Highlights
• Cenobamate is a novel anti-seizure medication that can lead to seizure freedom in individuals with drug-resistant epilepsy.
• Cenobamate is well tolerated, and discontinuation due to adverse effects is uncommon.
• Cenobamate may provide clinical benefit to patients with focal and generalized epilepsies.
Introduction
Epilepsy is a common neurological disorder affecting approximately 1%–2% of people worldwide. Reference Falco-Walter1 Approximately one-third of patients have drug-resistant epilepsy (DRE), which is defined as failure of adequate trials of two appropriately chosen and tolerated anti-seizure medications (ASMs). Reference Chen, Brodie, Liew and Kwan2,Reference Mesraoua, Brigo, Lattanzi, Abou-Khalil, Al Hail and Asadi-Pooya3 Furthermore, epilepsy is associated with a lower quality of life Reference Karakis, Boualam, Moura and Howard4 and increased morbidity and mortality than the general population, including a risk of sudden unexplained death in epilepsy. Reference Whitney, Strohm, Jeffs, Jones, Jack and RamachandranNair5 These issues, among others, have led to the continued development of ASMs and other therapies. The number of available ASMs, with novel mechanisms of action, has increased over the past decades. However, the odds of achieving seizure freedom after trialing two ASMs diminish significantly, with <5% probability of seizure freedom. Reference Chen, Brodie, Liew and Kwan2 In June 2023, Health Canada approved cenobamate as an adjunctive therapy in the management of focal seizures in adults with epilepsy over 18 years of age.
Cenobamate is an oral tetrazole alkyl mono-carbamate with dual, complementary mechanisms of action. Cenobamate enhances inactivation of voltage-gated sodium channels through preferential inhibition of the persistent component of the sodium current. Cenobamate also acts as a positive allosteric modulator of γ-aminobutyric acid type A ion channels. Reference Roberti, De Caro, Iannone, Zaccara, Lattanzi and Russo6 In two randomized placebo-controlled trials of cenobamate in adults, seizure freedom rates were approximately 25% after 12 weeks of observation. Reference Chung, French and Kowalski7,Reference Krauss, Klein and Brandt8 In an open-label extension study involving 1347 patients with DRE, 13% achieved seizure freedom, and over 70% experienced a >50% seizure frequency reduction, suggesting that cenobamate can outperform existing pharmacological treatment options. Reference Sperling, Klein and Aboumatar9
At BC Children’s Hospital, patients received cenobamate through an Early Access Program provided by the company, Paladin, as the medication was not yet reimbursed by the Canadian government. Given the limited access, cenobamate was prioritized for the most severely affected patients with DRE.
Methods
A retrospective single-center study was conducted to review all patients who trialed cenobamate from February 2024 to May 2025 at BC Children’s Hospital in Vancouver, Canada, the only tertiary epilepsy center for a province of 5 million people, which sees 2500 patients with complex epilepsy per year. Patients included were treated with cenobamate for at least three months and had adequate follow-up data including data on medications, seizure frequency and adverse effects (AEs). Patients were identified by their primary epileptologist, who prescribed the medication. A review of the medical records was performed to obtain clinical data, including age, sex, seizure duration, epilepsy etiology, family history of epilepsy, epilepsy surgery, number of ASMs previously tried, concomitant ASMs and AEs. Patient’s medical records were reviewed to collect data on seizure type (2017 International League Against Epilepsy [ILAE] classification Reference Fisher, Cross and French10 ) and seizure frequency. The latter was defined as the mean monthly seizure frequency since the prior visit (either three or six months) before starting cenobamate. For each patient, age at cenobamate initiation, maximum dose, duration on medication and AEs were collected. To determine treatment response, the seizure frequency before and after cenobamate initiation was compared. Treatment response was defined as >50% seizure frequency reduction when compared with the baseline, which is when cenobamate was initiated. Seizure type and etiology were classified according to the 2017 ILAE. Reference Fisher, Cross and French10 DRE is defined as ongoing seizures despite a trial of at least two appropriately chosen ASMs at adequate doses. Reference Mesraoua, Brigo, Lattanzi, Abou-Khalil, Al Hail and Asadi-Pooya3
Prior to initiating cenobamate, most epileptologists proactively reduced clobazam dosages that were above 10 mg to minimize AEs. Furthermore, the dose of other sodium channel blocking agents (particularly phenytoin) was reduced as the dose of cenobamate was titrated. Titration schedules were also slow, starting at 12.5 mg daily for two weeks and then increasing the dose every two weeks to a target dose of 100 mg. At that point, patients were reassessed, and if they were tolerating the medication, the dose was further increased as tolerated. Treatment responders were defined as those with a >50% seizure frequency reduction. Treatment-emergent AEs, concomitant ASM adjustments and reasons for cenobamate discontinuation were analyzed. In Kwan and Brodie’s study, ASM discontinuation due to AEs was also considered treatment failure. Reference Chen, Brodie, Liew and Kwan2
Data was summarized using descriptive statistics including median and ranges for continuous variables and frequencies and percentages for categorical variables. Institutional Research Ethics approval was obtained on February 27, 2025.
