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Xigris is a brand name for Drotrecogin Alfa. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Xigris is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The use of Xigris should be considered mainly in situations when therapy can be started within 24 hours after the onset of organ failure (for further information see section 5.1).
Verbatim from this product's EMA label. Tap a section to expand.
Xigris should be used by experienced doctors in institutions skilled in the care of patients with severe sepsis. 1). The recommended dose of Xigris is 24 μg/kg/hr (based on actual body weight) given as a continuous intravenous infusion for a total duration of 96 hours.
It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. If the infusion is interrupted for any reason, Xigris should be restarted at the 24 μg/kg/hr infusion rate and continued to complete the full recommended 96 hours of dosing administration.
Dose escalation or bolus doses of Xigris are not necessary to account for the interruption in the infusion. No dose adjustments are required in adult patients with severe sepsis with regard to age, gender, hepatic function (as measured by transaminase levels), renal function, obesity or co-administration of prophylactic heparin.
The pharmacokinetics of drotrecogin alfa (activated) have not been studied in patients with severe sepsis and pre-existing end stage renal disease and chronic hepatic disease.
Paediatrics:
Data from a placebo-controlled clinical trial which was stopped for futility after 477 patients 0 to 17 years-old had received the study treatment did not establish efficacy of Xigris in Medicinal product no longer authorised3 paediatric patients and showed a higher rate of central nervous system bleeding in the Xigris versus placebo group.
1).
Xigris increases the risk of bleeding. The Phase 3 international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (PROWESS) involved 850 drotrecogin alfa (activated)-treated and 840 placebo-treated patients.
7%, respectively. In both treatment groups, the majority of bleeding events were ecchymosis or gastrointestinal tract bleeding. The difference in the incidence of serious bleeding events between the two treatment groups occurred primarily during study drug administration.
A total of 2378 adult patients with severe sepsis received drotrecogin alfa (activated) in a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE). The incidence of serious bleeding events in the PROWESS and ENHANCE studies is provided below.
In these studies serious bleeding events included any intracranial haemorrhage, any life-threatening or fatal 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 serious by the investigator.
Medicinal product no longer authorised6 A Phase 3b international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (ADDRESS) of adult severe sepsis patients at low risk of death, involved 1317 drotrecogin alfa (activated)-treated and 1293 placebo-treated patients.
001). Bleeding events included serious bleeding events, bleeding events assessed as possibly study-drug related by the investigator, bleeding events associated with the need for a red blood cell transfusion, and bleeding events that led to permanent discontinuation of the study drug.
In the ADDRESS trial, serious bleeding events included any fatal bleed, any life-threatening bleed, any CNS bleed, or any bleeding event assessed as serious by the investigator. Serious bleeding events during the infusion period The following table lists the percent of patients in PROWESS and ENHANCE experiencing serious bleeding events by site of haemorrhage during the study drug infusion period (defined as the duration of infusion plus the next full calendar day following the end of the infusion).
No further study has confirmed the efficacy results of the single pivotal trial. Patients with single organ dysfunction and recent surgery Xigris is not approved for the treatment of patients with single organ dysfunction and should not be used in this particular subgroup of patients, especially if they had recent surgery (within 30 days).
1), 28- day and in-hospital mortality were higher in patients treated with drotrecogin alfa (activated) compared to placebo for the sub-population of patients with single organ dysfunction and recent surgery (n=98 in PROWESS and n=636 in ADDRESS).
Bleeding Drotrecogin alfa (activated) increases the risk of bleeding. In the following conditions, the risks of the administration of Xigris should be weighed against the anticipated benefits: • Recent administration (within 3 days) of thrombolytic therapy • Recent administration (within 7 days) of oral anticoagulants • Recent administration (within 7 days) of aspirin or other platelet inhibitors • Recent (within 3 months) ischaemic stroke • Any other condition in which the physician considers significant bleeding is likely Medicinal product no longer authorised4 For procedures with an inherent bleeding risk, discontinue Xigris for 2 hours prior to the start of the procedure.
Xigris may be restarted 12 hours after major invasive procedures or surgery if adequate haemostasis has been achieved. 8). Bleeding risk should be taken into account when considering the risk benefit for individual patients. Xigris may be restarted immediately after uncomplicated less invasive procedures if adequate haemostasis has been achieved.
, activated partial thromboplastin time (APTT), prothrombin time (PT) and platelet count) should be obtained during the infusion of Xigris. If sequential tests of haemostasis indicate an uncontrolled or worsening coagulopathy that significantly increases the risk of bleeding, the benefits of continuing the infusion must be weighed against the potential increased risk of bleeding for that patient.
