Staff Writers

Amgen Inc. headed off worse damage from Friday's news of the "black box" label warning for the firm's flagship red-blood cell boosters Aranesp and Epogen by pointing out that problems arise mainly in cases where the drugs are given at levels beyond those approved, and such cases rarely occur.

Richard Pazdur, director of the FDA's Office of Oncology Drug Products, called for "discretion on the part of the treating physician." They are exercising it, at least according to data gathered by researchers of cancer physicians, published separately Friday.

The label change itself, accepted by the FDA, could make life easier for the company May 10, when Amgen will take part in the agency's Oncologic Drugs Advisory Committee meeting to further discuss EPO drug issues. Pazdur said regulators are looking more closely at the whole class.

New warnings also will apply to EPO drugs that the FDA has yet to approve, including continuous EPO receptor activator from Switzerland-based F. Hoffmann-La Roche Ltd., which could mean delays beneficial to Amgen.

Amgen's shares (NASDAQ:AMGN) dipped $1.31 on Friday, to $60.86, on word that updated label information lets patients know of death risks plus chances of cardiovascular events and tumor growth when the erythropoietin products are used in off-label dose regimens or populations.

All three drugs are approved to treat anemia in chronic kidney failure patients and those on chemotherapy for cancer. Epogen (epoetin alfa) and its counterpart Procrit, marketed by New Brunswick, N.J.-based Johnson & Johnson, also are cleared for patients scheduled for major surgery to reduce blood transfusions and for anemia in certain HIV patients.

According to the new warning, the drugs - when given to target a hemoglobin level of >12 g/dL - boosted the risk of death and cardiovascular events, cut the time to tumor progression in patients with advanced head and neck cancer who got radiation therapy and shortened overall survival while hiking deaths because of disease progression at four months in metastatic breast cancer patients getting chemo.

Death risk also went up, according to the warning, when the anemia-therapies were given to target a hemoglobin of 12 g/dL in patients with active malignant disease who are not getting chemo or radiation. That's a nonapproved use. Another group included in the warning is preoperative patients who want to reduce allogeneic blood transfusions and are not already on clotbusters.

Thousand Oaks, Calif.-based Amgen's label specifies starting treatment at hemoglobin levels <12 g/dL, withholding therapy if they reach 13 g/dL and continuing the drug at levels <13 g/dL.

Some had worried that Aranesp (darbepoetin alfa) is given to patients with hemoglobin >13 g/dL, or begun at levels >12 g/dL, but Amgen's claim to the contrary won backing from a data query of about 1,100 electronic medical records collected by Supportive Oncology Services, an information company in Memphis, Tenn.

The data, included in a report by Robert Baird & Co. in Chicago, show that mean hemoglobin levels at the first Aranesp treatment is 10.2 g/dL, and mean levels at subsequent dosing is 10.8 g/dL. Patients who began treatment with >12 g/dL proved minimal in the survey (1.9 percent), and only 2.3 percent of subsequent doses were given to patients with >13 g/dL. Similar numbers had been offered by Amgen, showing 98 percent of patients begin treatment at <12 g/dL and only 97 percent are treated again with >13g/dL.

"With this negligible off-label use in chemotherapy-induced anemia, we believe tighter FDA language regarding hemoglobin maintenance would have little effect on [sales]," wrote analyst Chris Raymond in the Baird report.

Bret Holley with CIBC World Markets in New York did not see much consequence in the label change, either, since they reflect findings in studies already disclosed. He allowed that "there could be some incremental reductions in overall EPO usage over the longer term," plus dosing vigilance and limits in the cancer-anemia setting. But Amgen's stock value "may be overly discounting doomsday scenarios" for EPO drugs, "given the totality of historical safety data and physician experiences with the drugs."

Pazdur said doctors generally would target hemoglobin levels of 10 g/dL. The changed label language reflects a revision to past thinking that "more is better" in terms of dosing, explained Karen Weiss, the oncology office's deputy director.

Verbiage also has been stripped from the products' labels for cancer use with regard to improving fatigue and other patient-reported outcomes. The FDA will further review quality-of-life claims in the kidney disease setting before determining whether to make any changes there. Meanwhile, a "dear doctor" letter will inform physicians of the changes.

Fourth-quarter 2006 worldwide sales of Aranesp hit about $1.1 billion, a 27 percent increase over the period last year. Full year sales reached $4.1 billion, a 26 percent increase over 2005. Epogen sold $661 million during the quarter, which marked an increase of 6 percent, partly offset by the growing use of Aranesp (the second-generation Epogen) in hospitals.