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, 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 (see PRECAUTIONS, Drug Interactions)

· Prothrombin time-INR >3.0

· Recent (within 6 weeks) gastrointestinal bleeding

· Recent administration (within 3 days) of thrombolytic therapy

· Recent (within 3 months) ischemic stroke (see CONTRAINDICATIONS)

· Intracranial arteriovenous malformation or aneurysm

· Known bleeding diathesis

· Chronic severe hepatic disease

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.

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, initiation of Xigris may be reconsidered 12 hours after major invasive procedures or surgery or restarted immediately after uncomplicated less invasive procedures.

Laboratory Tests

Most patients with severe sepsis have a coagulopathy that is commonly associated with prolongation of the activated partial thromboplastin time (APTT) and the prothrombin time (PT). Xigris may variably prolong the APTT. Therefore, the APTT cannot be reliably used to assess the status of the coagulopathy during Xigris infusion. Xigris has minimal effect on the PT and the PT can be used to monitor the status of the coagulopathy in these patients.

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Xigris has not been adequately determined, as the assay sensitivity is inadequate to reliably detect all potential antibody responses. One patient in the phase 2 trial developed antibodies to Xigris without clinical sequelae. One patient in the phase 3 trial who developed antibodies to Xigris developed superficial and deep vein thrombi during the study, and died of multi-organ failure on day 36 post-treatment but the relationship of this event to antibody is not clear.

Xigris has not been readministered to patients with severe sepsis.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate potential c arcinogenicity of Xigris have not been performed.

Xigris was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or without rat liver metabolic activation.

The potential of Xigris to impair fertility has not been evaluated in male or female animals.

Pregnancy Category C

Animal reproductive studies have not been conduct ed with Xigris. It is not known whether Xigris can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Xigris should be given to pregnant women only if clearly needed.

Nursing Mothers

It is not known whether Xigris is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Xigris have not been established in the age group newborn (38 weeks gestational age) to 18 years. The efficacy of Xigris in adult patients with severe sepsis and high risk of death ca nnot be extrapolated to pediatric patients with severe sepsis.

Geriatric Use

In clinical studies evaluating 1821 patients with sev ere sepsis, approximately 50% of the patients were 65 years or older. No overall differences in safety or effectiveness were observed between these patients a nd younger patients.

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