Onfi Drug Interactions: What to Avoid and What to Tell Your Doctor

Onfi (clobazam) is a powerful anti-seizure medication with several important drug interactions. Some are life-threatening, and others require dose adjustments to keep your treatment safe and effective. Because LGS patients often take multiple medications simultaneously, understanding Onfi's interactions is especially important. This guide covers the most critical interactions and what you need to tell your doctor before starting any new medication.

Boxed Warning: Opioid Medications (Potentially Fatal)

Onfi carries the FDA's most serious warning level — a boxed warning — about the combination of benzodiazepines with opioid medications. Combining Onfi with opioids such as codeine, morphine, oxycodone, hydrocodone, fentanyl, or tramadol can result in:

• Profound sedation
• Respiratory depression (dangerously slowed or stopped breathing)
• Coma
• Death

If you currently take an opioid medication for any reason — including pain, cough, or addiction treatment — tell your doctor before starting Onfi. When this combination is unavoidable, it should be used with extreme caution at the lowest effective doses for the shortest time necessary, with close monitoring.

Major Interaction: Alcohol and CNS Depressants

Alcohol significantly interacts with Onfi. Drinking alcohol while taking clobazam increases clobazam's peak blood level by approximately 50%, dramatically increasing sedation and the risk of respiratory problems. Do not drink alcohol while taking Onfi.

Other CNS depressants that increase sedation risk with Onfi include:

• Other benzodiazepines (diazepam, lorazepam, alprazolam)
• Sedating antihistamines (diphenhydramine/Benadryl)
• Muscle relaxants (cyclobenzaprine, carisoprodol)
• Antipsychotics (quetiapine, clozapine, haloperidol)
• Sedating antidepressants (mirtazapine, trazodone)

Important Interaction: Cannabidiol (Epidiolex/CBD)

Cannabidiol (CBD), including the prescription form Epidiolex, is increasingly prescribed alongside clobazam in LGS patients. This combination requires careful monitoring because CBD inhibits CYP2C19, the enzyme responsible for metabolizing clobazam's active metabolite (N-desmethylclobazam). The result: when you add CBD to clobazam, N-desmethylclobazam levels can rise significantly, potentially causing excessive sedation or other adverse effects. Your neurologist may need to reduce your clobazam dose when starting CBD.

CYP2C19 Inhibitors: Medications That Raise Clobazam Levels

Because clobazam is metabolized by CYP2C19, medications that inhibit this enzyme will increase the levels of clobazam's active metabolite and may require a dose adjustment:

• Strong CYP2C19 inhibitors: Fluconazole (Diflucan), fluvoxamine (Luvox), ticlopidine — dose reduction of clobazam may be necessary.
• Moderate CYP2C19 inhibitors: Omeprazole (Prilosec), esomeprazole (Nexium) — monitor for increased sedation; dose adjustment may be needed.

CYP3A4 Inducers: Medications That Lower Clobazam Levels

Clobazam is also a weak CYP3A4 inducer and can reduce the effectiveness of drugs metabolized by CYP3A4. Conversely, strong CYP3A4 inducers can reduce clobazam levels. Anti-seizure medications that are also CYP3A4 inducers and may reduce clobazam effectiveness include:

• Carbamazepine (Tegretol)
• Phenytoin (Dilantin)
• Phenobarbital
• Rifampin (not an AED, but a powerful CYP inducer)

CYP2D6 Substrates: Drugs Whose Levels Are Raised by Clobazam

Onfi inhibits CYP2D6, which means it can increase blood levels of drugs that are metabolized by this enzyme. This may require dose reductions of these drugs:

• Certain antidepressants (fluoxetine, paroxetine, tricyclics)
• Certain antipsychotics (haloperidol, risperidone)
• Codeine (which requires CYP2D6 to convert to its active form morphine — clobazam may reduce codeine effectiveness)

Hormonal Contraceptives: Reduced Effectiveness

Onfi is a weak CYP3A4 inducer. Since many hormonal contraceptives (birth control pills, patches, rings) are metabolized by CYP3A4, their effectiveness may be reduced while taking clobazam. Women taking hormonal contraceptives should use additional non-hormonal contraception (e.g., condoms) during Onfi treatment and for 28 days after stopping Onfi.

What to Tell Your Doctor Before Starting Any New Medication

Before starting any new prescription or over-the-counter medication while on Onfi, inform your prescriber. This includes pain medications, sleep aids, antifungals, antidepressants, supplements, and herbal products. When starting a new drug, monitor for unusual sedation, behavioral changes, or breakthrough seizures — these can signal a clinically significant interaction. For a complete overview of Onfi side effects to watch for, see our guide on Onfi side effects.