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{{drugbox
{{Drugbox
| verifiedrevid = 457450996
| IUPAC_name = Activated human protein C
| IUPAC_name = Activated human protein C
| image =  
| image =
 
<!--Clinical data-->
| tradename = 
| Drugs.com = {{drugs.com|monograph|drotrecogin-alfa-activated}}
| pregnancy_category = C
| legal_status = Rx-only, not a controlled substance
| routes_of_administration = i.v. application only
 
<!--Pharmacokinetic data-->
| bioavailability = 100% (i.v. application only)
| metabolism = endogenous plasma protease inhibitors
| elimination_half-life = less than 2 hours
 
<!--Identifiers-->
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = NA
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 60202-16-6
| CAS_number = 60202-16-6
| ATC_prefix = B01
| ATC_prefix = B01
| ATC_suffix = AD10  
| ATC_suffix = AD10
| ATC_supplemental =  
| ATC_supplemental =
| PubChem =  
| PubChem =
| DrugBank = BTD00068
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| C=1786 | H=2779 | N=509 | O=519 | S=29
| DrugBank = DB00055
 
<!--Chemical data-->
| C=1786 | H=2779 | N=509 | O=519 | S=29  
| molecular_weight = 55000 g/mol
| molecular_weight = 55000 g/mol
| bioavailability = 100% (i.v. application only)
| metabolism = endogenous plasma protease inhibitors
| elimination_half-life = less than 2 hours
| pregnancy_category = C
| legal_status = Rx-only, not a controlled substance
| routes_of_administration = i.v. application only
}}
}}
__NOTOC__
__NOTOC__
{{SI}}
{{SI}}
{{CMG}}
{{CMG}}
==Overview==
==Overview==
'''Drotrecogin alpha (activated)''' ('''Xigris'''®, marketed by [[Eli Lilly and Company|Eli Lilly]]) is a [[recombinant]] form of human activated [[protein C]] that has [[thrombosis|anti-thrombotic]], [[anti-inflammatory]], and profibrinolytic properties. Drotrecogin alpha (activated) belongs to the class of [[serine protease]]s. It is used mainly in [[intensive care medicine]] as a treatment for severe [[sepsis]].
'''Drotrecogin alfa (activated)''' ('''Xigris''', marketed by [[Eli Lilly and Company]]) is a [[Recombinant DNA|recombinant]] form of human activated [[protein C]] that has [[thrombosis|anti-thrombotic]], [[anti-inflammatory]], and profibrinolytic properties. Drotrecogin alpha (activated) belongs to the class of [[serine protease]]s. Drotrecogin alfa has not been found to improve outcomes in people with severe sepsis. The manufacturer's aggressive strategies in marketing its use in severe sepsis have been criticized.<ref>{{cite web|url=http://blogs.scientificamerican.com/guest-blog/2011/11/02/lillys-shocker-or-the-post-marketing-blues|title=Lilly’s Shocker, or the Post-Marketing Blues|publisher=Scientific American|work=guest blog}}</ref>  On October 25, 2011, Eli Lilly & Co. withdrew Xigris from the market after a major study showed no efficacy for the treatment of [[sepsis]].<ref>{{cite web| title = Xigris (drotrecogin alfa (activated)) to be withdrawn due to lack of efficacy| work = Press release| publisher = European Medicines Agency| location = London, UK| url = http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fnews_and_events%2Fnews%2F2011%2F10%2Fnews_detail_001373.jsp&mid=WC0b01ac058004d5c1| archiveurl = http://www.webcitation.org/62icYBgm1| archivedate = 26 October 2011| date = 25 October 2011| accessdate = 26 October 2011}}</ref><ref>http://www.businessweek.com/news/2011-10-25/lilly-pulls-xigris-off-markets-after-sepsis-drug-fails-study.html</ref>


