warnings and cautions
5 WARNINGS AND PRECAUTIONS Immune reconstitution sufficient to protect from infection is unlikely to develop prior to 6 to 12 months after treatment with RETHYMIC. Given the immunocompromised condition of athymic patients, infection control measures should be followed until the development of thymic function can be established. ( 5.1 ) Monitor and treat patients at risk for the development of graft versus host disease (GVHD). ( 5.2 ) Monitor for the development of autoimmune disorders, including complete blood counts with differential, liver enzymes, serum creatinine, urinalysis, and thyroid function. ( 5.3 ) Pre-existing renal impairment is a risk factor for death. ( 5.4 ) Pre-existing cytomegalovirus infection may result in death prior to the development of thymic function. ( 5.5 ) Monitor for the development of lymphoproliferative disorder (blood cancer). ( 5.6 ) Transmission of infectious diseases may occur because RETHYMIC is derived from human tissue. ( 5.7 ) Immunizations should not be administered in patients who have received RETHYMIC until immune-function criteria have been met. ( 5.8 ) Patients should be tested for anti-HLA antibodies prior to treatment. ( 5.9 ) 5.1 Infection Control and Immunoprophylaxis Immune reconstitution sufficient to protect from infection is unlikely to develop prior to 6-12 months after treatment with RETHYMIC. Given the immunocompromised condition of athymic patients, follow infection control measures until the development of thymic function is established as measured through flow cytometry. This should include counseling patients and their caregivers on good handwashing practices and minimizing exposure to visitors. Monitor patients closely for signs of infection, including fever. If a fever develops, assess the patient by blood and other cultures and treat with antimicrobials as clinically indicated. Patients should be maintained on immunoglobulin replacement therapy until all of the following criteria are met: No longer on immunosuppression (at least 10% of CD3 + T cells are naïve in phenotype). At least 9 months post-treatment. Phytohemagglutinin (PHA) response within normal limits. Normal serum IgA is also desirable but not required. Two months after stopping immunoglobulin replacement therapy, the IgG trough level should be checked. If the IgG trough level is in the normal range for age, the patient can remain off of immunoglobulin replacement. If the IgG trough level is lower than the normal range for age, immunoglobulin replacement therapy should be restarted and continued for a year before being retested using the above guidelines. Prior to and after treatment with RETHYMIC, patients should be maintained on Pneumocystis jiroveci pneumonia prophylaxis until all of the following criteria are met: No longer on immunosuppression (at least 10% of CD3+ T cells are naïve in phenotype). At least 9 months post-treatment. PHA response within normal limits. CD4+ T cell count > 200 cells/mm 3 . 5.2 Graft versus Host Disease In clinical studies with RETHYMIC, GVHD occurred in 11 (10%) RETHYMIC-treated patients of whom 6 (55%) died. RETHYMIC may cause or exacerbate pre-existing GVHD. Seven patients (7%) experienced autologous GVHD, 3 patients (3%) experienced GVHD due to maternal cells and 1 patient (1%) experienced GVHD due to cells from a prior hematopoietic cell transplant (HCT). Risk factors for GVHD include atypical complete DiGeorge anomaly phenotype, prior HCT and maternal engraftment. GVHD may manifest as fever, rash, lymphadenopathy, elevated bilirubin and liver enzymes, enteritis, and/or diarrhea. Patients with elevated baseline T cell proliferative response to PHA > 5,000 cpm or > 20-fold over background should receive immunosuppressive therapies to decrease the risk of GVHD (Table 2 and Table 3). Development of GVHD symptoms should be closely monitored and promptly treated. 5.3 Autoimmune Disorders Thirty-seven patients (35%) in the RETHYMIC clinical program experienced autoimmune-related adverse reactions. These events included: thrombocytopenia (including idiopathic thrombocytopenic purpura) in 13 patients (12%), neutropenia in 9 patients (9%), proteinuria in 7 patients (7%), hemolytic anemia in 7 patients (7%), alopecia in 4 patients (4%), hypothyroidism in 2 patients (2%), autoimmune hepatitis in 2 patients (2%), and autoimmune arthritis (juvenile idiopathic and psoriatic arthritis) in 2 patients (2%). One patient (1%) each experienced transverse myelitis, albinism, hyperthyroidism, and ovarian failure. The onset of autoimmune related events ranged from the three days before the surgical implantation procedure until 16 years post-treatment. Most events occurred within the first year after treatment. Monitor complete blood counts with differential weekly for the first 2 months post-treatment and then monthly through 12 months post-treatment. Liver enzymes including aspartate aminotransferase and alanine aminotransferase, serum creatinine levels, and urinalysis should be performed monthly for 3 months and then every 3 months through 12 months post-treatment. Thyroid function studies should be performed prior to treatment and then at 6 months and 12 months post-treatment. After 12 months, testing should be performed annually. 