FDA label eb63d261-e74f-f8fa-e053-2a95a90a538a

WARNING: FATAL INFUSION REACTIONS, GRAFT VERSUS HOST DISEASE, ENGRAFTMENT SYNDROME AND GRAFT FAILURE Fatal infusion reactions: HEMACORD administration can result in serious, including fatal, infusion reactions. Monitor patients and discontinue HEMACORD infusion for severe reactions. [See Warnings and Precautions ( 5.1 , 5.2 )] Graft-vs-host disease (GVHD): GVHD is expected after administration of HEMACORD, and may be fatal. Administration of immunosuppressive therapy may decrease the risk of GVHD. [See Warnings and Precautions ( 5.3 )] Engraftment syndrome: Engraftment syndrome may progress to multiorgan failure and death. Treat engraftment syndrome promptly with corticosteroids. [See Warnings and Precautions ( 5.4 )] Graft failure: Graft failure may be fatal. Monitor patients for laboratory evidence of hematopoietic recovery. Prior to choosing a specific unit of HEMACORD, consider testing for HLA antibodies to identify patients who are alloimmunized. [See Warnings and Precautions ( 5.5 )] WARNING: FATAL INFUSION REACTIONS, GRAFT VERSUS HOST DISEASE, ENGRAFTMENT SYNDROME, AND GRAFT FAILURE See full prescribing information for complete boxed warning. Fatal infusion reactions: Monitor patients during infusion and discontinue for severe reactions. ( 5.1 , 5.2 ) Graft-vs-host disease (GVHD): GVHD may be fatal. Administration of immunosuppressive therapy may decrease the risk of GVHD ( 5.3 ) Engraftment syndrome: Engraftment syndrome may be fatal. Treat engraftment syndrome promptly with corticosteroids ( 5.4 ) Graft failure: Graft failure may be fatal. Monitor patients for laboratory evidence of hematopoietic recovery ( 5.5 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions ( 5.1 ) Infusion Reactions ( 5.2 ) Graft-versus-Host Disease ( 5.3 ) Engraftment Syndrome ( 5.4 ) Graft Failure ( 5.5 ) Malignancies of Donor Origin ( 5.6 ) Transmission of Serious Infections ( 5.7 ) Transmission of Rare Genetic Diseases ( 5.8 ) 5.1 Hypersensitivity Reactions Allergic reactions may occur with infusion of HPC, Cord Blood, including HEMACORD. Reactions include bronchospasm, wheezing, angioedema, pruritus and hives [see Adverse Reactions ( 6 )] . Serious hypersensitivity reactions, including anaphylaxis, also have been reported. These reactions may be due to dimethyl sulfoxide (DMSO), Dextran 40, or a plasma component of HEMACORD. HEMACORD may contain residual antibiotics if the cord blood donor was exposed to antibiotics in utero. Patients with a history of allergic reactions to antibiotics should be monitored for allergic reactions following HEMACORD administration. 5.2 Infusion Reactions Infusion reactions are expected to occur and include nausea, vomiting, fever, rigors or chills, flushing, dyspnea, hypoxemia, chest tightness, hypertension, tachycardia, bradycardia, dysgeusia, hematuria, and mild headache. Premedication with antipyretics, histamine antagonists, and corticosteroids may reduce the incidence and intensity of infusion reactions. Severe reactions, including respiratory distress, severe bronchospasm, severe bradycardia with heart block or other arrhythmias, cardiac arrest, hypotension, hemolysis, elevated liver enzymes, renal compromise, encephalopathy, loss of consciousness, and seizure also may occur. Many of these reactions are related to the amount of DMSO administered. Minimizing the amount of DMSO administered may reduce the risk of such reactions, although idiosyncratic responses may occur even at DMSO doses thought to be tolerated. The actual amount of DMSO depends on the method of preparation of the product for infusion. Limiting the amount of DMSO infused to no more than 1 gram per kilogram per day is recommended [see Overdosage ( 10 )]. If infusing more than one unit of HPC, Cord Blood, on the same day, do not administer subsequent units until all signs and symptoms of infusion reactions from the prior unit have resolved. Infusion reactions may begin within minutes of the start of infusion of HEMACORD, although symptoms may continue to intensify and not peak for several hours after completion of the infusion. Monitor the patient closely during this period. When a reaction occurs, discontinue the infusion and institute supportive care as needed. 