Kymriah

Description for Kymriah

KYMRIAH (tisagenlecleucel) is a CD19-directed genetically modified autologous T cell immunotherapy comprised of autologous T cells that are genetically modified using a lentiviral vector to encode an anti-CD19 chimeric antigen receptor (CAR). The CAR is comprised of a murine single-chain antibody fragment (scFv) specific for CD19, followed by a CD8 hinge and transmembrane region that is fused to the intracellular signaling domains for 4-1BB (CD137) and CD3 zeta.

KYMRIAH is prepared from the patient's peripheral blood mononuclear cells, which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells, then transduced with the lentiviral vector containing the anti-CD19 CAR transgene, and activated with anti-CD3/CD28 antibody coated beads. The transduced T cells are expanded in cell culture, washed, and formulated into a suspension, which then is cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in a patient-specific infusion bag. The product is thawed prior to administration [see DOSAGE AND ADMINISTRATION, HOW SUPPLIED/Storage and Handling]. The thawed product is a colorless to slightly yellow suspension of cells.

In addition to T cells, other cell populations, including monocytes, NK cells, and B cells, may be present. The formulation contains 31.25% (v/v) of Plasma-Lyte A, 31.25% (v/v) of 5% Dextrose/0.45% sodium chloride, 10 % Dextran 40 (LMD)/5% Dextrose, 20% (v/v) of 25% Human Serum Albumin (HSA), and 7.5% (v/v) Cryoserv® dimethylsulfoxide (DMSO).

A single dose of KYMRIAH may contain up to 2.5 x 108 CAR-positive viable T cells provided in a patient-specific infusion bag. Based on the patient's weight reported at the time of leukapheresis, one of two possible dose ranges will be prepared for the patient:

• For patients 50 kg or less: 0.2 to 5.0 x 10⁶ CAR-positive viable T cells per kg body weight
• For patients above 50 kg: 0.1 to 2.5 x 10⁸ CAR-positive viable T cells

The actual number of CAR-positive T cells in the product is reported on the Certificate of Analysis that is shipped with KYMRIAH. The volume of CAR-positive viable T cells in an infusion bag ranges from 10 mL to 50 mL.

ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in another section of the label:

• Cytokine Release Syndrome [see Warnings and Precautions (5.1)]
• Neurological Toxicities [see Warnings and Precautions (5.2)]
• Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome [see Warnings and Precautions (5.3)]
• Serious Infections [see Warnings and Precautions (5.5)]
• Prolonged Cytopenias [see Warnings and Precautions (5.6)]
• Hypogammaglobulinemia [see Warnings and Precautions (5.7)]

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 (ELIANA Study), 115 adults with r/r diffuse large B-cell lymphoma (JULIET Study), and 97 adults with r/r follicular lymphoma (ELARA Study) 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 ELIANA study (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. Selected Adverse Reactions Anytime After Infusion (≥ 10%) Following Treatment with KYMRIAH in Pediatric and Young Adult r/r B-cell ALL (N = 79)

Adverse reaction	All Grades (%)	Grades 3 or higher (%)
Blood and lymphatic system disorders	34	34
Febrile neutropenia	34	34
Cardiac disorders
Tachycardia	24	4
Gastrointestinal disorders
Vomiting	32	1
Diarrhea	29	1
Nausea	27	3
Abdominal painb	18	3
Constipation	18	0
General disorders and administration site conditions
Fever	42	13
Painc	25	3
Fatigued	23	0
Edemae	23	8
Immune system disorders
Cytokine release syndrome	77	48
Hypogammaglobulinemiaf	53	13
Infections and infestations
Infections–pathogen unspecified	57	27
Viral infectious disorders	37	22
Bacterial infectious disorders	29	16
Fungal infectious disorders	15	9
Metabolism and nutrition disorders
Decreased appetite	38	15
Hypocalcemia	20	6
Hyperferritinemiag	10	3
Musculoskeletal and connective tissue disorders
Musculoskeletal painh	32	4
Arthralgia	14	1
Nervous system disorders
Headachei	35	3
Encephalopathyj	30	9
Psychiatric disorders
Deliriumk	19	4
Anxiety	17	3
Sleep disorderl	11	0
Renal and urinary disorders
Acute kidney injurym	22	14
Respiratory, thoracic and mediastinal disorders
Coughn	27	0
Hypoxia	25	20
Dyspneao	19	14
Pulmonary edema	15	9
Nasal congestion	11	0
Oropharyngeal pain	10	0
Pleural effusion	10	4
Tachypnea	10	5
Skin and subcutaneous tissue disorders
Rashp	18	1
Vascular disorders
Hemorrhageq	32	10
Hypotension	29	20
Hypertension	19	5
[1]Tachycardia includes sinus tachycardia and tachycardia. bAbdominal pain includes abdominal pain, abdominal pain upper. cPain includes pain and pain in extremity.  dFatigue includes fatigue and malaise. eEdema includes face edema, fluid overload, generalized edema, localized edema, edema peripheral. fHypogammaglobulinemia includes hypogammaglobulinemia, immunoglobulins decreased, blood immunoglobulin G decreased, blood immunoglobulin A decreased, blood immunoglobulin M decreased, immunodeficiency, immunodeficiency common variable. gHyperferritinemia includes serum ferritin increased. hMusculoskeletal pain includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and noncardiac chest pain.   iHeadache includes headache and migraine. jEncephalopathy 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. kDelirium includes delirium, agitation, hallucination, hallucination visual, irritability, restlessness. lSleep disorder includes sleep disorder, insomnia and nightmare.  mAcute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, renal tubular dysfunction, renal tubular necrosis, and blood creatinine increased. nCough includes cough and productive cough. oDyspnea includes acute respiratory failure, dyspnea, respiratory distress, and respiratory failure. pRash includes dermatitis, rash, rash maculo-papular, rash papular, and rash pruritic. qHemorrhage includes anal hemorrhage, catheter site hemorrhage, cerebral hemorrhage, conjunctival hemorrhage, contusion, cystitis hemorrhagic, disseminated intravascular coagulation, epistaxis, gastrointestinal hemorrhage, gingival bleeding, hemarthrosis, hematemesis, hematuria, hemoptysis, heavy menstrual bleeding, melena, mouth hemorrhage, peritoneal hematoma, petechiae, pharyngeal hemorrhage, purpura, retinal hemorrhage, vaginal hemorrhage. [1] Cardiac failure includes cardiac failure, cardiac failure congestive, left ventricular dysfunction, right ventricular dysfunction.  bArrhythmia includes cardiac arrest. cSeizure includes generalized tonic-clonic seizure and seizure. dPeripheral neuropathy includes hyperasthesia, hypoasthesia, paresthesia. eSpeech disorder includes aphasia and dysarthria. fMotor dysfunction includes muscle spasms.

Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 3 were:  

Blood and lymphatic system disorders: coagulopathy (6%), hemophagocytic lymphohistiocytosis (6%), pancytopenia (3%)

Cardiac disorders: cardiac failure^a (9%), arrhythmia^b (4%)

Eye disorders: visual impairment (3%)

Gastrointestinal disorders: abdominal distention (4%), ascites (4%), stomatitis (4%), abdominal compartment syndrome (1%), dry mouth (1%)

General disorders and administration site conditions:chills (9%), asthenia (4%), influenza-like illness (3%), multiple organ dysfunction syndrome (3%)

Immune system disorders: infusion related reaction (6%), graft versus host disease (3%)

Investigations: prothrombin time prolonged (4%), fibrin D dimer increased (3%), weight decreased (3%)

Metabolism and nutrition disorders: tumor lysis syndrome (6%), hypercalcemia (4%)

Nervous system disorders: tremor (8%), seizure^c (6%), dizziness (5%), peripheral neuropathy^d (4%), speech disorder^e (3%), motor dysfunction^f (1%), neuralgia (1%)

Respiratory, thoracic, and mediastinal disorders: acute respiratory distress syndrome (4%), lung infiltration (1%)

Skin and subcutaneous tissue disorders: pruritus (9%), erythema (6%), hyperhidrosis (4%), night sweats (1%)

Vascular disorders: capillary leak syndrome (3%), thrombosis (3%), flushing (1%)

Laboratory Abnormalities

[1] Cardiac failure includes cardiac failure, cardiac failure congestive, left ventricular dysfunction, right ventricular dysfunction.  ^bArrhythmia includes cardiac arrest. ^cSeizure includes generalized tonic-clonic seizure and seizure. ^dPeripheral neuropathy includes hyperasthesia, hypoasthesia, paresthesia. ^eSpeech disorder includes aphasia and dysarthria. ^fMotor dysfunction includes muscle spasms.

Table 4. Grade 3 or 4 Laboratory Abnormalities Occurring in > 10% of Patients Following Treatment with KYMRIAH in Pediatric and Young Adult r/r B-cell ALL based on CTCAE^a (N = 79)

Laboratory abnormality	Grade 3 or 4 (%)
Hematology Blood fibrinogen decreased	11
Biochemistry Aspartate aminotransferase increased	29
Hypokalemia	28
Alanine aminotransferase increased	22
Hypophosphatemia	20
Hyperbilirubinemia	19
Hyperglycemia	13
aCTCAE = Common Terminology Criteria for Adverse Events version 4.03.

All patients experienced neutropenia, anemia and thrombocytopenia. See Table 5 for the incidences of ≥ Grade 3 prolonged thrombocytopenia and prolonged neutropenia in responding patients.  

Table 5. Prolonged Cytopenias Following Treatment with KYMRIAH in Pediatric and Young Adult r/r B-cell ALL

Prolonged cytopenia	N = 52 (%)	N = 52 (%)
	Day 28	Day 56
Prolonged neutropeniaa	40	17
Prolonged thrombocytopeniaa	27	12
a≥ Grade 3 observed within 14 days after Day 28 or Day 56 in responding patients.

Adult r/r Diffuse Large B-cell Lymphoma (DLBCL)

In the JULIET study (Study 2) 115 adults with r/r DLBCL received a single intravenous dose of KYMRIAH [see Clinical Studies (14.2)]. The most common adverse reactions (incidence > 20%) were CRS, infections-pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema, bleeding episodes, dyspnea, and headache.

The study population characteristics were median age of 56 years (range, 22 to 76 years), 80% DLBCL; a median of 3 prior lines of therapy (range, 1 to 6), 49% had a prior autologous hematopoietic stem cell transplantation, and 32% had received prior radiation therapy. One hundred seven patients (93%) received lymphodepleting chemotherapy prior to KYMRIAH, which included fludarabine (n = 85) or bendamustine (n = 22).

The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 6 below.

