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Pubblished: 2025-04-01

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Artikel

Managing Ontozry titration and concomitant medication: International Delphi panel recommendations

The goal of epilepsy treatment is seizure freedom, commonly achieved with antiseizure medications (ASMs). Poor seizure control increases risk of mortality, including sudden unexpected death in epilepsy and other physical and psychological comorbid conditions. Early emerging adverse events may impact adherence, decrease quality of life, and delay achieving optimal treatment dosages.1

Managing co-medications with cenobamate requires careful patient evaluation. Dose adjustments should therefore be made on a case-by-case basis, bearing in mind the concomitant ASM doses, seizure type and frequency, tolerability to ASMs, and comorbidities.1

Key points

These key points summarize the Delphi panel's consensus on best practices for initiating and managing cenobamate treatment in patients with focal-onset seizures.

Panel objectives

The Delphi panel aimed to develop consensus on best practices for managing patients during the 10-week titration of cenobamate and beyond. Goals included identifying appropriate candidates for cenobamate therapy, addressing challenges during treatment initiation, balancing efficacy and safety, and managing concomitant medications.

Patient Selection:1

  • In Europe, cenobamate is for patients with focal-onset seizures who have failed two prior ASMs due to lack of efficacy or tolerability.1
  • Patients with disabling or potentially hazardous seizures despite previous treatments are prioritized.1

  • A Delphi panel is a structured communication technique originally developed to achieve convergence of opinion concerning real-world knowledge solicited from experts within certain topic areas. It relies on a panel of experts who participate in multiple rounds of questionnaires.

    Process: Experts respond to a series of questionnaires in two or more rounds. After each round, a facilitator provides an anonymized summary of the experts' forecasts and reasons. This feedback allows participants to revise their previous answers in light of the replies of other members of the panel. The process can be modified to include for example a meeting instead of questionnaire.

    Goal: The aim is to achieve a convergence of opinion on a specific topic or to develop consensus among the panelists.

    Applications: It is commonly used in fields where there is incomplete or uncertain knowledge, such as forecasting, policy-making, and development for clinical recommendations.

    The Delphi method is valued for its ability to harness expert judgment in a systematic way, reduce the influence of dominant individuals, and provide a well-rounded perspective on the issue at hand.

    Reference: Hsu C & Sandford B. The Delphi Technique: Making Sense Of Consensus. Practical Assessment, Research, and Evaluation, 12(10), Available online: http://pareonline.net/getvn.asp?v=12&n=4 . Viewed 31.1.2025

Titration process1,2

Recommendations emphasize a careful and monitored titration process to manage efficacy and tolerability.

Standard titration follows 2-week intervals, but slower titration may be considered for certain patient groups (e.g., those with a history of severe rashes or those on multiple concomitant medications).

Importance of Co-Medication Management

Managing concomitant medications is crucial during and after the cenobamate titration period to maximize seizure control and minimize tolerability issues.1

    • Proactive Down-Titration: Recommended for patients on complex regimens with two or more ASMs or those on high doses of lacosamide (>400 mg/day) or clobazam (=40 mg/day).1
    • Reactive Down-Titration: Suggested for benzodiazepines if the patient experiences somnolence or fatigue. For those on phenobarbital or phenytoin, drug monitoring is suggested.1

  • Since cenobamate induces CYP450 isoenzymes (CYP3A4, CYP2B6) and inhibits CYP2C19, the levels of medications metabolized by these enzymes may change.1 Specifically:

    • Levels of drugs metabolized by CYP3A4 and CYP2B6 may decrease.1
    • Levels of drugs metabolized by CYP2C19 may increase.1

    Monitoring drug levels is recommended for medications with narrow therapeutic indices and those used chronically.1

  • Special patient groups may require individualized titration schedules and closer monitoring.1
    These groups include:

    • Patients with a history of severe rashes.1
    • Patients with a high burden of psychiatric medications.1
    • Patients on multiple concomitant medications (three or more ASMs).1

    • For patients taking oral contraceptives, drug levels should be monitored due to potential interactions.1
    • For patients with intellectual disabilities, additional support might be needed during the titration process.1

    Neurologists should consult specialists when questions arise about non-epilepsy concomitant medications.1

  • Regular monitoring is advised for patients on newer oral anticoagulants (e.g., dabigatran, rivaroxaban) and HIV antiretroviral medications to avoid significant interactions.1

    For patients undergoing chemotherapy or other oncology treatments, future research is needed to assess the efficacy and tolerability of cenobamate.1

  • Common treatment-emergent adverse events (TEAEs) include central nervous system-related effects (e.g., somnolence, fatigue).1

    Early efficacy of cenobamate has been observed at doses as low as 25 mg/day, which may allow for earlier reduction of other ASMs.1

    Open communication and close monitoring are vital during titration to manage expectations and address any tolerability issues promptly.1

    Patients should be evaluated when reaching the 100 mg/day dose to assess response and make necessary adjustments.1

    A post hoc analysis of a phase III open-label safety study showed that concomitant ASM dose reductions were associated with more patients remaining on cenobamate.3

    The reduction commonly due to CNS side effects occurred mainly during the cenobamate titration phase without reported cases of seizure exacerbation.

  • Close patient follow-up and access to healthcare providers during the titration period are important.1

  • The panel highlighted the need for ongoing research and real-world evidence to refine and support these recommendations.1

▼ Detta läkemedel är föremål för utökad övervakning.

Ontozry® (cenobamat) 12,5 mg odragerad tablett samt 25 mg, 50 mg, 100 mg, 150 mg och 200 mg filmdragerade tabletter. Rx F. ATC-kod: N03AX25 - antiepileptika, övriga antiepileptika. Indikation: Ontozry är indicerat som tilläggsbehandling av fokala anfall, med eller utan sekundär generalisering hos vuxna patienter med epilepsi, som inte kontrollerats tillräckligt trots tidigare behandling med minst två antiepileptika. Kontraindikationer: Överkänslighet mot den aktiva substansen eller mot något hjälpämne, ärftligt kort QT-syndrom. Varningar: Patienter ska instrueras att uppsöka läkare om tecken på självmordstankar/självmordsbeteende uppstår, samt om tecken och symptom på läkemedelsreaktion med eosinofili och systemiska symtom (DRESS) inträffar. Innehåller laktos. Cenobamat kan minska exponeringen av substanser som metaboliseras via CYP3A4, CYP2B6 samt öka exponeringen av substanser som metaboliseras via CYP2C19. Cenobamat rekommenderas inte till fertila kvinnor som inte använder preventivmedel eller vid amning. MAH: Angelini Pharma S.p.A.  Lokal kontakt: Angelini Pharma Nordics, nordic.medinfo@angelinipharma.com. Datum för senaste översyn av SPC: 2/2025. För pris och ytterligare information, se www.fass.se.

  1. Steinhoff B, Ben-Menachem E, Klein P et al. Therapeutic strategies during cenobamate treatment initiation: Delphi panel recommendations. Ther Adv Neurol Disord 2024, Vol. 17: 1–10
  2. Ontozry SmPC
  3. Aboumatar S, Ferrari L, Stern S et al. Reductions in concomitant antiseizure medication drug load during adjunctive cenobamate therapy: Post-hoc analysis of a subset of patients from a phase 3, multicenter, open-label study. Epilepsy Res. 2024;200:107306.

MAT-SE-0006-P Mar 2025

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