ELI LILLY AND COMPANY
Drotrecogin alpha (activated) (Xigris, marketed by Eli Lilly) 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. It is used mainly in intensive care medicine as a treatment for severe sepsis.
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.
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.
Xigris is the current brand name of activated drotrecogin alfa, manufactured by 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.
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:
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.
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.
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:
mg of drotrecogin = (patient weight, kg) X 24µg/kg/hour X (hours of infusion) / 1000
Several diagnostics are in development to identify the patient population that might benefit from treatment with drotrecogin alfa.
Biosite (Inverness) is running a clinical trial called RESPOND to study the role of using protein C levels to help determine dose and duration of Xigris treatment.
Sirius Genomics is developing a genetic test to stratify the general population into groups of potential responders to Xigris treatment.
Risks and 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
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.
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