Drotrecogin Alfa

Special Alerts

Drotrecogin: Health Canada Issues Safety Warning

Eli Lilly Canada Inc, in conjunction with Health Canada, has informed healthcare professionals of new product labeling based on safety information regarding drotrecogin alfa (Xigris®). The new labeling applies only to patients with single-organ dysfunction and recent surgery. These patients may not be at high risk of death, therefore, treatment with drotrecogin may not be indicated. The labeling revision is based on post-hoc exploratory subgroup analyses of the ADDRESS and PROWESS trials which showed that patients with single-organ dysfunction and recent surgery (within 30 days) demonstrated a numerically higher mortality rate when treated with drotrecogin as compared to placebo. Of note, the higher mortality rate was not statistically significant.

Additional information is available at http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/xigris_nth_e.html; last accessed February 7, 2005.

Pronunciation

(dro TRE coe jin AL fa)

U.S. Brand Names

Xigris®

Synonyms

Activated Protein C, Human, Recombinant; Drotrecogin Alfa, Activated; Protein C (Activated), Human, Recombinant

Generic Available

No

Canadian Brand Names

Xigris®

Use

Reduction of mortality from severe sepsis (associated with organ dysfunction) in adults at high risk of death (eg, APACHE II score 25)

Use - Unlabeled/Investigational

Purpura fulminans

Pregnancy Risk Factor

C

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to drotrecogin alfa or any component of the formulation; active internal bleeding; recent hemorrhagic stroke (within 3 months); severe head trauma (within 2 months); recent intracranial or intraspinal surgery (within 2 months); intracranial neoplasm or mass lesion; evidence of cerebral herniation; presence of an epidural catheter; trauma with an increased risk of life-threatening bleeding

Warnings/Precautions

Increases risk of bleeding; careful evaluation of risks and benefit is required prior to initiation (see Contraindications). Bleeding risk is increased in patients receiving concurrent therapeutic heparin, oral anticoagulants, glycoprotein IIb/IIIa antagonists, platelet aggregation inhibitors, or aspirin at a dosage of >650 mg/day (within 7 days). In addition, an increased bleeding risk is associated with prolonged INR (>3.0), gastrointestinal bleeding (within 6 weeks), decreased platelet count (<30,000/mm³), thrombolytic therapy (within 3 days), recent ischemic stroke (within 3 months), intracranial AV malformation or aneurysm, known bleeding diathesis, severe hepatic disease (chronic), or other condition where bleeding is a significant hazard or difficult to manage due to its location. Discontinue if significant bleeding occurs (may consider continued use after stabilization). Suspend administration for 2 hours prior to invasive procedures or other procedure with significant bleeding risk; may continue treatment immediately following uncomplicated, minimally-invasive procedures, but delay for 12 hours after major invasive procedures/surgery. During treatment, aPTT cannot be used to assess coagulopathy (PT/INR not affected).

Efficacy not established in adult patients at a low risk of death (APACHE II score <25). Patients with pre-existing nonsepsis-related medical conditions with a poor prognosis (anticipated survival <28 days), patients with acute pancreatitis (no established source of infection), HIV-infected patients with a CD4 count 50 cells/mm³, chronic dialysis patients, pre-existing hypercoagulable conditions, and patients who had received bone marrow, liver, lung, pancreas, or small bowel transplants were excluded from the clinical trial which established benefit. In addition, patients with a high body weight (>135 kg) were not evaluated. Safety and efficacy have not been established in pediatric patients.

Adverse Reactions

As with all drugs which may affect hemostasis, bleeding is the major adverse effect associated with drotrecogin alfa. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the dosage administered, concurrent use of multiple agents which alter hemostasis, and patient predisposition.

>10%

Dermatologic: Bruising

Gastrointestinal: Gastrointestinal bleeding

1% to 10%: Hematologic: Bleeding (serious 2.4% during infusion vs 3.5% during 28-day study period; individual events listed as <1%)

<1%: Gastrointestinal hemorrhage, intrathoracic hemorrhage, retroperitoneal bleeding, genitourinary bleeding, intracranial hemorrhage (0.2%; frequencies up to 2% noted in a previous trial without placebo control), skin/soft tissue bleeding, immune reaction (antibody production)

Overdosage/Toxicology

No reported experience with overdose. Hemorrhagic complications are likely consequence of overdose. Treatment is supportive, including immediate interruption of the infusion and monitoring for hemorrhagic complications. No known antidote.

Drug Interactions

No formal drug interaction studies have been conducted.

Antiplatelet agents: Aspirin (>650 mg/day), cilostazol, clopidogrel, dipyridamole, ticlopidine, or glycoprotein IIb/IIIa antagonists: Concurrent or recent use (aspirin or IIb/IIIa antagonists within 7 days) may increase risk of bleeding.

