Bleeding is the most commonly reported adverse reaction in patients receiving Xigris therapy [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. Patients administered Xigris (drotrecogin alfa) as treatment for severe sepsis experience many events which are potential sequelae of severe sepsis and may or may not be attributable to Xigris (drotrecogin alfa) therapy. In severe sepsis clinical trials, there were no types of non-bleeding adverse events suggesting a causal association with Xigris (drotrecogin alfa) .
Clinical Trial Experience
The data below describe the population of 8639 adult severe sepsis patients exposed to study drug (6506 Xigris (drotrecogin alfa) and 2133 placebo) in 2 placebo-controlled and 2 open-label studies of Xigris (drotrecogin alfa) . 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], serious bleeding events were observed during the 28-day study period in 3.5% of Xigris (drotrecogin alfa) -treated and 2.0% of placebo-treated patients, respectively. The difference in serious bleeding between Xigris (drotrecogin alfa) 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 Perioda in Study 1
|Total||20 (2.4%)||8 (1.0%)|
|Site of Hemorrhage|
|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 Study 1, two cases of intracranial hemorrhage (ICH) occurred during the infusion period for Xigris (drotrecogin alfa) -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 (drotrecogin alfa) -treated patients and 0.1% for placebo-treated patients. ICH has been reported in patients receiving Xigris (drotrecogin alfa) 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].
In Study 1, 25% of the Xigris (drotrecogin alfa) -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] 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 (drotrecogin alfa) infusion; the relationship of these events to Xigris (drotrecogin alfa) is uncertain.
In Study 4 [see Clinical Studies], a randomized trial of prophylactic heparin versus placebo in Xigris (drotrecogin alfa) -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 (drotrecogin alfa) . 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
|Serious Bleeding Eventsa (%)|
|Days 0-6||22 (2.3%)||24 (2.5%)|
|Days 0-28||38 (3.9%)||50 (5.2%)|
|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%)|
|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.
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 (drotrecogin alfa) 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 (drotrecogin alfa) activity in an in vitro assay.
In the 4 clinical studies, 1.6% (24/1493) placebo- and 1.5% (27/1855) Xigris (drotrecogin alfa) -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 (drotrecogin alfa) -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 (drotrecogin alfa) - 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 (drotrecogin alfa) 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 (drotrecogin alfa) 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 (drotrecogin alfa) 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 (drotrecogin alfa) . Samples available from six adult severe sepsis patients (Study 2) who had received a prior course of Xigris (drotrecogin alfa) were subsequently tested and all were negative for anti-human activated protein C antibody.