OMISIRGE Suspension for solution for infusion Ref.[116107] Active ingredients: Omidubicel

5.1 Graft-versus-Host Disease

Acute and chronic graft versus host disease (GvHD) have occurred following treatment with OMISIRGE [see Adverse Reactions (6.1)]. Acute GvHD manifests as maculopapular rash, gastrointestinal symptoms, and elevated bilirubin. Chronic GvHD manifests as skin rash, oral symptoms, ocular dryness, transaminase elevations, gastrointestinal symptoms, or serositis.

Patients treated with OMISIRGE should receive immunosuppressive drugs to decrease the risk of GvHD, and be monitored for signs and symptoms of GvHD, and treated if GvHD develops.

5.2 Hypersensitivity and Infusion-Related Reactions

Hypersensitivity and infusion-related reactions have occurred with OMISIRGE administration [see Adverse Reactions (6.1)].

Serious hypersensitivity reactions, including anaphylaxis, may be due to DMSO, residual gentamicin, Dextran 40, human serum albumin (HSA) and bovine material in OMISIRGE. OMISIRGE 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 OMISIRGE administration.

Signs and symptoms of hypersensitivity reactions may include bronchospasm, wheezing, angioedema, pruritus, hives, fever, and hypotension during or after OMISIRGE infusion.

Infusion-related reactions may begin within minutes of the start of infusion of OMISIRGE, although symptoms may continue to intensify and not peak for several hours after the completion of the infusion.

Premedicate patients with antipyretics, histamine antagonists, and corticosteroids and monitor closely for signs and symptoms of hypersensitivity and infusion-related reactions. When a reaction occurs, pause the infusion and institute supportive care as needed.

5.3 Autoimmune Cytopenias

Autoimmune cytopenias (AICs) have occurred with OMISIRGE administration in patients with SAA. AIC is characterized by thrombocytopenia, anemia, and neutropenia, alone or in combination, occurring weeks to months post-transplant, often after initial hematopoietic recovery.

Risk factors for post-transplant AIC include younger age, ATG-containing conditioning, underlying SAA, and delayed T cell chimerism.

Monitor blood counts prior to and after OMISIRGE infusion. Manage cytopenias according to local institutional guidelines.

5.4 Graft Failure

Graft failure has occurred with OMISIRGE administration [see Adverse Reactions (6.1)]. 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.

5.5 Malignancies of Donor Origin

Malignancy of donor origin including post-transplant lymphoproliferative disorder (PTLD) has occurred with OMISIRGE administration. PTLD manifests as a lymphoma-like disease favoring non-nodal sites. PTLD is usually fatal if not treated. 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 patients with persistent cytopenias.

A donor-cell derived myelodysplastic syndrome (MDS) has occurred with OMISIRGE administration. The natural history is presumed to be the same as that for de novo MDS. Monitor life-long for secondary malignancies.

In the event that a secondary malignancy occurs, contact Gamida Cell at (844) 477-7478.

5.6 Engraftment Syndrome

Engraftment syndrome may occur because OMISIRGE is derived from umbilical cord blood. Monitor patients for unexplained fever, rash, hypoxemia, weight gain, and pulmonary infiltrates in the peri-engraftment period. Treat with corticosteroids as soon as engraftment syndrome is recognized to ameliorate symptoms. If untreated, engraftment syndrome may progress to multiorgan failure and death.

5.7 Transmission of Serious Infections

Transmission of infectious disease may occur because OMISIRGE is derived from umbilical cord 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, West Nile Virus (WNV), transmissible spongiform encephalopathy (TSE) agents, vaccinia, and Zika virus (for umbilical cord blood collected since March 2016). 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, and WNV. OMISIRGE 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. OMISIRGE is tested for sterility, endotoxin, and mycoplasma. These measures do not totally eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents.

Testing of maternal and infant donor blood 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.

Product manufacturing includes bovine-derived reagents. While all animal-derived reagents are tested for animal viruses, bacteria, fungi, and mycoplasma before use, these measures do not eliminate the risk of transmitting these or other transmissible infectious diseases and disease agents.

