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Information for assessing people on simvastatin 80 mg/day Information for assessing people on simvastatin 80 mg/day

Key points

  • NPS encourages prescribers to review patients currently taking simvastatin 80 mg/day, following recent advice from the Therapeutics Goods Administration (TGA).
  • To reduce the risk of myopathy and rhabdomyolysis, the TGA has recommended limiting use of simvastatin 80 mg/day and has issued new contraindications and precautions for simvastatin.
  • Assess the need for intensive cholesterol lowering, taking into account the individual’s absolute cardiovascular risk and their LDL-cholesterol level.
  • Assess the individual’s risk of myopathy and check for any interacting drugs.
  • If the risk of myopathy outweighs the benefits of simvastatin 80 mg/day for the individual, reduce the dose or switch to a statin with a similar effect on LDL-cholesterol.

The TGA has recommended limiting use of simvastatin 80 mg/day

On 1 December 2011, the Therapeutics Goods Administration (TGA) issued new dosing recommendations, contraindications and precautions for prescribing simvastatin.

Prescribers are advised to limit the use of high dose simvastatin — 80 mg daily — to people at high risk of cardiovascular complications who have not achieved their treatment goals on lower doses and if the benefits are expected to outweigh the risks.1

The TGA’s recommendations were in response to a US Food and Drug Administration (FDA) review, which found that people taking simvastatin 80 mg daily had a greater risk of myopathy and rhabdomyolysis than people taking lower doses of the drug.1

There are also new contraindications and precautions

Do not use simvastatin in combination with gemfibrozil, cyclosporin, danazol or potent CYP3A4 inhibitors (e.g. erythromycin, itraconoazole). Switch to an alternative lipid-modifying drug with a lower potential for drug interactions or suspend simvastatin treatment (in the case of a contraindicated antibiotic or antifungal) if one of these medicines is required.1

Do not exceed the recommended dose limits of simvastatin for people taking amiodarone, calcium channel blockers (verapamil, diltiazem and amlodipine), fibrates other than gemfibrozil (which is contraindicated) and niacin (≥ 1 g/day).1 Closely monitor and consider reducing the simvastatin dose for people taking colchicine, fusidic acid or moderate CYP3A4 inhibitors.1,2

For full details of the new contraindications and precautions for simvastatin, see the TGA webpage.

Assess patients currently taking simvastatin 80 mg/day

Ask patients taking simvastatin 80 mg/day about muscle pain, tenderness, weakness and  cramps at their next visit. Investigate any muscle symptoms by checking creatine kinase (CK) levels.3 Discontinue simvastatin if myopathy is suspected (CK > 10 times upper limit of normal [ULN]) and consider switching to a different statin.1

Review the individual’s need for intensive LDL-cholesterol lowering therapy. Take into account the person’s absolute cardiovascular risk and whether their target level of LDL-cholesterol has been achieved. While meta-analyses show that intensive cholesterol lowering with high dose statins, such as simvastatin 80 mg/day, has a small added benefit for people with cardiovascular disease4–6, this has not been confirmed for people without established disease.

For more information about managing lipids and the role of statins, see NPS News 71: Managing lipids.

Assess the individual’s risk factors for myopathy

Review the following for patients currently taking simvastatin 80 mg/day:

  • Patient risk factors. Including age ≥ 65 years, female gender, renal and hepatic disease or impairment, diabetes, and/or uncontrolled hypothyroidism.1,3,7
  • Duration of simvastatin therapy. In the SEARCH trial (see below), the risk of muscle injury appeared to be higher in the first year of treatment.8
  • Interacting drugs. For the complete list of contraindicated drugs and precautions for the concomitant use of certain drugs, see the updated Product Information for simvastatin (Zocor), which is available on the TGA website.

Consider reducing the dose or switching to a statin with a similar LDL-cholesterol-lowering effect if the risks outweigh the benefits

If the risk of myopathy outweighs the benefit of simvastatin 80 mg daily, reduce the dose or switch to a statin with a similar effect on LDL-cholesterol lowering to that of simvastatin 80 mg daily (see Figure 1).

The FDA’s review of safety data for simvastatin included indirect comparison of statin trials and post-marketing surveillance data for all statins.9 These data suggest that the risk of myopathy with simvastatin 80 mg is greater than that for doses of other statins that have a similar LDL cholesterol-lowering effect.1,8

Figure 1:  Statin effect on LDL cholesterol10

Graph comparing effects of different statins on LDL cholesterol

Advice for patients

If you are currently taking simvastatin, be aware of the following

  • Muscle injury is a known side effect of all statins, but the risk is low for most people taking moderate doses of simvastatin (20 or 40 mg daily).
  • The risk of muscle injury is greater with higher doses of simvastatin (80 mg daily) or when certain other medicines are used with simvastatin.
  • See a doctor immediately if you experience muscle pain, tenderness, or weakness, dark or red coloured urine, or tiredness.
  • Check with your doctor or pharmacist before starting any new medicines, including non-prescription, over-the-counter and complementary medicines. Some medicines increase the risk of muscle injury with simvastatin and either should never be taken with it (e.g. erythromycin, gemfibrozil, cyclosporin) or can only be taken with it if the dose of simvastatin is low (e.g. diltiazem, verapamil, amiodarone).

