OBJECT DRUGS

Anxiolytics (CYP3A4 Substrates):

• Alprazolam (Xanax, etc.)
• Buspirone (BuSpar)
• Clonazepam (Klonopin)
• Clorazepate (Tranxene, etc.)
• Diazepam (Valium, etc.)
• Estazolam (ProSom)
• Flurazepam (Dalmane)
• Halazepam (Paxipam)
• Midazolam (Versed, oral)
• Prazepam (Centrex)
• Quazepam (Doral)
• Triazolam (Halcion)

PRECIPITANT DRUGS

Enzyme Inhibitors:

• Amiodarone (Cordarone, etc.)
• Amprenavir (Agenerase)
• Aprepitant (Emend)
• Atazanavir (Reyataz)
• Conivaptan (Vaprisol)
• Cyclosporine (Neoral, etc.)
• Darunavir (Prezista)
• Delavirdine (Rescriptor)
• Grapefruit
• Indinavir (Crixivan)
• Nelfinavir (Viracept)
• Ritonavir (Norvir)
• Saquinavir (Invirase)
• Telaprevir (Incivek)

Comment:

When given orally, alprazolam, midazolam and triazolam, undergo extensive first pass metabolism by CYP3A4 in the gut wall and liver. Other benzodiazepines such as clonazepam, clorazepate, diazepam, flurazepam, halazepam, prazepam, and quazepam are also at least partly metabolized by CYP3A4, and may also interact with CYP3A4 inhibitors. Intravenous midazolam is less affected than when it is given orally. The primary risk of these interactions is impairment of motor skills that could result in falls or motor vehicle accidents. Some of these combinations are listed as contraindicated by the manufacturer (e.g., amprenavir and atazanavir with midazolam or triazolam).

Class 3: Assess Risk & Take Action if Necessary

• Consider Alternative:
• Benzodiazepines: Consider other benzodiazepines: temazepam (Restoril), oxazepam (Serax), and lorazepam (Ativan) are largely glucuronidated, and are unlikely to be affected by CYP3A4 inhibitors.
• Grapefruit: Orange juice does not appear to inhibit CYP3A4.
• Monitor: Monitor for altered benzodiazepine response if the CYP3A4 inhibitor is initiated, discontinued, or changed in dosage. Warn patients about increased sedative effects.