[PHNUTR-L] FDA: Black Box Warning Ordered for Aranesp, Epogen, and Procrit

[Kathrynne Holden]

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Black Box Warning Ordered for Aranesp, Epogen, and Procrit
http://www.medpagetoday.com/ProductAlert/Prescriptions/dh/5231		
   	
By Peggy Peck, Managing Editor, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, 
University of California, San Francisco
March 09, 2007

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.
Action Points

     * Explain to interested patients that the FDA found there is no 
evidence that erythropoiesis-stimulating agents increase energy or ease 
fatigue for patients undergoing radiation or chemotherapy treatments.

     * Explain to patients that the FDA found there is evidence that 
increasing hemoglobin to more than 12 g/dL can increase the risk of 
thrombotic events and stimulate progression of some cancers.

     * Explain to patients who are taking erythropoiesis-stimulating 
agents that they will need to have hemoglobin measured two to six weeks 
after any dose titration.

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 < 13 g/dL. The frequency of deep venous 
thrombosis in patients treated with Procrit was 4.7% (16 patients), more 
than twice that of patients who received usual blood conservation care 
(frequency of 2.1%, seven patients).
     * Two clinical studies and an editorial published in the New 
England Journal of Medicine last November addressed safety concerns 
about the use of erythropoiesis stimulating agents in the treatment of 
anemia of chronic renal failure. The 1,400-patient CHOIR study 
demonstrated increases in serious and potentially life-threatening 
cardiovascular events when Procrit was administered to reach target 
hemoglobin levels 13.5 g/dL compared with a lower target-11.3 g/dL. The 
600-patient CREATE study trended toward more cardiovascular events in a 
pattern similar to the CHOIR study, thus strengthening the findings of 
the CHOIR study. The CREATE study examined the use of epoetin beta, a 
product not approved in the U.S.

Finally, the Centers for Medicare and Medicaid Services responded 
quickly to the FDA action by instructing local Medicare carriers that it 
plans to deny reimbursement for darbepoetin alfa and epoetin alfa used 
for anemia of cancer, although it will continue to cover the drugs when 
they are used to treat anemia due to chemotherapy.
-- 
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
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