How should pharmacists and physicians respond to new studies suggesting that widely used anti-anemia drugs may seriously harm
cancer patients? In March, the Food & Drug Administration reacted to the new data by placing boxed warnings on the drug labels
of ESAs (erythropoiesis-stimulating agents), urging doctors to use the smallest dosage possible—just enough to avoid the use
of blood transfusions. The warnings followed study findings that higher risks accompanied higher doses of ESAs. The risks
included worsening cancer, more frequent cardiovascular events, and a greater number of deaths than expected. These disturbing
results emerged most often when the drugs were aggressively administered off-label to target a hemoglobin of >12 g/dL.
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However, Roger M. Perlmutter, executive VP of research and development at Amgen, the largest producer of ESAs (also called
EPOs), disagrees that ESAs are widely overprescribed. He said at a recent media conference: "The majority of oncologists and
nephrologists are [already] maintaining hemoglobin levels not to exceed 12g/dL in approved indications."
In May the FDA convened a meeting of its Oncologic Drugs Advisory Committee (ODAC) to review dosing levels and other issues
related to the risks of using ESAs in anemic cancer patients—an estimated 500,000 in the United States. A separate conference
focusing on ESA treatment of anemia in kidney disease—a huge problem involving some 20 million Americans—will be held this
fall.
As Richard Pazdur, M.D., director of the FDA's Office of Oncology Drug Products, put it, "We want people to be aware that
these drugs were approved specifically to reduce or prevent blood transfusion. That is key to how these drugs should be used."
However, the drugs also have been used to counter fatigue and improve quality of life. Pazdur and other government experts emphasized at the ODAC meeting that blood transfusions are safer than they used to be
but that currently no one knows for sure if ESA benefits continue to be greater than the risks of transfusions. For example,
FDA pointed out that five randomized clinical trials showed shorter survival times in cancer patients receiving ESAs than
in controls getting red blood cell transfusions. Also, three randomized trials showed poorer tumor outcomes in cancer patients
receiving ESAs versus traditional blood transfusions. However, FDA guidelines were not followed in these experimental trials.
As a result of these and similar data, ODAC members voted to further tighten the reins on ESAs. Notably, they voted 15 to
2 to further restrict use of anti-anemia drugs in general pending the results of further safety studies. They also voted 12
to 5 to withhold the agents from patients with "certain types of cancer"—not specified but assumed by some attendees to be
head and neck cancer, non-small cell lung cancer, and breast cancer—since the trial results with these cancers were unfavorable.
Also, they voted 16 to 1 to stop administering anemia drugs when chemotherapy was finished and to reevaluate the patient's
needs.
The FDA usually heeds ODAC's recommendations, but Pazdur said after the meeting that it was too soon for the agency to make
any statements about its future actions.
All quiet in Cincinnati
Asked to comment on the controversy, Jane Pruemer, Pharm.D., BCOP, associate professor of clinical pharmacy practice, University
of Cincinnati College of Pharmacy, told Drug Topics there is no controversy in Cincinnati. "Our guidelines have been in place since 2004," she said. They include:
- Dosage adjustments for darbepoetin are targeting a hemoglobin maximum of 12 g/dL; patients are evaluated every four weeks
to this end.
- The dose is increased by 25% if the hemoglobin increase is under 1 g/dL in a four-week period; the dose is decreased by 25%
as the hemoglobin approaches 12 g/dL or if there's an increase in hemoglobin of 1 g/dL within a four-week period.
- If the patient hasn't improved after six to eight weeks of anti-anemia therapy with the correct dosage adjustments—plus vitamin
and mineral supplementation—stopping the therapy is considered.
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