If you are currently taking simvastatin 80 mg/day and have not had your dose reviewed by your doctor

  • keep taking your medicine unless advised by your doctor
  • ask your doctor to review your dose of simvastatin, as well as other medicines you are taking to ensure that your risk of muscle injury is minimised.

Resources for patients

  • An updated consumer medicine information (CMI) leaflet for simvastatin (Zocor) is available on the TGA website.
  • Medicines Line is an Australia-wide medicines information service for consumers. Consumers can call 1300 MEDICINE or 1300 633 424, Monday to Friday 9am to 5pm EST, (excluding NSW public holidays) for questions about simvastatin or any other medicines.

New safety information is based on a review of the SEARCH trial results

The new dosage limitation for simvastatin is based on a recent review of the SEARCH trial and other data sources by the FDA.8,9 The SEARCH trial compared rates of major vascular events for simvastatin 20 mg and simvastatin 80 mg, with or without vitamin B or folic acid, for people with a history of myocardial infarction. The trial included over 12,000 people and had a mean follow-up of 6.7 years.11 At the end of the trial, there were 2 cases of myopathy (defined as CK>10 times ULN with unexplained muscle weakness or pain) with simvastatin 20 mg (0.02%) compared with 52 cases for simvastatin 80 mg (0.9%). The rate of myopathy for simvastatin 80 mg/day was higher than that previously reported in trial data for simvastatin at this dose (0.53%).8 Rhabdomyolysis (defined as unexplained muscle weakness or pain with CK >40 times ULN) was reported in 22 patients (0.4%) who took simvastatin 80 mg daily and in no patients who took simvastatin 20 mg daily.8

In the SEARCH trial, there was no significant difference in rate of major vascular events for simvastatin 80 mg compared with simvastatin 20 mg (Risk ratio 0.94, 95% CI 0.88 to 1.01). While this finding may in part be due to a greater use of off-study statins in the simvastatin 20 mg group than in the 80 mg group, the risk-benefit profile of simvastatin 80 mg per day compared with the lower dose was not favourable.8,11

Risk of muscle injury is greater with higher doses of all statins

Statin-related myopathy occurs with all statins and the risk increases with higher doses.12,13 While the exact mechanism for muscle injury from statin therapy is not known, it appears to be related to the blood concentration of the statin, which is influenced by pharmacokinetics, dose, interacting drugs, and patient risk factors.3 In the SEARCH trial, many cases were associated with a genetic variant which results in reduced uptake of simvastatin in the liver.1

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

References

  1. Therapeutic Goods Administration. Risk of myopathy and rhabdomyolysis with simvastatin - new dosage recommendations and contraindications.  Medicines Safety Update, Vol 2, No 6. 2011. http://www.tga.gov.au/hp/msu-2011-06.htm#risk (accessed 7 December 2011).
  2. Merck Sharp & Dohme (Australia) Pty Ltd. Zocor Product Information (last updated 7 November 2011).  (accessed 8 December 2011).
  3. McKenney JM, Davidson MH, Jacobson TA, et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:89C-94C. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16581336
  4. Cooper A, Nherera L, Calvert N, et al. Clinical Guidelines and Evidence Review for Lipid Modification: cardiovascular risk assessment and the primary and secondary prevention of cardiovascular disease (revised March 2010). London: National Collaborating Centre for Primary Care and Royal College of General Practitioners, 2008. http://www.nice.org.uk/nicemedia/live/11982/40742/40742.pdf (accessed 12 August 2010).
  5. Josan K, Majumdar SR, McAlister FA. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ 2008;178:576-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18299547
  6. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21067804
  7. Adverse Drug Reaction Advisory Commitee. Australian Adverse Drug Reaction Bulletin.  Risk factors for myopathy and rhabdomyolysis with the statins. Canberra, 2004. http://www.tga.gov.au/hp/aadrb-0402.htm (accessed 8 September 2010).
  8. US Food and Drug Administration. FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury.  US Food and Drug Administration, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm (accessed 1 December 2011).
  9. Egan A, Colman E. Weighing the benefits of high-dose simvastatin against the risk of myopathy. The New England Journal of Medicine 2011;365:285-7. http://www.ncbi.nlm.nih.gov/pubmed/21675881
  10. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12829554
  11. Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010;376:1658-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21067805
  12. National Prescribing Centre (UK). What is the place in therapy of simvastatin 80mg/day in the light of recent MHRA guidance?  MeReC Bulletin,Volume 46, August 2010.  National Prescribing Centre (UK), 2010. http://www.npc.nhs.uk/merec/cardio/cdlipids/resources/merec_extra_no46.pdf (accessed 8 December 2011).
  13. Medicines and Healthcare products Regulatory Agency (MHRA). Yellow Cards which made a difference - high-dose rosuvastatin and rhabdomyolysis.  Drug Safety Update Nov 2011 vol 5, issue 4: A1.  MHRA, 2011. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON134928 (accessed 13 December 2011).

Date published: 2011-12-14 00:00:00

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