Preventive CardiologiesConcomitant use of cytochrome P450 3A4 inhibitors and simvastatin
Section snippets
Data from megatrials
Two-year safety data from 2 megatrials are available, the Scandinavian Simvastatin Survival Study (4S)5, 6 and the ongoing Heart Protection Study.7 In these analyses, myopathy is defined as unexplained muscle pain or weakness accompanied by an elevation of creatine kinase to ≥10 times the upper limit of normal. This level of creatine kinase elevation will exclude the vast majority of cases due to exercise or minor trauma.
Postmarketing adverse experience data
If it was hypothesized that concomitant therapy with calcium channel
Scandinavian simvastatin survival study
Four thousand four hundred forty-four patients with angina pectoris or previous myocardial infarction and serum cholesterol of 213 to 310 mg/dl (5.5 to 8.0 mmol/L) on a lipid-lowering diet were randomized to double-blind treatment with simvastatin 20 mg (titrated to 40 mg if required) or placebo for a median follow-up period of 5.4 years.5
A single case of myopathy was reported, after 4 years of therapy, in a woman taking simvastatin 20 mg6(Table II). Concomitant medication included diltiazem,
Discussion
The metabolism of simvastatin is quite complex, as shown in Figure 1 , and some factors relevant to drug interactions may not be generally appreciated. Simvastatin is an inactive lactone converted to the corresponding active acid by esterases and by nonenzymatic hydrolysis.10 Both the parent lactone form and the acid are normally present in very small amounts in plasma due to a high hepatic extraction ratio (approximately 95%).10 Because the liver is the pharmacologic target organ, this has the
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Genomics and Pharmacogenomics of Lipid-Lowering Therapies
2014, Handbook of Pharmacogenomics and Stratified MedicineUpdates on Cytochrome P450-Mediated Cardiovascular Drug Interactions
2010, Disease-a-MonthCitation Excerpt :Although the clinical significance of this finding is not clear, the manufacturer of simvastatin recommends to avoid concurrent use of simvastatin and verapamil, and if the two agents must be used together, the dose of simvastatin be kept at a maximum of 20 mg.41 One meta-analysis suggested that, overall, calcium channel blockers do not increase the risk of myopathy when used concomitantly with simvastatin.42 Diltiazem inhibits the metabolism of triazolam, probably by inhibiting the activity of CYP3A.43
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