F.D.A. Says Millions Got Unapproved Heart Pills

Doctors in the United States wrote more than four million prescriptions last year for nitroglycerin tablets, heart drugs placed under the tongue to reduce the chest pain angina or to stop a heart attack.

But the majority of the drugs sold had not been approved for sale, nor had their safety and effectiveness been vetted, by the Food and Drug Administration.

And many doctors, who discovered only last week that pharmacies were giving their patients unproved heart tablets, now say they have no way of knowing whether patients have suffered unnecessarily as a result.

“If it’s not approved and no one has tested it, we can’t be sure that it’s safe and effective,” said Dr. Harry M. Lever, a cardiologist at the Cleveland Clinic. If patients with angina took substandard or ineffective nitroglycerin tablets, Dr. Lever said, their pain might not subside and the problem could potentially progress to a heart attack.

The F.D.A., which in recent years has been cracking down on a decades-old backlog of unapproved drugs, sent warning letters last week to two drug makers ordering them to stop marketing unapproved nitroglycerin tablets. But the drugs are still being sold at pharmacies while the order takes effect.

The drug makers said they would comply with the order, but said that their tablets were safe.

The F.D.A. said that it had not examined the quality of the products it was ordering off the market but that it had recorded problems with other unapproved nitroglycerin products in the past. The agency advised people who take unapproved nitroglycerin to continue taking their tablets but to consult their doctors about replacement prescriptions.

Cardiologists regularly prescribe nitroglycerin to relieve chest pain associated with coronary artery disease. Placed under the tongue, the drug quickly dissolves into the blood, where it dilates the coronary artery, slightly decreasing blood pressure and reducing heart exertion.

When taken during an initial episode of chest pain, nitroglycerin can prevent a heart attack in 3 to 4 percent of patients, said Dr. Steven E. Nissen, a cardiologist at the Cleveland Clinic.

The problem of the unapproved tablets stems from a longstanding ambiguity about the rules for drugs whose use predates the establishment of the F.D.A. in 1927. Only one brand of nitroglycerin pills is federally approved: Nitrostat, made by Pfizer, on the market since 2000.

Many makers of various drugs, not only nitroglycerin tablets, have long contended that their medications did not require F.D.A. review because they were grandfathered as pre-1938 drugs. (The F.D.A.'s powers to require new drugs to demonstrate safety before being marketed came in 1938 with passage of the Food, Drug and Cosmetic Act.) But the agency is now disputing that interpretation of its rules. It took action on nitroglycerin tablets after looking into the matter and being struck by the large volume of prescriptions being filled with unapproved versions.

“These drugs are historical remnants,” said Michael Levy, a division director in the F.D.A.’s Center for Drug Evaluation and Research. “Pharmacies likely mistake them for generic drugs or for drugs likely to be grandfathered, neither of which is the case.”

Of the nearly 4.4 million prescriptions for under-the-tongue nitroglycerin tablets last year in this country, about 80 percent were filled with unapproved drugs, according to data from the research firm IMS Health.

Leading cardiologists said they were shocked to learn that for years their patients might have been taking crucial heart drugs whose safety and potency had not been vetted by the F.D.A.

“I was taken aback,” said Dr. Ralph G. Brindis, the president of the American College of Cardiology, a professional association representing nearly 26,000 cardiologists in the United States.

Dr. Harlan M. Krumholz, a professor of medicine at the Yale School of Medicine, said it would not have occurred to him that licensed pharmacies might be filling prescriptions with unapproved drugs. “Nobody ever teaches you that in medical school,” he said.

On March 16, the agency sent warning letters to two leading suppliers of the unapproved tablets, Konec Inc. of Tucson and Glenmark Generics Inc. of Mahwah, N.J., giving them 90 days to stop making the drugs and 180 days to stop shipping them.

In response to a query from a reporter, a spokesman for Glenmark Pharmaceuticals in Mumbai, India, the parent company of Glenmark Generics, sent a statement saying that the company intended to comply with the agency’s directive to stop making the unapproved drugs.

It added that the F.D.A. warning letter had not asked for a recall — an immediate action in which a company removes products for sale from the market.

The president of Konec, Enrique Durazo, said his company regularly conducted its own lab tests to ensure that its nitroglycerin pills had the equivalent potency and stability to the approved brand-name drug.

But the company has not conducted the kind of human tests, called bioequivalence studies, required for F.D.A. approval of generic drugs, he said. Konec now plans to conduct such tests and seek approval as a generic.

Pfizer, which according to IMS Health sold about 900,000 prescriptions of Nitrostat last year, says it had stepped up production of the drug and expected to be able to meet the entire market demand in the United States.

At CVS, the cash price for a pack of 100 tablets of 0.4-milligram Nitrostat is $21.99; the same amount of the Glenmark product costs $19.99.

With the F.D.A. giving Konec and Glenmark six months to continue marketing their unapproved nitroglycerin tablets, some major pharmacy companies said they planned to continue selling them.

“We still have the product available,” said Robert Elfinger, a spokesman for Walgreens, which sells the Glenmark nitroglycerin. “This is not a recall.”

A spokesman for CVS, which has been selling the Glenmark drug since early 2009, said that the company would make any changes in dispensing that the F.D.A. might require.

Nitroglycerin drugs are not to be confused with the explosive ingredient in dynamite. But even in drug form, nitroglycerin is an unstable chemical, which is why doctors say they cannot be sure how potent the unapproved versions might be.

Moreover, because patients have varied responses, some cardiologists say they now have no way of knowing whether they have been treating their patients with an inferior product.

Dr. Lever, of the Cleveland Clinic, for example, recalls a heart surgery patient telling him that something was wrong with her new tablets. They did not relieve chest pain, he recalled, and they did not cause side effects she had previously experienced.

She then gave the pills, a bottle of Glenmark tablets, to Dr. Lever.

Glenmark did not respond to a query from a reporter seeking comment about the matter.

Dr. Lever, who has kept the bottle in his desk ever since, recalled the episode after learning of the F.D.A.’s action last week.

“Every day, when I’m writing a prescription,” he said, “I’m thinking, ‘Is the patient going to get the right stuff?’ ”