Dosing & Uses
Dosage Forms & Strengths
injection, suspension
- Single-dose units contain specific amounts of T cells depending on the patient’s body weight that are suspended in a patient-specific infusion bag
- 2 x 10^6 CAR-positive viable T cells/kg of body weight, with a maximum of 2 x 10^8 CAR-positive viable T cells in ~68 mL
B-Cell Lymphoma
Indicated for adults with relapsed or refractory large B-cell lymphoma after ≥2 lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma
One treatment course consists of fludarabine- and cyclophosphamide-lymphodepleting chemotherapy followed by IV infusion of axicabtagene ciloleucel
Confirm availability of axicabtagene ciloleucel prior to starting lymphodepleting chemotherapy
Lymphodepleting chemotherapy
- 3 doses of fludarabine and cyclophosphamide infused IV on the fifth, fourth, and third day before infusion of axicabtagene ciloleucel
- Fludarabine 30 mg/m² IV qDay for 3 days
- Cyclophosphamide 500 mg/m² IV qDay for 3 days starting with the first dose of fludarabine
Premedication
- Premedicate with acetaminophen 650 mg PO and diphenhydramine 12.5 mg IV or PO ~1 hr before axicabtagene ciloleucel infusion
- Avoid prophylactic use of systemic corticosteroids at all times (may interfere with axicabtagene ciloleucel activity), except in the case of a life-threatening emergency
Axicabtagene ciloleucel IV infusion
- Administer after completing lymphodepleting chemotherapy
- Dosing of axicabtagene is based on the number of chimeric antigen receptor (CAR)-positive viable T cells
- Target dose is 2 x 10^6 CAR-positive viable T cells/kg body weight, not to exceed 2 x 10^8 CAR-positive viable T cells
- Administer autologously prepared, weight-based IV infusion for individual patient within 30 minutes by either gravity or peristaltic pump
- Do not use a leukocyte-depleting filter
- Also see Administration
Dosage Modifications
Cytokine release syndrome (CRS) management
Grade 1
- Symptoms: Fever, nausea, fatigue, headache, myalgia, malaise
- Symptomatic treatment only
Grade 2
- 1 or more of the following: Symptoms require moderate intervention; oxygen requirement <40% FiO2 or hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity
- Administer tocilizumab 8 mg/kg IV infused over 1 hr (not to exceed 800 mg)
- Repeat tocilizumab q8hr as needed if not responsive to IV fluids or increasing supplemental oxygen
- Not to exceed 3 doses in a 24-hr period or 4 doses in total
- Manage per Grade 3 if no improvement within 24 hr after initiating tocilizumab
Grade 3
- 1 or more of the following: Symptoms require aggressive intervention; oxygen requirement ≥40% FiO2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis
- Administer tocilizumab (see doses in CRS Grade 2)
- Administer methylprednisolone 1 mg/kg IV BID or equivalent dexamethasone (eg, 10 mg IV q6hr)
- Continue corticosteroid use until event is ≤Grade 1, then taper over 3 days
Grade 4
- 1 or more of the following: Life-threatening symptoms; requires ventilator support, continuous venovenous hemodialysis (CVVHD), or Grade 4 organ toxicity (excluding transaminitis)
- Administer methylprednisolone 1000 mg/day IV for 3 days; if improvement, then manage as above
Neurologic toxicity grading and management
Grade 2 with concurrent CRS
- Administer tocilizumab (see doses in CRS Grade 2)
- If no improvement within 24 hr after starting tocilizumab, administer dexamethasone 10 mg IV q6hr if not already taking other corticosteroids; continue dexamethasone use until the event is ≤Grade 1, then taper over 3 days
- Consider nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis
Grade 2 or 3 with NO concurrent CRS
- Administer dexamethasone 10 mg IV q6hr if not already taking other corticosteroids
- Continue until event is ≤Grade 1, then taper over 3 days
Grade 3 with concurrent CRS
- Administer tocilizumab (see doses in CRS Grade 2) AND
- Administer dexamethasone 10 mg IV q6hr if not already taking other corticosteroids; continue dexamethasone until event is ≤Grade 1, then taper over 3 days
- Consider nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis
Grade 4 with concurrent CRS
- Administer tocilizumab (see doses in CRS Grade 2)
- Administer methylprednisolone 1000 mg/day for 3 days with first dose of tocilizumab; if improvement, then manage as above
Grade 4 with NO concurrent CRS
- Administer methylprednisolone 1000 mg/day for 3 days; if improvement, then manage as above
Dosing Considerations
For autologous use only
Administer axicabtagene at a certified healthcare facility
Monitor signs/symptoms of CRS and neurologic toxicities for at least daily for 7 days following infusion
Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following infusion
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10% Any Grade
Cytokine release syndrome (94%)
Fever (86%)
Tachycardia (57%)
Encephalopathy (57%)
Hypotension (57%)
Fatigue (46%)
Headache (45%)
