Summary
To reduce the risk of myopathy and rhabdomyolysis, health professionals are advised of new recommendations to limit the use of high dose simvastatin (80 mg/day) and of new contraindications for the use of simvastatin with potent CYP3A4 inhibitors, gemfibrozil, cyclosporin or danazol (see box).They are also reminded of the need for lower doses when simvastatin is used concomitantly with drugs that interact with simvastatin and increase its absorption.
Simvastatin, like other inhibitors of HMG-CoA reductase, is known to cause myopathy and more rarely rhabdomyolysis. The risk of myopathy is dose related and is more likely to occur in the first year of treatment. Other risk factors include age ≥65 years, female gender, uncontrolled hypothyroidism and renal impairment. Myopathy can be the result of interactions with other drugs. Many cases may be associated with a genetic variant which results in reduced uptake of simvastatin by the liver.
A recent re-analysis by the US Food and Drug Administration of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial has confirmed the increased risk of myopathy and rhabdomyolysis with increasing doses of simvastatinsimvastatin.8 In the trial the incidence of myopathy increased from 0.02% among patients taking 20 mg of simvastatin daily to 0.9% among those taking 80 mg daily. The trial also found only a limited increase in benefit from the 80 mg dose compared with lower doses.
Following a review of these findings, the TGA is recommending limitations to the use of high dose simvastatin (80 mg/day) and changes to the contraindications. The TGA is working with the sponsors of simvastatin and simvastatin-containing medications to update the Product Information to provide increased warnings regarding the risk of myopathy associated with high doses of simvastatin, and to detail the new dosage recommendations and contraindications.
Key safety related updates for simvastatin*
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Risk of myopathy/rhabdomyolysis
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The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-based therapies with similar LDL-C lowering efficacy
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New dose recommendation
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The 80 mg/day dose of simvastatin should only be used in patients at high risk of cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks
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New contraindications
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Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone). If treatment with these medicines is unavoidable, simvastatin should be suspended during the course of treatment.
Concomitant administration of gemfibrozil, cyclosporin or danazol
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Precautions – interactions with other medicines
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Amiodarone: the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone
Calcium channel blockers:
– Verapamil or diltiazem: the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with verapamil or diltiazem
– Amlodipine: the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlodipine
Moderate inhibitors of CYP3A4: patients taking other medicines labelled as having a moderate inhibitor effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy
Other fibrates: concomitant use of gemfibrozil is contraindicated. The concomitant use of simvastatin and other fibrates should be avoided.
Niacin (≥1 g/day): the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with niacin (nicotinic acid) ≥1 g/day
Colchicine: there have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin in patients with renal insufficiency. Close clinical monitoring of patients taking this combination is advised.
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* These updates provide information on changes to the recommendations for simvastatin. For full prescribing information, see the Zocor Product Information available on the TGA website.
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Important information for health professionals
The 80 mg/day dose of simvastatin should only be used in patients at high risk of cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks.
Concomitant administration of simvastatin with potent CYP3A4 inhibitors, gemfibrozil, cyclosporin, or danazol is now contraindicated (see box for details).
Simvastatin is contraindicated in patients who have previously experienced myopathy secondary to other lipid lowering agents.
In patients taking simvastatin for whom an interacting agent is needed, a lower dose of simvastatin or an alternative statin with less potential for drug-drug interactions should be used.
Health professionals should advise patients who are commencing simvastatin therapy or whose dose is being increased, of the risk of myopathy and remind patients to report any unexplained muscle pain, tenderness or weakness to a health professional promptly.
Simvastatin therapy should be discontinued immediately if myopathy is suspected.
Health professionals are asked to report any suspected cases of myopathy to the TGA.