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Letter to Manufacturers |
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DEPARTMENT OF HEALTH AND HUMAN SERVICES October 16, 2003 Dear Manufacturer: FDA recognizes that when used for their labeled indications U.S. licensed Immune Globulin Intravenous (Human) (IGIV) products have a relatively high margin of safety. However, it is important to recognize that data from adequate and well-controlled clinical studies of IGIVs are modest and studies performed to date have limited power to detect rare or uncommon adverse events (AEs). A significant number of adverse reactions involving renal, cardiovascular, pulmonary, CNS, integumentary, and hematologic organ systems have been observed in association with IGIV infusion, reported postmarketing, and described in the literature. As a result of our review of post marketing reports and related literature1 - 9, CBER is hereby requiring all manufacturers of IGIV products to update the noted sections of their product labeling to include the following: Adverse Reactions Postmarketing "The following adverse reactions have been identified and reported during the post-approval use of IGIV products:
Respiratory
Cardiovascular
Neurological
Integumentary
Hematologic
General/Body as a Whole
Musculoskeletal
Gastrointestinal Because postmarketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently." Precautions Hemolysis "Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis1,2,3 Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration4 [See ADVERSE REACTIONS]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis [See PRECAUTIONS: LABORATORY TESTS]." Transfusion-Related Acute Lung Injury (TRALI) "There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV5. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1-6 hrs after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum [see PRECAUTIONS: LABORATORY TESTS]." Thrombotic Events "Thrombotic events have been reported in association with IGIV6,7,8 (See Adverse Reactions). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [See PRECAUTIONS: LABORATORY TESTS]." In addition please add LABORATORY TESTS as a subsection of PRECAUTIONS. Language to be included in this section: If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done [see PRECAUTIONS]. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum [see PRECAUTIONS]. Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [see PRECAUTIONS]. Please submit within 45 calendar days from the date of this letter a Special Labeling Supplement: Changes Being Effected (21CFR601.12(f)(2)). Please do not include any other changes to the package insert in the requested Special Labeling Supplement except those noted above. This includes changes that may have been previously submitted in supplements which may be pending at this time. Please indicate in the cover letter of the supplement the date by which you expect to implement the changes. If you have any questions concerning this letter, please contact Michael Wiack of the Division of Blood Applications, at 301-827-3524. Sincerely yours, --- signature ---
Basil Golding, M.D.
Literature Citations
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