In a patient on Xcopri (cenobamate) undergoing surgery, should the drug be continued perioperatively and are any anesthetic dose adjustments or special considerations needed?

Xcopri (Cenobamate) and Anesthesia

Continue Xcopri perioperatively without interruption, but alert the anesthesia team to expect increased CNS depressant effects and potential drug interactions requiring careful monitoring and possible anesthetic dose adjustments.

Key Perioperative Management Principles

Continue the Medication

The FDA label explicitly warns against abrupt discontinuation of Xcopri, as stopping seizure medications suddenly can precipitate status epilepticus—a life-threatening emergency 1. Xcopri should be continued through the perioperative period, including the day of surgery, consistent with general principles for antiepileptic drug management 2.

Critical Anesthetic Considerations

CNS Depression and Sedation:

• Xcopri causes significant somnolence, fatigue, dizziness, and gait disturbances 1
• The FDA label specifically warns that "other CNS depressants or alcohol may have additive effects" 1
• Anesthesiologists must reduce doses of sedatives, opioids, and general anesthetics to account for this synergistic CNS depression
• Enhanced monitoring for respiratory depression and prolonged emergence from anesthesia is essential

QT Interval Shortening:

• Xcopri causes QT shortening on ECG 1, 3
• The drug is contraindicated in patients with familial short QT syndrome 1
• Obtain a preoperative ECG and avoid concomitant use of other QT-shortening medications
• Monitor for cardiac arrhythmias, particularly fast heart rate or palpitations 1

Drug Interaction Management

Cytochrome P450 Effects: Cenobamate is both a CYP2C19 inhibitor and a CYP3A4/2B6 inducer 3. This creates potential interactions with:

• Anesthetic agents metabolized through these pathways
• Other perioperative medications (antiemetics, analgesics, cardiovascular drugs)
• Concomitant antiepileptic drugs requiring dose adjustments

Specific Anesthetic Implications:

• Expect reduced requirements for propofol, benzodiazepines, and volatile anesthetics due to GABA-A receptor potentiation 3
• Opioid requirements may be altered due to enhanced CNS depression
• Neuromuscular blocking agents should be monitored carefully as cenobamate affects sodium channels 3

Hepatic Monitoring

The FDA mandates baseline liver function tests (if not done within 3 months) and monitoring during treatment 1. Ensure recent liver function tests are available preoperatively, as hepatic impairment could affect anesthetic drug metabolism and increase risk of perioperative complications.

Common Pitfalls to Avoid

1. Do not discontinue Xcopri preoperatively even for "minor" procedures—the risk of breakthrough seizures or status epilepticus far outweighs theoretical anesthetic concerns
2. Do not use standard anesthetic dosing—start with reduced doses and titrate carefully
3. Do not overlook the QT shortening—this is unique among antiepileptics and requires specific cardiac monitoring
4. Do not assume linear pharmacokinetics—cenobamate exhibits non-linear kinetics, particularly at doses >300 mg, meaning plasma levels increase disproportionately with dose increases 3

Postoperative Considerations

• Resume oral Xcopri as soon as the patient can tolerate oral intake
• If prolonged NPO status is anticipated, consider nasogastric administration (tablets can be crushed and mixed with water per FDA label) 1
• Monitor closely for increased sedation when combining postoperative opioids with Xcopri
• Watch for signs of severe allergic reactions (DRESS syndrome), though these are more common during titration 1

The evidence strongly supports continuation of cenobamate perioperatively based on FDA warnings about withdrawal seizures 1, general antiepileptic drug management principles 2, and expert consensus that seizure control should not be compromised for elective surgery 4. The anesthesia team must simply adjust their approach to account for the drug's CNS depressant effects and unique cardiac effects.