• Individual multi-dose vials 10,000 U/2mL; NDC #59676-312-00;  Expiration date 12/10
• Cartons containing 4 multi-dose vials 10,000 U/2mL; NDC 59676-312-04;   Expiration date 12/10

ESAs treat anemia in patients with kidney disease or certain cancers by boosting red blood cells. However, several studies have linked the anemia drugs to cardiovascular problems and deaths.  They have also been tied to worsening tumors when used in cancer patients.  A year ago, the Food & Drug Administration (FDA) ordered a “black box” warning regarding cardiovascular problems and other safety issues posed by the drugs be included on their labels. In March, the FDA added a black box warning to the drugs’ labels cautioning doctors that the medications should be administered at the lowest dose possible in order to bring red blood cell counts to the lowest level necessary to avoid transfusions. Last month, that black box warning was modified to include more specific dosing information.  

Following the release of the Aranesp breast cancer study, the FDA announced that it would be holding yet another advisory panel meeting in March to discuss the safety of Aranesp, Apogent and Procrit.   The March meeting will be the fourth time the FDA has held such a meeting to discuss ESAs.  Following one of these meetings in May, the Centers for Medicare and Medicaid Services changed the reimbursement policy for Aranesp and other ESAs. Now doctors will only be paid for using a low dose of the drug.

None of this is good news for Amgen, as Aranesp is its biggest selling product. Amgen, based in Thousand Oaks, Calif., has lost about $19 billion in market value this year after studies showed its anemia drugs raised the risk of heart attack, stroke and death at high doses.  Last week, after it announced that it was considering more label changes, Amgen stock dropped more than 5 percent.  The worst possible outcome for Amgen would be if the latest breast cancer data convinced the FDA panel to vote to recommend against using ESAs to treat other cancers where there's been negative data as well, such as neck and head cancer.

Amgen also reported that participants who received Aranesp had numerically more deaths and reports of tumor growth than control group patients.  Amgen cautioned that the results-revealed amid concerns about the overuse and safety of the anemia drug class-were preliminary and conclusions should not be made until completion of the final study report.  A formal statistical analysis of survival is anticipated in early 2009.  The interim analysis shows the use of Aranesp to support neo-adjuvant chemotherapy has no significant impact on tumor response to chemotherapy at the time of surgery.  There were no deaths during the treatment period, researchers said; however, preliminary long-term, follow-up data revealed more deaths in the group receiving Aranesp, with more tumor progression events versus the control group.

The entire drug class, called erythropoiesis-stimulating agents (ESAs), has been under a microscope as debates rage over whether anemia drugs increase the risk of heart attack and stroke, and whether they may play a role in fueling the growth of cancer.

Labels for Aranesp, Epogen, and Procit had been updated to include revised dosage guidelines and information on the drugs' cardiovascular side effects. The modifications followed the Food and Drug Administration's (FDA) ordering of a black box warning-the strongest drug labeling-about cardiovascular problems and other safety. Amgen manufactures all three medications although Johnson & Johnson sells Procrit under a licensing agreement.  The drugs are part of a class of drugs known as erythropoiesis-stimulating agents (ESAs) that treat anemia in patients with kidney disease or certain cancers by boosting red blood cells.  Several studies linked the drugs to cardiovascular problems and deaths and have been tied to worsening tumors when used in cancer patients.  Soon after Epogen was introduced, some doctors attempted to use it to increase patients' hemoglobin-the part of the blood cell that carries oxygen-to levels as high as those in healthy patients (14). Two clinical trials showed the large dosage required to reach these levels could lead to heart problems and death and the black box warning cautioned doctors that the medications should be administered at the lowest dose possible to bring blood counts to the lowest level needed to avoid transfusions.  The modified black box warning now has more specific dosing information and states dosing should be individualized.  For kidney patients, the revised warning read that patients experienced greater risks for death and serious cardiovascular events when administered ESAs to target higher versus lower hemoglobin levels in two clinical studies' rather than the more generic warning that risks were seen when hemoglobin levels of greater than 12 were target.  Following the revised black box warning, Medicare announced it would not pay for Aranesp, Epogen and Procrit in patients whose hemoglobin levels were at 10 grams per deciliter.

Erythropoietin is in a class of drugs known as erythropoiesis-stimulating agents, or ESAs, which are intended to reduce the need for red blood cell transfusions in patients suffering from anemia. (Transfusions are considered a high-risk treatment.) The drug was initially approved for patients suffering from kidney failure, but its approved usage was expanded in 1993 to include cancer patients who were suffering from chemotherapy-induced anemia.

However, in a briefing document released by the FDA ahead of the meeting, the agency said, "Based on data provided to the FDA, there is no evidence that ESAs improve quality of life or cancer outcomes" in these chemotherapy patients. They also note that "data continue to accumulate regarding the increased risks of mortality and of possible tumor promotion from the use of ESAs." They cite a number of recent studies that have found "increased mortality" in ESA patients with cancer. "Given the data from recent clinical studies," the document notes, "it is appropriate to re-assess the safety of ESAs in patients with cancer and to re-evaluate the net clinical benefit of ESAs in this setting."

"As of March 2007," the FDA says, "there are five randomized clinical trials that demonstrated decreased survival times in cancer patients receiving ESAs compared with those receiving transfusion support. There are three randomized studies that demonstrate poorer tumor outcomes in cancer patients receiving ESAs compared with those receiving transfusion support." The FDA also noted that the risks of blood transfusions have lessened significantly since 1993, when it first approved ESAs for use in chemotherapy patients.

