Pediatrics — Data from a placebo-controlled clinical trial in pediatric patients did not establish efficacy of Xigris (see PRECAUTIONS and Clinical Studies), therefore no dosage recommendation can be made for pediatric patients with severe sepsis.

Drug-Drug Interactions — In a randomized, double-blind, placebo-controlled trial in adult patients with severe sepsis (XPRESS), co-administration of Xigris (24 mcg/kg/hr for 96 hours) and prophylactic heparin (enoxaparin 40 mg every 24 hours or unfractionated sodium heparin 5000 U every 12 hours administered subcutaneously) did not alter the clearance and steady-state concentrations of Xigris. No dosage adjustment of Xigris is recommended when co-administered with prophylactic heparin.

Clinical Studies

Study 1

The efficacy of Xigris was studied in an international, multi-center, randomized, double-blind, placebo-controlled trial (PROWESS) of 1690 patients with severe sepsis.¹ Entry criteria included a systemic inflammatory response presumed due to infection and at least one associated acute organ dysfunction. Acute organ dysfunction was defined as one of the following: cardiovascular dysfunction (shock, hypotension, or the need for vasopressor support despite adequate fluid resuscitation); respiratory dysfunction (relative hypoxemia (PaO₂/FiO₂ ratio < 250)); renal dysfunction (oliguria despite adequate fluid resuscitation); thrombocytopenia (platelet count < 80,000/mm³ or 50% decrease from the highest value the previous 3 days); or metabolic acidosis with elevated lactic acid concentrations. Patients received a 96-hour infusion of Xigris at 24 mcg/kg/hr or placebo starting within 48 hours after the onset of the first sepsis induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours, and 89% of patients received study drug within 24 hours after onset of the first organ dysfunction. Exclusion criteria encompassed patients at high risk for bleeding (see CONTRAINDICATIONS and WARNINGS: Bleeding), patients who were not expected to survive for 28 days due to a pre-existing, non-sepsis related medical condition, HIV positive patients whose most recent CD₄ count was ≤ 50/mm³, patients on chronic dialysis, and patients who had undergone bone marrow, lung, liver, pancreas, or small bowel transplantation.

The primary efficacy endpoint was all-cause mortality assessed 28 days after the start of study drug administration. Prospectively defined subsets for mortality analyses included groups defined by APACHE II score² (a score designed to assess risk of mortality based on acute physiology and chronic health evaluation, see http://www.sfar.org/scores2/scores2.html), protein C activity, and the number of acute organ dysfunctions at baseline. The APACHE II score was calculated from physiologic and laboratory data obtained within the 24-hour period immediately preceding the start of study drug administration irrespective of the preceding length of stay in the Intensive Care Unit.

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