==Pharmacology==
==Medical uses==
===Mechanism of action===
Drotrecogin alfa does not improve mortality in severe [[sepsis]] or septic shock but does increase bleeding risks. Therefore, a 2011 [[Cochrane review]] recommended that clinicians and policymakers not recommend its use.<ref>{{cite journal|last=Martí-Carvajal|first=AJ|author2=Solà, I |author3=Lathyris, D |author4=Cardona, AF |title=Human recombinant activated protein C for severe sepsis|journal=Cochrane database of systematic reviews (Online)|date=Apr 13, 2011|issue=4|pages=CD004388|pmid=21491390|doi=10.1002/14651858.CD004388.pub4|editor1-last=Martí-Carvajal|editor1-first=Arturo J}}</ref>
The specific mechanisms by which drotrecogin 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 factors|tumor necrosis factor]] production, by blocking [[leukocyte]] adhesion to [[selectin]]s, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium.{{Fact|date=February 2007}}


===Pharmacokinetics===
==Risks and contraindications==
If the dosage guidelines are followed, the drug reaches peak plasma levels after 2 hours and is completely cleared from plasma 2 hours after termination of the infusion period. Endogenous plasma protease inhibitors deactivate drotrecogin. Therefore, no dose adjustment is needed in elderly patients, or in patients with renal or hepatic dysfunction.
 
===Presentation===
Xigris is the current [[brand name]] of activated drotrecogin alfa, manufactured by [[Eli Lilly and Company|Eli Lilly]]. The drug is sold in vials containing either 5mg or 20mg, respectively. The FDA approved the drug in 2001 as was the case with the drug authorities in many other countries.
 
==Uses==
===Indications===
Drotrecogin 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 of 25 or greater).
 
Because of the risk of severe bleeding, associated with the use of Xigris®, the following guidelines have been additionally proposed, but are not FDA requirements:
* Drotrecogin should only be ordered by a Critical Care Medicine Attending Physician.  A second opinion is not necessary, including pharmacy, Infectious Disease and nursing. 
* Drotrecogin should only be administered in an Intensive Care Unit (ICU), or a patient awaiting transfer to an ICU.
 
Although drotrecogin has potent [[anticoagulant]] properties, it is not indicated as an anticoagulant/antithrombotic drug in patients without severe sepsis.
 
If used properly, drotrecogin is able to reduce mortality caused by severe sepsis significantly. The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study demonstrated that treatment with drotrecogin reduced 28-day mortality of patients with severe sepsis by 6.1%, and that it was particular effective in those with a high risk for death (e.g. APACHE II score of >24) where mortality reduction has reached 13.0%.  PROWESS was terminated early for a statistically significant positive efficacy signal - unethical to continue trial - as this would have meant exposing severe sepsis patients to possibly receiving placebo.  However, the drug was not effective in patients who had a low risk for death. Under the above mentioned assumptions as prerequisites for the use of Xigris®, drotrecogin is also a cost-effective drug.
 
Eli Lilly has recently issued 3 important additional warnings:{{Fact|date=February 2007}}
* Patients with single organ dysfunction due to sepsis (e.g., lung) and recent surgery (within 30 days before drotrecogin use) have had a higher mortalitity rate in the ADDRESS study. Treatment of these patient subgroup cannot be recommended and are generally considered non-indicated population.
* A recent study in pediatric patients with severe sepsis had to be discontinued (lack of positive results and severe side-effects).
*Clinicians should consider continuing prophylactic heparin at time of institution of Xigris infusion unless discontinuation of prophylactic heparin is considered medically necessary.


