Professional Drug Information > Xigris

Drotrecogin Alfa (Systemic)

VA CLASSIFICATION
Primary: BL119

Commonly used brand name(s): Xigris.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antithrombotic—

Indications

Accepted

Sepsis, severe, reduction of mortality in—Drotrecogin alfa 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 acute physiology and chronic health evaluation (APACHE) II scores.^{01}{03}

Note: Acute organ dysfunction defined as one of the following: cardiovascular dysfunction (shock, hypotension, or the need for vasopressor support despite adequate fluid resuscitation); respiratory dysfunction (relative hypoxemia [PaO₂/FiO₂ ratio less than 250]); renal dysfunction (oliguria despite adequate fluid resuscitation); thrombocytopenia (platelet count less than 80,000 per mm ³ or 50% decrease from the highest value the previous 3 days); or metabolic acidosis with elevated lactic acid concentrations.^{01}


Acceptance not established
Efficacy has not been established for reducing the mortality of adult patients with severe sepsis and a lower risk of death .^{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Drotrecogin alfa is a recombinant form of human Activated Protein C.^{01}
Molecular weight—
    Approximately 55 kilodaltons^{01}

Mechanism of action/Effect:

The specific mechanisms by which drotrecogin alfa exerts its effect on survival in patients with severe sepsis are not completely understood.^{01}

In patients with severe sepsis, drotrecogin alfa infusions produced dose dependent declines in D-dimer and IL-6. Compared to placebo, drotrecogin alfa 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.^{01}

Activated Protein C exerts an antithrombotic effect by proteolytic inactivation of Factors Va and VIIIa.^{01}{02} In vitro Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor production by monocytes, by blocking leukocyte adhesion to selectins, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium. In vitro Activated Protein C has indirect profibrinolytic activity through its ability to inhibit plasminogen activator inhibitor-1 and limiting generation of activated thrombin-activatable-fibrinolysis-inhibitor.^{01}

Absorption:

In patients with severe sepsis, steady-state concentrations (C _ss) are proportional to infusion rates of 12 to 30 micrograms per kg of body weight per hour.^{01}

Biotransformation:

Drotrecogin alfa and endogenous Activated Protein C are inactivated by endogenous plasma protease inhibitors.^{01}

Time to steady-state concentration

2 hours.^{01}

Steady-state concentration

45 nanograms per mL.^{01}

Duration of action:

2 hours post infusion— plasma concentrations fell below assay quantitation limit of 10 nanograms per mL.^{01}

Elimination:
    40 L per hr (range of 27 to 52 L per hr)— median clearance.^{01}


Precautions to Consider

Cross-sensitivity and/or related problems

Derived from an established human cell line, drotrecogin alfa has the potential for immunogenicity. The incidence of antibody development has not been adequately determined.^{01}

In clinical trials, two patients had a detectable antibody response, but the relationship of the clinical events to antibody formation is not clear.^{01}

Carcinogenicity

Long-term studies in animals to evaluate potential carcinogenicity of drotrecogin alfa have not been performed.^{01}

Mutagenicity

Drotrecogin alfa 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.^{01}

Pregnancy/Reproduction
Fertility—
The potential of drotrecogin alfa to impair fertility has not been evaluated in male or female animals.^{01}

Pregnancy—
Studies have not been performed in humans^{01}

Drotrecogin alfa should be given to pregnant women only if clearly needed.^{01}

Studies have not been performed in animals. ^{01}

FDA Pregnancy Category C.^{01}

Breast-feeding

It is not known whether drotrecogin alfa is distributed into breast milk or absorbed systemically after ingestion. Due to the potential for adverse effects to the nursing infant, a decision should be made whether to discontinue nursing or discontinue the medicine, taking into account the importance of the drug to the mother.^{01}

Pediatrics

Safety and efficacy have not been established in patients up to 18 years of age.^{01} The efficacy of drotrecogin alfa cannot be extrapolated to pediatric patients with severe sepsis.^{01}


Geriatrics


In clinical studies there was a greater reduction in mortality in patients with more severe physiologic disturbances, in patients with serious underlying disease predating sepsis, and in older patients.^{01}

