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Published: May 2004
ADR update

Myopathy with Statins: Check CK Levels and Interactions

Prescriber Update 25(1): 4-5.
May 2004

Dr Ruth Savage, Medical Assessor; Dr Michael Tatley, Director
Centre for Adverse Reactions Monitoring, Dunedin

Reports of myopathy and rhabdomyolysis with statins are a reminder to prescribers to measure creatine kinase (CK) levels in patients presenting with muscle pain or weakness.  The risk of myopathy may be increased by high doses of statins, especially in patients with co-morbidities, or in the presence of interacting medicines such as diltiazem.

Myopathy known to occur with statins

While the statins are effective in providing protection from coronary and cardiovascular events, they are known to cause myopathy (usually dose-related) and, rarely, rhabdomyolysis.1  A clinical diagnosis of myopathy is made when there is muscle pain or weakness accompanied by a creatine kinase (CK) level more than ten times the upper limit of normal.  Rhabdomyolysis is a severe form of myopathy with muscle breakdown leading to myoglobinuria, which may result in renal failure and death.2

New Zealand reports of rhabdomyolysis

The Centre for Adverse Reactions Monitoring (CARM) has received eight recent reports (including two fatalities) of rhabdomyolysis occurring in patients taking between 20mg and 80mg of a statin daily.  Six of these patients were taking simvastatin which, along with atorvastatin, is fully funded in New Zealand and therefore prescribed more often than the other available statins (i.e. fluvastatin and pravastatin).  All patients in the eight cases initially complained of myalgia or muscle weakness and were later diagnosed with rhabdomyolysis.  Two of the patients on simvastatin presented with urinary discoloration; one went on to develop acute renal failure.  The duration to onset of symptoms ranged from 2-12 weeks from initiation of, or change in, statin therapy.  The patients were between 54-79 years of age; five were taking other medicines known to interact with statins (i.e. four were taking simvastatin with diltiazem, and one bezafibrate with pravastatin).  Three patients had significant co-morbidities including chronic renal failure and hepatic cirrhosis; two patients had recently had their simvastatin dose increased to 60mg and 80mg daily.

Monitoring helps improve outcome

It is advisable to monitor patients for signs and symptoms of muscle pain, tenderness or weakness, particularly during both the initial months of statin therapy and subsequent dose increases.3,4  Creatine kinase measurements must be performed when symptoms occur.  Patients with additional risk factors (e.g. diabetes, older age, hypothyroidism, liver or renal disease1,5) merit closer monitoring as they may be more at risk of rhabdomyolysis.3

Statin treatment should be discontinued immediately if an elevated CK level is found (i.e. CK >10 x upper limit of normal6), or where myopathy is suspected or diagnosed.3,4  If there is a moderate rise in the CK level (i.e. 3-10 x upper limit of normal) then monitor CK levels weekly and seek specialist advice.6  It is worth noting that measuring CK levels when statin therapy is initiated will provide a reference baseline; however, undertaking regular CK levels is probably not useful in the absence of therapy changes or the development of co-morbidity.1

Concomitant medicines may increase risk of myopathy

The risk of myopathy or rhabdomyolysis with simvastatin alone is dose related; the incidence, determined from clinical trials, is approximately 0.03% at 20mg, 0.08% at 40mg and 0.4% at 80mg daily.  This risk is increased with concomitant fibrates, as they alone can cause myopathy.3  The risk is also increased when simvastatin and atorvastatin (both CYP 3A4 substrates; fluvastatin and pravastatin are not7) are used concomitantly with potent CYP 3A4 inhibitors (eg. erythromycin, itraconazole, amiodarone, verapamil).3,4  Diltiazem, a weaker inhibitor of CYP 3A4, is frequently prescribed with a statin.  Diltiazem increases the risk of rhabdomyolysis to 1% when given with simvastatin 80mg daily.3  However, fatal rhabdomyolysis has been reported in two New Zealand patients taking diltiazem whose simvastatin doses were increased to 40mg and 60mg daily, respectively.  Both had significant co-morbidity.8

To minimise the likelihood of interactions, lower starting doses of simvastatin and atorvastatin should be used in patients already on fibrates, cyclosporin, amiodarone, verapamil, and other potent CYP 3A4 inhibitors.3  Closer monitoring for signs and symptoms suggestive of myopathy is also recommended.4  For patients already taking simvastatin or atorvastatin, the statin dose should be reduced when interacting medicines are prescribed.  Diltiazem should not be co-prescribed with high doses of simvastatin or atorvastatin; and for all concurrent therapy, there should be closer monitoring.  Consider temporarily discontinuing these statins if short-term courses of azole antifungals or macrolide antibiotics are required.3  An alternative option would be to consider changing to pravastatin or fluvastatin.

Advise patients of warning symptoms

Prescribers should be aware that there is an increased risk of myopathy occurring in patients taking statins, and this risk may be further increased in the presence of co-morbidities or concurrent medicines.  Patients who are prescribed statins need to be informed of the importance of promptly reporting unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.3,4  Measure CK levels in patients who present with such symptoms.  Where myopathy is suspected or diagnosed, immediate withdrawal of the statin is recommended.

Competing interests (authors): none declared

Correspondence to Dr Michael Tatley, New Zealand Pharmacovigilance Centre, PO Box 913, Dunedin.

References
  1. Gotto AM, Jr. Safety and statin therapy: Reconsidering the risks and benefits. Arch Intern Med 2003;163:657-659.
  2. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001;35(9):1096-1107.
  3. Merck Sharp & Dohme (New Zealand) Limited. Lipex Data Sheet February 2003. www.medsafe.govt.nz/Profs/Datasheet/l/Lipextab.htm
  4. Pfizer Laboratories Limited. Lipitor Data Sheet 30 September 2003. www.medsafe.govt.nz/profs/Datasheet/l/Lipitortab.htm
  5. Australian Adverse Drug Reactions Advisory Committee (ADRAC). Risk factors for myopathy and rhabdomyolysis with the statins. Aust Adverse Drug React Bull 2004;23(1):2.
  6. New Zealand Guidelines Group. The Assessment and Management of Cardiovascular Risk - Best Practice Evidence-based Guideline, December 2003. www.nzgg.org.nz/guidelines/
    0035/CVD_Risk_Full.pdf#page=171
  7. Stockley IH (Ed). Stockley's Drug Interactions 6th edn. London: Pharmaceutical Press, 2002.
  8. Gladding P. Potentially lethal interaction between diltiazem and statins [Letter]. Ann Int Med 2004;140(8):676.