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Xigris Powder for Intravenous Infusion (Lilly)
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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.
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.
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 mcg/kg/hr treatment group.
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 mcg/kg/hr to 30 mcg/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.
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 mcg/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 mcg/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% versus 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 (Study 1)
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).
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 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 futility. 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.
INDICATIONS AND USAGE
Xigris is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (e.g., as determined by APACHE II, see CLINICAL STUDIES ).
Xigris is not indicated in adult patients with severe sepsis and lower risk of death ( see CLINICAL STUDIES ). Safety and efficacy have not been established in pediatric patients with severe sepsis.
Xigris increases the risk of bleeding. Xigris is contraindicated in patients with the following clinical situations in which bleeding could be associated with a high risk of death or significant morbidity:
Xigris is contraindicated in patients with known hypersensitivity to drotrecogin alfa (activated) or any component of this product.
Bleeding is the most common serious adverse effect associated with Xigris therapy. 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 the Phase 3 trial, 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:
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.
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, initiation of Xigris may be reconsidered 12 hours after major invasive procedures or surgery or restarted immediately after uncomplicated less invasive procedures.
Mortality in Patients with Single Organ Dysfunction and Recent Surgery
Among the small number of patients enrolled in PROWESS 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 to 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 a separate, randomized, placebo-controlled study (ADDRESS) of septic patients at high risk of death all-cause mortality was also higher in the Xigris group (28-day: 67/323; in-hospital: 76/325) compared to the placebo group (28-day: 44/313; in-hospital: 62/314). Patients with single organ dysfunction and recent surgery may not be at high risk of death irrespective of APACHE II score and therefore not among the indicated population.
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). Xigris may variably prolong the APTT. Therefore, the APTT cannot be reliably used to assess the status of the coagulopathy during Xigris infusion. Xigris has minimal effect on the PT and the PT can be used to monitor the status of the coagulopathy in these patients.
As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Xigris has not been adequately determined, as the assay sensitivity is inadequate to reliably detect all potential antibody responses. One patient in the Phase 2 trial developed antibodies to Xigris without clinical sequelae. One patient in the Phase 3 trial who developed antibodies to Xigris developed superficial and deep vein thrombi during the study, and died of multi-organ failure on day 36 post-treatment but the relationship of this event to antibody is not clear.
Xigris has not been readministered to patients with severe sepsis.
Drug interaction studies with Xigris have not been performed in patients with severe sepsis. However, since there is an increased risk of bleeding with Xigris, caution should be employed when Xigris is used with other drugs that affect hemostasis ( see CLINICAL PHARMACOLOGY , WARNINGS ). Approximately 2/3 of the patients in the Phase 3 study received either prophylactic low dose heparin (unfractionated heparin up to 15,000 units/day) or prophylactic doses of low molecular weight heparins as indicated in the prescribing information for the specific products. Concomitant use of prophylactic low dose heparin did not appear to affect safety, however, its effects on the efficacy of Xigris have not been evaluated in an adequate and well-controlled clinical trial.
Drug/Laboratory Test Interaction
Because Xigris may affect the APTT assay, Xigris 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 may result in an apparent factor concentration that is lower than the true concentration. Xigris 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).
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.
Pregnancy Category C
Animal reproductive studies have not been conducted with Xigris. It is not known whether Xigris can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Xigris should be given to pregnant women only if clearly needed.
It is not known whether Xigris is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of Xigris have not been established in the age group newborn (38 weeks gestational age) to 18 years. The efficacy of Xigris in adult patients with severe sepsis and high risk of death cannot be extrapolated to pediatric patients with severe sepsis.
In clinical studies evaluating 1821 patients with severe sepsis, approximately 50% of the patients were 65 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.
Bleeding is the most common adverse reaction associated with Xigris.
In the Phase 3 study, serious bleeding events were observed during the 28-day study period in 3.5% of Xigris-treated and 2.0% of placebo-treated patients, respectively. The difference in serious bleeding between Xigris and placebo occurred primarily during the infusion period and is shown in Table 2. 1 Serious bleeding events were defined as any intracranial hemorrhage, any life-threatening bleed, any bleeding event requiring the administration of >/=3 units of packed red blood cells per day for 2 consecutive days, or any bleeding event assessed as a serious adverse event.
In PROWESS, 2 cases of intracranial hemorrhage (ICH) occurred during the infusion period for Xigris-treated patients and no cases were reported in the placebo patients. The incidence of ICH during the 28-day study period was 0.2% for Xigris-treated patients and 0.1% for placebo-treated patients. ICH has been reported in patients receiving Xigris in non-placebo controlled trials with an incidence of approximately 1% during the infusion period. The risk of ICH may be increased in patients with risk factors for bleeding such as severe coagulopathy and severe thrombocytopenia ( see WARNINGS ).
In PROWESS, 25% of the Xigris-treated patients and 18% of the placebo-treated patients experienced at least one bleeding event during the 28-day study period. In both treatment groups, the majority of bleeding events were ecchymoses or gastrointestinal tract bleeding.
Other Adverse Reactions
Patients administered Xigris as treatment for severe sepsis experience many events which are potential sequelae of severe sepsis and may or may not be attributable to Xigris therapy. In clinical trials, there were no types of non-bleeding adverse events suggesting a causal association with Xigris.
There is no known antidote for Xigris. In case of overdose, immediately stop the infusion and monitor closely for hemorrhagic complications ( see Human Pharmacokinetics ).
In postmarketing experience there been a limited number of medication error reports of excessive rate of Xigris infusion for short periods of time (median 2 hours). No unexpected adverse events were observed during the overdose period. However, this information is insufficient to assess whether Xigris overdose is associated with an increased hemorrhage risk beyond that observed with Xigris administered at the recommended dose.
DOSAGE AND ADMINISTRATION
Xigris should be administered intravenously at an infusion rate of 24 mcg/kg/hr (based on actual body weight) for a total duration of infusion of 96 hours. Dose adjustment based on clinical or laboratory parameters is not recommended ( see PRECAUTIONS ).
If the infusion is interrupted, Xigris should be restarted at the 24 mcg/kg/hr infusion rate. Dose escalation or bolus doses of Xigris are not recommended.
In the event of clinically important bleeding, immediately stop the infusion ( see WARNINGS ).
Preparation and Administration Instructions:
Dilution and Administration Instructions for an Intravenous Infusion Pump Using an Infusion Bag:
Dilution and Administration Instructions for a Syringe Pump:
Xigris is available in 5 mg and 20 mg single-use vials containing sterile, preservative-free, lyophilized drotrecogin alfa (activated).
5 mg Vials
20 mg Vials
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.
Literature revised June 23, 2005
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