Decreased appetite (44%)
Chills (40%)
Diarrhea (38%)
Nausea (34%)
Hypoxia (32%)
Tremor (31%)
Cough (30%)
Vomiting (26%)
Infections, pathogen unspecified (26%)
Constipation (23%)
Arrhythmia (23%)
Dizziness (21%)
Edema (19%)
Motor dysfunction (19%)
Dyspnea (19%)
Aphasia (18%)
Pain in extremity (17%)
Delirium (17%)
Weight decreased (16%)
Hypogammaglobulinemia (15%)
Back pain (15%)
Hypertension (15%)
Abdominal pain (14%)
Muscle pain (14%)
Pleural effusion (13%)
Renal insufficiency (12%)
Dry mouth (11%)
Dehydration (11%)
>10% Grades 3-4
Lymphopenia (100%)
Leukopenia (96%)
Neutropenia (93%)
Anemia (66%)
Thrombocytopenia (58%)
Hypophosphatemia (50%)
Encephalopathy (29%)
Hyponatremia (19%)
Fever (16%)
Infections, pathogen unspecified (16%)
Hypotension (15%)
Cytokine release syndrome (13%)
Hyperuricemia (13%)
Direct bilirubin increased (13%)
Hypoxia (11%)
1-10% Any Grade
Arthralgia (10%)
Thrombosis (10%)
Pulmonary edema (9%)
Rash (9%)
Cardiac failure (6%)
Ataxia (6%)
Fungal infections (5%)
Cardiac arrest (4%)
Seizure (4%)
Capillary leak syndrome (3%)
Coagulopathy (2%)
Dyscalculia (2%)
Myoclonus (2%)
Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (1%)
Hypersensitivity (1%)
1-10% Grades 3-4
Hypokalemia (10%)
Increased ALT (10%)
Bacterial infections (9%)
Arrhythmia (7%)
Aphasia (6%)
Delirium (6%)
Hypertension (6%)
Renal insufficiency, grades 3-4 (5%)
Diarrhea, grades 3-4 (4%)
Viral infections (3%)
Fatigue (3%)
Dehydration (3%)
Dyspnea (3%)
Tachycardia (2%)
Decreased appetite (2%)
Pain in extremity (2%)
Tremor (2%)
Pleural effusion (2%)
Vomiting (1%)
Abdominal pain (1%)
Edema (1%)
Motor dysfunction (1%)
Back pain (1%)
Muscle pain (1%)
Headache (1%)
Dizziness (1%)
Thrombosis (1%)
Warnings
Black Box Warnings
Cytokine release syndrome
- Cytokine release syndrome (CRS), including fatal or life-threatening reactions, reported in a majority of patients (see Adverse Effects)
- Median time to CRS onset was 2 days (range: 1-12 days)
- Median duration of CRS was 7 days (range: 2-58 days)
- Key manifestations of CRS include high fever, hypotension, tachycardia, hypoxia, and chills
- Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)
- Do not administer to patients with active infection or inflammatory disorders
Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids
- Ensure that 2 doses of tocilizumab are available on site prior to initiating axicabtagene ciloleucel (see Dosage Modifications)
- Monitor for CRS signs or symptoms daily for at least 7 days at the certified healthcare facility following treatment; continue monitoring for 4 weeks following the infusion
- Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time
- At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated
Neurological toxicities
- Neurological toxicities, which may be severe or life-threatening, can occur following treatment, including concurrently with CRS
- The majority of neurological toxicities occurred within 8 weeks after treatment
- The most common neurological toxicities were encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, and anxiety (also see Adverse Effects)
- Prolonged encephalopathy lasting up to 173 days was observed
- Serious events, including leukoencephalopathy and seizures, occurred in clinical trials
- Fatal and serious cases of cerebral edema also occurred
- Monitor for neurological events after treatment; provide supportive care as needed
Restricted access program
- Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS
- Further information is available at www.yescarta-rems.com or 1-844-454-KITE (5483)
REMS requirements
- Healthcare facilities that dispense and administer axicabtagene ciloleucel must be enrolled and comply with the REMS requirements
- Certified healthcare facilities must have onsite immediate access to tocilizumab and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hr after axicabtagene ciloleucel IV infusion, if needed for treatment of CRS
- Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer axicabtagene ciloleucel are trained about the management of CRS and neurological toxicities
Contraindications
None
Cautions
Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment in a majority of patients (see Black Box Warnings and Adverse Effects)
Neurological toxicities, which may be severe or life-threatening, can occur following treatment (see Black Box Warnings)
Available only through a restricted access program (see Black Box Warnings)
Allergic reactions may occur during infusion; serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) or residual gentamicin in the product
Serious infections, including life-threatening or fatal infections, reported; before administering, infection prophylaxis for neutropenia should follow local guidelines; monitor for signs and symptoms of infection after treatment and treat appropriately
