Ontozry (Cenobamate)
Antiepileptic Drug for Adjunctive Treatment of Focal Seizures in Adults
Quick Facts About Ontozry
Key Takeaways
- Ontozry (cenobamate) is an adjunctive antiepileptic drug for adults with focal-onset seizures who have not responded to at least two other antiepileptic medications.
- It features a unique dual mechanism: enhancement of sodium channel slow inactivation and positive GABA-A receptor modulation, distinguishing it from most other antiepileptic drugs.
- Slow dose titration starting at 12.5 mg is mandatory to reduce the risk of a serious hypersensitivity reaction called DRESS syndrome.
- Clinical trials demonstrated that approximately 21% of patients on the 400 mg dose achieved complete seizure freedom — an unusually high rate for an add-on epilepsy therapy.
- Cenobamate interacts with several medications, including hormonal contraceptives, phenytoin, clobazam, and lamotrigine, requiring careful dose adjustment by a physician.
What Is Ontozry and What Is It Used For?
Ontozry contains the active substance cenobamate, which belongs to the class of drugs known as antiepileptic agents (also called antiseizure medications or anticonvulsants). Epilepsy is a neurological disorder characterised by recurrent, unprovoked seizures caused by abnormal electrical activity in the brain. According to the World Health Organization (WHO), epilepsy affects approximately 50 million people worldwide, making it one of the most common neurological diseases globally.
Cenobamate was specifically developed for the treatment of focal-onset seizures (previously called partial-onset seizures) in adults. Focal seizures originate in a specific, localised area of one hemisphere of the brain. They may remain localised (simple or complex focal seizures) or may spread to involve both hemispheres, a process known as secondary generalisation. When a focal seizure generalises, it can cause tonic-clonic convulsions (previously known as grand mal seizures), which involve loss of consciousness and rhythmic jerking of the limbs.
Ontozry is authorised exclusively for adjunctive (add-on) therapy, meaning it is taken alongside one or more other antiepileptic medications. It is indicated for patients who have not achieved sufficient seizure control despite prior treatment with at least two antiepileptic drugs. This positions cenobamate as a treatment option for drug-resistant or refractory epilepsy, which affects approximately 30% of all epilepsy patients according to the International League Against Epilepsy (ILAE).
How Does Cenobamate Work?
Cenobamate has a unique dual mechanism of action that distinguishes it from most other antiepileptic drugs currently available. Understanding how it works helps explain both its efficacy and its side-effect profile.
Sodium channel modulation: Cenobamate enhances the slow inactivation of voltage-gated sodium channels. These channels are critical for the generation and propagation of electrical impulses (action potentials) along nerve fibres. By promoting the inactive state of these channels, cenobamate reduces the ability of neurons to fire repetitively at the high frequencies that characterise epileptic activity. Notably, cenobamate preferentially enhances slow inactivation rather than fast inactivation — a mechanism that is distinct from traditional sodium channel blockers such as carbamazepine and phenytoin, and may contribute to its superior efficacy in some patients.
GABA-A receptor modulation: In addition to its action on sodium channels, cenobamate acts as a positive allosteric modulator of GABA-A receptors. GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter in the brain. By enhancing the function of GABA-A receptors, cenobamate increases inhibitory neurotransmission, which counterbalances the excessive excitatory activity underlying seizures. This dual mechanism — reducing excitation while simultaneously boosting inhibition — is believed to account for cenobamate’s notable clinical effectiveness.
Clinical Efficacy
The efficacy of cenobamate has been demonstrated in rigorous, randomised, double-blind, placebo-controlled clinical trials. In the pivotal phase II trial (Study C013), patients receiving cenobamate 200 mg daily achieved a median seizure reduction of 55.6% compared to 21.5% with placebo. The responder rate (patients with ≥50% seizure reduction) was approximately 50% at 200 mg and 64% at 400 mg, compared to 25% with placebo.
Particularly noteworthy is the seizure-freedom rate observed in clinical trials. In the phase III trial (Study C017), 21.1% of patients on cenobamate 400 mg/day and 11.2% on 200 mg/day achieved seizure freedom during the maintenance period. These rates are substantially higher than the 1–5% seizure-freedom rates typically seen with other adjunctive antiepileptic therapies, making cenobamate one of the most effective add-on treatments for focal epilepsy identified in clinical trials to date.
What Should You Know Before Taking Ontozry?
Before initiating treatment with Ontozry, your prescribing physician will conduct a thorough evaluation of your medical history, current medications, and overall health to determine whether this drug is appropriate for you. Several important factors must be considered, as outlined below.
