IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Xigris increases the risk of bleeding. Xigris is contraindicated in the following clinical situations where bleeding could lead to significant morbidity or death:
- Active internal bleeding
- Recent (within 3 months) hemorrhagic stroke
- Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma
- Trauma with an increased risk of life-threatening bleeding
- Presence of an epidural catheter
- Intracranial neoplasm or mass lesion or evidence of cerebral herniation
WARNINGS and PRECAUTIONS
Bleeding
Bleeding is the most common serious adverse effect associated with Xigris therapy. Each patient being considered for therapy with Xigris should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy.
Certain conditions, many of which led to exclusion from the Phase 3 trial (PROWESS), are likely to increase the risk of bleeding with Xigris therapy. Therefore, for patients with severe sepsis who have one or more of the following conditions, the increased risk of bleeding should be carefully considered when deciding whether to use Xigris therapy:
- Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolic event
- Platelet count <30,000 x 106/L, even if the platelet count is increased after transfusions
- Prothrombin time-INR >3.0
- Recent (within 6 weeks) gastrointestinal bleeding
- Recent administration (within 3 days) of thrombolytic therapy
- Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa inhibitors
- Recent administration (within 7 days) of aspirin >650 mg per day or other platelet inhibitors
- Recent (within 3 months) ischemic stroke
- Intracranial arteriovenous malformation or aneurysm
- Known bleeding diathesis
- Chronic severe hepatic disease
- Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location
Should clinically important bleeding occur, immediately stop the infusion of Xigris. Continued use of other agents affecting the coagulation system should be carefully assessed. Once adequate hemostasis has been achieved, continued use of Xigris may be reconsidered.
Mortality In Patients with Single Organ Dysfunction and Recent Surgery
Among the small number of patients in PROWESS, with single organ dysfunction and recent surgery (surgery within 30 days prior to study treatment), all-cause mortality was numerically higher in the Xigris group (28 day: 10/49; in hospital: 14/48) compared with the placebo group (28 day: 8/49; in hospital: 8/47).
In an analysis of the subset of patients with single organ dysfunction and recent surgery from the ADDRESS study, which enrolled septic patients not at high risk of death, all cause mortality was also higher in the Xigris group (28 day: 67/323; in hospital: 76/325) compared with the placebo group (28 day: 44/313; in hospital: 62/314). Single organ dysfunction patients with recent surgery may not be at high risk of death irrespective of APACHE II score. Therefore, these patients may not be among the indicated population.
Patients on Prophylactic Heparin when Xigris is Initiated
Clinicians should consider continuing heparin for venous thromboembolism (VTE) prophylaxis when initiating Xigris, unless discontinuation is medically necessary. In a randomized study of prophylactic heparin versus placebo in 1935 adult severe sepsis patients treated with Xigris, mortality and the rate of serious adverse events were increased in the subgroup of 434 patients whose heparin was stopped on study entry by randomization to placebo plus Xigris. This finding was based on prospectively defined exploratory subgroup analyses; however, the explanation for the finding is unclear. The safety of prophylactic heparin when concomitantly administered with Xigris in adult patients with severe sepsis was evaluated with low molecular weight heparin enoxaparin (40 mg every 24 hours) and unfractionated sodium heparin (5000 U every 12 hours), but was not evaluated with unfractionated sodium heparin 5000 U when dosed every 8 hours.
Invasive Procedures
Invasive procedures increase the risk for bleeding with Xigris. Such procedures, including arterial and central venous punctures, should be minimized during the Xigris infusion. Puncture of a noncompressible site should be avoided during the infusion. Xigris should be discontinued 2 hours prior to undergoing an invasive surgical procedure or procedures with an inherent risk of bleeding. Once adequate hemostasis has been achieved, Xigris may be restarted 12 hours after surgery and major invasive procedures or immediately after uncomplicated less invasive procedures.
ADVERSE REACTIONS
Bleeding is the most common adverse reaction associated with Xigris therapy. 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. The difference in serious bleeding occurred primarily during infusion. The incidence of intracranial hemorrhage (ICH) was 0.2% for Xigris-treated and 0.1% for placebo-treated patients. ICH has been reported in Xigris-treated patients in non-placebo controlled trials with an incidence of approximately 1% during infusion. The risk of ICH may be increased in patients with risk factors for bleeding such as severe coagulopathy and severe thrombocytopenia. Should clinically important bleeding occur, immediately stop the Xigris infusion.
In the PROWESS 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. The difference in serious bleeding occurred primarily during infusion.
The incidence of intracranial hemorrhage (ICH) during the 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 non-placebo 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.
*APACHE (Acute Physiology And Chronic Health Evaluation).
Please refer to the full Prescribing Information for Xigris.