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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity and infusion-related reactions : Monitor patients for hypersensitivity and infusion-related reactions during and after infusion. ( 5.1 ) Engraftment failure : Monitor patients for signs and symptoms of engraftment failure. In case of engraftment failure, infuse the non-transduced back-up hematopoietic stem cells according to local standards. ( 5.2 ) Cytopenias : Severe cytopenias, including anemia, neutropenia, and thrombocytopenia have occurred for several weeks following reduced intensity conditioning and WASKYRA ® infusion. Monitor patients for signs and symptoms of cytopenia for at least 8 weeks after treatment with WASKYRA and manage accordingly. ( 5.3 ) Serious infections : Serious infections have occurred with WASKYRA ® administration. Increased susceptibility to infections may occur due to concomitant administration of rituximab and conditioning regimen. Monitor patients for signs and symptoms of infection before and after WASKYRA infusion and treat appropriately. ( 5.4 ) Transmission of an infectious agent : All infections thought to be transmitted by WASKYRA ® should be reported to Fondazione Telethon ETS at 1- 888- 212- 6928. ( 5.5 ) Hepatic veno-occlusive disease : Monitor patients for signs and symptoms of veno-occlusive disease including assessment of liver function tests for one month after WASKYRA ® infusion ( 5.6 ) Risk of oncogenesis : There is a lifelong risk of lentiviral vector (LVV)-mediated insertional oncogenesis and secondary malignancy after treatment with WASKYRA ® . Monitor patients after treatment with WASKYRA ® for the development of malignancies. ( 5.7 ) Interference with HIV testing : Patients who have received WASKYRA ® may test positive by polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion, resulting in a false positive test for HIV. Do not screen patients who have received WASKYRA ® for HIV infection using a PCR-based assay. ( 5.8 ) Blood, organ, tissue and cell donation : Patients treated with WASKYRA ® should not donate blood, organs, tissues and cells for transplantation at any time in the future. ( 5.9 ) 5.1 Hypersensitivity and Infusion Related Reactions Hypersensitivity and infusion related reactions, including anaphylaxis may occur with WASKYRA ® infusion due to DMSO as an excipient in WASKYRA ® . Monitor patients for signs and symptoms of hypersensitivity and infusion-related reactions during and after the WASKYRA ® infusion. When more than one bag of WASKYRA ® is needed, prior to infusion it should be ensured that the volume of product to be infused is compatible with the recommended limit of DMSO, i.e., the total volume of DMSO administered should remain < 1% of the patient’s estimated plasma volume. The maximum volume of WASKYRA ® to be administered should therefore remain < 20% of the patient’s estimated plasma volume. Also, when more than one bag of WASKYRA ® is needed, only one bag of medicinal product should be infused at a time. 5.2 Engraftment failure Engraftment failure defined as failure to reach an absolute neutrophil count (ANC) > 500 cells/μL associated with no evidence of bone marrow recovery (i.e., hypocellular marrow) by day 60 may potentially occur after WASKYRA ® infusion. Monitor patients for signs and symptoms of engraftment failure. In case of engraftment failure, infuse the non-transduced back-up hematopoietic stem cells according to local standards. 5.3 Cytopenias Severe cytopenias, including anemia, neutropenia, and thrombocytopenia have occured for several weeks following reduced intensity conditioning and WASKYRA ® infusion [see Adverse Reactions (6.1) ] . Monitor patients for signs and symptoms of cytopenia for at least 8 weeks after treatment with WASKYRA ® . Manage patients with supportive transfusion according to clinical practice. If neutropenia persists beyond six to seven weeks after WASKYRA ® infusion, despite the use of granulocyte colony – stimulating factor, consider administration of the non-transduced back up stem cells or alternative treatments. 5.4 Serious Infections Serious infections have occurred with WASKYRA ® administration [see Adverse Reactions (6.1) ]. Increased susceptibility to infections may occur to concomitant administration of rituximab and conditioning regimen. Monitor patients for signs and symptoms of infection before and after WASKYRA ® infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Maintain immunoglobulin G serum level above 5 g/l to prevent potential infections associated with severe hypogammaglobinemia, resulting from disease – related immune deficiency, rituximab administration and conditioning. Any blood products required after WASKYRA ® infusion should be irradiated. 5.5 Transmission of an infectious agent Transmission of infectious disease or agents may occur with WASKYRA ® treatment because it is manufactured using human and bovine-derived reagents, which are tested for human and animal viruses, bacteria, fungi, and mycoplasma before use. Additionally, WASKYRA ® is tested for sterility and mycoplasma at release. These measures do not eliminate the risk of transmitting these or other infectious diseases or agents. All infections thought to be transmitted by WASKYRA ® should be reported to Fondazione Telethon ETS at 1-888-212-6928. 5.6 Hepatic veno-occlusive disease Hepatic veno-occlusive disease has occurred with WASKYRA ® treatment [see Adverse Reactions (6.1) ]. Monitor patients for signs and symptoms of veno-occlusive disease including assessment of liver function tests during the first month after WASKYRA ® infusion. 5.7 Risk of oncogenesis There is a lifelong risk of lentiviral vector (LVV)-mediated insertional oncogenesis and secondary malignancy after treatment with WASKYRA ® [see Adverse Reactions (6.1) ]. Monitor patients after treatment with WASKYRA ® for the development of malignancies. In the event that a malignancy occurs, contact Fondazione Telethon ETS at 1-888-212-6928 to obtain instructions on collecting patient samples for testing. 5.8 Interference with HIV testing Patients who have received WASKYRA ® may test positive by polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion, resulting in a false positive test for HIV. Do not screen patients who have received WASKYRA ® for HIV infection using a PCR-based assay. 5.9 Blood, organ, tissue and cell donation Patients treated with WASKYRA ® should not donate blood, organs, tissues and cells for transplantation at any time in the future. This information is provided in the Patient Alert Card which should be given to the patient after treatment.
