Xigris

Generic Name: Drotrecogin Alfa (Activated)
Class: Other Miscellaneous Therapeutic Agents
Chemical Name: Drotrecogin Alfa (Activated) for Injection
CAS Number: 42617-41-4

Warning(s)

Special Alerts:

[Posted 10/25/2011] ISSUE: FDA notified healthcare professionals and the public that on October 25, 2011, Eli Lilly and Company announced a worldwide voluntary market withdrawal of drotrecogin alfa (activated) [Xigris]. In a recently completed clinical trial (PROWESS-SHOCK trial), drotrecogin alfa (activated) failed to show a survival benefit for patients with severe sepsis and septic shock.

BACKGROUND: Drotrecogin alfa (activated) is indicated for the reduction of mortality in adult patients with severe sepsis who have a high risk of death.

RECOMMENDATION: For more information visit the FDA website at: and .

Introduction

Biosynthetic (recombinant DNA origin) form of human activated protein C with antithrombotic, anti-inflammatory, and profibrinolytic properties.1 2 5 6

Uses for Xigris

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Severe Sepsis

Used for mortality reduction in adults with severe sepsis and a high risk of death (e.g., as determined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score of ≥25).1 2 4 7 9 International guidelines for the management of severe sepsis and septic shock suggest use in patients who generally have multiple organ failure and an APACHE score of ≥25.21

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Efficacy not established and use not recommended in patients with a lower risk of death (e.g., APACHE II score <25) or in pediatric patients.1 2 11 16 18 21 22

Accurate diagnosis of severe sepsis and assessment of risk of death are critical when considering patients for therapy.1 11

Xigris Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Discontinue therapy 2 hours prior to an invasive surgical procedure or procedures with an inherent risk of bleeding.1 9 Once adequate hemostasis is achieved, reconsider reinitiating therapy at initial recommended doses 12 hours after major invasive procedures or surgery or immediately following uncomplicated, less invasive procedures.1

  • Immediately discontinue therapy in patients with clinically important bleeding.1

Administration

Administer by continuous IV infusion using a controlled infusion device (i.e., infusion pump or syringe pump).1 9

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Do not admix or infuse concomitantly with other drugs.1 (See Compatibility under Stability.)

Reconstitution

Determine appropriate number of vials to reconstitute by calculating the amount of drug required for a particular infusion period based on patient’s actual body weight (in kg) and duration of infusion (in hours); round total amount to nearest 5-mg increment to avoid wastage.1 A maximum infusion period of 12 hours is recommended for each infusion bag or syringe; multiple infusions are required to cover recommended 96-hour duration of therapy.1

Reconstitute vial containing 5 or 20 mg of drotrecogin alfa (activated) with 2.5 or 10 mL of sterile water for injection, respectively, to provide solutions containing 2 mg/mL.1

Swirl vial gently to ensure dissolution; do not invert or shake vial.1 Must be diluted further before IV administration.1

Reconstituted solutions contain no preservatives; solutions preferably should be diluted immediately after reconstitution.1 If not used immediately, solution may be stored at 20–25°C, but must be used within 3 hours.1

Dilution

Dilute reconstituted solution with 0.9% sodium chloride injection in an IV infusion bag or syringe compatible with a syringe pump according to the manufacturer’s directions to yield a concentration of 100–200 mcg/mL.1

Administer at room temperature within 12 hours of dilution; if not used immediately, store at 2–8°C for up to 12 hours.1 Total in-use time, including dilution, refrigeration, and administration, should not exceed 24 hours.1 4 10

Rate of Administration

Administer by IV infusion at 24 mcg/kg per hour for a total of 96 hours.1 9 If infusion is interrupted for >1 hour, extend infusion time to account for interruptions (i.e., allow for a total infusion duration of 96 hours) unless the interruption lasts for ≥36 hours.4

When administering the drug at low flow rates (< approximately 5 mL/hr), prime syringe pump for approximately 15 minutes at a flow rate of approximately 5 mL/hour.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Dosage escalation or loading doses are not recommended.1

Dosage adjustment based on clinical or laboratory parameters is not recommended.1

Adults

Severe Sepsis
IV

24 mcg/kg per hour for a total of 96 hours.1 9

Special Populations

Renal Impairment

Dosage adjustment not required in patients with renal impairment undergoing hemodialysis or peritoneal dialysis.1

