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Most common adverse reactions (incidence greater than 20%) are hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, bleeding, hypotension, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium.
The following serious adverse reactions are discussed in greater detail in another section of the label:
- Cytokine Release Syndrome [see WARNINGS AND PRECAUTIONS]
- Neurological Toxicities [see WARNINGS AND PRECAUTIONS]
- Infections and Febrile Neutropenia [see WARNINGS AND PRECAUTIONS]
- Prolonged Cytopenias [see WARNINGS AND PRECAUTIONS]
- Hypogammaglobulinemia [see WARNINGS AND PRECAUTIONS]
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 reflect exposure to KYMRIAH in the clinical trial (Study 1) in which 68 patients with pediatric and young adult relapsed/ refractory (R/R) B-cell ALL received CAR-positive viable T cells.
Based on a recommended dose which was weight-based, all patients received a single intravenous dose of KYMRIAH [see Clinical Studies]. The most common adverse reactions were cytokine release syndrome (79%), hypogammaglobulinemia (43%), infections-pathogen unspecified (41%), pyrexia (40%), decreased appetite (37%), headache (37%), encephalopathy (34%), hypotension (31%), bleeding episodes (31%), tachycardia (26%), nausea (26%), diarrhea (26%), vomiting (26%), viral infectious disorders (26%), hypoxia (24%), fatigue (22%), acute kidney injury (22%), and delirium (21%).
Eleven deaths were reported for patients who received KYMRIAH, of which 2 deaths occurred within 30 days of infusion. Seven were disease-related, three were attributed to infections, and one to intracerebral hemorrhage. Of the two deaths before Day 30, one patient died with CRS and progressive leukemia and the second patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred.
The adverse reactions with greater or equal to 10% incidence for any Grade are summarized in Table 2.
Table 2: Selected Adverse Reactions (≥ 10%) Following Treatment with KYMRIAH (N=68)
|Adverse Reaction||All Grades (%)||Grades 3 or Higher (%)|
|General disorders and administration site conditions|
|Immune system disorders|
|Cytokine release syndrome||79||49|
|Infections and infestations|
|Viral infectious disorders||26||18|
|Bacterial infectious disorders||19||13|
|Fungal infectious disorders||13||7|
|International normalized ratio increased||13||0|
|Metabolism and nutrition disorders|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||16||1|
|Nervous system disorders|
|Renal and urinary disorders|
|gAcute kidney injury||22||13|
|Respiratory, thoracic and mediastinal disorders|
|aTachycardia includes tachycardia and sinus tachycardia. |
bAbdominal pain includes abdominal pain, abdominal pain upper, gastrointestinal pain, abdominal pain lower.
cHypogammaglobulinemia includes hypogammaglobulinemia, immunoglobulins decreased, blood immunoglobulin G decreased, blood immunoglobulin A decreased, blood immunoglobulin M decreased, hypogammaglobulinemia.
dHeadache includes headache and migraine.
eEncephalopathy includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, posterior reversible encephalopathy syndrome, somnolence, and automatism.
fDelirium includes delirium, agitation, hallucination, hallucination visual, irritability, restlessness.
gAcute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, renal tubular dysfunction, renal tubular necrosis.
Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were:
Blood and lymphatic system disorders: disseminated intravascular coagulation (9%), histiocytosis lymphocytic hemophagocytosis (7%), coagulopathy (6%), Grade 3 and Grade 4 hypofibrinogenemia with Grade 3 and 4 CRS (16%)
Cardiac Disorders: cardiac arrest (4%), cardiac failure (7%)
Gastrointestinal disorders: abdominal compartment syndrome (1%)
General disorders and administration site conditions: multiple organ dysfunction syndrome (3%)
Immune system disorders: graft versus host disease (1%)
Investigations: blood creatinine increased (7%), activated partial thromboplastin time prolonged (6%)
Nervous System: intracranial hemorrhage (1%), seizure (3%)
Respiratory, thoracic, and mediastinal disorders: respiratory distress (6%), respiratory failure (6%), acute respiratory distress syndrome (4%)
Metabolism and nutrition disorders: tumor lysis syndrome (6%)
Vascular disorders: capillary leak syndrome (3%)Laboratory Abnormalities
Selected laboratory abnormalities worsening from baseline Grade 0-2 to Grade 3-4 are shown in Table 3.
