FOSAMAX AND DRUG WARNINGS

Jaw Ailment Shows Industry Moves Slowly on Drug Warnings
The Wall Street Journal
Geeta Anand
December 8, 2004

After eight operations on patients whose jawbones turned out to be dead, oral surgeon Salvatore Ruggiero began doing some research in February 2001. He scoured the patients' medical records and discovered they had something in common: They were cancer patients taking a drug called Aredia to combat bone loss.

Dr. Ruggiero, chief of oral and maxillofacial surgery at the Long Island Jewish Medical Center, says that year he phoned the drug's maker, Novartis AG, to find out if there were other reports of patients on Aredia suffering from osteonecrosis of the jaws, or jawbone death.

He says he also reported his cases on MedWatch, the Food and Drug Administration's computer system for tracking dangerous side effects from drugs.

Since then, Dr. Ruggiero has gathered 90 cases in which patients taking Aredia and Novartis's successor drug, Zometa, have experienced dental problems so severe they have lost portions of their jaws. Other oral surgeons have been reporting the same problem. It wasn't until November 2003 that Novartis first noted the possible side effect on the drugs' package inserts.

Dr. Ruggiero's experience in bringing his patients' jaw problems to the attention of Novartis and the FDA underscores how challenging it is -- and how long it can take -- for companies and regulators to act on potentially dangerous side effects of marketed drugs. The issue has been at the center of two pharmaceutical debacles this year: the drug industry's delayed recognition of suicide risk associated with pediatric antidepressant use, and Merck & Co.'s withdrawal of the painkiller Vioxx after a clinical trial linked long-term use to the risk of heart attack and stroke.

In September of 2004, Novartis at the direction of the FDA added a "precaution" to the drugs' labels and sent letters warning doctors of the potential side effect. "Osteonecrosis of the jaws has been reported in patients with cancer receiving treatment regimens including" Aredia and Zometa, the label says. Novartis says as of September it had received 500 case reports of jaw problems in people taking Aredia and Zometa.

The oral surgeons believe that the two Novartis drugs, which are useful in stopping cancer cells from dissolving bone, end up causing problems in the jaws of some patients precisely because they interfere with the bone-dissolving process. New cells don't grow unless the old ones are killed off. The bone doesn't heal following dental work and is more prone to infections.

Novartis officials say they acted as quickly as they could when the potential problems with Aredia and Zometa were brought to their attention. They say their records indicate they first heard from Dr. Ruggiero in July 2002 and it wasn't until January 2003 that he detailed his case reports.

Novartis says it still isn't convinced the drugs are the cause of the osteonecrosis, and it has commissioned two studies to try to find out. The process will take at least another year to complete.

That's too long, says Dr. Ruggiero, who says patients are suffering needlessly because the public hasn't been kept informed about the heightened risks of dental work in people taking these drugs. Oncologists need to know about the potential problems too, so they can spot them earlier. "Many people lost their jaws or portions of their jaws, and that didn't need to happen," he says.

Suzanne Strakhov, 71 years old, a Northport, N.Y., substance-abuse counselor who has metastatic breast cancer, developed the jaw problem in late 2001 or early 2002 after taking Aredia for about a year. An oral surgeon removed four teeth and scraped the bone underneath to promote healing. When the wounds didn't heal, her surgeon referred her to Dr. Ruggiero, an expert in this area.

Dr. Ruggiero diagnosed her problem almost immediately. He scraped the bone two more times trying to kill the infection, but was finally forced to remove another tooth and part of her jaw, she says. Last year, an infection erupted in her jaw that caused her chin to swell and landed her in the hospital for four days on intravenous antibiotics. "It's been a terrible ordeal, but I'm happy to be here," Ms. Strakhov says.

Months after he first reported his cases on MedWatch, Dr. Ruggiero says he didn't hear from the FDA or see any changes in the drugs' package inserts. He called MedWatch, using the number on the FDA Web site, in 2002 to ask whether the agency had received his information. "How many of these do I have to put on before something gets done?" he recalls asking. A MedWatch official assured him she had seen the cases and was waiting for a critical mass before approaching Novartis, he says.

An FDA spokeswoman said the agency won't discuss Dr. Ruggiero's MedWatch reports or communication with Novartis because it is privileged. But she said it takes time for the agency to analyze reports on MedWatch and figure out if there is a strong link with the medicine in question.

Dr. Ruggiero says he began making regular calls to Novartis directly to report his growing osteonecrosis caseload. He says Novartis sent someone to go through his files some time in 2002. Deborah Bunsire, senior price president and North American region head of Novartis's oncology division, says her records indicate the company sent representatives to view Dr. Ruggiero's cases in 2003.

The company had heard about a presentation Dr. Ruggiero made at an oral-surgery meeting in January of that year linking osteonecrosis of the jaw with the two Novartis drugs. Dr. Ruggiero says Novartis officials told him they were continuing to investigate the problem and still weren't certain that their two drug were causing the condition.

In the summer of 2003, another oral surgeon, Robert Marx, a department chief at the University of Miami's Miller School of Medicine, called Novartis to say he was writing a medical alert in the Journal of Oral and Maxillofacial Surgery warning of the problem with the two drugs. He says he also phoned the FDA.

Dr. Marx says he'd long suspected a link between the drugs and the jaw problems but had waited to call Novartis and the FDA until he was certain. He had 36 cases of osteonecrosis of the jaws that he believed were linked to the two drugs. His article was published in the journal's September 2003 issue.

That month, Novartis filed a notice with the FDA stating it wanted to report the osteonecrosis cases in the drugs' package insert.

By December 2003, Dr. Ruggiero had 54 patients with osteonecrosis of the jaw. Novartis invited Drs. Ruggiero and Marx to a meeting of oncologists and top company scientists in San Antonio. At the meeting, the oral surgeons say, the Novartis officials seemed skeptical of the existence of a link with their drugs. Why hadn't the jaw problems come up in the company's animal studies or in clinical trials? The drugs are used for multiple myeloma and other cancers that have spread to the bone. Patients taking the drugs are usually very sick and taking many other medicines, including steroids and chemotherapy drugs, which also are associated with a higher incidence of osteonecrosis of the jaw.

The Novartis officials talked about commissioning more studies to find out if there really was a link. The oral surgeons say they urged Novartis not to wait for the years it would take to do studies that would prove beyond doubt there was a problem. "We need to make the public aware of this problem. People are losing their jaws over this," Dr. Ruggiero recalls saying.

Novartis officials again met with Dr. Ruggiero, Dr. Marx and oncologists in New Jersey. Novartis officials said they wanted to publish a consensus paper advising doctors of the symptoms and how to treat them. A draft of the paper circulated among the group, but it hasn't been published yet. Novartis says some of the oncologists were skeptical about the purported link between the osteonecrosis cases and the drugs.

A patient advocacy group, the International Myeloma Foundation, surveyed 1,203 myeloma and breast-cancer patients and found 75 reporting a diagnosis of osteonecrosis of the jaw. Another 77 said they had experienced symptoms including exposed bone and bone spurs. "We found a very strong correlation with taking these drugs and developing osteonecrosis," says Brian Durie, a hematologist and co-founder of the foundation.

If you suffer from jaw osteonecrosis (ONJ) or death of the jaw as a result of taking Fosamax you should contact an attorney. Please fill out the form below and your submission will be forwarded to an experienced attorney.