Drotrecogin alfa
Encyclopedia
Drotrecogin alfa (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 protease
s. Drotrecogin alfa has not been found to improve outcomes in people with severe sepsis. The ethicalness of the marketing campaign for its use in severe sepsis has been questioned. On October 25th, 2011, Eli Lilly & Co. withdrew Xigris from the market after a major study showed no efficacy for the treatment of sepsis.
or septic shock but does increase bleeding risks therefore a 2011 Cochrane review recommended that clinicians and policy makers not recommend its use.
Eli Lilly has recently issued 3 important additional warnings:
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.
, warfarin
, clopidogrel
). However, the use of low dose prophylactic Heparin did not affect safety when given concurrently with drotrecogin.
(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 selectin
s, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium.
. The drug is sold in vials containing either 5 mg or 20 mg, respectively. The FDA approved the drug in 2001 as was the case with the drug authorities in many other countries.
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.
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. 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. 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.
(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.
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:
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.
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
) is a recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
form of human activated protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
that has anti-thrombotic
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
, anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
, and profibrinolytic properties. Drotrecogin alpha (activated) belongs to the class of serine protease
Serine protease
Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...
s. Drotrecogin alfa has not been found to improve outcomes in people with severe sepsis. The ethicalness of the marketing campaign for its use in severe sepsis has been questioned. On October 25th, 2011, Eli Lilly & Co. withdrew Xigris from the market after a major study showed no efficacy for the treatment of sepsis.
Medical uses
Drotrecogin alfa does not improve mortality in severe sepsisSepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
or septic shock but does increase bleeding risks therefore a 2011 Cochrane review recommended that clinicians and policy makers not recommend its use.
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 >650mg/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:
- 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. aspirinAspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
, warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
, clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...
). However, the use of low dose prophylactic Heparin did not affect safety when given concurrently with drotrecogin.
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-1Plasminogen activator inhibitor-1
Plasminogen activator inhibitor-1 also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the SERPINE1 gene....
(PAI-1). In vitro data also suggest that activated protein C may exert an anti-inflammatory effect by inhibiting tumor necrosis factor
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
production, by blocking leukocyte adhesion to selectin
Selectin
Selectins are a family of cell adhesion molecules . All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding...
s, and by limiting the thrombin-induced inflammatory responses within the microvascular endothelium.
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 LillyEli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
. The drug is sold in vials containing either 5 mg or 20 mg, respectively. The FDA approved the drug in 2001 as was the case with the drug authorities in many other countries.
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."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.
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
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
(NEJM) accuses the company of initiating false reports of a shortage of the drug to boost sales. 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. 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.
FDA approval
In the USA drotrecogin was FDA approved for the reduction of mortality in adult patients with severe sepsisSepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
(sepsis associated with acute organ dysfunction) who have a high risk of death (as determined by APACHE II
APACHE II
APACHE II is a severity-of-disease classification system , one of several ICU scoring systems...
scores of 25 or greater). Evidence however is not sufficiently strong for its use to become standard of care.
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.
External links
- Official site
- Information (PDF) on the drug from the Food and Drug AdministrationFood and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA).