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Xigris (Drotrecogin Alfa (Activated)) - Description and Clinical Pharmacology



Xigris (drotrecogin alfa (activated)) is a recombinant form of human activated protein C. An established human cell line possessing the complementary DNA for the inactive human protein C zymogen secretes the protein into the fermentation medium. Fermentation is carried out in a nutrient medium containing the antibiotic geneticin sulfate. Geneticin sulfate is not detectable in the final product. Human protein C is enzymatically activated by cleavage with thrombin and subsequently purified.

Drotrecogin alfa (activated) is a serine protease with the same amino acid sequence as human plasma-derived activated protein C. Drotrecogin alfa (activated) is a glycoprotein of approximately 55 kilodalton molecular weight, consisting of a heavy chain and a light chain linked by a disulfide bond. Drotrecogin alfa (activated) and human plasma-derived activated protein C have the same sites of glycosylation, although some differences in the glycosylation structures exist.

Xigris is supplied as a sterile, lyophilized, white to off-white powder for intravenous infusion. The 5 and 20 mg vials of Xigris contain 5.3 mg and 20.8 mg of drotrecogin alfa (activated), respectively. The 5 and 20 mg vials of Xigris also contain 40.3 and 158.1 mg of sodium chloride, 10.9 and 42.9 mg of sodium citrate, and 31.8 and 124.9 mg of sucrose, respectively.


Mechanism of Action

Activated protein C exerts an antithrombotic effect by inhibiting Factors Va and VIIIa. In vitro data indicate that activated protein C may have indirect profibrinolytic activity through its ability to inhibit plasminogen activator inhibitor-1 (PAI-1) and may exert an anti-inflammatory effect by limiting the chemotactic response of leukocytes to inflammatory cytokines, an inhibitory process mediated by leukocyte cell surface activated protein C receptor. In addition, in vivo data suggest activated protein C may reduce interactions between leukocytes and the microvascular endothelium. In vitro bacterial phagocytosis by neutrophils and monocytes is not affected.


The specific pharmacologic effects by which Xigris exerts its effect on survival in patients with severe sepsis are not completely understood. In patients with severe sepsis, Xigris infusions of 48 or 96 hours produced dose-dependent declines in D-dimer and IL-6. Compared with placebo, Xigris-treated patients experienced more rapid declines in D-dimer, PAI-1 levels, thrombin-antithrombin levels, prothrombin F1.2, IL-6, more rapid increases in protein C and antithrombin levels, and normalization of plasminogen. As assessed by infusion duration, the maximum observed pharmacodynamic effect of drotrecogin alfa (activated) on D-dimer levels occurred at the end of 96 hours of infusion for the 24 mcg/kg/hr treatment group.


Drotrecogin alfa (activated) and endogenous activated protein C are inactivated by endogenous plasma protease inhibitors. Plasma concentrations of endogenous activated protein C in healthy subjects and patients with severe sepsis are usually below detection limits.

In patients with severe sepsis, Xigris infusions of 12 mcg/kg/hr to 30 mcg/kg/hr produce steady-state concentrations (Css) that are proportional to infusion rates. In Study 1 [see Clinical Studies ], the median clearance of drotrecogin alfa (activated) was 40 L/hr (interquartile range of 27 to 52 L/hr) in adults with severe sepsis. The median Css of 45 ng/mL (interquartile range of 35 to 62 ng/mL) was attained within 2 hours after starting the infusion. In the majority of patients, plasma concentrations of drotrecogin alfa (activated) fell below the assay's quantitation limit of 10 ng/mL within 2 hours after stopping the infusion. Plasma clearance of drotrecogin alfa (activated) in patients with severe sepsis is approximately 50% higher than that in healthy subjects.

Specific Populations:

Patients with Renal Impairment Patients with end stage renal disease requiring chronic renal replacement therapy were excluded from Study 1 [see Clinical Studies]. In patients without sepsis undergoing hemodialysis (n=6), plasma clearance (mean ± SD) of drotrecogin alfa (activated) administered on non-dialysis days was 30 ± 8 L/hr. Plasma clearance of drotrecogin alfa (activated) was 23 ± 4 L/hr in patients without sepsis undergoing peritoneal dialysis (n=5). These clearance rates did not meaningfully differ from those in normal healthy subjects (28 ± 9 L/hr) (n=190). No dosage adjustment is necessary for patients with renal impairment requiring hemodialysis or peritoneal dialysis.