Table 6. Selected Adverse Reactions Anytime After Infusion Reported in ≥ 10% Following Treatment with KYMRIAH in Adult r/r DLBCL (N = 115)

Adverse reaction	All Grades (%)	Grades 3 or higher (%)
Blood and lymphatic system disorders      Febrile neutropenia	17	17
Cardiac disorders      Tachycardiaa	13	3
Arrhythmiab	10	5
Gastrointestinal disorders      Diarrhea	31	1
Nausea	29	1
Constipation	17	1
Abdominal painc	10	2
General disorders and administration site conditions      Fever	35	5
Fatigued	27	6
Edemae	27	3
Painf	14	3
Chills	12	0
Immune system disorders      Cytokine release syndrome	74	23
Hypogammaglobulinemiag	17	6
Infections and infestations      Infections-pathogen unspecified	48	26
Bacterial infectious disorders	17	8
Fungal infectious disorders	11	5
Viral infectious disorders	11	2
Investigations      Weight decreased	12	4
Metabolism and nutrition disorders      Decreased appetite	14	4
Musculoskeletal and connective tissue disorders      Arthralgia	14	0
Musculoskeletal painh	13	1
Nervous system disorders      Headachei	21	1
Encephalopathyj	16	11
Peripheral neuropathyk	12	3
Dizzinessl	12	2
Psychiatric disorders         Anxiety	10	1
Sleep disorderm	10	0
Renal and urinary disorders      Acute kidney injuryn	17	6
Respiratory, thoracic and mediastinal disorders      Dyspneao	21	6
Coughp	17	0
Skin and subcutaneous tissue disorders         Rashq	11	0
Vascular disorders      Hypotensionr	25	9
Hemorrhages	22	8
[1]Tachycardia includes sinus tachycardia and tachycardia. [1] Cardiac failure includes cardiac failure congestive. b Arrhythmia includes atrial fibrillation, cardiac arrest, supraventricular tachycardia, and ventricular extrasystoles. c Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain upper. d Fatigue includes fatigue and malaise. e Edema includes face edema, fluid overload, fluid retention, generalized edema, localized edema, edema peripheral, peripheral swelling. f Pain includes pain and pain in extremity. g Hypogammaglobulinemia includes blood immunoglobulin G decreased, immunodeficiency, immunoglobulins decreased and hypogammaglobulinemia. h Musculoskeletal pain includes back pain, flank pain, musculoskeletal chest pain, neck pain, and non-cardiac chest pain. i Headache includes headache and migraine. j Encephalopathy includes cognitive disorder, confusional state, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, metabolic encephalopathy and thinking abnormal. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms. k Peripheral neuropathy includes paraesthesia, hypoaesthesia, hyperaesthesia, peripheral sensory neuropathy, neuropathy peripheral, cranial nerve paralysis, demyelinating polyneuropathy, Horner’s syndrome, polyneuropathy, and sciatica. l Dizziness includes dizziness, presyncope, and syncope. m Sleep disorder includes insomnia and sleep disorder. n Acute kidney injury includes acute kidney injury, blood creatinine abnormal, and blood creatinine increased. o Dyspnea includes dyspnea, dyspnea exertional, respiratory distress, and respiratory failure. p Cough includes cough, productive cough, and upper-airway cough syndrome. q Rash includes dermatitis, dermatitis acneiform, dermatitis contact, rash, rash maculo-papular, rash papular, and rash pruritic. r Hypotension includes hypotension and orthostatic hypotension. s Hemorrhage includes anal hemorrhage, blood urine present, cerebral hemorrhage, contusion, cystitis hemorrhagic, disseminated intravascular coagulation, duodenal ulcer hemorrhage, epistaxis, eye contusion, gastrointestinal hemorrhage, hematemesis, hematochezia, hematuria, large intestinal hemorrhage, melena, mouth hemorrhage, petechiae, pharyngeal hemorrhage, post procedural hemorrhage, pulmonary hemorrhage, purpura, retinal hemorrhage, traumatic hematoma, tumor hemorrhage, upper gastrointestinal hemorrhage.

Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 5 were:

Blood and lymphatic system disorders: pancytopenia (3%), hemophagocytic lymphohistiocytosis (2%), B-cell aplasia (1%)

Cardiac disorders: cardiac failure^a (1%)

Eye disorders: visual impairment^[1] (6%)

Gastrointestinal disorders: vomiting (9%), stomatitis (6%), dry mouth (5%), abdominal distension (4%), ascites (3%)

General disorders and administration site conditions: influenza-like illness (9%), asthenia (7%), multiple organ dysfunction syndrome (3%)

Immune system disorders: infusion related reaction (3%)

Investigations: fibrin D dimer increased (4%)

Metabolism and nutrition disorders: hypocalcemia (5%), hypercalcemia (4%), hyperferritinemia^c (4%), tumor lysis syndrome (2%) 

Musculoskeletal and connective tissue disorders: myalgia (5%)

[1] Visual impairment includes vision blurred and visual impairment. ^cHyperferritinemia includes serum ferritin increased. ^dMotor dysfunction includes muscle spasms, muscle twitching, myoclonus and myopathy. ^eTremor includes dyskinesia and tremor.

[1] Visual impairment includes vision blurred and visual impairment. ^cHyperferritinemia includes serum ferritin increased. ^dMotor dysfunction includes muscle spasms, muscle twitching, myoclonus and myopathy. ^eTremor includes dyskinesia and tremor.

