brexucabtagene autoleucel (Rx)

Brand and Other Names:Tecartus
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Dosing & Uses

AdultPediatric

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
  • 2x 106 CAR-positive viable T cells/kg of body weight, with a maximum of 2x 108 CAR-positive viable T cells in ~68 mL

Mantle Cell Lymphoma

Indicated for relapsed or refractory mantle cell lymphoma (MCL)

One treatment course consists of fludarabine- and cyclophosphamide-lymphodepleting chemotherapy followed by IV infusion of brexucabtagene autoleucel

Confirm availability of brexucabtagene autoleucel before starting lymphodepleting chemotherapy

Lymphodepleting chemotherapy

  • 3 doses of fludarabine and cyclophosphamide infused IV on the fifth, fourth, and third day before infusion of brexucabtagene autoleucel
  • 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

Brexucabtagene autoleucel IV infusion

  • For autologous use only; administer after completing lymphodepleting chemotherapy
  • Dose based on the number of chimeric antigen receptor (CAR)-positive viable T cells
  • Target dose is 2x 106 CAR-positive viable T cells/kg body weight, not to exceed 2x 108 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

Acute Lymphoblastic Leukemia

Indicated for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)

One treatment course consists of fludarabine- and cyclophosphamide-lymphodepleting chemotherapy followed by IV infusion of brexucabtagene autoleucel

Confirm availability of brexucabtagene autoleucel before starting lymphodepleting chemotherapy

Lymphodepleting chemotherapy

  • Fludarabine 25 mg/m2 IV over 30 minutes on the fourth, third, and second day before infusion of brexucabtagene autoleucel
  • Cyclophosphamide 900 mg/m2 IV over 60 min on second day before infusion brexucabtagene autoleuce

Brexucabtagene autoleucel IV infusion

  • For autologous use only; administer after completing lymphodepleting chemotherapy
  • Dose based on the number of chimeric antigen receptor (CAR)-positive viable T cells
  • Target dose is 1x 106 CAR-positive viable T cells/kg body weight, not to exceed 1x 108 CAR-positive viable T cells

Dosage Modifications

Cytokine release syndrome (CRS) management

  • Grade 1
    • Symptoms: Fever, nausea, fatigue, headache, myalgia, malaise
    • If not improving after 24 hr, administer tocilizumab 8 mg/kg IV over 1 hr; not to exceed 800 mg
  • Grade 2
    • 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
    • If improving, discontinue tocilizumab
    • If no improvement after 24 hr of starting tocilizumab, administer methylprednisolone (1 mg/kg IV BID or dexamethasone 10 mg IV q6hr) until Grade 1, then taper corticosteroids
  • Grade 3
    • 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
    • Tocilizumab administration per Grade 2; if improving, discontinue
    • Corticosteroid dose as for Grade 2; taper if improving or manage as Grade 4 if not improving
  • Grade 4
    • Life-threatening symptoms; requires ventilator support, continuous venovenous hemodialysis, or Grade 4 organ toxicity (excluding transaminitis)
    • Tocilizumab administration per Grade 2; if improving, discontinue
    • Methylprednisolone 1000 mg IV qDay for 3 days; taper if improving or consider alternate immunosuppressants if not improving

Neurologic toxicity grading and management

Grades 2, 3, or 4: Consider nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis

  • Grade 1
    • Concurrent CRS: Administer tocilizumab as described for Grade 1 CRS
    • No concurrent CRS: Supportive care
  • 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
  • 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
    • If Grade 3 and not improving, manage as Grade 4 (ie, IV methylprednisolone)
  • 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
  • Grade 4 with concurrent CRS
    • Administer tocilizumab (see doses in CRS Grade 2)
    • Administer methylprednisolone 1000 mg/day IV 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 IV for 3 days; if improvement, then manage as above
    • If not improving, consider alternate immunosuppressants

Dosing Considerations

Administer at a certified healthcare facility

Monitor signs/symptoms of CRS and neurologic toxicities for at least daily for 14 days following infusion

Instruct patients to remain within proximity of the certified healthcare facility at least 4 weeks following infusion