Studies performed in approximately 910 patients 65 years of age or older have not demonstrated geriatrics-specific problems that would limit the usefulness of drotrecogin alfa in the elderly.^{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Drug interactions have not been studied in patients with severe sepsis.^{01}

» Anticoagulants, oral or^{01}{03}
» Glycoprotein IIb/IIIa inihibitors^{01}{02}{03}    (the risk of bleeding must be weighed against the anticipated benefits when drotrecogin alfa is used within 7 days of these medications^{01})


» Aspirin or^{01}
» Platelet inhibitors^{01}    (the risk of bleeding must be weighed against the anticipated benefits when drotrecogin alfa is used within 7 days of aspirin (more than 650 mg per day) or other platelet inhibitors^{01})


» Heparin^{01}    (concurrent use of 15 units per kg of body weight per hour or greater has not been studied^{03} and may increase the risk of bleeding^{01})


» Thrombolytic agents^{01}    (the risk of bleeding must be weighed against the anticipated benefits when drotrecogin alfa is used within 3 days of these medications^{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
APTT assay    (drotrecogin alfa may variably prolong the APTT (activated partial thromboplastin time). Present in plasma samples, it may interfere with one-stage coagulation assays based on the APTT (such as factor VIII, IX, and XI assays); this interaction may result in an apparent factor concentration that is lower than the true concentration^{01})


Note: Drotrecogin alfa has minimal effect on the PT (prothrombin time) and does not interfere with one-stage factor assays such as factor II, V, VII, and X assays.^{01}


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Catheter, epidural, or^{01}
» Cerebral herniation, or^{01}
» Internal bleeding, active, or^{01}
» Intracranial or intraspinal surgery, within 2 months, or^{01}
» Intracranial mass lesion, or^{01}{02}{03}
» Intracranial neoplasm, or^{01}
» Stroke, hemorrhagic, within 3 months, or^{01}
» Trauma, with increased risk of life-threatening bleeding^{01}    (drotrecogin alfa is contraindicated due to the increased risk of bleeding, which could be associated with a high risk of death or significant morbidity^{01})


» Hypersensitivity to drotrecogin alfa^{01}
» Surgical procedure, invasive or with bleeding risk    (drotrecogin alfa should be discontinued 2 hours prior to surgery. After hemostasis has been established, reinitiation of therapy may be considered 12 hours after major invasive procedures or restarted immediately after uncomplicated less invasive procedures.^{01})


Risk-benefit should be considered when the following medical problems exist
Aneurysm, intracranial, or^{01}
Arteriovenous malformation, intracranial, or^{01}
Bleeding diathesis, or^{01}
Hepatic disease, chronic and severe, or^{01}
Platelet count less than 30,000 x 10 ⁶ per L^{01}
Prothrombin time-INR greater than 3.0^{01}    (may increase the risk of bleeding^{01})


» Gastrointestinal bleeding    (the risk of bleeding must be weighed against the anticipated benefits when drotrecogin alfa is used within 6 weeks of this condition^{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Bleeding
^{01}
Note: In clinical trials, 25% of treated patients experienced at least one bleeding event, mainly ecchymoses or gastrointestinal tract bleeding, during a 28-day study period. Serious bleeding, defined as any intracranial hemorrhage, any life-threatening bleed, any bleeding event requiring the administration of more than 3 units of packed red blood cells per day for 2 consecutive days, or any bleeding event assessed as a serious adverse event, occurred in 3.5% of treated patients.^{01}
If clinically important bleeding occurs, drotrecogin alfa should be immediately discontinued.^{01} After hemostasis has been established, reinstitution of therapy may be considered.^{01}






Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Treatment of overdose


Specific treatment:
There is no known antidote for drotrecogin alfa. In case of overdose, stop drotrecogin alfa infusion immediately.^{01}



Monitoring:
Patients experiencing an overdose should be monitored closely for hemorrhagic complications.^{01}



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Drotrecogin Alfa (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to drotrecogin alfa
Other medications, especially aspirin, glycoprotein IIb/IIIa inhibitors, heparin, oral anticoagulants, platelet inhibitors, and thrombolytic agents.
Other medical problems, especially active internal bleeding, cerebral herniation, use of epidural catheter, gastrointestinal bleeding, hemorrhagic stroke, intracranial mass lesion or neoplasm, recent intracranial or intraspinal surgery, surgical procedure (invasive or with bleeding risk), or trauma with risk of bleeding.

