The recommended minimum dose is 2.5 x 107 nucleated cells/kg at cryopreservation. Multiple units may be required in order to achieve the appropriate dose.

Matching for at least 4 of 6 HLA-A antigens, HLA-B antigens, and HLA-DRB1 alleles is recommended. The HLA typing and nucleated cell content for each individual unit of HEMACORD are documented on the container label and/or in accompanying records.

2.2 Preparation for Infusion

Allergic reactions may occur with infusion of hematopoietic progenitor cells, cord blood (HPC-C), 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.

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 antipyretic, 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 gm/kg/day is recommended. [See Overdosage (10)]

If infusing more than one unit of HPC-C 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 (GVHD)

Acute and chronic 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/uL 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-C 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-C 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. 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); however, this is not a donor selection criterion. The result 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 HPC-C collection takes place, the ability to exclude rare genetic diseases is severely limited.

6 ADVERSE REACTIONS

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-C manufactured by various cord blood banks in patients treated using a total nucleated cell dose ≥2.5 x 107/kg on a single-arm trial or expanded access use (The COBLT Study). The population was 60% male and 40% female of median age 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 bradycardia. Hypertension and any grades 3-4 infusion related reactions occurred more frequently in patients receiving HPC-C in volumes greater than 150 milliliters and in pediatric patients. The rate of serious adverse cardiopulmonary reactions was 0.8%.

For patients who received HEMACORD, information on infusion reactions was from voluntary reports for 244 patients. The population included 56% males and 44% females of median age 25 years (range 0.2-73 years). Preparative regimens and graft-vs-host disease prophylaxis were not standardized. The reactions were not graded. Eighteen percent of patients had an infusion reaction. The most common infusion reactions 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 was pooled for 120 adult and 1179 pediatric patients transplanted with an HPC-C total nucleated cell dose ≥2.5 x 107/kg. Sixty-six percent (n=862) of the 1299 patients in the docket and public data 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 (range, 2.5-73.8) x 107/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 on other adverse reactions were available for 155 patients treated with HEMACORD at a total nucleated cell dose ≥2.5 x 107/kg from voluntary reports. For these patients, Day-100 mortality from all causes was 25%. Primary graft failure occurred in 15%; 43% developed grades 2-4 acute graft-vs-host disease; and 20% 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-C 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with HEMACORD. It is also not known whether HEMACORD can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. There are no adequate and well-controlled studies in pregnant women. HEMACORD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.4 Pediatric Use

HPC-C has been used in pediatric patients with disorders affecting the hematopoietic system that are inherited, acquired, or resulted from myeloablative treatment. [See Dosage and Administration (2), Adverse Reactions (6), and Clinical Studies (14)]

8.5 Geriatric Use

Clinical studies of HPC-C did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently to HEMACORD than younger subjects. In general, administration of HEMACORD to patients over age 65 should be cautious, reflecting their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Disease

HEMACORD contains Dextran 40 which is eliminated by the kidneys. The safety of HEMACORD has not been established in patients with renal insufficiency or renal failure.

10 OVERDOSAGE

10.1 Human Overdosage Experience

There has been no experience with overdosage of HPC-C in human clinical trials. Single doses of HEMACORD up to 57.6 x 107 TNC/kg have been administered. HPC-C prepared for infusion may contain dimethyl sulfoxide (DMSO). The maximum tolerated dose of DMSO has not been established, but it is customary not to exceed a DMSO dose of 1 gm/kg/day when given intravenously. Several cases of altered mental status and coma have been reported with higher doses of DMSO.

10.2 Management of Overdose

For DMSO overdosage, general supportive care is indicated. The role of other interventions to treat DMSO overdosage has not been established.

11 DESCRIPTION

Hematopoietic stem/progenitor cells from HPC-C migrate to the bone marrow where they divide and mature. The mature cells are released into the bloodstream, where some circulate and others migrate to tissue sites, partially or fully restoring blood counts and function, including immune function, of blood-borne cells of marrow origin. [See Clinical Studies (14)]

In patients with enzymatic abnormalities due to certain severe types of storage disorders, mature leukocytes resulting from HPC-C transplantation may synthesize enzymes that may be able to circulate and improve cellular functions of some native tissues. However, the precise mechanism of action is unknown.

14 CLINICAL STUDIES