General Information

Drotrecogin-alpha is a recombinant form of human activated protein C used to treat severe sepsis. (Severe sepsis is defined as sepsis associated with acute organ dysfunction.) Drotrecogin-alpha has anti-inflammatory, antithrombotic, and profibrinolytic properties.

Indications for Use

Drotrecogin-α 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 (as determined by APACHE II scores)

• Drotrecogin-alpha should only be ordered by a Critical Care Medicine Attending Physician with approval from a second Critical Care Medicine Attending Physician (our institution).

• The Drotrecogin alpha-activated criteria for use sheet must be completed and placed in the patient chart prior to ordering

• Drotrecogin-alpha can only be administered in an Intensive Care Unit (ICU), or a patient awaiting transfer to an ICU.

Pharmacology

The specific mechanisms by which drotrecogin-alpha (activated protein C) exerts its effect on survival in patients with severe sepsis is not completely understood. In vitro data suggest that activated protein C exerts an antithrombotic effect by inhibiting factors Va and VIIIa, and that it has indirect profibrinolytic activity by inhibiting plasminogen activator-inhibitor-1 (PAI-1). In vitro data also suggest that activated protein C may exert an anti-inflammatory effect by inhibiting tumor necrosis factor production, by blocking leukocyte adhesion to selectins, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium.

Pharmacokinetics

• Peak concentrations of drotrecogin-alpha are seen 2 hours after starting the infusion.

• Plasma concentrations of drotrecogin-alpha fall to undetectable levels 2 hours after stopping the infusion.

• Inactivation of drotrecogin-alpha is through endogenous plasma protease inhibitors.

• No dose adjustment is needed in elderly patients, or in patients with renal or hepatic dysfunction.

Precautions

The following patients are at an increased risk for bleeding complications due to drotrecogin-alpha therapy, and a careful risk/benefit assessment should be made prior to initiating therapy.

• Therapeutic Heparin (>15 units/kg/hr)

• Platelet count <30,000/mm3

• Recent (within 6 weeks) gastrointestinal bleeding

• Recent administration (within 3 days) of thrombolytic therapy

• Recent administration (within 7 days) of oral anticoagulants or GP IIb/IIIa inhibitors

• Recent administration (within 7 days) of >650mg/day of aspirin or other platelet inhibitors

• Recent (within 3 months) ischemic stroke

• Known or suspected intracranial AV malformation or aneurysm

• Known bleeding diathesis except for acute coagulopathy related to sepsis

• Chronic severe hepatic disease

• HIV infection in association with a last known CD4 count of <50/mm3

• Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location

Because drotrecogin-alpha is a therapeutic protein, there exists a potential for immunogenicity. Antibodies against drotrecogin have been observed. There is insufficient data at this time to quantify the risk, but extreme caution should be exercised if a patient has previously received drotrecogin-alpha.

Contraindications

The following patients should not receive drotrecogin-alpha:

• Active internal bleeding

• Recent (within 3 months) hemorrhagic stroke

• Recent (within 2 months) intracranial/intraspinal surgery/severe head trauma

• Trauma patients with an increased risk of life threatening bleeding

• Presence of an epidural catheter

• Known or suspected intracranial neoplasm or mass lesion

• Known hypersensitivity to drotrecogin alpha-activated or any component

• Acute pancreatitis without a proven source of infection

• Pregnancy

• Advance directive or patient, family, or physician favor to withhold aggressive treatment or DNR/DNI

• Patient is not expected to survive >28 days because of an uncontrollable medical condition

• Patient is moribund with perceived imminent death within 24 hours

Pharmacy Preparation Guidelines

1. Determine the number of Xigris vials (5 mg and 20 mg ) that will be needed to make the infusion bag . This can be determined by referring to the attached dosing chart. Vials will be stored in the refrigerator (do not freeze).

2. Reconstitution of Xigris Vials5 mg vials must be reconstituted with 2.5 ml Sterile Water for Injection, USP0 mg vials must be reconstituted with 10 ml Sterile Water for Injection, USP

When reconstituted, final concentration = 2 mg/ml of Xigris

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.