Nervous system disorders: motor dysfunction^d (6%), tremor^e (6%), speech disorder^[1] (4%), neuralgia^g (3%), seizure^h (3%), ataxia^[2] (2%), ischemic cerebral infarction (1%)

Psychiatric disorders: delirium^j (5%)

Respiratory, thoracic, and mediastinal disorders: hypoxia (8%), oropharyngeal pain^[3] (8%), pleural effusion (5%), nasal congestion (4%), pulmonary edema^l (3%), tachypnea (3%) 

Skin and subcutaneous tissue disorders: night sweats (5%), pruritus (4%), hyperhidrosis (4%), erythema (2%) Vascular disorders: thrombosis^m (6%), hypertension (4%), capillary leak syndrome (1%)

Laboratory Abnormalities

Table 7. Grade 3 or 4 Laboratory Abnormalities Occurring in > 10% of Patients Following KYMRIAH Infusion in Adult r/r DLBCL Patients Based on CTCAE^a N = 115

Laboratory parameter	Grade 3 or 4 (%)
Hematology Lymphopenia	95
Neutropenia	82
Leukopenia	78
Anemia	59
Thrombocytopenia	56
Biochemistry Hypophosphatemia	24
Hypokalemia	13
aCTCAE = Common Terminology Criteria for Adverse Events version 4.03.

Adult r/r Follicular Lymphoma (FL) 

The safety of KYMRIAH was evaluated in the ELARA study (Study 3), a trial that included 97 patients with r/r FL who received a single intravenous dose of KYMRIAH [see Clinical Studies (14.3)]. Patients with a history of CNS disorders or autoimmune disease requiring systemic immunosuppression were ineligible. The median age was 57 years (range, 29 to 73 years), 34% were female, 75% were White, 13% were Asian, and 1% were Black or African American. 

The most common adverse reactions (incidence > 20%) were CRS, infections-pathogen unspecified, fatigue, musculoskeletal pain, headache, and diarrhea.  

The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 8 below.

Table 8. Selected Adverse Reactions Anytime After Infusion Reported in ≥ 10% Following Treatment with KYMRIAH in Adult r/r FL (N = 97)

Adverse reaction	All Grades (%)	Grades 3 or higher (%)
Blood and lymphatic system disorders Febrile neutropenia	13	13
Gastrointestinal disorders      Diarrhea	24	2
Nausea	16	2
Constipation	16	0
Abdominal paina	10	1
General disorders and administration site conditions      Fatigueb	27	3
Fever	19	1
Immune system disorders      Cytokine release syndrome	53	0
Hypogammaglobulinemiac	18	1
Infections and infestations      Infections-pathogen unspecified	38	12
Viral infectious disorders	18	5
Musculoskeletal and connective tissue disorders      Musculoskeletal paind	25	1
Arthralgia	10	0
Nervous system disorders      Headachee	25	2
Respiratory, thoracic and mediastinal disorders      Coughf	19	0
Skin and subcutaneous tissue disorders      Rashg g	10	0
Abdominal pain includes abdominal pain and abdominal pain upper. bFatigue includes asthenia, fatigue, and malaise. cHypogammaglobulinemia includes blood immunoglobulin G decreased and hypogammaglobulinemia. dMusculoskeletal pain includes back pain, bone pain, flank pain, muscle discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and non-cardiac chest pain. [1]Headache includes headache and migraine. [2]Cough includes cough and productive cough. [3]Rash includes rash, rash maculo-papular, and rash papular.

Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 8 were:  

Blood and lymphatic system disorders: pancytopenia (3%), hemolysis^a (2%), coagulopathy^b (2%) Cardiac disorders: tachycardia^c (2%), arrhythmia^d (4%)

Eye disorders: visual impairment^e (4%)

Gastrointestinal disorders: vomiting (9%), stomatitis^f (4%), abdominal distension (2%), dry mouth (2%)

General disorders and administration site conditions: edema^g (9%), pain^h (8%), chills (6%)

Immune system disorders: infusion related reaction (3%), graft versus host diseaseⁱ (1%), hemophagocytic lymphohistiocytosis (1%)

Infections and infestations: bacterial infectious disorders (7%), fungal infectious disorders (2%)

Investigations: weight decreased (7%)

Metabolism and nutrition disorders: decreased appetite (8%), tumor lysis syndrome (2%)

Nervous system disorders: dizziness^[1] (8%), motor dysfunction^[2] (9%), peripheral neuropathy^l (7%), immune effector cellassociated neurotoxicity syndrome (4%), encephalopathy (3%), tremor (3%) Psychiatric disorders: sleep disorder^m (6%), anxiety (2%), delirium (1%)

Renal and urinary disorder: acute kidney injuryⁿ (4%)

Respiratory, thoracic, and mediastinal disorders: dyspnea^o (8%), pleural effusion (6%), oropharyngeal pain (5%), nasal congestion (2%), rhinorrhea (2%) 

Skin and subcutaneous tissue disorders: pruritus (9%), night sweats (3%), erythema (2%), hyperhidrosis (1%) Vascular disorders: hypotension^p (9%), hemorrhage^[3] (6%), hypertension (5%), thrombosis^r (1%)

Laboratory Abnormalities

Table 9. Grade 3 or 4 Laboratory Abnormalities Occurring in > 10% of Patients Following KYMRIAH Infusion in Adult r/r FL Patients Based on CTCAE^a (N = 97*)

Laboratory abnormality	Grade 3 or 4 (%)
Hematology Neutropenia	63
Leukopenia	40
Thrombocytopenia	21
Anemia	20
Lymphopenia	19
Biochemistry Hypophosphatemia	12
aCTCAE = Common Terminology Criteria for Adverse Events version 4.03. *Evaluable population (n = 91 to 97) for each laboratory value included number of patients who had both baseline (before KYMRIAH infusion) and at least one post-KYMRIAH infusion on-study laboratory value available.

