonstrated that cenobamate is very persistent (vP) in aquaticsystems (see section 6.6).

Tablet and film-coated tablet contentlactose monohydratemagnesium stearate (E470b)microcrystalline cellulose (E460)silica, colloidal anhydrous (E551)sodium starch glycolate

Film-coating25 mg and 100 mg film-coated tabletsindigo carmine aluminium lake (E132)iron oxide red (E172)iron oxide yellow (E172)macrogolpartially hydrolysed poly(vinyl alcohol) (E1203)talc (E553b)titanium dioxide (E171)50 mg film-coated tabletsiron oxide yellow (E172)macrogolpartially hydrolysed poly(vinyl alcohol) (E1203)talc (E553b)titanium dioxide (171)150 mg and 200 mg film-coated tabletsiron oxide red (E172)iron oxide yellow (E172)macrogolpartially hydrolysed poly(vinyl alcohol) (E1203)talc (E553b)titanium dioxide (E171)

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

PVC/aluminium blisters

Ontozry Treatment Initiation pack 12.5 mg tablets and 25 mg film-coated tablets

Pack of 14 tablets of 12.5 mg and 14 film-coated tablets of 25 mg

Ontozry 50 mg film-coated tablets50 mg - packs of 14, 28 or 84

Ontozry 100 mg film-coated tablets100 mg - packs of 14, 28 or 84

Ontozry 150 mg film-coated tablets150 mg - packs of 14, 28 or 84

Ontozry 200 mg film-coated tablets200 mg - packs of 14, 28 or 84

Not all pack sizes may be marketed.

Cenobamate is very persistent (vP) in aquatic systems. Any unused medicinal product or wastematerial should be disposed of in accordance with local requirements.

The crushed tablet can also be administered via a nasogastric feeding tube (NG), in this case thetablet can be crushed to a powder and mixed with water (25 ml).

Refer to section 4.2 for detailed information on administration through a nasogastric tube.

Angelini Pharma S.p.A

Viale Amelia 70, 00181

Rome - Italy

EU/1/21/1530/001

EU/1/21/1530/002

EU/1/21/1530/003

EU/1/21/1530/004

EU/1/21/1530/005

EU/1/21/1530/006

EU/1/21/1530/007

EU/1/21/1530/008

EU/1/21/1530/009

EU/1/21/1530/010

EU/1/21/1530/011

EU/1/21/1530/012

EU/1/21/1530/013

Date of first authorisation: 26/03/2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu