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Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study.
- Source :
-
Epilepsia [Epilepsia] 2020 Jun; Vol. 61 (6), pp. 1099-1108. Date of Electronic Publication: 2020 May 12. - Publication Year :
- 2020
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Abstract
- Objective: During the development of cenobamate, an antiseizure medication (ASM) for focal seizures, three cases of drug reaction with eosinophilia and systemic symptoms (DRESS) occurred. To mitigate the rate of DRESS, a start-low, go-slow approach was studied in an ongoing, open-label, multicenter study. Also examined were long-term safety of cenobamate and a method for managing the pharmacokinetic interaction between cenobamate, a 2C19 inhibitor, and concomitant phenytoin or phenobarbital.<br />Methods: Patients 18-70 years old with uncontrolled focal seizures taking stable doses of one to three ASMs were enrolled. Cenobamate 12.5 mg/d was initiated and increased at 2-week intervals to 25, 50, 100, 150, and 200 mg/d. Additional biweekly 50 mg/d increases to 400 mg/d were allowed. During titration, patients taking phenytoin or phenobarbital could not have their cenobamate titration rate or other concomitant ASMs adjusted; phenytoin/phenobarbital doses could be decreased by 25%-33%.<br />Results: At data cutoff (median treatment duration = 9 months), 1347 patients were enrolled, of whom 269 (20.0%) discontinued, most commonly due to adverse events (n = 137) and consent withdrawn for reason other than adverse event (n = 74); 1339 patients received ≥1 treatment dose (median modal dose = 200 mg). The most common treatment-emergent adverse events (TEAEs) were somnolence (28.1%), dizziness (23.6%), and fatigue (16.6%). Serious TEAEs occurred in 108 patients (8.1%), most commonly seizure (n = 14), epilepsy (n = 5), and pneumonia, fall, and dizziness (n = 4 each). No cases of DRESS were identified. In the phenytoin/phenobarbital groups, 43.4% (36/114) and 29.7% (11/51) of patients, respectively, had their doses decreased. At the end of titration, mean plasma phenytoin/phenobarbital levels were generally comparable to baseline.<br />Significance: No cases of DRESS were identified in 1339 patients exposed to cenobamate using a start-low (12.5 mg/d), go-slow titration approach. Cenobamate was generally well tolerated in the long term, with no new safety issues found. Phenytoin/phenobarbital dose reductions (25%-33%), when needed during cenobamate titration, maintained stable plasma levels.<br /> (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
- Subjects :
- Adolescent
Adult
Aged
Anticonvulsants blood
Carbamates blood
Chlorophenols blood
Double-Blind Method
Drug Therapy, Combination
Female
Humans
Male
Middle Aged
Seizures blood
Tetrazoles blood
Treatment Outcome
Young Adult
Anticonvulsants administration & dosage
Carbamates administration & dosage
Chlorophenols administration & dosage
Seizures diagnosis
Seizures drug therapy
Tetrazoles administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1528-1167
- Volume :
- 61
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Epilepsia
- Publication Type :
- Academic Journal
- Accession number :
- 32396252
- Full Text :
- https://doi.org/10.1111/epi.16525