Other Subpopulations In adult patients with severe sepsis, small differences were detected in the plasma clearance of drotrecogin alfa (activated) with regard to age, gender, hepatic impairment, and obesity. No dose adjustment is required based on these factors alone or in combination.

Drug Interactions:

Prophylactic Heparin In a randomized, double-blind, placebo-controlled trial in adult patients with severe sepsis (Study 4), coadministration 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 drotrecogin alfa (activated). No dosage adjustment of Xigris is recommended when coadministered with prophylactic heparin [see Clinical Studies].


Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate potential carcinogenicity of Xigris have not been performed.

Xigris was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or without rat liver metabolic activation.

The potential of Xigris to impair fertility has not been evaluated in male or female animals.


Study 1: Treatment of Adult Severe Sepsis Patients

The efficacy of Xigris was studied in an international, multi-center, randomized, double-blind, placebo-controlled trial (“PROWESS”) of 1690 patients with severe sepsis. 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 and Precautions ], patients who were not expected to survive for 28 days due to a preexisting, 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.

All-cause mortality was assessed 28 days after the start of study drug administration. Prospectively defined subsets for mortality analyses included groups defined by APACHE II score [see References]  (a score designed to assess risk of mortality based on a cute p hysiology a nd c hronic h ealth e valuation), 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.

The study was terminated after a planned interim analysis due to significantly lower mortality in patients on Xigris than in patients on placebo. At 28 days, the overall mortality rates were 25% for the Xigris-treated group and 31% for the placebo-treated group (p=0.005) (see Table 3).

Baseline APACHE II score was correlated with risk of death; among patients receiving placebo, those with the lowest APACHE II scores had a 12% mortality rate, while those in the 2nd, 3rd, and 4th APACHE quartiles had mortality rates of 26%, 36%, and 49%, respectively. The observed mortality difference between Xigris and placebo was limited to the half of patients with higher risk of death, i.e., APACHE II score ≥25, the 3rd and 4th quartile APACHE II scores, where the 28-day mortality rates were 31% for the Xigris-treated group and 44% for the placebo-treated group (p=0.0002) (see Table 3). The efficacy of Xigris has not been established in patients with lower risk of death, e.g., APACHE II score <25.

Table 3: 28-Day All-Cause Mortality for All Patients and for Subgroups Defined by APACHE II Score in Study 1

a Total N=Total number of patients in group.

XigrisPlaceboAbsolute Mortality Difference (%)Relative Risk (RR)95% CI for RR
Total NaDeathsTotal NaDeaths
Overall 850210 (25%)840259 (31%)-60.810.70, 0.93
APACHE II quartile (score)
1st + 2nd (3-24) 43682 (19%)43783 (19%)00.990.75, 1.30
3rd + 4th (25-53) 414128 (31%)403176 (44%)-130.710.59, 0.85

Of measures used, the APACHE II score was most effective in classifying patients by risk of death within 28 days and by likelihood of benefit from Xigris, but other important indicators of risk or severity also supported an association between likelihood of Xigris benefit and risk of death. For patients with 1, 2, 3, and 4 or more organ dysfunctions, absolute reductions in mortality of 2%, 5%, 8%, and 11% with Xigris were observed (relative risk of 0.92, 0.80, 0.76, and 0.78, respectively).

Similarly, each of the three major components of the APACHE II score (acute physiology score, chronic health score, age score) identified a higher risk population with larger mortality differences associated with treatment. That is, the reduction in mortality was greater in patients with more severe physiologic disturbances, in patients with serious underlying disease predating sepsis, and in older patients.

Treatment-associated reductions in mortality were observed in patients with normal protein C levels and those with low protein C levels. No substantial differences in Xigris treatment effects were observed in subgroups defined by gender, ethnic origin, or infectious agent.

Long-Term Follow-up of Patients in Study 1

The one-year survival status was provided for 93% of the 1690 Study 1 subjects. For patients with APACHE II score ≥25, mortality was lower for the Xigris group compared with the placebo group through 90 days (41% versus 52%; RR: 0.72, 95% CI: 0.59-0.88) and through 1 year (48% versus 59%; RR: 0.73, 95% CI: 0.60-0.88).

However, for patients with APACHE II score <25, mortality was higher for the Xigris group compared with the placebo group through 90 days (27% versus 25%; RR: 1.09, 95% CI: 0.84-1.42) and through 1 year (35% versus 28%; RR: 1.24, 95% CI: 0.97-1.58).

