FDA Approves Alternate Administration Routes for Antiseizure Medication Cenobamate

News
Article

The FDA has approved a label update on the administration options for SK Life Science’s cenobamate, a treatment approved for adults with partial-onset seizures.

 Louis Ferrari, RPh, MBA, vice president of medical affairs at SK Life Science

Louis Ferrari, RPh, MBA

Credit: SK Life Science

According to a new announcement, the FDA has granted approval for 2 new administration options for SK Life Science’s cenobamate CV (Xcopri), a previously approved antiseizure medication (ASM) for adults with partial-onset seizures. The treatment tablets can now be crushed and mixed with water and either administered by mouth as an oral suspension or via a nasogastric tube, providing additional flexibility for dosing.1

This label update is supported by findings from an open-label, randomized, single-center, 3-period, 6-sequence, balanced crossover study that assessed the pharmacokinetics (PK) and safety of 3 cenobamate administration routes in 24 healthy participants (ages 18-50 years). Between all 3 administration routes, which included swallowing an intact tablet, as a crushed tablet suspended in water and taken orally, and as a crushed tablet suspended in water and administered via a nasogastric tube, investigators observed bioequivalence to the originally approved administration route (test-to-reference ratios for PK parameters [Cmax, AUClast, and AUC0-inf] 90% CIs, 80%-125%).2

"We were very pleased to see this information become part of the newly approved label for cenobamate CV. This is an important administration option for both patients and their caregivers who need an option when patients may not have the ability to swallow a whole tablet. We studied the administration of cenobamate CV in 2 methods: Crushing the tablet and mixing with a small amount water and swallowing it orally, or crushing the tablet, mixing it with water and administering it through a nasogastric tube. Both methods were shown to be equivalent to swallowing a whole tablet,” Louis Ferrari, RPh, MBA, vice president of medical affairs at SK Life Science, told NeurologyLive®.

Top Clinical Takeaways

  • The FDA's approval of new administration options for cenobamate enhances accessibility for patients with epilepsy who struggle to swallow tablets whole.
  • Findings from a study demonstrating bioequivalence between different administration routes contributed to the label update for cenobamate.
  • The expanded options for administering cenobamate provide flexibility for both patients and healthcare providers, addressing an unmet need in managing epilepsy treatment.

In the study, participants received 1 dose each of cenobamate 200 mg as an intact tablet administered with 240 mL of water (treatment A), a crushed tablet suspended in 240 mL of water and taken orally (treatment B), and a crushed tablet suspended in 240 mL of water and administered via nasogastric tube (treatment C). All of the administrated doses were done in a fasting state, with a 13-day washout in between the doses. Additionally, investigators collected blood samples for PK assessments from predose to 264 hours after each treatment on days 1, 14, and 27.

READ MORE: Real-World Data Confirms Safety of Long-Term Cenobamate in Epilepsy

Researchers used natural log-transformed cenobamate PK parameters to predict relative bioavailability as well as constructed 90% CIs using a mixed-effects model approach with treatment, sequence, and period as fixed effects and subject in sequence as random effect. Notably, an absence of effect was concluded if the 90% CIs fell in the 80%-125% predefined boundaries.

"Having administration options as to how a medication can be given is always a plus. Also, patients can be assured that the method of administration has been studied and shown to be comparable to the standard oral administration of cenobamate CV. Patients who have a nasogastric tube in place may also benefit from the administration of the crushed tablet in suspension," Ferrari added.

Presented at the 2023 American Epilepsy Society (AES) annual meeting, held December 1-5, in Orlando, Florida, by Janice Laramy, PharmD, PhD, associate director at SK Life Science, test-to-reference ratios for treatment B compared with treatment A were: Cmax, 95.6% (90% CI, 89.6%-102%); AUClast, 90.9% (90% CI, 87.2%-94.7%), and AUC0-inf, 92.8% (90% CI, 89.6%-96.0%). In addition, test-to-reference ratios for treatment C compared with treatment A were: Cmax, 101.7% (90% CI, 95.4%-108.4%), AUClast, 93.3% (90% CI, 89.6%-97.2%), and AUC0-inf, 94.1% (90% CI, 91.0%-97.3%).2

"Until now the only approved method of administration was to swallow a whole tablet. Patients who are not able to swallow or have an NG tube in place, now have the opportunity, to have the tablet crushed and administered either orally or through a nasogastric tube," Ferrari said. "Having the ability to receive cenobamate CV in this manner is particularly important for hospitalized or institutionalized patients who can benefit from the medication."

The FDA initially approved cenobamate in November 2019, which was supported by data from 2 pivotal trials (Study 013, NCT01397968; Study 017, NCT01866111) that assessed the efficacy and safety of the treatment in more than 1900 patients.3 In the trials, findings showed that cenobamate significantly reduced partial-onset seizure frequency, with up to 20% of patients who achieved seizure-free status during the maintenance phases.

