From the Guidelines
The combination of gemfibrozil and atorvastatin should be avoided due to the increased risk of rhabdomyolysis, with estimates suggesting a higher risk compared to using atorvastatin alone 1. The risk of rhabdomyolysis is significantly increased when these two medications are used together, which is attributed to the inhibition of OATP2-mediated hepatic uptake of atorvastatin by gemfibrozil, leading to higher statin blood levels and increased risk of muscle damage 1.
Key Considerations
- Gemfibrozil increases the AUC of atorvastatin and its active metabolites by 1.2- to 1.4-fold, which may contribute to the increased risk of muscle-related toxicity 1.
- The American College of Cardiology/American Heart Association recommends avoiding combination therapy with any statin and gemfibrozil due to concerns for increased risk of muscle-related toxicity 1.
- Alternative fibrates like fenofibrate have less interaction with statins and may be considered if combination therapy is necessary, as they have a lower risk of rhabdomyolysis compared to gemfibrozil 1.
Monitoring and Precautions
- Patients taking the combination of gemfibrozil and atorvastatin should be advised to immediately report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by fever or malaise.
- Regular monitoring of creatine kinase levels and liver function tests is recommended for patients on this combination.
- If both medications are deemed necessary, the atorvastatin dose should be kept as low as possible (typically no more than 10-20mg daily) with careful monitoring for muscle symptoms.
From the FDA Drug Label
Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium. The chance of Rhabdomyolysis in patients taking gemfibrozil and atorvastatin is increased due to the potential for myopathy.
- The concomitant use of gemfibrozil with atorvastatin is not recommended due to the increased risk of myopathy and rhabdomyolysis 2. The exact frequency of rhabdomyolysis cannot be reliably estimated from the available data.
From the Research
Rhabdomyolysis Risk with Gemfibrozil and Atorvastatin
- The risk of rhabdomyolysis with the combination of gemfibrozil and atorvastatin is a rare but serious complication of lipid-lowering therapy 3, 4, 5, 6.
- Statin and fibrate combination increases the risk of rhabdomyolysis possibly by pharmacodynamic interactions 3.
- Advanced age, diabetes, hypothyroidism, polypharmacy, and renal impairment are known to increase the risk of rhabdomyolysis 3, 4.
Factors Influencing Rhabdomyolysis Risk
- Use of medications affecting statin metabolism, higher doses of statins, renal insufficiency, diuretics, and hypothyroidism are predisposing factors to the development of myopathy from the combination 4.
- Concurrent use of gemfibrozil and cerivastatin is contraindicated due to the risk of rhabdomyolysis 5.
Management and Prevention
- Management strategies for rhabdomyolysis include fluid resuscitation and urine alkalinization 3.
- Renal indications such as refractory hyperkalemia, acidosis, fluid overload, or uremic complications mandate renal replacement therapy in rhabdomyolysis 3.
- Patients should be advised to watch for generalized muscle pain or weakness, and if it occurs, stop medications and report symptoms immediately 4.
- Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia 7.