Contraindications
Ontozry must not be taken in the following situations:
- Hypersensitivity: Do not take Ontozry if you are allergic to cenobamate or to any of the inactive ingredients in the formulation (including lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, or magnesium stearate).
- Congenital short QT syndrome: Ontozry is absolutely contraindicated in patients with familial (congenital) short QT syndrome, a rare inherited cardiac condition characterised by abnormally short QT intervals on the electrocardiogram (ECG). Cenobamate has been shown to shorten the QT interval in a dose-dependent manner, and in patients who already have a shortened QT interval, this could increase the risk of dangerous cardiac arrhythmias.
Warnings and Precautions
A serious hypersensitivity reaction called DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) has been reported with cenobamate. This potentially life-threatening reaction typically occurs within the first few weeks to months of treatment and may include high fever, rash (initially on the face that can spread), swollen lymph glands, elevated liver enzymes, and eosinophilia (elevated white blood cells). Adherence to the mandatory slow titration schedule significantly reduces this risk. If you develop any of these symptoms, seek medical attention immediately.
Speak with your doctor or pharmacist before taking Ontozry, or during treatment, if any of the following apply:
- Suicidal thoughts or behaviour: A small number of patients treated with antiepileptic drugs, including cenobamate, have experienced thoughts of self-harm or suicide. The risk is present from the first week of treatment. If you experience such thoughts at any point, contact your doctor immediately. Family members and caregivers should also be alert to changes in mood or behaviour.
- Serious skin reactions: As described above, DRESS syndrome is a rare but serious concern. Early recognition of symptoms — including fever, facial rash, spreading skin eruption, and swollen glands — is essential for prompt treatment and favourable outcomes.
- QT interval effects: Since cenobamate can shorten the QT interval, your doctor may order an ECG before starting treatment if there is concern about your cardiac health. Patients with pre-existing cardiac conditions should be monitored closely.
- CNS depression: Cenobamate can cause drowsiness, dizziness, and fatigue, particularly during dose titration. These effects are additive with other CNS-depressant drugs and alcohol.
Pregnancy and Breastfeeding
Ontozry may reduce the effectiveness of hormonal contraceptives (including oral pills, patches, and implants). You must use an effective non-hormonal method of contraception during treatment and for at least four weeks after discontinuation. Discuss suitable options with your doctor.
The safety of cenobamate during human pregnancy has not been fully established. Animal reproductive studies have shown adverse effects at doses relevant to the clinical setting. As with all antiepileptic drugs, the decision to use Ontozry during pregnancy must weigh the potential risks to the foetus against the significant danger that uncontrolled seizures pose to both the mother and the unborn child. If you are pregnant, think you may be pregnant, or are planning to become pregnant, consult your doctor before taking or continuing this medicine.
It is not known whether cenobamate passes into breast milk in humans. Because of the potential for adverse effects in nursing infants, breastfeeding is not recommended during treatment with Ontozry. Your doctor can advise you on the best approach for feeding your baby while you are on this medication.
Alcohol
Alcohol consumption should be avoided while taking Ontozry. Cenobamate can amplify the effects of alcohol, including drowsiness and impaired coordination. Even moderate alcohol intake may significantly increase sedation and the risk of falls or accidents when combined with this medication.
Driving and Operating Machinery
Ontozry can cause somnolence (drowsiness), dizziness, fatigue, and visual disturbances, particularly during the titration phase and after dose increases. These effects may impair your ability to drive, cycle, or operate machinery safely. Do not drive or use heavy machinery until you understand how Ontozry affects you personally, and only when your reaction time is not impaired.
Children and Adolescents
Ontozry is not recommended for use in children and adolescents under 18 years of age. The safety and efficacy of cenobamate have not been studied in paediatric populations. Clinical trials were conducted exclusively in adult patients, and no paediatric dosing recommendations are available. Research into paediatric use is ongoing, but until adequate data are available, this drug should only be prescribed to adults.
How Does Ontozry Interact with Other Drugs?
Because cenobamate is both a substrate and a modulator of various hepatic enzymes, it has a clinically significant interaction profile. Cenobamate induces CYP3A4 and CYP2B6 (reducing the effectiveness of drugs metabolised by these enzymes) while inhibiting CYP2C19 (increasing levels of drugs metabolised by this enzyme). It also interacts with certain drug transporters. Always inform your doctor about all medications you are currently taking, have recently taken, or plan to take.