5.3 Graft-versus-Host Disease Acute and chronic graft-versus-host disease (GVHD) may occur in patients who have received HEMACORD. Classic acute GVHD is manifested as fever, rash, elevated bilirubin and liver enzymes, and diarrhea. Patients transplanted with HEMACORD also should receive immunosuppressive drugs to decrease the risk of GVHD. [See Adverse Reactions ( 6.1 ).] 5.4 Engraftment Syndrome Engraftment syndrome is manifested as unexplained fever and rash in the peri-engraftment period. Patients with engraftment syndrome also may have unexplained weight gain, hypoxemia, and pulmonary infiltrates in the absence of fluid overload or cardiac disease. If untreated, engraftment syndrome may progress to multiorgan failure and death. Begin treatment with corticosteroids once engraftment syndrome is recognized in order to ameliorate the symptoms. [See Adverse Reactions ( 6.1 ).] 5.5 Graft Failure Primary graft failure, which may be fatal, is defined as failure to achieve an absolute neutrophil count greater than 500 per microliter blood by Day 42 after transplantation. Immunologic rejection is the primary cause of graft failure. Patients should be monitored for laboratory evidence of hematopoietic recovery. Consider testing for HLA antibodies in order to identify patients who are alloimmunized prior to transplantation and to assist with choosing a unit with a suitable HLA type for the individual patient. [See Adverse Reactions ( 6.1 ).] 5.6 Malignancies of Donor Origin Patients who have undergone HPC, Cord Blood, transplantation may develop post-transplant lymphoproliferative disorder (PTLD), manifested as a lymphoma-like disease favoring non-nodal sites. PTLD is usually fatal if not treated. The incidence of PTLD appears to be higher in patients who have received antithymocyte globulin. The etiology is thought to be donor lymphoid cells transformed by Epstein-Barr virus (EBV). Serial monitoring of blood for EBV DNA may be warranted in high-risk groups. Leukemia of donor origin also has been reported in HPC, Cord Blood, recipients. The natural history is presumed to be the same as that for de novo leukemia. 5.7 Transmission of Serious Infections Transmission of infectious disease may occur because HEMACORD is derived from human blood. Disease may be caused by known or unknown infectious agents. Donors are screened for increased risk of infection with human immunodeficiency virus (HIV), human T-cell lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (HCV), T. pallidum, T. cruzi, West Nile Virus (WNV), transmissible spongiform encephalopathy (TSE) agents, and vaccinia. Donors are also screened for clinical evidence of sepsis, and communicable disease risks associated with xenotransplantation. Maternal blood samples are tested for HIV types 1 and 2, HTLV types I and II, HBV, HCV, T. pallidum , WNV, and T. cruzi. HEMACORD is tested for sterility. There may be an effect on the reliability of the sterility test results if the cord blood donor was exposed to antibiotics in utero. These measures do not totally eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents. Report the occurrence of a transmitted infection to the New York Blood Center at 1-866-767-NCBP (1-866-767-6227). Testing is also performed for evidence of donor infection due to cytomegalovirus (CMV). Test results may be found on the container label and/or in accompanying records. 5.8 Transmission of Rare Genetic Diseases HEMACORD may transmit rare genetic diseases involving the hematopoietic system for which donor screening and/or testing has not been performed [see Adverse Reactions ( 6.1 )] . Cord blood donors have been screened by family history to exclude inherited disorders of the blood and marrow. HEMACORD has been tested to exclude donors with sickle cell anemia, and anemias due to abnormalities in hemoglobins C, D, and E. Because of the age of the donor at the time HEMACORD collection takes place, the ability to exclude rare genetic diseases is severely limited.

