Xigris

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 score ≥ 25).

Limitations of use:

Xigris is not indicated in adult patients with severe sepsis and a lower risk of death (e.g., APACHE II score < 25).

Xigris is not indicated in pediatric patients.

Recommended Dosing and Administration Overview

Xigris 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 are not recommended.

If the infusion is interrupted, Xigris should be restarted at the 24 mcg/kg/hr infusion rate.

In the event of clinically important bleeding, immediately stop the infusion.

Xigris 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 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.

Preparation of the Concentrated Solution

Note: Reconstitute vials of lyophilized Xigris only with Sterile Water for Injection, USP.

1. Use appropriate aseptic technique during the preparation of Xigris for intravenous administration.
2. Calculate the approximate amount of Xigris needed based upon the patient's actual body weight and duration of infusion period. The maximum duration of infusion from one infusion bag or syringe is 12 hours. Multiple infusion periods will be needed to cover the entire 96-hour duration of administration.
   mg of Xigris = (patient weight, kg) x (24 mcg/kg/hr) x (hours of infusion) ÷ (1000)
   Round the actual amount of Xigris to be prepared to the nearest 5 mg increment to avoid discarding reconstituted Xigris.
3. Determine the number of vials of Xigris needed to make up this amount.
4. Reconstitute each vial of Xigris only with Sterile Water for Injection, USP. The 5 mg vials must be reconstituted with 2.5 mL. The 20 mg vials must be reconstituted with 10 mL. 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. The resulting Xigris concentration of the solution is 2 mg/mL.
5. Xigris contains no antibacterial preservatives; the intravenous solution should be prepared immediately after 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.
6. Inspect the reconstituted Xigris in the vials for particulate matter and discoloration before further dilution. Do not use vials if particulate matter is visible or the solution is discolored.

Dilution and Administration Instructions for an Intravenous Infusion Pump Using an Infusion Bag

Complete “Preparation of Concentrated Solution” steps 1-6 above, then complete the next 7 steps.

1. 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 0.1 mg/mL and 0.2 mg/mL. Bag volumes between 50 mL and 250 mL are typical.
2. Confirm that the intended bag volume will result in an acceptable final concentration.
   Final concentration, mg/mL = (actual Xigris amount, mg) ÷ (bag volume, mL)
   If the calculated final concentration is not between 0.1 mg/mL and 0.2 mg/mL, select a different bag volume and recalculate the final concentration.
3. Slowly withdraw the reconstituted Xigris solution from the vial(s) and add the reconstituted Xigris into the 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.
4. Calculate the actual duration of the infusion period for the diluted Xigris.
   Infusion period, hours = (actual Xigris amount, mg) x (1000) ÷ (patient weight, kg) ÷ (24 mcg/kg/hr)
5. Account for the added volume of reconstituted Xigris (0.5 mL per mg of Xigris used) and the volume of bag saline solution removed (if saline solution is removed prior to adding the reconstituted Xigris ).
   Final bag volume, mL = (starting bag volume, mL) + (reconstituted Xigris volume, mL) - [saline volume removed (if any), mL]
6. Calculate the actual infusion rate of the diluted Xigris.
   Infusion rate, mL/hr = (final bag volume, mL) ÷ (infusion period, hours)
7. After preparation in an infusion bag, 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, including dilution, refrigeration, and administration, is 24 hours.

Dilution and Administration Instructions for a Syringe Pump

Complete “Preparation of Concentrated Solution” steps 1-6 above, then complete the next 7 steps.

1. The solution of reconstituted Xigris must be further diluted with 0.9% Sodium Chloride Injection, USP to a final concentration of between 0.1 mg/mL and 0.2 mg/mL.
2. Confirm that the intended solution volume will result in an acceptable final concentration.
   Final concentration, mg/mL = (actual Xigris amount, mg) ÷ (solution volume, mL)
   If the calculated final concentration is not between 0.1 to 0.2 mg/mL, select a different volume and recalculate the final concentration.
3. 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 volume of diluted Xigris. Gently invert and/or rotate the syringe to obtain a homogeneous solution.
4. Calculate the actual duration of the infusion period for the diluted Xigris.
   Infusion period, hours = (actual Xigris amount, mg) x (1000) ÷ (patient weight, kg) ÷ (24 mcg/kg/hr)
5. Calculate the actual infusion rate of the diluted Xigris.
   Infusion rate, mL/hr = (solution volume, mL) ÷ (infusion period, hours)
6. When administering Xigris using a syringe pump 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.
7. After preparation in a syringe, 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, including dilution, refrigeration, and administration, is 24 hours.

Xigris increases the risk of bleeding. Xigris is contraindicated in the following clinical situations where bleeding could lead to significant morbidity or death:

• 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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 , 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
• 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
• 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.

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.

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.

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 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.

Use In Specific Populations

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.

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.

Bleeding is the most commonly reported adverse reaction in patients receiving Xigris therapy. 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.

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 , 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

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.

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) 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 , 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

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.

There is no known antidote for Xigris. 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 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.

The specific pharmacologic effects by which Xigris exerts its effect on survival in patients with severe sepsis are not completely understood. In patients with severe sepsis, Xigris infusions of 48 or 96 hours produced dose-dependent declines in D-dimer and IL-6. Compared with placebo, Xigris -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 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.