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 a strong inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system, which is responsible for metabolizing many medications including simvastatin.

Mechanism of Interaction

The interaction between simvastatin and ketoconazole occurs through inhibition of the CYP3A4 enzyme pathway. Simvastatin is extensively metabolized by CYP3A4 in the liver and intestines. Ketoconazole is a potent CYP3A4 inhibitor that significantly reduces the metabolism of simvastatin, leading to dramatically increased plasma concentrations of the active statin. Studies have shown that ketoconazole can increase simvastatin exposure by up to 20-fold, creating dangerously high levels of the medication in the bloodstream.

Risks and Symptoms

The primary risk of this interaction is severe muscle toxicity, including myopathy (muscle pain and weakness) and potentially life-threatening rhabdomyolysis (muscle breakdown). Elevated simvastatin levels can cause muscle cell damage, leading to symptoms such as unexplained muscle pain, tenderness, weakness, and dark-colored urine. Rhabdomyolysis can result in kidney damage, electrolyte imbalances, and in severe cases, kidney failure or death. The risk is dose-dependent and significantly higher when simvastatin levels are elevated due to CYP3A4 inhibition by ketoconazole.

Management and Precautions

The concurrent use of simvastatin and ketoconazole is generally contraindicated and should be avoided. If antifungal treatment is necessary in patients taking simvastatin, consider temporarily discontinuing the statin or switching to an alternative antifungal agent with less CYP3A4 inhibition potential. If the combination cannot be avoided in exceptional circumstances, simvastatin should be discontinued during ketoconazole therapy and for several days after completion. Patients should be counseled to report any muscle pain, weakness, or dark urine immediately. Healthcare providers should monitor creatine kinase levels and assess for signs of muscle toxicity. Alternative statins with different metabolic pathways, such as pravastatin or rosuvastatin, may be considered as they are less affected by CYP3A4 inhibition.

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.