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Xigris (Drotrecogin Alfa (Activated)) - Warnings and Precautions




Bleeding is the most common serious adverse reaction experienced by patients receiving Xigris. Each patient being considered for therapy with Xigris should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy.

Certain conditions, many of which led to exclusion from Study 1 [see Clinical Studies ], are likely to increase the risk of bleeding with Xigris therapy. For individuals with one or more of the following conditions, the increased risk of bleeding should be carefully considered when deciding whether to use Xigris therapy:

  • Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolic event [see Drug Interactions]
  • Platelet count <30,000 x 106/L, even if the platelet count is increased after transfusions
  • Prothrombin time-INR >3.0
  • Recent (within 6 weeks) gastrointestinal bleeding
  • Recent administration (within 3 days) of thrombolytic therapy
  • Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors
  • Recent administration (within 7 days) of aspirin >650 mg per day or other platelet inhibitors
  • Recent (within 3 months) ischemic stroke [see Contraindications (4)]
  • Intracranial arteriovenous malformation or aneurysm
  • Known bleeding diathesis
  • Chronic severe hepatic disease
  • Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location

Should clinically important bleeding occur, immediately stop the infusion of Xigris. Continued use of other agents affecting the coagulation system should be carefully assessed. Once adequate hemostasis has been achieved, continued use of Xigris may be reconsidered.

Mortality in Patients with Single Organ Dysfunction and Recent Surgery

In Study 1, among the small number of patients with single organ dysfunction and recent surgery (surgery within 30 days prior to study treatment), all-cause mortality was numerically higher in the Xigris group (28-day: 10/49; in-hospital: 14/48) compared with the placebo group (28-day: 8/49; in-hospital: 8/47).

In an analysis of the subset of patients with single organ dysfunction and recent surgery from Study 2, which enrolled septic patients not at high risk of death, all-cause mortality was also higher in the Xigris group (28-day: 67/323; in-hospital: 76/325) compared with the placebo group (28-day: 44/313; in-hospital: 62/314). Single organ dysfunction patients with recent surgery may not be at high risk of death irrespective of APACHE II score. Therefore, these patients may not be among the indicated population.

Patients on Prophylactic Heparin when Xigris is Initiated

Clinicians should consider continuing heparin for venous thromboembolism (VTE) prophylaxis when initiating Xigris, unless discontinuation is medically necessary. In a randomized study of prophylactic heparin versus placebo in 1935 adult severe sepsis patients treated with Xigris, mortality and the rate of serious adverse events were increased in the subgroup of 434 patients whose heparin was stopped on study entry by randomization to placebo-plus-Xigris. This finding was based on prospectively defined exploratory subgroup analyses; however, the explanation for the finding is unclear. The safety of prophylactic heparin when concomitantly administered with Xigris in adult patients with severe sepsis was evaluated with low molecular weight heparin enoxaparin (40 mg every 24 hours) and unfractionated sodium heparin (5000 U every12 hours), but was not evaluated with unfractionated sodium heparin 5000 U when dosed every 8 hours [see Clinical Studies ].

Invasive Procedures

Invasive procedures increase the risk for bleeding with Xigris. Such procedures, including arterial and central venous punctures, should be minimized during the Xigris infusion. Puncture of a noncompressible site should be avoided during the infusion. Xigris should be discontinued 2 hours prior to undergoing an invasive surgical procedure or procedures with an inherent risk of bleeding. Once adequate hemostasis has been achieved, Xigris may be restarted 12 hours after surgery and major invasive procedures or immediately after uncomplicated less invasive procedures.

Laboratory Tests for Coagulopathy

Most patients with severe sepsis have a coagulopathy that is commonly associated with prolongation of the activated partial thromboplastin time (APTT) and the prothrombin time (PT). The activated partial thromboplastin time (APTT) cannot be reliably used to assess the degree of the coagulopathy during Xigris infusion since Xigris variably prolongs the APTT [see Drug Interactions].

The prothrombin time (PT) may be used to monitor the degree of the coagulopathy in patients treated with Xigris because Xigris has minimal effect on the PT [see Drug Interactions ].

Drotrecogin alfa (activated) present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as factor VIII, IX, and XI assays). This interference will result in a measured factor concentration that is lower than the actual concentration. Drotrecogin alfa (activated) present in plasma samples does not interfere with one-stage factor assays based on the PT (such as factor II, V, VII, and X assays) [see Drug Interactions].



Pregnancy Category C Animal reproduction studies have not been conducted with Xigris. It is also not known whether Xigris can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. In published case reports, there were no major malformations or other adverse outcomes reported following treatment with Xigris during pregnancy. Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Xigris should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether drotrecogin alfa (activated) is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Xigris, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

A placebo-controlled trial in pediatric patients (Study 3) did not establish safety and effectiveness of Xigris in the pediatric patient population [see Indications and Usage and Clinical Studies].

Geriatric Use

In Study 1, which evaluated 1690 patients with severe sepsis, 48 percent were 65 years and over, while 23 percent were 75 and over. No overall difference in safety was observed between these patients and younger patients. Reduction in mortality was observed in both geriatric and younger patients.

Page last updated: 2008-10-29

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