OBJECT DRUGS

Opioid Analgesics:

• Alfentanil (Alfenta)
• Fentanyl (Sublimaze, etc.)
• Methadone (Dolophine, etc.)
• Oxycodone (Percocet, etc.)
• Sufentanil (Sufenta)

PRECIPITANT DRUGS

Enzyme Inhibitors:

• Amiodarone Cordarone)
• Amprenavir (Agenerase)
• Aprepitant (Emend)
• Atazanavir (Reyataz)
• Boceprevir (Victrelis)
• Ceritinib (Zykadia)
• Cimetidine (Tagamet, etc.)
• Cobicistat (Stribild)
• Conivaptan (Vaprisol)
• Cyclosporine (Neoral, etc.)
• Darunavir (Prezista)
• Delavirdine (Rescriptor)
• Diltiazem (Cardizem, etc.)
• Dronedarone (Multaq)
• Fluvoxamine (Luvox, etc.)
• Grapefruit
• Imatinib (Gleevec)
• Indinavir (Crixivan)
• Lapatinib (Tykerb)
• Lomitapide (Juxtapid)
• Mifepristone (Korlym)
• Nefazodone
• Nelfinavir (Viracept)
• Ritonavir (Norvir)
• Saquinavir (Invirase)
• Telaprevir (Incivek)
• Verapamil (Isoptin, etc.)

Comment:

These enzyme inhibitors may inhibit the elimination of these opioids via CYP3A4 metabolism and possibly other pathways. Excessive opioid effects have been reported. The magnitude of the interaction may vary considerably depending on the inhibitor. Some inhibitors (e.g., cyclosporine, nefazodone) are more potent than weaker inhibitors such as cimetidine. Nonetheless, cimetidine produced a large increase in alfentanil half-life and large reduction in alfentanil clearance (ranitidine had no effect). In patients on methadone maintenance amprenavir modestly decreased R- and S- methadone plasma concentrations, suggesting that amprenavir can act as both an inhibitor and an inducer, perhaps via different pathways. There was no evidence of methadone withdrawal in the patients, but patients on the combination should be monitored for altered methadone response. Methadone is primarily metabolized by CYP2B6 and will be affected by inhibitors of this enzyme [clopidogrel (Plavix), cyclophosphamide (Cytoxan), ticlopidine (Ticlid) ].The mifepristone product information states that concurrent use of fentanyl is contraindicated.

Class 3: Assess Risk & Take Action if Necessary

• Consider Alternative:
• Calcium channel blockers: Calcium channel blockers other than diltiazem and verapamil are unlikely to inhibit CYP3A4.
• Cimetidine: Famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac) have minimal effects on drug metabolism.
• Grapefruit: Orange juice does not appear to inhibit CYP3A4.
• Antidepressants: Sertraline (Zoloft), citalopram (Celexa), venlafaxine (Effexor), and paroxetine (Paxil) appear less likely to inhibit CYP3A4 than fluvoxamine, and much less likely than nefazodone. Fluoxetine (Prozac) appears to be a weak inhibitor of CYP3A4.
• Monitor: Monitor for evidence of excessive and/or prolonged opioid effects, including sedation and respiratory depression.