Xigris

Included as part of the PRECAUTIONS section.

Xigris is part of the drug class:

• Antithrombotic Enzymes

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 106/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.

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.

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)].

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.

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)].

Pregnancy

Pregnancy Category C Animal reproduction studies have not been conducted with Xigris. It is also not known whether Xigris 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 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 should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It 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, 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 Use

A placebo-controlled trial in pediatric patients (Study 3) did not establish safety and effectiveness of Xigris in the pediatric patient population [see Indications and Usage (1) and Clinical Studies (14.4)].

Geriatric Use

In 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.

There is no known antidote for Xigris. In case of overdose, immediately stop the infusion and monitor closely for hemorrhagic complications [see Clinical Pharmacology (12.3)].

In postmarketing experience there have been a limited number of medication error reports of excessive rate of Xigris 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 overdose is associated with an increased hemorrhage risk beyond that observed with Xigris administered at the recommended dose.

Study 1: Treatment of Adult Severe Sepsis Patients

The efficacy of Xigris was studied in an international, multi-center, randomized, double-blind, placebo-controlled trial (“PROWESS”) of 1690 patients with severe sepsis. Entry criteria included a systemic inflammatory response presumed due to infection and at least one associated acute organ dysfunction. Acute organ dysfunction was defined as one of the following: cardiovascular dysfunction (shock, hypotension, or the need for vasopressor support despite adequate fluid resuscitation); respiratory dysfunction (relative hypoxemia [PaO2/FiO2 ratio <250]); renal dysfunction (oliguria despite adequate fluid resuscitation); thrombocytopenia (platelet count <80,000/mm3 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 mcg/kg/hr or placebo starting within 48 hours after the onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours, and 89% of patients received study drug within 24 hours after onset of the first organ dysfunction. Exclusion criteria encompassed patients at high risk for bleeding [see Contraindications (4) and Warnings and Precautions (5.1)], patients who were not expected to survive for 28 days due to a preexisting, non-sepsis related medical condition, HIV-positive patients whose most recent CD4 count was ≤50/mm3, patients on chronic dialysis, and patients who had undergone bone marrow, lung, liver, pancreas, or small bowel transplantation.

All-cause mortality was assessed 28 days after the start of study drug administration. Prospectively defined subsets for mortality analyses included groups defined by APACHE II score [see References (15)] (a score designed to assess risk of mortality based on acute physiology and chronic health evaluation), protein C activity, and the number of acute organ dysfunctions at baseline. The APACHE II score was calculated from physiologic and laboratory data obtained within the 24-hour period immediately preceding the start of study drug administration irrespective of the preceding length of stay in the intensive care unit.

The study was terminated after a planned interim analysis due to significantly lower mortality in patients on Xigris than in patients on placebo. At 28 days, the overall mortality rates were 25% for the Xigris-treated group and 31% for the placebo-treated group (p=0.005) (see Table 3).

Baseline APACHE II score was correlated with risk of death; among patients receiving placebo, those with the lowest APACHE II scores had a 12% mortality rate, while those in the 2nd, 3rd, and 4th APACHE quartiles had mortality rates of 26%, 36%, and 49%, respectively. The observed mortality difference between Xigris and placebo was limited to the half of patients with higher risk of death, i.e., APACHE II score ≥25, the 3rd and 4th quartile APACHE II scores, where the 28-day mortality rates were 31% for the Xigris-treated group and 44% for the placebo-treated group (p=0.0002) (see Table 3). The efficacy of Xigris has not been established in patients with lower risk of death, e.g., APACHE II score <25.

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. For patients with 1, 2, 3, and 4 or more organ dysfunctions, absolute reductions in mortality of 2%, 5%, 8%, and 11% with Xigris were observed (relative risk of 0.92, 0.80, 0.76, and 0.78, 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 of Patients in Study 1

The one-year survival status was provided for 93% of the 1690 Study 1 subjects. For patients with APACHE II score ≥25, mortality was lower for the Xigris group compared with 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 with 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).

Study 2: Benefit Not Demonstrated in Treatment of Adult Severe Sepsis Patients Not at High Risk of Death

A randomized, double-blind, placebo-controlled trial (“ADDRESS”) of Xigris (96-hour infusion of Xigris at 24 mcg/kg/hr) was performed in adult patients with severe sepsis who were not at high risk of death. Most patients had APACHE II score <25 or only one sepsis-induced organ failure. The study was stopped at an interim analysis after enrollment of 2640 patients due to no observed benefit. All-cause mortality at 28 days after randomization was 18% (243/1333) in patients randomized to Xigris and 17% (221/1307) in patients randomized to placebo (RR: 1.08, 95% CI: 0.91-1.27).

