Clinicians in Europe must now perform liver function tests before starting treatment and during therapy with Ontozry (cenobamate). In its April 2026 meeting, the European Medicines Agency’s (EMA’s) Pharmacovigilance Risk Assessment Committee (PRAC) established new liver monitoring protocols after reviewing cases of severe hepatic injury with hepatic failure in patients taking this epilepsy drug. 

Ontozry is indicated as adjunctive therapy for adults with focal seizures, with or without secondary generalization, that are inadequately controlled after treatment with at least two prior antiepileptic medicinal products.

Cenobamate modulates neuronal excitability through dual mechanisms: It enhances inhibitory neurotransmission by acting as a positive allosteric modulator of GABA_A receptors, and it reduces excitatory signaling by inhibiting voltage-gated sodium currents (with a preference for the persistent component). This stabilizes neuronal membranes, suppresses hypersynchronous firing, and decreases the propagation of epileptic activity in the brain.

The drug is available as tablets taken once daily. The dosage begins at 12.5 mg daily and is increased over several weeks to a target of 200 mg, with potential increases up to 400 mg if seizures remain uncontrolled.

The EMA had previously concluded that the drug’s benefits outweigh its risks and authorized it for use in the European Union on March 26, 2021.

Clinical Monitoring Requirements 

Clinicians must perform immediate clinical assessment and liver function tests in patients who develop symptoms suggesting hepatic injury, including fatigue, loss of appetite, right upper abdominal discomfort, dark urine, or jaundice. Patients should receive counseling to seek medical attention immediately if they experience signs or symptoms indicating liver injury.

When hepatic injury is suspected or identified, clinicians should consider dose reduction or discontinuation of Ontozry, following guidelines in the Summary of Product Characteristics. Unless necessary, abrupt discontinuation should be avoided to minimize the risk for rebound seizures. The PRAC recommended adding hepatic injury as a rare side effect that may occur in up to 1 in 1000 people to the product information, along with warnings for patients and clinicians.

Implementation and Safety Profile 

The direct healthcare professional communication for Ontozry will be forwarded to the EMA’s Committee for Medicinal Products for Human Use. Once adopted, it will be distributed to clinicians by the marketing authorization holder according to an agreed communication plan and published on the “Direct Healthcare Professional Communications” page and in national registers in European Union Member States.