FDA label bbd5e014-9d5d-4fea-bb0f-c5b58171cac9

5 WARNINGS AND PRECAUTIONS Anaphylaxis and severe hypersensitivity reactions are possible. Should symptoms occur, treatment with the product should be discontinued, and emergency treatment should be administered. ( 5.1 ) The anticoagulant effect of drugs that use antithrombin to exert their anticoagulation may be altered when ATryn is added or withdrawn. To avoid excessive or insufficient anticoagulation, regularly perform coagulation tests suitable for the anticoagulant used, at close intervals, especially in the first hours following the start or withdrawal of ATryn and monitor patients for bleeding or thrombosis. ( 5.2 ) 5.1 Hypersensitivity Reactions Allergic-type hypersensitivity reactions are possible. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur during administration, treatment must be discontinued immediately and emergency treatment should be administered. 5.2 Coagulation Monitoring Tests The anticoagulant effect of drugs that use antithrombin to exert their anticoagulation may be altered when ATryn is added or withdrawn. To avoid excessive or insufficient anticoagulation, coagulation tests suitable for the anticoagulant used (e.g., aPTT and anti-Factor Xa activity) are to be performed regularly, at close intervals, and in particular in the first hours following the start or withdrawal of ATryn. Additionally, monitor the patients for the occurrence of bleeding or thrombosis in such situation.

6 ADVERSE REACTIONS The most common adverse reactions reported in clinical trials at a frequency of ≥ 5% are hemorrhage and infusion site reaction. The serious adverse reaction that has been reported in clinical studies is hemorrhage (intra-abdominal, hemarthrosis and post procedural). Most common adverse reactions reported in clinical trials at a frequency of ≥ 5% were hemorrhage and infusion site reaction. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact rEVO Biologics, Inc. at 1-800-610-3776 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial s Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions that occurred in clinical trials with hereditary AT deficient patients are shown in Table 4 by System Organ Class. Table 4: Adverse Reactions in Hereditary AT Deficient Patients (one per patient, 2% of total population, n=47) Gastrointestinal Disorders Intra-abdominal Hemorrhage General Disorders and Administration Site Disorders Application Site Pruritus Feeling Hot Non-cardiac Chest Pain Investigations Hepatic Enzyme Abnormal Musculoskeletal and Connective Tissue Disorders Hemarthrosis Renal and Urinary Disorders Hematuria Vascular Disorders Hematoma Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to antithrombin (Recombinant) in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In clinical trials, serum samples were collected from individuals before treatment and at various time points (1, 7, 21-30, 60 and 90 days) after one or more treatments with ATryn. Samples were screened by enzyme-linked immunosorbent assays (ELISA) for IgM and IgG antibodies to antithrombin (Recombinant). Serum samples that were screen-positive were tested by a confirmatory assay: either a radio-immunoprecipitation assay or by an inhibition of binding dose response ELISA. Samples that were confirmed positive in the confirmatory assay were to be tested using a thrombin inhibitory activity assay to assess the endogenous antithrombin level. Serum samples were also collected from individuals before treatment and at various time points after one or more treatments with ATryn to assess the potential for an immune response to residual goat milk proteins in ATryn. Pre- and post-treatment serum samples were analyzed by an immunodot blot assay. No confirmed specific immunological reaction was seen in any of the patients tested, nor were there any clinical adverse reactions that might indicate such a response. In post-marketing patient registry studies, seven patients (four pregnant, three surgical) were enrolled in the studies after a single exposure to ATryn. Patient serum samples were collected within one week from initiation of treatment and on days 1, 7 and 28 days from initiation of treatment and were tested to detect antibodies against antithrombin (Recombinant), goat and goat milk proteins. No antibodies were detected.

<table><colgroup><col width="400"/></colgroup><tbody><tr><td><content styleCode="italics">Gastrointestinal Disorders</content></td></tr><tr><td> Intra-abdominal Hemorrhage</td></tr><tr><td><content styleCode="italics">General Disorders and Administration Site Disorders</content></td></tr><tr><td> Application Site Pruritus</td></tr><tr><td> Feeling Hot</td></tr><tr><td> Non-cardiac Chest Pain</td></tr><tr><td><content styleCode="italics">Investigations</content></td></tr><tr><td> Hepatic Enzyme Abnormal</td></tr><tr><td><content styleCode="italics">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr><td> Hemarthrosis</td></tr><tr><td><content styleCode="italics">Renal and Urinary Disorders</content></td></tr><tr><td> Hematuria</td></tr><tr><td><content styleCode="italics">Vascular Disorders</content></td></tr><tr><td> Hematoma</td></tr></tbody></table>