The highest approved dose of simvastatin -- 80 mg -- should be used only in those patients who have already been taking it for at least 12 months without signs of myopathy, the FDA announced Wednesday.
The 80-mg dose should not be used in new patients or those taking lower doses of the drug who need to lower their cholesterol further, the agency said in a safety alert, which outlined label changes and dose limitations for the drug.
"The risk of muscle injury with statins has not received adequate regulatory attention in the past," said Curt Furberg, MD, PhD, a pharmacologist at Wake Forest University. "Thus, this action by the FDA is long overdue."
He added in an email to ABC News and ľֱ, however, "I get a feeling that [simvastatin] is being singled out. As I see it, this is a general statin problem, not just a [simvastatin] problem."
The FDA first announced that the 80-mg dose of simvastatin was associated with an increased risk of myopathy and rhabdomyolysis in March 2010, but the agency did not make specific recommendations about limiting its use pending a formal safety review.
That review included a deeper look into the SEARCH trial, in which the 80-mg dose was associated with a higher rate of myopathy than the 20-mg dose (0.9% versus 0.02%).
After evaluating the SEARCH data and information from the FDA's Adverse Event Reporting System, the agency decided to limit use of the highest dose to those patients who have not had any muscle problems following use of at least a year.
Cam Patterson, MD, a cardiologist at the University of North Carolina at Chapel Hill, noted that most patients who are taking simvastatin are not taking the 80-mg dose.
"However," he added in an email, "this will further restrict the use of simvastatin to patients with milder lipid disorders and will provide more incentive for physicians to prescribe potent statins like Crestor [rosuvastatin] and Lipitor [atorvastatin]."
Patterson indicated that lower cost might be the only reason to continue using simvastatin, as the more potent statins are better at reducing cardiac events and may carry a lower risk of side effects.
"When Lipitor goes off patent in a few months then even that advantage will disappear and it would be very difficult for me to understand why simvastatin would be prescribed under any scenario," he said.
The labels of both generic and branded (Zocor) forms of simvastatin, as well as the label for the simvastatin-ezetimibe combination (Vytorin), have been changed to reflect the new dosing limitations.
Those labels, in addition to that of the simvastatin-niacin combination (Simcor) -- which is not available with the highest dose of the statin -- have also been changed to reflect a greater number of medications that may interact with simvastatin to increase the risk of myopathy.
According to the new label, posaconazole (Noxafil) should not be used with any dose of simvastatin.
Three other medications -- gemfibrozil, cyclosporine, and danazol -- were shifted from acceptable use with low-dose simvastatin to the contraindication category.
Amiodarone, verapamil, and diltiazem should not be used with more than 10 mg of simvastatin daily, according to the new labels, which is lower than the previously acceptable dose.
In addition, patients who are taking amlodipine and ranolazine (Ranexa) should take no more than 20 mg of simvastatin daily.
The FDA said that the risk of myopathy with the 80-mg dose of simvastatin appears to be higher during the first year of treatment and when the statin is used in combination with patients taking calcium channel blockers, particularly diltiazem.
In SEARCH, about 60% of myopathy cases were associated with a genetic variant that results in an increase in the plasma concentration of simvastatin by affecting uptake in the liver.
The FDA advised healthcare professionals to switch patients for whom the 40-mg dose of simvastatin is not sufficient to other cholesterol-lowering treatments and to switch patients who need to be started on a drug that interacts with simvastatin to another statin with less potential for interaction.
In the safety communication, the agency pointed out that the 80-mg dose of atorvastatin results in greater LDL-cholesterol-lowering than the 80-mg dose of simvastatin (55% versus 47%).
In an email, Carl Lavie, a cardiologist at the John Ochsner Heart and Vascular Institute in New Orleans, pointed out that the 80-mg dose of atorvastatin has not been associated with an increase in myopathy or rhabdomyolysis.
Even so, he said, clinicians have been switching patients to simvastatin because of the cheaper cost, as atorvastatin is not yet available in generic (although it will be later this year).
"These warnings from the FDA should re-emphasize the potential toxicity [of high-dose simvastatin]," Lavie said.
This article was developed in collaboration with ABC News.