There is no known antidote for Xigris (drotrecogin alfa). In case of overdose, immediately stop the infusion and monitor closely for hemorrhagic complications.
In postmarketing experience there have been a limited number of medication error reports of excessive rate of Xigris (drotrecogin alfa) infusion for short periods of time (median 2 hours). No unexpected adverse events were observed during the overdose period. However, this information is insufficient to assess whether Xigris (drotrecogin alfa) overdose is associated with an increased hemorrhage risk beyond that observed with Xigris (drotrecogin alfa) administered at the recommended dose.
Xigris (drotrecogin alfa) increases the risk of bleeding. Xigris (drotrecogin alfa) is contraindicated in the following clinical situations where bleeding could lead to significant morbidity or death:
Bleeding is the most commonly reported adverse reaction in patients receiving Xigris therapy. 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 ExperienceThe 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 , 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
| 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 |
| Otherb | 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 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.
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) 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 , 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
| Heparin-plus-Xigris N=976 |
Placebo-plus-Xigris N=959 |
|
| Serious Bleeding Eventsa (%) | ||
| Days 0-6 | 22 (2.3%) | 24 (2.5%) |
| Days 0-28 | 38 (3.9%) | 50 (5.2%) |
| ICHb (%) | ||
| 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.
Xigris (drotrecogin alfa) ® 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 score ≥ 25).
Limitations of use:
Xigris (drotrecogin alfa) is not indicated in adult patients with severe sepsis and a lower risk of death (e.g., APACHE II score < 25).
Xigris (drotrecogin alfa) is not indicated in pediatric patients.
The specific pharmacologic effects by which Xigris (drotrecogin alfa) exerts its effect on survival in patients with severe sepsis are not completely understood. In patients with severe sepsis, Xigris (drotrecogin alfa) infusions of 48 or 96 hours produced dose-dependent declines in D-dimer and IL-6. Compared with placebo, Xigris (drotrecogin alfa) -treated patients experienced more rapid declines in D-dimer, PAI-1 levels, thrombin-antithrombin levels, prothrombin F1.2, IL-6, more rapid increases in protein C and antithrombin levels, and normalization of plasminogen. As assessed by infusion duration, the maximum observed pharmacodynamic effect of drotrecogin alfa (activated) on D-dimer levels occurred at the end of 96 hours of infusion for the 24 mcg/kg/hr treatment group.
Drotrecogin alfa (activated) and endogenous activated protein C are inactivated by endogenous plasma protease inhibitors. Plasma concentrations of endogenous activated protein C in healthy subjects and patients with severe sepsis are usually below detection limits.
In patients with severe sepsis, Xigris (drotrecogin alfa) infusions of 12 mcg/kg/hr to 30 mcg/kg/hr produce steady-state concentrations (Css) that are proportional to infusion rates. In Study 1 , the median clearance of drotrecogin alfa (activated) was 40 L/hr (interquartile range of 27 to 52 L/hr) in adults with severe sepsis. The median Css of 45 ng/mL (interquartile range of 35 to 62 ng/mL) was attained within 2 hours after starting the infusion. In the majority of patients, plasma concentrations of drotrecogin alfa (activated) fell below the assay's quantitation limit of 10 ng/mL within 2 hours after stopping the infusion. Plasma clearance of drotrecogin alfa (activated) in patients with severe sepsis is approximately 50% higher than that in healthy subjects.
Pregnancy Category C — Animal reproduction studies have not been conducted with Xigris (drotrecogin alfa). It is also not known whether Xigris (drotrecogin alfa) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. In published case reports, there were no major malformations or other adverse outcomes reported following treatment with Xigris (drotrecogin alfa) during pregnancy. Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Xigris (drotrecogin alfa) should be given to a pregnant woman only if clearly needed.
Xigris (drotrecogin alfa) is supplied in single-use vials of 5 mg and 20 mg drotrecogin alfa (activated) as a sterile, preservative-free, lyophilized white to off-white powder for reconstitution.
Xigris (drotrecogin alfa) is supplied in 5 mg and 20 mg single-use vials containing sterile, preservative-free, lyophilized drotrecogin alfa (activated).
5 mg vial individually packaged in a carton — NDC 0002-7559-01
20 mg vial individually packaged in a carton — NDC 0002-7561-01
Storage and Handling Lyophilized PowderXigris (drotrecogin alfa) vials should be stored in a refrigerator 2° to 8°C (36° to 46°F). Do not freeze. Protect vials of Xigris (drotrecogin alfa) from light. Retain in carton until time of use.
Reconstituted SolutionAvoid exposing Xigris (drotrecogin alfa) solutions to heat and/or direct sunlight. The intravenous solution should be prepared immediately after reconstitution of the Xigris (drotrecogin alfa) in the vial(s). If the vial of reconstituted Xigris (drotrecogin alfa) 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.
Intravenous infusion pump using an infusion bag — After final dilution and preparation, the intravenous solution should be used at controlled room temperature 20° to 25°C (68° to 77°F) within 12 hours. If the intravenous solution is not administered immediately, the solution should be refrigerated at 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 with an infusion bag, including dilution, refrigeration, and administration, is 24 hours.
Intravenous infusion using a syringe pump — After final dilution and preparation, the intravenous solution should be used at controlled room temperature 20° to 25°C (68° to 77°F) within 12 hours. If the intravenous solution is not administered immediately, the solution should be refrigerated at 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 with a syringe pump, including dilution, refrigeration, and administration, is 24 hours.