===Monitoring===
* If evidence of bleeding (e.g., epistaxis, hematemesis, dizziness or faintness, hematuria, abdominal swelling or pain, skin bruises, back pain) is found the following parameters should be obtained: hemoglobin, hematocrit, coagulation panel, urinalysis, complete blood counts periodically; INR, as drotrecogin has minimal effect on PT, and the PT/INR ratio may be used to follow the development of coagulopathy in these patients.
* Drotrecogin may variably prolong the APTT. Therefore, APTT cannot be reliably used to assess the status of the coagulopathy during drotrecogin therapy.
* Monitoring of protein C or activated protein C levels during therapy of sepsis is unwarranted as "therapeutic" levels of drotrecogin, or of endogenous activated protein C, are unknown.
===Dosage regime===
Drotrecogin is to be given in multiple infusions covering a total period of 96 hours. The maximum duration of one infusion is 12 hours. The dosage is calculated using the formula:<ref>{{cite web |url=http://www.xigris.com/resources/dosing.jsp?reqNavId=4.5&altNavId?reqNavId=3.6|title= Xigris dosing tables|accessdate=2006-10-24 }}</ref>
<blockquote>mg of drotrecogin = (patient weight, kg) X 24µg/kg/hour X (hours of infusion) / 1000</blockquote>
==Risks and contraindications==
===Contraindications===
===Contraindications===
The following patients should not receive drotrecogin:
The following patients should not receive drotrecogin:
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* Recent (within 3 months) hemorrhagic stroke  
* Recent (within 3 months) hemorrhagic stroke  
* Recent (within 2 months) intracranial/intraspinal surgery/severe head trauma  
* Recent (within 2 months) intracranial/intraspinal surgery/severe head trauma  
* Trauma patients with an increased risk of life threatening bleeding  
* Trauma patients with an increased risk of life-threatening bleeding  
* Presence of an epidural catheter  
* Presence of an epidural catheter  
* Known or suspected intracranial neoplasm or mass lesion  
* Known or suspected intracranial neoplasm or mass lesion  
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* Recent administration (within 3 days) of thrombolytic therapy  
* 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 oral anticoagulants or GP IIb/IIIa inhibitors  
* Recent administration (within 7 days) of >650mg/day of aspirin or other platelet inhibitors  
* Recent administration (within 7 days) of >650&nbsp;mg/day of aspirin or other platelet inhibitors  
* Recent (within 3 months) ischemic stroke  
* Recent (within 3 months) ischemic stroke  
* Known or suspected intracranial AV malformation or aneurysm  
* Known or suspected intracranial AV malformation or aneurysm  
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* Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location  
* 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.
* 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.
Eli Lilly has recently issued 3 important additional warnings:{{Citation needed|date=February 2007}}
* Patients with single organ dysfunction due to sepsis (e.g., lung) and recent surgery (within 30 days before drotrecogin use) have had a higher mortalitity rate in the ADDRESS study. Treatment of this patient subgroup cannot be recommended and are generally considered non-indicated population.
* A recent study in pediatric patients with severe sepsis had to be discontinued (lack of positive results and severe side-effects).
*Clinicians should consider continuing prophylactic heparin at time of institution of Xigris infusion unless discontinuation of prophylactic heparin is considered medically necessary.


===Side-effects===
===Side-effects===
Although patients at high risk of bleeding were excluded from the phase III clinical study (PROWESS), 25% of patients treated with drotrecogin and 18% of those receiving placebo experienced at least one bleeding event (principally ecchymoses or GI bleeding) during the 28-day study period. During treatment serious bleeding events (e.g., intracranial hemorrhage, any life-threatening bleeding event, any bleeding event requiring administration of at least 3 units of packed red blood cells daily for 2 consecutive days) occurred in 2.4% of patients treated with drotrecogin and in 1% of those receiving placebo. No significant differences between geriatric patients and younger patients regarding bleeding events in the drotrecogin group have been found.  
Although patients at high risk of bleeding were excluded from the phase III clinical study (PROWESS), 25% of patients treated with drotrecogin and 18% of those receiving placebo experienced at least one bleeding event (principally ecchymoses or GI bleeding) during the 28-day study period. During treatment serious bleeding events (e.g., intracranial hemorrhage, any life-threatening bleeding event, any bleeding event requiring administration of at least 3 units of packed red blood cells daily for 2 consecutive days) occurred in 2.4% of patients treated with drotrecogin and in 1% of those receiving placebo. No significant differences between geriatric patients and younger patients regarding bleeding events in the drotrecogin group have been found.


