US warns of rhabdomyolysis risk with cardiovascular drugs
This article was originally published in Scrip
The US FDAis warning healthcare providers about the increased risk of rhabdomyolysis in patients who concomitantly use the anti-arrhythmic drug amiodarone (Wyeth's Cordarone and generics) and high doses of the cholesterol-lowering agent simvastatin (Merck & Co's Zocor and generics). The risk is dose-related and increases when the simvastatin dose exceeds 20mg daily.
Simvastatin labelling was revised in 2002 to describe the increased rhabdomyolysis risk when high doses of the statin are given concomitantly with amiodarone, but the FDA has continued to receive adverse event reports despite the labelling changes. From January 2003 to January 2008, there were 52 reports of rhabdomyolysis associated with the concomitant use of amiodarone and simvastatin. 15 of these cases were considered life-threatening, and there was one death.
Although all statins carry a potential rhabdomyolysis risk, it is more pronounced when simvastatin is given concomitantly with amiodarone. From 2003 to 2008 there were six reports of rhabdomyolysis associated with use of amiodarone and other statins – one each for atorvastatin (Pfizer's Lipitor), lovastatin (Merck's Mevacor and generics, Sciele Pharma/Watson Laboratories' Altoprev) and fluvastatin (Novartis's Lescol), and three with rosuvastatin (AstraZeneca's Crestor).
metabolic pathway
The interaction is attributed to amiodarone's inhibition of the cytochrome P450 3A4 enzyme, which is the same enzyme that metabolises simvastatin. Prescribers should consider using another statin for patients taking amiodarone if they require more than 20mg simvastatin daily to meet their lipid goals. The agency's advisory encompasses simvastatin combination products, including Merck/Schering-Plough 's Vytorin (with ezetimibe) and Abbott's Simcor (with extended-release niacin).
Currently, amiodarone labelling states: "HMG-CoA reductase inhibitors that are CYP3A4 substrates (including simvastatin and atorvastatin) in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis." The FDA said amiodarone labelling would be revised to warn of an increased risk of rhabdomyolysis when the drug is administered with simvastatin doses exceeding 20mg/day. The agency has no data on how varying the amiodarone dose affects the rhabdomyolysis risk.
Precautionary language about increased rhabdomyolysis risk with concomitant amiodarone is included in the labels for lovastatin-containing products. The Lipitor label does not specifically mention interactions with amiodarone, and the FDA said there is no plan to add a precaution about concomitant use. Pravastatin (Bristol-Myers Squibb's Pravachol and generics) and Crestor are not significantly metabolised by the CYP 3A4 pathway, so there is less risk with concomitant use, the agency said. It described Lescol as a weak statin with little clinical utility.