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YESCARTA is a brand name for Axicabtagene Ciloleucel, supplied as a suspension. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: YESCARTA (axicabtagene ciloleucel) is a CD19-directed genetically modified autologous T cell immunotherapy indicated for: • the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL) that is refractory to first-line chemoimmunotherapy or that relapses within 12…
Verbatim from this product's HC label. Tap a section to expand.
YESCARTA should be administered by experienced health professionals at specialized treatment centers (see WARNINGS AND PRECAUTIONS). 1 Dosing Considerations • For autologous use only; do NOT infuse YESCARTA if the information on the patient- specific label on the infusion bag does not match the intended patient.
• For intravenous (IV) use only; do NOT use a leukodepleting filter. • Single infusion product. • Do NOT irradiate YESCARTA. • Consider delaying lymphodepleting chemotherapy and YESCARTA treatment if the patient has one or more of the following conditions: clinically significant cardiac dysfunction, pulmonary dysfunction, renal insufficiency, acute neurologic toxicity, active uncontrolled infection or inflammation, and active graft-versus host disease (see CLINICAL TRIALS).
2 Recommended Dose and Dosage Adjustment Adults YESCARTA is provided as a single-dose, one-time treatment in a patient-specific infusion bag. Each single infusion bag of YESCARTA contains a suspension of anti-CD19 chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL.
The target dose is 2 x 106 CAR-positive Serious Warnings and Precautions • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Delay YESCARTA treatment if a patient has active uncontrolled infection or inflammatory disorders, active graft-versus-host disease (GVHD) or unresolved serious adverse reactions from prior therapies.
Monitor for CRS after treatment with YESCARTA. Provide supportive care, tocilizumab, or tocilizumab and corticosteroids, as needed (see WARNINGS AND PRECAUTIONS). • Neurologic adverse reactions, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or independently of CRS.
Monitor for neurologic adverse reactions after treatment with YESCARTA. Provide supportive care, tocilizumab (if with concurrent CRS), or corticosteroids, as needed (see WARNINGS AND PRECAUTIONS). • YESCARTA should be administered by experienced health professionals at specialized treatment centres (see WARNINGS AND PRECAUTIONS).
4 x 106 cells/kg), with a maximum of 2 x 108 CAR-positive viable T cells for patients 100 kg and above. Pediatrics (< 18 years of age) Health Canada has not authorized an indication for pediatric use. Geriatrics (≥ 65 years of age) No dose adjustments are required for patients 65 years of age or older.
2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.
Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. The adverse reactions described in this section reflect exposure to YESCARTA in one randomized, open-label study (ZUMA-7) and one open-label, single-arm study (ZUMA-1) in which 170 and 108 adult patients, respectively, with relapsed or refractory LBCL, and 148 patients with relapsed/refractory iNHL (including FL [n = 124]), who received CAR-positive T cells based on the recommended dose which was weight-based (see CLINICAL TRIALS).
7 months in iNHL patients. Relapsed or Refractory LBCL ZUMA-7 The safety of YESCARTA was evaluated in ZUMA-7, a study in which patients with primary refractory or first relapsed LBCL (predominantly DLBCL or HGBL), after first line chemoimmunotherapy, received YESCARTA (N=170) or standard of care therapy (SOCT, n=168).
SOCT was defined as 2 to 3 cycles of second-line chemoimmunotherapy (R-ICE, R- DHAP, R-ESHAP, or R-GDP), with responders being eligible to receive high-dose therapy (HDT, n=64) followed by an autologous stem cell transplant (ASCT, n=62) (see CLINICAL TRIALS).
Only patients who intended to proceed to HDT and ASCT (if a response to second- line therapy was attained) were eligible. Patients with a history of central nervous system (CNS) disorders (such as seizures or cerebrovascular ischemia), serious or uncontrolled infection, or autoimmune disease requiring systemic immunosuppression were ineligible.
