P&T Portfolio on Xigris

February 18, 2002

Xigris for sepsis

 

HEALTH-SYSTEM EDITION

P&T PORTFOLIO

Generic name

Drotrecogin alfa (activated)

Proprietary name/manufacturer

XIGRIS / Lilly

FDA-approved indication

Drotrecogin alfa is approved for the reduction of mortality in adult patients with severe sepsis (associated with acute organ dysfunction) who have a high risk of death.

Pharmacology

Drotrecogin alfa is a recombinant form of human activated protein C. The specific mechanisms by which drotrecogin exerts its effect are not completely understood. However, like endogenous activated protein C, recombinant drotrecogin alfa possesses profibrinolytic, antithrombotic, and anti-inflammatory activities that may abrogate many systemic responses seen in septic patients. In addition, levels of protein C are reduced in most patients during sepsis, related in part to consumption during the coagulation process and impaired conversion of protein C to activated protein C.

Efficacy

The approval of drotrecogin was based upon an international multicenter controlled clinical trial involving 1,690 patients (PROWESS study). The primary efficacy endpoint in this study was all-cause mortality assessed 28 days after the start of the study drug. Results from this study found that 25% of patients receiving drotrecogin alfa died within 28 days, compared with 31% in the placebo group. However, the mortality rate difference was limited to patients with a higher risk of death, and the efficacy of drotrecogin has not been established in patients with a lower risk of death. The patients most likely to benefit are those with more severe physiologic disturbances, those with serious underlying disease predating sepsis, and older patients.

Contraindications

• Active internal bleeding

• Recent (within three months) hemorrhagic stroke

• Recent (within two months) intracranial or intraspinal surgery, or severe head trauma

• Trauma with an increased risk of bleeding

• Presence of an epidural catheter

• Intracranial neoplasm or mass lesion or evidence of cerebral herniation

• Hypersensitivity to drotrecogin or product components

Warnings

Due to an increased risk of bleeding, the use of drotrecogin alfa should be carefully considered in patients with the following conditions:

• Concurrent therapeutic heparin

• Platelet count < 30,000 x 10(6)/L, even if the platelet count is increased after transfusions

• Prothrombin time-INR > 3.0.

• Recent (within six months) GI bleeding

• Recent administration (within three days) of thrombolytic therapy

• Recent administration (within seven days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors

• Recent administration (within seven days) of aspirin > 650 mg per day or other platelet inhibitors

• Recent (within three months) ischemic stroke

• Intracranial arteriovenous malformation or aneurysm

• Known bleeding diathesis

• Chronic severe hepatic disease

• Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location

Drotrecogin alfa should be discontinued two hours prior to undergoing an invasive surgical procedure or procedures with an inherent risk of bleeding.

Dose

24 mcg/kg/hr by intravenous infusion over 96 hours

Cost (AWP)*

Cost per vial: 5-mg vial, $210; 20-mg vial, $840
Cost per 96-hour course: $6,800

*AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

Conclusion/comments

Drotrecogin alfa, a recombinant form of human activated protein C, demonstrated efficacy in the treatment of adult patients with severe sepsis who have a high risk of death. It is not indicated in patients with moderate sepsis and no evidence of organ dysfunction or in pediatric patients. Serious bleeding is a major concern with drotrecogin and patients must be closely monitored. Sepsis occurs in 300,000 to 500,000 patients annually in the United States, and despite advances in technology and health care, the rate of death from severe sepsis ranges from 30%-50%. In view of this, new treatments are needed, and drotrecogin alfa is the first product specifically approved for this indication. Detailed drug use criteria and monitoring guidelines should be developed for use in conjunction with drotrecogin therapy.

 

Published February 2002. Content based on medical literature and product information available at the time.

 

 



P&T Portfolio on Xigris.

Drug Topics

2002;4:HSE16.