What medications can potentially cause rhabdomyolysis?

Medications That Can Cause Rhabdomyolysis

Statins, particularly when combined with gemfibrozil, fibrates, or CYP3A4 inhibitors, are the most common medication-related cause of rhabdomyolysis, with gemfibrozil-statin combinations carrying a 10-fold higher risk than fenofibrate-statin combinations. 1

High-Risk Statin Combinations (Contraindicated or Avoid)

Gemfibrozil + Any Statin

• Gemfibrozil combined with simvastatin is absolutely contraindicated 2
• Gemfibrozil with lovastatin, pravastatin, fluvastatin, pitavastatin, atorvastatin, and rosuvastatin should be avoided 3
• Rhabdomyolysis reports are 15 times higher with gemfibrozil-statin combinations (8.6 per million prescriptions) compared to fenofibrate-statin combinations (0.58 per million) 3
• The combination of gemfibrozil with lovastatin, pravastatin, and simvastatin is potentially harmful and should be avoided 3

Strong CYP3A4 Inhibitors + Statins (Simvastatin, Atorvastatin, Lovastatin)

Concomitant use of strong CYP3A4 inhibitors with simvastatin is contraindicated 2

Azole Antifungals:

• Itraconazole, ketoconazole, posaconazole, voriconazole 2, 4
• With atorvastatin: do not exceed 20 mg daily when using itraconazole 4

Macrolide Antibiotics:

• Erythromycin and clarithromycin 1, 2, 4
• Clarithromycin with simvastatin has documented cases of rhabdomyolysis 5
• With atorvastatin: do not exceed 20 mg daily when using clarithromycin 4

HIV Protease Inhibitors:

• Nelfinavir, ritonavir, saquinavir, amprenavir, indinavir 1, 2
• Tipranavir plus ritonavir with atorvastatin is not recommended 4
• With atorvastatin and nelfinavir: do not exceed 40 mg daily 4

HCV Protease Inhibitors:

• Boceprevir, telaprevir 2
• Glecaprevir plus pibrentasvir with atorvastatin is not recommended 4

Other Contraindicated Combinations

• Cyclosporine + any statin (contraindicated with simvastatin and atorvastatin) 1, 2, 4
• Danazol + simvastatin (contraindicated) 2

Moderate-Risk Medications Requiring Dose Adjustment

Calcium Channel Blockers + Statins

• Verapamil, diltiazem, amlodipine with simvastatin 2
• With simvastatin: do not exceed 10 mg daily for verapamil or diltiazem; do not exceed 20 mg daily for amlodipine 2

Antiarrhythmics + Statins

• Amiodarone, dronedarone, ranolazine with simvastatin 2
• With simvastatin: do not exceed 20 mg daily for amiodarone or ranolazine; do not exceed 10 mg daily for dronedarone 2

Other Fibrates

• Fenofibrate has significantly lower risk than gemfibrozil but still increases rhabdomyolysis risk 3
• In the FIELD study (n=9,795), no patients on statin-fenofibrate combination experienced rhabdomyolysis 3
• Fenofibrate may be considered with low- or moderate-intensity statins when benefits outweigh risks 3

Additional Medications Associated with Rhabdomyolysis

Niacin (Lipid-Modifying Doses)

• Doses ≥1 gram/day increase myopathy risk when combined with statins 1, 2, 4
• Cases of myopathy and rhabdomyolysis documented with atorvastatin-niacin combination 4

Daptomycin

• Temporarily suspend simvastatin in patients taking daptomycin 2
• Both drugs independently cause myopathy; risk is increased with coadministration 2

Colchicine

• Increases risk of myopathy and rhabdomyolysis when combined with statins 2

Diuretics (Thiazides)

• Thiazide-induced hypokalemia and volume depletion predispose to muscle injury 6
• Documented case of severe rhabdomyolysis with simvastatin, hydrochlorothiazide, and empagliflozin combination 6

SGLT2 Inhibitors

• May potentiate statin toxicity through dehydration and electrolyte imbalance 6
• Empagliflozin combined with simvastatin and thiazides documented to cause severe rhabdomyolysis 6

Critical Patient Risk Factors That Amplify Medication Risk

• Age ≥65 years 2
• Uncontrolled hypothyroidism 2, 7
• Renal impairment 2, 7
• Female sex and small body size 1
• Polypharmacy 1, 7
• Diabetes mellitus 8
• Dehydration and electrolyte abnormalities (particularly hypokalemia) 6

Clinical Pitfalls to Avoid

The most dangerous oversight is prescribing gemfibrozil with any statin—this combination should never be used. 3, 2 If fibrate therapy is needed with a statin, fenofibrate is the only acceptable option 3.

Macrolide antibiotics are commonly prescribed without checking for statin use—clarithromycin and erythromycin with CYP3A4-metabolized statins (simvastatin, atorvastatin, lovastatin) create high risk 2, 4, 5. Consider azithromycin as an alternative, or temporarily suspend the statin during short-term antibiotic therapy 2.

Rhabdomyolysis can present late, even after drug discontinuation—one case documented presentation 1 month after gemfibrozil was stopped 8. Maintain vigilance for delayed presentations.

Men have twice the risk of rhabdomyolysis compared to women across all statins, with highest risk observed for pravastatin (ROR=2.30) and atorvastatin (ROR=2.03) 9.