XIGRIS Powder for solution for infusion Ref.[9395] Active ingredients: Drotrecogin alfa

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). In each of two randomised, placebo-controlled trials, PROWESS and ADDRESS (see section 5.1), 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

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. The incidence of serious bleeding events with Xigris was higher in patients with recent [within 30 days] surgery than in “medical” patients without surgery (see section 4.8). 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.

As a component of routine care, measures of haemostasis (e.g., 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.

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.

This medicinal product contains approximately 68 mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Caution should be employed when Xigris is used with other drugs that affect haemostasis (see sections 4.3 and 4.4) including Protein C, thrombolytics (e.g. streptokinase, tPA, rPA and urokinase), oral anticoagulants (e.g. warfarin), hirudins, antithrombin, aspirin and other anti platelets agents, e.g. non- steroidal anti-inflammatory drugs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (such as abciximab, eptifibatide, tirofiban) and prostacyclins such as iloprost.

Co-administration of low-dose heparin for prophylaxis of venous thrombotic events (VTE)

Low-dose heparin for VTE prophylaxis may be co-administered with drotrecogin alfa (activated). In a randomised study of heparin versus placebo (XPRESS) in 1935 adult severe sepsis patients, all treated with drotrecogin alfa (activated), prophylactic heparin did not adversely affect mortality (heparin 28.3% versus placebo 31.9% in the overall ITT population, and heparin 30.3% versus placebo 26.9% in patients with multiple organ dysfunction treated within 24 hours of their first sepsis-induced organ dysfunction (n=890)). In the subgroup of 885 patients who were already receiving prophylactic heparin at study entry, mortality was 26.9% in the group randomised to continue heparin versus 35.6% in the group whose randomisation (to placebo) led to the discontinuation of heparin. However the reasons for this difference are unknown and could be related to other factors.

Additionally there was no increased risk of serious bleeding, including central nervous system (CNS) bleeding. Prophylactic heparin increased the risk of non-serious bleeding (see section 4.8). There was no statistical difference in the rates of VTE between study arms.

Animal studies with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development have not been conducted with Xigris. Therefore, the potential risk for humans is unknown. Xigris should not be used during pregnancy unless clearly necessary.

It is not known whether Xigris is excreted in human milk or if there is a potential effect on the breast-fed infant. Therefore, the patient should not breast feed whilst treated with Xigris.

Not relevant.

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. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 24.9% and 17.7%, 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.

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. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 10.9% and 6.4%, respectively (p<0.001). 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).

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.
² Patients 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).

During the infusion period in PROWESS and ENHANCE the incidence of serious bleeding events with Xigris was numerically higher in patients with recent [within 30 days] surgery than in patients without surgery (PROWESS: 3.3% vs 2.0%; ENHANCE: 5.0% vs 3.1% respectively. Placebo rates in PROWESS 0.4% vs 1.2% respectively).

In ADDRESS, the percent of treated patients experiencing a serious bleeding event by site of haemorrhage was similar to that observed in PROWESS. The incidence of serious bleeding events during infusion (defined as study Day 0 through study Day 6) was 31 (2.4%) and 15 (1.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (p=0.02). The incidence of CNS bleeds during infusion was 4 (0.3%) and 3 (0.2%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. Recent surgery (within 30 days prior to study entry) was associated with a numerically higher risk of serious bleeding during infusion in both the Xigris-treated and the placebo-treated patients (Xigris: 3.6% in patients with recent surgery versus 1.6% in patients without recent surgery; placebo: 1.6% versus 0.9% respectively).

In XPRESS, a randomised study of prophylactic heparin versus placebo in adult severe sepsis patients, all treated with drotrecogin alfa (activated), serious bleeding rates were consistent with those observed in previous studies over the treatment period of 0-6 days, and prophylactic heparin did not increase the risk of serious bleeding compared to placebo (2.3% vs 2.5%, respectively), including CNS bleeding (0.3% on both arms). However prophylactic heparin increased the risk of non-serious bleeding compared with placebo (8.7% vs 5.7%, respectively; p= 0.0116).

Serious bleeding events during the 28-day study period

In PROWESS, the incidence of serious bleeding events during the 28-day study period was 3.5% and 2.0% in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The incidence of CNS bleeds during the 28-day study period was 0.2% and 0.1% for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The risk of CNS bleeding may increase with severe coagulopathy and severe thrombocytopenia (see sections 4.3 and 4.4).

In the open-label ENHANCE study, the incidence of serious bleeding events during the 28-day study period was 6.5%, and the incidence of CNS bleeds during the 28-day study period was 1.5%.

In the placebo-controlled ADDRESS study, the incidence of serious bleeding events during the 28-day study period was 51 (3.9%) and 28 (2.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (p=0.01). The incidence of CNS bleeds during the 28-day study period was 6 (0.5%) and 5 (0.4%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively.

In XPRESS serious bleeding rates were consistent with those observed in previous studies during the 28-day study period (days 0-28). Prophylactic heparin did not increase the risk of serious bleeding compared to placebo (3.9% vs 5.2%, respectively), including CNS bleeding (1.0% vs 0.7%, respectively).

In the phase 1 studies, adverse events with a frequency of ≥ 5% included headache (30.9%), ecchymosis (23.0%), and pain (5.8%).

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.