In light of these findings, the advisory committee voted to ban the use of these drugs on patients with certain types of cancer. The committee also recommended placing greater restrictions on its overall usage, including stopping the use of ESAs once chemotherapy treatments are over. The committee unanimously decided that more studies were necessary because most of the previous research was conducted on patients receiving higher than recommended dosages of the drug.

There are about a million cancer patients receiving chemotherapy in the Unites States every year, and nearly half of them receive ESAs to treat chemotherapy-induced anemia. When the drugs were approved for use in anemic cancer patients in 1993, their effects on overall survival rates and on tumor promotion were not tested at all. The only test at the time was to see whether or not the drugs reduced the need for blood transfusions.

Over-prescription of Procrit, Aranesp, and a third drug, Epogen, has become a major health-care problem in the United States. In March, a warning was added to labels to make sure that only the minimum dosage necessary to avoid transfusions would be prescribed. "Recently completed studies describe an increased risk of death, blood clots, strokes, and heart attacks in patients with chronic kidney failure when ESAs were given at higher than recommended doses," the FDA said in March. "In other studies, more rapid tumor growth occurred in patients with head and neck cancer who received these higher doses.

"In studies where ESAs were given at recommended doses, an increased risk of death was reported in patients with cancer who were not receiving chemotherapy and an increased risk of blood clots was observed in patients following orthopedic surgery."

The labeling change was the fourth time in the past decade that the products' label warnings were forced to be updated. At the time, Dr. Steven Galson, director of FDA's Center for Drug Evaluation and Research, said, "The new studies provide significant new information for both prescribers and patients, and the new information applies to all ESAs, which share the same mechanism of action. The safety of these products will be discussed when the Oncologic Drugs Advisory Committee (ODAC) meets in May and further revisions to the labeling may occur after that meeting." A meeting addressing the risks of ESAs on kidney patients will take place later this year.

ESAs are "genetically engineered forms of the naturally occurring human protein, erythropoietin." Erythropoietin is produced by the kidneys and increases red-blood-cell levels. Currently, the FDA has only approved these drugs for treating anemia in patients with chronic kidney failure and in patients whose anemia is a result of chemotherapy. Combined domestic sales of ESAs reached approximately $10 billion last year alone. Anemia drugs are currently Medicare's largest drug expenditure.

The Food and Drug Administration's outside panel of experts voted overwhelmingly in favor of expanding warnings about the risks of death, blood clots and other side effects for Amgen's Aranesp and Johnson & Johnson's Procrit.

Wall Street analysts said prior to the meeting that the biggest threat to the revenue the companies get from these drugs would be if panelists wanted to add warning labels that would limit prescribing the drugs to certain patients.

A drop in anemia drug sales would pose a much larger challenge to biotech maker Amgen than to diversified competitor Johnson & Johnson. Last year Aranesp was Amgen's best-selling product with sales of $4.1 billion, or nearly 30 percent of full-year revenue. When combined with Epogen, a version of the drug used only in kidney failure patients on dialysis, the medication accounts for more than half of Amgen's annual sales.

The panel of experts, at a meeting in a hotel here, also voted unanimously that the companies should be required to conduct new studies to definitively prove the safety of the two widely prescribed drugs. Anemia drugs accounted for $10 billion in revenue for these two companies last year alone.

The FDA is not required to follow the panel's recommendations although it typically does.

Johnson & Johnson and Amgen have conducted more than a dozen studies of the drugs to date although panelists Thursday said what is needed is a large, comprehensive study of whether people who take the drugs die sooner than those who don't.

In March, the FDA ordered warnings be added to the drugs' labels after recent studies showed using the drugs outside of approved guidelines could increase the growth of tumors and the risk of death in some patients.

It was not made clear during Thursday's meeting whether the additional warnings favored by panelists would apply to all uses of the drugs or just non-approved use.

Many physicians prescribe anemia drugs aggressively to raise their patients' red blood cell levels to that of a healthy person, believing the higher red blood cell levels improves quality of life.

In presentations to the panel Thursday, FDA staff focused on four studies suggesting overprescribing or prescribing for unapproved uses could in fact increase a patient's risk of death.

Still, a majority of panelists voted against requesting that product packaging be changed to recommended lower dosing levels.

"We will be working with the FDA as they consider the committee's recommendations," said Amgen spokeswoman Tricia Hawkins.

A spokeswoman for Johnson & Johnson stressed that the company has not seen negative side effects from its drug when used as directed.

"When used according to the label, Procrit is safe and effective, and has an acceptable risk-benefit profile," said J&J's Stephanie Fagan.

Aranesp and Procrit are man-made versions of a naturally occurring protein that increases production of red blood cells. The drugs are approved to treat the blood disorder anemia when it is caused by chemotherapy and kidney disease.

FDA's meeting did not address use of the drugs in kidney patients. The agency said it would hold a seperate meeting on that issue in the fall.

Aftershocks from the newest recommendations could be felt later this year as the Center for Medicare and Medicaid Services reconsiders when and how much it pays for anemia drugs. The agency, which provides health care to more than 80 million Americans, has said it will use FDA's analysis of the drugs' safety in its reassessment.

Medicare officials have already told local plan providers they can stop paying for Aranesp and Procrit when used in cancer patients who are not on chemotherapy because that use is not government approved. Amgen said last month that action alone would probably cost the company $500 million in sales this year.

While it's difficult to predict what additional payment changes might be made, analysts worry the agency could stop paying for the drugs under certain circumstances. Medicare officials are scheduled to release preliminary guidelines in September.

• doctors monitor patients' levels of red blood cells and use the lowest possible dose to avoid the need for blood transfusions.
• doctors and patients carefully weigh the risks of using anemia drugs vs. the risk of a transfusion if anemia gets too bad.

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