| Label: Refrigerate. Do not shake.
Mechanism of Action
Activated protein C exerts an antithrombotic effect by inhibiting Factors Va and VIIIa. In vitro data indicate that activated protein C may have indirect profibrinolytic activity through its ability to inhibit plasminogen activator inhibitor-1 (PAI-1) and may exert an anti-inflammatory effect by limiting the chemotactic response of leukocytes to inflammatory cytokines, an inhibitory process mediated by leukocyte cell surface activated protein C receptor. In addition, in vivo data suggest activated protein C may reduce interactions between leukocytes and the microvascular endothelium. In vitro bacterial phagocytosis by neutrophils and monocytes is not affected.
Pharmacodynamics
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.
Dosage and administration:
Xigris should be administered intravenously at an infusion rate of 24 mcg/kg/hr x 96 hours. If the infusion is interrupted, Xigris should be restarted at the initial infusion rate and continued to complete the recommended duration of infusion. Dose escalation or bolus doses of Xigris are not recommended. In the event of clinically important bleeding, immediately stop the infusion. No dosage adjustment is required regardless of age, hepatic impairment, or renal impairment.
Preparation: 12 hour infusion bags: Actual Patient Weight (kg) x Dose (24 mcg/kg/hr) = Amount of Xigris needed per hour.Amount of Xigris needed/hr (µg/hr) x 12 hours ÷ 1000 = mg of Xigris needed per 12 hours – round to the nearest 5-mg increment. The solution of reconstituted Xigris is typically diluted into an infusion bag (0.9% Sodium Chloride) to a final concentration of between 100 mcg/mL - 200 mcg/mL.
Vial dilution: Prior to administration, 5 mg vials must be reconstituted with 2.5 mL of Sterile Water for Injection, USP, and 20 mg vials of Xigris must be reconstituted with 10 mL of Sterile Water for Injection, USP. The resulting concentration of the solution isapproximately 2 mg/mL of Xigris. Slowly add the Sterile Water for Injection, USP tothe vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved. Because Xigris contains no antibacterial preservatives, the intravenous solution should be prepared immediately upon 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. Before further dilution or administration, the product should be inspectedvisually for particulate matter and discoloration. Do not use vials if particulate matter is visible or solution is discolored.
Stability:
After preparation, the intravenous solution should be used at controlled room temperature 20° to 25°C within 14 hours. If the intravenous solution isnot administered immediately, the solution may be stored refrigerated 2° to 8°Cfor up to 12 hours. If the prepared solution is refrigerated prior to administration, the maximum time limit for use of the intravenous solution, including preparation, refrigeration, and administration, is 24 hours.
Instructions for a Syringe Pump: See package insert (The solution of reconstituted Xigris must be further diluted with 0.9% Sodium Chloride Injection, USP to a final concentration of between 100 µg/mL and 1000 µg/mL.)
Actions: Recombinant form of human Activated Protein C. Activated Protein C exerts an antithrombotic effect by inhibiting Factors Va and VIIIa.
Indications: reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death. Efficacy has not been established in adult patients with severe sepsis and lower risk of death.
Contraindications: 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 AND 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 [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 package insert for Drug Interactions]
- 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]
- 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)].
Source: [package insert] |
