was firm [250));:<80,000/mm 3 or 50% decrease from the highest value the previous 3 days); or metabolic acidosis with elevated lactic acid concentrations. Patients received a 96 hour infusion of Xigris at 24 µg/kg/hr or placebo starting within 48 hours after the onset of the first sepsis induced organ dysfunction. Exclusion criteria encompassed patients at high risk for bleeding ( see CONTRAINDICATIONS and WARNINGS ), 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> /=25, the 3rd and 4th quartile APACHE II scores (Table 1). The efficacy of Xigris has not been established in patients with lower risk of death, e.g., APACHE II score <25. Table 1: 28-Day All-Cause Mortality for All Patients and for Subgroups Defined by APACHE II Score a Xigris Total N b N c (%) Placebo Total N N (%) Absolute Mortality Difference (%) Relative Risk (RR) 95% CI for RR Overall 850 210 (25) 840 259 (31) -6 0.81 0.70, 0.93 APACHE II quartile (score) 1 st + 2 nd (3-24) 436 82 (19) 437 83 (19) 0 0.99 0.75, 1.30 3 rd + 4 th (25-53) 414 128 (31) 403 176 (44) -13 0.71 0.59, 0.85 a For more information on calculating the APACHE II score, see: http://www.sfar.org/scores2/scores2.html b Total N = Total number of patients in group. c N = Number of deaths in group. Of measures used, the APACHE II score was most effective in classifying patients by risk of death within 28 days and by likelihood of benefit from Xigris, but other important indicators of risk or severity also supported an association between likelihood of Xigris benefit and risk of death. Absolute reductions in mortality of 2%, 5%, 8% and 11% with Xigris were observed for patients with 1, 2, 3, and 4 or more organ dysfunctions, respectively. Similarly, each of the three major components of the APACHE II score (acute physiology score, chronic health score, age score) identified a higher risk population with larger mortality differences associated with treatment. That is, the reduction in mortality was greater in patients with more severe physiologic disturbances, in patients with serious underlying disease predating sepsis, and in older patients. Treatment-associated reductions in mortality were observed in patients with normal protein C levels and those with low protein C levels. No substantial differences in Xigris treatment effects were observed in subgroups defined by gender, ethnic origin, or infectious agent. Long-Term Follow-Up The one-year survival status was provided for 93% of the 1690 PROWESS subjects. For patients with APACHE II score> /=25, mortality was lower for the Xigris group compared to the placebo group through 90-days (41% versus 52%; RR: 0.72, 95% CI: 0.59-0.88) and through 1 year (48% versus 59%; RR: 0.73, 95% CI: 0.60-0.88). However, for patients with APACHE II score <25, mortality was higher for the Xigris group compared to the placebo group through 90-days (27% versus 25%; RR: 1.09, 95% CI: 0.84-1.42) and through 1 year (35% versus 28%; RR: 1.24, 95% CI: 0.97-1.58). Indications and Usage Xigris is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (e.g., as determined by APACHE II, see CLINICAL STUDIES ). Safety and efficacy have not been established in adult patients with severe sepsis and lower risk of death ( see CLINICAL STUDIES , Long-Term Follow-Up ). Safety and efficacy have not been established in pediatric patients with severe sepsis. Contraindications Xigris increases the risk of bleeding. Xigris is contraindicated in patients with the following clinical situations in which bleeding could be associated with a high risk of death or significant morbidity: Active internal bleeding Recent (within 3 months) hemorrhagic stroke Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma Trauma with an increased risk of life-threatening bleeding Presence of an epidural catheter Intracranial neoplasm or mass lesion or evidence of cerebral herniation Xigris is contraindicated in patients with known hypersensitivity to drotrecogin alfa (activated) or any component of this product. Warnings Bleeding is the most common serious adverse effect associated with Xigris therapy. Each patient being considered for therapy with Xigris should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy. Certain conditions, many of which led to exclusion from the Phase 3 trial, are likely to increase the risk of bleeding with Xigris therapy. For individuals with one or more of the following conditions, the increased risk of bleeding should be carefully considered when deciding whether to use Xigris therapy: Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolic event ( see PRECAUTIONS , Drug Interactions ) Platelet count> <30,000 10 6 /L, even if the platelet count is increased after transfusions Prothrombin time-INR> 3.0 Recent (within 6 weeks) gastrointestinal bleeding Recent administration (within 3 days) of thrombolytic therapy Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors Recent administration (within 7 days) of aspirin >650 mg per day or other platelet inhibitors Recent (within 3 months) ischemic stroke ( see CONTRAINDICATIONS ) Intracranial arteriovenous malformation or aneurysm Known bleeding diathesis Chronic severe hepatic disease Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location Should clinically important bleeding occur, immediately stop the infusion of Xigris. Continued use of other agents affecting the coagulation system should be carefully assessed. Once adequate hemostasis has been achieved, continued use of Xigris may be reconsidered. Xigris should be discontinued 2 hours prior to undergoing an invasive surgical procedure or procedures with an inherent risk of bleeding. Once adequate hemostasis has been achieved, initiation of Xigris may be reconsidered 12 hours after major invasive procedures or surgery or restarted immediately after uncomplicated less invasive procedures. Precautions Laboratory Tests Most patients with severe sepsis have a coagulopathy that is commonly associated with prolongation of the activated partial thromboplastin time (APTT) and the prothrombin time (PT). Xigris may variably prolong the APTT. Therefore, the APTT cannot be reliably used to assess the status of the coagulopathy during Xigris infusion. Xigris has minimal effect on the PT and the PT can be used to monitor the status of the coagulopathy in these patients. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Xigris has not been adequately determined, as the assay sensitivity is inadequate to reliably detect all potential antibody responses. One patient in the Phase 2 trial developed antibodies to Xigris without clinical sequelae. One patient in the Phase 3 trial who developed antibodies to Xigris developed superficial and deep vein thrombi during the study, and died of multi-organ failure on day 36 post-treatment but the relationship of this event to antibody is not clear. Xigris has not been readministered to patients with severe sepsis. Drug Interactions Drug interaction studies with Xigris have not been performed in patients with severe sepsis. However, since there is an increased risk of bleeding with Xigris, caution should be employed when Xigris is used with other drugs that affect hemostasis ( see CLINICAL PHARMACOLOGY , WARNINGS ). Approximately 2/3 of the patients in the Phase 3 study received either prophylactic low dose heparin (unfractionated heparin up to 15,000 units/day) or prophylactic doses of low molecular weight heparins as indicated in the prescribing information for the specific products. Concomitant use of prophylactic low dose heparin did not appear to affect safety, however, its effects on the efficacy of Xigris have not been evaluated in an adequate and well-controlled clinical trial. Drug/Laboratory Test Interaction Because Xigris may affect the APTT assay, Xigris present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as factor VIII, IX, and XI assays). This interference may result in an apparent factor concentration that is lower than the true concentration. Xigris 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). Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate potential carcinogenicity of Xigris have not been performed. Xigris 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. The potential of Xigris to impair fertility has not been evaluated in male or female animals. Pregnancy Category C Animal reproductive studies have not been conducted with Xigris. It is not known whether Xigris can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Xigris should be given to pregnant women only if clearly needed. Nursing Mothers It is not known whether Xigris is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Xigris have not been established in the age group newborn (38 weeks gestational age) to 18 years. The efficacy of Xigris in adult patients with severe sepsis and high risk of death cannot be extrapolated to pediatric patients with severe sepsis. Geriatric Use In clinical studies evaluating 1821 patients with severe sepsis, approximately 50% of the patients were 65 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Adverse Reactions Bleeding Bleeding is the most common adverse reaction associated with Xigris. In the Phase 3 study, serious bleeding events were observed during the 28-day study period in 3.5% of Xigris-treated and 2.0% of placebo-treated patients, respectively. The difference in serious bleeding between Xigris and placebo occurred primarily during the infusion period and is shown in Table 2. 1 Serious bleeding events were defined as any intracranial hemorrhage, any life-threatening 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 a serious adverse event. Table 2: Number of Patients Experiencing a Serious Bleeding Event by Site of Hemorrhage During the Study Drug Infusion Period a in PROWESS 1 Xigris N=850 Placebo N=840 Total 20 (2.4%) 8 (1.0%) Site of Hemorrhage Gastrointestinal 5 4 Intra-abdominal 2 3 Intra-thoracic 4 0 Retroperitoneal 3 0 Intracranial 2 0 Genitourinary 2 0 Skin/soft tissue 1 0 Other b 1 1 a Study drug infusion period is defined as the date of initiation of study drug to the date of study drug discontinuation plus the next calendar day. b Patients requiring the administration of >/=3 units of packed red blood cells per day for 2 consecutive days without an identified site of bleeding. In PROWESS, 2 cases of intracranial hemorrhage (ICH) occurred during the infusion period for Xigris-treated patients and no cases were reported in the placebo patients. The incidence of ICH during the 28-day study period was 0.2% for Xigris-treated patients and 0.1% for placebo-treated patients. ICH has been reported in patients receiving Xigris in non-placebo controlled trials with an incidence of approximately 1% during the infusion period. The risk of ICH may be increased in patients with risk factors for bleeding such as severe coagulopathy and severe thrombocytopenia ( see WARNINGS ). In PROWESS, 25% of the Xigris-treated patients and 18% of the placebo-treated patients experienced at least one bleeding event during the 28-day study period. In both treatment groups, the majority of bleeding events were ecchymoses or gastrointestinal tract bleeding. Other Adverse Reactions Patients administered Xigris as treatment for severe sepsis experience many events which are potential sequelae of severe sepsis and may or may not be attributable to Xigris therapy. In clinical trials, there were no types of non-bleeding adverse events suggesting a causal association with Xigris. Overdosage There is no known antidote for Xigris. In case of overdose, immediately stop the infusion and monitor closely for hemorrhagic complications ( see Human Pharmacokinetics ). Post-marketing experience: There have been some reports