Hepatic Impairment

Dosage adjustment not required.1

Geriatric Patients

Dosage adjustment not required.1

Cautions for Xigris

Contraindications

  • Active internal bleeding.1 7 9

  • Recent (within 3 months) hemorrhagic stroke.1 7 9

  • Recent (within 2 months) intracranial or intraspinal surgery or severe head trauma.1 7 9

  • Trauma with an increased risk of life-threatening bleeding.1 7 9

  • Presence of an epidural catheter.1 7 9

  • Intracranial neoplasm or mass lesion, or evidence of cerebral herniation.1 7 9

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Hematologic Effects

Serious bleeding events, including intracranial hemorrhage, have occurred in patients receiving drotrecogin alfa (activated) therapy.1 2 14 16 19 20 Possible increased risk of bleeding in patients with one or more of the following conditions: concurrent heparin therapy to treat an active thrombotic or embolic event; platelet counts <30,000/mm3 (even if the platelet count is increased after transfusions); PT-INR >3; recent (within 6 weeks) GI bleeding; recent (within 3 days) thrombolytic therapy; recent (within 7 days) administration of oral anticoagulants, platelet glycoprotein (GP IIb/IIIa) inhibitors or other platelet-aggregation inhibitors (e.g., > 650 mg of aspirin daily); recent (within 3 months) ischemic stroke (see Contraindications under Cautions); intracranial arteriovenous malformation or aneurysm; known bleeding diathesis; chronic severe hepatic disease; or any other condition in which bleeding constitutes a substantial hazard or would be particularly difficult to manage because of its location.1

In a retrospective study of patients who received drotrecogin alfa (activated) for sepsis, serious bleeding events and deaths occurred in substantially more patients with baseline bleeding risk factors than those without such risk factors.13 14 15 FDA is currently investigating these preliminary findings and is working with the manufacturer to further evaluate the risk of serious bleeding and mortality in patients receiving drotrecogin alfa (activated).13 Pending completion of the safety review, FDA states that clinicians should carefully weigh the anticipated benefits of drotrecogin alfa (activated) against the risk of bleeding in any patient being considered for therapy.1 13

Some clinicians suggest avoiding use in patients with baseline bleeding risk factors.14 15 If clinically important bleeding occurs, immediately discontinue therapy.1 22 Also evaluate continued use of other agents affecting the coagulation system.1 (See Specific Drugs under Interactions.) Manufacturer states that resumption of therapy may be considered once adequate hemostasis has been achieved;1 however, some clinicians recommend against reinitiation of therapy in patients who develop severe bleeding during the infusion.22 (See General under Dosage and Administration.)

Patients with Single-Organ Dysfunction and Recent Surgery

Higher mortality reported in placebo-controlled clinical studies within a small subset of patients receiving drotrecogin alfa (activated) therapy who had single-organ dysfunction and recent surgery (i.e., within 30 days prior to treatment).1 2 11 16 Some of these patients had a lower risk of death (e.g., APACHE II score <25 or sepsis-induced single-organ failure at any APACHE II score) than that of the indicated population for this drug.1 11 16 22

Patients with single-organ dysfunction and recent surgery may not be at high risk of death (regardless of APACHE II score); drotrecogin alfa (activated) therapy is not recommended in such patients.1 11 21 22

Concomitant Administration of Prophylactic Heparin

Higher rates of mortality demonstrated in patients receiving drotrecogin alfa (activated) who discontinue prophylactic enoxaparin or unfractionated heparin therapy.1 20 Consider continuing low molecular weight heparin for prophylaxis of venous thromboembolism in patients receiving drotrecogin alfa (activated) unless discontinuance is medically necessary.1 20

Laboratory Test Interferences

May interfere with one-stage coagulation assays (e.g., factor VIII, IX, XI assays) based on aPTT; minimal effect on PT.1

Invasive Procedures

Discontinue drug prior to any invasive procedure (e.g., surgery) associated with an inherent risk of bleeding.1 9 (See General under Dosage and Administration.)

Minimize invasive procedures, including arterial and venous punctures, during drotrecogin alfa (activated) therapy; avoid establishing IV access at noncompressible sites (e.g., subclavian or jugular veins).1 (See Hematologic Effects under Cautions.)

