Summary

Simvastatin and ketoconazole have a major drug interaction that significantly increases simvastatin blood levels, leading to elevated risk of serious muscle toxicity including myopathy and rhabdomyolysis. This combination is generally contraindicated due to the high clinical significance of the interaction.

Introduction

Simvastatin is a widely prescribed HMG-CoA reductase inhibitor (statin) used to lower cholesterol and reduce cardiovascular risk. It belongs to the class of lipid-lowering medications that work by blocking cholesterol synthesis in the liver. Ketoconazole is a potent antifungal medication from the azole class, used to treat serious systemic fungal infections. It is also available in topical formulations for superficial fungal infections. Both medications are metabolized through the cytochrome P450 system, which creates the potential for significant drug interactions.

Mechanism of Interaction

The interaction between simvastatin and ketoconazole occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Simvastatin is extensively metabolized by CYP3A4 in the liver and intestines. Ketoconazole is a potent inhibitor of CYP3A4, blocking the normal metabolism of simvastatin. This inhibition leads to dramatically increased plasma concentrations of simvastatin and its active metabolites, potentially increasing levels by 10-20 fold or more. The reduced clearance of simvastatin results in prolonged exposure to higher drug concentrations than intended.

Risks and Symptoms

The primary risk of this interaction is severe muscle toxicity, including myopathy, myositis, and potentially life-threatening rhabdomyolysis. Elevated simvastatin levels increase the risk of muscle pain, weakness, and muscle breakdown. Rhabdomyolysis can lead to kidney damage, electrolyte imbalances, and in severe cases, kidney failure or death. Patients may also experience elevated liver enzymes and hepatotoxicity. The risk is dose-dependent and increases with higher simvastatin doses, advanced age, kidney disease, hypothyroidism, and concurrent use of other interacting medications. This interaction is considered clinically significant and potentially dangerous.

Management and Precautions

The combination of simvastatin and ketoconazole is generally contraindicated and should be avoided. If antifungal treatment is necessary in patients taking simvastatin, consider alternative antifungal agents with less CYP3A4 inhibition, such as fluconazole (though still requires monitoring) or non-azole antifungals when appropriate. If ketoconazole is essential, simvastatin should be temporarily discontinued during treatment and for several days after ketoconazole completion. Alternative statins with different metabolic pathways, such as pravastatin or rosuvastatin, may be considered as they have minimal CYP3A4 metabolism. Patients should be counseled to report any muscle pain, weakness, or dark urine immediately. Healthcare providers should review all medications for potential interactions before prescribing either drug.

Simvastatin interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided while taking simvastatin as they can significantly increase blood levels of the medication, potentially leading to serious side effects including muscle damage (rhabdomyolysis). Large amounts of alcohol should be avoided as both simvastatin and alcohol can affect liver function, and combining them may increase the risk of liver problems. Simvastatin should be taken consistently with regard to meals - it can be taken with or without food, but taking it at the same time each day (preferably in the evening) helps maintain consistent blood levels.

Ketoconazole interactions with food and lifestyle

Ketoconazole requires an acidic environment for optimal absorption. Take ketoconazole with food or an acidic beverage to enhance absorption. Avoid taking ketoconazole with antacids, H2 blockers, or proton pump inhibitors as these medications reduce stomach acid and significantly decrease ketoconazole absorption. If antacids must be used, take them at least 2 hours after ketoconazole. Alcohol should be avoided during ketoconazole treatment as both ketoconazole and alcohol can cause liver toxicity, and concurrent use may increase the risk of hepatotoxicity. Grapefruit juice may increase ketoconazole blood levels and should be avoided to prevent increased risk of side effects.