CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 212839Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Division of Risk Management (DRISK} Office of Medication Error Prevention and Risk Management (OMEPRM} Office of Surveillance and Epidemiology (OSE} Center for Drug Evaluation and Research (CDER) Application Type NOA Application Number 212839 PDUFA Goal Date November 21, 2019 OSE RCM # 2018-2560 Reviewer Name(s) Lindsey W. Crist, PharmD, BCPS Team Leader Donella Fitzgerald, PharmD Deputy Division Director Jamie Wilkins, PharmD Review Completion Date November 19, 2019 Subject Evaluation of Need for a REMS Established Name Cenobamate Trade Name Xcopri Name of Applicant SK Life Science, Inc Therapeutic Class Antiepileptic Formulation(s) Tablets for oral use: 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg and 200 mg Dosing Regimen Initial Dosage Week 1and2 12.S mg once daily Titrat ion Regimen Week 3 and 4 2S mg once daily Week s and 6 SO mg once daily Week 7 and 8 100 mg once daily Week 9and10 1SO mg once daily Maintenance Dosage Week 11 and thereafter 200 mg once daily Maximum Dosage If needed based on clinical response 400 mg once daily and tolerability, may increase by SO mg once daily every two weeks 1 Reference ID 4522028 Table of Contents EXECUTIVE SUMMARY ......................................................................................................................................................... 3 1 Introduction ..................................................................................................................................................................... 3 2 Background ...................................................................................................................................................................... 3 2.1 Product Information ........................................................................................................................................... 3 2.2 Regulatory History ............................................................................................................................................... 4 3 Therapeutic Context and Treatment Options .................................................................................................... 4 3.1 Description of the Medical Condition .......................................................................................................... 4 3.2 Description of Current Treatment Options ............................................................................................... 5 4 Benefit Assessment ....................................................................................................................................................... 6 5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 7 5.1 Serious Adverse Events ..................................................................................................................................... 8 5.1.1 Deaths .............................................................................................................................................................. 8 5.1.2 Nonfatal Serious Adverse Events ......................................................................................................... 9 5.2 Adverse Events of Special Interest .............................................................................................................. 10 5.2.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) .................................. 10 5.2.2 QT Shortening ............................................................................................................................................ 11 6 Expected Postmarket Use ......................................................................................................................................... 12 7 Risk Management Activities Proposed by the Applicant ............................................................................. 12 8 Discussion of Need for a REMS ............................................................................................................................... 12 9 Conclusion & Recommendations ........................................................................................................................... 13 10 Appendices ................................................................................................................................................................ 13 10.1 References ............................................................................................................................................................. 13 10.2 Summary of Treatment Options for Partial Onset Seizures ............................................................. 15 2 Reference ID: 4522028 EXECUTIVE SUMMARY This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity XCopri (cenobamate) is necessary to ensure the benefits outweigh its risks. SK Life Science, Inc. submitted a New Drug Application (NDA) 212839 for cenobamate with the proposed indication for the treatment of partial-onset seizures in adult patients. The risks associated with cenobamate include drug reaction with eosinophilia and systemic symptoms (DRESS), QT shortening, and class risks associated with antiepileptic agents including suicidal behavior and ideation, neurologic adverse reactions, and risk of increased seizures and status epilepticus with rapid withdrawal. The applicant did not submit a REMS with this application but proposed a risk management plan that includes routine pharmacovigilance and recommendations for labeling to address the risk of drug reaction with eosinophilia and systemic symptoms (DRESS). The Division of Risk Management (DRISK) has determined that a REMS is not necessary to ensure the benefits of cenobamate outweigh its risks. Healthcare providers who treat epilepsy should be familiar with the risks of antiepileptics including the risk of DRESS. The risks associated with cenobamate can be communicated through labeling. A Medication Guide will be included for informing patients of the risk of DRESS, clinical features, and the appropriate management. 1 Introduction This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity (NME) XCopri (cenobamate) is necessary to ensure the benefits outweigh its risks. SK Life Science, Inc. submitted a New Drug Application (NDA) 212839 for cenobamate with the proposed indication for the treatment of partial-onset seizures in adult patients. This application is under review in the Division of Neurology 2 (DN2). The applicant did not submit a REMS with this application but proposed a risk management plan that includes routine pharmacovigilance and recommendations for labeling to address the risk of drug reaction with eosinophilia and systemic symptoms (DRESS). 2 Background 2.1 PRODUCT INFORMATION XCopri (cenobamate), a new molecular entitya, is an antiepileptic proposed for the treatment of partial- onset seizures in adult patients. The mechanism of action for cenobamate’s antiepileptic effects is not fully understood. Cenobamate has been shown to reduce repetitive neuronal firing by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium 1 current. It is also a positive allosteric modulator of the γ-aminobutyric acid (GABAA) ion channel. Cenobamate is proposed as immediate release oral tablets available in 12.5 mg, 25 mg, 50 mg, 150 mg, and 200 mg strengths. The Applicant’s proposed dosage regimen includes a titration to the maintenance dose of (b) (4) mg daily; however, the review division determined that the labeled maintenance dose will be 200 mg (see Section 4). The proposed titration is summarized in Table 1 a Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity. 3 Reference ID: 4522028 below . The proposed packaging includes t it rat ion packs and maintenance packs. Cenobamate will be administered in the outpatient and inpatient sett ing for chronic maint enance therapy for epilepsy. b Cenobamate is not currently approved in any jurisdiction. Table 1. Cenobamate Tit ration Schedule2 Initial Dosage Week 1 and2 12.S mg once daily Tit rat ion Regimen Week 3 and 4 2S mg once daily Week Sand 6 SO mg once daily Week 7 and 8 100 mg once daily Week 9and 10 1SO mg once daily Maintenance Dosage Week 11 and thereafter 200 mg once daily Maximum Dosage If needed based on clinical response and tolerability, 400 mg once daily may increase by SO mg once daily every two weeks Source: Adapted from proposed prescribing information for cenobamate, NOA 212839 2.2 REGULATORY HISTORY The following is a summary of t he regulatory hist ory for NOA 212839 relevant to this review : • 11/ 21/ 2018: NOA 212839 submission for the treat ment of partial-onset seizures in adult patients received. • 4/ 25/2019: A mid-cycle communication meeting was held between t he Agency and t he Applicant via teleconference. The Agency informed the Applicant t hat the significant saf ety issues and risk management approach for DRESS remain under review . The Agency also communicated safety concerns with the proposed packaging configurations. • 08/ 21/ 2019: A late cycle meeting was held between t he Agency and the Applicant . No discussion on a REMS occurred at the meeting,