Drotrecogin alfa (activated)

Drotrecogin Alfa (activated) is used in the treatment of:

• Sepsis

Drotrecogin Alfa (activated) is used in the prevention of:

• Shock, Septic

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

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.

General Pharmacology

Activated Protein C exerts an antithrombotic effect by inhibiting Factors Va and VIIIa. In vitro data indicate that Activated Protein C has indirect profibrinolytic activity through its ability to inhibit plasminogen activator inhibitor-1 (PAI-1) and limiting generation of activated thrombin-activatable-fibrinolysis-inhibitor. Additionally, in vitro data indicate that Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor production by monocytes, by blocking leukocyte adhesion to selectins, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium.

Pharmacodynamics

The specific mechanisms 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 to 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 µg/kg/hr treatment group.

Human Pharmacokinetics

Xigris 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 µg/kg/hr to 30 µg/kg/hr rapidly produce steady state concentrations (C ss ) that are proportional to infusion rates. In the Phase 3 trial ( see CLINICAL STUDIES ), the median clearance of Xigris was 40 L/hr (interquartile range of 27 to 52 L/hr). The median C ss of 45 ng/mL (interquartile range of 35 to 62 ng/mL) was attained within 2 hours after starting infusion. In the majority of patients, plasma concentrations of Xigris fell below the assay's quantitation limit of 10 ng/mL within 2 hours after stopping infusion. Plasma clearance of Xigris in patients with severe sepsis is approximately 50% higher than that in healthy subjects.

Special Populations

In adult patients with severe sepsis, small differences were detected in the plasma clearance of Xigris with regard to age, gender, hepatic dysfunction or renal dysfunction. Dose adjustment is not required based on these factors alone or in combination ( see PRECAUTIONS ).

End stage renal disease --Patients with end stage renal disease requiring chronic renal replacement therapy were excluded from the Phase 3 study. In patients without sepsis undergoing hemodialysis (n=6), plasma clearance (mean ± SD) of Xigris administered on non-dialysis days was 30 ± 8 L/hr. Plasma clearance of Xigris 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).

Pediatrics --Safety and efficacy have not been established in pediatric patients with severe sepsis ( see INDICATIONS AND USAGE ), therefore no dosage recommendation can be made. The pharmacokinetics of a dose of 24 µg/kg/hr of Xigris appear to be similar in pediatric and adult patients with severe sepsis.

Drug-Drug Interactions --Formal drug interactions studies have not been conducted.

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 (PaO 2 /FiO 2 ratio <250)); renal dysfunction (oliguria despite adequate fluid resuscitation); thrombocytopenia (platelet count <80,000/mm 3 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 µg/kg/hr or placebo starting within 48 hours after the onset of the first sepsis induced organ dysfunction. Exclusion criteria encompassed patients at high risk for bleeding ( see CONTRAINDICATIONS and WARNINGS ), 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 CD 4 count was </=50/mm 3 , 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 score 2 (a score designed to assess risk of mortality based on a cute p hysiology a nd c hronic h ealth e valuation, 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.

The study was terminated after a planned interim analysis due to significantly lower mortality in patients on Xigris than in patients on placebo (210/850, 25% vs. 259/840, 31% p=0.005, see Table 1).

Baseline APACHE II score, as measured in PROWESS, 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 (Table 1). The efficacy of Xigris has not been established in patients with lower risk of death, e.g., APACHE II score <25.

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. Absolute reductions in mortality of 2%, 5%, 8% and 11% with Xigris were observed for patients with 1, 2, 3, and 4 or more organ dysfunctions, 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

The one-year survival status was provided for 93% of the 1690 PROWESS subjects. For patients with APACHE II score >/=25, mortality was lower for the Xigris group compared to 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 to 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).

Xigris is available in 5 mg and 20 mg single-use vials containing sterile, preservative-free, lyophilized drotrecogin alfa (activated).

Vials:

5 mg Vials

  NDC 0002-7559-01

20 mg Vials

  NDC 0002-7561-01

Xigris should be stored in a refrigerator 2° to 8°C (36° to 46°F). Do not freeze. Protect unreconstituted vials of Xigris from light. Retain in carton until time of use. Do not use beyond the expiration date stamped on the vial.

1. Bernard GR, et al. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis. N Engl J Med. 2001;344:699-709
2. Knaus WA, et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-29

Literature revised November 14, 2003

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