Drotrecogin alfa

Caution should be employed when drotrecogin alfa is used with other drugs that affect haemostasis including Protein C, thrombolytics (e.g. streptokinase, tPA, rPA and urokinase), oral anticoagulants (e.g. warfarin), hirudins, antithrombin, aspirin and other anti platelets agents, e.g. non- steroidal anti-inflammatory drugs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (such as abciximab, eptifibatide, tirofiban) and prostacyclins such as iloprost.

Animal studies with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development have not been conducted with drotrecogin alfa. Therefore, the potential risk for humans is unknown. Drotrecogin alfa should not be used during pregnancy unless clearly necessary.

It is not known whether drotrecogin alfa is excreted in human milk or if there is a potential effect on the breast-fed infant. Therefore, the patient should not breast feed whilst treated with drotrecogin alfa.

Not relevant.

Drotrecogin alfa increases the risk of bleeding.

The Phase 3 international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (PROWESS) involved 850 drotrecogin alfa (activated)-treated and 840 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 24.9% and 17.7%, respectively. In both treatment groups, the majority of bleeding events were ecchymosis or gastrointestinal tract bleeding. The difference in the incidence of serious bleeding events between the two treatment groups occurred primarily during study drug administration.

A total of 2378 adult patients with severe sepsis received drotrecogin alfa (activated) in a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE).

The incidence of serious bleeding events in the PROWESS and ENHANCE studies is provided below. In these studies serious bleeding events included any intracranial haemorrhage, any life-threatening or fatal bleed, any bleeding event requiring the administration of ≥3 units of packed red blood cells per day for 2 consecutive days, or any bleeding event assessed as serious by the investigator.

A Phase 3b international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (ADDRESS) of adult severe sepsis patients at low risk of death, involved 1317 drotrecogin alfa (activated)-treated and 1293 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 10.9% and 6.4%, respectively (p<0.001). Bleeding events included serious bleeding events, bleeding events assessed as possibly study-drug related by the investigator, bleeding events associated with the need for a red blood cell transfusion, and bleeding events that led to permanent discontinuation of the study drug. In the ADDRESS trial, serious bleeding events included any fatal bleed, any life-threatening bleed, any CNS bleed, or any bleeding event assessed as serious by the investigator.

Serious bleeding events during the infusion period

The following table lists the percent of patients in PROWESS and ENHANCE experiencing serious bleeding events by site of haemorrhage during the study drug infusion period (defined as the duration of infusion plus the next full calendar day following the end of the infusion).

¹ CNS bleeding is defined as any bleed in the central nervous system including the following types of haemorrhage: Petechial, parenchymal, subarachnoid, subdural, and stroke with haemorrhagic transformation.
² Patients requiring the administration of ≥3 units of packed red blood cells per day for 2 consecutive days without an identified site of bleeding
³ In ENHANCE six patients experienced multiple serious bleeding events during the study drug infusion period (94 events observed in 85 patients).

During the infusion period in PROWESS and ENHANCE the incidence of serious bleeding events with drotrecogin alfa was numerically higher in patients with recent [within 30 days] surgery than in patients without surgery (PROWESS: 3.3% vs 2.0%; ENHANCE: 5.0% vs 3.1% respectively. Placebo rates in PROWESS 0.4% vs 1.2% respectively).

In ADDRESS, the percent of treated patients experiencing a serious bleeding event by site of haemorrhage was similar to that observed in PROWESS. The incidence of serious bleeding events during infusion (defined as study Day 0 through study Day 6) was 31 (2.4%) and 15 (1.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (p=0.02). The incidence of CNS bleeds during infusion was 4 (0.3%) and 3 (0.2%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. Recent surgery (within 30 days prior to study entry) was associated with a numerically higher risk of serious bleeding during infusion in both the drotrecogin alfa-treated and the placebo-treated patients (Drotrecogin alfa: 3.6% in patients with recent surgery versus 1.6% in patients without recent surgery; placebo: 1.6% versus 0.9% respectively).

In XPRESS, a randomised study of prophylactic heparin versus placebo in adult severe sepsis patients, all treated with drotrecogin alfa (activated), serious bleeding rates were consistent with those observed in previous studies over the treatment period of 0-6 days, and prophylactic heparin did not increase the risk of serious bleeding compared to placebo (2.3% vs 2.5%, respectively), including CNS bleeding (0.3% on both arms). However prophylactic heparin increased the risk of non-serious bleeding compared with placebo (8.7% vs 5.7%, respectively; p= 0.0116).

Serious bleeding events during the 28-day study period

In PROWESS, the incidence of serious bleeding events during the 28-day study period was 3.5% and 2.0% in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The incidence of CNS bleeds during the 28-day study period was 0.2% and 0.1% for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The risk of CNS bleeding may increase with severe coagulopathy and severe thrombocytopenia.

In the open-label ENHANCE study, the incidence of serious bleeding events during the 28-day study period was 6.5%, and the incidence of CNS bleeds during the 28-day study period was 1.5%.

In the placebo-controlled ADDRESS study, the incidence of serious bleeding events during the 28-day study period was 51 (3.9%) and 28 (2.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (p=0.01). The incidence of CNS bleeds during the 28-day study period was 6 (0.5%) and 5 (0.4%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively.

In XPRESS serious bleeding rates were consistent with those observed in previous studies during the 28-day study period (days 0-28). Prophylactic heparin did not increase the risk of serious bleeding compared to placebo (3.9% vs 5.2%, respectively), including CNS bleeding (1.0% vs 0.7%, respectively).

In the phase 1 studies, adverse events with a frequency of ≥ 5% included headache (30.9%), ecchymosis (23.0%), and pain (5.8%).