Proper use of this medication

» Proper dosing

Precautions while using this medication
» Importance of following instructions of health care professional to prevent serious bleeding


Side/adverse effects
Signs of potential side effects, especially bleeding.


Parenteral Dosage Forms

DROTRECOGIN ALFA FOR INJECTION

Usual Adult Dose
Reduction of mortality in patients with severe sepsis at high risk of death
Intravenous, 24 mcg per kg of body weight per hour for a total of 96 hours.^{01}

Note: If the infusion is interrupted, drotrecogin alfa should be restarted at the 24 mcg per kg of body weight per hour infusion rate. Dose escalation or bolus doses are not recommended.^{01}



Usual Pediatric Dose
Reduction of mortality in patients with severe sepsis
Safety and efficacy have not been established.^{01}


Usual Geriatric Dose
See Usual adult dose.

Size(s) usually available:
U.S.—


5-mg vial containing 5.3 mg of drotrecogin alfa (activated) (Rx) [Xigris (sodium chloride 40.3 mg) ( sodium citrate 10.9 mg) (sucrose 31.8 mg)]^{01}


20-mg vial containing 20.8 mg of drotrecogin alfa (activated) [Xigris (sodium chloride 158.1 mg) (sodium citrate 42.9 mg) (sucrose 124.9 mg)]^{01}

Packaging and storage:
Unreconstituted vials: Store in a refrigerator between 36 and 46° F (2 and 8° C). Protect from light. Retain in carton until time of use. Do not freeze. Do not use beyond the expiration date.^{01}

Reconstituted intravenous solution: May be stored at controlled room temperature between 59 and 86° F (15 and 30° C), but the infusion must be started within 3 hours.^{01}{03}

Preparation of dosage form:
Reconstitute the 5-mg vial with 2.5 mL of Sterile Water for Injection, USP and the 20-mg vial with 10 mL of Sterile Water for Injection, USP.^{01} The resulting concentration of drotrecogin alfa is 2 mg per mL.^{01}

Do not invert or shake the vial. Gently swirl the vial until all of the powder is completely dissolved.^{01}

Withdraw the appropriate amount of reconstituted drotrecogin alfa and add to an infusion bag of sterile 0.9% Sodium Chloride Injection. When adding the reconstituted 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 homogenous solution.^{01}

Do not transport the infusion bag between locations using mechanical delivery systems.^{01}

Inspect visually for particulate matter and discoloration prior to administration.^{01}

Drotrecogin alfa should be administered via a dedicated intravenous line or a dedicated lumen of a multilumen central venous catheter.^{01}

Intravenous infusion pump administration—The solution of reconstituted drotrecogin alfa is typically diluted into an infusion bag containing sterile 0.9% Sodium Chloride Injection to a final concentration between 100 and 200 micrograms per mL.^{01}

Syringe pump administration—The solution of reconstituted drotrecogin alfa is typically diluted with sterile 0.9% Sodium Chloride Injection to a final concentration between 100 and 1000 micrograms per mL. When administering at low concentrations (less than approximately 200 micrograms per mL) at low flow rates (less than approximately 5 mL per hour), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 mL per hour.^{01}

Stability:
Intravenous administration must be completed within 12 hours after the intravenous solution is prepared.^{01}

Incompatibilities
No incompatibilities have been observed between drotrecogin alfa and glass infusion bottles or infusion bags and syringes made of polyvinylchloride, polyethylene, polypropylene, or polyolefin.^{01}

The only solutions that can be administered through the same line with drotrecogin alfa are 0.9% sodium chloride injection, Lactated Ringer's injection, dextrose injection, or dextrose and sodium chloride injection.^{01}

Developed: 06/30/2002
Revised: 07/31/2002

References

1. Product Information: Xigris™, drotrecogin alfa. Eli Lilly, Indianapolis, IN, (PI revised 11/2001) reviewed 6/2002.
   

2. Expert Committee comment, 07/17/2002.
   

3. Manufacturer comment, 07/17/2002.
   

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