Critic Faults FDA For Tardy Warning On Simvastatin Risk

Jun 9, 2011

The fact that 80 daily milligrams of simvastatin (brand name Zocor) can cause serious muscle damage has been known for years. So why did it take the Food and Drug Administration so long to tell doctors and patients they should avoid that dose?

The answer reveals a lot about the FDA's reluctance to restrict use of a popular drug — much less move to take it off the market — even when there are safer alternatives.

The FDA on Wednesday said use of the 80 milligram dose of simvastatin should "be sharply curtailed because of the risk of muscle injury." The agency says doctors should avoid starting patients on that dose, too, though patients who've been on it for a year or more without problems can continue.

Cardiologist Steven Nissen of the Cleveland Clinic, one of the FDA's most persistent gadflies, says the label change is too little and far too late.

"Most knowledgeable experts were very worried about this dose of the drug," Nissen told Shots. "I stopped prescribing it in 2004. Here we are, seven years later, and they're finally getting around to restricting it."

The stakes are high. Simvastatin is the second-most prescribed drug in the U.S. and by far the most widely prescribed cholesterol-lowering drug. Doctors write more than twice as many prescriptions for it as for Lipitor (atorvastatin, generically). The FDA says 2.1 million Americans take the 80-mg dose of simvastatin.

The risk of this dose is unusually clear.

Almost a decade ago, the FDA required a label change on 80-mg simvastatin warning that interactions with other common drugs could cause a muscle condition called rhabdomyolysis, which can cause kidney failure and death.

Then in 2004, a large randomized study called the A to Z Trial found a higher rate of muscle damage, including rhabdymyolysis and a less severe form, among patients on the 80-mg dose of simvastatin. Other, smaller studies were pointing the same way.

Four years later, in late 2008, an even larger study called SEARCH found 53 cases of muscle damage among 6,000 patients on 80-mg simvastatin, versus three cases among the 6,000 patients on a 20-mg dose.

The accumulating evidence eventually prompted the FDA to analyze reports it gets, on a voluntary basis, in its Adverse Event Reporting System.

Dr. Amy Egan, the FDA's deputy director for safety in the division that deals with statin drugs, tells Shots that about half the 148 reports of death from rhabdomyolysis were among patients taking 80-mg simvastatin – a danger signal, since simvastatin makes up 31 percent of statin use.

Egan acknowledges the process leading up to this week's restriction on the drug has been slow.

"There's been criticism as to why this took so much time," Egan says. "But basically we had to go back to the statin sponsors and have them submit additional data from their large clinical trials." Six companies market statin drugs.

Nissen says the agency should have taken 80-mg simvastatin off the market years ago, since there are safer alternatives.

But Egan says the FDA didn't want to do that.

"We have been working with the sponsor (Merck) the past several months to come up with a plan that would allow us to keep the 80-milligram dose on the market so we would not disrupt the care of patients taking that dose," Egan says.

Interestingly, the argument came down to the cost of the drug.

"While we cannot factor costs into our decision, this is the cheapest and most potent generic statin available," Egan says. "We're talking about four cents a day versus $1.20 a day. So for people who pay for medications on their own, those people would be certainly disadvantaged and may have to stop their statins. And we felt the public health impact of that was certainly worse than leaving the drug on the market."

But that calculus is about to change. Generic Lipitor will become available in November.

And no study has suggested that patients who need high-dose atorvastatin to meet their cholesterol goal are at any risk of muscle damage.

Nissen says simvastatin's low cost is what has kept many people on it, despite the accumulating evidence of risk. "It has been pushed very hard by pharmacy benefit managers as a means to save costs," he says.

The FDA says it will monitor use of 80-mg simvastatin over the coming year to see if the new label change really does limit its use. Egan says the agency doesn't know how many people have been taking it for less than a year, or "how many people out there are walking around with symptoms" of muscle damage.

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