Eli Lilly and Company Indianapolis, IN 46285. Literature Revised October 9, 2008.
Included as part of the PRECAUTIONS section.
PRECAUTIONS BleedingBleeding is the most common serious adverse reaction experienced by patients receiving Xigris (drotrecogin alfa). Each patient being considered for therapy with Xigris (drotrecogin alfa) 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 , are likely to increase the risk of bleeding with Xigris (drotrecogin alfa) 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 (drotrecogin alfa) therapy:
Should clinically important bleeding occur, immediately stop the infusion of Xigris (drotrecogin alfa). Continued use of other agents affecting the coagulation system should be carefully assessed. Once adequate hemostasis has been achieved, continued use of Xigris (drotrecogin alfa) may be reconsidered.
Mortality in Patients with Single Organ Dysfunction and Recent SurgeryIn 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 (drotrecogin alfa) 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 (drotrecogin alfa) 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.
Patients on Prophylactic Heparin when Xigris (drotrecogin alfa) is InitiatedClinicians should consider continuing heparin for venous thromboembolism (VTE) prophylaxis when initiating Xigris (drotrecogin alfa) , unless discontinuation is medically necessary. In a randomized study of prophylactic heparin versus placebo in 1935 adult severe sepsis patients treated with Xigris (drotrecogin alfa) , 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 (drotrecogin alfa). 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 (drotrecogin alfa) 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.
Invasive ProceduresInvasive procedures increase the risk for bleeding with Xigris (drotrecogin alfa). Such procedures, including arterial and central venous punctures, should be minimized during the Xigris (drotrecogin alfa) infusion. Puncture of a noncompressible site should be avoided during the infusion. Xigris (drotrecogin alfa) 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 (drotrecogin alfa) may be restarted 12 hours after surgery and major invasive procedures or immediately after uncomplicated less invasive procedures.
Laboratory Tests for CoagulopathyMost 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 (drotrecogin alfa) infusion since Xigris variably prolongs the APTT.
The prothrombin time (PT) may be used to monitor the degree of the coagulopathy in patients treated with Xigris (drotrecogin alfa) because Xigris (drotrecogin alfa) has minimal effect on the PT .
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).
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term studies in animals to evaluate potential carcinogenicity of Xigris (drotrecogin alfa) have not been performed. Xigris (drotrecogin alfa) 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 (drotrecogin alfa) to impair fertility has not been evaluated in male or female animals.
Use In Specific Populations PregnancyPregnancy Category C — Animal reproduction studies have not been conducted with Xigris (drotrecogin alfa). It is also not known whether Xigris (drotrecogin alfa) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. In published case reports, there were no major malformations or other adverse outcomes reported following treatment with Xigris (drotrecogin alfa) during pregnancy. Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Xigris (drotrecogin alfa) should be given to a pregnant woman only if clearly needed.
Nursing MothersIt is not known whether drotrecogin alfa (activated) is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Xigris (drotrecogin alfa) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric UseA placebo-controlled trial in pediatric patients (Study 3) did not establish safety and effectiveness of Xigris (drotrecogin alfa) in the pediatric patient population.
Geriatric UseIn Study 1, which evaluated 1690 patients with severe sepsis, 48 percent were 65 years and over, while 23 percent were 75 and over. No overall difference in safety was observed between these patients and younger patients. Reduction in mortality was observed in both geriatric and younger patients.
Xigris (drotrecogin alfa) should be administered intravenously at an infusion rate of 24 mcg/kg/hr (based on actual body weight) for a total duration of infusion of 96 hours. Dose adjustment based on clinical or laboratory measurements is not recommended . Dose escalation or bolus doses of Xigris (drotrecogin alfa) are not recommended.
If the infusion is interrupted, Xigris (drotrecogin alfa) should be restarted at the 24 mcg/kg/hr infusion rate.
In the event of clinically important bleeding, immediately stop the infusion .
Xigris (drotrecogin alfa) should be administered via a dedicated intravenous line or a dedicated lumen of a multilumen 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 (drotrecogin alfa) solutions to heat and/or direct sunlight. Studies conducted at the recommended concentrations indicate the Xigris (drotrecogin alfa) intravenous solution to be compatible with glass infusion bottles, and infusion bags and syringes made of polyvinylchloride, polyethylene, polypropylene, or polyolefin.
Preparation of the Concentrated SolutionNote: Reconstitute vials of lyophilized Xigris (drotrecogin alfa) only with Sterile Water for Injection, USP.
Complete “Preparation of Concentrated Solution” steps 1-6 above, then complete the next 7 steps.
Complete “Preparation of Concentrated Solution” steps 1-6 above, then complete the next 7 steps.
Prophylactic Heparin — In a randomized, double-blind, placebo-controlled trial in adult patients with severe sepsis (Study 4), coadministration of Xigris (drotrecogin alfa) (24 mcg/kg/hr for 96 hours) and prophylactic heparin (enoxaparin 40 mg every 24 hours or unfractionated sodium heparin 5000 U every 12 hours administered subcutaneously) did not alter the clearance and steady-state concentrations of drotrecogin alfa (activated). No dosage adjustment of Xigris (drotrecogin alfa) is recommended when coadministered with prophylactic heparin.