No other side-effects have been observed so far.
No other side-effects have been observed so far.
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===Interactions===
===Interactions===
Drug interactions with drotrecogin have not been systematically studied in patients with severe sepsis. Caution should be exercised when using other drugs that affect hemostasis concomitantly with drotrecogin (e.g. [[aspirin]], [[warfarin]], [[clopidogrel]]). However, the use of low dose prophylactic Heparin did not affect safety when given concurrently with drotrecogin.  
Drug interactions with drotrecogin have not been systematically studied in patients with severe sepsis. Caution should be exercised when using other drugs that affect hemostasis concomitantly with drotrecogin (e.g. [[aspirin]], [[warfarin]], [[clopidogrel]]). However, the use of low dose prophylactic Heparin did not affect safety when given concurrently with drotrecogin.
 
==Pharmacology==
 
===Mechanism of action===
The specific mechanisms by which drotrecogin 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 factors|tumor necrosis factor]] production, by blocking [[leukocyte]] adhesion to [[selectin]]s, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium.{{Citation needed|date=February 2007}}


==Marketing controversy==
===Pharmacokinetics===
If the dosage guidelines are followed, the drug reaches peak plasma levels after two hours and is completely cleared from plasma two hours after termination of the infusion period. Endogenous plasma protease inhibitors deactivate drotrecogin. Therefore, no dose adjustment is needed in elderly patients, or in patients with renal or hepatic dysfunction.
 
===Presentation===
Xigris is the current [[brand name]] of activated drotrecogin alfa, manufactured by [[Eli Lilly and Company|Eli Lilly]]. The drug is sold in vials containing either 5&nbsp;mg or 20&nbsp;mg, respectively. The United States' [[Food and Drug Administration]] (FDA) approved the drug in 2001 as was the case with the drug authorities in many other countries.
 
==Society and culture==
 
===Marketing controversy===


In 2001, Eli Lilly's chairman, president and CEO, Sidney Taurel, told shareholders: "No medicine better symbolizes our mission than Xigris," calling it "one of our industry's genuine breakthroughs."<ref>[http://lilly.com/investor/annual_report/lillyar2001editorial.pdf Eli Lilly Annual Report, 2001]</ref>
In 2001, Eli Lilly's chairman, president and CEO, Sidney Taurel, told shareholders: "No medicine better symbolizes our mission than Xigris," calling it "one of our industry's genuine breakthroughs."<ref>[http://lilly.com/investor/annual_report/lillyar2001editorial.pdf Eli Lilly Annual Report, 2001]</ref>


Xigris was designed to fight sepsis, a condition that kills more than 200,000 Americans annually. It is the only approved drug for sepsis, and it costs $8,000 to treat a single patient. Lilly hoped it would be a blockbuster, with sales of at least a billion dollars a year. But after five years on the market, sales are only $200 million.  
Xigris was designed to fight sepsis, a condition that kills more than 200,000 Americans annually. It is the only approved drug for sepsis, and it costs $8,000 to treat a single patient. Lilly hoped it would be a blockbuster, with sales of at least a billion dollars a year. But after five years on the market, sales were only $200 million.


