Volume 6, Issue 3 October 2012
Simvastatin is metabolised through the CYP3A4 pathway. Concomitant use of CYP3A4 inhibitors has the potential to increase exposure to simvastatinPrueksaritanont T, Gorham LM, Ma B et al. In vitro metabolism of simvastatin in humans [sbt]Identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 1997;25:1191-1199. Both amlodipine and diltiazem are substrates and inhibitors of CYP3A42. Katoh M, Nakajima M, Shimada N, Yamazaki H, Yokoi T. Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: prediction of in vivo drug-drug interactions. Eur J Clin Pharmacol 2000;55:843-852 3. Sutton D, Butler AM, Nadin L, Murray M. Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibtion of CYP3A4 activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther 1997;282:294-300 and therefore increase the plasma concentration (AUC0-24h) and maximum plasma concentration (Cmax) of simvastatin when they are co-administered.
Studies have found that after 10 days of amlodipine (10 mg), the AUC0-24h of simvastatin and simvastatic acid following a single dose of simvastatin 80 mg increased by 1.58- and 1.77- fold respectively, compared with that following a single dose of simvastatin 80 mg without prior amlodipine administrationUS product information for Zocor. http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf. Use of amlodipine 5 mg with simvastatin 5 mg resulted in a proportionally smaller increase in simvastatin plasma concentrationNishio S, Watanabe H, Kosuge K, Uchida S, Hayashi H, Ohashi K. Interaction between amlodipine and simvastatin in patients with hypercholesterolemia and hypertension. Hypertens Res 2005;28:223-227.
Similarly, studies with diltiazem 120 mg twice daily for 10 days increased the AUC0-24h of simvastatin and simvastatic acid following a single dose of simvastatin 80 mg by 3.10 and 2.69 fold (compared with a single dose of simvastatin 80 mg without prior diltiazem treatment). Increases in AUC as high as 5 fold with simvastatin 20mg and diltiazem (120mg twice daily) have been reportedMousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 2000;67:267-274.
Although based on a small number of cases, the incidence of myopathy across a number of large trials increased when simvastatin 40 mg was administered with amlodipine. Similarly the incidence of muscle symptoms specifically associated with rises in creatine kinase (CK) with simvastatin 40 mg was between 2 – 3-fold greater in the presence of amlodipine compared with its absenceFDA review (2011). http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/019766s077.pdf. The cumulative total of patients experiencing raised CK levels in the Heart Protection Study (HPS)Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. The Lancet 2003 June 14;361(9374):2005-16 was 1% for patients taking 40 mg simvastatin plus amlodipine, versus 0.36% for patients taking simvastatin alone. Consistent with this, the 5-year SEARCH clinical trial9 also demonstrated increases in the incidence of CK elevations with simvastatin 80 mg plus amlodipine which were not observed with simvastatin 20 mg plus amlodipine.
While the absolute incidence of myopathy is low, the prescribing of simvastatin 40 mg is high and amlodipine is a common co-medication. Additionally many patients at potential risk of muscle symptoms are excluded from clinical trials. Thus the relatively small increased risk imposed by amlodipine could translate into a significant number of additional adverse muscle effects in practice.
These observations are supported by reported cases of adverse muscle reactions. For example, in the FDA report, there were 42 reports of rhabdomyolysis with simvastatin 40 mg plus amlodipine, compared with 20 reports with simvastatin 20 mg plus amlodopine. It must be remembered that such ratios are affected by many factors, such as relative prescribing rates.
In agreement with pharmacokinetic data, greater CK elevations were observed in SEARCH ,Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. 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. The Lancet 2010;376:1658-1669 with simvastatin 80 mg when administered with diltiazem, compared with simvastatin 80 mg alone. This translated to a significant 3-fold increase in the incidence of myopathy when diltiazem was administered with high-dose simvastatin. The incidence of CK elevations was lower when diltiazem was administered with simvastatin 20 mg compared with 80 mg, and was similar to the incidence with simvastatin 20 mg alone.
The HPS trial demonstrated that simvastatin 40 mg has a clearly positive benefit-risk profile vs placebo  , however, the additional benefit of simvastatin 40 mg versus 20 mg is anticipated to be smaller. As with all statins, most of the low-density lipoprotein (LDL)-lowering effect is apparent at lower doses of simvastatin (~75% of maximum effect is apparent with 20 mg) and only an additional 6% effect would be expected by doubling the dose from 20 mg to 40 mgSchachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update Fundam Clin Pharmacol 2005;19:117-125. SEARCH  also failed to demonstrate any additional benefit of 80 mg vs 20 mg in terms of mortality and morbidity, a result which did not change with duration of treatment.
Alternative prescribing options are available for patients in whom the lower dose of simvastatin is not considered appropriate. There are currently no restrictions for co-administration of any of the other marketed statins with amlodipine. If switching to another statin is considered, the recommendations for monitoring or dose reduction for other interacting medicines should be taken into account.
In summary, the available evidence supports the recommendation that the maximum daily dose of simvastatin should not exceed 20 mg when co-administered with amlodipine or diltiazem:
In the absence of further evidence, the recommendation for a maximum daily dose of simvastatin of 20 mg applies with amlodipine at doses of both 10 mg and 5 mg.
Advice for prescribers: