Summary

Simvastatin and itraconazole have a significant drug interaction that can lead to dangerously elevated simvastatin levels and increased risk of serious muscle toxicity. This interaction is considered contraindicated due to the high potential for severe adverse effects including rhabdomyolysis.

Introduction

Simvastatin is an HMG-CoA reductase inhibitor (statin) commonly prescribed to lower cholesterol and reduce cardiovascular risk. It is metabolized primarily by the CYP3A4 enzyme system. Itraconazole is a triazole antifungal medication used to treat various fungal infections, including systemic mycoses and dermatophyte infections. Itraconazole is a potent inhibitor of the CYP3A4 enzyme, which creates the potential for significant drug interactions with medications metabolized by this pathway.

Mechanism of Interaction

The interaction between simvastatin and itraconazole occurs through competitive inhibition of the CYP3A4 enzyme system. Simvastatin is extensively metabolized by CYP3A4 to its active metabolite and undergoes significant first-pass metabolism. When itraconazole is co-administered, it potently inhibits CYP3A4, dramatically reducing simvastatin's metabolism and clearance. This results in substantially increased plasma concentrations of simvastatin, potentially increasing levels by 10-20 fold or more, leading to enhanced pharmacological effects and toxicity risk.

Risks and Symptoms

The primary clinical risk of this interaction is severe muscle toxicity, including myopathy and potentially life-threatening rhabdomyolysis. Elevated simvastatin levels can cause muscle pain, weakness, and in severe cases, muscle breakdown leading to kidney damage and electrolyte imbalances. Other risks include hepatotoxicity with elevated liver enzymes. The interaction is dose-dependent, but even low doses of simvastatin can become problematic when combined with itraconazole. This combination is associated with numerous case reports of serious adverse events and is considered a high-risk interaction.

Management and Precautions

The combination of simvastatin and itraconazole is contraindicated and should be avoided. If antifungal treatment is necessary in patients taking simvastatin, consider temporarily discontinuing simvastatin during itraconazole therapy. Alternative management strategies include switching to a statin with less CYP3A4 dependence (such as pravastatin or rosuvastatin) or using alternative antifungal agents with less CYP3A4 inhibition potential. If the combination cannot be avoided in exceptional circumstances, simvastatin should be discontinued at least 24-48 hours before starting itraconazole and not resumed until several days after itraconazole completion. Patients should be counseled about muscle pain symptoms and advised to seek immediate medical attention if they occur.

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.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.