Postmarketing Experience

Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. 

The following adverse events have been identified during postmarketing use of KYMRIAH.

• Anaphylactic reaction
• Neoplasms: T cell malignancies

Immunogenicity

In clinical studies, humoral immunogenicity of KYMRIAH was measured by determination of anti-murine CAR19 antibodies (anti-mCAR19) in serum pre- and post-administration. The majority of patients, 91% in ELIANA (Study 1),

94% in JULIET (Study 2), and 66% in ELARA (Study 3), tested positive for pre-dose anti-mCAR19 antibodies prior to

KYMRIAH infusion. Treatment induced anti-mCAR19 antibodies were detected in 9% and 33% of the patients in JULIET and ELARA, respectively. However, the preexisting and treatment-induced antibodies were not associated with an impact on clinical response and did not have an impact on the initial expansion and persistence of KYMRIAH. Persistence of KYMRIAH was similar between patients with positive post-infusion anti-mCAR19 antibodies compared with patients with negative post-infusion anti-mCAR19 antibodies. There is no evidence that the presence of preexisting and treatment-induced anti-mCAR19 antibodies impact the safety or effectiveness of KYMRIAH.

T cell immunogenicity responses were not observed in r/r ALL, r/r DLBCL, or r/r FL patients.

Drug Interactions for Kymriah

HIV and the lentivirus used to make KYMRIAH have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false-positive results in patients who have received KYMRIAH.

Warnings for Kymriah

Included as part of the PRECAUTIONS section.

Precautions for Kymriah

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 system¹) 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 system¹) 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 system²). 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 (including pulmonary toxicity, cardiac toxicity, or hypotension), active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden [see Dosage and Administration (2.3)].

Risk factors for severe CRS in the pediatric and young adult r/r B-cell ALL population are high pre-infusion tumor burden (greater than 50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes.

Confirm that a minimum of two doses of tocilizumab are available on site prior to infusion of KYMRIAH.

Monitor patients daily during the first week following KYMRIAH infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 2 weeks after treatment with KYMRIAH. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated [see Dosage and Administration (2.3, 2.4)].

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)].

Neurological Toxicities

Neurological toxicities, including severe or life-threatening reactions, occurred following treatment with KYMRIAH. Neurologic toxicities occurred in 56 (71%) of the 79 patients with r/r ALL, including ≥ Grade 3 in 22%. The median times to the first event and duration were 6 days from infusion (range, 1 to 301) and 7 days, respectively.

Neurologic toxicities occurred in 69 (60%) of the 115 patients with r/r DLBCL, including ≥ Grade 3 in 19%. The median times to the first event and duration were 5 days (range, 1 to 368) and 17 days, respectively.

Neurologic toxicities occurred in 42 (43%) of the 97 patients with r/r FL, including ≥ Grade 3 in 6%. The median times to the first event and duration were 8 days (range, 1 to 345) and 5 days, respectively.

Among patients who had a neurological toxicity, 84% occurred within 8 weeks following KYMRIAH infusion. Resolution occurred within 3 weeks in 71% of patients with r/r ALL, 50% of patients with r/r DLBCL, and 74% of patients with r/r FL. Encephalopathy lasting up to 70 days was noted.

The onset of neurological toxicity can be concurrent with CRS, following resolution of CRS or in the absence of CRS.

The most common neurological toxicities observed with KYMRIAH include headache (35% in r/r ALL; 21% in r/r DLBCL; 25% in r/r FL), encephalopathy (30% in r/r ALL; 16% in r/r DLBCL; 3% in r/r FL), delirium (19% in r/r ALL;

5% in r/r DLBCL; 1% in r/r FL), anxiety (16% in r/r ALL; 10% in r/r DLBCL; 2% in r/r FL), sleep disorders (11% in r/r ALL; 10% in r/r DLBCL; 6% in r/r FL), dizziness (5% in r/r ALL; 12% in r/r DLBCL; 8% in r/r FL), tremor (8% in r/r ALL; 6% in r/r DLBCL; 3% in r/r FL), and peripheral neuropathy (4% in r/r ALL; 12% in r/r DLBCL; 7% in r/r FL). Other manifestations included seizures and aphasia. 

Monitor patients daily during the first week following KYMRIAH infusion for signs and symptoms of neurologic toxicities. Rule out other causes of neurological symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 2 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed [see Dosage and Administration (2.3)]. Advise patients to avoid driving for at least 2 weeks following infusion.

Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [see Patient Counseling Information (17)].

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS), which can be life-threatening or fatal, has occurred following treatment with KYMRIAH. HLH was reported in 6% (5/79) of patients with r/r ALL (time to onset ranged from 3 to 18 days) and 2% (2/115) of patients with r/r DLBCL (times to onset were Day 7 and Day 10); all HLH events occurred during ongoing CRS and resolved. One patient (1%) with r/r FL developed HLH > 1 year after receiving KYMRIAH with a fatal outcome. The patient did not have CRS during or immediately preceding HLH. Treatment of HLH should be administered as per institutional standards.