6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥ 20%) are catheter related infections, bacterial and viral infections, diarrhea, vomiting, stomatitis, liver injury, head injury, rhinitis, cough, rash, petechiae, hypersensitivity, anemia, febrile neutropenia, epistaxis, pyrexia, catheter site complications. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fondazione Telethon ETS at toll-free phone 1-888-212-6928 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 data described in this section reflects exposure to WASKYRA ® in two clinical studies, Study 1 (201228) and Study 2 (OTL-103-4) as well as patients in expanded access program (EAP). A total of 27 patients received a single infusion of WASKYRA ® at a dose range of 7 to 31×10 6 CD34 + cells/kg (median dose: 16.90×10 6 CD34 + cells/kg). The median duration of the follow up was 5.67 years (range: 0.37-13.26 years) [see Clinical Studies (14) ]. During the above-mentioned clinical trials no adverse reactions attributable to the gene therapy were reported. There were 45 serious adverse reactions reported in 21 patients including catheter-related infections (n=11), bacterial and viral infections (n=10), pyrexia (n=3), prolonged neutropenia (n=2), vomiting (n=2), veno-occlusive disease (n=1), aspergillus infection (n=1). One patient died approximately 4.5 months after WASKYRA ® infusion due to neurological decompensation. Table 1: Adverse Reactions Occurring in ≥10% of Patients (N=27) Adverse Reactions Any Grade n (%) Grade 3 or higher n (%) Infections and Infestations - - Catheter related infection 16 (59) 14 (52) Respiratory tract infection Is a composite that includes multiple related terms. 18 (67) 4 (15) Conjunctivitis * 10 (37) 0 Cytomegalovirus infection * 8 (30) 4 (15) Epstein-Barr virus infection 5 (19) 1 (4) Gastroenteritis 5 (19) 2 (7) Ear infection 4 (15) 0 Oral candidiasis 4 (15) 0 Urinary tract infection * 5 (19) 3 (11) Balanoposthitis 3(11) 0 Gastrointestinal disorders - - Diarrhea * 16 (59) 3 (11) Vomiting 12 (44) 5 (19) Liver injury * 16 (59) 3 (11) Stomatitis 6 (22) 3 (11) Hematochezia 5 (19) 0 Abdominal pain 3 (11) 0 Constipation 3 (11) 0 Nervous System disorders - - Head Injury* 10 (37) 1 (4) Headache 4 (15) 2 (7) Respiratory, thoracic and mediastinal disorders - - Rhinitis 9 (33) 0 Cough * 8 (30) 0 Wheezing 4 (15) 0 Oropharyngeal pain 3 (11) 1 (4) Skin and subcutaneous tissue disorders - - Rash Rash includes eczema, rash, urticaria, dermatitis, dry skin, erythema. 23 (85) 9 (33) Petechiae 16 (59) 1 (4) Immune system disorders - - Hypersensitivity * 6 (22) 4 (15) Lymphadenopathy 4 (15) 1 (4) Blood and lymphatic system disorders - - Anemia * 11 (41) 4 (15) Immune thrombocytopenia 4 (15) 4 (15) Febrile neutropenia 7 (26) 6 (22) Epistaxis 9 (33) 0 Mouth hemorrhage 3 (11) 0 Traumatic hematoma * 4 (15) 0 General disorders and administration site conditions - - Pyrexia 11 (41) 6 (22) Catheter site complications Catheter site complications includes Catheter site inflammation, Catheter site hemorrhage, Unintentional medical device removal. 10 (37) 1 (4) Note: Adverse reactions are defined as adverse events occurred during conditioning and year 1 following WASKYRA ® administration. Other clinically significant adverse reactions that occurred in < 20% patients include papillary thyroid cancer diagnosed in one patient with a familial history of Graves' disease at 5-years post treatment. The tumor cells did not contain viral vector gene sequences. Table 2. Laboratory Abnormalities that Worsened from Baseline in ≥ 10% of Patients (N=27) Laboratory Abnormality All Grade n (%) Grade 3 or 4 n (%) Neutrophils decreased 10 (37) 9 (33) Eosinophils increased 7 (26) 1 (4) Electrolyte imbalance Electrolyte imbalance includes hypokalemia, hyperkalemia, hyponatremia, hypomagnesemia 11 (41) 6 (22) Creatinine increased 3 (11) 0 Calcium decreased 3 (11) 0