What medications can cause rhabdomyolysis?

Medications That Cause Rhabdomyolysis

Several medications are known to cause rhabdomyolysis, with statins and their interactions with other drugs being the most well-documented causes. The risk varies significantly based on specific medications and combinations.

Statins (HMG-CoA Reductase Inhibitors)

Statins alone can cause rhabdomyolysis, though the risk is relatively low with monotherapy:

• Incidence of myopathy with statins alone: 0.08-0.09% 1
• Risk increases with higher doses (simvastatin 80 mg: 0.61% vs. 20 mg: 0.03%) 2
• Rhabdomyolysis rates with simvastatin: approximately 0.4% with 80 mg dose 2

High-Risk Drug Combinations

Statin + Fibrate Combinations

• Gemfibrozil + statins: This combination is contraindicated due to significantly increased rhabdomyolysis risk 3, 2

  • Gemfibrozil inhibits OATP1B1/3-mediated hepatic uptake of statins and CYP2C8 3
  • Reports of rhabdomyolysis were approximately 10-fold higher with gemfibrozil compared to fenofibrate when combined with statins 3

• Fenofibrate + statins: Lower risk than gemfibrozil but still increases myopathy risk 3

  • FDA Adverse Event data: 0.58 cases per million prescriptions (fenofibrate) vs. 8.6 per million (gemfibrozil) 3

Statin + Strong CYP3A4 Inhibitors

• Azole antifungals (itraconazole, ketoconazole, posaconazole, voriconazole) 2, 4
• Macrolide antibiotics (erythromycin, clarithromycin) 2, 5, 6
• HIV protease inhibitors (nelfinavir, ritonavir, darunavir/ritonavir) 2
• HCV protease inhibitors (boceprevir, telaprevir) 2
• Other: cobicistat-containing products, nefazodone 2

Other High-Risk Combinations

• Cyclosporine + statins: Contraindicated due to increased rhabdomyolysis risk 2
• Danazol + statins: Contraindicated 2
• Daptomycin + statins: FDA recommends temporary suspension of statin therapy 1, 2
• Amiodarone, dronedarone, ranolazine + statins: Require statin dose limitations 2
• Calcium channel blockers + statins: Require statin dose limitations 2
• Colchicine + statins: Cases of rhabdomyolysis reported 2
• Niacin (≥1 gram/day) + statins: Increased risk, particularly in Chinese patients 2

Risk Factors for Medication-Induced Rhabdomyolysis

• Age ≥65 years 2
• Uncontrolled hypothyroidism 2, 7
• Renal impairment 2, 7
• Chinese ethnicity (particularly with certain combinations) 2
• Higher statin doses 2
• Multiple medications 1
• Complex medical problems 1
• Use of diuretics 7

Mechanism of Drug Interactions

The primary mechanisms for drug interactions leading to rhabdomyolysis include:

• Inhibition of CYP450 enzyme system (particularly CYP3A4 for most statins except pravastatin) 4
• Inhibition of drug transporters (OATP1B1/3) affecting hepatic uptake 3, 2
• Direct toxic effects on muscle tissue (e.g., gemfibrozil) 7
• Impaired renal clearance of statins or their metabolites 2

Prevention Strategies

• Avoid contraindicated combinations (gemfibrozil, cyclosporine, danazol with statins) 3, 2
• When statin-fibrate combination is needed, prefer fenofibrate over gemfibrozil 3
• Temporarily suspend statin therapy when using daptomycin 1, 2
• Adjust statin doses when used with amiodarone, dronedarone, ranolazine, or calcium channel blockers 2
• Avoid grapefruit juice with statins 2
• Monitor for signs of myopathy (muscle pain, tenderness, weakness) 2

Common Pitfalls

• Failure to recognize drug interactions with statins, particularly with commonly prescribed antibiotics like clarithromycin 5
• Not adjusting statin doses when adding interacting medications 2
• Overlooking patient risk factors (age, renal function, hypothyroidism) 2, 7
• Continuing statins during acute illness with high risk of renal failure 2
• Not educating patients about symptoms of myopathy that warrant immediate medication discontinuation 7