US FDA probing deaths in German study involving J&J's anti-anemia drugs

Preliminary results from a German study suggest that stroke patients' use of anti-anemia drugs such as Aranesp, Procrit and Epogen might end up boosting their risk for death, the US Food and Drug Administration (FDA) warned on Friday.

The goal of the study was to see if high doses of the anti-anemia drug Eprex could improve the ability of stroke patients to take care on their own after recovering from a stroke. The hope was that the drug would be neuroprotective, but use of Eprex now appears linked to a near doubling of mortality.

Eprex is known generically as epoetin alfa. Johnson & Johnson sells epoetin alfa under the name Procrit. Amgen Inc also sells a version under the name Epogen. The blockbuster drugs are part of a class called erythropoiesis-stimulating agents (ESAs), which are approved for treating patients with kidney disease and cancer.

Preliminary safety findings in the 522-patient trial revealed that 16 per cent of those treated with epoetin alfa died within 90 days of the start of treatment compared with 9 per cent in the placebo group. About half of the deaths in both groups occurred within the first seven days of treatment. Intracranial hemorrhage was the cause of death in 4 per cent of the patients in the active drug arm; it accounted for death in 1 per cent of controls.

This is not the first time that these drugs have come under scrutiny. In the US, medications like Procrit were marketed heavily as anemia treatments, particularly for cancer patients and those with kidney failure. However, in July of this year, the FDA called on manufacturers of Aranesp and Procrit to add a warning label that could limit their use for cancer patients.

This is mentioned in the latest statement put out on the FDA's website which says, ''On April 22, 2008, FDA notified the manufacturer of Epogen/Procrit and Aranesp of its decision to require additional safety-related changes to the labeling for these products.''

These changes were spurred by studies that showed these types of medications might cause tumors to spread and also raise patients' risks for bleeding. These findings resulted in an FDA advisory committee recommending in June that while the drugs should remain on the market, they should not be used in patients whose cancer is curable. The committee also voted to recommend against the drugs' use in patients with breast or head and neck cancer.

The aforementioned statement mentions, ''FDA's action to require these safety labeling changes follows the completion of the review of information received in November 2007 and December 2007 and are in keeping with the recommendations made at the March 13, 2008 Oncologic Drugs Advisory Committee meeting. Amgen has been ordered to make the additional changes under new authorities provided in the FDA Amendments Act of 2007 and has 5 days to appeal or 15 days to submit a supplement containing the labeling changes.''

"These drugs are not licensed in the United States for this particular use," noted Dr. Kathy Robie-Suh, a team leader in the division of medical imaging and hematology at the Center for Drug Evaluation and Research, part of the FDA's Office of New Drugs and Office of Drug Safety.

"The drug has been approved for about 19 years for treating anemia in patients with acute renal [kidney] failure and in other settings," Robie-Suh said. "Today's warning doesn't have any bearing on the particular label uses of the product in the United States," she said.

The FDA noted that treatment of anemia was not a goal of the German study and most of the patients in the study were not anemic. Moreover, the doses used in the trial "were considerably higher than the doses recommended for the treatment of anemia as described in the FDA-approved labeling for the product."

The FDA said it was "aware of other clinical trials using epoetin alfa for potential neuroprotective effects" and that the results from the German trial suggested that patients in those ongoing trials should be closely monitored for adverse outcomes.

Based on the German findings, the FDA said those ongoing trials should be re-evaluated to determine "whether the potential benefits for enrolled patients outweigh the risks in these trials." The FDA said that it expects to receive more data on the study "within the next several weeks," and when the agency's analysis is complete it will "communicate our conclusions and recommendations to the public."

Friday's FDA notice was issued after Ortho Biotech - the division of the pharmaceutical giant Johnson and Johnson, which makes Procrit - alerted the agency to the results of the German trial. According to J&J spokesman Mark Wolfe, the study was initiated by the researcher, with the company providing funding and supplies of the drug but was not involved in the trial's design or conduct.

"Ortho Biotech has become aware of preliminary data from an investigator-initiated experimental study of the effects of Epoetin alfa in patients with acute ischemic stroke," the company said in a 17 September statement. "Ortho Biotech has reported this information to the US Food and Drug Administration and to European regulatory authorities. Additional analyses are under way to better understand these preliminary results."