5mg/dL. The median age of the study population was 59 years (range: 21 to 81 years); 66% were male. The baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 54% of patients and 1 in 46% of patients. The most common non-laboratory adverse reactions (incidence ≥ 20%) occurring in the YESCARTA treatment arm include fever, CRS, fatigue, encephalopathy, hypotension, YESCARTA (axicabtagene ciloleucel) Page 18 of 51 tachycardia, diarrhea, headache, nausea, musculoskeletal pain, chills, cough, tremor, transaminases increased, unspecified pathogen infections, dizziness, decreased appetite, hypoxia, edema, abdominal pain, and constipation.
Please see the Serious Warnings and Precautions Box at the beginning of Part I:
Health Professional Information. General YESCARTA should be administered in a treatment facility with personnel trained in handling and administering YESCARTA and in the management of patients treated with YESCARTA, including monitoring and managing CRS and neurotoxicity.
The facility should have immediate access to appropriate emergency equipment and intensive care unit. YESCARTA is intended solely for autologous use and should under no circumstances be administered to other patients. Before infusion, the patient’s identity must match the patient identifiers on the YESCARTA infusion bag and cassette.
Do NOT infuse YESCARTA if the information on the patient-specific label does not match the intended patient (see DOSAGE AND ADMINISTRATION). Patients with central nervous system (CNS) lymphoma were excluded from the pivotal studies.
Therefore, the safety and efficacy of YESCARTA have not been established in this population. For other patient selection criteria, see CLINICAL TRIALS. Patients treated with YESCARTA should not donate blood, organs, tissues and cells for transplantation.
Secondary Malignancies Patients treated with YESCARTA may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy of T-cell origin occurs, contact the company to obtain instructions on patient samples to collect for testing.
Driving and Operating Machinery Due to the potential for neurologic events, including altered mental status or seizures, patients receiving YESCARTA are at risk for altered or decreased consciousness or coordination in the 8 YESCARTA (axicabtagene ciloleucel) Page 9 of 51 weeks following YESCARTA infusion.
Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period. Endocrine and Metabolism Tumour lysis syndrome (TLS) TLS may occur in patients treated with conditioning chemotherapy and YESCARTA.
YESCARTA is contraindicated in patients who are hypersensitive to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
YESCARTA (axicabtagene ciloleucel) Page 5 of 51
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3 Reconstitution Not applicable. 4 Administration YESCARTA is for autologous use only. The patient’s identity must match the patient identifiers on the YESCARTA cassette and infusion bag. Do not infuse YESCARTA if the information on the patient-specific label does not match the intended patient.
Ensure that 4 doses of tocilizumab and access to emergency equipment are available prior to infusion and during the recovery period (see WARNINGS AND PRECAUTIONS). Preparing Patient for YESCARTA Infusion Confirm availability of YESCARTA prior to starting the lymphodepleting regimen.
Pre-treatment (lymphodepleting chemotherapy) • Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m2 IV and fludarabine 30 mg/m2 intravenously on the 5th, 4th, and 3rd day before infusion of YESCARTA. 5 to 25 mg intravenously or 25 mg orally approximately 1 hour before YESCARTA infusion.
• AVOID prophylactic use of systemic corticosteroids, as it may interfere with the activity of YESCARTA. Preparation of YESCARTA for Infusion • Coordinate the timing of YESCARTA thaw and infusion. Confirm the infusion time in advance, and adjust the start time of YESCARTA thaw such that it will be available for infusion when the patient is ready.
• Confirm that the patient’s identity matches the patient identifiers on the YESCARTA cassette. • Do NOT remove the YESCARTA product bag from the cassette if the information on the patient-specific label does not match the intended patient.
Instead, immediately contact Kite Konnect at 1-833-236-5483. YESCARTA (axicabtagene ciloleucel) Page 7 of 51 • Once the patient’s identity is confirmed, remove the YESCARTA product bag from the cassette and check that the patient information on the cassette label matches the bag label.
