Published: 6 March 2014

Statins and CYP Interactions

Prescriber Update 35(1): 12–13
March 2014

Key Messages

  • Simvastatin and to a lesser extent atorvastatin are metabolised by the hepatic isoenzyme CYP3A4.
  • CYP3A4 inhibitors may increase the plasma concentration of these statins, increasing the risk of adverse reactions such myopathy and/or rhabdomyolysis.
  • If a potent CYP3A4 inhibitor such as erythromycin must be used, then simvastatin or atorvastatin therapy should be stopped for the duration of therapy.
  • Fluvastatin, pravastatin and rosuvastatin are not significantly metabolised by CYP3A4 and are less susceptible to CYP interactions.
  • CYP3A4 inducers may reduce the effectiveness of some statins; therefore, lipid profiles should be monitored if co-prescribed.

Simvastatin and atorvastatin, two widely prescribed cholesterol lowering medicines, are both metabolised by the isoenzyme cytochrome P450 3A4 (CYP3A4). Simvastatin undergoes more pre-systemic metabolism than atorvastatin. This results in lower bioavailability and simvastatin is therefore more susceptible to medicine interactions1.

Nevertheless, the co-prescription of a CYP3A4 inhibitor may lead to an increase in the plasma concentration of either statin, increasing the risk of adverse effects such as myopathy and/or rhabdomyolysis.

Symptoms of myopathy include muscle pain, weakness and tenderness, which may occur with or without raised concentrations of creatine kinase. Rhabdomyolysis, a more severe form of skeletal muscle damage, is the occurrence of muscle related symptoms with creatine kinase greater than 10 times the upper limit of normal2.

The risk of rhabdomyolysis is estimated at approximately 3.4 cases per 100,000 person-years with standard-dose statin therapy3. However, this increases with higher therapeutic doses and by prescribing statins in combination with interacting medicines3.

Statin therapy should be discontinued immediately if myopathy is suspected or diagnosed. Patients using lipophilic statins (atorvastatin and simvastatin) may be more susceptible to the risk of myopathy due to an increased ability to enter muscle cells and alter membrane structure4.

Strong CYP3A4 inhibitors are contraindicated with the use of simvastatin (Table 1). The dose of simvastatin should be restricted with the concomitant use of moderate CYP3A4 inhibitors5. Other CYP3A4 inhibitors should be used with caution or the combination avoided if possible6.

Table 1: Examples of medicines that interact with simvastatin and atorvastatin

Interacting medicines Simvastatin Atorvastatin
Potent CYP3A4 Inhibitors
Macrolide Antibiotics
(eg, Erythromycin, Clarithromycin)
Azole Antifungals
(eg, Itraconazole, Ketoconazole, Posaconazole, Voriconazole)
Protease Inhibitors
(eg, Ritonavir, Telaprevir, Boceprevir)
Combination contraindicated Use with caution and monitor. Avoid combination if possible
Moderate CYP3A4 Inhibitors
Nicotinic Acid (>1 g/day)
Do not exceed 20 mg/day Use with caution and monitor
Minor CYP3A4 Inhibitors
Case reports of rhabdomyolysis. Use with caution and monitor No clinically significant interactions
CYP3A4 Inducers
St John's Wort
Probable reduction in concentration. Monitor lipid profile Possible reduction in concentration. Monitor lipid profile

If use of a potent CYP3A4 inhibitor is unavoidable (eg, macrolide antibiotic), then the statin should be stopped during the duration of therapy.

CYP3A4 inducers, such as carbamazepine and rifampicin, may reduce the plasma concentrations of atorvastatin and simvastatin. If a CYP3A4 inducer is co-prescribed, then lipid profiles should be monitored and a dose adjustment made if necessary.

Fluvastatin, pravastatin and rosuvastatin are not significantly metabolised by CYP3A4. Fluvastatin and to a minor extent rosuvastatin are metabolised by CYP2C9, and are less subject to clinically significant CYP interactions. However, caution is still recommended when co-prescribing known CYP inhibitors.

Pravastatin is excreted largely unchanged from the parent compound (is not significantly metabolised by CYP enzymes) and therefore is not subject to CYP interactions.


  1. Neuvonen PJ, Niemi M, Backman JT. 2006. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clinical Pharmacology and Therapeutics 80(6): 565–581.
  2. Sathasivam S, Lecky B. 2008. Statin induced myopathy. BMJ 337: a2286.
  3. Catapano AL. 2012. Statin-induced myotoxicity: pharmacokinetic differences among statins and the risk of rhabdomyolysis, with particular reference to pitavastatin. Current Vascular Pharmacology 10(2): 257–267.
  4. Neuvonen PJ, Backman JT, Niemi M. 2008. Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clinical Pharmacokinetics 47: 463–474.
  5. Flockhart DA. 2007. Drug Interactions: Cytochrome P450 Drug Interaction Table. URL: (accessed 23 January 2014).
  6. Pfizer New Zealand Limited. 2013. Lipitor Data Sheet. 18 June 2013. URL: (accessed 27 January 2014).