Safety and efficacy not established

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Interactions

Interaction Checker

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    Contraindicated

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                  Minor (0)

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                    Adverse Effects

                    >10% (Any Grade)

                    MCL

                    • Pyrexia (94%)
                    • Cytokine release syndrome (91%)
                    • Hypotension (57%)
                    • Encephalopathy (51%)
                    • Fatigue (49%)
                    • Tachycardia (45%)
                    • Infection (43%)
                    • Chills (41%)
                    • Hypoxia (40%)
                    • Cough (38%)
                    • Tremor (38%)
                    • Musculoskeletal pain (37%)
                    • Edema (35%)
                    • Nausea (35%)
                    • Headache (35%)
                    • Constipation (29%)
                    • Diarrhea (28%)
                    • Decreased appetite (26%)
                    • Dyspnea (24%)
                    • Rash (22%)
                    • Pleural effusion (21%)
                    • Aphasia (20%)
                    • Viral infection (18%)
                    • Dizziness (18%)
                    • Renal insufficiency (18%)
                    • Hypertension (18%)
                    • Thrombosis (17%)
                    • Abdominal pain (17%)
                    • Pain (17%)
                    • Motor dysfunction (17%)
                    • Oral pain (16%)
                    • Hypogammaglobulinemia (16%)
                    • Anxiety (16%)
                    • Vomiting (13%)
                    • Bacterial infection (13%)
                    • Decreased urine output (11%)

                    ALL

                    • Fever (96%)
                    • Cytokine release syndrome (92%)
                    • Hypotension (69%)
                    • Tachycardias (63%)
                    • Encephalopathy (63%)
                    • Nausea (41%)
                    • Chills (40%)
                    • Headache (38%)
                    • Fatigue (37%)
                    • Febrile neutropenia (35%)
                    • Diarrhea (32%)
                    • Musculoskeletal pain (32%)
                    • Rash (31%)
                    • Hypoxia (31%)
                    • Edema (29%)
                    • Tremor (29%)
                    • Infection with pathogen unspecified (28%)
                    • Constipation (24%)
                    • Decreased appetite (22%)
                    • Vomiting (21%)
                    • Abdominal pain (19%)
                    • Delirium (18%)
                    • Coagulopathy (17%)
                    • Arrhythmia (15%)
                    • Bacterial infections (15%)
                    • Muscular weakness (14%)
                    • Pain (13%)
                    • Fungal infections (13%)
                    • Dizziness (13%)
                    • Hemorrhage (13%)
                    • Hypertension (13%)
                    • Insomnia (13%)
                    • Cough (12%)
                    • Dyspnea (12%)
                    • Anxiety (12%)

                    >10% (Grade ≥3)

                    MCL

                    • Leukopenia (95%)
                    • Neutropenia (95%)
                    • Lymphopenia (86%)
                    • Thrombocytopenia (63%)
                    • Anemia (55%)
                    • Hypophosphatemia (30%)
                    • Hypotension (27%)
                    • Infection (24%)
                    • Encephalopathy (24%)
                    • Hypocalcemia (21%)
                    • Hypoxia (20%)
                    • Cytokine release syndrome (18%)
                    • Increased blood uric acid (17%)
                    • Hyponatremia (16%)
                    • Increased AST/ALT (15%)
                    • Pyrexia (15%)
                    • Hypertension (11%)

                    ALL

                    • Fever (96%)
                    • Cytokine release syndrome (92%)
                    • Hypotension (69%)
                    • Tachycardias (63%)
                    • Encephalopathy (63%)
                    • Nausea (41%)
                    • Chills (40%)
                    • Headache (38%)
                    • Fatigue (37%)
                    • Febrile neutropenia (35%)
                    • Diarrhea (32%)
                    • Musculoskeletal pain (32%)
                    • Rash (31%)
                    • Hypoxia (31%)
                    • Edema (29%)
                    • Tremor (29%)
                    • Infection with pathogen unspecified (28%)
                    • Constipation (24%)
                    • Decreased appetite (22%)
                    • Vomiting (21%)
                    • Abdominal pain (19%)
                    • Delirium (18%)
                    • Coagulopathy (17%)
                    • Arrhythmia (15%)
                    • Bacterial infections (15%)
                    • Muscular weakness (14%)
                    • Pain (13%)
                    • Fungal infections (13%)
                    • Dizziness (13%)
                    • Hemorrhage (13%)
                    • Hypertension (13%)
                    • Insomnia (13%)
                    • Cough (12%)
                    • Dyspnea (12%)
                    • Anxiety (12%)

