New Safety Recommendations Issued for ONTOZRY (cenobamate) Following Review of Liver Injury Cases

Following a dedicated working session held between April 7th and 10th, 2026, the European Medicines Agency’s (EMA) Committee for Medicinal Products Risk Assessment (PRAC) has issued updated recommendations aimed at enhancing the safety profile of ONTOZRY (cenobamate) tablets, an anti-epileptic medication. The review was prompted by the analysis of serious liver injury cases, including instances of hepatic insufficiency, observed in patients undergoing treatment with this drug.

Background and Context of the Review

ONTOZRY, containing the active substance cenobamate, is a relatively new anti-epileptic drug approved for the adjunctive treatment of partial-onset seizures in adult patients with epilepsy. Its mechanism of action involves modulating voltage-gated sodium channels and inhibiting GABAA receptors, contributing to a reduction in neuronal excitability. Since its initial market authorization, ongoing pharmacovigilance activities have been crucial in monitoring its real-world safety and efficacy.

The PRAC’s focus on liver-related adverse events stems from the inherent risk of hepatotoxicity associated with various antiepileptic drugs. While liver injury is a known, albeit rare, potential side effect for many medications, it necessitates rigorous monitoring and clear guidance for both healthcare professionals and patients. The recent review by the PRAC underscores the agency’s commitment to proactively addressing emerging safety concerns and ensuring that the benefits of ONTOZRY continue to outweigh its risks.

The PRAC’s analysis specifically investigated cases where patients treated with ONTOZRY experienced severe hepatic adverse events. A key finding highlighted by the committee was that "most of these cases occurred during the concomitant use of other antiepileptic drugs." This observation suggests a potential synergistic or additive effect on liver function when ONTOZRY is administered alongside other anti-epileptic agents, a common practice in managing complex epilepsy cases. The concomitant use of multiple antiepileptic drugs can complicate treatment regimens and increase the likelihood of drug-drug interactions, necessitating careful consideration of each medication’s individual risk profile and its potential impact in combination.

Chronology of Safety Assessment and Recommendations

The timeline leading to these updated recommendations can be traced through the ongoing pharmacovigilance process:

• Initial Approval and Post-Marketing Surveillance: Upon ONTOZRY’s market authorization, comprehensive post-marketing surveillance systems were activated to detect and evaluate any unexpected adverse events. This would have included the routine collection and analysis of spontaneous reports from healthcare professionals and patients.
• Emergence of Liver Injury Reports: Over time, reports of liver injury, including hepatic insufficiency, began to be documented in patients treated with ONTOZRY. These reports would have been collated and analyzed by the pharmacovigilance units of the marketing authorization holder and national competent authorities.
• PRAC Signal Detection and Review: The accumulation of these reports would have triggered a "signal" for potential safety concern within the EMA’s pharmacovigilance framework. The PRAC, responsible for evaluating safety signals for human medicines, would then initiate a formal review of all available data.
• Dedicated Working Session (April 7-10, 2026): The most recent and critical phase involved a focused working session by the PRAC. During this period, committee members meticulously reviewed clinical data, scientific literature, and expert opinions pertaining to ONTOZRY-associated liver injury. This intensive review culminated in the formulation of new safety recommendations.
• Publication of Recommendations and Support Material Updates: Following the PRAC’s conclusions, the next step involves updating the official product information, including the Summary of Product Characteristics (SmPC) and the patient information leaflet (PIL). This process is followed by direct communication to healthcare professionals to ensure prompt dissemination of the updated guidance.

Key Recommendations for Enhanced Patient Safety

The PRAC’s updated recommendations are designed to proactively manage the risk of liver injury and are structured around three core pillars: pre-treatment assessment, ongoing monitoring, and recognition of early warning signs.

Hepatic Assessment: Pre-Treatment Screening and Ongoing Surveillance

A cornerstone of the new guidance is the emphasis on robust hepatic monitoring. The PRAC recommends that patients initiating ONTOZRY therapy undergo specific liver function tests.

• Pre-Treatment Evaluation: Prior to the commencement of ONTOZRY treatment, healthcare professionals are advised to perform a baseline liver function test. This baseline assessment is critical for establishing a patient’s individual liver function status before exposure to the medication. It allows for the identification of any pre-existing hepatic conditions that might increase their susceptibility to drug-induced liver injury.
• Monitoring During Treatment: Following the initiation of ONTOZRY, regular monitoring of liver function is mandated. The frequency and timing of these tests will be detailed in the updated SmPC and PIL, but it is understood that this will involve periodic checks throughout the treatment course. This ongoing surveillance is designed to detect any deviations from the patient’s baseline liver function that could indicate an emerging problem.

