Drotrecogin alfa-Recombinant
Human Activated Protein C (Xigris™)

Volume V, Number 1 | January/February 2002
Jeffrey P. Gonzales, Pharm.D.

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Introduction

Drotrecogin alfa [recombinant Human Activated Protein C (Xigris™)], was recently approved by the FDA for the reduction of mortality in adult patients with severe sepsis who have a high risk of death as determined by APACHE II. In the United States, sepsis is the leading cause of death in non-coronary intensive care units. Severe sepsis is characterized by at least two of the systemic inflammatory response syndrome (SIRS) criteria (Table 1) and the evidence of organ dysfunction (e.g., hypotension, renal failure, lactic acidosis). Severe sepsis occurs at a rate of 750,000 cases/year and is responsible for approximately $17 billion in the United States. The mortality rate for severe sepsis ranges from 20 to 50%. Drotrecogin alfa is the only medication to be approved by the FDA for the treatment of severe sepsis.

Table 1. The SIRS Criteria

Pharmacology and Pharmaco-dynamics

Drotrecogin alfa has three main mechanisms of action: 1) anticoagulant, 2) anti-inflammatory, and 3) pro-fibrinolytic. Drotrecogin alfa is a potent anticoagulant through the inhibition of coagulation Factors Va and VIIIa, which subsequently inhibits thrombin formation. In vitro data suggest that drotrecogin alfa also has anti-inflammatory properties mainly through indirect TNF-a inhibition. Additionally, drotrecogin alfa limits thrombin-induced inflammatory responses and inhibits TNF-a production by monocytes. The profibrinolytic activities of drotrecogin alfa occur through the inhibition of plasminogen activator inhibitor (PAI-1).

In patients with severe sepsis, drotrecogin alfa displays dose-dependent reductions in D-dimer and IL-6. Also, compared to placebo, drotrecogin alfa has a more pronounced reduction in PAI-1 levels, D-dimer, thrombin-antithrombin levels, prothrombin, IL-6, and more rapid increases in protein C and antithrombin levels.

Pharmacokinetics

Drotrecogin alfa demonstrates a biphasic half-life (t½), with a t½a and t½ß of 13 minutes and 1.63 hours, respectively. Drotrecogin alfa is inactivated by endogenous plasma protease inhibitors. Due to the short half-life and metabolism, rapid elimination of the drug occurs after stopping the infusion. The volume of distribution (Vd) is comparable to the extracellular volume (16 to 20 L) in healthy volunteers.

Clinical Study

Drotrecogin alfa was approved by the FDA based on the results from a multi-center, randomized, double-blind, placebo-controlled trial of 1,690 patients with severe sepsis (PROWESS; recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis). The primary endpoint was the effect of drotrecogin alfa on all cause mortality at 28 days. Secondary endpoints included a pharmacokinetic analysis, safety analysis, and evaluation of the impact of drotrecogin alfa on organ dysfunction. The trial included patients with a documented infection or suspected infection, at least three SIRS criteria, and at least one acute organ dysfunction (< 48 hours in duration). The trial excluded patients who were considered to be at a high risk of bleeding (e.g., hemorrhagic stroke, major trauma, thrombocytopenia, and recent thrombolytic, antiplatelet, or anticoagulant therapy) or patients with a futile prognosis. Pediatric and immunocompromised (i.e., transplant patients and HIV-positive patients with a CD4+ <50/mm³) patients were also excluded. Patients were randomized to receive drotrecogin alfa at 24 mcg/kg/min or placebo for a total of 96 hours. Patients were monitored for 28 days or until expiration for outcomes analysis. The PROWESS study was stopped after the second interim analysis showed a statistically significant mortality benefit. Results of the PROWESS study (See Table 2) showed an absolute risk reduction in mortality of 6.1% (24.7% drotrecogin alfa and 30.8% placebo) and a relative risk reduction of 19.4% (p=0.005). The number-needed-to-treat analysis suggested that one life could be saved for every 16 patients treated with drotrecogin alfa. Baseline APACHE II scores were 24.6 for drotrecogin alfa and 25.0 for placebo. The majority of patients (80%) were admitted directly from home and approximately 75% of patients required mechanical ventilation, vasopressors, and/or had two or more organ dysfunctions. The lung and abdomen were the most common sites of infection and there were similar treatment effects between both gram-positive infections and gram-negative infections. During the infusion period, drotrecogin alfa significantly reduced D-dimer and IL-6 levels from baseline. Drotrecogin alfa treatment resulted in a more rapid resolution of cardiovascular and respiratory dysfunction over a seven day period.

