Is atorvastatin (Lipitor) contraindicated in combination with cyclosporine (Sandimmune)?

From the Guidelines

Atorvastatin can be used in combination with cyclosporine, but with caution and close monitoring, as the dose of atorvastatin should not exceed 10 mg daily to minimize the risk of muscle-related toxicity. When considering the combination of these medications, it is crucial to weigh the potential benefits against the risks of adverse effects, particularly muscle damage. According to the American Heart Association's scientific statement 1, while certain statin combinations with immunosuppressive agents like cyclosporine are potentially harmful and should be avoided, atorvastatin can be considered for use with cyclosporine, albeit with specific dose limitations. The key recommendation is to limit the atorvastatin dose to 10 mg daily when coadministered with cyclosporine to avoid increased risk of muscle-related toxicity, emphasizing the need for close monitoring of creatinine kinase levels and signs or symptoms of muscle damage.

Some important considerations when combining atorvastatin with cyclosporine include:

• The metabolism and potential for drug-drug interactions, as cyclosporine can affect the pharmacokinetics of atorvastatin by inhibiting its metabolism and transport, thus potentially increasing atorvastatin blood levels.
• The importance of dose adjustment, as indicated by the recommendation to not exceed 10 mg of atorvastatin daily, to mitigate the risk of adverse effects.
• Alternative statins, such as fluvastatin, pravastatin, or rosuvastatin, may be considered if the risk profile is deemed too high, as these have different metabolic pathways that are less affected by cyclosporine, according to 1.
• Close monitoring for muscle pain, weakness, and regular assessment of creatine kinase levels is essential to detect early signs of muscle toxicity when atorvastatin is used with cyclosporine.

Given the potential for significant drug interactions and the consequent risk of morbidity and mortality, particularly from rhabdomyolysis, a cautious approach is warranted. This involves careful patient selection, dose adjustment, and vigilant monitoring for adverse effects, as guided by the recommendations from 1.

From the FDA Drug Label

Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with atorvastatin is not recommended Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium.

Atorvastatin (Lipitor) is contraindicated in combination with cyclosporine (Sandimmune), as the concomitant use of these medications increases the risk of myopathy and rhabdomyolysis due to increased atorvastatin plasma levels 2, 2, 2.

From the Research

Atorvastatin and Cyclosporine Interaction

• The concomitant administration of atorvastatin and cyclosporine has been shown to increase the serum concentration of 3-hydroxy-3-methylglutaryl coenzyme A, which may be associated with the elevation of creatine kinase and an increased risk of myopathy 3.
• Cyclosporine is a moderate inhibitor of the cytochrome P450 CYP3A4 isoenzyme, which is known to increase the serum level of atorvastatin 3, 4.
• Studies have reported cases of rhabdomyolysis in patients treated with atorvastatin and cyclosporine concomitantly 5.
• However, a retrospective cohort analysis found no statistical difference in the incidence of statin intolerance in renal transplant recipients receiving atorvastatin and cyclosporine compared to those receiving atorvastatin and tacrolimus 6.

Clinical Implications

• The interaction between atorvastatin and cyclosporine may increase the risk of myopathy and rhabdomyolysis 3, 5.
• Clinicians should be aware of this possible drug interaction and carefully monitor patients receiving these two drugs concomitantly 5.
• Conversion to tacrolimus and atorvastatin may be a safe and effective lipid-lowering therapy in cyclosporine-treated heart transplant recipients with dyslipidemia refractory to fluvastatin 7.

Pharmacokinetic Interactions

• Cyclosporine increases the systemic exposure of atorvastatin, which may be due to inhibition of statin transport in the liver 4.
• The mechanism of interaction between cyclosporine and atorvastatin is not solely caused by inhibition of CYP3A4 metabolism, but also by inhibition of statin transport in the liver 4.