OBJECT DRUGS

HMG-CoA Reductase Inhibitors:

• Atorvastatin (Lipitor)
• Lovastatin (Mevacor, etc.)
• Simvastatin (Zocor)

PRECIPITANT DRUGS

Enzyme Inhibitors:

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

Comment:

Lovastatin and simvastatin undergo extensive first-pass metabolism by CYP3A4; inhibitors of CYP3A4 increase the risk of myopathy, in some cases leading to rhabdomyolysis and acute renal failure. Some of these combinations (e.g., atazanavir + lovastatin or simvastatin) are listed as contraindicated in the product information. Atorvastatin (Lipitor) undergoes less first-pass metabolism by CYP3A4 than lovastatin or simvastatin, so the risk of myopathy when combined with CYP3A4 inhibitors appears to be less. Nonetheless, some cases have been reported. The mifepristone product information states that concurrent use of simvastatin or lovastatin is contraindicated. Ticagrelor is considered a weak CYP3A4 inhibitor, but it may increase simvastatin and simvastatin acid AUC by over 50%; atorvastatin was less affected by ticagrelor.

Class 2: Use Only if Benefit Felt to Outweigh Risk

• Use Alternative:
• HMG-CoA Reductase Inhibitors: Pravastatin (Pravachol) is not metabolized by cytochrome P450 isozymes. Fluvastatin (Lescol) and rosuvastatin (Crestor) are metabolized by CYP2C9 and may not be affected by CYP3A4 inhibitors. Erythromycin, for example, slightly decreased the AUC of rosuvastatin. Pitavastatin (Livalo), pravastatin, and rosuvastatin all appear to be OATP substrates, and some of the above enzyme inhibitors might affect OATP. For example, erythromycin substantially increases pitavastatin concentrations, possibly through inhibition of OATP. [Note: Cyclosporine increases systemic exposure to all statins, although the risk of myopathy appears less with pravastatin.]
• Antidepressants: Sertraline (Zoloft), citalopram (Celexa), venlafaxine (Effexor), and paroxetine (Paxil) appear unlikely to inhibit CYP3A4, and fluoxetine (Prozac) appears to be a weak inhibitor of CYP3A4.
• Grapefruit: Orange juice does not appear to inhibit CYP3A4.
• Circumvent/Minimize: If CYP3A4 inhibitors are used, consider reducing statin dose based on current statin product information.
• Monitor: Patients receiving lovastatin, simvastatin or atorvastatin and a CYP3A4 enzyme inhibitor should be monitored for evidence of myopathy (muscle pain or weakness) and myoglobinuria (dark urine). Myopathy is usually associated with increased serum CK concentrations.