Final sterility test results may not be available at the time of use, but Quality Assurance (QA) will communicate any positive results from sterility testing to the physician. Report the occurrence of transmitted infection to Gamida Cell at (844) 477-7478.

5.8 Transmission of Rare Genetic Diseases

OMISIRGE may transmit rare genetic diseases involving the hematopoietic system because it is derived from umbilical cord blood. Cord blood donors have been screened 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 cord blood collection takes place, the ability to exclude rare genetic diseases is severely limited. Report the occurrence of transmitted rare genetic disease to Gamida Cell at (844) 477-7478.

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.

Hematologic Malignancies

The safety of OMISIRGE is based on data from Study P0501 for 52 patients transplanted with OMISIRGE and 56 patients transplanted with umbilical cord blood (UCB) [see Clinical Studies (14)]. The median duration of follow up for the overall safety population was 14 months (range, 1-19 months). All patients received myeloablative preparative regimens and GvHD prophylaxis with tacrolimus or cyclosporin plus mycophenolate mofetil.

Fatal adverse reactions occurred in 17% of patients treated with OMISIRGE, including infection (6%), acute GvHD (6%), veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) (2%), thrombotic thrombocytopenic purpura (TTP)/thrombotic microangiopathy (TMA) (2%), and pulmonary hemorrhage (2%). Fatal adverse reactions occurred in 29% of subjects treated with UCB, including infection/sepsis (11%), respiratory disorders (11%), GvHD (5%), and VOD/SOS (2%).

The most common non-laboratory adverse reactions occurring in ≥10% of patients in Study P0501 are listed in Table 2 below. The most common Grade 3-5 adverse reactions for patients treated with OMISIRGE, were pain (33%), mucosal inflammation (31%), hypertension (25%), and gastrointestinal toxicity (19%).

Table 2. Adverse Reactions in ≥10% of Patients with Hematologic Malignancies Following Transplantation with OMISIRGE (N-52) or UCB (N=56) in Study P0501:

Abbreviation: CTCAE: common terminology criteria for adverse events; n: number; UCB: umbilical cord blood.
^* Fatigue includes asthenia and fatigue
^† Infections and infestations were graded according to the BMT-CTN grading system
^‡ Acute Graft-versus-host disease was graded according to the Consensus Conference on Acute GvHD grading
^§ Chronic Graft-versus-host disease was graded according to the 2014 NIH consensus criteria
^¶ Hemorrhage include cystitis hemorrhagic, epistaxis, gastrointestinal hemorrhage, hemorrhage, pulmonary alveolar hemorrhage, subarachnoid hemorrhage, and upper gastrointestinal hemorrhage
^# Respiratory failure includes acute respiratory distress syndrome, acute respiratory failure, hypoxia, and respiratory failure
^Þ Renal impairment includes acute kidney injury, blood creatinine increased and renal failure

Table 3 summarizes selected chemistry abnormalities by treatment arm for patients treated in Study P0501.

Table 3. Chemistry Laboratory Abnormalities in ≥10% of Patients in Study P0501:

Abbreviation: N: number; UCB: umbilical cord blood.

Severe Aplastic Anemia

The safety data described in this section reflects exposure of OMISIRGE in one clinical study (Study 17-H-0091) for the treatment of severe aplastic anemia (SAA). A total of 17 patients received a single dose of OMISIRGE with a median dose of 8.5 × 10⁶ cells/kg CD34+ cells (range, 2.3-21.4 cells/kg CD34+ cells). Three out of 17 patients received OMISIRGE with haploidentical CD34+ cells [see Clinical Studies (14)]. All patients received a reduced intensity preparative conditioning regimen of cyclophosphamide, fludarabine, TBI and horse-ATG, and GvHD prophylaxis according to institutional guidelines. The median duration of follow-up was 25 months (range, 2-60 months).