Eli Lilly used the Belsito & Company PR firm in a marketing campaign to promote Xigris, its drug for treatment of sepsis. A report in the [[New England Journal of Medicine]] (NEJM) accuses the company of initiating false reports of a shortage of the drug to boost sales.<ref>[http://content.nejm.org/cgi/content/extract/355/16/1640] Peter Q. Eichacker, Charles Natanson, Robert L. Danner,
Eli Lilly used the Belsito & Company PR firm in a marketing campaign to promote Xigris, its drug for treatment of sepsis. A report in the [[New England Journal of Medicine]] (NEJM) accused the company of initiating false reports of a shortage of the drug to boost sales.<ref name="pmid17050887">{{cite journal | author = Eichacker PQ, Natanson C, Danner RL | title = Surviving sepsis--practice guidelines, marketing campaigns, and Eli Lilly | journal = N. Engl. J. Med. | volume = 355 | issue = 16 | pages = 1640–2 |date=October 2006 | pmid = 17050887 | doi = 10.1056/NEJMp068197 | url =  }}</ref> Belsito and Company spread the word that the drug was being "rationed" and physicians were being 'systematically forced' to decide who would live and who would die. As part of this effort, Lilly provided a group of physicians and bioethicists with a $1.8 million grant to form the Values, Ethics, and Rationing in Critical Care (VERICC) Task Force, purportedly to address ethical issues raised by rationing in the intensive care unit. Finally, the Surviving Sepsis Campaign was established, in theory to raise awareness of severe sepsis and generate momentum toward the development of treatment guidelines.
"Surviving Sepsis — Practice Guidelines, Marketing Campaigns, and Eli Lilly". NEJM Volume 355:1640-1642. (10 2006)</ref> Belsito and Company spread the word that the drug was being "rationed" and physicians were being 'systematically forced' to decide who would live and who would die. As part of this effort, Lilly provided a group of physicians and bioethicists with a $1.8 million grant to form the Values, Ethics, and Rationing in Critical Care (VERICC) Task Force, purportedly to address ethical issues raised by rationing in the intensive care unit. Finally, the Surviving Sepsis Campaign was established, in theory to raise awareness of severe sepsis and generate momentum toward the development of treatment guidelines.  


This marketing campaign is especially troublesome because Xigris has been linked to increased risk of serious bleeding in patients who use it as well as other concerns. "Controversy surrounds both the drug study itself and the FDA approval," wrote NEJM editor-at-large Richard P. Wenzel, MD in 2002.<ref>[http://www.medscape.com/viewarticle/442255]
This marketing campaign was especially troublesome because Xigris has been linked to increased risk of serious bleeding in patients who used it as well as other concerns. "Controversy surrounds both the drug study itself and the FDA approval," wrote NEJM editor-at-large Richard P. Wenzel, MD in 2002.<ref name="urlMedscape.com Log In">{{cite web | url = http://www.medscape.com/viewarticle/442255 | title = Controversy Brews Over Xigris' Role in Treating Sepsis | author = Barclay L | authorlink = | date = 2002-10-01 | format = | work = Medscape Medical News | publisher = WebMD LLC | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2010-09-19 }}</ref>  The FDA approved the drug despite the advisory committee's split vote (10 to 10) due to concerns about the validity of the claimed efficacy and safety findings on the basis of a single trial.
Laurie Barclay, MD. "Controversy Brews Over Xigris' Role in Treating Sepsis". Medscape Medical News. Oct 1, 2002</ref>  The FDA approved the drug despite the advisory committee's split vote (10 to 10) due to concerns about the validity of the claimed efficacy and safety findings on the basis of a single trial.


Eli Lilly spokeswoman Judy Kay Moore insists that the company did not mastermind the ethics task force or steer the guideline-writing process. It was only a coincidence, Moore says, that the ethics task force and the Surviving Sepsis Campaign used the same P.R. firm, Belsito and Company.<ref>[http://www.npr.org/templates/story/story.php?storyId=6298643 National Public Radio October 18, 2006]</ref>
Eli Lilly spokeswoman Judy Kay Moore insisted that the company did not mastermind the ethics task force or steer the guideline-writing process. It was only a coincidence, Moore says, that the ethics task force and the Surviving Sepsis Campaign used the same P.R. firm, Belsito and Company.<ref name="urlReport: Lilly Promoted Drug Under False Pretenses : NPR">{{cite web | url = http://www.npr.org/templates/story/story.php?storyId=6298643 | title = Report: Lilly Promoted Drug Under False Pretenses | author = Knox R | authorlink = | date = 2006-10-18 | format = | work = All Things Considered | publisher = National Public Radio | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2010-09-19 }}</ref>