Results
From February 2024 and May 2025, 36 patients were treated with cenobamate. Patient demographics are summarized in Table 1. The etiology of epilepsy was structural (n = 18) and genetic (n = 13). Of structural etiologies, this included cortical malformations (n = 6), stroke (n = 3) and nonspecific volume loss (n = 3). Mesial temporal sclerosis (n = 2), tumor (n = 2), focal cortical dysplasia (n = 1) and traumatic brain injury. Genetic etiologies included three patients with chromosomal abnormalities (including ring chromosome 14, isodicentric chromosome 15 deletion) and six patients with tuberous sclerosis complex (TSC), which was classified as genetic for this paper. The etiology was unknown for three patients and inflammatory for one patient. Most patients had developmental delay (n = 27), and a subset had autism (n = 10) or a neurodevelopmental disorder (n = 16). One patient had Lennox–Gastaut syndrome.
Patient demographics
Note: CNB = cenobamate; n = number of patients; ASM = anti-seizure medication; VNS = vagal nerve stimulator.
The median age of seizure onset for this cohort was four years of age. Most patients had focal seizures (n = 23), and the remainder had generalized tonic-clonic seizures, epileptic spasms, tonic seizures or atypical absences (Table 1). Multiple seizure types were seen in 15 patients (41%). No patients had primary generalized epilepsy. At baseline, prior to cenobamate initiation, the median monthly seizure frequency was 17, with 15 patients having >30 seizures per month (daily), 4 patients experiencing <4 seizures per month (less than weekly) and the remaining 17 patients having an intermediate number of seizures. Further information on seizure frequency and demographics is summarized in Table 2.
Seizure management for the current patient cohort
Note: ASM = anti-seizure medication; mo = months.
At the time of cenobamate initiation, patients had previously tried a median of nine ASMs (range: 3–20). Eighteen patients underwent epilepsy surgery, 4 had corpus callosotomies and 14 had focal resections. Prior to cenobamate initiation, 11 patients had a vagal nerve stimulator implanted, and 3 patients had previously trialed the ketogenic diet. At the time of initiation of cenobamate, five patients were on pharmaceutical-grade cannabidiol. The median age of initiation of cenobamate was 17.5 years of age (range: 8–23 years). The median duration of follow-up for these patients was 11 months (range: 5–21 months). Eighteen patients (50%) had >50% seizure reduction, with five (14%) patients achieving seizure freedom. Eight patients (22%) had no worthwhile improvement on cenobamate (25%–50% seizure reduction), and one patient experienced an increase in seizure frequency. Of the 8 patients who had no worthwhile improvement, they had a median age of 17.5 years; 6/8 had an underlying structural etiology, and 2/8 had a genetic etiology. These patients had an average of >30 seizures per month at initiation of cenobamate. Out of six patients with TSC who were treated with cenobamate, four (67%) responded, and one (17%) achieved seizure freedom. For patients with genetic etiologies (including TSC), 7/13 (54%) patients were responders. For patients with structural etiologies, 7/17 (41%) were responders. After starting cenobamate, half of the patients (50%) were able to wean off at least one ASM, which included lacosamide (n = 4), eslicarbazepine (n = 4) or brivaracetam (n = 4). Furthermore, 17/36 patients (47%) were able to reduce the dose of at least one ASM after initiating cenobamate.
Of 36 patients, 19 (53%) experienced AEs, with dizziness (n = 8) and drowsiness (n = 7) being the most common. Among patients who experienced dizziness, three were on concomitant clobazam, while the remainder were on concomitant sodium channel ASM, including eslicarbazepine (n = 5), lamotrigine (n = 5), lacosamide (n = 3) or oxcarbazepine (n = 1). To reduce AEs, sodium channel agents were weaned, such as lamotrigine (n = 2). For patients experiencing drowsiness, there was no consistent concomitant ASM associated with this AE, and symptoms improved in three patients after weaning sodium channel ASMs and/or clobazam and in one patient after reducing other ASM, including vigabatrin and rufinamide. Less frequent AEs included nausea, vomiting, agitation, constipation, imbalance and appetite reduction. Eight patients (22%) were on concomitant clobazam, with AEs occurring in 5/8 (63%) of patients. Of the patients who experienced AEs with concomitant clobazam, three had reduced the dose of clobazam before initiation of cenobamate. Two patients discontinued cenobamate, one due to agitation and the other due to drowsiness. No patient discontinued cenobamate due to medication ineffectiveness.
