OBJECT DRUGS

• Phenytoin (Dilantin, etc.)

PRECIPITANT DRUGS

Enzyme Inhibitors:

• Amiodarone (Cordarone, etc.)
• Androgens
• Capecitabine (Xeloda)
• Ceritinib (Zykadia)
• Chloramphenicol
• Cimetidine (Tagamet, etc.)
• Co-trimoxazole (Bactrim)
• Danazol (Danocrine)
• Delavirdine (Rescriptor)
• Disulfiram (Antabuse)
• Efavirenz (Sustiva)
• Fluconazole (Diflucan)
• Fluorouracil (5-FU)
• Fluoxetine (Prozac, etc.)
• Fluvoxamine (Luvox, etc.)
• Imatinib (Gleevec)
• Isoniazid (INH)
• Leflunomide (Arava)
• Metronidazole (Flagyl, etc.)
• Sulfinpyrazone (Anturane)
• Tamoxifen (Nolvadex)
• Ticlopidine (Ticlid)
• Voriconazole (Vfend)

Comment:

Inhibitors of CYP2C9 (and to a lesser extent CYP2C19) may increase phenytoin and fosphenytoin (Cerebyx) levels; phenytoin toxicity may occur. Depending on the baseline phenytoin serum concentration, it may take as long as several weeks for phenytoin toxicity to occur after starting an inhibitor. If isoniazid is combined with rifampin in a patient on phenytoin, phenytoin concentrations may actually decrease because the enzyme induction produced by rifampin may outweigh the enzyme inhibition of the isoniazid. Also, keep in mind that phenytoin induces several CYP450 isozymes (CYP3A4, CYP2C9, CYP1A2, etc.) and it may reduce the plasma concentrations of many of the inhibitors listed here.

Class 3: Assess Risk & Take Action if Necessary

• Consider Alternative:
• Azole Antifungals: Ketoconazole (Nizoral), posaconazole (Noxafil), and itraconazole (Sporanox) appear to be less likely to affect phenytoin.
• Cimetidine: Famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac) have minimal effects on drug metabolism.
• Fluvastatin: Statins other than fluvastatin do not appear to inhibit CYP2C9.
• SSRIs: The use of SSRIs that do not inhibit CYP2C9 [eg, paroxetine (Paxil) or venlafaxine (Effexor) ] should be considered.
• Monitor: Monitor for altered phenytoin effect if an inhibitor is initiated, discontinued, or changed in dosage. Evidence of phenytoin toxicity includes nystagmus, ataxia, diplopia, drowsiness, and lethargy; severe cases may result in asterixis and coma.