Is there an interaction between Highly Active Antiretroviral Therapy (HAART) and Clobazam?

Potential Drug Interactions Between HAART and Clobazam

There is a documented interaction between clobazam and etravirine-based HAART regimens that can lead to increased concentrations of clobazam and its active metabolite N-desmethylclobazam, potentially causing neurotoxic symptoms. 1

Mechanism of Interaction

• Clobazam is primarily metabolized by CYP3A4 and CYP2C19 enzymes 2, 1
• Components of HAART can significantly affect these metabolic pathways:
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have variable effects on CYP450 enzymes: nevirapine induces, delavirdine inhibits, and efavirenz both induces and inhibits these enzymes 3
  • Etravirine (an NNRTI) induces CYP3A4 while inhibiting CYP2C9 and CYP2C19, potentially increasing clobazam and N-desmethylclobazam levels 1
  • Protease inhibitors (PIs) can cause severe hepatotoxicity, which may compound the metabolic effects on clobazam 4

Clinical Implications

• Increased clobazam and N-desmethylclobazam concentrations can lead to:
  • Excessive sedation 1
  • Fatigue 5
  • Neurotoxic symptoms 1
• At steady state, N-desmethylclobazam has 3-4 times greater exposure than clobazam, making metabolite accumulation a significant concern 2

Monitoring Recommendations

• Monitor for signs of clobazam toxicity when used with HAART:
  • Excessive sedation 1
  • Cognitive impairment 1
  • Ataxia 1
• Consider therapeutic drug monitoring of clobazam and N-desmethylclobazam levels when used with HAART components that affect CYP2C19 or CYP3A4 2, 1
• Be vigilant for hepatotoxicity, as both HAART (particularly PIs and nevirapine) and benzodiazepines can affect liver function 4

Management Strategies

• When possible, consider integrase inhibitor-based HAART regimens without pharmacologic boosters, as they have fewer drug interactions with medications like clobazam 3
• Dose adjustment of clobazam may be necessary when used with HAART components that inhibit CYP2C19 (like etravirine) 1
• If signs of toxicity develop, consider reducing the clobazam dose while maintaining the HAART regimen 5, 1
• Consult www.hiv-druginteractions.org for specific drug-drug interaction information when prescribing these medications together 4

Special Considerations

• Patients with hepatitis B or C coinfection are at higher risk for hepatotoxicity with HAART 4 and may require closer monitoring when also taking clobazam
• The interaction potential may vary significantly between different HAART regimens, with integrase inhibitors generally having fewer interactions than NNRTIs or PIs 3
• Pharmacokinetic interactions may be bidirectional, affecting both the antiretroviral and antiepileptic efficacy 6