OBJECT DRUGS
Anxiolytics/Hypnotics (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
Antimicrobials:
- Clarithromycin (Biaxin, etc.)
- Erythromycin (E-Mycin, etc.)
- Fluconazole (Diflucan)
- Itraconazole (Sporanox, etc.)
- Ketoconazole (Nizoral, etc.)
- Posaconazole (Noxafil)
- Quinupristin (Synercid)
- Telithromycin (Ketek)
- Troleandomycin (TAO)
- Voriconazole (Vfend)
Comment:
When given orally, alprazolam, midazolam and triazolam undergo extensive first pass metabolism by CYP3A4 in the gut wall and liver, so CYP3A4 inhibitors can dramatically increase plasma concentrations. Other benzodiazepines such as clonazepam, clorazepate, diazepam, flurazepam, halazepam, prazepam, and quazepam are also partly metabolized by CYP3A4. Intravenous midazolam is much less affected than oral midazolam. The primary risk of these interactions is impairment of motor skills that could result in falls or motor vehicle accidents.
Class 3: Assess Risk & Take Action if Necessary
- Consider Alternative:
- Azole Antifungals: Fluconazole appears to be a less potent inhibitor of CYP3A4; but in larger doses it also inhibits CYP3A4. Terbinafine (Lamisil) does not appear to affect CYP3A4.
- Benzodiazepines: Consider other benzodiazepines: temazepam (Restoril), oxazepam (Serax), and lorazepam (Ativan) are largely glucuronidated, and unlikely to be affected by CYP3A4 inhibitors.
- Macrolide Antibiotics: Unlike erythromycin, clarithromycin and troleandomycin, azithromycin (Zithromax) and dirithromycin* do not appear to inhibit CYP3A4. (* not available in US)
- Telithromycin: The use of azithromycin (Zithromax) or a quinolone antibiotic should be considered.
- Monitor: Monitor for altered benzodiazepine response if CYP3A4 inhibitor is initiated, discontinued or changed in dose. Warn patients about increased sedative effects.