Published: 15 December 2014

Simvastatin Interactions and Fatal Reports

Prescriber Update 35(4): 55-56
December 2014

Key Messages

  • Simvastatin is contraindicated with the concomitant use of potent CYP3A4 inhibitors due to the increased risk of serious adverse reactions.
  •  If a potent CYP3A4 inhibitor must be used, simvastatin must be stopped for the duration of therapy.
  • Predisposing risk factors for life-threatening myopathy and rhabdomyolysis with simvastatin include age of 65 years or older, female, uncontrolled hypothyroidism and renal impairment.

The Centre for Adverse Reactions Monitoring (CARM) continues to receive reports of life-threatening and fatal cases of rhabdomyolysis with the concomitant use of medicines that interact with simvastatin. Healthcare professionals are reminded that the concomitant administration of simvastatin with a potent cytochrome P450 3A4 (CYP3A4) inhibitor is contraindicated.

CYP3A4 inhibitors dramatically increase the plasma concentration of simvastatin, which results in potentially life-threatening adverse reactions such as myopathy and rhabdomyolysis (breakdown of skeletal muscle) with or without acute renal failure. Advanced age (≥ 65 years), female gender, uncontrolled hypothyroidism and renal impairment may also increase the risk of myopathy and rhabdomyolysis.

Examples of potent CYP3A4 inhibitors include:

Since 2000, CARM has received a total of 14 reports associated with this interaction, all of which were fatal. In seven reports, the patient's death was due to the adverse reaction. In the other seven reports, simvastatin may have contributed to the fatal outcome. In the majority of cases, patients were aged ≥ 65 years. The most commonly reported interactions occurred following the initiation of a macrolide or azole antifungal (strong CYP3A4 inhibitors) for acute infection while taking long-term simvastatin therapy. In patients who took the moderate CYP3A4 inhibitor diltiazem, adverse reactions occurred after an increase in simvastatin dose.

Atorvastatin is metabolised by CYP3A4 to a lesser extent than simvastatin. Although CYP3A4 inhibitors are not contraindicated with atorvastatin, they should be avoided if possible. Fluvastatin, pravastatin and rosuvastatin are not significantly metabolised by CYP3A4 and should be considered in patients requiring long-term treatment with a statin and CYP3A4 inhibitor.

Further information about medicines that interact with simvastatin may be found in the medicine data sheet at