drotrecogin alfa (activated)

Pharmacologic classification: recombinant human activated protein C
Therapeutic classification: anti-infective
Pregnancy risk category C

Available forms
Available by prescription only
Injection: 5 mg, 20 mg

Indications and dosages
 Reduction of mortality in patients with severe sepsis (sepsis from acute organ dysfunction) who are at risk for dying. Adults: 24 mcg/kg/hr I.V. infusion for a total of 96 hours.

Anti-infective action: The antisepsis action of drotrecogin alfa is unknown. Drug is thought to produce dose-dependent reductions in D-dimer and IL-6. Activated protein C exerts an antithrombic effect by inhibiting factors Va and VIIIa. Compared with patients given placebo, those treated with drotrecogin alfa experienced more rapid declines in D-dimer, PAI-1 levels, thrombin-antithrombin levels, prothrombin F1.2, and IL-6; more rapid increases in protein C and antithrombin levels; and normalization of plasminogen.

Absorption: Administered I.V.
Distribution: No information available.
Metabolism: No information available.
Excretion: No information available.

Route Onset Peak Duration
I.V. Unknown Unknown Unknown

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or its components. Also contraindicated in those with 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.
  Use cautiously with other drugs that affect hemostasis. The increased risk of bleeding should be considered in patients taking heparin (15 units/ kg/hr or more) and in those with a platelet count less than 30,000 × 106/L (even if platelet count is increased after transfusions), a PT/INR greater than 3.0, recent (within 6 weeks) GI 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 (more than 650 mg/day) or other platelet inhibitors, recent (within 3 months) ischemic stroke, intracranial arteriovenous malformation or aneurysm, bleeding diathesis, chronic severe liver disease, and other conditions in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

Drug-drug. Drugs that affect hemostasis: Increases risk of bleeding. Use together cautiously.

Adverse reactions
Hematologic: hemorrhage.

Effects on lab test results
• May prolong PT and activated partial thromboplastin time.

Overdose and treatment
There is no known antidote. If overdose occurs, immediately stop infusion and monitor patient closely for hemorrhagic complications.

Special considerations
• Use aseptic technique during preparation.
• Before administration, reconstitute 5-mg vials with 2.5 ml sterile water for injection, USP and 20-mg vials with 10 ml of sterile water for injection, USP. Resulting concentration is about 2 mg/ml. Slowly add the sterile water for injection to vial and avoid inverting or shaking vial. Gently swirl each vial until powder is completely dissolved.
• Further dilute reconstituted solution with sterile normal saline injection. Withdraw appropriate amount of reconstituted drug into a prepared infusion bag of sterile normal saline injection. When adding the drug, direct stream to side of bag to minimize agitation of the solution.
• Gently invert infusion bag to obtain a homogenous solution. Don’t transport infusion bag between locations by way of mechanical delivery systems.
• Prepare I.V. solution immediately after reconstitution because drug contains no preservative.
• If reconstituted vial isn’t used immediately, it may be held at controlled room temperature (59° to 86° F) [15° to 30° C]) but must be used within 3 hours.
• I.V. administration must be completed within 12 hours after I.V. solution is prepared.
• Inspect for particle matter and discoloration before administration.
• If infusion is interrupted, restart at the 24-mcg/ kg/hour infusion rate. Dose escalation, bolus doses, and dosage adjustment based on clinical or laboratory parameters aren’t recommended.
• Monitor patient closely for bleeding. If clinically important bleeding occurs, immediately stop infusion.
• Stop drug 2 hours before an invasive surgical procedure with a risk of bleeding. After hemostasis has been achieved, consider restarting drug 12 hours after major invasive procedures or surgery or immediately after uncomplicated, less invasive procedures.
• Because drug may prolong aPTT, it can’t be reliably used to assess the status of the coagulopathy during infusion. Drug has minimal effect on PT, however, so PT can be used to monitor the status of the coagulopathy.
• When using an I.V. pump for administration, the solution of reconstituted drug is typically diluted into an infusion bag containing sterile normal saline injection to a final concentration of between 100 and 200 mcg/ml.
• When using a syringe pump for administration, the reconstituted solution is typically diluted with sterile normal saline injection to a final concentration of between 100 and 1,000 mcg/ml. When giving at low concentrations (less than about 200 mcg/ml) at low flow rates (less than about 5 ml/hour), prime the infusion set for about 15 minutes at a flow rate of about 5 ml/hour.
• Administer via a dedicated I.V. line or lumen of a multilumen central venous catheter. The only other solutions that can be given through the same line are 0.9% sodium chloride injection, lactated Ringer’s injection, dextrose, or dextrose and saline mixtures.
• The potential for immunogenicity to drug exists.
• Avoid exposing drug to heat or direct sunlight.
• Store in a refrigerator at 35° to 46° F (2° to 8° C). Don’t freeze.
Pregnant patients
• Drug should be used in pregnant women only if clearly needed.
Breast-feeding patients
• It isn’t known whether drug appears in breast milk or is absorbed systemically after ingestion. Because of the potential for adverse effects in the breast-fed infant, stop either breast-feeding or drug, taking into account importance of drug to the mother.
Pediatric patients
• Safety and effectiveness haven’t been established.
Geriatric patients
• No overall differences in safety or effectiveness exist for elderly patients.

Patient education
• Inform patient of potential adverse reactions.
• Instruct patient to promptly report signs of bleeding.
• Advise patient that bleeding may occur for up to 28 days after treatment.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use