The assessment on the safety and efficacy of cenobamate, an inhibitor of the persistent sodium current and positive allosteric modulator of the γ-aminobutyric acid (GABAA) ion channel, in the 2 pivotal trials included 655 adults with partial-onset seizures with or without secondary generalization. Patients experienced seizures for a mean of 24 years, with a median of 8.5 seizures per 28 days during the baseline period of 8 weeks. Patients were randomized to doses of 100, 200, and 400 mg compared with placebo, with the therapy reducing the median number of seizures per 28 days.

One of the pivotal trials, presented at the 2018 American Academy of Neurology Annual Meeting, was an 18-week, randomized double-blind, dose-response study where 437 patients received 100 mg cenobamate (n = 108), 200 mg (n = 110), 400 mg (n = 111), or placebo (n = 108). All told, median seizure frequencies decreased for all doses of cenobamate, with the 100 mg/day experiencing a 35.5% reduction, the 200 mg/day observing a 55.0% reduction, and the 400 mg/day seeing a 55.0% reduction. In comparison, the placebo group experienced a 24.0% reduction.4

The median frequencies for simple partial seizures also decreased with all doses of cenobamate (100 mg: 48.0%; 200 mg: 63.0%; and 400 mg: 58.5%) compared with placebo, which showed a 7.0% reduction. The median frequencies for complex partial seizures and secondary generalized tonic-clonic seizures decreased with the 200-mg dose, 55.0% and 91.0%, respectively, as well as the 400-mg dose, 60.0% and 78.0%, respectively. In comparison, the placebo group observed reductions of 28.5% and 33.0%, respectively.

Because of 3 drug reaction incidences with eosinophilia and systemic symptoms (DRESS) syndrome in the early phase study, cenobamate was further assessed to determine the ability to mitigate this risk. In a trial including more than 1300 patients, gradually increasing doses of cenobamate-12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg-were administered daily at 2-week intervals. Biweekly increases of 50 mg/day to increase the dosage to 400 mg/day were allowed, and no incidences of DRESS were observed in the phase 3 trial.5

REFERENCES
1. XCOPRI® (cenobamate tablets) CV Receives FDA Approval for Alternate Methods of Administration That Include Crushed Tablet in Liquid Suspension Taken Orally or Through a Nasogastric Tube. News Release. SK Life Science. Published April 11, 2024. Accessed April 11, 2024.
2. Laramy J, Ferrari L. Relative Bioavailability of Cenobamate 200 Mg Administered as a Crushed Tablet Either Orally or via a Nasogastric Tube versus an Intact 200 Mg Cenobamate Tablet. Presented at: AES 2023; December 1-5; Orlando, FL. Abstract 2.257 https://aesnet.org/abstractslisting/relative-bioavailability-of-cenobamate-200-mg-administered-as-a-crushed-tablet-either-orally-or-via-a-nasogastric-tube-versus-an-intact-200-mg-cenobamate-tablet
3. FDA Approves XCOPRI® (cenobamate tablets), an Anti-Epileptic Drug (AED) from SK Biopharmaceuticals, Co., Ltd., and U.S. Subsidiary SK Life Science, Inc. News Release. SK Life Science. Published November 21, 2019. Accessed April 10, 2024. https://www.sklifescienceinc.com/pdf/FDA_Approves_XCOPRI_(cenobamate_tablets)_an_Anti-Epileptic_Drug_(AED)_from_SK_Biopharmaceuticals_Co._Ltd._and_U.S._Subsidiary_SK_Life_Science_Inc.pdf
4. SK life science announces FDA acceptance of NDA submission for cenobamate, an investigational antiepileptic drug. News Release. SK Life Science. Published February 4, 2019. Accessed April 10, 2024. sklifescienceinc.com/pdf/SKLSI%20NDA%20Acceptance%20Press%20Release%20-FINAL-Updated%202-3-19.pdf.
5. Sperling M, Klein P, Kamin M. Safety of cenobamate (YKP3089) as an adjunctive treatment for uncontrolled partial seizures in a large, multi-center, open-label study. Presented at: American Epilepsy Society Annual Meeting; New Orleans, LA; December 2, 2018. aesnet.org/meetings_events/annual_meeting_abstracts/view/500991.
Related Videos
Ro'ee Gilron, PhD
Monica Verduzco-Gutierrez, MD
Shahid Nimjee, MD, PhD
Peter J. McAllister, MD, FAAN
Video 6 - "Utilization of Neuroimaging in Alzheimer’s Disease"
Video 5 - "Contribution of Multiple Pathways to the Development of Alzheimer’s Disease"
Michael Levy, MD, PhD
© 2024 MJH Life Sciences

All rights reserved.