"The US Food and Drug Administration (FDA) is investigating the "rare but serious" risk for slowed or difficult breathing in children 17 and younger treated with the opioid analgesic tramadol.
"This risk may be increased in children tr"...
Bleeding is the most common serious adverse reaction experienced by patients receiving Xigris (drotrecogin alfa) . Each patient being considered for therapy with Xigris (drotrecogin alfa) should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy.
Certain conditions, many of which led to exclusion from Study 1 [see Clinical Studies], are likely to increase the risk of bleeding with Xigris (drotrecogin alfa) therapy. For individuals with one or more of the following conditions, the increased risk of bleeding should be carefully considered when deciding whether to use Xigris (drotrecogin alfa) therapy:
- Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolic event [see DRUG INTERACTIONS]
- 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 [see CONTRAINDICATIONS]
- 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 (drotrecogin alfa) . Continued use of other agents affecting the coagulation system should be carefully assessed. Once adequate hemostasis has been achieved, continued use of Xigris (drotrecogin alfa) may be reconsidered.
Mortality in Patients with Single Organ Dysfunction and Recent Surgery
In Study 1, among the small number of patients with single organ dysfunction and recent surgery (surgery within 30 days prior to study treatment), all-cause mortality was numerically higher in the Xigris (drotrecogin alfa) 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 Study 2, which enrolled septic patients not at high risk of death, all-cause mortality was also higher in the Xigris (drotrecogin alfa) 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 (drotrecogin alfa) is Initiated
Clinicians should consider continuing heparin for venous thromboembolism (VTE) prophylaxis when initiating Xigris (drotrecogin alfa) , unless discontinuation is medically necessary. In a randomized study of prophylactic heparin versus placebo in 1935 adult severe sepsis patients treated with Xigris (drotrecogin alfa) , 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 (drotrecogin alfa) . 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 (drotrecogin alfa) 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 every12 hours), but was not evaluated with unfractionated sodium heparin 5000 U when dosed every 8 hours [see Clinical Studies].
Invasive procedures increase the risk for bleeding with Xigris (drotrecogin alfa) . Such procedures, including arterial and central venous punctures, should be minimized during the Xigris (drotrecogin alfa) infusion. Puncture of a noncompressible site should be avoided during the infusion. Xigris (drotrecogin alfa) 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 (drotrecogin alfa) may be restarted 12 hours after surgery and major invasive procedures or immediately after uncomplicated less invasive procedures.
Laboratory Tests for Coagulopathy
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). The activated partial thromboplastin time (APTT) cannot be reliably used to assess the degree of the coagulopathy during Xigris (drotrecogin alfa) infusion since Xigris variably prolongs the APTT [see DRUG INTERACTIONS].
The prothrombin time (PT) may be used to monitor the degree of the coagulopathy in patients treated with Xigris (drotrecogin alfa) because Xigris (drotrecogin alfa) has minimal effect on the PT [see DRUG INTERACTIONS].
Drotrecogin alfa (activated) 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 will result in a measured factor concentration that is lower than the actual concentration. Drotrecogin alfa (activated) 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) [see DRUG INTERACTIONS].
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate potential carcinogenicity of Xigris (drotrecogin alfa) have not been performed. Xigris (drotrecogin alfa) 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 (drotrecogin alfa) to impair fertility has not been evaluated in male or female animals.
Use In Specific Populations
Pregnancy Category C — Animal reproduction studies have not been conducted with Xigris (drotrecogin alfa) . It is also not known whether Xigris (drotrecogin alfa) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. In published case reports, there were no major malformations or other adverse outcomes reported following treatment with Xigris (drotrecogin alfa) during pregnancy. Due to the limited number of exposed pregnancies, these postmarketing data do not reliably estimate the frequency or absence of adverse outcomes. Xigris (drotrecogin alfa) should be given to a pregnant woman only if clearly needed.
It is not known whether drotrecogin alfa (activated) is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Xigris (drotrecogin alfa) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
A placebo-controlled trial in pediatric patients (Study 3) did not establish safety and effectiveness of Xigris (drotrecogin alfa) in the pediatric patient population [see INDICATIONS and Clinical Studies].
In Study 1, which evaluated 1690 patients with severe sepsis, 48 percent were 65 years and over, while 23 percent were 75 and over. No overall difference in safety was observed between these patients and younger patients. Reduction in mortality was observed in both geriatric and younger patients.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 9/1/2009
Additional Xigris Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.