Source: European Medicines Agency (EU) Revision Year: 2012 Publisher: Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA, Houten, The Netherlands
Pharmacotherapeutic group: antithrombotic agents, enzymes
ATC code: B01AD10
This medicinal product has been authorised under “Exceptional Circumstances”. This means that for scientific reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.
Xigris is a recombinant version of the natural plasma-derived activated Protein C, from which it differs only by unique oligosaccharides in the carbohydrate portion of the molecule. Activated Protein C is a crucial coagulation regulator. It limits thrombin formation by inactivating factors Va and VIIIa, thereby providing negative feedback regulation of coagulation. Excessive coagulation activation in the microcirculatory bed plays a significant part in the pathophysiology of severe sepsis. Furthermore, Activated Protein C is an important modulator of the systemic response to infection and has antithrombotic and profibrinolytic properties. Xigris has similar properties to those of endogenous human Activated Protein C.
In placebo-controlled clinical trials in patients with severe sepsis, Xigris exerted an antithrombotic effect by limiting thrombin generation and improved sepsis-associated coagulopathy, as shown by a more rapid improvement in markers of coagulation and fibrinolysis. Xigris caused a more rapid decline in thrombotic markers such as D-dimer, prothrombin F1.2, and thrombin-antithrombin levels and a more rapid increase in Protein C and antithrombin levels. Xigris also restored endogenous fibrinolytic potential, as evidenced by a more rapid trend toward normalisation in plasminogen levels and a more rapid decline in plasminogen activator inhibitor-1 levels. Additionally, patients with severe sepsis treated with Xigris had a more rapid decline in interleukin-6 levels, a global marker of inflammation, consistent with a reduction in the inflammatory response.
Xigris was studied in one Phase 3 international, multi-centre, randomised, double-blind, placebo- controlled trial (PROWESS) in 1690 patients with severe sepsis. Severe sepsis is defined as sepsis associated with acute organ dysfunction. Patients meeting the clinical diagnosis of severe sepsis had a) known or suspected infection, b) clinical evidence of systemic response to infection including fever or hypothermia, leucopenia or leucocytosis, tachycardia and tachypnoea, and c) acute organ dysfunction. Organ dysfunction was defined as shock, hypotension or the need for vasopressor support despite adequate fluid resuscitation, relative hypoxemia (ratio of partial pressure of oxygen in arterial blood in mmHg to the percentage of oxygen in the inspired air expressed as a decimal (PaO2/FiO2 ratio) <250), oliguria despite adequate fluid resuscitation, marked reduction in blood platelet counts, and/or elevated lactic acid concentrations.
Exclusion criteria encompassed patients at high risk of bleeding (see sections 4.3 and 4.4), 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/mm³, patients on chronic dialysis, and patients who had undergone bone marrow, lung, liver, pancreas or small bowel transplantation, and patients with acute clinical pancreatitis without a proven source of infection.
In the PROWESS trial, treatment was initiated within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours. Patients were given a 96-hour constant rate infusion of Xigris at 24 μg/kg/hr (n=850) or placebo (n=840). Xigris was added to best standard care. Best standard care includes adequate antibiotics, source control and supportive treatment (fluids, inotropes, vasopressors and support of failing organs, as required).
Patients treated with Xigris experienced improved 28-day survival compared to those treated with placebo. At 28 days, the overall mortality rates were 24.7% for the Xigris-treated group and 30.8% for the placebo-treated group (p=0.005).
Significant absolute death reduction was limited to the subgroup of patients with greater disease severity i.e. baseline APACHE II score ≥25 or at least 2 acute organ dysfunctions at baseline. (The APACHE II score is designed to assess the risk of mortality based on acute physiology and chronic health evaluation). In the subgroup of patients with an APACHE II score ≥25 at baseline, the mortality was 31% in the Xigris group (128 out of 414) and 44% in the placebo group (176 out of 403). No death reduction was observed in the subgroup of patients with lower disease severity. In the subgroup of patients with at least 2 acute organ dysfunctions at baseline, the mortality was 26.5% in the Xigris group (168 out of 634) and 33.9% in the placebo group (216 out of 637). No significant death reduction was observed in the subgroup of patients with less than 2 acute organ dysfunctions at baseline.
A consistent treatment effect on mortality with Xigris administration was observed across patient subgroups defined by age, gender and infection type.
Survival status was assessed in a follow-up study of PROWESS survivors. In-hospital and 3 month survival status was reported for 98% and 94% of the 1690 PROWESS subjects respectively. In the overall population, the in-hospital mortality was significantly lower in patients on Xigris than in patients on placebo (29.4% vs. 34.6%; p=0.023). Survival through 3 months was also better in the Xigris group compared to placebo (log rank p=0.048). These data confirmed that the benefit of Xigris is limited to the more severely affected sepsis patients such as patients with multiple organ failure and shock.
In a Phase 3b international, single-arm, open-label clinical trial (ENHANCE), 2378 adult patients with severe sepsis received drotrecogin alfa (activated). The entry criteria were similar to those employed in PROWESS. Patients received drotrecogin alfa (activated) within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 25 hours. At 28 days, the mortality rate in the Phase 3b study was 25.3%. The mortality rate was lower for patients treated within 24 hours of organ dysfunction compared to those treated after 24 hours, even after adjustment for differences in disease severity.
