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Xigris

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Xigris

Xigris

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

The specific pharmacologic effects by which Xigris (drotrecogin alfa) exerts its effect on survival in patients with severe sepsis are not completely understood. In patients with severe sepsis, Xigris (drotrecogin alfa) infusions of 48 or 96 hours produced dose-dependent declines in D-dimer and IL-6. Compared with placebo, Xigris (drotrecogin alfa) -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.

Pharmacokinetics

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 (drotrecogin alfa) 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 (drotrecogin alfa) (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 (drotrecogin alfa) is recommended when coadministered with prophylactic heparin [see Clinical Studies].

Clinical Studies

Study 1: Treatment of Adult Severe Sepsis Patients

The efficacy of Xigris (drotrecogin alfa) 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 (drotrecogin alfa) 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 acute physiology and chronic health evaluation), 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 (drotrecogin alfa) than in patients on placebo. At 28 days, the overall mortality rates were 25% for the Xigris (drotrecogin alfa) -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 (drotrecogin alfa) 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 (drotrecogin alfa) -treated group and 44% for the placebo-treated group (p=0.0002) (see Table 3). The efficacy of Xigris (drotrecogin alfa) 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

Xigris Placebo Absolute Mortality Difference (%) Relative Risk (RR) 95% CI for RR
Total Na Deaths Total Na Deaths
Overall 850 210 (25%) 840 259 (31%) -6 0.81 0.70, 0.93
APACHE II quartile (score)
1st + 2nd (3-24) 436 82 (19%) 437 83 (19%) 0 0.99 0.75, 1.30
3rd + 4th (25-53) 414 128 (31%) 403 176 (44%) -13 0.71 0.59, 0.85
a Total N=Total number of patients in group.

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 (drotrecogin alfa) , but other important indicators of risk or severity also supported an association between likelihood of Xigris (drotrecogin alfa) 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 (drotrecogin alfa) 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 (drotrecogin alfa) 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 (drotrecogin alfa) 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 (drotrecogin alfa) 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 (drotrecogin alfa) (96-hour infusion of Xigris (drotrecogin alfa) 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 (drotrecogin alfa) 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 (drotrecogin alfa) 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 (drotrecogin alfa) 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 (drotrecogin alfa) (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 (drotrecogin alfa) 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 (drotrecogin alfa) -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 (drotrecogin alfa) -treated patients versus 0/26 placebo-treated patients; > 60 days: 7/216 Xigris (drotrecogin alfa) -treated patients versus 5/211 placebo-treated patients).

All-cause mortality at 28 days was similar in the Xigris (drotrecogin alfa) 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 (drotrecogin alfa) in pediatric patients with severe sepsis.

Study 4: Coadministration of Heparin for VTE Prophylaxis in Xigris (drotrecogin alfa) -Treated Patients

A randomized, double-blind, placebo-controlled trial (“XPRESS”) investigated the safety of heparin for VTE prophylaxis when concomitantly administered with Xigris (drotrecogin alfa) (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 (drotrecogin alfa) 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 (drotrecogin alfa) . Outside the Xigris (drotrecogin alfa) treatment period (prior to study entry and following Xigris (drotrecogin alfa) 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 (drotrecogin alfa) group (enoxaparin and unfractionated heparin combined) and placebo-plus-Xigris (drotrecogin alfa) 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 (drotrecogin alfa) and placebo-plus-Xigris (drotrecogin alfa) 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 (drotrecogin alfa) group over days 0-6 (heparin-plus-Xigris (drotrecogin alfa) 3/976, 0.3% versus placebo-plus-Xigris (drotrecogin alfa) , 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 (drotrecogin alfa) 35.5% (154/434) versus heparin-plus-Xigris (drotrecogin alfa) 26.8% (122/455)] and higher rate of serious adverse events [placebo-plus-Xigris (drotrecogin alfa) 18.0% (78/434) versus heparin-plus-Xigris (drotrecogin alfa) 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 (drotrecogin alfa) and placebo-plus-Xigris (drotrecogin alfa) groups.

REFERENCES

Knaus WA, et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-829.

Last reviewed on RxList: 9/1/2009
This monograph has been modified to include the generic and brand name in many instances.

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