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warnings and cautions
5 WARNINGS AND PRECAUTIONS Bleeding: Weigh the increased risk of bleeding against benefits of Xigris for patients with certain conditions. Stop Xigris infusion if clinically important bleeding occurs. ( 5.1 ) Mortality in patients with single organ dysfunction and recent surgery: These patients may not be at a high risk of death and may not be among the indicated population. ( 5.2 ) Use in patients on prophylactic heparin: Consider continuing heparin prophylaxis when initiating Xigris, unless discontinuation is medically necessary. ( 5.3 ) Invasive procedures: Minimize invasive procedures during Xigris infusion. Discontinue Xigris 2 hours prior to major invasive procedures. ( 5.4 ) 5.1 Bleeding Bleeding is the most common serious adverse reaction experienced by patients receiving Xigris. 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 Study 1 [see Clinical Studies ( 14.1 )] , 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 Drug Interactions ( 7.1 )] Platelet count <30,000 x 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 ( 4 )] 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. 5.2 Mortality in Patients with Single Organ Dysfunction and Recent Surgery In Study 1, among the small number of patients with single organ dysfunction and recent surgery (surgery within 30 days prior to study treatment), all-cause mortality was numerically higher in the Xigris group (28-day: 10/49; in-hospital: 14/48) compared with the placebo group (28-day: 8/49; in-hospital: 8/47). In an analysis of the subset of patients with single organ dysfunction and recent surgery from Study 2, which enrolled septic patients not at high risk of death, all-cause mortality was also higher in the Xigris group (28-day: 67/323; in-hospital: 76/325) compared with the placebo group (28-day: 44/313; in-hospital: 62/314). Single organ dysfunction patients with recent surgery may not be at high risk of death irrespective of APACHE II score. Therefore, these patients may not be among the indicated population. 5.3 Patients on Prophylactic Heparin when Xigris is Initiated Clinicians should consider continuing heparin for venous thromboembolism (VTE) prophylaxis when initiating Xigris, unless discontinuation is medically necessary. In a randomized study of prophylactic heparin versus placebo in 1935 adult severe sepsis patients treated with Xigris, mortality and the rate of serious adverse events were increased in the subgroup of 434 patients whose heparin was stopped on study entry by randomization to placebo-plus-Xigris. This finding was based on prospectively defined exploratory subgroup analyses; however, the explanation for the finding is unclear. The safety of prophylactic heparin when concomitantly administered with Xigris in adult patients with severe sepsis was evaluated with low molecular weight heparin enoxaparin (40 mg every 24 hours) and unfractionated sodium heparin (5000 U every12 hours), but was not evaluated with unfractionated sodium heparin 5000 U when dosed every 8 hours [see Clinical Studies ( 14.5 )] . 5.4 Invasive Procedures Invasive procedures increase the risk for bleeding with Xigris. Such procedures, including arterial and central venous punctures, should be minimized during the Xigris infusion. Puncture of a noncompressible site should be avoided during the infusion. 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, Xigris may be restarted 12 hours after surgery and major invasive procedures or immediately after uncomplicated less invasive procedures. 5.5 Laboratory Tests for Coagulopathy 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). The activated partial thromboplastin time (APTT) cannot be reliably used to assess the degree of the coagulopathy during Xigris infusion since Xigris variably prolongs the APTT [see Drug Interactions ( 7.3 )] . The prothrombin time (PT) may be used to monitor the degree of the coagulopathy in patients treated with Xigris because Xigris has minimal effect on the PT [see Drug Interactions ( 7.3 )] . 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). This interference will result in a measured factor concentration that is lower than the actual concentration. 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) [see Drug Interactions ( 7.3 )] .
6 ADVERSE REACTIONS Bleeding is the most commonly reported adverse reaction in patients receiving Xigris therapy [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . 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 severe sepsis clinical trials, there were no types of non-bleeding adverse events suggesting a causal association with Xigris. Bleeding is the most commonly reported adverse reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience The data below describe the population of 8639 adult severe sepsis patients exposed to study drug (6506 Xigris and 2133 placebo) in 2 placebo-controlled and 2 open-label studies of Xigris. The population was 18-99 years of age, of whom 42% were female and 58% were male. The ethnic/racial origin of these patients was the following: Caucasian 79.5%, African descent 5.8%, Hispanic 5.3%, East/Southeast Asian 3.4%, and Other origin 6.0%. These studies used the standard dose regimen of 24 mcg/kg/hr for 96 hours total duration of infusion. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Study 1 [see Clinical Studies ( 14.1 )] , 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 1. Serious bleeding events included any intracranial hemorrhage, 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 a serious adverse event. Table 1: Number of Patients Experiencing a Serious Bleeding Event by Site of Hemorrhage During the Study Drug Infusion Period a in Study 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. 