Laboratory Monitoring

Do not use aPTT to monitor degree of coagulopathy; may use PT instead.1

Sensitivity Reactions

Antibody Formation

Antibodies to drotrecogin alfa (activated) reported in 1.5% of patients in clinical trials; a few patients tested positive for neutralizing antibodies.1 No apparent correlation between presence of antibodies and adverse effects.1

Limited experience with readministration (i.e., >1 course of therapy) of drotrecogin alfa (activated) in patients with severe sepsis;1 no hypersensitivity reactions or evidence of antibody development reported.1 4

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether drotrecogin alfa (activated) is distributed into milk.1 Discontinue nursing or the drug, taking into account the importance of the drug to the mother.1

Pediatric Use

Safety and efficacy not demonstrated in children <18 years of age;1 18 not indicated for use in pediatric patients with severe sepsis.1 21 22

Interim analysis of a randomized, double-blind study evaluating safety and efficacy in pediatric patients with severe sepsis showed that treatment with drotrecogin alfa (activated) was highly unlikely to result in improvement in the primary end point (composite time to complete organ failure resolution over a 14-day period) compared with placebo; as a result, the study was discontinued before completion.1 18 In addition, the rate of CNS bleeding was numerically greater in the drotrecogin alfa (activated) group than in the placebo group.1 18 Of patients with intracranial hemorrhage, the majority were <60 days of age.18 The incidence of 28-day all-cause mortality, fatal CNS bleeding, serious adverse events, overall serious bleeding events, and major amputations appeared to be similar between the groups.1 18

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.1

Common Adverse Effects

Bleeding (e.g., ecchymoses, GI bleeding, intracranial hemorrhage).1

Interactions for Xigris

Specific Drugs

Drug

Interaction

Comments

Antiplatelet agents (e.g., aspirin, GP IIb/IIIa-receptor inhibitors)

Potential increased risk of bleeding1

Use with caution1

Anticoagulants, oral

Potential increased risk of bleeding1

Use with caution1

Heparin

Concomitant use of enoxaparin 40 mg every 24 hours or sub-Q unfractionated heparin sodium 5000 units every 12 hours did not increase risk of serious bleeding, but increased incidence of nonserious bleeding;1 clearance and steady-state plasma concentrations of drotrecogin alfa (activated) not altered1

No dosage adjustment necessary1

NSAIAs

Potential increased risk of bleeding1

Use with caution1

Thrombolytic agents

Potential increased risk of bleeding1

Use with caution1

Xigris Pharmacokinetics

Absorption

Plasma Concentrations

Steady-state plasma drotrecogin alfa (activated) concentrations are rapidly attained (e.g., within 2 hours) after the start of infusion and rapidly decrease after the end of infusion.1

Elimination

Metabolism

Drotrecogin alfa (activated) and endogenous activated protein C are inactivated by endogenous plasma protease inhibitors.1

Special Populations

Plasma clearance of the drug in patients with severe sepsis is approximately 50% higher than that in healthy individuals.1

In patients without sepsis undergoing peritoneal dialysis or hemodialysis, clearance of drotrecogin alfa (activated) was similar to that observed in healthy individuals.1

Stability

Storage

Parenteral

Powder for Injection

2–8°C.1 Do not freeze; protect from light.1

If the reconstituted solution is not used immediately, store at 20–25°C and use within 3 hours.1

Diluted IV Solutions

Administer within 12 hours if stored at 20–25°C.1

Alternatively, store at 2–8°C for a maximum of 12 hours prior to administration.1 4 10 If refrigerated, total in-use time, including dilution, preparation, refrigeration, and administration, should not exceed 24 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Compatible with glass infusion bottles or infusion bags and syringes made of polyvinyl chloride, polyethylene, polypropylene, or polyolefin.1

Solution Compatibility

Compatible

Sodium chloride 0.9%

Drug Compatibility
Y-Site Compatibility

Compatible

Dextrose 5%

Dextrose and sodium chloride injections

Lactated Ringer’s injection

Sodium chloride 0.9%

Actions

  • A serine protease structurally similar to endogenous human plasma-derived activated protein C that has antithrombotic, anti-inflammatory, and profibrinolytic properties but does not exhibit direct antimicrobial activity.1 2 5 6

  • Produces the same biologic effects as endogenous activated protein C.4

  • Produces dose-dependent decreases in D-dimer (a breakdown product of cross-linked fibrin) and interleukin-6, which are markers of coagulopathy and inflammation, respectively; however precise mechanism of action is not known.1 2 3 4 5 6

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of informing patients of potential risks and benefits associated with therapy, including risk of severe bleeding.1 (See Hematologic Effects under Cautions.)