The results of Studies 1 and 2 do not provide evidence of benefit of Xigris in patients with severe sepsis who are not at high risk of death (e.g., patients with single-organ dysfunction or APACHE II score <25). Xigris is not indicated for such patients.

Study 3: Benefit Not Demonstrated in Treatment of Pediatric Severe Sepsis Patients

A randomized, double-blind, placebo-controlled trial (“RESOLVE”) of Xigris (96-hour infusion at 24 mcg/kg/hr) was conducted in 477 pediatric patients with severe sepsis (age limits ≥38 weeks corrected gestational age to <18 years). Patients were required to have both sepsis-induced cardiovascular and respiratory organ dysfunction (defined as treatment with vasoactive agents despite adequate fluid resuscitation and invasive mechanical ventilation).

The study was stopped after a planned interim analysis showed Xigris was unlikely to show statistically significant improvement over placebo, a composite endpoint based on time to resolution of organ dysfunction (cardiovascular, respiratory, and renal), incorporating also unresolved organ dysfunction and mortality.

Central nervous system bleeding occurred in a greater number of Xigris-treated patients during the 28-day study period; this difference was most pronounced in patients aged 60 days or younger (≤60 days: 4/24 Xigris-treated patients versus 0/26 placebo-treated patients; >60 days: 7/216 Xigris-treated patients versus 5/211 placebo-treated patients).

All-cause mortality at 28 days was similar in the Xigris and placebo groups, as were the rates of all serious bleeding events, all serious adverse events, fatal CNS bleeding events, and major amputations.

The results of this study do not provide evidence of benefit of Xigris in pediatric patients with severe sepsis.

Study 4: Coadministration of Heparin for VTE Prophylaxis in Xigris-Treated Patients

A randomized, double-blind, placebo-controlled trial (“XPRESS”) investigated the safety of heparin for VTE prophylaxis when concomitantly administered with Xigris (96-hour infusion at 24 mcg/kg/hr) in adult patients with severe sepsis who were at high risk of death (n=1935).

Patients were randomized 1:1:2 to receive low molecular weight heparin enoxaparin (40 mg every 24 hours), unfractionated sodium heparin (5000 U every 12 hours), or placebo administered concomitantly with the Xigris infusion. The XPRESS trial did not evaluate the safety of dosing unfractionated heparin every 8 hours in adult patients with severe sepsis when concomitantly administered with Xigris. Outside the Xigris treatment period (prior to study entry and following Xigris infusion), the use of commercially available heparin was left to the discretion of the investigator.

The 28-day all-cause mortality was similar between the heparin-plus-Xigris group (enoxaparin and unfractionated heparin combined) and placebo-plus-Xigris group (28.2%, 275/976, and 31.8%, 305/959, respectively; RR: 0.89, 95% CI: 0.77-1.02). There were no significant differences between the heparin-plus-Xigris and placebo-plus-Xigris groups in the rate of either venous thrombotic or serious bleeding events, including intracranial hemorrhage. Prophylactic heparin increased the risk of non-serious bleeding compared with placebo over the treatment period of 0-6 days. The rate of ischemic stroke was lower in the heparin-plus-Xigris group over days 0-6 (heparin-plus-Xigris 3/976, 0.3% versus placebo-plus-Xigris, 12/959, 1.3%).

In the subgroup of 889 patients receiving commercially available heparin at study entry, those patients randomized to placebo had higher mortality [placebo-plus-Xigris 35.5% (154/434) versus heparin-plus-Xigris 26.8% (122/455)] and higher rate of serious adverse events [placebo-plus-Xigris 18.0% (78/434) versus heparin-plus-Xigris 11.6% (53/455)] compared with patients in whom commercial heparin was replaced by study heparin [see Warnings and Precautions (5.3)]. Increased serious adverse events in this subgroup included cardiac, gastrointestinal, and venous thrombotic events. In patients not receiving commercial heparin at study entry, mortality and the rate of serious adverse events were similar between heparin-plus-Xigris and placebo-plus-Xigris groups.

Knaus WA, et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-829.

Xigris is administered in the intensive care unit, and in this setting, patients may be unresponsive or may have difficulty comprehending counseling information.

Patients and patients' caregivers should be informed by their healthcare provider of the potential benefits and risks associated with Xigris, including the most common side effect, bleeding. Patients with clinical conditions likely to increase the risk of bleeding should be carefully evaluated and anticipated benefits weighed against potential risks associated with Xigris therapy [see Contraindications (4), Warnings and Precautions (5.1), and Adverse Reactions (6)].

Literature Revised October 9, 2008

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VL 7561

Drotrecogin alfa (activated)

Xigris®

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