==External Links==
Xigris was withdrawn by the manufacturer in 2011.
* [http://www.xigris.com/ Official site]
 
* [http://www.fda.gov/medwatch/SAFETY/2005/xigris_USPI_17Dec04.pdf Information] (PDF) on the drug from the [[Food and Drug Administration]] (FDA).
===FDA approval===
In the USA drotrecogin was FDA approved 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 of 25 or greater).  Evidence however is not sufficiently strong for its use to become standard of care.<ref name="pmid12324562">{{cite journal | author = Warren HS, Suffredini AF, Eichacker PQ, Munford RS | title = Risks and benefits of activated protein C treatment for severe sepsis |journal = N. Engl. J. Med. | volume = 347 | issue = 13 | pages = 1027–30 |date=September 2002 | pmid = 12324562 | doi = 10.1056/NEJMsb020574 | url =  }}</ref>
 
Because of the risk of severe bleeding, associated with the use of Xigris, the following guidelines have been additionally proposed, but are not FDA requirements:
* Drotrecogin should only be ordered by a critical care specialist with experience weighing the risks and benefits of this medication.
* Drotrecogin should only be administered in a critical care area such as an Intensive Care Unit (ICU), or other unit with very frequent observation and monitoring.
 
On October 25, 2011, Eli Lilly and Company announced a worldwide voluntary market withdrawal of Xigris [drotrecogin alfa (activated)]. In a recent study, Xigris failed to show a survival benefit for patients with severe sepsis and septic shock.<ref>http://www.fda.gov/Drugs/DrugSafety/ucm277114.htm</ref>
 
==Research==
This is still research to isolate activated protein C mutants that lack anticoagulant properties.<ref name="Angus 2013">{{cite journal|last1=Angus|first1=Derek C.|last2=van der Poll|first2=Tom|title=Severe Sepsis and Septic Shock|journal=New England Journal of Medicine|date=29 August 2013|volume=369|issue=9|pages=840–851|doi=10.1056/NEJMra1208623|pmid=23984731}}</ref>


==References==
==References==
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{{Antithrombotics}}
{{Antithrombotics}}
{{Intensive care medicine}}


[[Category:Eli Lilly and Company]]
[[Category:Intensive care medicine]]
[[Category:Antithrombotic enzymes]]
[[Category:Withdrawn drugs]]
[[Category:Drug]]
[[Category:Drug]]
[[Category:Antithrombotic enzymes]]

Latest revision as of 20:16, 18 August 2015

Drotrecogin alfa
Clinical data
AHFS/Drugs.comMonograph
Pregnancy
category
  • C
Routes of
administration		i.v. application only
ATC code
Legal status
Legal status
  • Rx-only, not a controlled substance
Pharmacokinetic data
Bioavailability100% (i.v. application only)
Metabolismendogenous plasma protease inhibitors
Elimination half-lifeless than 2 hours
Identifiers
CAS Number
DrugBank
ChemSpider
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC1786H2779N509O519S29
Molar mass55000 g/mol
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Drotrecogin alfa (activated) (Xigris, marketed by Eli Lilly and Company) is a recombinant form of human activated protein C that has anti-thrombotic, anti-inflammatory, and profibrinolytic properties. Drotrecogin alpha (activated) belongs to the class of serine proteases. Drotrecogin alfa has not been found to improve outcomes in people with severe sepsis. The manufacturer's aggressive strategies in marketing its use in severe sepsis have been criticized.[1] On October 25, 2011, Eli Lilly & Co. withdrew Xigris from the market after a major study showed no efficacy for the treatment of sepsis.[2][3]

Medical uses

Drotrecogin alfa does not improve mortality in severe sepsis or septic shock but does increase bleeding risks. Therefore, a 2011 Cochrane review recommended that clinicians and policymakers not recommend its use.[4]

Risks and contraindications

Contraindications

The following patients should not receive drotrecogin:

  • 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 or any component

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/h)
  • 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 >650 mg/day of aspirin or other platelet inhibitors
  • Recent (within 3 months) ischemic stroke
  • Known or suspected intracranial AV malformation or aneurysm
  • Known bleeding diathesis (e.g., hemophilia) 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.

