Xigris - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 20 mg of Drotrecogin alfa (activated).

After reconstitution with 10 ml of Water for Injection each ml contains 2 mg of Drotrecogin alfa (activated).

Drotrecogin alfa (activated) is a recombinant version of the endogenous activated Protein produced by genetic engineering from an established human cell line.

Excipient: Each vial contains approximately 68 mg sodium.

For a full list of excipients, see 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for infusion. Xigris is supplied as a lyophilised, white to off-white powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 he onset of organ failure (for further information see section 5.1).

nced doctors in institutions skilled in the care of patients with severe

Treatment should be started within 48 hours, and preferably within 24 hours, of onset of the first documented sepsis-induced organ dysfunction (see section 5.1).

mended dose of Xigris is 24 pg/kg/hr (based on actual body weight) given as a continuous s infusion for a total duration of 96 hours. It is recommended that Xigris be infused with an mp to accurately control the infusion rate. If the infusion is interrupted for any reason,

Xigris should be restarted at the 24 pg/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 paediatric patients and showed a higher rate of central nervous system bleeding in the Xigris versus placebo group. Xigris is contraindicated in children below the age of 18 (see section 4.3 and 5.1).

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients or to bovine thrombin (a trace residue from the manufacturing process).

Drotrecogin alfa (activated) is contraindicated in children below the age of 18 years (see section 5.1).

4.4

Patients with single organ dysfunction and recent surgery

arproved for the treatment of patients with single organ dysfunction and should not be ticular subgroup of patients, especially if they had recent surgery (within 30 days). In andomised, placebo-controlled trials, PROWESS and ADDRESS (see section 5.1), 28–

-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.                                      or

opathy (including platelet count) indicate severe or worsening uing 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) readministration. 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.

4.5 Interaction with other medicinal products and other forms of interaction

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. nonsteroidal anti-inflammatory drugs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (such as abciximab, eptifibatide, tirofiban) and prostacyclins such as iloprost.

4.7 Effects on ability to dri

s the risk of bleedin tersoeeng.

international, multi-centre, randomised, double-blind, placebo-controlled clinical trial ) involved 850 drotrecogin alfa (activated)-treated and 840 placebo-treated patients. centage 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. 2Patients requiring the administration of >  3 units of packed red blood cells per day for 2 consecutive days without an identified site of bleeding

3In 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).

4.9 Overdose

5. PHARMACOLOGICAL PROPERTIES

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.

Mechanism of Action

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,

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.

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PROWESS Follow-up Study

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.

Further Clinical Experience

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, doubleblind, 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.

Paediatric patients

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.

5.2 Pharmacokinetic properties

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).                               ­or

served in monkeys at, or in small excess of, the maximum human exposure during repeated s, 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).

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sucrose

Sodium chloride Sodium citrate Citric acid Hydrochloric acid Sodium hydroxide

6.2 Incompatibilities

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

6.3 Shelf life

6.4 Special precautions for storagetemperature (15°C-30°C) for aStore in a refrigerator (2°C-8°6.5 Nature and contents of containerPowder in Type I glass vial. Pack ofter carton in order to protect from light.6.6

4. The solution of reconstituted Xigris must be further diluted with sterile 0.9% Sodium Chloride Injection to a final concentration of between 100 pg/ml and 200 pg/ml. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% SodiumChloride Injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems.5. After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30°C).After preparation, the intravenous infusion solution can be used at room temperature (15 to 30°C) for a period up to 14 hours.6.Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.7.It is recommended that Xigris be infused with an infusion pump to accurately co infusion rate. The solution of reconstituted Xigris should be diluted into an infusio containing sterile 0.9% Sodium Chloride Injection to a final concentration of be 100 pg/ml and 200 pg/ml.8.When administering drotrecogin alfa (activated) at low flow rates (les 5 ml/hr), the infusion set must be primed for approximately 15 minute approximately 5 ml/hr.proximately w rate of9.Xigris should be administered via a dedicated intravenous li multilumen central venous catheter. The ONLY other sol through the same line are 0.9% Sodium Chloride Inje Dextrose or Dextrose and Saline mixtures.dedicated lumen of a that can be administered ctated Ringer’s Injection,10.Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated stered.11.Care should be taken to a bodyweight and infused f accordingly.gris at the appropriate rate, calculated based on kg of correct duration. It is recommended that the bag be labelled7.MARKETITHORISATION HOLDER

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 August 2002.

Date of latest renewal:

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency (EMEA):