Antithrombin III: Concurrent or recent use (within 12 hours) may increase risk of bleeding.

Danaparoid: Concurrent or recent use may increase risk of bleeding.

Heparin: Concurrent use of heparin at therapeutic rates of infusion may increase the risk of bleeding. However, the use of low-dose prophylactic heparin does not appear to affect safety.

LMWHs: Concurrent or recent use (within 12 hours) may increase risk of bleeding. Primary clinical trial permitted dosages used prophylactically.

NSAIDs: Concurrent use may increase risk of bleeding. Approximately 4-6 half-lives are required for antiplatelet effects to decrease.

Thrombolytic agents: Use within 3 days of drotrecogin alfa may increase risk of bleeding.

Warfarin; Use within 7 days of drotrecogin alfa and/or elevation of INR 3 may increase risk of bleeding.

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Recent use/intake of herbs with anticoagulant or antiplatelet activity (including cat's claw, feverfew, garlic, ginkgo, ginseng, and horse chestnut seed) may increase the risk of bleeding.

Stability

Store vials under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light. Do not freeze. Reconstitute 5 mg vials with 2.5 mL and 20 mg vials with 10 mL sterile water for injection (resultant solution ~2 mg/mL). Must be further diluted (within 3 hours of reconstitution) in 0.9% sodium chloride, typically to a concentration between 100 mcg/mL and 200 mcg/mL when using infusion pump and between 100 mcg/mL and 1000 mcg/mL when infused via syringe pump. Although product information states administration must be completed within 12 hours of preparation, additional studies (data on file, Lilly Research Laboratories) show that the final solution is stable for 14 hours at 15°C to 30°C (59°F to 86°F). If not used immediately, a prepared solution may be stored in the refrigerator for up to 12 hours. The total expiration time (refrigeration and administration) should be 24 hours from time of preparation.

Compatibility

Stable in NS; only NS, dextrose, LR, or dextrose/saline mixtures may be infused through the same line.

Y-site administration: Compatible: Ceftriaxone, cisatracurium, fluconazole, nitroglycerin, potassium chloride, vasopressin. Incompatible: Amiodarone, ampicillin/sulbactam sodium, ceftazidime, ciprofloxacin, clindamycin, cyclosporine, dobutamine hydrochloride, dopamine hydrochloride, epinephrine hydrochloride, fosphenytoin, furosemide, gentamicin sulfate, heparin sodium, human serum albumin, imipenem/cilastatin sodium, insulin human (regular), levofloxacin, magnesium sulfate, metronidazole, midazolam hydrochloride, nitroprusside sodium, norepinephrine bitartrate, piperacillin/tazobactam sodium, potassium phosphate, ranitidine hydrochloride, ticarcillin/clavulanate, tobramycin sulfate, vancomycin hydrochloride

Mechanism of Action

Inhibits factors Va and VIIIa, limiting thrombotic effects. Additional in vitro data suggest inhibition of plasminogen activator inhibitor-1 (PAF-1) resulting in profibrinolytic activity, inhibition of macrophage production of tumor necrosis factor, blocking of leukocyte adhesion, and limitation of thrombin-induced inflammatory responses. Relative contribution of effects on the reduction of mortality from sepsis is not completely understood.

Pharmacodynamics/Kinetics

Duration: Plasma nondetectable within 2 hours of discontinuation

Metabolism: Inactivated by endogenous plasma protease inhibitors; mean clearance: 40 L/hour; increased with severe sepsis (~50%)

Half-life elimination: 1.6 hours

Dosage

I.V.:

Children and Adults: Purpura fulminans (unlabeled use): 24 mcg/kg/hour

Adults: Sepsis: 24 mcg/kg/hour for a total of 96 hours; stop infusion immediately if clinically-important bleeding is identified

Dosage adjustment in renal impairment: No specific adjustment recommended.

Administration

Infuse separately from all other medications. Only dextrose, normal saline, dextrose/saline combinations, and lactated Ringer's solution may be infused through the same line. May administer via infusion pump. Administration of prepared solution must be completed within 12 hours of preparation. Suspend administration for 2 hours prior to invasive procedures or other procedure with significant bleeding risk; may continue treatment immediately following uncomplicated, minimally-invasive procedures, but delay for 12 hours after major invasive procedures/surgery.

Monitoring Parameters

Monitor for signs and symptoms of bleeding, hemoglobin/hematocrit, PT/INR, platelet count

Test Interactions

May interfere with one-stage coagulation assays based on the aPTT (such as factor VIII, IX, and XI assays).