Hypersensitivity Reactions

Allergic reactions may occur with infusion of KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to the DMSO or dextran 40 in KYMRIAH. Observe patients for hypersensitivity reactions during the infusion. 

Serious Infections 

Infections, including life-threatening or fatal infections, occurred following treatment with KYMRIAH. Infections occurred in 57 (72%) of the 79 patients with r/r ALL; 38 patients (48%) experienced ≥ Grade 3 infections, including fatal infections in 2 patients (3%).

Infections occurred in 67 (58%) of the 115 patients with r/r DLBCL; 38 patients (33%) experienced ≥ Grade 3 infections, including fatal infection in 1 patient (1%).

Infections occurred in 50 (52%) of the 97 patients with r/r FL; 20 patients (21%) experienced ≥ Grade 3 infections, including fatal infection in 1 patient (1%).

Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Patients with active uncontrolled infection should not start KYMRIAH treatment until the infection is resolved. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately [see Dosage and Administration (2.3)]. Febrile neutropenia (≥ Grade 3) was also observed in 34% of patients with r/r ALL, 17% of patients with r/r DLBCL, and

13% of patients with r/r FL after KYMRIAH infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated.

Viral Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells.

There is no experience with manufacturing KYMRIAH for patients with a positive test for HIV or with active HBV or active HCV. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. 

Prolonged Cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. 

In the ELIANA study (Study 1), ≥ Grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia (40%), and thrombocytopenia (27%) among 52 responding patients. At 56 days following KYMRIAH, 17% and 12% of responding patients had ≥ Grade 3 neutropenia or thrombocytopenia, respectively.

In the JULIET study (Study 2), ≥ Grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included thrombocytopenia (39%) and neutropenia (25%) among 115 treated patients.

In the ELARA study (Study 3), ≥ Grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included thrombocytopenia (17%) and neutropenia (16%) among 97 treated patients.

Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GMCSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.

Hypogammaglobulinemia

Hypogammaglobulinemia and agammaglobulinemia related to B-cell aplasia can occur in patients after KYMRIAH infusion. 

Hypogammaglobulinemia was reported in 53% of patients treated with KYMRIAH for r/r ALL, 17% of patients with r/r DLBCL, and 18% of patients with r/r FL [see Clinical Pharmacology (12.3)].

Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines. Immunization with Live Vaccine The safety of immunization with live vaccines during or following KYMRIAH treatment has not been studied. Vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during KYMRIAH treatment, and until immune recovery following treatment with KYMRIAH.

Pregnant women who have received KYMRIAH may have hypogammaglobulinemia. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH.

Secondary Malignancies

Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their cancer. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19- directed genetically modified autologous T cell immunotherapies, including KYMRIAH. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes [see Boxed Warning, Adverse Reactions (6.2), Patient Counseling Information (17)].

Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Novartis Pharmaceuticals Corporation at 1-844-4KYMRIAH to obtain instructions on patient samples to collect for testing.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity assays and carcinogenicity assessment in rodent models were not performed for KYMRIAH. In vitro expansion studies with transduced T cells (KYMRIAH) from healthy donors and patients showed no evidence for transformation and/or immortalization of T cells. In vivo studies in immunocompromised mice did not show signs of abnormal cell growth or signs of clonal cell expansion for up to 7 months after cell injection. A genomic insertion site analysis was performed on KYMRIAH products from 14 individual donors (12 patients and 2 healthy volunteers). There was no evidence for preferential integration near genes of concern, or preferential outgrowth of cells harboring integration sites of concern.

No studies on the effects of KYMRIAH on fertility have been conducted.

Patient Information for Kymriah

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Ensure that patients understand the risk of manufacturing failure. This has been reported in up to 9% of manufacturing attempts. In case of a manufacturing failure, a second manufacturing of KYMRIAH may be attempted. In addition, while the patient awaits the product, additional chemotherapy (not the lymphodepletion) may be necessary and may increase the risk of adverse events during the pre-infusion period.

Prior to infusion, advise patients of the following risks:

• Cytokine Release Syndrome (CRS) -- Report signs and symptoms of CRS (high fever, difficulty breathing, chills/shaking chills, severe nausea, severe vomiting, severe diarrhea, severe muscle pain, severe joint pain, very low blood pressure, or dizziness/lightheadedness) to their healthcare professional [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].
• Neurological Toxicities -- Report altered or decreased consciousness, delirium, confusion, agitation, seizures, difficulty speaking and understanding, or loss of balance to their healthcare professional [see Warnings and Precautions (5.2), Adverse Reactions (6.1)].
• Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) -- Presenting signs and symptoms are similar to those of CRS and infections [see Warnings and Precautions (5.3), Adverse Reactions (6.1)].
• Serious Infections -- KYMRIAH may cause serious infections. Advise patients that they will be screened for HBV, HCV, and HIV before collection of cells [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].
• Hypogammaglobulinemia -- Patients may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with KYMRIAH. Patients should tell their physician about their treatment with KYMRIAH before receiving a live vaccine [see Warnings and Precautions (5.7), Adverse Reactions (6.1)].
• Prolonged Cytopenia -- Patient may exhibit signs or symptoms associated with bone marrow suppression (i.e., neutropenia, thrombocytopenia and anemia) for several weeks following lymphodepleting chemotherapy and KYMRIAH [see Warnings and Precautions (5.6)].
• Secondary Malignancies -- Secondary malignancies, including T cell malignancies, have occurred [see Boxed Warning, Warnings and Precautions (5.8), Adverse Reactions (6.2)].