Table 2. PROWESS Trial: Results

Adapted from the drotrecogin alfa product insert.

In the PROWESS trial, all adverse effects consisted of bleeding complications. During the 28-day study period, there was a trend towards more serious bleeding complications in the treatment group compared to placebo, 3.5% and 2.0% (p=0.06) respectively. Moreover, bleeding complications were significantly greater during the 96 hour infusion, which occurred 2.4% in the drotrecogin alfa patients compared to 1.0% in the placebo patients (p=0.024). Patients that had the highest risk of bleeding complications included: gastrointestinal ulceration, aPTT > 120 sec, INR > 3, traumatic injury, or platelet count < 30,000/mm³. Four fatal bleeding complications occurred during the drotrecogin alfa infusion period compared to only one fatal bleeding complication after the placebo infusion was completed.

Adverse Effects

Since drotrecogin alfa is a potent anticoagulant, the main adverse effect is an increased risk of bleeding. Drotrecogin alfa is contraindicated in patients in which bleeding could be associated with a high risk of death or significant morbidity. The contraindications are: 1) active internal bleeding, 2) recent (within 3 months) hemorrhagic stroke, 3) recent (within 2 months) intra-cranial or intraspinal surgery, or severe head trauma, 4) trauma with an increase of life-threatening bleeding, 5) presence of epidural catheter, 6) intracranial neoplasm or mass lesion or evidence of cerebral herniation. Moreover, patients with a number of conditions that increased their risk of bleeding (e.g., platelets < 30,000/mm³, PT-INR > 3, recent GI bleeding, recent ischemic stroke) were excluded in the Phase III trial. There have been no reports of non-bleeding adverse effects with drotrecogin alfa.

Administration and Dose

Drotrecogin alfa is a lyophilized powder that must be reconstituted prior to dilution. Drotrecogin alfa is stable in 0.9% NS at a concentration of 100 to 200 mcg/ml. It must be administered through a dedicated intravenous line. Currently, there are no compatibility studies regarding the administration with other medications; however, drotrecogin alfa may be administered concurrently with 0.9% NS, lactated ringers, or dextrose solutions through the same line. The diluted bag will be hand-delivered by the Department of Pharmacy and the bag should not be shaken. The infusion bag will be dispensed as an 8-hour continuous infusion, as drotrecogin alfa has a 14-hour expiration. Also, the bag should not be exposed to heat or direct sunlight.

Monitoring Parameters

If a surgical or percutaneous procedure needs to be performed, drotrecogin alfa should be stopped 2 hours prior to the procedure. If adequate hemostasis has been achieved, drotrecogin alfa can be restarted 1 hour after a percutaneous procedure and 12 hours after a surgical procedure. If evidence of gastro-intestinal (GI) bleeding occurs, drotrecogin alfa should be stopped immediately and an endoscopy should be performed to rule out active bleeding. All patients on drotrecogin alfa should receive stress ulcer prophylaxis, such as a histamine-2 antagonist (famotidine) or sucralfate. If a patient requires full-dose therapeutic heparin for the treatment of a thrombotic event or there is evidence of an acute bleeding event, the drotrecogin alfa infusion should be stopped immediately.

Cost

Drotrecogin alfa therapy is expensive with a cost of approximately $42 per mg. The average cost for a 70 kg patient is $7,000 per treatment period. The average cost for a 100 kg patient is $10,000 per treatment period. Therefore, drotrecogin alfa costs approximately $100/kg for the 96-hour treatment period.

Restrictions

At the Cleveland Clinic Foundation, drotrecogin alfa is restricted to attending physicians due to concerns of safety and appropriate use (See Figure 1 and Table 3). Orders written by fellows, residents, or attending physicians who are not approved to use drotrecogin alfa will not be dispensed by the pharmacy. Two health care professionals (one MD, one PharmD) must review the case and approve the agent for use. Discrepancies will be forwarded to Steven LaRosa, MD, Infectious Diseases attending physician (one of the principal investigators on the PROWESS study), and Jennifer Long, PharmD, Infectious Diseases Clinical Specialist/Pharmacist.

Table 3. Approval Process

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