Serious adverse reactions were reported in 15 patients including infections (n=15), diarrhea (n=3), nausea/vomiting (n=4), pyrexia (n=2), hypoxia (n=2), thrombotic microangiopathy (n=1), cardiac arrest (n=1), pericarditis (n=1), colitis (n=1), febrile neutropenia (n=1), cholecystitis (n=1), portal vein thrombosis (n=1), graft versus host disease (n=1), weight decreased (n=1), dehydration (n=1), Guillain-Barre Syndrome (n=1), uterine hemorrhage (n=1), pleural effusion (n=1), pulmonary hemorrhage (n=1), and respiratory failure (n=1).

One patient (6%) treated with OMISIRGE had a fatal adverse event. The patient engrafted but died on Day 62 from disseminated adenovirus infection.

The most common adverse reactions occurring in ≥15% of patients in Study 17-H-0091 are listed in Table 4 below.

CTCAE Grade 3-5 non-laboratory adverse reactions in the SAA Study with greater or equal to 15% incidence are summarized in Table 4. The most common Grade 3-5 adverse reactions for patients treated with OMISIRGE were febrile neutropenia (41%), bacterial infections (41%), hyperglycemia (41%), Epstein-Barr virus infection (29%), immune thrombocytopenia (24%) and pneumonia (24%).

Table 4. Adverse Reactions in ≥15% of Patients with SAA Following Transplantation with OMISIRGE (N=17) in Study 17-H-0091:

Abbreviation: n: number.
^* Includes skin infection, clostridium difficile infection, device related infections and urinary tract infections.
^† Is a composite that includes multiple related terms.
^‡ Includes hypertension, headache and hypoxia.
^§ Includes dyspnea, respiratory distress and respiratory failure.

Other clinically significant adverse reactions occurring in <15% of patients include the following: Post-transplant lymphoproliferative disorder in two patients (12%), primary graft failure (defined as failure to achieve an absolute neutrophil count ≥500 cells/µl for 3 consecutive measurements on different days) in 1 patient (6%), and engraftment syndrome in 1 patient (6%).

Table 5 summarizes laboratory abnormalities that worsened from baseline in ≥15% of patients in Study 17-H-0091.

Table 5. Laboratory Abnormalities that Worsened from Baseline in ≥15% of Patients in Study 17-H-0091 (N=17):

Abbreviation: N: number.

Risk Summary

There are no available data with OMISIRGE use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with OMISIRGE to assess whether it can cause fetal harm when administered to a pregnant woman. In Study 17-H-0091, one patient reported two pregnancies, one at 9 months and one at 3.5 years post-transplant. There were no reported birth complications or neonatal concerns.

OMISIRGE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the United States (U.S.) general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Risk Summary

There is no information regarding the presence of OMISIRGE in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OMISIRGE and any potential adverse effects on the breastfed infant from OMISIRGE or from the underlying maternal condition.

Pregnancy Testing

Pregnancy status of females with reproductive potential should be verified. Sexually-active females of reproductive potential should have a pregnancy test prior to starting the conditioning regimen for OMISIRGE.

Contraception

See the prescribing information for the medications used for conditioning for information on the need for effective contraception in patients who receive a conditioning regimen.

There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with OMISIRGE.

Infertility

There are no data on the effect of OMISIRGE on fertility.

The safety and efficacy of OMISIRGE have been established in pediatric patients with hematologic malignancy 12 years of age and older and in pediatric patients with severe aplastic anemia (SAA) 6 years of age and older.

The use of OMISIRGE in pediatric patients with hematologic malignancy was supported by evidence from one clinical study (Study P0501) which included 2 pediatric patients age 12 to 16 years. The use of OMISIRGE in pediatric patients with SAA was supported by evidence from one clinical study (Study 17-H-0091) which included 7 pediatric patients age 6 to 16 years of age.

Clinical studies of OMISIRGE did not include patients aged 65 and over; therefore, it cannot be determined whether patients 65 years and over respond differently from younger patients.