Advise patients of the need to:

• Patients should be instructed to contact Novartis Pharmaceuticals Corporation at 1-844-4KYMRIAH if they get secondary malignancies [see Warnings and Precautions (5.8)].
• Avoid driving for at least 2 weeks.

OVERDOSAGE

No information provided

Contraindications for Kymriah

No information provided

Clinical Pharmacology for Kymriah

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.

Pharmacodynamics

Due to the on-target effect of KYMRIAH, a period of B-cell aplasia is expected.

Among evaluable pediatric and young adult r/r B-cell ALL patients with an ongoing response at Month 24, 33% had no detectable B cells at baseline prior to infusion. At Month 24, 88% had no detectable B cells. 

Most adult r/r DLBCL patients had B-cell depletion at baseline prior to infusion due to previous treatment with rituximab.

Recovery of B-cell levels were observed with longer follow-up in some of the responding DLBCL patients after KYMRIAH infusion. Among evaluable adult r/r DLBCL and FL patients with an ongoing response at Month 24, all patients had no detectable B cells at baseline prior to infusion or at Month 24.

Pharmacokinetics/Cellular Kinetics

Following infusion, KYMRIAH exhibited an initial rapid expansion followed by a bi-exponential decline in pediatric and young adult r/r B-cell acute lymphoblastic leukemia (ALL) patients, adult r/r diffuse large B-cell lymphoma patients, and adult r/r follicular lymphoma patients.

A summary of pharmacokinetic parameters of KYMRIAH is provided in Table 10 below.

Table 10. Pharmacokinetic Parameters of KYMRIAH in Pediatric and Young Adult r/r B-cell ALL, Adult r/r DLBCL, and Adult r/r FL

Parameter	Summary statistics	Pediatric ALL responding patients N = 62	Pediatric ALL nonresponding patients N = 8	r/r DLBCL responding patients (CR and PR) N = 34	r/r DLBCL nonresponding patients (SD/PD/ unknown) N = 34	r/r FL responding patients (CR and PR) N = 77	r/r FL nonresponding patients (SD/PD) N = 12
Cmax (copies/mcg)	Geometric mean (CV%), n	34,700 (155.4), 61	20,000 (71.6), 7	5,210 (256.5), 33	6,450 (408.2), 32	6,250 (344), 64	3,000 (1190), 8
Tmax (day)	Median [min; max], n	9.91 [0.008; 27], 61	20.0 [0.03; 62.7], 7	9.83 [5.73; 16.8], 33	8.39 [3.04; 27.7], 32	9.94 [2.62; 28.0], 64	13.0 [7.73; 16.0], 8
AUC0-28d (copies/mcg*day)	Geometric mean (CV%), n	318,000 (177.8), 61	156,000 (99.4), 6	58,200 (165.1), 30	75,800 (292.3), 25	56,900 (270), 63	20,100 (18100), 7
T½ (day)	Geometric mean (CV%), n	16.8 (155.9), 54	2.52 (171.9), 3	45.3 (157.7), 21	13.6 (167.0), 22	44.0 (296), 42	24.4 (180), 6
Description of Pharmacokinetics in Pediatric and Young Adult r/r B-cell ALL (up to 25 years of age)

The C_max and AUC_0-28d were similar between CR/CRi patients compared with non-responding (NR) patients.

KYMRIAH was present in the blood as well as bone marrow and was measurable beyond 2 years. Blood to bone marrow partitioning suggested that KYMRIAH distribution in bone marrow was 44% of that present in blood at Day 28 while at Months 3 and 6 KYMRIAH distributed at 67% and 69%, respectively, indicating high distribution to bone marrow.

Children < 10 years and between 10-18 years of age had similar- to 1.7-fold higher C_max and AUC_0-28d than adults.

Due to small sample size and high variability, it is difficult to assess the impact of age on the pharmacokinetics of

KYMRIAH.

Description of Pharmacokinetics in Adult r/r DLBCL

The C_max and AUC_0-28d were similar between responding and non-responding (NR) patients.

KYMRIAH was present in adult r/r DLBCL patients up to 18 months in peripheral blood and up to 9 months in the bone marrow for patients having a complete response (CR). The median time of maximal expansion of transgene levels (T_max) in peripheral blood occurred at 9-10 days in both responding and non-responding patients. 

Description of Pharmacokinetics in Adult r/r FL

KYMRIAH has been detected for up to 18 months in peripheral blood and up to 3 months in bone marrow for patients who achieved a response. The median time of maximal expansion of transgene levels (T_max) in peripheral blood occurred at 10 days in responding and 13 days in non-responding patients.

The blood to bone marrow partitioning in bone marrow was nearly 50% at Month 3 in responding patients.

Tocilizumab and Corticosteroid used for CRS Management

The geometric mean AUC_0-28d value of responders was 183% higher compared to non-responders, while the geometric mean C_max value was 108% higher in responders compared to non-responders. Considering the high inter-individual variability, small number of non-responders, overlapping expansion ranges observed between responders and non-responders, the exposure differences should be interpreted with caution.

Some patients required tocilizumab and corticosteroids for the management of CRS. KYMRIAH continues to expand and persist following treatment as per the CRS management algorithm (see Table 1). Patients who have higher expansion tended to have higher CRS Grades [see Warnings and Precautions (5.1)].

