Bleeding

Bleeding is the most common adverse reaction associated with Xigris.

In the phase 3 study, serious bleeding events were observed during the 28-day study period in 3.5% of Xigris treated and 2.0% of placebo treated patients, respectively. The difference in serious bleeding between Xigris and placebo occurred primarily during the infusion period and is shown in Table 2.¹ Serious bleeding events were defined as any intracranial hemorrhage, any life-threatening 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 a serious adverse event.

Table 2: Number of Patients Experiencing a Serious Bleeding Event by Site of Hemorrhage During the Study Drug Infusion Period^a in PROWESS¹

^aStudy drug infusion period is defined as the date of initiation of study drug to the date of study drug discontinuation plus the next calendar day.

^bPatients requiring the administration of ≥3 units of packed red blood cells per day for 2 consecutive days without an identified site of bleeding.

In PROWESS, 2 cases of intracranial hemorrhage (ICH) occurred during the infusion period for Xigris treated patients and no cases were reported in the placebo patients. The incidence of ICH during the 28-day study period was 0.2% for Xigris treated patients and 0.1% for placebo treated patients. ICH has been reported in patients receiving Xigris in nonplacebo controlled trials with an incidence of approximately 1% during the infusion period. The risk of ICH may be increased in patients with risk factors for bleeding such as severe coagulopathy and severe thrombocytopenia (see WARNINGS).

In PROWESS, 25% of the Xigris-treated patients and 18% of the placebo-treated patients experienced at least one bleeding event during the 28-day study period. In both treatment groups, the majority of bleeding events were ecchymoses or gastrointestinal tract bleeding.

Patients administered Xigris as treatment for severe sepsis experience many events which are potential sequelae of severe sepsis and may or may not be attributable to Xigris therapy. In clinical trials, there were no types of non-bleeding adverse events suggesting a causal association with Xigris.

Drug interaction studies with Xigris have not been performed in patients with severe sepsis. However, since there is an increased risk of bleeding with Xigris, caution should be employed when Xigris is used with other drugs that affect hemostasis (see CLINICAL PHARMACOLOGY, WARNINGS). Approximately 2/3 of the patients in the Phase 3 study received either prophylactic low dose heparin (unfractionated heparin up to 15,000 units/day) or prophylactic doses of low molecular weight heparins as indicated in the prescribing information for the specific products. Concomitant use of prophylactic low dose heparin did not appear to affect safety, however, its effects on the efficacy of Xigris have not been evaluated in an adequate and well-controlled clinical trial.

Drug/Laboratory Test Interaction

Because Xigris may affect the APTT assay, Xigris present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as factor VIII, IX, and XI assays). This interference may result in an apparent factor concentration that is lower than the true concentration. Xigris present in plasma samples does not interfere with one-stage factor assays based on the PT (such as factor II, V, VII, and X assays).

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