Assessing the statins
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Editor, – We refer to the article 'Assessing the statins' by E. Hurley (Aust Prescr 1999;22:114-7). Recent updates to the pravastatin product information in relation to the drug interaction potential of the statins reflect a different perspective to that conveyed by the article.
Following a review by the Therapeutic Goods Administration a new paragraph has been inserted in the 'Drug Interactions' section. This reads:
'Unlike simvastatin and atorvastatin, pravastatin is not significantly metabolised in vivo by cytochrome P450 3A4. Therefore, plasma concentrations of pravastatin are not significantly elevated when cytochrome P450 3A4 is inhibited by agents such as diltiazem and itraconazole.
In interaction studies with aspirin, gemfibrozil, nicotinic acid or probucol, no statistically significant differences in bioavailability were seen ...'
Further, we are unaware of data supporting the assertion that there is significantP450 2C9 and 2D6 isoenzyme involvement in the metabolism of pravastatin.
Simvastatin, but not pravastatin, has been associated with rhabdomyolysis in a population at high risk of drug-drug interactions (cardiac transplant patients).1
The article represented a degree of uniformity among the statins that is not supported by the approved product information, a situation that we feel deserves clarification for your readers.
Bristol Myers-Squibb Pharmaceuticals
Noble Park, Vic.
Ms Eve Hurley, the author of the article, comments:
In vivo data on pravastatin's hepatic metabolism and the likelihood of drug interactions through CYP P450 3A4 are useful, and superior to results of an in vitro study which found moderate affinity for P450 2C9, 2D6and 3A4.2 However, the section regarding interaction studies (which include gemfibrozil and nicotinic acid) if taken out of context, could give the impression that it is 'safe' to use these drugs in combination with pravastatin. The product information also includes information about gemfibrozil significantly increasing concentrations of a metabolite of pravastatin and the combination being 'not generally recommended'.
Rhabdomyolysis has been reported very rarely with statins, including pravastatin.3 Statins are well tolerated and have few clinically important interactions. My review did not include information on the management of interactions, which are given in the Australian Medicines Handbook. In preference to listing approved indications, the major clinical studies (on which the indications are based) were summarised, enabling prescribers to assess the potential benefits of treatment for their patients.
- Keogh AM, Macdonald PS, Aboyoun C, Mundy JA, McCaffrey D, Spratt PM. Pravastatin confers superior survival after cardiac transplantation when compared to simvastatin. J Heart Lung Transplant. In press 2000.
- Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes(CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol1996;50:209-15.
- Pravachol product information. MIMS Annual. 23rd ed. Sydney: MIMS Australia; 1999. p. 2-162-4.