Eli Lilly has recently issued 3 important additional warnings:[citation needed]

  • Patients with single organ dysfunction due to sepsis (e.g., lung) and recent surgery (within 30 days before drotrecogin use) have had a higher mortalitity rate in the ADDRESS study. Treatment of this patient subgroup cannot be recommended and are generally considered non-indicated population.
  • A recent study in pediatric patients with severe sepsis had to be discontinued (lack of positive results and severe side-effects).
  • Clinicians should consider continuing prophylactic heparin at time of institution of Xigris infusion unless discontinuation of prophylactic heparin is considered medically necessary.

Side-effects

Although patients at high risk of bleeding were excluded from the phase III clinical study (PROWESS), 25% of patients treated with drotrecogin and 18% of those receiving placebo experienced at least one bleeding event (principally ecchymoses or GI bleeding) during the 28-day study period. During treatment serious bleeding events (e.g., intracranial hemorrhage, any life-threatening bleeding event, any bleeding event requiring administration of at least 3 units of packed red blood cells daily for 2 consecutive days) occurred in 2.4% of patients treated with drotrecogin and in 1% of those receiving placebo. No significant differences between geriatric patients and younger patients regarding bleeding events in the drotrecogin group have been found.

No other side-effects have been observed so far.

In the meantime a second study encompassing approximately 2,000 adult patients has been completed and the results showed a comparable side-effect profile.

Interactions

Drug interactions with drotrecogin have not been systematically studied in patients with severe sepsis. Caution should be exercised when using other drugs that affect hemostasis concomitantly with drotrecogin (e.g. aspirin, warfarin, clopidogrel). However, the use of low dose prophylactic Heparin did not affect safety when given concurrently with drotrecogin.

Pharmacology

Mechanism of action

The specific mechanisms by which drotrecogin 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.[citation needed]

Pharmacokinetics

If the dosage guidelines are followed, the drug reaches peak plasma levels after two hours and is completely cleared from plasma two hours after termination of the infusion period. Endogenous plasma protease inhibitors deactivate drotrecogin. Therefore, no dose adjustment is needed in elderly patients, or in patients with renal or hepatic dysfunction.

Presentation

Xigris is the current brand name of activated drotrecogin alfa, manufactured by Eli Lilly. The drug is sold in vials containing either 5 mg or 20 mg, respectively. The United States' Food and Drug Administration (FDA) approved the drug in 2001 as was the case with the drug authorities in many other countries.

Society and culture

Marketing controversy

In 2001, Eli Lilly's chairman, president and CEO, Sidney Taurel, told shareholders: "No medicine better symbolizes our mission than Xigris," calling it "one of our industry's genuine breakthroughs."[5]

Xigris was designed to fight sepsis, a condition that kills more than 200,000 Americans annually. It is the only approved drug for sepsis, and it costs $8,000 to treat a single patient. Lilly hoped it would be a blockbuster, with sales of at least a billion dollars a year. But after five years on the market, sales were only $200 million.

Eli Lilly used the Belsito & Company PR firm in a marketing campaign to promote Xigris, its drug for treatment of sepsis. A report in the New England Journal of Medicine (NEJM) accused the company of initiating false reports of a shortage of the drug to boost sales.[6] Belsito and Company spread the word that the drug was being "rationed" and physicians were being 'systematically forced' to decide who would live and who would die. As part of this effort, Lilly provided a group of physicians and bioethicists with a $1.8 million grant to form the Values, Ethics, and Rationing in Critical Care (VERICC) Task Force, purportedly to address ethical issues raised by rationing in the intensive care unit. Finally, the Surviving Sepsis Campaign was established, in theory to raise awareness of severe sepsis and generate momentum toward the development of treatment guidelines.

