Tisagenlecleucel

1 INDICATIONS AND USAGE KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of: Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. ( 1.1 ) Adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Limitations of Use : KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma. ( 1.2 ) Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1.3 ) 1.1 Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia KYMRIAH is indicated for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. 1.2 Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma KYMRIAH is indicated for treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma. 1.3 Adult Relapsed or Refractory Follicular Lymphoma KYMRIAH is indicated for treatment of adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies (14.3)] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

12.1 Mechanism of Action KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. The CAR is comprised of a murine single-chain antibody fragment which recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T cell activation and antitumor activity, while 4-1BB enhances the expansion and persistence of KYMRIAH. Upon binding to CD19-expressing cells, the CAR transmits a signal to promote T cell expansion, activation, target cell elimination, and persistence of the KYMRIAH cells.

2 DOSAGE AND ADMINISTRATION For autologous use only. For intravenous use only. Administer a lymphodepleting regimen if needed before infusion of KYMRIAH. ( 2.2) Do NOT use a leukodepleting filter. ( 2.2 ) Verify the patient’s identity prior to infusion. ( 2.2 ) Premedicate with acetaminophen and an H1-antihistamine. ( 2.2 ) Confirm availability of tocilizumab prior to infusion. ( 2.2 , 5.1 ) Dosing of KYMRIAH is based on the number of chimeric antigen receptor (CAR)-positive viable T cells. Pediatric and Young Adult B-cell ALL (up to 25 years of age) • For patients 50 kg or less, administer 0.2 to 5.0 x 10 6 CAR-positive viable T cells per kg body weight intravenously. ( 2.1 ) • For patients above 50 kg, administer 0.1 to 2.5 x 10 8 total CAR-positive viable T cells (non-weight based) intravenously. ( 2.1 ) Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and Follicular Lymphoma • Administer 0.6 to 6.0 x 10 8 CAR-positive viable T cells intravenously. ( 2.1 ) Note: The patient identifier number may be preceded by the letters DIN or Aph ID. Figure 1. KYMRIAH Infusion Bag 2.1 Recommended Dose For autologous use only. For intravenous use only. Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells. Based on the patient weight reported at the time of leukapheresis: - Patients 50 kg or less: administer 0.2 to 5.0 x 10 6 CAR-positive viable T cells per kg body weight. - Patients above 50 kg: administer 0.1 to 2.5 x 10 8 CAR-positive viable T cells. Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and Follicular Lymphoma KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells. - For adult patients: administer 0.6 to 6.0 x 10 8 CAR-positive viable T cells. 2.2 Administration Preparing Patient for KYMRIAH Administration with Lymphodepletion - Confirm availability of KYMRIAH prior to starting the lymphodepleting regimen. Pediatric and Young Adult Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia Lymphodepleting chemotherapy: Fludarabine (30 mg/m 2 intravenously daily for 4 days) and cyclophosphamide (500 mg/m 2 intravenously daily for 2 days starting with the first dose of fludarabine). Infuse KYMRIAH 2 to 14 days after completion of the lymphodepleting chemotherapy. Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and r/r Follicular Lymphoma • Lymphodepleting chemotherapy: Fludarabine (25 mg/m 2 intravenously daily for 3 days) and cyclophosphamide (250 mg/m 2 intravenously daily for 3 days starting with the first dose of fludarabine). • Alternate lymphodepleting chemotherapy: bendamustine 90 mg/m 2 intravenously daily for 2 days if a patient experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen. • Infuse KYMRIAH 2 to 11 days (r/r DLBCL) or 2 to 6 days (r/r FL) after completion of the lymphodepleting chemotherapy. • Lymphodepleting chemotherapy may be omitted if a patient is experiencing significant cytopenia, e.g., white blood cell (WBC) count is less than 1 x 10 9 /L within 1 week prior to KYMRIAH infusion. Preparation of KYMRIAH for Infusion and Administration Delay the infusion of KYMRIAH if a patient has unresolved serious adverse reactions (including pulmonary reactions, cardiac reactions, or hypotension) from preceding chemotherapies, active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden following lymphodepleting chemotherapy [see Warnings and Precautions (5.1)]. A KYMRIAH dose may be contained in one to three cryopreserved patient specific infusion bag(s). Verify the number of bags received for the dose of KYMRIAH with the Certificate of Conformance (CoC) and Certificate of Analysis (CoA). Coordinate the timing