A total of 2640 adult patients with severe sepsis who were at low risk of death (e.g. patients with APACHE II<25 or with only one sepsis-induced organ failure) were enrolled in a randomised, double- blind, placebo-controlled trial (ADDRESS). The trial was stopped for futility after an interim analysis. No benefit of drotrecogin alfa (activated) was observed in the subgroup of 872 patients at low risk of death with multiple organ dysfunction, so ADDRESS did not confirm the efficacy results of the PROWESS study. In the multiple organ dysfunction subgroup of ADDRESS the 28-day placebo mortality was 21.9%, similar to the single organ dysfunction subgroup of PROWESS (21.2%), confirming the lack of efficacy in patients with severe sepsis who are at low risk of death.
Xigris is contraindicated in children below the age of 18 years (see also sections 4.2 and 4.3). Data from a placebo-controlled clinical trial (RESOLVE) did not establish efficacy of Xigris in paediatric patients suffering from severe sepsis, acute infection, systemic inflammation and respiratory and cardiovascular organ dysfunction. This trial was stopped for futility after 477 patients had received the study drug (out of 600 patients intended). A planned interim analysis (with 400 patients enrolled) showed a low likelihood of demonstrating a significant difference in the primary endpoint of “Composite Time to Complete Organ Failure Resolution” (CTCOFR score of 9.8 versus 9.7 mean days over 14 days). There was also no difference in 28-day mortality (17.1% versus 17.3% in the Xigris and placebo groups, respectively).
Investigators attributed 2 deaths in the Xigris group and 5 deaths in the placebo group to bleeding events. There was a higher rate of central nervous system (CNS) bleeding in the drotrecogin alfa (activated) versus the placebo group. Over the infusion period (study days 0-6) the number of patients experiencing CNS bleeding was 5 versus 1 (2.1% versus 0.4%) for the overall population (drotrecogin alfa (activated) versus placebo), with 4 of the 5 events in the drotrecogin alfa (activated) group occurring in patients ≤60 days old or ≤3.5 kg bodyweight. Fatal CNS bleeding events, serious bleeding events (over the infusion period and over the 28-day study period), serious adverse events, and major amputations were similar in the drotrecogin alfa (activated) and placebo groups.
In placebo controlled clinical trials, the treatment effect was most evident at sites enrolling larger numbers of patients.
Drotrecogin alfa (activated) and endogenous human Activated Protein C are inactivated in plasma by endogenous protease inhibitors but the mechanism by which they are cleared from plasma is unknown. Plasma concentrations of endogenous Activated Protein C in healthy subjects and patients with severe sepsis are usually below detection limits (<5 ng/ml) and do not significantly influence the pharmacokinetic properties of drotrecogin alfa (activated).
In healthy subjects, greater than 90% of the steady state condition is attained within 2 hours following the start of a constant-rate intravenous infusion of Xigris. Following the completion of an infusion, the decline in plasma drotrecogin alfa (activated) concentrations is biphasic and is comprised of a rapid initial phase (t½α=13 minutes) and a slower second phase (t½β=1.6 hours). The short half-life of 13 minutes accounts for approximately 80% of the area under the plasma concentration curve and governs the initial rapid accrual of plasma drotrecogin alfa (activated) concentrations towards the steady-state. Plasma drotrecogin alfa (activated) steady-state concentrations are proportional to the infusion rate over a range of infusion rates from 12 μg/kg/hr to 48 μg/kg/hr. The mean steady-state plasma concentration of drotrecogin alfa (activated) in healthy subjects receiving 24 μg/kg/hr is 72 ng/ml.
In patients with severe sepsis, infusion of drotrecogin alfa (activated) from 12 μg/kg/hr to 30 μg/kg/hr rapidly produced steady-state plasma concentrations that were proportional to infusion rates. In the Phase 3 trial, the pharmacokinetics of drotrecogin alfa (activated) were evaluated in 342 patients with severe sepsis administered a 96-hour continuous infusion at 24 μg/kg/hr. The pharmacokinetics of drotrecogin alfa (activated) were characterised by attainment of steady-state plasma concentration within 2 hours following the start of the infusion. In the majority of patients, measurements of Activated Protein C beyond 2 hours after termination of the infusion were below the quantifiable limit, suggesting rapid elimination of drotrecogin alfa (activated) from the systemic circulation. The plasma clearance of drotrecogin alfa (activated) is approximately 41.8 l/hr in sepsis patients as compared with 28.1 l/hr in healthy subjects.
In patients with severe sepsis, the plasma clearance of drotrecogin alfa (activated) was significantly decreased by renal impairment and hepatic dysfunction, but the magnitude of the differences in clearance (<30%) does not warrant any dosage adjustment.
Changes observed in monkeys at, or in small excess of, the maximum human exposure during repeated dose studies, were all related to the pharmacological effect of Xigris and include beside the expected prolongation of APTT, decreases in haemoglobin, erythrocytes and haematocrit, and increases in reticulocyte count and PT.
Drotrecogin alfa (activated) 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.
Carcinogenicity studies and animal reproduction studies have not been conducted with Xigris. However, with respect to the latter, the potential risk for humans being unknown, Xigris should not be used during pregnancy unless clearly necessary (see section 4.6).
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