Pediatric and young adult r/r B-cell ALL patients (N = 28) treated with tocilizumab had 298% and 183% higher KYMRIAH AUC_0-28d and C_max, respectively, as compared to patients (N = 46) who did not receive tocilizumab. In addition, patients who received corticosteroids for CRS management (N = 17) had 280% higher AUC_0-28d compared with patients who did not receive corticosteroids (N = 31).

Adult r/r DLBCL patients treated with tocilizumab (N = 18) had 238% (n = 14) and 311% (n = 16) higher KYMRIAH AUC_0-28d and C_max, respectively, as compared to patients (N = 97) who did not receive tocilizumab. In addition, patients who received corticosteroids for CRS management (N = 12) had 104% and 179% higher AUC_0-28d and C_max, respectively, as compared with patients who did not receive corticosteroids (N = 79). 

Adult r/r FL patients treated with tocilizumab (N = 14) had 245% (n = 12) and 312% (n = 11) higher KYMRIAH AUC_0-28d and C_max, respectively, as compared to patients (N = 76) who did not receive tocilizumab. Three patients received corticosteroids for CRS management while all other patients received corticosteroids for other reasons, therefore a formal comparison for exposure differences by use of corticosteroids cannot be performed. 

Hepatic and renal impairment studies of KYMRIAH were not conducted.

MEDICATION GUIDE
KYMRIAH^® (pronounced KIM-RYE-AH)
(tisagenlecleucel)
suspension, for intravenous infusion

Read this Medication Guide before you start your KYMRIAH treatment. The more you know about your treatment, the more active you can be in your care. Talk with your healthcare provider if you have questions about your health condition or treatment. Reading this Medication Guide does not take the place of talking with your healthcare provider about your treatment.

What is the most important information I should know about KYMRIAH?

KYMRIAH may cause side effects that are severe or life-threatening. Call your healthcare provider or get emergency help right away if you get any of the following:

• difficulty breathing
• fever (100.4°F/38°C or higher)
• chills/shaking chills
• confusion
• severe nausea, vomiting, diarrhea
• severe muscle or joint pain
• very low blood pressure
• dizziness/lightheadedness

It is important that you tell your healthcare providers that you have received KYMRIAH. Your healthcare providers may give you other medicines to treat your side effects.

What is KYMRIAH?

KYMRIAH is made from your own white blood cells and is a prescription cancer treatment used in patients up to 25 years old who have acute lymphoblastic leukemia (ALL) that is either relapsing (went into remission, then came back) or refractory (did not go into remission after receiving other leukemia treatments). It is also used in patients with large Bcell lymphoma or follicular lymphoma, two types of non-Hodgkin lymphoma, that have relapsed or are refractory after having at least two other kinds of treatment.

How will I get KYMRIAH?

Since KYMRIAH is made from your own white blood cells, your healthcare provider has to take some of your blood. This is called “leukapheresis.” It takes 3 to 6 hours and may need to be repeated. A tube (intravenous catheter) will be placed in your vein to collect your blood.

Your blood cells are frozen and sent to the manufacturing site to make KYMRIAH. It takes about 3-4 weeks from the time your cells are received at the manufacturing site and shipped back to your healthcare provider, but the time may vary. 

While waiting for KYMRIAH to be made, your healthcare provider may give you therapy to stabilize your cancer. 

In addition, before you get KYMRIAH, your healthcare provider may give you chemotherapy for a few days to prepare your body. 

When your body is ready, your healthcare provider will give you KYMRIAH through a tube (intravenous catheter) in your vein. This usually takes less than one hour.

You should plan to stay close to a healthcare facility for at least 2 weeks after getting KYMRIAH. Your healthcare provider will check to see if your treatment is working and help you with any side effects that occur.

What should I avoid after receiving KYMRIAH?

• Avoid driving for at least 2 weeks after you get KYMRIAH.
• Do not donate blood, organs, tissues, sperm, oocytes, and other cells.

What are the possible or reasonably likely side effects of KYMRIAH?

The most common side effects of KYMRIAH are:

• difficulty breathing
• fever (100.4°F/38°C or higher)
• chills/shaking chills
• confusion
• severe nausea, vomiting, diarrhea
• severe muscle or joint pain
• very low blood pressure
• dizziness/lightheadedness
• headache

KYMRIAH can increase the risk of life-threatening infections that may lead to death. Tell your healthcare provider right away if you develop fever, chills, or any signs or symptoms of an infection. 

KYMRIAH can lower one or more types of your blood cells (red blood cells, white blood cells, or platelets). After treatment, your healthcare provider will test your blood to check for this. Tell your healthcare provider right away if you get a fever, are feeling tired, weak, or short of breath, or have bruising or bleeding. 

Having KYMRIAH in your blood may cause a false-positive HIV test result by some commercial tests.

KYMRIAH may increase your risk of getting cancers, including certain types of blood cancers. Your healthcare provider should monitor you for this.

These are not all the possible side effects of KYMRIAH. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of KYMRIAH.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

Do not use KYMRIAH for a condition for which it was not prescribed.

Talk to your healthcare provider about any concerns. You can ask your healthcare provider for information about KYMRIAH that is written for healthcare professionals.

Distributed by:
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936.  US License Number 1244
© Novartis

For more information, go to KYMRIAH.com or call 1-888-669-6682.

This Medication Guide has been approved by the U.S. Food and Drug Administration.