Table 3: Selected Other Laboratory Abnormalities Worsening from Baseline Grade 0-2 to Grade 3-4 Following Treatment with KYMRIAH based on CTCAEa (N=68)
|Grade 3 or 4 (%)|
|Increased Aspartate Aminotransferase||28|
|Increased Alanine Aminotransferase||21|
|aCTCAE = Common Terminology Criteria for Adverse Events version 4.03|
All patients experienced neutropenia, anemia and thrombocytopenia. See Table 4 for the incidences of Grade 3 and Grade 4 prolonged thrombocytopenia and prolonged neutropenia in responding patients.
Table 4: Prolonged Cytopenias Following Treatment with KYMRIAH
|Day 28||Day 56|
|aGrade 3 and 4 observed within 14 days after Day 28 or Day 56 in responding patients|
In clinical studies, humoral immunogenicity of KYMRIAH was measured by determination of anti-murine CAR19 antibodies (anti-m CAR19) in serum pre- and post-administration. The majority of patients (86%) tested positive for pre-dose anti-m CAR19 antibodies in Study 1; 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-m CAR19 antibodies compared with patients with negative post-infusion anti-m CAR19 antibodies. There is no evidence that the presence of preexisting and treatment-induced anti-mCAR19 antibodies impact the safety or effectiveness of KYMRIAH.
Included as part of the PRECAUTIONS section.
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.
Following infusion of KYMRIAH in pediatric and young adult relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) patients, KYMRIAH exhibited an initial rapid expansion followed by a bi-exponential decline. KYMRIAH should be administered within 30 minutes of thawing at approximately 10-20 mL per minute.
A summary of pharmacokinetic parameters of KYMRIAH is provided in Table 5 below.
Table 5: Pharmacokinetic Parameters of KYMRIAH
|Parameter||Summary Statistics||Responding Patients |
|Non-Responding Patients |
|Cmax (copies/mcg)||Geometric mean (CV%), n||34,700 (155.4), 61||20,000 (71.6%), 7|
|Tmax‡ (day)||Median [min;max], n||9.91 [0.008;27], 61||20.0 [0.03;62.7], 7|
|AUC0-28d (copies/mcg*day)||Geometric mean (CV%), n||318,000 (177.8), 61||156,000 (99.4), 6|
|T½(day)||Geometric mean (CV%), n||16.8 (155.9), 54||2.52 (171.9), 3|
|‡A total of 7 patients had an early Tmax (< 0.03 days), the next lowest Tmax occurred at 5.7 days. Early Tmax may not be representative of the true maximal expansion, but rather representative of the amount of transgene present in the catheter from which sample was collected.|
The Cmax and AUC0-28d were approximately 2-fold higher in 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 1.5 to 2-fold higher Cmax and AUC0-28d than adults. Due to small sample size and high variability, it is difficult to assess the impact of age on the pharmacokinetics of KYMRIAH.
Some patients required tocilizumab and corticosteroids for the management of CRS. KYMRIAH continues to expand and persist following tocilizumab administration. Patients who have higher expansion are associated with higher CRS Grades [see WARNINGS AND PRECAUTIONS]. Patients (n=18) treated with tocilizumab had 265% and 183% higher KYMRIAH AUC0-28d and Cmax, respectively, as compared to patients (n=44) who did not receive tocilizumab. Similarly, patients who received corticosteroids had 89% higher AUC0-28d compared with patients who did not receive corticosteroids.
Hepatic and renal impairment studies of KYMRIAH were not conducted.
