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Xigris 20mg powder for solution for infusion, 5mg powder for solution for infusion

1. Name Of The Medicinal Product

Xigris* 5mg powder for solution for infusion.

Xigris 20mg powder for solution for infusion.

2. Qualitative And Quantitative Composition

Xigris 5mg: Each vial contains 5mg of Drotrecogin alfa (activated).

After reconstitution with 2.5ml of Water for Injection each ml contains 2mg of Drotrecogin alfa (activated).

Excipient: Each vial contains approximately 17mg sodium.

Xigris 20mg: Each vial contains 20mg of drotrecogin alfa (activated).

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

Excipient: Each vial contains approximately 68mg sodium.

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

For a full list of excipients, see section 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 after the onset of organ failure (for further information see section 5.1).

4.2 Posology And Method Of Administration

Xigris should be used by experienced doctors in institutions skilled in the care of patients with severe sepsis.

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).

The recommended dose of Xigris is 24?g/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?g/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 sections 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).

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

• 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 anaesthesia, 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 hospitalisation, 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) Gastro-intestinal 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.

 

4.4 Special Warnings And Precautions For Use

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 neutralised 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 Factor 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 neutralising 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.

Xigris 5mg: This medicinal product contains approximately 17mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Xigris 20mg: This medicinal product contains approximately 68mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

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., 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 1,935 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.

4.6 Pregnancy And Lactation

Animal studies with respect to effects on pregnancy, embryonal/foetal development, parturition, and post-natal 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.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

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 gastro-intestinal 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 2,378 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

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 1,317 drotrecogin alfa (activated)-treated and 1,293 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 percentage 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).

Site of Haemorrhage

Drotrecogin Alfa

(Activated)

[PROWESS]

n = 850

Placebo

[PROWESS]

n = 840

Drotrecogin Alfa

(Activated)

[ENHANCE]

n = 2,378

Gastro-intestinal

5 (0.6%)

4 (0.5%)

19 (0.8%)

Intra-abdominal

2 (0.2%)

3 (0.4%)

18 (0.8%)

Intra-thoracic

4 (0.5%)

0

11 (0.5%)

Retroperitoneal

3 (0.4%)

0

4 (0.2%)

Central nervous system (CNS)1

2 (0.2%)

0

15 (0.6%)

Genito-urinary

2 (0.2%)

0

0

Skin/soft tissue

1 (0.1%)

0

16 (0.7%)

Nasopharyngeal

0

0

4 (0.2%)

Joint/bone

0

0

1 (0.04%)

Site unknown2

1 (0.1%)

1 (0.1%)

6 (0.3%)

Total

20 (2.4%)

8 (1.0%)

853 (3.6%)

 

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.

2 Patients requiring the administration of

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% versus 2.0%; ENHANCE: 5.0% versus 3.1% respectively. Placebo rates in PROWESS 0.4% versus 1.2% respectively).

In ADDRESS, the percentage 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% versus 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% versus 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% versus 5.2%, respectively), including CNS bleeding (1.0% versus 0.7%, respectively).

In the Phase 1 studies, adverse events with a frequency of

4.9 Overdose

In clinical trials and in post-marketing experience there have been reports of accidental overdosing. In the majority of cases, no reactions have been observed. For the other reports, the observed events were consistent with known undesirable effects of the drug (see section 4.8), effects of the drug on laboratory tests (see section 4.4), or consequences of the underlying condition of sepsis.

There is no known antidote for drotrecogin alfa (activated). In case of overdose, immediately stop the infusion (see section 5.2).

5. Pharmacological Properties

5.1 Pharmacodynamic 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, 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.

Pharmacodynamic Effects

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.

Clinical Efficacy

Xigris was studied in one Phase 3, international, multi-centre, randomised, double-blind, placebo-controlled trial (PROWESS) in 1,690 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 CD4 count was 3, 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?g/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

A consistent treatment effect on mortality with Xigris administration was observed across patient subgroups defined by age, gender, and infection type.

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 1,690 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% versus 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), 2,378 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 2,640 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.

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

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 (<5ng/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 (t?? = 13 minutes) and a slower second phase (t?? = 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?g/kg/hr to 48?g/kg/hr. The mean steady-state plasma concentration of drotrecogin alfa (activated) in healthy subjects receiving 24?g/kg/hr is 72ng/ml.

In patients with severe sepsis, infusion of drotrecogin alfa (activated) from 12?g/kg/hr to 30?g/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 24µg/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.

5.3 Preclinical Safety Data

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).

6. Pharmaceutical Particulars

6.1 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 mentioned in section 6.6.

6.3 Shelf Life

3 years.

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?C- 30?C). After preparation, the intravenous infusion solution can be used at room temperature (15?C- 30?C) for a period up to 14 hours.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C-8°C). Keep the vial in the outer carton in order to protect it from light.

6.5 Nature And Contents Of Container

Powder in Type I glass vial. Pack of 1 vial.

6.6 Special Precautions For Disposal And Other Handling

1.

Use appropriate aseptic technique during the preparation of Xigris for intravenous administration.

2.

Calculate the dose and the number of Xigris vials needed.

 

 

Xigris 5mg: Each Xigris vial contains 5mg of drotrecogin alfa (activated).

 

 

Xigris 20mg: Each Xigris vial contains 20mg of drotrecogin alfa (activated).

 

 

The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount.

3.

Xigris 5mg: Prior to administration, 5mg vials of Xigris must be reconstituted with 2.5ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).

 

 

Xigris 20mg: Prior to administration, 20mg vials of Xigris must be reconstituted with 10ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).

 

 

Slowly add the sterile water for injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved.

4.

The solution of reconstituted Xigris must be further diluted with sterile 0.9% sodium chloride injection to a final concentration of between 100?g/ml and 200?g/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% sodium chloride 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 control the infusion rate. The solution of reconstituted Xigris should be diluted into an infusion bag containing sterile 0.9% sodium chloride injection to a final concentration of between 100µg/ml and 200µg/ml.

8.

When administering drotrecogin alfa (activated) at low flow rates (less than approximately 5ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5ml/hr.

9.

Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multi-lumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% sodium chloride injection, lactated Ringer's injection, dextrose, or dextrose and saline mixtures.

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) administered.

11.

Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly.

7. Marketing Authorisation Holder

Eli Lilly Nederland BV, Grootslag 1-5, 3991 RA Houten, The Netherlands.

8. Marketing Authorisation Number(S)

5mg vial:

EU/1/02/225/001

20mg vial:

EU/1/02/225/002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation:

22 August 2002

Date of latest renewal:





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