6 ADVERSE REACTIONS Pediatric and Young Adult B-cell ALL (up to 25 years of age): The most common adverse reactions (incidence greater than 20%) are CRS, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, hemorrhage, musculoskeletal pain, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, tachycardia, edema, fatigue, and acute kidney injury. ( 6.1 ) Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma: The most common adverse reactions (incidence greater than 20%) are CRS, infections-pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema, hemorrhage, dyspnea, and headache. ( 6.1 ) Adult Relapsed or Refractory Follicular Lymphoma: The most common adverse reactions (incidence greater than 20%) are CRS, infections-pathogens unspecified, fatigue, musculoskeletal pain, headache, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 the WARNINGS AND PRECAUTIONS and in this section reflect exposure to KYMRIAH in three non-randomized, single-arm studies in which 79 pediatric and young adult patients with relapsed/refractory (r/r) B-cell ALL (Study 1: CCTL019B2202), 115 adults with r/r diffuse large B-cell lymphoma (Study 2: CCTL019C2201), and 97 adults with r/r follicular lymphoma (Study 3: CCTL019E2202) received a single dose of CAR-positive viable T cells. Pediatric and Young Adult r/r B-cell Acute Lymphoblastic Leukemia (ALL) (up to 25 years of age) Based on a recommended dose which was weight-based, all 79 patients in the Study 1 received a single intravenous dose of KYMRIAH [see Clinical Studies (14.1)] . The most common adverse reactions (> 20%) were CRS (77%), infections-pathogen unspecified (57%), hypogammaglobulinemia (53%), fever (42%), decreased appetite (38%), viral infectious disorders (38%), headache (35%), febrile neutropenia (34%), hemorrhage (32%), musculoskeletal pain (32%), vomiting (32%), encephalopathy (30%), bacterial infectious disorders (29%), diarrhea (29%), hypotension (29%), cough (27%), nausea (27%), pain (25%), hypoxia (25%), tachycardia (24%), edema (23%), fatigue (23%), and acute kidney injury (22%). The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 3. Table 3. Adverse Reactions in ≥ 10% of Pediatric and Young Adults Patients with r/r B-cell ALL in Study 1 (N = 79) a Includes multiple related composite terms. b Encephalopathy includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, and automatism. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms. c Dyspnea includes acute respiratory failure, dyspnea, respiratory distress, and respiratory failure. Adverse reaction All Grades (%) Grades 3 or higher (%) Blood and lymphatic system disorders Febrile neutropenia 34 34 Cardiac disorders Tachycardia a 24 4 Gastrointestinal disorders Vomiting 32 1 Diarrhea 29 1 Nausea 27 3 Abdominal pain a 18 3 Constipation 18 0 General disorders and administration site conditions Fever 42 13 Pain a 25 3 Fatigue a 23 0 Edema a 23 8 Immune system disorders Cytokine release syndrome 77 48 Hypogammaglobulinemia a 53 13 Infections and infestations Infections-pathogen unspecified 57 27 Viral infectious disorders 37 22 Bacterial infectious disorders 29 16 Fungal in

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Monitor for hypersensitivity reactions during infusion. ( 5.4 ) Serious Infections: Monitor patients for signs and symptoms of infection; treat appropriately. ( 5.5 ) Prolonged Cytopenias: Patients may exhibit ≥ Grade 3 cytopenias for several weeks following KYMRIAH infusion. Prolonged neutropenia has been associated with increased risk of infection. ( 5.6 ) Hypogammaglobulinemia: Monitor and provide replacement therapy until resolution. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH. ( 5.7 ) Secondary Malignancies: T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including KYMRIAH. In the event that a secondary malignancy occurs after treatment with KYMRIAH, contact Novartis Pharmaceuticals Corporation at 1-844-4KYMRIAH. ( 5.8 ) 5.1 Cytokine Release Syndrome Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 61 (77%) of the 79 pediatric and young adult patients with r/r ALL receiving KYMRIAH, including ≥ Grade 3 CRS (Penn grading system 1 ) occurring in 48% of patients. The median times to onset and resolution of CRS were 3 days (range, 1 to 22; 1 patient with onset after Day 10) and 8 days (range, 1 to 36), respectively. Of the 61 patients with CRS, 31 (51%) received tocilizumab. Ten (16%) patients received two doses of tocilizumab and 3 (5%) patients received three doses of tocilizumab; 17 (28%) patients received addition of corticosteroids (e.g., methylprednisolone). CRS occurred in 85 (74%) of the 115 adult patients with r/r DLBCL receiving KYMRIAH, including ≥ Grade 3 CRS (Penn grading system 1 ) occurring in 23% of patients. The median times to onset and resolution of CRS were 3 days (range, 1 to 51; 1 patient with onset after Day 10) and 7 days (range, 2 to 30), respectively. Of the 85 patients with CRS, 19 (22%) received systemic tocilizumab or corticosteroids. Seven (8%) patients received a single dose of tocilizumab and 11 (13%) patients received two doses of tocilizumab; 11 (13%) patients received corticosteroids in addition to tocilizumab. One patient received corticosteroids for CRS without concomitant tocilizumab, and two patients received corticosteroids for persistent neurotoxicity after resolution of CRS. CRS occurred in 51 (53%) of the 97 adult patients with r/r FL receiving KYMRIAH; all were Grade 1 or 2 CRS (Lee grading system 2 ). The median times to onset and resolution of CRS were 4 days (range, 1 to 14) and 4 days (range, 1 to 13), respectively. Of the 51 patients with CRS, 15 (29%) received systemic anticytokine treatment with tocilizumab. Three (6%) patients required 3 dosages of tocilizumab, 4 (8%) patients required 2 dosages and 8 (16%) patients required single dose of tocilizumab. Two (4%) patients received corticosteroids in addition to tocilizumab. Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive leukemia, and one patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Of the 3 r/r DLBCL patients who died within 30 days of infusion, all had CRS in the setting of stable to progressive underlying disease, one of whom developed bowel necrosis. Among patients with CRS, key manifestations include fever (93% in r/r ALL; 85% in r/r DLBCL; 92% in r/r FL), hypotension (69% in r/r ALL; 45% in r/r DLBCL; 40% in r/r FL), hypoxia (57% in r/r ALL; 35% in r/r DLBCL; 19% in r/r FL), and tachycardia (26% in r/r ALL; 13% in r/r DLBCL; 2% in r/r FL). CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy. Delay the infusion of KYMRIAH after lymphodepleting chemotherapy if the patient has unresolved serious adverse reactions from preceding chemotherapies (includi

4 CONTRAINDICATIONS None. None. ( 4 )