Major Drug Interactions
| Interacting Drug | Effect | Clinical Action |
|---|---|---|
| Phenytoin | Cenobamate inhibits CYP2C19, causing increased phenytoin levels (risk of toxicity) | Phenytoin dose reduction required; monitor plasma levels |
| Clobazam | Cenobamate inhibits CYP2C19, increasing active metabolite levels of clobazam | Clobazam dose reduction may be needed |
| Phenobarbital | Cenobamate may increase phenobarbital levels via CYP2C19 inhibition | Monitor for excessive sedation; dose adjustment may be required |
| Lamotrigine | Cenobamate may reduce lamotrigine levels through enzyme induction | Monitor lamotrigine levels; dose increase may be necessary |
| Oral contraceptives | CYP3A4 induction reduces effectiveness of hormonal contraceptives | Use non-hormonal contraception during treatment and 4 weeks after stopping |
| Midazolam | CYP3A4 induction significantly reduces midazolam exposure | Midazolam may be less effective; dose adjustment required |
Other Notable Interactions
In addition to the major interactions listed above, cenobamate may affect or be affected by several other medications. These include:
- Bupropion: Cenobamate induces CYP2B6, which may reduce bupropion levels. This could decrease the effectiveness of bupropion when used for smoking cessation or depression.
- Omeprazole: As a CYP2C19 inhibitor, cenobamate may increase omeprazole levels. While usually not clinically significant, this may require monitoring in long-term use.
- Baricitinib: Cenobamate may affect levels of baricitinib, used for inflammatory joint conditions and eczema.
- Empagliflozin: Possible interaction affecting blood glucose control in diabetes patients.
- Sitagliptin: May interact through shared metabolic pathways, potentially affecting diabetes management.
- Antibiotics (cefaclor, penicillin G): Cenobamate may affect the renal transport of these antibiotics.
Always carry a complete, up-to-date list of all your medications — including over-the-counter drugs and supplements — to every medical appointment. Many drug interactions with cenobamate can be safely managed with appropriate dose adjustments, but your prescriber needs full information to make these decisions.
What Is the Correct Dosage of Ontozry?
The dosing of Ontozry follows a carefully designed titration schedule that is essential for patient safety. The slow dose escalation was implemented based on clinical data showing that rapid titration was associated with a significantly higher incidence of DRESS syndrome. Your doctor will prescribe the exact dose for each stage, and it is crucial that you follow this schedule precisely.
Adults (18 years and older)
| Period | Daily Dose | Duration |
|---|---|---|
| Titration – Step 1 | 12.5 mg once daily | Weeks 1–2 |
| Titration – Step 2 | 25 mg once daily | Weeks 3–4 |
| Titration – Step 3 | 50 mg once daily | Weeks 5–6 |
| Titration – Step 4 | 100 mg once daily | Weeks 7–8 |
| Titration – Step 5 | 150 mg once daily | Weeks 9–10 |
| Maintenance | 200 mg once daily | From week 11 onwards |
| Optional higher dose | Up to 400 mg once daily | If needed, further increases every 2 weeks |
The recommended maintenance dose is between 200 mg and 400 mg taken once daily. Your doctor will determine the optimal dose based on your individual response and tolerability. Ontozry should be taken at approximately the same time each day. It can be taken with or without food, during the day or in the evening, according to your preference and daily routine.
How to Take Ontozry
Swallow the tablets whole with a glass of water. The tablets should not be split in half, as they are not designed for division. However, if you have difficulty swallowing, the tablets can be crushed and mixed with water. Crushed tablets can also be administered via a nasogastric (NG) tube following a specific protocol: crush the prescribed dose, mix with 25 ml of water, shake well, administer through the tube using a syringe, then flush with an additional 10 ml of water to ensure the full dose is delivered.
Missed Dose
If you miss a dose and fewer than 12 hours have passed since the scheduled time, take the missed dose as soon as you remember. If more than 12 hours have elapsed, skip the missed dose entirely and take the next dose at your regular time. Never take a double dose to make up for a missed one, as this significantly increases the risk of side effects including severe drowsiness and dizziness.
Overdose
If you take more Ontozry than prescribed, contact your doctor or local poison control centre immediately. Symptoms of overdose may include pronounced dizziness, extreme drowsiness, and fatigue. There is no specific antidote for cenobamate overdose; treatment is supportive and symptom-based. In a hospital setting, healthcare providers will monitor vital signs and provide appropriate medical care.
Stopping Treatment
Never reduce the dose of or stop taking Ontozry without consulting your doctor. Abrupt discontinuation of any antiepileptic drug can trigger rebound seizures, including potentially dangerous status epilepticus (prolonged seizure activity). Your doctor will create a gradual dose-reduction plan if treatment needs to be stopped.
Elderly Patients
No specific dose adjustment is recommended for elderly patients based solely on age. However, older adults may be more sensitive to the CNS effects of cenobamate (drowsiness, dizziness, impaired coordination) and may also have reduced renal or hepatic function. Clinicians typically exercise caution and may titrate more slowly in elderly patients, with careful monitoring for adverse effects.