Discussion
This study is one of the first reports of the experience of using cenobamate in Canada in the pediatric and young adult patient population. Similar to other small real-world studies, cenobamate was an effective adjunctive medication for patients with highly DRE. Reference Agashe, Worrell and Britton11–Reference Varughese, Shah, Karkare and Kothare15 In patients with highly refractory epilepsy, cenobamate resulted in a responder rate of approximately 50%. Furthermore, 14% of patients achieved seizure freedom, which is greater than the expected rate of seizure freedom, described after trial of >3 prior ASMs. Reference Chen, Brodie, Liew and Kwan2 AEs were common in this cohort but could often be managed by reducing concomitant ASMs. A minority of patients (5.5%) discontinued the medication due to AEs.
Efficacy
As is common with new ASMs, our patient cohort consisted of highly refractory individuals with a median duration of epilepsy of 13.5 years before starting cenobamate. Most patients in this cohort underwent epilepsy surgery or neuromodulation before initiation of cenobamate. Despite having significantly refractory epilepsy before initiation of cenobamate, treatment response was high, at approximately 50%, with 14% achieving seizure freedom. A retrospective multicenter study from 2 German tertiary centers included 98 highly refractory adult patients, many of whom had undergone epilepsy surgery and neuromodulation. Patients had a median of 10.5 ASMs. Approximately 50% experienced >50% seizure reduction, with seizure freedom rates of 18% at 6 months, 16.7% at 12 months and 3% at 18 months. Reference Lauxmann, Heuer and Heckelmann14 Our findings, with a median follow-up of 11 months, are consistent with these results.
Notably, our cohort included many patients with genetic etiologies. The most common was TSC, chromosomal abnormalities such as ring chromosome 14 and isodicentric chromosome 15 deletions and monogenic disorders like Rett syndrome and KCNT1-related epilepsy. Of the six patients with TSC in our cohort, 66% had >50% seizure reduction, and one achieved seizure freedom. In a retrospective review Reference Aungaroon, Cooke, Ritter, Krueger, Horn and Franz16 of 54 adult and pediatric patients with tuberous sclerosis, a >50% reduction in seizures was achieved in 59% of patients, and 10% obtained seizure freedom. In our study, there was a greater percentage of responders, and a similar percentage achieved seizure freedom. Reference Aungaroon, Cooke, Ritter, Krueger, Horn and Franz16 Differences in results may be due to the small sample size of our cohort and follow-up duration, although the younger age of patients may indicate that earlier treatment could convey better outcomes.
Our cohort included many individuals with developmental delay (26/35). Of this group, 50% of patients were clinical responders, and three achieved seizure freedom. One prior study by Freido et al. Reference Friedo, Greshake, Makridis and Straub17 examined 12 patients with intellectual disability treated with cenobamate, and 55% were clinical responders, though none achieved seizure freedom. Our data further supports the fact that cenobamate can be a useful adjunctive therapy for patients with DRE and developmental delay.
Although cenobamate has been approved for focal epilepsy, two patients with both generalized and focal seizures were responders in our study. One patient with Lennox–Gastaut syndrome initially achieved three months of seizure freedom, but this was followed by a return to baseline seizure frequency. The benefit of cenobamate in patients with combined generalized and focal epilepsy was observed in a cohort of 13 patients, where 70% of patients were responders and the mean reduction of seizures was 58%. Reference Agashe, Worrell and Britton11 Our cohort further supports that cenobamate can be effective in both focal and combined focal and generalized epilepsy.
