OBJECT DRUGS

Immunosuppressants:

• Cyclosporine (Neoral, etc.)
• Everolimus (Afinitor)
• Sirolimus (Rapamune)
• Tacrolimus (Prograf, etc.)

PRECIPITANT DRUGS

Enzyme Inhibitors:

• Amiodarone (Cordarone, etc.)
• Amprenavir (Agenerase)
• Androgens
• Aprepitant (Emend)
• Atazanavir (Reyataz)
• Berberine (Goldenseal)
• Boceprevir (Victrelis)
• Ceritinib (Zykadia)
• Chloroquine (Aralen)
• Cobicistat (Stribild)
• Conivaptan (Vaprisol)
• Contraceptives, Oral
• Danazol (Danocrine)
• Darunavir (Prezista)
• Delavirdine (Rescriptor)
• Diltiazem (Cardizem, etc.)
• Dronedarone (Multaq)
• Fluvoxamine (Luvox, etc.)
• Grapefruit
• Imatinib (Gleevec)
• Indinavir (Crixivan)
• Lapatinib (Tykerb)
• Lomitapide (Juxtapid)
• Methoxsalen (Oxsoralen, etc.)
• Mifepristone (Korlym)
• Nefazodone
• Nelfinavir (Viracept)
• Nicardipine (Cardene, etc.)
• Ritonavir (Norvir)
• Saquinavir (Invirase)
• Telaprevir (Incivek)
• Verapamil (Isoptin, etc.)

Comment:

The enzyme inhibitors listed here may inhibit cyclosporine, sirolimus, and tacrolimus elimination via CYP3A4 and/or P-glycoprotein (PGP), thus potentially increasing immunosuppressant effect and toxicity. Oral contraceptives also appear to increase cyclosporine plasma levels, although the mechanism is not clear. Aprepitant is a CYP3A4 inhibitor, but it had only a small effect on intravenous tacrolimus; oral tacrolimus would probably be more affected. Methoxsalen produced modest increases in cyclosporine concentrations, but some subjects had substantial increases.

Class 2: Use Only if Benefit Felt to Outweigh Risk

• Use Alternative: Use alternative to CYP3A4 inhibitor if possible.
• Antidepressants: Sertraline (Zoloft), citalopram (Celexa), venlafaxine (Effexor), and paroxetine (Paxil) appear less likely to inhibit CYP3A4 than fluvoxamine. Fluoxetine (Prozac) appears to be a weak inhibitor of CYP3A4.
• Calcium channel blockers: Calcium channel blockers other than diltiazem and verapamil are unlikely to inhibit CYP3A4.
• Grapefruit: Orange juice does not appear to inhibit CYP3A4.
• Monitor: If cyclosporine, sirolimus, or tacrolimus is initiated in the presence of CYP3A4 inhibitor therapy, it would be prudent to start with conservative doses of the immunosuppressant. Monitor for altered immunosuppressant effect if an enzyme inhibitor is initiated, discontinued, or changed in dosage. Substantial dosage reductions for the immunosuppressant may be needed in some cases.