Children
Ontozry is not approved for use in patients under 18 years of age. No paediatric dosing recommendations have been established, as the drug has not been studied in children or adolescents.
What Are the Side Effects of Ontozry?
Like all medicines, Ontozry can cause side effects, although not everyone experiences them. Most side effects are related to the drug’s action on the central nervous system and tend to be dose-dependent, occurring more frequently at higher doses and during the titration phase. Understanding the frequency categories helps you assess the likelihood of experiencing each effect.
Very Common
- Somnolence (drowsiness) and fatigue or severe tiredness (exhaustion)
- Dizziness
- Vertigo (sensation of spinning or unsteadiness)
- Coordination problems, difficulty walking, or balance disturbances (ataxia, gait disturbance, abnormal coordination)
- Headache
Common
- Memory impairment and confusion
- Irritability
- Difficulty finding words or speech problems
- Nystagmus (rapid involuntary eye movements), blurred vision, double vision (diplopia)
- Nausea, vomiting, constipation, or diarrhoea
- Dry mouth
- Skin rash, itching (pruritus)
- Swollen eyelids, swollen arms or legs (peripheral oedema)
- Elevated liver enzyme levels in blood tests
Uncommon
- Allergic reactions
- Suicidal thoughts or thoughts of self-harm
Rare
- DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) — a severe skin and systemic hypersensitivity reaction with fever, rash, swollen lymph nodes, elevated liver enzymes, and eosinophilia
Most of the common side effects — particularly drowsiness, dizziness, and coordination difficulties — tend to occur during the initial weeks of treatment and during dose increases. They typically diminish in intensity as the body adapts to the medication. The mandatory slow titration schedule is specifically designed to minimise these effects. If any side effect becomes severe or persistent, discuss it with your doctor, who may adjust your dose or recommend supportive measures.
It is important to note that the side-effect profile of cenobamate is generally comparable to other antiepileptic drugs. A notable finding from clinical trials is that the risk of DRESS syndrome is substantially reduced when the recommended slow titration is followed. In early clinical development, when faster titration was used, DRESS occurred at a rate of approximately 3 in 953 patients. After implementation of the slow titration schedule, no cases of DRESS were reported in subsequent trials enrolling over 1,300 patients.
It is important to report suspected side effects after a medicine has been authorised. This allows continuous monitoring of the medicine’s benefit-risk balance. You can report side effects directly to your national medicines regulatory authority (such as the MHRA in the UK, the FDA in the US, or the EMA in Europe).
How Should You Store Ontozry?
Proper storage of medication ensures that it remains safe and effective throughout its shelf life. For Ontozry, the storage requirements are straightforward:
- Keep out of sight and reach of children at all times.
- Store at room temperature. No special storage conditions are required — the tablets do not need refrigeration and are not sensitive to temperature within normal household ranges.
- Keep the tablets in their original blister packaging to protect them from moisture and light until you are ready to take them.
- Do not use Ontozry after the expiry date stated on the carton and blister pack after “EXP.” The expiry date refers to the last day of the stated month.
- Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to safely dispose of medicines that are no longer needed. These measures help protect the environment.
What Does Ontozry Contain?
Understanding the composition of your medication is important, particularly if you have known allergies or intolerances to specific excipients (inactive ingredients). Ontozry tablets contain the following:
Active Ingredient
The active substance is cenobamate. The tablets are available in six strengths: 12.5 mg (uncoated), 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg (all film-coated except 12.5 mg).
Inactive Ingredients (Excipients)
The tablet core contains: microcrystalline cellulose (E460), lactose monohydrate, sodium starch glycolate, colloidal anhydrous silica (E551), and magnesium stearate (E470b).
Ontozry tablets contain lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
The film-coating composition varies by tablet strength and determines the tablet colour:
- 12.5 mg tablets: Uncoated, round, white to off-white, debossed “AV” on one side and “12” on the other.
- 25 mg tablets: Brown film-coated, round. Coating contains indigo carmine aluminium lake (E132), red and yellow iron oxide (E172), macrogol, partially hydrolysed poly(vinyl alcohol) (E1203), talc (E553b), and titanium dioxide (E171).
- 50 mg tablets: Yellow film-coated, round. Coating contains yellow iron oxide (E172), macrogol, partially hydrolysed poly(vinyl alcohol) (E1203), talc (E553b), and titanium dioxide (E171).
- 100 mg tablets: Brown film-coated, round. Same coating as 25 mg tablets.
