Activated Protein C
- Xigris, Drotecogin alfa (activated)
- Drotrecogin alfa is indicated in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death with an APACHE II score of >25 Note: – Drotrecogin alfa is an expensive drug and its use in severe sepsis remains controversial. It should only be administered with ICU Consultant authorisation.
PRESENTATION AND ADMINISTRATION:
- IV: Calculate the dose and the number of drotrecogin alfa vials needed. Each drotrecogin alfa vial contains 5mg of drotrecogin alfa. The vial contains an excess of drotrecogin alfa to facilitate delivery of the label amount. Prior to administration, 5 mg vials must be reconstituted with 2.5 ml sterile water for injection. The resulting concentration of the solution is approximately 2 mg/ml of drotrecogin alfa. Slowly add the sterile water for injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved.
- The solution of reconstituted drotrecogin alfa must be further diluted with sterile 0.9% sodium chloride. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa solution from the vial. Add the reconstituted drotrecogin alfa into a prepared infusion bag of sterile 0.9% sodium chloride. When adding the drotrecogin alfa 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.
- Compatible with the following IV fluids: Normal saline, 5% dextrose, Glucose and Sodium Chloride, Hartmanns
- Do not mix with other medicines – use a dedicated lumen.
- Because drotrecogin alfa contains no antibacterial preservatives, the intravenous solution should be prepared immediately upon reconstitution of the drotrecogin alfa in the vial(s). If the vial of reconstituted drotrecogin alfa is not used immediately, it may be held at room temperature, but must be used within 3 hours. Intravenous administration must be completed within 12 hours after the intravenous solution is prepared. Off-license – studies indicate that infusions (100-200mcg/ml) are stable for up to 14 hours at room temperature. Also, these infusions can be stored at 2-8°C for up to 12 hours and then administered completing infusion within 24 hours of preparation.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. When using an intravenous infusion pump to administer the drug, the solution of reconstituted drotrecogin alfa is typically diluted into an infusion bag containing sterile 0.9% sodium chloride injection to a final concentration of between 100 and 200mcg/ml. When using a syringe pump to administer the drug, the solution of reconstituted drotrecogin alfa is typically diluted with sterile 0.9% sodium chloride injection to a final concentration of between 100 and 1000 mcg/ml.
- Use a low protein binding infusion set. When administering drotrecogin alfa at low concentrations (less than approximately 200 mcg/ml) at low flow rates (less than approximately 5 ml/h), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 ml/h.
- Drotrecogin alfa should be administered via a dedicated intravenous line or a dedicated lumen of a multilumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% sodium chloride injection, lactated Ringer’s injection, dextrose, or dextrose and saline mixtures.
Dosing Guide for 12 hour infusion bags [TABLE]
- IV: Drotrecogin alfa should be administered intravenously at an infusion rate of 24 mcg/kg/ hr for a total duration of infusion of 96 hours. If the infusion is interrupted, drotrecogin alfa should be restarted at the 24 mcg/kg/hr infusion rate.
DOSAGE IN RENAL FAILURE AND RENAL REPLACEMENT THERAPY:
- Dose as in normal renal function
DOSAGE IN PAEDIATRICS:
- IV: Available data do not support use in paediatrics see PRECAUTIONS Paediatric Use
- Xigris [drotrecogin alfa (activated)] is a recombinant form of human Activated Protein C. Activated Protein C exerts an antithrombotic effect by inhibiting Factors Va and VIIIa. In vitro data indicate that Activated Protein C has indirect profibrinolytic activity through its ability to inhibit plasminogen activator inhibitor-1 (PAI-1) and limiting generation of activated thrombin-activatable-fibrinolysis-inhibitor. Additionally, in vitro data indicate that Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumour necrosis factor production by monocytes, by blocking leukocyte adhesion to selectins, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium.
Drotrecogin alfa increases the risk of bleeding. Drotrecogin alfa is contraindicated in patients with the following clinical situations in which bleeding could be associated with a high risk of death or significant morbidity:
- 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.
- Bleeding is the most common serious adverse effect associated with drotrecogin alfa therapy. Each patient being considered for therapy with 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 clinical trials, are likely to increase the risk of bleeding with drotrecogin alfa therapy. Therefore, for patients with severe sepsis who have one or more of the following conditions, the increased risk of bleeding should be carefully considered when deciding whether to use drotrecogin alfa therapy:
- Concurrent therapeutic heparin
- Platelet count <30,000, even if the platelet count is increased after transfusions.
- 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 >650mg 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 drotrecogin alfa. Continued use of other agents affecting the coagulation system should be carefully assessed. Once adequate hemostasis has been achieved, continued use of drotrecogin alfa may be reconsidered.
- 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, initiation of drotrecogin alfa may be reconsidered 12 hours after major invasive procedures or surgery or restarted immediately after uncomplicated less invasive procedures.
- General: Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving drotrecogin alfa has not been adequately determined, as the assay sensitivity is inadequate to reliably detect all potential antibody responses. One patient in the Phase 2 trial developed antibodies to drotrecogin alfa without clinical sequelae. One patient in the Phase 3 trial who developed antibodies to drotrecogin alfa developed superficial and deep vein thrombi during the study, and died of multi-organ failure on day 36 post-treatment but the relationship of this event to antibody is not clear. Drotrecogin alfa has not been readministered to patients with severe sepsis.
- Laboratory Tests: No tests in addition to routine ICU tests are required.
- Drug/Laboratory Test Interactions: 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). Drotrecogin alfa may variably prolong the APTT. Therefore, the APTT cannot be reliably used to assess the status of the coagulopathy during drotrecogin alfa infusion. Drotrecogin alfa has minimal effect on the PT and the PT can be used to monitor the status of the coagulopathy in these patients.
IMPORTANT DRUG INTERACTIONS FOR THE ICU
- Drug interactions with drotrecogin alfa have not been studied in patients with severe sepsis. Caution should be employed when drotrecogin alfa is used with other drugs that affect haemostasis. Approximately 2/3 of the patients in the Phase 3 study received prophylactic low dose heparin. Concomitant use of prophylactic low dose heparin did not appear to affect safety and should be continued.
- Serious bleeding events occur in approximately 1 in 100 patients and include intracranial haemorrhage, gastrointestinal haemorrhage and retroperitoneal haemorrhage.