• Inspect the product bag for any breaches of container integrity such as breaks or cracks before thawing. If the bag is compromised, follow the local guidelines (or call Kite Konnect at 1-833-236-5483). • Place the infusion bag inside a second sterile bag or per local guidelines.
• Thaw YESCARTA at approximately 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain, continue to gently mix the contents of the bag.
Small clumps of cellular material should disperse with gentle manual mixing. Do NOT wash, spin down, and/or re-suspend YESCARTA in new medium prior to infusion. Thawing should take approximately 3-5 minutes. • Once thawed, YESCARTA may be stored at room temperature (20°C to 25°C) for up to 3 hours.
Do NOT refreeze. Administration • For autologous use only. • Ensure that 4 doses of tocilizumab and access to emergency equipment are available prior to infusion and during the recovery period. • Do NOT use a leukodepleting filter. • Central venous access is recommended for the infusion of YESCARTA.
• Confirm the patient’s identity matches the patient identifiers on the YESCARTA product bag. 9% sodium chloride solution prior to infusion. • Infuse the entire content of the YESCARTA bag within 30 minutes by either gravity or a peristaltic pump.
YESCARTA is stable at room temperature (20°C to 25°C) for up to 3 hours after thaw. Do NOT refreeze. • Gently agitate the product bag […]
Serious adverse reactions occurred in 51% of patients. The most common serious adverse reactions (> 2%) included CRS, fever, encephalopathy (including aphasia, confusional state, somnolence), hypotension, unspecified pathogen infections (including pneumonia), B-cell lymphoma, viral infection, neutropenia, tremor, and arrhythmia.
The most common (≥ 10%) Grade 3 or higher reactions included leukopenia, neutropenia, lymphopenia, anemia, thrombocytopenia, encephalopathy, hyponatremia, hyperglycemia, and hypotension. Fatal treatment emergent adverse events occurred in 4% of YESCARTA treated patients and 1% of SOCT patients (reporting until day 150 post-randomization or until the initiation of new lymphoma therapy, whichever occurred first).
Deaths due to adverse events in the YESCARTA treatment arm, without regard for relationship to treatment, were due to myocardial infarction, progressive multifocal leukoencephalopathy, hepatitis B reactivation, sepsis, and COVID-19; and in the SOCT arm were due to cardiac arrest and acute respiratory distress syndrome.
Sixty-six percent (112/170) of patients received tocilizumab after infusion of YESCARTA. Table 4 summarizes the adverse reactions that occurred in at least 10% of patients treated with YESCARTA and Table 7 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients.
Table 4 Summary of Adverse Reactions Observed in at Least 10% of Patients Treated with YESCARTA in ZUMA-7 Adverse Reaction YESCARTA N=170 Standard of Care Therapy N=168 Any Grade n (%) Grade 3 or Higher n (%) Any Grade n (%) Grade 3 or Higher n (%) Cardiac Disorders Tachycardia a 74 (44) 4 (2) 25 (15) 1 (1) Arrhythmia b 25 (15) 5 (3) 10 (6) 0 (0) Gastrointestinal Disorders Diarrhea c 71 (42) 5 (3) 68 (40) 11 (7) Nausea 69 (41) 3 (2) 116 (69) 9 (5) Abdominal pain d 34 (20) 6 (4) 45 (27) 2 (1) Constipation 34 (20) 0 (0) 58 (35) 0 (0) Vomiting 33 (19) 0 (0) 55 (33) 1 (1) General Disorders and Administration Site Conditions Fever e 158 (93) 15 (9) 43 (26) 1 (1) Fatigue f 88 (52) 11 (6) 95 (57) 5 (3) Chills 47 (28) 1 (1) 14 (8) 0 (0) Edema g 38 (22) 2 (1) 41 (24) 2 (1) Hepatobiliary Disorders Transaminases increased h 44 (26) 3 (2) 19 (11) 4 (2) YESCARTA (axicabtagene ciloleucel) Page 19 of 51 Adverse Reaction YESCARTA N=170 Standard of Care Therapy N=168 Any Grade n (%) Grade 3 or Higher n (%) Any Grade n (%) Grade 3 or Higher