of accidental overdosing. In the majority of these cases (which included patients receiving up to 60 times the recommended dose administration rate), no reactions have been observed. For the other reports, the observed events were consistent with known effects of the drug and/or sequelae of the underlying condition of sepsis. Dosage and Administration Xigris should be administered intravenously at an infusion rate of 24 µg/kg/hr for a total duration of infusion of 96 hours. Dose adjustment based on clinical or laboratory parameters is not recommended ( see PRECAUTIONS ). If the infusion is interrupted, Xigris should be restarted at the 24 µg/kg/hr infusion rate. Dose escalation or bolus doses of Xigris are not recommended. In the event of clinically important bleeding, immediately stop the infusion ( see WARNINGS ). Preparation and administration instructions: Use appropriate aseptic technique during the preparation of Xigris for intravenous administration. Calculate the dose and the number of Xigris vials needed. Each 5 mg and 20 mg vial of Xigris contains an excess of Xigris to facilitate delivery of the labeled amount. Prior to administration, 5 mg vials must be reconstituted with 2.5 mL of Sterile Water for Injection, USP, and 20 mg vials of Xigris must be reconstituted with 10 mL of Sterile Water for Injection, USP. The resulting concentration of the solution is approximately 2 mg/mL of Xigris. Slowly add the Sterile Water for Injection, USP to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved. Because Xigris contains no antibacterial preservatives, the intravenous solution should be prepared immediately upon reconstitution of the Xigris in the vial(s). If the vial of reconstituted Xigris is not used immediately, it may be held at controlled room temperature 20 to 25 C (68 to 77 F), but must be used within 3 hours. Before further dilution or administration, the product should be inspected visually for particulate matter and discoloration. Do not use vials if particulate matter is visible or solution is discolored. Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multilumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% Sodium Chloride Injection, USP; Lactated Ringer's Injection, USP; Dextrose Injection, USP; and Dextrose and Sodium Chloride Injection, USP. Avoid exposing Xigris solutions to heat and/or direct sunlight. Studies conducted at the recommended concentrations indicate the Xigris intravenous solution to be compatible with glass infusion bottles, and infusion bags and syringes made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. Dilution and Administration Instructions for an Intravenous Infusion Pump: The solution of reconstituted Xigris must be further diluted into an infusion bag containing 0.9% Sodium Chloride Injection, USP to a final concentration of between 100 µg/mL and 200 µg/mL. Slowly withdraw the reconstituted Xigris solution from the vial(s) and add the reconstituted Xigris into a prepared infusion bag of 0.9% Sodium Chloride Injection, USP. When injecting the Xigris into the infusion bag, direct the stream to the side of the bag to minimize the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag using mechanical transport systems such as pneumatic-tube systems that may cause vigorous agitation of the solution. After preparation, the intravenous solution should be used at controlled room temperature 20 to 25 C (68 to 77 F) within 14 hours. If the intravenous solution is not administered immediately, the solution may be stored refrigerated 2 to 8 C (36 to 46 F) for up to 12 hours. If the prepared solution is refrigerated prior to administration, the maximum time limit for use of the intravenous solution, including preparation, refrigeration, and administration, is 24 hours. Dilution and Administration Instructions for a Syringe Pump: The solution of reconstituted Xigris must be further diluted with 0.9% Sodium Chloride Injection, USP to a final concentration of between 100 µg/mL and 1000 µg/mL. Slowly withdraw the reconstituted Xigris solution from the vial(s) into a syringe that will be used in the syringe pump. Into the same syringe, slowly withdraw 0.9% Sodium Chloride Injection, USP to obtain the desired final concentration of Xigris. Gently invert and/or rotate the syringe to obtain a homogenous solution. When administering Xigris using a syringe pump at low concentrations (less than approximately 200 µg/mL) at low flow rates (less than approximately 5 mL/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 mL/hr. After preparation, the intravenous solution should be used at controlled room temperature 20 to 25 C (68 to 77 F) within 12 hours. The maximum time limit for use of the intravenous solution, including preparation and administration, is 12 hours. How Supplied Xigris is available in 5 mg and 20 mg single-use vials containing sterile, preservative-free, lyophilized drotrecogin alfa (activated). Vials: 5 mg Vials NDC 0002-7559-01 20 mg Vials NDC 0002-7561-01 Xigris should be stored in a refrigerator 2 to 8 C (36 to 46 F). Do not freeze. Protect unreconstituted vials of Xigris from light. Retain in carton until time of use. Do not use beyond the expiration date stamped on the vial. References Bernard GR, et al. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis. N Engl J Med. 2001;344:699-709 Knaus WA, et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-29 Literature revised November 14, 2003 Eli Lilly and Company Indianapolis, IN 46285, USA www.lilly.com PV 3425 AMP PRINTED IN USA Copyright 2001, 2003, Eli Lilly and Company. All rights reserved. PRODUCT PHOTO(S): NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size. The product samples shown here have been supplied by the manufacturer. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. 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