Clinical StudiesRelapsed Or Refractory (R/R) B-cell Acute Lymphoblastic Leukemia (ALL)
The efficacy of KYMRIAH in pediatric and young adults with R/R B-cell precursor ALL was evaluated in an open-label, multicenter single-arm trial (Study 1). In total, 107 patients were screened, 88 were enrolled, 68 were treated, and 63 were evaluable for efficacy. Nine percent of the enrolled subjects did not receive the product due to manufacturing failure. The 63 evaluable patients included 35 males and 28 females of median age 12 years (range, 3-23 years). Seventy-three percent of patients were white, 10% were Asian, and 17% were of other races. Six (10%) had primary refractory disease, 30 (48%) had one prior stem cell transplantation, 5 patients (8%) had two stem cell transplantations. Treatment consisted of lymphodepleting chemotherapy (fludarabine 30 mg/m² daily for 4 days and cyclophosphamide 500 mg/m² daily for 2 days) followed by a single dose of KYMRIAH. Of the 22 patients who had a WBC count < 1000/μL, 20 received lymphodepleting chemotherapy prior to KYMRIAH while 2 received KYMRIAH infusion without lymphodepleting chemotherapy. Fifty-three patients received bridging chemotherapy between time of enrollment and lymphodepleting chemotherapy.
The efficacy of KYMRIAH was established on the basis of complete remission (CR) within 3 months after infusion, the duration of CR, and proportion of patients with CR and minimal residual disease (MRD) < 0.01% by flow cytometry (MRD-negative) (Table 6). Among the 63 infused patients, 52 (83%) achieved CR/CRi, all of which were MRD-negative. With a median follow-up of 4.8 months from response, the median duration of CR/CRi was not reached (range: 1.2 to 14.1+ months). Median time to onset of CR/CRi was 29 days with onset of CR/CRi between 26 and 31 days for 50/52 (96%) responders. The stem cell transplantation rate among those who achieved CR/CRi was 12% (6/52).
Table 6 shows the efficacy results from this study.
Table 6: Efficacy Results in Pediatric and Young Adult Patients with R/R B-cell Precursor ALL
|95% CI||(71%, 91%)|
|CR or CRi with MRD-negative bone marrow5,6||52 (83%)|
|95% CI||(71%, 91%)|
|Duration of Remission7||N=52|
|Median (months)||Not reached|
|95% CI||(7.5, NE8)|
|1CR/CRi was calculated based on all patients who received KYMRIAH and completed at least 3 months follow-up, or discontinued earlier prior to the data cut-off. Requires remission status to be maintained for at least 28 days without clinical evidence of relapse. |
2 The null hypothesis of CR/CRi less than or equal to 20% was rejected.
3CR (complete remission) was defined as less than 5% of blasts in the bone marrow, no evidence of extramedullary disease, and full recovery of peripheral blood counts (platelets greater than 100,000/microliter and absolute neutrophil counts [ANC] greater than 1,000/microliter) without blood transfusion.
4CRi (complete remission with incomplete blood count recovery) was defined as less than 5% of blasts in the bone marrow, no evidence of extramedullary disease, and without full recovery of peripheral blood counts with or without blood transfusion.
5MRD (minimal residual disease) negative was defined as MRD by flow cytometry less than 0.01%.
6The null hypothesis of MRD-negative remission rate less than or equal to 15% was rejected.
7DOR (duration of remission) was defined as time since onset of CR or CRi to relapse or death due to underlying cancer, whichever is earlier, censoring for new cancer therapy including stem cell transplantation (N=52).
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
- severe nausea, vomiting, diarrhea
- severe muscle or joint pain
- very low blood pressure
It is important that you tell your health care providers that you have received KYMRIAH. Your healthcare providers may give you other medicines to treat your side effects.
What is KYMRIAH?
KYMRIAH 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). KYMRIAH is made from your own white blood cells.
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 to make KYMRIAH, but the time may vary.
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 within 2 hours of the location where you received your treatment for at least 4 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?
- Do not drive, operate heavy machinery, or do other dangerous things for 8 weeks after you get KYMRIAH because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.
- Do not donate blood, organs, tissues and cells for transplantation.
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
- severe nausea, vomiting, diarrhea
- severe muscle or joint pain
- very low blood pressure
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, or have bruising or bleeding.
