What is the safety and usage protocol for combining Levetiracetam (Levipil) with Clobazam (Frisium)?

Combining Levetiracetam (Levipil) with Clobazam (Frisium)

Levetiracetam and clobazam can be safely combined for seizure management, with both medications having complementary mechanisms of action and favorable safety profiles when used together. 1

Efficacy of the Combination

• Levetiracetam is an effective non-enzyme-inducing antiepileptic drug (AED) recommended for various seizure types, including generalized tonic-clonic seizures 1
• Clobazam can be an effective add-on therapy when seizures are not controlled with a single AED, significantly reducing seizure frequency when added to other medications 2
• The combination has shown efficacy in controlling seizures that are resistant to monotherapy, with documented cases showing complete seizure control when used together 3, 4

Dosing Considerations

• For levetiracetam, typical dosing ranges from 1000-3000 mg/day in adults, with loading doses of 30-60 mg/kg IV (maximum 4500 mg) for status epilepticus 5
• Clobazam is typically used as an add-on therapy at doses that should be titrated gradually to minimize side effects 2
• When combining these medications, a slower titration rate of levetiracetam is recommended, especially in patients with risk factors for behavioral side effects 6

Safety Profile and Monitoring

• Levetiracetam has advantages over enzyme-inducing AEDs (like phenytoin, phenobarbital, carbamazepine) as it has minimal drug interactions and does not affect the cytochrome P450 system 1
• Clobazam, as a benzodiazepine, may cause fatigue, somnolence, and potential weight gain when used as an add-on therapy 2
• The most common adverse effects to monitor for include:
  • Behavioral abnormalities with levetiracetam (6.9% discontinuation rate due to behavioral issues) 6
  • Sedation and somnolence, particularly with clobazam 2, 3

Risk Factors for Adverse Effects

• Factors associated with higher risk of behavioral side effects from levetiracetam include:
  • History of psychiatric disorders
  • Rapid titration of levetiracetam
  • Diagnosis of symptomatic generalized epilepsy 6
• Patients with these risk factors should have levetiracetam titrated more slowly and be monitored more closely for behavioral changes 6

Practical Recommendations

• Start with lower doses of both medications and titrate gradually to minimize side effects 2, 6
• Monitor for behavioral changes, particularly in patients with pre-existing psychiatric conditions 6
• Assess seizure control and quality of life regularly to determine effectiveness of the combination 2
• If behavioral side effects occur with levetiracetam, consider slowing the titration or reducing the dose before discontinuing 6
• Both medications can be used in status epilepticus, with levetiracetam being a recommended second-line agent for benzodiazepine-resistant status epilepticus 1, 7

Special Considerations

• The combination may be particularly useful in patients with comorbidities or on multiple medications due to levetiracetam's minimal drug interactions 1, 5
• Levetiracetam has shown safety in patients with porphyria cutanea tarda, where many other AEDs are contraindicated 3
• In patients with refractory epilepsy, this combination may improve quality of life measures including seizure worry, emotional well-being, and cognitive function 2