5.4 Renal Impairment Ten patients with renal impairment (elevated serum creatinine at baseline) were treated in studies with RETHYMIC. Five of these patients died within 1 year and a sixth patient died 3 years after treatment with RETHYMIC. Renal impairment at baseline is considered a risk factor for death. 5.5 Cytomegalovirus Infection In clinical studies with RETHYMIC, 4 out of 4 patients with preexisting CMV infection prior to treatment with RETHYMIC died. The benefits/risks of treatment should be considered prior to treating patients with pre-existing CMV infection. 5.6 Malignancy Because of the underlying immune deficiency, patients who receive RETHYMIC may be at risk of developing post-treatment lymphoproliferative disorder (blood cancer). The infant tissue donor is screened for Epstein-Barr virus (EBV) and cytomegalovirus (CMV), but patients should be tested for EBV and CMV using PCR prior to and 3 months following treatment with RETHYMIC, or after any exposure to or suspected infection with CMV or EBV. 5.7 Transmission of Serious Infections and Transmissible Infectious Diseases Transmission of infectious disease may occur because RETHYMIC is derived from human tissue. 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), Treponema pallidum, Trypanosoma cruzi , West Nile virus (WNV), transmissible spongiform encephalopathy (TSE) agents, vaccinia. Donors are also screened for clinical evidence of sepsis, and communicable disease risks associated with xenotransplantation. Blood samples (from the infant tissue donor or the birth mother, as applicable) are tested for HIV types 1, 2, and O, HTLV types I and II, HBV, HCV, T. pallidum , WNV, and T. cruzi . Blood from the infant tissue donor is also tested for Toxoplasma gondii , Epstein-Barr virus (EBV) and CMV. RETHYMIC is tested for sterility, endotoxin, and mycoplasma. These measures do not eliminate the risk of transmitting these or other infectious diseases and disease agents. Testing of maternal and infant donor blood is also performed for evidence of donor infection due to cytomegalovirus (CMV). Product manufacturing includes porcine- and 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 and mycoplasma test results are not available at the time of use, but manufacturing personnel will communicate any positive results from sterility testing to the physician. Report the occurrence of transmitted infection to Sumitomo Pharma America at 833-369-9868. 5.8 Vaccine Administration Immunizations should not be administered in patients who have received RETHYMIC until immune-function criteria have been met. Inactivated vaccines: Inactivated vaccines may be administered once all of the following criteria are met: Immunosuppressive therapies have been discontinued. Immunoglobulin (IgG) replacement therapy has been discontinued. The total CD4 + T cell count is > 200 cells/mm 3 and there are more CD4 + T cells than CD8 + T cells (CD4 + > CD8 + ). It is recommended that no more than 2 inactivated vaccines be given per month. Live Vaccines: Live virus vaccines should not be administered until patients have met the criteria for inactivated vaccines and received vaccinations with inactivated agents (e.g., tetanus toxoid). No additional vaccines (live or inactivated), except the inactivated influenza vaccine, should be given within 6 months after vaccination with a measles-containing vaccine or within 2 months after the varicella vaccine. Consider verifying response to vaccination with appropriate testing, in particular varicella and measles. 5.9 Anti-HLA Antibodies All patients should be screened for anti-HLA antibodies prior to receiving RETHYMIC. Patients testing positive for anti-HLA antibodies should receive RETHYMIC from a donor who does not express those HLA alleles. 5.10 HLA Typing HLA matching is required in patients who have received a prior hematopoietic cell transplantation (HCT) or a solid organ transplant. Patients who have received a prior HCT are at increased risk of developing GVHD after RETHYMIC if the HCT donor did not fully match the recipient. To minimize this risk, HLA matching of RETHYMIC to recipient alleles that were not expressed in the HCT donor is recommended.