Study 2: Benefit Not Demonstrated in Treatment of Adult Severe Sepsis Patients Not at High Risk of Death

A randomized, double-blind, placebo-controlled trial (“ADDRESS”) of Xigris (96-hour infusion of Xigris at 24 mcg/kg/hr) was performed in adult patients with severe sepsis who were not at high risk of death. Most patients had APACHE II score <25 or only one sepsis-induced organ failure. The study was stopped at an interim analysis after enrollment of 2640 patients due to no observed benefit. All-cause mortality at 28 days after randomization was 18% (243/1333) in patients randomized to Xigris and 17% (221/1307) in patients randomized to placebo (RR: 1.08, 95% CI: 0.91-1.27).

The results of Studies 1 and 2 do not provide evidence of benefit of Xigris in patients with severe sepsis who are not at high risk of death (e.g., patients with single-organ dysfunction or APACHE II score <25). Xigris is not indicated for such patients.

Study 3: Benefit Not Demonstrated in Treatment of Pediatric Severe Sepsis Patients

A randomized, double-blind, placebo-controlled trial (“RESOLVE”) of Xigris (96-hour infusion at 24 mcg/kg/hr) was conducted in 477 pediatric patients with severe sepsis (age limits ≥38 weeks corrected gestational age to <18 years). Patients were required to have both sepsis-induced cardiovascular and respiratory organ dysfunction (defined as treatment with vasoactive agents despite adequate fluid resuscitation and invasive mechanical ventilation).

The study was stopped after a planned interim analysis showed Xigris was unlikely to show statistically significant improvement over placebo, a composite endpoint based on time to resolution of organ dysfunction (cardiovascular, respiratory, and renal), incorporating also unresolved organ dysfunction and mortality.

Central nervous system bleeding occurred in a greater number of Xigris-treated patients during the 28-day study period; this difference was most pronounced in patients aged 60 days or younger (≤60 days: 4/24 Xigris-treated patients versus 0/26 placebo-treated patients; >60 days: 7/216 Xigris-treated patients versus 5/211 placebo-treated patients).

All-cause mortality at 28 days was similar in the Xigris and placebo groups, as were the rates of all serious bleeding events, all serious adverse events, fatal CNS bleeding events, and major amputations.

The results of this study do not provide evidence of benefit of Xigris in pediatric patients with severe sepsis.

Study 4: Coadministration of Heparin for VTE Prophylaxis in Xigris-Treated Patients

A randomized, double-blind, placebo-controlled trial (“XPRESS”) investigated the safety of heparin for VTE prophylaxis when concomitantly administered with Xigris (96-hour infusion at 24 mcg/kg/hr) in adult patients with severe sepsis who were at high risk of death (n=1935).

Patients were randomized 1:1:2 to receive low molecular weight heparin enoxaparin (40 mg every 24 hours), unfractionated sodium heparin (5000 U every 12 hours), or placebo administered concomitantly with the Xigris infusion. The XPRESS trial did not evaluate the safety of dosing unfractionated heparin every 8 hours in adult patients with severe sepsis when concomitantly administered with Xigris. Outside the Xigris treatment period (prior to study entry and following Xigris infusion), the use of commercially available heparin was left to the discretion of the investigator.

The 28-day all-cause mortality was similar between the heparin-plus-Xigris group (enoxaparin and unfractionated heparin combined) and placebo-plus-Xigris group (28.2%, 275/976, and 31.8%, 305/959, respectively; RR: 0.89, 95% CI: 0.77-1.02). There were no significant differences between the heparin-plus-Xigris and placebo-plus-Xigris groups in the rate of either venous thrombotic or serious bleeding events, including intracranial hemorrhage. Prophylactic heparin increased the risk of non-serious bleeding compared with placebo over the treatment period of 0-6 days. The rate of ischemic stroke was lower in the heparin-plus-Xigris group over days 0-6 (heparin-plus-Xigris 3/976, 0.3% versus placebo-plus-Xigris, 12/959, 1.3%).

In the subgroup of 889 patients receiving commercially available heparin at study entry, those patients randomized to placebo had higher mortality [placebo-plus-Xigris 35.5% (154/434) versus heparin-plus-Xigris 26.8% (122/455)] and higher rate of serious adverse events [placebo-plus-Xigris 18.0% (78/434) versus heparin-plus-Xigris 11.6% (53/455)] compared with patients in whom commercial heparin was replaced by study heparin [see Warnings and Precautions]. Increased serious adverse events in this subgroup included cardiac, gastrointestinal, and venous thrombotic events. In patients not receiving commercial heparin at study entry, mortality and the rate of serious adverse events were similar between heparin-plus-Xigris and placebo-plus-Xigris groups.

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