Can overdose (OD) of multiple medications (polypharmacy) cause rhabdomyolysis?

From the Guidelines

Yes, polypharmacy overdose can cause rhabdomyolysis, as evidenced by the most recent and highest quality study available 1. Rhabdomyolysis is a serious condition characterized by the breakdown of skeletal muscle tissue, releasing myoglobin and other cellular contents into the bloodstream, which can lead to kidney damage. Multiple medications commonly involved in overdoses can trigger this condition, including statins (like simvastatin, atorvastatin), antipsychotics (such as olanzapine, haloperidol), stimulants (cocaine, amphetamines, MDMA), and certain antidepressants. The risk increases significantly when multiple drugs are taken together, especially those that affect muscle metabolism or cause prolonged immobilization. Symptoms of rhabdomyolysis include muscle pain, weakness, dark urine, and kidney dysfunction. Treatment requires immediate medical attention, including IV fluids to prevent kidney failure, discontinuation of the offending medications, and sometimes dialysis in severe cases. The mechanism typically involves direct toxic effects on muscle cells, excessive muscle activity from seizures or agitation, or metabolic derangements that compromise muscle cell integrity. Patients with underlying conditions like diabetes, liver disease, or prior muscle disorders are at higher risk for developing this complication.

Some key points to consider:

• Polypharmacy is a significant risk factor for rhabdomyolysis, particularly in older adults with multiple comorbidities 1.
• Certain medications, such as statins, antipsychotics, and stimulants, are more likely to cause rhabdomyolysis when taken in combination with other drugs 1.
• The use of multiple medications can lead to drug-to-drug interactions, drug-to-disease interactions, and medication nonadherence, increasing the risk of adverse drug events (ADEs) 1.
• Deprescribing, or the process of reducing or discontinuing medications, can be an effective strategy for managing polypharmacy and preventing ADEs 1.

Overall, polypharmacy overdose is a significant risk factor for rhabdomyolysis, and healthcare providers should be aware of the potential risks and take steps to minimize them, including careful medication management and monitoring for signs of rhabdomyolysis 1.

From the FDA Drug Label

1. 1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin Simvastatin exposure can be significantly increased with concomitant administration of inhibitors of CYP3A4 and OATP1B1 Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with simvastatin Daptomycin Clinical Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both simvastatin and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration

Polypharmacy Overdose (OD) and Rhabdomyolysis:

• The FDA drug label for simvastatin indicates that the risk of myopathy and rhabdomyolysis is increased with concomitant use of certain drugs, including strong CYP3A4 inhibitors, cyclosporine, danazol, gemfibrozil, amiodarone, dronedarone, ranolazine, calcium channel blockers, lomitapide, daptomycin, and niacin.
• Key Finding: The label does not directly address whether a polypharmacy overdose can cause rhabdomyolysis.
• Clinical Decision: Given the information provided, it is unclear whether a polypharmacy overdose can cause rhabdomyolysis. 2

From the Research

Polypharmacy and Rhabdomyolysis

• Polypharmacy, or the use of multiple medications, can increase the risk of adverse reactions, including rhabdomyolysis, a serious condition characterized by muscle breakdown 3, 4, 5, 6, 7.
• The combination of statins and gemfibrozil, in particular, has been associated with an increased risk of rhabdomyolysis, as reported in several studies 3, 4, 5, 6, 7.
• Factors that may contribute to the development of rhabdomyolysis in patients taking statins and gemfibrozil include renal insufficiency, higher doses of statins, and concomitant use of other medications that affect statin metabolism 3.

Statin and Gemfibrozil Combination Therapy

• The use of statins and gemfibrozil together can increase the risk of myopathy and rhabdomyolysis, with reporting rates varying depending on the specific statin and fibrate used 5, 6.
• Fenofibrate, a type of fibrate, may be associated with a lower risk of rhabdomyolysis when used in combination with statins compared to gemfibrozil 6.
• Clinicians should be aware of the potential risks of rhabdomyolysis associated with statin and gemfibrozil combination therapy and monitor patients closely for signs and symptoms of muscle toxicity 3, 5.

Case Reports and Studies

• Several case reports and studies have documented the occurrence of rhabdomyolysis in patients taking statins and gemfibrozil, highlighting the importance of careful monitoring and prompt discontinuation of therapy if symptoms occur 3, 4, 7.
• The recovery time for patients who experience rhabdomyolysis can vary, with some cases requiring hospitalization and dialysis 4.