2.1 Dosing

The recommended minimum dose is 2.5 x 10 7 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

HEMACORD should be prepared by a trained healthcare professional.

• Do not irradiate HEMACORD.
• See the appended detailed instructions for preparation of HEMACORD for infusion.
• Once prepared for infusion, HEMACORD may be stored at 4 to 25°C for up to 4 hours if DMSO is not removed, and at 4°C for up to 24 hours if DMSO is removed in a washing procedure [see Instructions for Preparation for Infusion] .
• The recommended limit on DMSO administration is 1 gram per kg body weight per day [see Warnings and Precautions ( 5.2) and Overdosage ( 10)].

2.3 Administration

HEMACORD should be administered under the supervision of a qualified healthcare professional experienced in hematopoietic progenitor cell transplantation.

1. Confirm the identity of the patient for the specified unit of HEMACORD prior to administration.
2. Confirm that emergency medications are available for use in the immediate area.
3. Ensure the patient is hydrated adequately.
4. Premedicate the patient 30 to 60 minutes before the administration of HEMACORD. Premedication can include any or all of the following: antipyretics, histamine antagonists, and corticosteroids.
5. Inspect the product for any abnormalities such as unusual particulates and for breaches of container integrity prior to administration. Prior to infusion, discuss all such product irregularities with the laboratory issuing the product for infusion.
6. Administer HEMACORD by intravenous infusion. Do not administer in the same tubing concurrently with products other than 0.9% Sodium Chloride, Injection (USP). HEMACORD may be filtered through a 170 to 260 micron filter designed to remove clots. Do NOT use a filter designed to remove leukocytes.
7. For adults, begin infusion of HEMACORD at 100 milliliters per hour and increase the rate as tolerated. For children, begin infusion of HEMACORD at 1 milliliter per kg per hour and increase as tolerated. The infusion rate should be reduced if the fluid load is not tolerated. The infusion should be discontinued in the event of an allergic reaction or if the patient develops a moderate to severe infusion reaction. [See Warnings and Precautions ( 5.2) and Adverse Reactions ( 6).]
8. Monitor the patient for adverse reactions during, and for at least six hours after, administration. Because HEMACORD contains lysed red cells that may cause renal failure, careful monitoring of urine output is also recommended.

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.

6.1 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%.

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.

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, Cord Blood, 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, Cord Blood, (from multiple cord blood banks) did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. In general, administration of HEMACORD to patients over age 65 years 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.

10.1 Human Overdosage Experience

There has been no experience with overdosage of HPC, Cord Blood, in human clinical trials. Single doses of HEMACORD up to 57.6 x 10 7 TNC/kg have been administered. HPC, Cord Blood, 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.

12.1 Mechanism of Action

Hematopoietic stem/progenitor cells from HPC, Cord Blood, 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, Cord Blood, 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.

1 REQUIRED EQUIPMENT, REAGENTS, AND SUPPLIES

Equipment Biological Safety Cabinet (BSC)
Refrigerated blood bank centrifuge
Plasma extractor
Digital balance
Tube sealer compatible with PVC plastic
Automated cell counter
Microscope and chamber for determining cell count and viability (optional)
Water bath (4 liters or more)
Canister opening tool
Orbital Rotator

Reagents
5% Albumin (human), USP
10% Dextran 40, USP
Bacterial culture bottles (aerobic and anaerobic)

Supplies
Cell Wash/Infusion Bag Set (Transplant Set) (included with HEMACORD)
Sterile Disposable Syringes: 3 mL, 30 mL and 60 mL
Sterile tubing
18 gauge injection needles
Sterile gloves
Hemostats
Sterile small plastic zipper-lock bags
Alcohol prep pads
Iodine swab sticks
Sampling site couplers
Tubes for cell counts, progenitor assays (optional)
Protective cryogloves
Transfer pack containers 300 mL
Instructions for preparation for infusion

2 VERIFICATION OF PRODUCT IDENTITY

HEMACORD is shipped frozen in a steel canister that is contained in an insulating foam sleeve. HEMACORD must be kept at or below -150 °C, either inside the container used for shipping (Dry-Shipper) or in a Liquid Nitrogen (LN 2)-cooled storage device at the Transplant Center (recommended).

The bar-coded ID label of the product is affixed to the canister (Figure 1).

Figure 1

1. Check the HEMACORD ID label to confirm its identity with the ID of the expected product as soon as it is received.
2. Wearing protective cryogloves, transfer the HEMACORD from the Dry-Shipper to the vapor phase of a LN 2 storage tank.
3. Use the canister opening tool to pry canister open at top and bottom, as shown below in Figures 2 and 3.

   

   Figure 2.

