FDA Safety Changes: Sepsis Drug Withdrawn From All Markets

Activated drotrecogin alfa is a recombinant form of human activated protein C. It was approved by the US Food and Drug Administration (FDA) nearly a decade ago to lower mortality rates in adults with severe sepsis and high mortality risk.
However, the efficacy of activated drotrecogin alfa has always been controversial. The original vote by the FDA advisory panel that recommended approval was 20 to 20. As of 2007, trials had failed to replicate favorable results from the pivotal Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study.
Eli Lilly is withdrawing activated drotrecogin alfa (Xigris), a drug intended to treat severe sepsis in high-risk patients, from all markets including the United States in the wake of a new study showing that the agent did no better than a placebo in reducing mortality risk.
The European Medicines Agency (EMA), the European equivalent of the FDA, announced on October 25 that the manufacturer had informed it of the decision to pull activated drotrecogin alfa from the market worldwide, as well as discontinue all ongoing clinical trials involving the drug.
The EMA stated that clinicians should stop ongoing treatment of patients with activated drotrecogin alfa and should no longer prescribe the agent to new patients — a warning repeated by the FDA.
The FDA announcement was also part of a worldwide voluntary market withdrawal of activated drotrecogin alfa. The agency warned that the drug should not be started in new patients and should be stopped in patients currently receiving the drug. Also, it has mandated that all remaining Xigris products be returned to the supplier.
Activated drotrecogin alfa is a recombinant form of human activated protein C. The drug’s efficacy has been questioned ever since the FDA authorized its use in the United States almost 10 years ago.
In an October 25 press release, the EMA stated that its Committee for Medicinal Products for Human Use had concluded in 2007 that ongoing studies could not reproduce the initial efficacy results reported by a pivotal clinical trial called the PROWESS trial. The committee asked the manufacturer to conduct a new test to confirm that "the benefits of Xigris outweigh its risks to patients with septic shock."
The new study, called PROWESS-SHOCK, reported a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study, according to the EMA, which did not deem the difference statistically significant. The risk for severe bleeding events, the main risk of the drug, was 1.2% and 1.0% for the activated drotrecogin alfa and placebo groups, respectively, "suggesting there is no increased harm." In contrast, a study published in 2009 had reported an increased risk for serious bleeding events and death in patients with sepsis who were treated with the drug.
Previous Study Findings: 2009
The 2009 study was a retrospective medical record review of 73 patients who received activated drotrecogin alfa (Gentry CA, Gross KB, Sud B, Drevets DA: Adverse outcomes associated with the use of drotrecogin alfa (activated) in patients with severe sepsis and baseline bleeding precaution. Crit Care Med. 2009;37:19-25).
Among 20 patients with risk factors of bleeding, serious bleeding events occurred in 7 patients (35%) vs only 2 (3.8%) of 53 patients without any bleeding risk factors. Mortality rate was 65% for patients with baseline risk factors of bleeding (13 of 20 patients) and 24.5% for patients without any bleeding risk factors at baseline (13 of 53 patients).
Definitive conclusions could not be drawn from these data because of study limitations including retrospective design and small sample size.
Baseline bleeding risk factors in this study were the same as described in the Contraindications and Warnings and Precautions sections of the Xigris package insert:
• Active internal bleeding
• Recent hemorrhagic stroke (within 3 months)
• Recent intracranial or intraspinal surgery (within 2 months), or severe head trauma
• Trauma with an increased risk of life-threatening bleeding
• Presence of an epidural catheter
• Intracranial neoplasm or mass lesion or evidence of cerebral herniation
More information about the withdrawal of activated drotrecogin alfa is available on the Web sites of the EMA andFDA.
News Author: Robert Lowes
Laurie Barclay, MD, contributed to this synopsis.
Source: Medscape

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