DUCORD: Package Insert and Label Information

DUCORD- human cord blood hematopoietic progenitor cell solution
Duke University School of Medicine, Carolinas Cord Blood Bank

WARNING: FATAL INFUSION REACTIONS, GRAFT VERSUS HOST DISEASE, ENGRAFTMENT SYNDROME, AND GRAFT FAILURE

Fatal infusion reactions: DUCORD administration can result in serious, including fatal, infusion reactions. Monitor patients and discontinue DUCORD infusion for severe reactions. [See Warnings and Precautions (5.1, 5.2)]

Graft-vs-host disease (GVHD): GVHD is expected after administration of DUCORD, 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 DUCORD, consider testing for HLA antibodies to identify patients who are alloimmunized. [See Warnings and Precautions (5.5)]

1 INDICATIONS AND USAGE

DUCORD, HPC (Hematopoietic Progenitor Cell), Cord Blood, is an allogeneic cord blood hematopoietic progenitor cell therapy indicated for use in unrelated donor hematopoietic progenitor stem cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment.

The risk benefit assessment for an individual patient depends on the patient characteristics, including disease, stage, risk factors, and specific manifestations of the disease, on characteristics of the graft, and on other available treatments or types of hematopoietic progenitor cells.

2 DOSAGE AND ADMINISTRATION

  • For intravenous use only.
  • Do not irradiate.

Unit selection and administration of DUCORD should be done under the direction of a physician experienced in hematopoietic progenitor cell transplantation.

2.1 Dosing

The recommended minimum dose is 2.5 × 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 DUCORD are documented on the container label and/or in accompanying records.

2.2 Preparation for Infusion

DUCORD should be prepared by a trained healthcare professional.

2.3 Administration

DUCORD 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 DUCORD 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 DUCORD. Premedication should include any or all of the following: antipyretic, 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 DUCORD by intravenous infusion. Do not administer in the same tubing concurrently with products other than 0.9% Sodium Chloride, Injection (USP). DUCORD may be filtered through a 170 to 260 micron filter designed to remove clots. Do NOT use a filter designed to remove leukocytes.
  7. DUCORD should be infused over 15 to 60 minutes depending on the volume of the product and the weight of the patient. The rate of infusion should not exceed a maximum of 5 milliliters per kilogram per hour. 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 DUCORD contains lysed red cells that may cause renal failure, careful monitoring of urine output is also recommended.

NOTE: If product is being prepared for a multi-unit infusion, infuse units independently.

Should a reaction occur, appropriately manage the reaction before the second unit is thawed for infusion.

3 DOSAGE FORMS AND STRENGTHS

Each unit of DUCORD contains a minimum of 9.0 × 108 total nucleated cells with a minimum of 1.25 × 106 viable CD34+ cells, suspended in 10% dimethyl sulfoxide (DMSO) and 1% Dextran 40, at the time of cryopreservation.

The exact pre-cryopreservation nucleated cell content is provided on the container label and in accompanying records.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Allergic reactions may occur with infusion of HPC, Cord Blood, including DUCORD. 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, hydroxyethylstarch, or a plasma component of DUCORD.

DUCORD 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 DUCORD 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 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 gram per kilogram per day is recommended. [See Overdosage (10)]

Infusion reactions may begin within minutes of the start of infusion of DUCORD, 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.

If infusing more than one unit of DUCORD on the same day, do not administer subsequent units until all signs and symptoms of infusion reactions from the prior unit have resolved.

5.3 Graft-versus-Host Disease

Acute and chronic graft-versus-host disease (GVHD) may occur in patients who have received DUCORD. Classic acute GVHD is manifested as fever, rash, elevated bilirubin and liver enzymes, and diarrhea. Patients transplanted with DUCORD 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. Once engraftment syndrome is recognized, begin treatment with corticosteroids 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 nonnodal 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 DUCORD 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. DUCORD is tested for sterility. There may be an effect on the reliability of the sterility test results if the cord blood donor was treated with antibiotics. These measures do not totally eliminate the risk of 6 of 30 transmitting these or other transmissible infectious diseases and disease agents. Report the occurrence of a transmitted infection to Duke University School of Medicine, Carolinas Cord Blood Bank at 1-919-668-1102.

Testing is also performed for evidence of donor infection due to cytomegalovirus (CMV).

Test results may be found in accompanying records.

5.8 Transmission of Rare Genetic Diseases

DUCORD 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. DUCORD 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 DUCORD 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.

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.

The safety assessment of DUCORD is based primarily on review of the data submitted to the FDA dockets from various sources, the dataset for the COBLT Study, and published literature.

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 × 107 /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 388 infusions for patients who received DUCORD at a total nucleated cell dose of ≥2.5×107 /kg. The population included 57% males and 43% females with median age of 16 years (range 0.1-79 years). Preparative regimens and graft-vs-host disease prophylaxis were not standardized. The reactions were not graded. Nineteen percent of infusions (n=72) were associated with an infusion reaction. The most common infusion reactions, occurring in >1% of infusions, were hypertension (15%), nausea or vomiting (3.4%), bradycardia (1.8%), and chest pain (1.3%).

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 × 107 /kg. Of these, 66% (n=862) underwent transplantation as treatment for hematologic malignancy. The preparative regimens and graft-vshost disease prophylaxis varied. The median total nucleated cell dose was 6.4 × 107 /kg (range, 2.5-73.8 107 /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 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 the COBLT Study, 15% of the patients developed engraftmentsyndrome.

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