This marketing campaign was especially troublesome because Xigris has been linked to increased risk of serious bleeding in patients who used it as well as other concerns. "Controversy surrounds both the drug study itself and the FDA approval," wrote NEJM editor-at-large Richard P. Wenzel, MD in 2002.[7] The FDA approved the drug despite the advisory committee's split vote (10 to 10) due to concerns about the validity of the claimed efficacy and safety findings on the basis of a single trial.

Eli Lilly spokeswoman Judy Kay Moore insisted that the company did not mastermind the ethics task force or steer the guideline-writing process. It was only a coincidence, Moore says, that the ethics task force and the Surviving Sepsis Campaign used the same P.R. firm, Belsito and Company.[8]

Xigris was withdrawn by the manufacturer in 2011.

FDA approval

In the USA drotrecogin was FDA approved 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 of 25 or greater). Evidence however is not sufficiently strong for its use to become standard of care.[9]

Because of the risk of severe bleeding, associated with the use of Xigris, the following guidelines have been additionally proposed, but are not FDA requirements:

  • Drotrecogin should only be ordered by a critical care specialist with experience weighing the risks and benefits of this medication.
  • Drotrecogin should only be administered in a critical care area such as an Intensive Care Unit (ICU), or other unit with very frequent observation and monitoring.

On October 25, 2011, Eli Lilly and Company announced a worldwide voluntary market withdrawal of Xigris [drotrecogin alfa (activated)]. In a recent study, Xigris failed to show a survival benefit for patients with severe sepsis and septic shock.[10]

Research

This is still research to isolate activated protein C mutants that lack anticoagulant properties.[11]

References

  1. ↑ "Lilly's Shocker, or the Post-Marketing Blues". guest blog. Scientific American.
  2. ↑ "Xigris (drotrecogin alfa (activated)) to be withdrawn due to lack of efficacy". Press release. London, UK: European Medicines Agency. 25 October 2011. Archived from the original on 26 October 2011. Retrieved 26 October 2011.
  3. ↑ http://www.businessweek.com/news/2011-10-25/lilly-pulls-xigris-off-markets-after-sepsis-drug-fails-study.html
  4. ↑ Martí-Carvajal, AJ; Solà, I; Lathyris, D; Cardona, AF (Apr 13, 2011). Martí-Carvajal, Arturo J, ed. "Human recombinant activated protein C for severe sepsis". Cochrane database of systematic reviews (Online) (4): CD004388. doi:10.1002/14651858.CD004388.pub4. PMID 21491390.
  5. ↑ Eli Lilly Annual Report, 2001
  6. ↑ Eichacker PQ, Natanson C, Danner RL (October 2006). "Surviving sepsis--practice guidelines, marketing campaigns, and Eli Lilly". N. Engl. J. Med. 355 (16): 1640–2. doi:10.1056/NEJMp068197. PMID 17050887.
  7. ↑ Barclay L (2002-10-01). "Controversy Brews Over Xigris' Role in Treating Sepsis". Medscape Medical News. WebMD LLC. Retrieved 2010-09-19.
  8. ↑ Knox R (2006-10-18). "Report: Lilly Promoted Drug Under False Pretenses". All Things Considered. National Public Radio. Retrieved 2010-09-19.
  9. ↑ Warren HS, Suffredini AF, Eichacker PQ, Munford RS (September 2002). "Risks and benefits of activated protein C treatment for severe sepsis". N. Engl. J. Med. 347 (13): 1027–30. doi:10.1056/NEJMsb020574. PMID 12324562.
  10. ↑ http://www.fda.gov/Drugs/DrugSafety/ucm277114.htm
  11. ↑ Angus, Derek C.; van der Poll, Tom (29 August 2013). "Severe Sepsis and Septic Shock". New England Journal of Medicine. 369 (9): 840–851. doi:10.1056/NEJMra1208623. PMID 23984731.
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