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 4

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Drotrecogin Alfa (Activated)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV infusion

5 mg

Xigris

Lilly

20 mg

Xigris

Lilly

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2012, Selected Revisions October 1, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Eli Lilly and Company. Xigris (drotrecogin alfa [activated]) injection prescribing information. Indianapolis, IN; 2008 Oct.

2. Bernard GR, Vincet JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344:699-709. [IDIS 461713] [PubMed 11236773]

3. Matthay MA. Severe sepsis—a new treatment with both anticoagulant and antiinflammatory properties. N Engl J Med. 2001; 344:759-62. [IDIS 461714] [PubMed 11236781]

4. Eli Lilly and Company. Indianapolis, IN: Personal communication.

5. Mann HJ. Recombinant human activated protein C in severe sepsis. Am J Health-Syst Pharm. 2002; 59(Suppl 1):S19-23. [IDIS 478158] [PubMed 11885409]

6. Kinasewitz GT,, Margolis B, Freebairn C et al. Changes in markers of coagulation and inflammation in patients with severe sepsis treated with recombinant human activated protein C. Crit Care Med. 2000; 28(Suppl 12):A68.

7. Anon. FDA approves first biologic treatment for sepsis. Rockville, MD: Food and Drug Administration; 2001 Nov 21. From FDA web site.

8. Anti-infective Drugs Advisory Committee. Gaithersburg, MD: Food and Drug Administration; 2001 Oct 16. From FDA web site.

9. Anon. Activated protein C (Xigris) for severe sepsis. Med Lett Drugs Ther. 2002; 44:17-18. [PubMed 11856952]

10. Vanscoy G. Addendum. Am J Health-Syst Pharm. 2002; 59(Suppl):S28-9.

11. Eisenberg P. Dear healthcare professional letter regarding important drug warning for Xigris. Indianapolis, IN: Eli Lilly and Company; 2005 Feb 4.

12. Food and Drug Administration. Xigris (drotrecogin alfa [activated]) [Apr 21, 2005: Eli Lilly]. Medwatch 2005 safety alert. Rockville, MD; April 2005. From FDA website.

13. Food and Drug Administration. Early communication about an ongoing safety review of Xigris (drotrecogin alfa [activated]). Rockville, MD; 2009 June 18. From FDA website.

14. Gentry CA, Gross KB, Sud B et al. Adverse outcomes associated with the use of drotrecogin alfa (activated) in patients with severe sepsis and baseline bleeding precautions. Crit Care Med. 2009; 37:19-25. [PubMed 19050637]

15. Sweeney DA, Natanson C, Eichacker PQ. Recombinant human activated protein C, package labeling, and hemorrhage risks. Crit Care Med. 2009; 37:327-9. [PubMed 19112285]

16. Abraham E, Laterre PF, Garg R et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005; 353:1332-41. [PubMed 16192478]

17. Angus DC, Laterre PF, Helterbrand J et al. The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis. Crit Care Med. 2004; 32:2199-206. [PubMed 15640631]

18. Nadel S, Goldstein B, Williams MD et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007; 369:836-43. [PubMed 17350452]

19. Vincent JL, Bernard GR, Beale R et al. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med. 2005; 33:2266-77. [PubMed 16215381]

20. Levy M, Levi M, Williams MD et al. Comprehensive safety analysis of concomitant drotrecogin alfa (activated) and prophylactic heparin use in patients with severe sepsis. Intensive Care Med. 2009; 35:1196-203. [PubMed 19367397]

21. Dellinger RP, Levy MM, Carlet JM et al, for the International Surviving Sepsis Campaign Guidelines Committee. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008; 36:296-327. [PubMed 18158437]

22. Toussaint S, Gerlach H. Activated Protein C for sepsis. New Engl J Med 2009; 361:2646-52. [PubMed 20042756]

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