Article: Drotrecogin alfa

Basic Chemical, Pharmacological and Marketing Data

Drotrecogin alpha (activated) is a recombinant form of human activated protein C that has antithrombotic, antiinflammatory, and profibrinolytic properties. It has no direct antibacterial activities, however. Drotrecogin alpha (activated) belongs to the class of serine proteases.

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 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.

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.

The National Institute for Health Care Management (NIHCM) has not listed the drug as 'highly innovative' in the category novel vaccines and recombinant drugs. This issue is controversely discussed in the article http://members.phrma.org/publications/publications/admin/2002-11-11.620.PDF (see references).

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 with approval from a second Critical Care Medicine Attending Physician.

• 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 should never be used as an anticoagulant/antithrombotic drug in patients without severe sepsis, but only for the treatment of severe sepsis as indicated.

Contraindications and Precautions

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
• Acute pancreatitis without a proven source of infection
• Pregnancy (treatment should be considered only, if the possible benefit for the mother weighs out the risk for the embryo or fetus)
• Nursing : It is not known whether drotrecogin is excreted in the milk of nursing mothers. Either breast-feeding or Xigris® should be discontinued taking into account the importance of drotrecogin to the mother.
• Patients under 18 yrs. of age (see additional warning issued by Lilly below)
• Patient is not expected to survive >28 days because of an uncontrollable medical condition
• Patient is moribund with perceived imminent death within 24 hours
• APACHE scores <25, because overall mortality in treated patients may be higher than in untreated control groups

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/hr)
• 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.

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.

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 affect on PT, and the PT/INR ratio may be used to follow the development of coagulopathy in these patients.

• Caution : 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

Xigris® 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 Xigris = (patient weight, kg) X 24µg/kg/hour X (hours of infusion) / 1000

Dosing schedules provided by Lilly also exist for dosage determination.

Recent Warnings

Eli Lilly has recently issued 2 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 PROWESS study. Treatment of these patient subgroup cannot be recommended.

• A recent study in pediatric patients with severe sepsis had to be discontinued (lack of positive results and severe side-effects).

Undertreatment Issue

Recently, the issue has been raised, if patients with severe sepsis fulfilling the treatment requirements for Xigris® are undertreated for the fear of bleeding complications. This may in fact be the case, leading to a higher overall mortality than necessary and higher socioeconomic costs (longer ICU-stay, and longer disability to resume work). Additionally, ICU-clinicians may be tempted to think about Xigris® in terms of additional cost only and wrongly. No conclusive evidence and exact numbers can be given at this stage, however.

Summary of Results

If used properly, Xigris® is able to reduce mortality caused by severe sepsis signifcantly. 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 (Acute Physiology and Chronic Health Evaluation II [APACHE II] score of >24) where mortality reduction has reached 13.0%. 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. (quote from Medscape, adapted for use in Wikipedia)