EMA Issues Urgent Safety Alert for Cenobamate Following Severe Liver Injury Reports
核心洞察
The European Medicines Agency (搜索)'s Pharmacovigilance Risk Assessment Committee issued a direct healthcare professional communication regarding severe liver injury (搜索) cases associated with cenobamate (Ontozry), an anti-seizure medication.
PRAC (搜索) recommended mandatory liver function monitoring before and during treatment, with most severe cases occurring when cenobamate was used alongside other anti-seizure medications.
The regulatory action represents a shift toward more aggressive pharmacovigilance signal escalation, bypassing standard label updates in favor of direct prescriber communications for severe safety signals.
The European Medicines Agency (搜索)'s Pharmacovigilance Risk Assessment Committee (PRAC (搜索)) has issued a direct healthcare professional communication regarding severe liver injury (搜索) cases associated with cenobamate (Ontozry), marking a significant escalation in regulatory response to post-market safety signals for CNS medications.
Severe Hepatic Safety Signal Emerges
PRAC (搜索)'s April 2026 meeting highlights revealed that cases of severe liver injury (搜索) with hepatic failure (搜索) have been reported in patients treated with cenobamate, a sodium channel and GABA-A receptor (搜索) modulator approved for focal-onset seizures in adults. Most cases occurred when the medicine was used alongside other anti-seizure medications, according to the regulatory committee's assessment.
The decision to mandate direct communication to prescribers—rather than relying on standard label amendments—reflects what regulatory experts describe as an increasingly aggressive approach to pharmacovigilance signal management. PRAC (搜索)'s use of this regulatory tool, described as "the equivalent of a flare gun," indicates the committee's determination that routine safety information dissemination channels were insufficient to protect patients in real time.
New Monitoring Requirements Implemented
Following its review of the hepatic injury cases, PRAC (搜索) has established comprehensive monitoring protocols for cenobamate prescribers. Healthcare professionals are now required to conduct liver function tests before starting treatment with Ontozry and throughout the treatment period. The committee specifically recommends prompt clinical evaluation and liver function testing for patients presenting with symptoms indicating liver injury (搜索), including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
Patients must be advised to immediately seek medical attention if they experience signs or symptoms suggesting liver injury (搜索). When liver injury is suspected or detected, prescribers should consider dose reduction or discontinuation of cenobamate, following guidelines in the summary of product characteristics to minimize the risk of rebound seizures through abrupt discontinuation.
PRAC (搜索) has recommended adding liver injury (搜索) as a rare side effect—occurring in up to 1 in 1,000 people—to Ontozry's product information. Previously, increased liver enzyme levels were listed as a common side effect, potentially affecting up to 1 in 10 patients.
Broader Implications for CNS Drug Development
The cenobamate safety action represents what industry analysts characterize as "Pharmacovigilance Signal Escalation as Protocol Design Driver," reflecting three converging pressures on drug development: accelerated approval timelines compressing post-market data maturity, increasing PRAC (搜索) willingness to mandate direct professional communications, and structural lag between regulatory safety signals and investigational protocol amendments.
Cenobamate was authorized in Europe under the brand name Ontozry based on strong efficacy data from pivotal Phase 3 trials sponsored by SK Life Science (搜索). The drug's distinctive mechanism—reducing epileptic seizure frequency through dual action on sodium channels (搜索) and positive allosteric modulation of GABA-A receptors—supported its approval for focal seizures (搜索) in adults, including those that spread to secondary generalization.
Operational Impact on Clinical Trials
The regulatory action is expected to trigger immediate operational changes for sponsors conducting CNS trials, particularly those involving compounds with hepatic metabolism profiles. Clinical trial sites running investigational CNS studies should expect sponsor protocol amendments adding hepatic monitoring visit windows, lowering thresholds for unscheduled laboratory assessments, and introducing data safety monitoring board reporting triggers for transaminase elevations.
The structural gap between Phase 3 trial safety monitoring and post-approval pharmacovigilance infrastructure has become increasingly apparent. Pivotal epilepsy (搜索) trials typically enroll controlled populations—adults with refractory focal seizures (搜索) screened for baseline hepatic function and excluded for comorbidities that confound liver enzyme interpretation. This controlled environment differs significantly from post-approval populations that may include patients with undiagnosed hepatic vulnerabilities and polypharmacy interactions not represented in clinical trials.
Regulatory Framework Evolution
PRAC (搜索)'s decision reflects the European pharmacovigilance framework anchored in Regulation (EU) No 1235/2010, which grants the committee authority to recommend urgent safety restrictions and direct professional communications when routine label updates are deemed insufficient for patient protection. This regulatory posture aligns with the FDA's emerging framework around real-world pharmacovigilance integration, as outlined in its 2023 discussion paper on using real-world data to support safety evaluations.
The expectation that post-approval safety signals be detected, triaged, and escalated on timelines supporting direct professional communications—rather than the standard 60-to-90 day Periodic Safety Update Report cycle—demands enhanced signal detection infrastructure. This requirement extends beyond large pharmaceutical companies to mid-tier sponsors operating in high-sensitivity therapeutic areas.
For CROs managing post-approval safety studies and Periodic Safety Update Report obligations in Europe, the cenobamate decision raises questions about signal triage documentation and compliance with Good Pharmacovigilance Practice Module VII requirements. If severe liver injury (搜索) signals were accumulating in EudraVigilance with sufficient density to prompt direct healthcare professional communication, the timing of when these signals first crossed reviewable thresholds in earlier reporting cycles will likely face regulatory scrutiny.