Watchful Eye on Drug Side Effects Pays Off

Rare Eprex-linked anemia caught early and then stemmed

WEDNESDAY, Sept. 29, 2004 (HealthDayNews) -- Beginning in 1998, changes in the formulation and administration of a drug called Eprex sparked a rise in a dangerous form of severe anemia among European and Canadian patients, new research shows.

The drug -- most commonly used to fight fatigue in cancer or kidney dialysis patients -- was linked to 175 cases of pure red-cell aplasia, in which bone marrow ceases to produce red blood cells. Patients who developed the syndrome required daily blood transfusions until powerful drugs restored blood cell production.

Fortunately, say the authors of a report in the Sept. 30 issue of the New England Journal of Medicine, the cooperation and expertise of various international agencies led to an early spotting of this rare side effect and "a decrease of more than 80 percent worldwide in the incidence of this severe syndrome."

"This represents what we'd like to think of as a success story, in terms of how drug monitoring detected a problem and suggested potential explanations for why the problem occurred," said Dr. Anne Trontell, deputy director of the Office of Drug Safety at the U.S. Food and Drug Administration. Her commentary appears in the same issue of the journal.

Eprex belongs to the recombinant human erythropoietin (epoetin) family of biotech drugs used to fight anemia and fatigue in cancer and dialysis patients. Millions of prescriptions for epoetin drugs such as Epogen, Eprex and Procrit are written every year for an estimated $10 billion in annual sales, making these medications the most lucrative biotech products currently on the market.

While Epogen and Procrit are commonly prescribed in the United States, Eprex has been unavailable due to patent issues. It is widely used elsewhere, however.

Pre-approval clinical trials showed no evidence of Eprex-linked pure red-cell aplasia. However, in 1998, European and Canadian health officials became concerned that the human-sourced albumin protein then used in Eprex might raise risks for the spread of Creutzfeldt-Jakob disease, the human form of mad cow disease.

Spurred by those concerns, albumin was removed from Eprex. At the same time, practitioners were instructed to inject the drug beneath the skin, rather than provide it to patients intravenously.

Following those changes, reports of epoetin-linked pure red-cell aplasia began to surface in both Canada and Europe.

In their study, researchers led by Dr. Charles L. Bennett, a professor of medicine at Northwestern University, describe the multinational effort that went into identifying the incidence and cause of this epoetin-linked syndrome.

Overall, 191 epoetin users worldwide -- all of them on long-term kidney dialysis -- came down with the life-threatening anemia, according to the researchers. Of these, 175 were found to be receiving Eprex, usually through subcutaneous injection.

"One of the leading theories is that what's causing this is the development of [immune] antibodies," explained study co-researcher Dr. Benjamin Kim of Northwestern Memorial Hospital. According to this hypothesis, Eprex administered under the skin may linger near immune-system lymph nodes, helping to trigger this rare antibody response.

When the pattern became clear, government health agencies, first in Europe and then in Canada and Australia, mandated changes in the drug's manufacture and means of administration. These moves are credited with triggering an 83 percent decline in Eprex-linked pure red cell aplasia, with cases falling to pre-1998 levels by April 2004.

Bennett stressed that his monitoring group is not connected with the FDA, and instead works independently, using funds from a grant from the National Cancer Institute.

In fact, he and Kim believe the FDA's role in monitoring the safety of drugs already on the market should be minimal.

Throughout the epoetin effort, "we did spend a lot of time in direct communication with the [pharmaceutical] company, to get information," Bennett pointed out. "And because we are not a regulatory agency, we could do that. If we were the FDA, we might not have the same communication and collaboration."

Bennett believes that some type of federally funded drug safety review board, separate from a regulatory agency such as the FDA, might be better suited to these kinds of efforts.

Trontell disagreed with that assessment, however.

"FDA regulations require drug companies to report these events to us, and our Office of Compliance monitors on a periodic basis whether companies are following these procedures," she explained. In fact, Trontell said, much of the data in Bennett's study is sourced directly from the FDA.

More information

To learn more about the epoetin family of medications, head to the American Cancer Society.

SOURCES: Anne Trontell, M.D., M.P.H., deputy director, Office of Drug Safety, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Md.; Charles L. Bennett, M.D. Ph.D., M.P.P., associate director, VA Midwest Center for Health Services and Policy Research, and professor, medicine, Northwestern University Feinberg School of Medicine, Chicago; Benjamin Kim, M.D., division of medicine, Northwestern University Feinberg School of Medicine, Chicago; Sept. 30, 2004, New England Journal of Medicine
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