Adverse effects
Well-documented AEs of cenobamate include fatigue, dizziness, gait disturbances and tremor, which are often worse due to interaction with other medications such as clobazam and other sodium channel-acting ASMs such as phenytoin. Reference Elliott, Ridley-Pryor, Gienapp and Wheless13,Reference Lauxmann, Heuer and Heckelmann14 Cenobamate interacts with a number of ASMs, including increasing levels of clobazam and decreasing levels of other medications such as lamotrigine and levetiracetam. Reference Roberti, De Caro, Iannone, Zaccara, Lattanzi and Russo6 Somnolence was frequently reported in a sample of 13 adolescents, Reference Elliott, Ridley-Pryor, Gienapp and Wheless13 none of whom discontinued treatment due to AEs. Cenobamate is contraindicated in patients with short QT syndrome. Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) has been reported in rare cases with higher starting doses and rapid titration of cenobamate. Reference Roberti, De Caro, Iannone, Zaccara, Lattanzi and Russo6
Within our cohort, dizziness and fatigue were common. The relatively small number of patients who experienced AEs with clobazam (5/8) may be due to the fact that clobazam doses greater than 10 mg were proactively lowered prior to initiation of cenobamate. Dizziness was the most common AE in our cohort, seen in eight patients. Dizziness was often associated with concomitant sodium channel agents such as eslicarbazepine. Therefore, clinicians should be aware that lowering sodium channel agents, especially phenytoin, can reduce associated AEs. This is consistent with prior consensus guidelines from Spain by Toledo et al. that suggest discontinuation of a sodium channel agent with the addition of cenobamate if the patient is on two or more sodium channel agents. Reference Carreño, Gil-Nagel, Serratosa, Toledo, Rodriguez-Uranga and Villanueva18 Notably, no patients in our cohort experienced DRESS syndrome, consistent with other recently published cohorts, highlighting the importance of slow titration schedules. Reference Agashe, Worrell and Britton11–Reference Varughese, Shah, Karkare and Kothare15,Reference Makridis and Kaindl19
Cenobamate is considered to have a relatively favorable cognitive and psychiatric side effect profile. Krauss et al. Reference Krauss, Chung, Ferrari, Stern and Rosenfeld20 found similar AE rates to placebo, and a seven-year open-label study Reference Krauss, Klein and Brandt21 reported less than 2% discontinuation due to these effects. However, pooled trial data noted three suicide attempts in the cenobamate group, with none in the control group. Makridis et al. also looked at neuropsychological AEs (impulsive/agitated behavior) and identified that these AEs were observed in a minority of the sample (19%). Reference Makridis and Kaindl19 In our study, one patient (2.7%) discontinued treatment due to severe agitation, suggesting that these AEs should be screened for cenobamate initiation.
Within our cohort, 2/36 (5%) of patients discontinued cenobamate due to AEs, including agitation and drowsiness. No clear pattern of medication interactions could explain the severity of these AEs. One patient, who was on concomitant eslicarbazepine, phenytoin and gabapentin, withdrew due to agitation. Another patient, on concomitant brivaracetam, perampanel and clonazepam, withdrew due to somnolence. Somnolence has been reported as a common AE for patients on cenobamate. Reference Elliott, Ridley-Pryor, Gienapp and Wheless13,Reference Lauxmann, Heuer and Heckelmann14,Reference Friedo, Greshake, Makridis and Straub17
Study limitations include a retrospective design. Therefore, consistent baseline pre-treatment data and systematic seizure diaries to document seizure frequency were not maintained. There was also a variable frequency of clinical follow-up visits, depending on treatment response, target dosages, ASM adjustments and AE screening. Since this study describes early experience with cenobamate, most patients had highly refractory epilepsy, which may not be representative of all patients prescribed the medication.
Conclusion
Cenobamate is an effective ASM in a group of patients with highly DRE, including individuals with intellectual disability. Its favorable tolerability profile, with only 5% discontinuation due to AEs, further supports its clinical value. This study highlights the profound impact of cenobamate in Canada’s pediatric population and underscores the importance of continued access and funding. To fully realize its potential, larger multicenter studies with longer follow-up and objective measures are essential for advancing our understanding of this novel ASM and optimizing patient outcomes.
Author contributions
AF: Data collection, writing, editing.
LH: Data collection, editing.
MC: Data collection, editing.
AD: Conceptualization, data collection, writing, editing.
Funding statement
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. All work was done at BC Children’s Hospital.
Competing interests
AF does not report any conflicts of interest. LH reports payment/honoraria from Jazz Pharmaceuticals and is a board member of the BC Epilepsy Society. MC reports receiving funding for grants from Xenon Pharmaceuticals, Zogenix International LTD, BC Children’s Research Institute, Sick Kids Foundation, EISAI Inc., Takeda Pharmaceuticals, Marinus Pharmaceuticals, Dravet Syndrome Foundation, GRIN Therapeutics Inc. and Jazz Pharmaceuticals. MC also reports receiving honoraria for speaking at educational events, with honoraria given to the Epilepsy Research and Development fund. AD does not report any conflicts of interest.
Ethical standards
Approved by the University of British Columbia/Children’s and Women’s Health Centre of British Columbia Research Ethics Board (UBC C&W REB) H24-03266.
Target article
Initial Experience with Cenobamate for Drug Refractory Epilepsy at a Canadian Pediatric Tertiary Care Center
Related commentaries (1)
Reviewer Comment on Freibauer et al. “Initial Experience with Cenobamate for Drug Refractory Epilepsy at a Canadian Pediatric Tertiary Care Center”