FDA Warns Aleve May Increase Heart RisksDec 21, 2004 | Los Angeles Times
Three days after warning that the prescription painkiller Celebrex can increase the risk of heart attacks and strokes, federal health officials Monday raised questions about the potential for similar problems with a principal over-the-counter alternative, Aleve.
"This is a very confusing situation," said Dr. Sandra Kweder, deputy director of the Food and Drug Administration's Office of New Drugs. But the FDA stopped short of urging patients to seek alternatives to Aleve, its generic versions or its prescription forms Naprosyn and Anaprox, as the agency had done Friday with Celebrex.
Instead, officials urged consumers buying the over-the-counter medication to follow label directions carefully and advised that patients taking the prescription versions consult their physicians.
The announcement about Aleve, which is manufactured by German drug maker Bayer, came after the stock markets had closed.
"Bayer Healthcare LLC consumer care division was notified of the trial suspension today," spokesman William O'Donnell said in a statement. "The company has not yet seen the data and therefore is unable to comment on the study at this time. We are investigating the matter and in the meantime we are in agreement with the FDA's recommendation that consumers carefully follow instructions on the label."
The concerns about Aleve were prompted by preliminary findings from a study by the National Institute on Aging, which sought to determine whether naproxen the drug's generic name could help reduce the risk of developing Alzheimer's disease. The study, which began in 2001, followed about 2,400 volunteers ages 70 and older who were considered at risk of developing Alzheimer's because of their family history.
Patients taking Aleve were found to have about a 50% greater chance of suffering strokes or heart attacks than those taking a placebo, said Dr. John Breitner of the Veterans Administration Puget Sound Health Care System, the study's principal investigator.
Breitner described the results as a "weak signal" of problems with naproxen and said that he could not yet comment on whether the findings were statistically significant.
The trial also had sought to test whether Celebrex could help prevent the onset of Alzheimer's. Patients were divided into three groups: some people taking a placebo, some taking Aleve, and some taking Celebrex.
No increased risk of heart problems was found among those taking Celebrex, Breitner said. Yet a separate federal study on cancer prevention found a strong indicator of heart risk among patients taking high doses of Celebrex. After those findings were announced Friday, Breitner said researchers decided to stop giving Celebrex to the patients in the Alzheimer's study.
Then, given the signs of a possible problem with Aleve, investigators decided they could not continue to administer that drug without resolving questions.
"We had to face the dilemma of whether we would continue to treat with naproxen, when naproxen appeared to be giving a more negative signal," Breitner said. "In light of that, we elected to suspend both treatments."
Breitner said the cancer study's findings on Celebrex were stronger than the Alzheimer's study data on Aleve.
But he could not explain why no evidence of problem with Celebrex was detected in the Alzheimer's study. Some experts say that rare side effects sometimes do not emerge even in studies of several thousand patients.
A total of 70 patients in the Alzheimer's study suffered heart attacks or strokes, said Breitner, including those taking Aleve, Celebrex and a placebo. Twenty-three died.
Patients in the study were given 220 milligrams of Aleve twice a day, the same dose recommended for over-the-counter use. Consumers buying Aleve for their own use are advised not to take it for more than 10 days without consulting a doctor.
Steven Chen, an assistant professor at the USC School of Pharmacy, said he thought it would be surprising if naproxen truly increased the risk of heart attacks and strokes. If anything, he said, the drug is supposed to make blood clots less likely because it decreases the stickiness of platelets in the blood.
Chen said that the withdrawal of the painkiller Vioxx in late September due to increased cardiovascular risk did not come as a surprise because studies had already shown that it raised the risk of heart attacks and strokes. The same was not the case for naproxen.
"It's the first time we've seen anything like this with Naprosyn," he said, referring to the drug by its prescription brand. "I think it will likely surprise the medical community, but I don't think anybody will take it to heart unless it can be substantiated" by another study that is designed specifically to look at effects of the drug upon the heart.
Drugstore.com, an Internet outlet, continued filling orders for naproxen Monday after the FDA statement was released because the advice was to follow label instructions. But spokesman Greg French said the company was monitoring the situation with its pharmacists, the FDA and manufacturers.
"We're advising any patients with questions to talk to their doctors, especially if they are taking dosages off label," French said. "It's something we are anxiously watching."
If the need should arise, French said, the company could contact every person to whom it had sold a naproxen product since it started shipping drugs in 1999.
The latest developments could raise questions about an entire class of medications known as nonsteroidal anti-inflammatory drugs, or NSAIDs. They are used to treat a variety of ailments, including headaches, menstrual cramps, arthritis and gout. Another popular NSAID is ibuprofen, sold under the brand names Advil and Motrin as well as generically.
The FDA is planning to hold a meeting in February to discuss the safety implications of a subset of NSAIDs Cox-2 inhibitors that includes Celebrex and Vioxx, the drug that Merck & Co. pulled off the market this fall.
Until now, there has been no hint that well-established NSAIDs like Aleve could cause heart problems. Naproxen was first sold by prescription in 1976 and was approved for over-the-counter sales in 1994.
"We are not aware of any previous studies looking at the long-term risk associated with older" anti-inflammatory drugs, said the FDA's Kweder. "This is the first evidence that we have seen that suggests that there is a risk. We agree that this is confusing."
The FDA does not intend to take any immediate regulatory action on naproxen, Kweder added. One thing the agency could do is commission more studies.
"In the context of naproxen, this is the first preliminary evidence that reaches a level of concern for us to do further study," said Dr. Elias A. Zerhouni, director of the National Institutes of Health.
Breitner said he had more questions than answers. "I have no knowledge of whether this is unique to naproxen, or whether it may be a problem for all NSAIDs," he said. "We've never had the opportunity to study that.
Dr. Steven K. Galson, head of the FDA's Center for Drug Evaluation and Research, emphasized the preliminary nature of the new findings. "I don't think that patients should be overly concerned about the information released today," he said.
But Dr. Gregg C. Fonarow, professor of cardiovascular medicine at UCLA, noted that "these medicines were originally studied in the short term for treatment of pain, and their cardiovascular effects were never really well scrutinizedâ€¦. Now they're being used in higher doses longer term, and we're seeing they indeed can increase the risk for myocardial infarction and strokes."
Both inflammation and blood clotting involve some of the same chemicals, so it is not altogether surprising that a drug affecting one process might affect the other, he said.
Separately on Monday, Pfizer Inc. stopped advertising Celebrex directly to consumers. The company's decision came after a request by the FDA over the weekend. Celebrex had been one of the most heavily promoted of drugs, with television ads aimed at arthritis patients, featuring middle-aged people celebrating active lives.
Pfizer's stock, which took a beating on Friday, fell again Monday to $24.29, $1.46 below the previous close. Bloomberg News reported Monday that the company's market value had fallen by $35 billion over the last two trading days.
David Webster, a healthcare consultant in Bethlehem, Pa., said the naproxen news would not have a long-lasting effect on Bayer's financial results because the drug had been used for more than 30 years without apparent consequences.
"There's a heightened sensitivity about safety, particularly in this class of drugs," Webster said. "So any drug that's associated either directly or tangentially with these concerns will experience a dose of bad publicity."
Leiner Health Products, a Carson-based manufacturer that makes naproxen sold under private labels by large retailers, was reviewing the FDA advisory, said Gale Bensussen, company president.
He said the advisory was an important reminder to consumers taking over-the-counter drugs to follow label instructions.
"These are serious medicines that are very effective for treating things like arthritis and, with aging population, a lot more people are taking them," Bensussen said. "These products are safe and effective if you follow the label use."