6 ADVERSE REACTIONS Day-100 mortality from all causes was 25%. The most common infusion-related adverse reactions (≥ 5%) are hypertension, vomiting, nausea, bradycardia, and fever. Mortality, from all causes, at 100 days post-transplant was 25% ( 5 , 6.1 ) The most common infusion-related adverse reactions (≥5%) are hypertension, vomiting, nausea, bradycardia, and fever ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact the New York Blood Center at 1-866-767-NCBP (1-866-767-6227) and FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials 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. Infusion Reactions The data described in Table 1 reflect exposure to 442 infusions of HPC, Cord Blood, (from multiple cord blood banks) in patients treated using a total nucleated cell dose ≥2.5 x 10 7 /kg on a single-arm trial or expanded access use (The COBLT Study). The population was 60% male and the median age was 5 years (range 0.05-68 years), and included patients treated for hematologic malignancies, inherited metabolic disorders, primary immunodeficiencies, and bone marrow failure. Preparative regimens and graft-vs.-host disease prophylaxis were not standardized. The most common infusion reactions were hypertension, vomiting, nausea, and sinus bradycardia. Hypertension and any grades 3-4 infusion related reactions occurred more frequently in patients receiving HPC, Cord Blood, in volumes greater than 150 milliliters and in pediatric patients. The rate of serious adverse cardiopulmonary reactions was 0.8%. Table 1: Incidence of Infusion-Related Adverse Reactions Occurring in ≥ 1% of Infusions (The COBLT Study) Any grade Grade 3-4 Any reaction 65.4% 27.6% Hypertension 48.0% 21.3% Vomiting 14.5% 0.2% Nausea 12.7% 5.7% Sinus bradycardia 10.4% 0 Fever 5.2% 0.2% Sinus tachycardia 4.5% 0.2% Allergy 3.4% 0.2% Hypotension 2.5% 0 Hemoglobinuria 2.1% 0 Hypoxia 2.0% 2.0% Information on infusion reactions was available from voluntary reports for 244 patients who received HEMACORD. The population included 56% males and 44% females with median age of 25 years (range 0.2-73 years). Preparative regimens and graft-vs.-host disease prophylaxis were not standardized. The reactions were not graded. An infusion reaction occurred in 18% of patients. The most common infusion reactions, occurring in ≥ 1% of patients, were hypertension (14%), nausea (5%), vomiting (4%), hypoxemia (3%), dyspnea (1%), tachycardia (1%), and cough (1%). The rate of serious adverse cardiopulmonary reactions was 0.1%. Other Adverse Reactions For other adverse reactions, the raw clinical data from the docket were pooled for 1299 (120 adult and 1179 pediatric) patients transplanted with HPC, Cord Blood, (from multiple cord blood banks) with total nucleated cell dose ≥ 2.5 x 10 7 /kg. Of these, 66% (n=862) underwent transplantation as treatment for hematologic malignancy. The preparative regimens and graft-vs.-host disease prophylaxis varied. The median total nucleated cell dose was 6.4 x 10 7 /kg (range, 2.5-73.8 x 10 7 /kg). For these patients, Day-100 mortality from all causes was 25%. Primary graft failure occurred in 16%; 42% developed grades 2-4 acute graft-vs.-host disease; and 19% developed grades 3-4 acute graft-vs.-host disease. Data from published literature and from observational registries, institutional databases, and cord blood bank reviews reported to the docket for HPC, Cord Blood, (from multiple cord blood banks) revealed nine cases of donor cell leukemia, one case of transmission of infection, and one report of transplantation from a donor with an inheritable genetic disorder. The data are not sufficient to support reliable estimates of the incidences of these events. In a study of 364 patients, 15% of the patients developed engraftment syndrome.

<table width="500"><caption>Table 1: Incidence of Infusion-Related Adverse Reactions Occurring in &#x2265; 1% of Infusions (The COBLT Study)</caption><tbody><tr><td/><td align="center">Any grade</td><td align="center">Grade 3-4</td></tr><tr><td>Any reaction</td><td align="center">65.4%</td><td align="center">27.6%</td></tr><tr><td>Hypertension</td><td align="center">48.0%</td><td align="center">21.3%</td></tr><tr><td>Vomiting</td><td align="center">14.5%</td><td align="center">0.2%</td></tr><tr><td>Nausea</td><td align="center">12.7%</td><td align="center">5.7%</td></tr><tr><td>Sinus bradycardia</td><td align="center">10.4%</td><td align="center">0</td></tr><tr><td>Fever</td><td align="center">5.2%</td><td align="center">0.2%</td></tr><tr><td>Sinus tachycardia</td><td align="center">4.5%</td><td align="center">0.2%</td></tr><tr><td>Allergy</td><td align="center">3.4%</td><td align="center">0.2%</td></tr><tr><td>Hypotension</td><td align="center">2.5%</td><td align="center">0</td></tr><tr><td>Hemoglobinuria</td><td align="center">2.1%</td><td align="center">0</td></tr><tr><td>Hypoxia</td><td align="center">2.0%</td><td align="center">2.0%</td></tr></tbody></table>