   

   Figure 3.

4. Work carefully to avoid damaging the frozen plastic product bag.
5. Check the bar-coded label on the product against your records to verify that the bar-coded and visually-readable printed number absolutely conforms to the information previously provided and the documentation included with the HEMACORD product.
6. Document this check on the “Unit Receipt Form” document received with the product.

3 METHOD

4. ADMINISTRATIVE REQUIREMENTS

1. Prepare a report on the procedure. Note the condition of the HEMACORD bag, including whether and at what stage leaks or cracks were detected. Record the following:
            HEMACORD ID number
            Date of receipt of the HEMACORD
            Liquid Nitrogen Storage conditions in your facility
            Date of thawing
            Volume of the final product
            Total nucleated cell (TNC) count, CD34+ content
            Viability of the cells recovered (TNC or CD34+ cells) and the method used
            Results of bacterial and fungal cultures
2. E-mail or fax a copy of the report to the New York Blood Center, Inc.
            Email: ncbp@nybloodcenter.org
            Fax: (718) 707-3747
3. Keep a copy for your processing lab records.
4. Return the dry shipper to the New York Blood Center, Inc. The return address is:
            New York Blood Center, Inc.
            National Cord Blood Program
            45-01 Vernon Blvd.
            Long Island City, NY 11101
            Ph: (718) 706-5211
            Fax: (718) 707-3741

5. EMERGENCY PRODUCT RECOVERY IN THE EVENT OF A CONTAINER FAILURE

1. To prevent accidental fracture, handle the HEMACORD bags with extreme caution when removing them from the protective metal cassettes, during inspection, and during the thawing process.
2. Perform the thawing process in a controlled laboratory environment that provides appropriate equipment and supplies for post-thaw sampling and/or bag rescue, as well as dedicated space and personnel for product preparation.
3. To mitigate the extreme temperature change from storage at -196 °C (Liquid Nitrogen phase) to thawing at 38°C, and possible sudden vaporization of liquid nitrogen in recess of the bag or tubing, hold the HEMACORD bag in the vapor phase for a few minutes following removal from the liquid phase of nitrogen before removal for thawing.
4. To prevent an accidental drop onto the floor, handle HEMACORD bags over a flat surface, such as a table.
5. Place HEMACORD bags in individual sterile zipper-locked bags prior to thawing to facilitate salvage of the product and to reduce contamination in case of an unanticipated problem.
6. If the HEMACORD bag is obviously fractured upon removal from cold storage, or if it fractures during the thawing process, please notify the Processing Laboratory of the National Cord Blood Program at the New York Blood Center [phone number: 718-706-5211 or 1-866-767-NCBP (1-866-767-6227)] as soon as possible. Notify the transplant physician and the laboratory director immediately.
7. It is the transplant physician’s (or designee’s) responsibility to determine whether the HEMACORD product will be used or discarded and whether additional product(s) are to be requested for infusion.
8. If the transplant physician (or designee) determines that the product in a ruptured bag should be used, the HEMACORD product may be recovered as follows:
   1. Place the ruptured bag into the sterile zipper-locked plastic bag to prevent further loss and/or contamination of the product during the thawing process.
   2. Thaw the product according to the Section 3 above. Small leaks or tears of the ruptured bag can be blocked off with hemostat clips.
   3. Withdraw the thawed product from the freezing bag and any product from the zipper-locked bag into one or more 60 mL syringe(s) with sterile tubing attached.
   4. Inside a biological safety cabinet, transfer the product into a new bag using a sterile syringe. (This new bag could be either the sterile transplant bag that is provided with the HEMACORD product or a bag of a stocked salvage kit that should be readily available in the thawing laboratory for use in these situations.)
   5. Save an aliquot of the product to send for gram stain and bacterial and fungal cultures.
   6. Dilute (reconstitute) the thawed HEMACORD and remove the cryoprotectant according to the procedure described above or administer the diluted product to the patient as per transplant physician’s instructions.
   7. It is the transplant physician’s (or designee’s) responsibility to determine whether to treat the patient with broad-spectrum antibiotic coverage and the necessity for an infectious disease consultation.
   8. If possible, place the ruptured bag (with or without the product) into a biohazard bag and save for reference when notifying the National Cord Blood Program at the New York Blood Center. This staff will notify the manufacturer and provide information for returning the bag to the manufacturer for evaluation.
   9. Notify the National Cord Blood Program at the New York Blood Center [phone number: 718-706-5211 or 1-866-767-NCBP (1-866-767-6227)].

Distributed by:
New York Blood Center, Inc.
45-01 Vernon Boulevard
Long Island City, NY 11101
License No. 0465
Issued: 02/2012