Viral reactivation can occur; hepatitis B virus (HBV) reactivation can result in fulminant hepatitis, hepatic failure, and death; perform screening for HBV, hepatitis C virus (HCV), and HIV in accordance with clinical guidelines before collection of cells for manufacturing
Prolonged cytopenias may occur and last for several weeks following lymphodepleting chemotherapy and axicabtagene ciloleucel infusion; monitor blood cell counts
B-cell aplasia and hypogammaglobulinemia can occur; monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines
Secondary malignancies may develop; monitor patient life-long for secondary malignancies
Owing to the potential for neurological events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following treatment; advise patients to refrain from driving and engaging in hazardous occupations or activities
Immunization with live viral vaccines
- The safety of immunization with live viral vaccines during or following treatment has not been studied
- Vaccination with live-virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during axicabtagene ciloleucel treatment, and until immune recovery afterwards
Pregnancy
Pregnancy
Data are not available in pregnant women
No animal reproductive and developmental toxicity studies have been conducted
Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia
Therefore, axicabtagene ciloleucel is not recommended for women who are pregnant, and pregnancy after infusion should be discussed with the treating physician
Pregnancy status of females with reproductive potential should be verified; sexually active females of reproductive potential should have a pregnancy test prior to starting treatment
Contraception: See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy; limited exposure data available concerning the duration of contraception following treatment with axicabtagene ciloleucel
Lactation
Unknown if distributed in human breast milk
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
CD19-directed genetically modified autologous T cell immunotherapy that involves reengineering a patient’s own T cells to express a chimeric antigen receptor (CAR) to identify and bind to CD19-expressing malignant and normal B cells
Following anti-CD19 CAR T-cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta costimulatory domains activate downstream signaling cascades that lead to T cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines
This cascade of events leads to killing of CD19-expressing cells
Absorption
Peak plasma time: 7-14 days
Peak plasma concentration, median: 43.6 cells/mcL (responsive patients); 21.2 cells/mcL (nonresponsive [NR] patients)
AUC (0-28d): 557.1 days·cells/mcL (responsive patients); 222 days·cells/mcL (NR patients)
Cmax and AUC in responsive patients were, respectively, 205% and 251% higher compared with the corresponding level in NR patients
Concurrent use of tocilizumab: 262% and 232% higher anti-CD19 CAR T cells as measured by AUC (0-28d) and Cmax, respectively, as compared with patients without tocilizumab
Concurrent use of corticosteroids: 217% and 155% higher AUC (0-28d) and Cmax compared with patients who did not receive corticosteroids
Administration
IV Preparation
Confirm infusion time in advance, and adjust start time for thaw so that axicabtagene is available for infusion when recipient is ready
Confirm patient identity prior to preparation, and match the patient's identity with the patient identifiers on the axicabtagene infusion bag; axicabtagene is for autologous use only
Inspect the infusion bag for any breaks or cracks before thawing; if bag is compromised, do not infuse the contents; contact Kite at 1-844-454-KITE
Place infusion bag inside a second, sterile bag as per local guidelines
Thaw infusion bag at 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
Do not wash, spin down, and/or resuspend axicabtagene ciloleucel in new media prior to infusion
Once thawed, stored at room temperature (20-25°C) for up to 3 hr
IV Administration
For autologous use only
Ensure that tocilizumab and 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
Prime tubing with 0.9% NaCl prior to infusion
Infuse entire contents of the bag within 30 minutes by either gravity or a peristaltic pump
Thawed infusion bag is stable at room temperature for up to 3 hr
Gently agitate the product bag during infusion to prevent cell clumping
After completing infusion, rinse tubing with 0.9% NaCl at the same infusion rate to ensure all product is delivered
Follow local biosafety guidelines applicable for handling and disposal of such products
Storage
Frozen product
- Store infusion bag in the vapor phase of liquid nitrogen ≤-238°F (≤-150°C) supplied in a liquid nitrogen dry shipper
- Use closed, break-proof, leak-proof containers when transporting infusion bags within the facility
Thawed infusion bag
- Stored at room temperature 68-77°F (20-25°C) for up to 3 hr
Images
Patient Handout
Formulary
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