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. This medication can only be administered by infusion. You will be monitored closely. Report immediately any unusual or acute abdominal pain or headache, or respiratory difficulty. You will be more susceptible to bleeding and bruising; remain in bed and ring for assistance to avoid falling or injuring yourself. Avoid sharps of any kind (knives, scissors, needles, nail clippers, etc; shave with a safety razor). Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Breast-feeding is not recommended.

Additional Information

Prepared by recombinant DNA technology in human cell line

Anesthesia and Critical Care Concerns/Other Considerations

The inclusion criteria for the PROWESS trial (N Eng J Med, 2001, 344:699-709) may help in patient selection since it is the sole published clinical trial evaluating a fixed dose of drotrecogin alfa in severe sepsis. The patients included had a known or suspected infection, three or more signs of systemic inflammatory syndrome (SIRS) and sepsis-induced acute organ dysfunction. Indicators of infection included: White cells in a normally sterile body fluid, perforated viscus, radiographic evidence of pneumonia in association with purulent sputum, a syndrome associated with a high risk of infection (eg, ascending cholangitis). Modified (SIRS) criteria (needed 3 criteria): A core temperature of 38°C (100.4°F) or 36°C (96.8°F); heart rate 90 bpm except in patient with a medical condition known to increase the heart rate or those receiving treatment that would prevent tachycardia; respiratory rate 20 breaths/minute, a PaCO2 32 mm Hg, or the use of mechanical ventilation; WBC count 12000/mm³, 4000/mm³, or a differential count with >10% immature neutrophils. Criteria for organ dysfunction included arterial blood pressure 90 mm Hg or a MAP 70 mm Hg for at least 1 hour despite adequate fluid resuscitation, adequate intravascular volume status, or the use of vasopressors; urine output <0.5 mL/kg/hour for 1 hour despite adequate fluid resuscitation; PaO2/FiO2 250 in the presence of other dysfunctional organ systems or 200 if the lung is the only dysfunctional organ; platelet count <80,000/mm³ or acute decrease by 50%; unexplained metabolic acidosis with a high plasma lactate level.

Drotrecogin alfa should not be given to patients with clinical signs of mild-moderate sepsis (low risk septic patients with APACHE II scores <25) who do not have evidence of acute end-organ injury. By design, the study also excluded patients with a higher risk of bleeding. Incidence of bleeding may be higher in these patients than reported in study.

Drotrecogin alfa has a shorter stability time than was originally suggested. This may lead to some confusion. Additional studies (data on file, Lilly Research Laboratories) show that the final solution is stable for 14 hours at controlled room temperature 15°C to 30°C (59°F to 86°F). If not used immediately, a prepared solution may be stored in the refrigerator for up to 12 hours. The total expiration time (refrigeration and administration) should be 24 hours from time of preparation. Due to brief stability consider these dilutions for infusion pumps: 5 mg/50 mL, 10 mg/100 mL, 15 mg/150 mL, 20 mg/200 mL.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: As with all drugs which may affect hemostasis, bleeding is the major adverse effect associated with drotrecogin alfa. Hemorrhage may occur at virtually any site; risk is dependent on multiple variables, including the dosage administered, concurrent use of multiple agents which alter hemostasis, and patient predisposition.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Injection, powder for reconstitution [preservative free]: 5 mg [contains sucrose 31.8 mg], 20 mg [contains sucrose 124.9 mg]

References

Bachli EB, Vavricka SR, Walter RB, et al, "Drotrecogin Alfa (Activated) for the Treatment of Meningococcal Purpura Fulminans,"Intensive Care Med, 2003, 29(2):337.

Bernard GR, Ely EW, Wright TJ, et al, "Safety and Dose Relationship of Recombinant Human Activated Protein C for Coagulopathy in Severe Sepsis,"Crit Care Med, 2001, 29(11):2051-9.

Bernard GR, Vincent JL, Laterre PF, et al, "Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis,"N Engl J Med, 2001, 344(10):699-709.

Cone LA, Waterbor RB, and Sofonio MV, "Purpura Fulminans Due to Streptococcus pneumoniae Sepsis Following Gastric Bypass,"Obes Surg. 2004, 14(5):690-4.

Mann HJ, Demmon SL, Boelk DA, et al, "Physical and Chemical Compatibility of Drotrecogin Alfa (Activated) With 34 Drugs During Simulated Y-Site Administration,"Am J Health Syst Pharm, 2004, 61(24):2664-71.

International Brand Names

Xigris® (AR, BE, CA, CH, CO, DE, DK, ES, FI, FR, GB, IE, IL, NO, PL, RO, SE, SG, ZA)