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 Adverse Cases


Back Reported Adverse Drug Reaction Cases
Risk factors for myopathy and rhabdomyolysis with the statins

Four statins (HMG CoA inhibitors) are available in Australia for the treatment of hypercholesterolaemia: simvastatin, atorvastatin, pravastatin and fluvastatin. Each of the statins may cause myalgia or rhabdomyolysis. Cerivastatin was removed from the market worldwide because of an unacceptably high rate of rhabdomyolysis, including fatal cases, particularly when used with gemfibrozil.1

The rates of muscle disorders observed in clinical trials of statins have not been significantly different from those with placebo,2 but wider clinical use involves individuals having multiple disease states or taking potentially interacting medication. Recent reviews indicate that factors which increase the plasma concentrations of statins are associated with an increase in the risk of myalgia, myopathy and, particularly, rhabdomy-olysis.3,4 For simvastatin and atorvastatin which are metabolised by the liver enzyme CYP3A4 these factors are presented in Table 1.

Table 1: Factors increasing the risk of muscle disorders with simvastatin and atorvastatin

Substances inhibiting metabolism by CYP3A4

cyclosporin, diltiazem, verapamil, macrolide antibiotics, azole antifungals, protease inhibitors, grapefruit juice

Medicine inhibiting metabolism by other means

gemfibrozil

Disease states

diabetes, hypothyroidism, renal and hepatic disease

Advanced age

≥ 70 years

High statin dose

≥ 40 mg/day

ADRAC has received 91 reports of rhabdomyolysis with simvastatin and 26 with atorvastatin, as well as many reports of myalgia, myopathy or creatine kinase (CK) increase. Table 2 (top section) shows the percentage of cases with identified risk factors, as defined in Table 1. For simvastatin the factors listed most commonly in reports describing rhabdomyolysis were age ≥ 70 years (40 reports) dose ≥ 40 mg (33), cyclosporin (19), gemfibrozil (21), diltiazem (20) and diabetes (15). Over half of the simvastatin cases with rhabdomyolysis had more than one identified risk factor. Individuals with several risk factors may be at risk of developing rhabdomyolysis, rather than a less serious muscle disorder.

A feature of the cases of rhabdomyolysis is that long term statin therapy was well tolerated until after a change in medication (e.g. increase in the dose of statin, or addition of clarithromycin or diltiazem).

Table 1: Factors increasing the risk of muscle disorders with simvastatin and atorvastatin

 

Substances inhibiting metabolism by CYP3A4

cyclosporin, diltiazem, verapamil, macrolide antibiotics, azole antifungals, protease inhibitors, grapefruit juice

Medicine inhibiting metabolism by other means

gemfibrozil

Disease states

diabetes, hypothyroidism, renal and hepatic disease

Advanced age

≥ 70 years

High statin dose

≥ 40 mg/day

 

Pravastatin and fluvastatin are not metabolised by CYP3A4 and are less subject to increases in plasma concentration by interaction with other drugs. ADRAC reports of muscle disorders with these statins are shown in Table 2 (bottom section). The dominant risk factors for pravastatin and fluvastatin were advanced age and high dose. The lower number of cases of rhabdomyolysis with these statins is probably associated with the lesser likelihood of drug interaction, but is also related to the lower usage in Australia (From 1992 to November 2003, 85% of statin prescriptions have been for simvastatin or atorvastatin).

High doses of statins should be used with caution in the elderly, in patients with renal or hepatic insufficiency, hypothyroidism or diabetes. Particular caution should be observed in patients taking simvastatin or atorvastatin with these conditions, if gemfibrozil, cyclosporin or diltiazem are being taken concomitantly. Consideration should be given to temporary discontinuation of simvastatin or atorvastatin, if short-term macrolide antibiotic or azole antifungal therapy is required. Patients should be advised to report to their doctor if muscle aches, pains or weakness develop.

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References:
  1. Cerivastatin and rhabdomyolysis - avoid gemfibrozil. Aust Adv Drug Reactions Bull 2001;20(1):3.
  2. Gotto AM. Safety and statin therapy. Arch Intern Med 2003;163:657-9.
  3. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA 2003;289:1681-90.
  4. Ballantyne CM, Corsini A, Davidson MH et al. Risk for myopathy with statin therapy in high risk patients. Arch Intern Med 2003;163:553-64.
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