3. Remove an amount of fluid from the IV bag equal to the amount of Xigris solution that will be added.

Withdraw the appropriate amount of reconstituted Xigris solution from the vials and add to either a 100 ml or 250 ml bag of 0.9% Sodium Chloride (refer to dosing chart). When adding 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.

4. Stability

Reconstituted vials should be used immediately to make the infusion bag. If not used immediately, they are stable only for 3 hours at room temperature.

Xigris infusion bag is stable for 14 hours from preparation. The bag must be hand delivered to the nursing unit as soon as it is made and checked by a Pharmacist.

5. Labeling (in addition to standard labeling, must contain the following)Drotrecogin Alpha (Xigris) _____ mcg/mlInfusion Rate _____ ml/hrTotal Volume _____ mlExpiration: 14 Hours

6. Manual Dosing Calculation (in the event that there is a patient < 40 kg or > 135 kg)

Step 1 – Calculate the amount of Xigris needed for a 12 hour infusion • Actual Patient Weight (kg) x Dose (24 mcg/kg/hr) = Amount of Xigris needed per hour (mcg/hr)• Amount of Xigris needed per hour (mcg/hr) x 12 hours = mg Xigris needed (12 hr infusion)1000• Round up or down to the nearest 5 mg increment

Step 2 - Determine the Concentration in the bag • Amount of Xigris needed for 12 hour infusion (from Step 1) x 1000 = Final Conc. (mcg/ml)Total Volume of Bag Final Concentration is typically between 100 – 200 mcg/ml

Step 3 – Calculate Final Rate • Amount of Xigris (mcg/hr) – from Step 1 = Rate (ml/hr)Final Conc. (mcg/ml) – from Step 2

Dosing and Administration

• The dose of drotrecogin-alpha is 24 mcg/kg/hr based on total body weight as a continuous infusion for 96 hours

• The pharmacy will prepare 12 hour infusion bags and will calculate the appropriate infusion rate.

• Pharmacy should be notified at least 1 hour before the next infusion bag is needed

• Drotrecogin-alpha must be administered by a dedicated intravenous line or a dedicated lumen of a multilumen catheter. The ONLY other solutions that can be administered through the same line are 0.9% Sodium Chloride injection, Lactated Ringer’s Injection, and Dextrose or Dextrose/Saline mixtures.

• Drotrecogin-alpha should be discontinued 2 hours prior to undergoing an invasive surgical procedure or procedures with an inherent risk of bleeding. Once hemostasis has been achieved, drotrecogin-alpha may be reconsidered 12 hours after major invasive procedures or surgery or restarted immediately after uncomplicated less invasive procedures. (To complete a total of 96 hours of therapy)

• Should clinically important bleeding occur while on drotrecogin-α therapy, immediately stop the infusion. Once adequate hemostasis has been achieved, continued use of drotrecogin-α may be reconsidered. (To complete a total of 96 hours of therapy)

Adverse Events

• The main adverse event associated with drotrecogin-alpha therapy is bleeding.

• There are no other adverse events that have been associated with drotrecogin-alpha.

Drug/Drug Interactions

• Drug interactions with drotrecogin-alpha have not been studied in patients with severe sepsis.

• Caution should be exercised when using other drugs that affect hemostasis with drotrecogin-alpha.

• The use of low dose prophylactic heparin did not affect safety when given concurrently with drotrecogin-alpha.

Monitoring

Compatibility and Stability of Drotrecogin-alpha

• Drotrecogin-alpha must be administered by a dedicated intravenous line or a dedicated lumen of a multilumen catheter

• The ONLY other solutions that can be administered through the same line are 0.9% Sodium Chloride injection, Lactated Ringer’s Injection, and Dextrose or Dextrose/Saline mixtures.

• All bags of drotrecogin-alpha are stable for 14 hours once mixed. The pharmacy will prepare bags that will have 12 hour infusion times

Check List

Drotrecogin alpha-activated (Xigris): Criteria Form Criteria for Use in Adults (> 18 yrs of age)

Figure 1

Figure 2