Having KYMRIAH in your blood may cause a false-positive HIV test result by some commercial tests.
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.
For more information, go to KYMRIAH.com or call 1-844-NVS-CART (1-844-687-2278).
What are some things I need to know or do while I take Kymriah?
- Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
- Avoid driving and doing other tasks or actions that call for you to be alert for at least 8 weeks after getting Kymriah. If you have any questions, call your doctor or pharmacist.
- Have blood work checked as you have been told by the doctor. Talk with the doctor.
- This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
- You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
- You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
- If you have had hepatitis B before or carry the virus, talk with your doctor. Drugs like this one can cause the virus to become active. This can lead to very bad and sometimes deadly liver problems.
- Hepatitis and HIV testing will be done before taking Kymriah.
- Talk with your doctor before getting any vaccines. Some types of vaccines must not be given for at least 2 weeks before starting this medicine, during care, and for some time after care ends.
- This medicine may add to the chance of getting some types of cancer. Talk with the doctor.
- Do not donate blood, organs, or tissues or cells. Talk with your doctor to see when you can do these things after getting Kymriah (tisagenlecleucel).
- This medicine is taken with other drugs. Be sure you know about the warnings, benefits, and risks of these other drugs. Talk with the doctor if you have questions or concerns about any of the drugs.
- If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting this medicine. Talk with your doctor.
- Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Kymriah while you are pregnant.
- Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
If OVERDOSE is suspected
If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
What happens if I overdose?
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
What should I avoid after receiving tisagenlecleucel?
This medicine can cause weakness, drowsiness, confusion, problems with memory or coordination, and seizures. Avoid driving or operating machinery for at least 8 weeks after you are treated with tisagenlecleucel.
Do not donate blood, an organ, or any tissues or cells from your own body.
Do not receive a "live" vaccine while using tisagenlecleucel, or you could develop a serious infection. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.
Tisagenlecleucel side effects
Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.
A serious side effect of tisagenlecleucel is called cytokine release syndrome (CRS). Tell your caregivers right away if you have signs of this condition: fever, chills, trouble breathing, body aches, vomiting, diarrhea, or feeling light-headed. Your caregivers will have medication available to quickly treat CRS if it occurs.
Also tell your caregivers or seek emergency medical attention if you have signs of life-threatening nerve problems: problems with speech, problems with thinking or memory, confusion, or a seizure.
Also call your doctor at once if you have:
headaches, unusual tiredness;
tremors, anxiety, agitation;
unusual thoughts or behavior;
trouble speaking or understanding what is said to you; or
signs of infection--fever, chills, flu symptoms, mouth sores, skin sores, easy bruising or bleeding, cough, trouble breathing.
Common side effects may include:
nausea, vomiting, diarrhea, loss of appetite;
headache, confusion, feeling tired;
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Commonly used brand name(s)
In the U.S.
Available Dosage Forms:
Therapeutic Class: Antineoplastic Agent
Kymriah Side Effects
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor or nurse immediately if any of the following side effects occur:More common
- back pain
- blue lips, fingernails, or skin
- blurred vision
- chest pain or discomfort
- confusion as to time, place, or person
- coughing that sometimes produces a pink frothy sputum
- decreased urine output
- difficult, fast, noisy breathing
- dilated neck veins
- dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
- extreme fatigue
- fast, pounding, or irregular heartbeat or pulse
- holding false beliefs that cannot be changed by fact
- increased sweating
- loss of consciousness
- lower back or side pain
- mood or mental changes
- muscle twitching
- painful or difficult urination
- pale skin
- pounding in the ears
- rapid shallow breathing
- rapid weight gain
- slow or fast heartbeat
- stiff neck
- swelling of the face, arms, fingers, feet, or lower legs
- trembling and shaking of hands
- troubled breathing at rest
- unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
- unusual excitement, nervousness, or restlessness
- weight gain
- Change in the amount of urine
- cloudy urine
- headache, sudden or severe
- stomach pain
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:More common
- decreased appetite
- difficulty in moving
- joint pain
- muscle pain or stiffness
- nasal congestion
- pain in the arms or legs
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.