OBJECT DRUGS

HMG-CoA Reductase Inhibitors:

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

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:

Lovastatin and simvastatin undergo extensive first-pass metabolism by CYP3A4; antimicrobials that inhibit CYP3A4 increase the risk of myopathy, rhabdomyolysis and acute renal failure. 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, including a fatal case of rhabdomyolysis possibly due to atorvastatin and fluconazole.

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, but it appears to be a OATP substrate. Some of the above antimicrobials might affect OATP. Erythromycin substantially increases pitavastatin (Livalo) concentrations, possibly through inhibition of OATP. Rosuvastatin (Crestor) is also an OATP substrate, but erythromycin slightly decreases rosuvastatin plasma concentrations. Fluvastatin (Lescol) and rosuvastatin (Crestor) are metabolized by CYP2C9 and may interact with fluconazole and voriconazole.
• Azole Antifungals: Fluconazole appears to be a weaker inhibitor of CYP3A4 than itraconazole or ketoconazole. In larger doses it may inhibit CYP3A4 and should be used cautiously with lovastatin or simvastatin. Single doses of fluconazole would be unlikely to increase the risk of statin toxicity. Terbinafine (Lamisil) does not appear to inhibit CYP3A4.
• Macrolides: Unlike other macrolides, azithromycin (Zithromax) and dirithromycin^* do not appear to inhibit CYP3A4 and would not be expected to interact with lovastatin or simvastatin. (^* not available in US)
• Telithromycin: The use of azithromycin (Zithromax) or a quinolone antibiotic should be considered.
• Circumvent/Minimize: Discontinuation of the statin during antimicrobial treatment should be considered.
• Monitor: The patient should be alert for evidence of myopathy (muscle pain or weakness) and myoglobinuria (dark urine).