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 In Study 1, two 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 and Precautions ( 5.1 )] . In Study 1, 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. Additional information on adverse events has been obtained in the controlled study of patients not at a high risk of death (Study 2) [see Clinical Studies ( 14.3 )] and an open label, uncontrolled study of 2378 adult patients with severe sepsis that enrolled both patients at high risk of death and not at high risk of death. The incidence rates and nature of treatment-associated adverse events in Study 2 were generally similar to that seen on Study 1. In the open label, uncontrolled study, serious bleeding occurred in 3.6% of patients during the infusion period, and 6.5% during the 28 day study period. Intracranial hemorrhage occurred among 0.6% of patients during the infusion period and 1.5% within 28 days. Most of the post-infusion ICH events occurred within 1 week of the Xigris infusion; the relationship of these events to Xigris is uncertain. In Study 4 [see Clinical Studies ( 14.5 )] , a randomized trial of prophylactic heparin versus placebo in Xigris-treated severe sepsis patients, rates of serious bleeding, including ICH, were consistent with rates observed in previous studies. Prophylactic heparin did not increase the risk of serious bleeding, including ICH, in patients receiving Xigris. Non-serious bleeding was increased in patients receiving prophylactic heparin compared with placebo over the treatment period of 0-6 days ( see Table 2 ). Table 2: Bleeding Event Rates in Study 4 a Serious bleeding events included any fatal bleed, any life-threatening bleed, any CNS bleed, or any bleeding event assessed as serious by the investigator. b ICH includes any bleed in the central nervous system, including the following types of hemorrhage — petechial, parenchymal, subarachnoid, subdural, and stroke with hemorrhagic transformation. Heparin-plus-Xigris N=976 Placebo-plus-Xigris N=959 Serious Bleeding Events a (%) Days 0-6 22 (2.3%) 24 (2.5%) Days 0-28 38 (3.9%) 50 (5.2%) ICH b (%) Days 0-6 3 (0.3%) 3 (0.3%) Days 0-28 10 (1.0%) 7 (0.7%) Overall Bleeding (Serious and Non-serious) Events (%) Days 0-6 105 (10.8%) 78 (8.1%) Days 0-28 121 (12.4%) 105 (10.9%) 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In severe sepsis clinical studies (Study 1, 2, 4 and the open-label, uncontrolled study), serum samples were collected from 1493 adult patients who received placebo or no study drug and 1855 adult patients who received Xigris for evaluation of anti-human activated protein C IgA/IgG/IgM antibodies with an enzyme-linked immunosorbent assay (ELISA). Plasma samples from patients positive in this detection assay were also tested for their ability to neutralize Xigris activity in an in vitro assay. In the 4 clinical studies, 1.6% (24/1493) placebo- and 1.5% (27/1855) Xigris-treated patients had negative baseline and positive post-baseline anti-human activated protein C antibodies. Three of the 24 placebo- and 5 of the 27 Xigris-treated patients tested positive for neutralizing IgG antibodies in the in vitro APTT assay. Positive rates were comparable for both anti-human activated protein C and neutralizing antibody between Xigris- and placebo-treated patients by sampling time. No apparent correlation of antibody development to adverse reactions was observed among this limited number of patients. There was no evidence anti-human activated protein C antibodies detected represented a specific immune response to Xigris therapy. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody positivity in an assay may be influenced by several factors including assay design, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Xigris with the incidence of antibodies to other products may be misleading. Re-administration — There have been no company-sponsored clinical trials in severe sepsis specifically studying Xigris re-administration. Neither safety nor efficacy has been demonstrated in this use. In Study 2 and Study 4, no hypersensitivity reactions were reported in 10 patients who received a second course of Xigris. Samples available from six adult severe sepsis patients (Study 2) who had received a prior course of Xigris were subsequently tested and all were negative for anti-human activated protein C antibody.
adverse reactions table
<table ID="t1" width="100%"> <caption>Table 1: Number of Patients Experiencing a Serious Bleeding Event by Site of Hemorrhage During the Study Drug Infusion Period<sup>a</sup> in Study 1</caption> <col align="left" width="60.000%"/> <col align="left" width="20.000%"/> <col align="left" width="20.000%"/> <tfoot> <tr> <td align="left" colspan="3" valign="top"> <paragraph styleCode="footnote"> <sup>a</sup> 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.</paragraph> </td> </tr> <tr> <td align="left" colspan="3" valign="top"> <paragraph styleCode="footnote"> <sup>b</sup> Patients requiring the administration of ≥3 units of packed red blood cells per day for 2 consecutive days without an identified site of bleeding.</paragraph> </td> </tr> </tfoot> <tbody> <tr> <td align="left" styleCode="Botrule" valign="top"/> <td align="center" styleCode="Botrule" valign="top"> <content styleCode="bold">Xigris</content> <content styleCode="bold">N=850</content> </td> <td align="center" styleCode="Botrule" valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">N=840</content> </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Total</content> </td> <td align="center" valign="top"> <content styleCode="bold">20 (2.4%)</content> </td> <td align="center" valign="top"> <content styleCode="bold">8 (1.0%)</content> </td> </tr> <tr> <td align="left" valign="top">Site of Hemorrhage</td> <td align="center" valign="top"/> <td align="center" valign="top"/> </tr> <tr> <td align="left" valign="top">Gastrointestinal</td> <td align="center" valign="top">5</td> <td align="center" valign="top">4</td> </tr> <tr> <td align="left" valign="top">Intra-abdominal</td> <td align="center" valign="top">2</td> <td align="center" valign="top">3</td> </tr> <tr> <td align="left" valign="top">Intra-thoracic</td> <td align="center" valign="top">4</td> <td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Retroperitoneal</td> <td align="center" valign="top">3</td> <td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Intracranial</td> <td align="center" valign="top">2</td> <td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Genitourinary</td> <td align="center" valign="top">2</td> <td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Skin/soft tissue</td> <td align="center" valign="top">1</td> <td align="center" valign="top">0</td> </tr> <tr> <td align="left" valign="top">Other<sup>b</sup> </td> <td align="center" valign="top">1</td> <td align="center" valign="top">1</td> </tr> </tbody> </table>