Hypersensitivity to the active substance, to any of the excipients or to bovine thrombin (a trace residue from the manufacturing process). 1). Because drotrecogin alfa (activated) may increase the risk of bleeding, Xigris is contraindicated in the following situations: • Active internal bleeding • Patients with intracranial pathology; neoplasm or evidence of cerebral herniation • Concurrent heparin therapy ≥ 15 International Units/kg/hr • Known bleeding diathesis except for acute coagulopathy related to sepsis • Chronic severe hepatic disease • Platelet count < 30,000 x 106/l, even if the platelet count is increased after transfusions • Patients at increased risk for bleeding (for example): a) any major surgery, defined as surgery that requires general or spinal anesthesia, performed within the 12-hour period immediately preceding drug infusion, or any postoperative patient who demonstrates evidence of active bleeding, or any patient with planned or anticipated surgery during the drug infusion period.
b) history of severe head trauma that required hospitalization, intracranial or intraspinal surgery, or haemorrhagic stroke within the previous 3 months, or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion; patients with an epidural catheter or who are anticipated to receive an epidural catheter during drug infusion c) history of congenital bleeding diatheses d) gastrointestinal bleeding within the last 6 weeks that has required medical intervention unless definitive surgery has been performed e) trauma patients at increased risk of bleeding
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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6%) 1 CNS bleeding is defined as any bleed in the central nervous system including the following types of haemorrhage: Petechial, parenchymal, subarachnoid, subdural, and stroke with haemorrhagic transformation. 2Patients requiring the administration of ≥ 3 units of packed red blood cells per day for 2 consecutive days without an identified site of bleeding 3 In ENHANCE six patients experienced multiple serious bleeding events during the study drug infusion period (94 events observed in 85 patients).
1% respectively. 2% respectively). In ADDRESS, the percent of treated patients experiencing a serious bleeding event by site of haemorrhage was similar to that observed in PROWESS. 02). 2%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively.
9% respectively). 3% on both arms). 0116). 0% in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. 1% for drotrecogin alfa (activated)- treated and placebo-treated patients, respectively. 4). 5%. In the placebo-controlled ADDRESS study, the incidence of serious […]
Laboratory tests Drotrecogin alfa (activated) has minimal effect on the PT. Prolongation of the APTT in patients with severe sepsis receiving Xigris may be due to the underlying coagulopathy, the pharmacodynamic effect of drotrecogin alfa (activated), and/or the effect of other concurrent medicinal products.
The pharmacodynamic effect of drotrecogin alfa (activated) on the APTT assay is dependent on the reagent and instrument used to perform the assay and the time that elapses between sample acquisition and assay performance. Drotrecogin alfa (activated) that is present in a blood or plasma sample drawn from a patient who is being infused with the drug will be gradually neutralized by endogenous plasma protease inhibitors present in the sample.
Virtually no measurable activity of drotrecogin alfa (activated) is present 2 hours after obtaining the blood sample. Due to these biological and analytical variables, the APTT should not be used to assess the pharmacodynamic effect of drotrecogin alfa (activated).
In addition, approximately 2 hours after terminating the infusion of the drug, there is virtually no measurable activity of drotrecogin alfa (activated) remaining in the circulation of the patient; blood samples drawn for APTT determination after this point are no longer affected by the drug.
The interpretation of sequential determinations of the PT and/or APTT should take these variables into consideration. Because drotrecogin alfa (activated) may affect the APTT assays, drotrecogin alfa (activated) present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as factor VIII, IX, and XI assays).
Drotrecogin alfa (activated) present in plasma samples does not interfere with one-stage factor assays based on the PT (such as Factors II, V, VII and X assays). If sequential measures of coagulopathy (including platelet count) indicate severe or worsening coagulopathy, the risk of continuing the infusion should be weighed against the expected benefit.
Immunogenicity In adult patients in severe sepsis clinical studies, the frequency of anti-human Activated Protein C IgA/IgG/IgM antibodies or neutralizing antibodies is low and is similar between drotrecogin alfa (activated) and placebo-treated patients tested.
In patients developing antibodies adverse events were not more frequent in drotrecogin alfa (activated) than in placebo patients. There was no evidence that the antibodies detected represented a specific immune response to drotrecogin alfa (activated) therapy.
There have been no clinical trials in severe sepsis specifically studying drotrecogin alfa (activated) re- administration. However, a small number of patients in severe sepsis controlled clinical trials received a prior course of drotrecogin alfa (activated).
No hypersensitivity reactions were reported in these patients. Samples available were subsequently tested and all were negative for anti-human Activated Protein C antibody. No anti-activated Protein C antibody formation was detected in healthy subjects, even after repeat administration.
However, the possibility of allergic reactions to constituents of the preparation cannot be completely excluded in certain predisposed patients. If allergic or anaphylactic reactions occur, treatment should be discontinued immediately and appropriate therapy initiated.
If Xigris is readministered to patients, caution should be employed. Medicinal product no longer authorised5 This medicinal product contains approximately 68 mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.