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 cell breakdown, which can lead to muscle pain, weakness, and elevated creatine kinase levels. Rhabdomyolysis can cause kidney damage due to the release of muscle proteins into the bloodstream. Additional risks include hepatotoxicity and potential cardiovascular complications. The interaction is considered clinically significant and high-risk, with some guidelines recommending complete avoidance of this combination.

Management and Precautions

The preferred management approach is to avoid concurrent use of simvastatin and ketoconazole whenever possible. If antifungal therapy is necessary, consider alternative antifungal agents with less CYP3A4 inhibition, such as fluconazole (though still requires caution) or non-azole antifungals. If the combination cannot be avoided, simvastatin should be temporarily discontinued during ketoconazole treatment. For patients requiring both medications, close monitoring is essential, including baseline and periodic creatine kinase levels, liver function tests, and assessment for muscle symptoms. Patients should be educated about signs of muscle toxicity and advised to report muscle pain, weakness, or dark urine immediately. Consider consulting with a pharmacist or specialist for alternative treatment strategies.

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.