Identifying Signs and Symptoms of Liver Damage

Crucially, the updated recommendations equip both healthcare providers and patients with the knowledge to recognize potential indicators of liver involvement. Patients are to be thoroughly informed about the signs and symptoms that may suggest hepatic impairment. These include:

• Jaundice: Yellowing of the skin and the whites of the eyes, a classic sign of liver dysfunction due to impaired bilirubin metabolism.
• Dark Urine: Urine that appears darker than usual, which can be indicative of increased bilirubin levels in the urine.
• Pale Stools: Stools that are lighter in color than normal, suggesting a reduction in bile pigment.
• Abdominal Pain: Discomfort or pain in the upper right quadrant of the abdomen, where the liver is located.
• Nausea and Vomiting: These non-specific symptoms can also accompany liver inflammation.
• Fatigue and Weakness: General feelings of tiredness and lack of energy, often associated with systemic illness, including liver disease.
• Loss of Appetite: A reduced desire to eat.

These symptoms must be presented to patients in a clear and accessible manner to facilitate their prompt identification.

The presence of any of these warning signs should trigger immediate medical attention. The PRAC specifies that upon the occurrence of these symptoms:

• Immediate Medical Consultation: Patients must be instructed to seek immediate medical advice from their healthcare provider.
• Liver Function Testing: A healthcare professional should promptly conduct liver function tests to assess the extent of any hepatic abnormality.
• Dose Adjustment or Treatment Discontinuation: Based on the findings of the liver function tests and the clinical presentation, a decision will be made regarding dose reduction or discontinuation of ONTOZRY.

Posological Adjustments in Cases of Hepatic Impairment

In instances where hepatic impairment is suspected or confirmed, specific management strategies are to be implemented.

• Dose Reduction or Cessation: The recommendations emphasize that in the event of suspected or detected hepatic injury, a reduction in the dose of ONTOZRY or complete cessation of the treatment should be considered. This decision-making process must strictly adhere to the updated recommendations outlined in the SmPC.
• Risk of Rebound Seizures: A critical consideration highlighted by the PRAC is the potential risk of rebound seizures if ONTOZRY is abruptly discontinued. As with many anti-epileptic medications, a sudden cessation can lead to a rebound in seizure activity, which can be severe and dangerous. Therefore, any decision to stop the treatment must carefully weigh this risk.
• Gradual Withdrawal Protocol: The current version of the SmPC already provides guidance for discontinuing the treatment, recommending a gradual tapering over at least two weeks, unless an immediate discontinuation is necessitated by safety concerns. This phased approach aims to minimize the risk of withdrawal symptoms, including rebound seizures.

Supporting Data and Existing Information

The PRAC’s recommendations build upon existing knowledge regarding the potential side effects of ONTOZRY. It is already documented that an increase in liver enzymes, specifically alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT), is listed as a frequent adverse effect. This means it can occur in up to 1 in 10 individuals treated with the drug. This existing information underscores the need for vigilance and reinforces the rationale behind enhanced monitoring protocols.

Furthermore, the current SmPC outlines specific dosage adjustments for patients with hepatic insufficiency. In such cases, a reduction in target doses by up to 50% is advised, with a maximum recommended daily dose of 200 mg, as opposed to the 400 mg daily limit for patients without hepatic impairment. Importantly, cenobamate is not recommended for individuals with severe hepatic insufficiency. The new recommendations are expected to refine and potentially expand upon these existing guidelines.

Implications and Broader Impact

The PRAC’s updated recommendations for ONTOZRY signify a proactive approach to patient safety within the European Union’s regulatory framework. The emphasis on pre-treatment screening and ongoing monitoring, coupled with clear guidance on symptom recognition and management, aims to empower healthcare professionals and patients alike in mitigating the risk of serious liver injury.

Direct Communication to Healthcare Professionals: To ensure the swift and effective implementation of these new safety measures, the PRAC has recommended that a direct communication be sent to healthcare professionals (DHPCs) across the EU. This communication will serve to alert prescribers and pharmacists to the updated recommendations concerning hepatic surveillance in patients treated with ONTOZRY. This targeted dissemination of information is crucial for ensuring that the updated safety protocols are integrated into clinical practice without delay. The DHPC will be issued by the marketing authorization holder for ONTOZRY after its adoption by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

Impact on Prescribing Practices: These updated guidelines will likely influence prescribing patterns for ONTOZRY. Clinicians will need to be more diligent in their pre-treatment assessment and routine monitoring of liver function. The potential for drug-drug interactions, particularly with other antiepileptic medications, will also require even greater consideration during the prescribing process.

Patient Awareness and Empowerment: The enhanced information provided to patients about recognizing the signs of liver damage is a significant step towards patient empowerment. By being informed about potential risks and knowing when to seek medical attention, patients can play a more active role in managing their treatment and ensuring their safety.

Future Research and Development: The PRAC’s findings may also inform future research and development efforts for cenobamate and other antiepileptic drugs. Further investigation into the mechanisms underlying ONTOZRY-induced liver injury, especially in the context of polytherapy, could lead to the development of more personalized treatment strategies and potentially safer drug formulations or combinations.

The update to the Summary of Product Characteristics (SmPC) and the patient information leaflet (PIL) will formalize these recommendations. The PRAC’s diligent work in scrutinizing safety data and providing updated guidance is a testament to the continuous effort to ensure that medications like ONTOZRY can be used as safely and effectively as possible, balancing the significant therapeutic benefits for epilepsy patients with the imperative of minimizing potential harms.