OBJECT DRUGS

Anxiolytics/Hypnotics (CYP3A4 Substrates):

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

PRECIPITANT DRUGS

Antimicrobials:

• Ciprofloxacin (Cipro, etc.)
• 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. Many other benzodiazepines are also partly metabolized by CYP3A4, and may also interact with CYP3A4 inhibitors. Intravenous midazolam is less affected than oral midazolam, but prolonged sedation may occur. 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 other than ciprofloxacin 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.