Black Box Warning Ordered for Aranesp, Epogen, and Procrit

ROCKVILLE, Md., March 9 -- The FDA warned today that aggressive use of erythropoiesis-stimulating agents to raise hemoglobin to a target of 12 g/dL or higher was associated with "serious and life-threatening side-effects and or/death."

The agency ordered a black-box warning for the drugs that recommended the lowest possible dose to slowly raise the hemoglobin concentration to the lowest level that will avoid the need for a blood transfusion.

Moreover, the FDA said that there has never been any evidence to support claims made in direct-to-consumer advertising that treatment with darbepoetin (Aranesp), epoetin alfa (Epogen), or epoetin alfa (Procrit) could increase energy or ease fatigue in patients undergoing cancer therapy.

For cancer patients who are not on chemotherapy, the FDA said that erythropoiesis-stimulating agents did not benefit anemia. But they appeared to shorten time to death.

At a press briefing, Richard Pazdur, M.D., director of the Office of Oncology Drug Products at the FDA's Center for Drug Evaluation and Research, said that on the basis of data from several recently reported clinical trials, a black box warning had been added to the labels of the three drugs.

The warning states:

• Avoid serious cardiovascular and arterial and venous thromboembolic events by using the lowest dose of Aranesp, Epogen, or Procrit that will gradually raise the hemoglobin concentration to the lowest level sufficient to avoid the need for blood transfusion
• Aranesp, Epogen, and Procrit and other erythropoiesis-stimulating agents increased the risk for death and for serious cardiovascular events when dosed to achieve a target a hemoglobin of greater than 12 g/dL.
• Use of erythropoiesis-stimulating agents to achieve a target hemoglobin of 12 g/dL or greater in cancer patients shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy; shortened overall survival and increased deaths attributed to disease progression in patients with metastatic breast cancer receiving chemotherapy; and increased the risk of death in patients with active malignant disease not under treatment with chemotherapy or radiation therapy. Erythropoiesis-stimulating agents are not indicated for this patient population.
• Patients treated before surgery with epoetin alfa to reduce allogenic red blood cell transfusions had a higher incidence of deep vein thrombosis. Aranesp is not approved for this indication.

Karen Weiss, M.D., deputy director of the FDA's Office of Oncology Drug Products, said the FDA became concerned when it started to receive results from a number of trials investigating aggressive use of erythropoiesis-stimulating agents to raise hemoglobin to targets higher than the targets on the drug label.

The results of those "more is better" studies were uniformly bad-ranging from increased cardiovascular events to progression of cancer.

A puzzling aspect of the FDA action today was the acknowledgement that there was no evidence to support marketing claims that the drugs could restore energy or reduce fatigue for patient in chemotherapy or radiation therapy.

Rafel Dwain Rieves, M.D., acting director, division of medical imaging and hematology products, said those claims were an extension of quality-of-life labeling from studies in renal dialysis patients.

But Dr. Rieves said that even the renal labeling was not supported by good quality-of-life measures, but rather results of a series of questionnaires that asked open-ended questions about a wide range of topics including sex life, appetite, happiness, and energy.

Dr. Pazdur said that going forward, all patients should be started on the lowest possible dose of Aranesp, Epogen, or Procrit.

Additionally, for all patients, physicians should:

• Measure hemoglobin twice a week for two to six weeks after any dosage adjustment to ensure that hemoglobin has stabilized in response to the dose change.
• Withhold the dose of the erythropoiesis-stimulating agents if the hemoglobin increase exceeds 12 g/dL or rises by 1g/dL in any two-week period.

The label was also changed to include this evidence from recently reported clinical trials:

• Interim results from the Danish Head and Neck Cancer Study Group trial (DAHANCA 10), an open-label, randomized trial that compared radiation therapy alone to radiation plus Aranesp in treatment of advanced head and neck cancer found that three-year loco-regional control was significantly worse for patients in the Aranesp arm (P =0.01) and overall survival favored those not treated with Aranesp, but the difference was not statistically significant. The trial was terminated Dec. 1, 2006.
• Results similar to the DAHANCA 10 study-increased tumor progression and decreased survival-were reported by Henke, et al at the May 4, 2004, meeting of the Oncologic Drugs Advisory Committee.
• In January 2007 the FDA was notified of the results of a 989 patient, multi-center, double-blind, randomized, placebo-controlled study of Aranesp in anemic cancer patients who are not receiving chemotherapy. The target hemoglobin in the Aranesp treatment group was 12 g/dl. The study results provided to the FDA show Aranesp did not reduce the need for red blood cell transfusions and showed an increase in mortality in patients receiving Aranesp compared to those receiving placebo (hazard ratio 1.25; 95% confidence interval: 1.04, 1.51).
• The FDA was notified in February 2007 of the final results of a double-blind, placebo controlled study to evaluate whether use of epoetin alpha in anemic non-small cell lung cancer patients not on chemotherapy improved their quality of life. The epoetin alfa dose was titrated to maintain a hemoglobin level of 12 to 14 g/dL; epoetin alfa was dosed at 40,000 IU every week. The study was terminated early when the data safety monitoring committee determined that the median time to death was 68 days in the epoetin alfa arm versus 131 days in the placebo arm (P=0.040 and the majority of deaths were due to disease progression. Also treatment with epoetin alfa did not significantly reduce the need for transfusion or improve the quality of life.
• In February 2007, the FDA was notified by Roche that it was suspending a study of a new erythropoiesis-stimulating agent because of safety concerns. The study was a multi-center, randomized, dose-finding assessment of a pegylated epoetin beta product in anemic patients with Stage IIIB or IV non-small cell lung cancer who were receiving first line chemotherapy. Three dosing regimens of the investigational drug were being compared with Aranesp (given according to an FDA-approved dosing regimen). The dose of pegylated epoetin beta was titrated to maintain the hemoglobin level between 11 and 13 g/dL. An interim analysis, after randomization of 153 patients, demonstrated a numerical imbalance in the number of deaths across the four arms of the study.
• The FDA was notified in February 2007 of the preliminary results of a 681-patient, multicenter, randomized, open-label, non-inferiority study of Procrit compared with the standard of care in adult patients undergoing elective spinal surgery. Procrit was administered according to the dosage and administration section of the label for pretreatment hemoglobin values >10 and