warnings and cautions
5 WARNINGS AND PRECAUTIONS IgA-deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions. Discontinue use if a hypersensitivity reaction occurs. Epinephrine should be immediately available to treat any acute severe hypersensitivity reactions ( 5.1 ). Aseptic meningitis syndrome has been reported to occur infrequently with IGIV treatment and with Vivaglobin treatment ( 5.2 ). Monitor patients for reactions reported to occur with IGIV treatment that may occur with Vivaglobin, including renal dysfunction/failure, thrombotic events, hemolysis, and transfusion-related acute lung injury (TRALI) ( 5.3 ). Vivaglobin is made from human plasma and may contain infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent ( 5.4 ). 5.1 Hypersensitivity Reactions Severe hypersensitivity reactions may occur ( see Patient Counseling Information [17.2] ). In case of hypersensitivity, discontinue the Vivaglobin infusion immediately and institute appropriate treatment. Epinephrine should be immediately available to treat any acute severe hypersensitivity reactions. Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including anaphylaxis and shock) after administration of blood components containing IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Vivaglobin contains ≤1.7 mg/mL IgA ( see Description [11] ). The minimum concentration of IgA that will provoke a hypersensitivity reaction is not known; therefore all IgG preparations carry the risk of inducing an anaphylactic reaction to IgA. 5.2 Aseptic Meningitis Syndrome (AMS) AMS has been reported to occur infrequently with IGIV treatment 5 and with Vivaglobin treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. AMS is characterized by signs and symptoms including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. Cerebrospinal fluid (CSF) studies frequently show pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. 5.3 Reactions Reported with IGIV Treatment The following reactions have been reported to occur with IGIV treatment and may occur with IGSC treatment. Renal Dysfunction/Failure Renal dysfunction/failure, osmotic nephropathy, and death may occur with use of human immune globulin products. Ensure that patients are not volume depleted and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Vivaglobin and at appropriate intervals thereafter. Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure. 1 If renal function deteriorates, consider discontinuing Vivaglobin. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are overweight or use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), administer Vivaglobin at the minimum rate practicable. Thrombotic Events Thrombotic events may occur with use of human immune globulin products. 2-4 Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity. Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Vivaglobin at the minimum rate practicable. Hemolysis Vivaglobin may contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin (Coombs') test result and hemolysis. 6-8 Delayed hemolytic anemia can develop subsequent to immune globulin therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported. 9 Monitor recipients of Vivaglobin for clinical signs and symptoms of hemolysis. If these are present after Vivaglobin infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving Vivaglobin, perform adequate cross-matching to avoid exacerbating on-going hemolysis. Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients administered human immune globulin products. 10 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Typically, it occurs within 1 to 6 hours following transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. Monitor recipients of Vivaglobin for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient's serum. 5.4 Transmissible Infectious Agents Because Vivaglobin is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of Vivaglobin. Report all infections thought possibly to have been transmitted by Vivaglobin to the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . The physician should discuss the risks and benefits of this product with the patient before prescribing or administering it to the patient ( see Patient Counseling Information [17.2] ). 5.5 Laboratory Tests After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient's blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs') test.