Update on drotrecogin alfa (Xigris®) and increased risk of bleeding

The HSA Pharmacovigilance Branch would like to bring to the attention of healthcare professionals a recent retrospective study that revealed an increase risk of death and serious bleeding events in patients with baseline bleeding tendencies treated with drotrecogin alfa (XigrisÒ, Eli Lilly)

Xigris® is a recombinant form of human activated Protein C, licensed in Singapore for the reduction of mortality in adult patients with severe sepsis (i.e. sepsis associated with acute organ dysfunction) who have a high risk of death. It has been registered in Singapore since August 2002.

Results from recent retrospective study

In February 2009, the US Food and Drug Administration (FDA) issued an early safety communication¹ about its ongoing safety review of Xigris®. The investigation stemmed from the results of a retrospective medical record review published in a recent issue of Critical Care Medicine. ² This review was aimed at assessing the safety of Xigris® when used in patients with or without baseline bleeding risk factors. Findings from this review shed some light on the safety profile of drotrecogin alfa when used in patients with specific baseline bleeding risk factors, since this group of patients was excluded in earlier key clinical trials involving drotrecogin alfa. Seventy-three patients who received drotrecogin alfa from two tertiary care institutions between 2002 and 2005 were reviewed, regardless of whether they met indications according to product labeling or clinical practice guidelines.

The study revealed that serious bleeding events occurred in seven of 20 patients (35%) who were predisposed to bleeding tendencies (such as recent oral anticoagulant or platelet inhibitor therapy, severe hepatic disease, use of heparin, platelet count < 30,000/mm³, recent gastrointestinal bleed and recent thrombolytic therapy) vs. only two of 53 (3.8%) patients without any bleeding tendencies. However, there were no clear trends by type of baseline bleeding risk factors and type or incidence of serious bleeding event. More patients with bleeding risk factors died (13 out of 20; 65%) compared with patients without any risk factors for bleeding (13 out of 53; 24.5%).

In response to the above finding of an increased risk of death and serious bleeding events in patients with baseline bleeding risk factors treated with Xigris®, FDA is working with Eli Lilly to further evaluate the incidence of serious bleeding events and mortality in patients who receive Xigris®. In the meantime, the US FDA and Eli Lilly have recommended that prescribers carefully weigh the increased risk of bleeding against the benefits of Xigris® when using this drug.

Safety findings from earlier studies

Apart from the recent study described above, there had been other studies that investigated the risk of mortality associated with Xigris® in other specific patient groups. It is noteworthy that these trials excluded patients at high risk of bleeding.

Xigris® was approved by the FDA after the international, multicentre, randomized, double blind, placebo trial of 1,690 patients with severe sepsis, Recombinant Human Activated PROtein C Worldwide Evaluation in Severe Sepsis (PROWESS), demonstrated a significant reduction in mortality at 28 days, in patients receiving Xigris® compared to placebo (24.7% vs 30.8%, p=0.005).³ Upon exploratory subgroup analysis, significant absolute death reduction was found to be limited to the subgroup of patients with greater disease severity, i.e. baseline APACHE II score >25 or at least 2 acute organ dysfunctions at baseline but not in the subgroup of patients with lower disease severity.⁴

Following the approval of Xigris®, ADDRESS⁵ (Administration of Drotrecogin Alfa in Early Stage Severe Sepsis), which investigated the efficacy and safety of drotrecogin alfa (activated) in adult patients with early stage severe sepsis (i.e. a lower risk of death), was conducted. It. This study was terminated early based on a low likelihood of detecting statistically significant reduction in the 28-day mortality in patients at low risk of death from sepsis. A post hoc analysis of the ADDRESS clinical trial database and reanalysis of the PROWESS clinical trial database were carried out. The results of these analyses showed higher 28-day and in-hospital mortality (within 90 days after the start of infusion) and increased serious bleeding events in drotrecogin alfa patients with single organ dysfunction and recent surgery within 30 days prior to study treatment than those who received placebo.

In 2005, the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE)⁶ trial was stopped following a numerical increase in the rate of central nervous system (CNS) bleeding in the Xigris® versus the placebo group. Over the six-day infusion period, the number of patients experiencing CNS bleeding was five versus one (2.1% drotrecogin alfa versus 0.4% placebo). Fatal CNS bleeding events, serious bleeding events, serious adverse events and major amputations were similar in the drotrecogin alfa and placebo groups. Xigris® is not indicated for use in paediatric patients with severe sepsis.

Local Situation

To date, HSA has received one suspected local ADR report of diffuse cerebral haemorrhage in a 62 year old male, probably related to the use of Xigris® for severe sepsis. The adverse event occurred a day after Xigris® was administered at a therapeutic dose of 1.55mg/hr for 96 hours. It is not known if the patient had presdisposing risk factors for bleeding.

In light of the new data from the recent retrospective study, healthcare professionals are encouraged to carefully weigh the benefits versus risk of using Xigris® in patients predisposed to bleeding. Healthcare professionals are also encouraged to report suspected adverse drug reactions associated with drotrecogin alfa to the Pharmacovigilance Branch of HSA.

References

1. FDA Early Safety Communication about ongoing safety review of Xigris

2. Crit Care Med 2009;37(1):19-25.

3. New Eng J Med, Vol. 344, No. 10:699-709.

4. http://www.fda.gov/CDER/drug/early_comm/drotrecogin_alfa.html APACHE II score >25. The APACHE II score (Acute Physiology and Chronic Health Evaluation II) is a commonly-used severity of disease classification system calculated for critically ill patients after admission to an intensive care unit.

5. New Eng J Med, Vol. 353, No.13: 1332-1341.

6. European Public Assessment Report. Procedural steps taken and scientific information after the authorisation of Xigris®.http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-en8b.pdf