n (%) Immune System Disorders Cytokine release syndrome 157 (92) 11 (6) 0 (0) 0 (0) Immunoglobulins decreased i 19 (11) 0 (0 1 (1) 0 (0) Infections and Infestations Infections with pathogen unspecified 44 (26) 13 (8) 36 (21) 11 (7) Viral infections 25 (15) 6 (4) 8 (5) 1 (1) Bacterial infections 17 (10) 8 (5) 18 (11) 11 (7) Fungal infections 17 (10) 1 (1) 7 (4) 1 (1) Metabolism and Nutrition Disorders Decreased appetite 42 (25) 7 (4) 42 (25) 6 (4) Hypoalbuminemia 23 (14) 1 (1) 12 (7) 0 (0) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain j 67 (39) 2 (1) 64 (38) […]
To minimize the risk of TLS, patients with elevated uric acid or high tumour burden should receive prophylactic treatment (allopurinol, or an alternative prophylaxis) prior to YESCARTA treatment. Immune Cytokine release syndrome (CRS) CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA.
CRS occurred in 92% of patients with LBCL and 78% of patients with FL (82% of patients with indolent non-Hodgkin lymphoma [iNHL] overall), including ≥ Grade 3 (Lee grading system1) CRS in 8% of patients with LBCL and 6% of patients with FL (7% of patients with iNHL overall).
The median time to onset of CRS was 3 days (range: 1 to 12 days) for patients with LBCL and 4 days (range: 1 to 15 days) for patients with FL/iNHL overall and the median duration of CRS was 7 days (range: 2 to 58 days) for patients with LBCL and 6 days (range: 1 to 27 days) for patients with FL/iNHL overall.
The most common manifestations of CRS (>10%) include fever (94%), hypotension (43%), tachycardia (37%), chills (24%), hypoxia (22%), and headache (15%). CRS can cause end organ dysfunctions. Serious events that may be associated with CRS include: fever; hypotension; hypoxia; tachycardia; tachypnea; cardiac arrhythmias (including atrial fibrillation/flutter and ventricular tachycardia); renal insufficiency; headache; ejection fraction decreased; cardiac failure; dyspnea; cardiac arrest; metabolic acidosis; aspartate aminotransferase increased; alanine aminotransferase increased; blood bilirubin increased; coagulopathy; capillary leak syndrome; and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (see ADVERSE REACTIONS).
In a subsequent cohort of LBCL patients (ZUMA-1, Cohort 4), tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events (see Table 2). CRS occurred in 93% of patients and 2% had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event.
5 days (range: 2 to 16 days). Key manifestations of CRS (> 5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. Ensure that 4 doses of tocilizumab are available prior to infusion of YESCARTA.
Monitor patients at least daily for 7 days at the specialized healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to remain within proximity of a specialized clinical facility for at least 4 weeks and to seek immediate medical attention, should signs or symptoms of CRS occur at any time (see Monitoring and Laboratory Tests, WARNINGS AND PRECAUTIONS).
An algorithm has been developed to guide the management of CRS in patients treated with YESCARTA (Table 2). At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.
YESCARTA (axicabtagene ciloleucel) Page 10 of 51 Management of CRS Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Manage CRS according to the recommendations in Table 2.
Patients with Grade 1 CRS should be managed with vigilant supportive care and monitored for infection and fluid balance. , hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry.
For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. Patients with medically significant cardiac dysfunction should be managed by standards of critical care. For severe or life-threatening CRS, consider intensive care supportive therapy.
Table 2 CRS Grading and Management […]