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FDA orders labeling changes for ESAs
The indication requires a hemoglobin level of ≤10 g/dL for treatment initiation for all patients.
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The FDA has ordered safety labeling changes to darbepoetin alfa and epoetin alfa, indicating that treatment should not be initiated in any patient unless the hemoglobin level is ≤10 g/dL.
The ordered changes also require a statement that the treatment is not indicated for any patient receiving myelosuppressive therapy when the anticipated outcome is cure.
Proposed labeling from the companies for darbepoetin alfa (Aranesp, Amgen) and for epoetin alfa (Epogen, Amgen; Procrit, OrthoBiotech) had suggested some patients with comorbid conditions could receive the drugs if their hemoglobin levels were ≥ 10 g/dL and they could not tolerate the degree of anemia.
According to the letter that the FDA issued to Amgen, this proposed labeling is “unacceptable because it undermines other components of the dosing directions which instruct health care providers to maintain the lowest hemoglobin necessary to avoid red blood cell transfusions.”
The FDA also said that there are no sufficient data indicating specific comorbid conditions in which maintaining a higher hemoglobin level results in improved survival or decreased morbidity.
Medicare beneficiaries are already experiencing these restrictions. The National Coverage Decision issued by the Centers for Medicare and Medicaid Services last year restricts coverage of erythropoiesis-stimulating agents only to patients who have hemoglobin levels <10 g/dL.
Curative treatment
The proposed labeling from the companies also suggested that the drugs are indicated for patients receiving curative therapy, “when red blood cell transfusion is not a treatment option.” According to the FDA letter, “neither the FDA nor an external expert could identify a clinical setting in which red blood cell transfusion is not an option.”
The Oncologic Drugs Advisory Committee has convened three times to analyze the safety of ESAs. At the most recent meeting in May, the panel voted to modify the drug’s indication to exclude patients receiving curative treatment. – by Emily Shafer
The first major label change is that ESAs are not indicated for patients receiving myelosuppresssive therapy when the anticipated outcome is cure. This is new and based on the recent ODAC recommendation. The major groups would be patients receiving adjuvant chemotherapy for breast cancer or colorectal cancer, and for patients receiving chemotherapy for Hodgkin's disease and intermediate grade non-Hodgkin's lymphoma.
For the breast/colorectal adjuvant group, I am not sure how many patients will be affected. The labeling now states that ESAs are not indicated when patients are treated for curative intent, but it is also not contraindicated, which leaves room for discussion between the patients and physicians, depending upon the insurer. Patients with intermediate-grade lymphoma or Hodgkin's disease, even those with late-stage disease are generally treated with curative intent. But once again, although ESAs are 'not indicated,' there is room for discussion, depending upon the insurer.
There are two other parts to the label. One is that therapy should not be initiated for patients with hemoglobin levels <10 g/dL, which has not changed. The labeling previously advised that if the hemoglobin exceeds a level needed to avoid red blood cell transfusion or exceeds 12 g/dL, then the drug should be withheld. The new label removed the statement 'or exceeds 12 g/dL,' which removes the upper limit. Theoretically, this should not affect administration of ESAs. However, it may cause some confusion with private insurers, some of whom are currently allowing use of ESAs for maintenance in patients with hemoglobin levels between 10 g/dL and 12 g/dL. Medicare does not allow this, but many private insurers do. The fact that it has been removed may confuse insurers, but it should not change the use of these drugs.
For Medicare, there is currently no indication that the national coverage decision will change. There is always the potential that CMS will propose a new national coverage determination. For private insurers, there is nothing in the new labeling that would indicate changes in coverage. We have yet to see what the result will be in the private insurance community, and for Medicare.
– Samuel Silver, MD, PhD
HemOnc Today Editorial Board member