- 150 mg tablets: Light orange film-coated, round. Coating contains red and yellow iron oxide (E172), macrogol, partially hydrolysed poly(vinyl alcohol) (E1203), talc (E553b), and titanium dioxide (E171).
- 200 mg tablets: Light orange film-coated, oval. Same coating as 150 mg tablets.
All tablets are debossed with “AV” on one side and the strength number on the other side for easy identification.
Pack Sizes
Ontozry is available in the following pack configurations:
- Treatment initiation pack: Contains 14 tablets of 12.5 mg and 14 film-coated tablets of 25 mg, covering the first four weeks of treatment.
- Maintenance packs (50 mg, 100 mg, 150 mg, 200 mg): Available in packs of 14, 28, or 84 film-coated tablets.
Not all pack sizes may be marketed in your country. Ontozry is manufactured by Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.p.A. in Ancona, Italy, and the marketing authorisation holder is Angelini Pharma S.p.A., Rome, Italy.
Frequently Asked Questions About Ontozry
Ontozry (cenobamate) is used as adjunctive (add-on) therapy for the treatment of focal-onset seizures in adults with epilepsy. It is prescribed when at least two other antiepileptic medications have failed to provide adequate seizure control. Focal seizures start in one area of the brain and may or may not spread to both hemispheres (secondary generalisation). Ontozry is taken alongside existing antiepileptic medications, not as a standalone treatment.
Ontozry has demonstrated impressive efficacy in clinical trials. At the 200 mg dose, approximately 56% of patients achieved a 50% or greater reduction in seizure frequency. Most notably, seizure-freedom rates of 11–21% were observed, which is substantially higher than the 1–5% rates typically seen with other adjunctive antiepileptic drugs. These results have positioned cenobamate as one of the most effective add-on therapies for drug-resistant focal epilepsy.
The mandatory slow titration (starting at 12.5 mg and increasing every two weeks) was implemented to minimise the risk of DRESS syndrome, a potentially life-threatening hypersensitivity reaction. Early clinical development used faster titration schedules and saw cases of DRESS. After implementing the slower titration, no cases were reported in subsequent large trials. This gradual approach also helps reduce the incidence of common side effects like drowsiness and dizziness.
No, alcohol should be avoided while taking Ontozry. Cenobamate can amplify the effects of alcohol, leading to increased drowsiness, impaired coordination, and slowed reaction times. Even small amounts of alcohol can significantly increase the sedative effects of the medication, raising the risk of falls, accidents, and other injuries.
Yes, Ontozry can reduce the effectiveness of hormonal contraceptives, including birth control pills, patches, and hormonal implants. This is because cenobamate induces the liver enzyme CYP3A4, which speeds up the breakdown of the hormones in these contraceptives. Women of childbearing potential should use a reliable non-hormonal method of contraception (such as a copper IUD or barrier methods) during treatment and for at least four weeks after stopping Ontozry.
If fewer than 12 hours have passed since your missed dose, take it as soon as you remember. If more than 12 hours have passed, skip the missed dose and take your next dose at the usual time. Never take a double dose to compensate. If you are unsure, contact your doctor or pharmacist for guidance. Consistent daily dosing is important for maintaining seizure control.
References
- European Medicines Agency (EMA). Ontozry (cenobamate) — Summary of Product Characteristics (SmPC). Last updated 2025. Available at: EMA – Ontozry.
- Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurology. 2020;19(1):38–48. doi:10.1016/S1474-4422(19)30399-0.
- Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology. 2020;94(22):e2311–e2322. doi:10.1212/WNL.0000000000009530.
- International League Against Epilepsy (ILAE). ILAE Classification of the Epilepsies: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512–521.
- World Health Organization (WHO). Epilepsy: A Public Health Imperative. Geneva: WHO; 2019. Available at: WHO Epilepsy Report.
- National Institute for Health and Care Excellence (NICE). Epilepsies in children, young people and adults. NICE guideline [NG217]. Updated 2024.
- Lattanzi S, Trinka E, Zaccara G, et al. Third-Generation Antiseizure Medications for Adjunctive Treatment of Focal-Onset Seizures in Adults: A Systematic Review and Network Meta-analysis. Drugs. 2022;82(2):199–218.
- Angelini Pharma. Ontozry (cenobamate) Patient Information Leaflet. April 2025.
Editorial Team
Medical Writing
iMedic Medical Editorial Team — Specialists in neurology and clinical pharmacology with experience in epilepsy care and antiepileptic drug therapy.
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All medical information on iMedic is based on peer-reviewed research and international guidelines. Our editorial process follows the GRADE evidence framework. We have no commercial funding or pharmaceutical company sponsorship.