                    1-10% (All Grades)

                    MCL

                    • Coagulopathy (10%)
                    • Dysphagia (10%)
                    • Bradycardia (10%)
                    • Nonventricular arrhythmia (10%)
                    • Fungal infection (9%)
                    • Rash (9%)
                    • Dry mouth (7%)
                    • Ataxia (7%)
                    • Hemorrhage (7%)
                    • Dehydration (6%)
                    • Respiratory failure (6%)
                    • Seizure (5%)
                    • Pulmonary edema (4%)
                    • Increased ICP (2%)

                    1-10% (Grade ≥3)

                    MCL

                    • Hypokalemia (10%)
                    • Renal insufficiency (9%)
                    • Aphasia (7%)
                    • Dizziness (6%)
                    • Bacterial infection (6%)
                    • Dyspnea (6%)
                    • Diarrhea (5%)
                    • Delirium (5%)
                    • Pleural effusion (5%)
                    • Nonventricular arrhythmias (4%)
                    • Viral infection (4%)
                    • Motor dysfunction (4%)
                    • Rash (4%)
                    • Thrombosis (4%)
                    • Coagulopathy (2%)
                    • Dysphagia (2%)
                    • Edema (2%)
                    • Pain (2%)
                    • Musculoskeletal pain (2%)
                    • Tremor (2%)
                    • Neuropathy (2%)
                    • Nausea (1%)
                    • Fatigue (1%)
                    • Hypogammaglobulinemia (1%)
                    • Headache (1%)
                    • Urine output decreased (1%)

                    ALL

                    • Bacterial infections (8%)
                    • Tachycardias (6%)
                    • Hypertension (6%)
                    • Diarrhea (6%)
                    • Coagulopathy (5%)
                    • Edema (5%)
                    • Delirium (5%)
                    • Fungal infections (5%)
                    • Musculoskeletal pain (5%)
                    • Hemorrhage (4%)
                    • Vomiting (3%)
                    • Arrhythmia (1%)
                    • Nausea (1%)
                    • Fatigue (1%)
                    • Pain (1%)
                    • Decreased appetite (1%)
                    • Muscular weakness (1%)
                    • Headache (1%)
                    • Tremor (1%)
                    • Dizziness (1%)
                    • Dyspnea (1%)
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                    Warnings

                    Black Box Warnings

                    Cytokine release syndrome

                    • Cytokine release syndrome (CRS), including fatal or life-threatening reactions, reported in a majority of patients
                    • Do not administer to patients with active infection or inflammatory disorders
                    • Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids

                    Neurological toxicities

                    • Neurologic toxicities, including life-threatening reactions, reported; these may occur concurrently with CRS or after CRS resolution; monitor and provide supportive care and/or corticosteroids as needed
                    • The most common neurological toxicities were encephalopathy, headache, tremor, aphasia, and delirium
                    • Monitor for neurological events for at least 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities

                    Restricted access program

                    • Available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS program
                    • Further information is available at www.yescartatecartusrems.com or 1-844-454-KITE (5483)
                    • REMS requirements
                      • Healthcare facilities that dispense and administer brexucabtagene autoleucel 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 brexucabtagene autoleucel IV infusion, if needed for treatment of CRS
                      • Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer brexucabtagene autoleucel 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)

                    Available only through a restricted access program

                    Allergic reactions may occur during infusion; serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide or residual gentamicin in the product

                    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, 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 brexucabtagene autoleucel 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

                    Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), including life-threatening reactions reported; patients with HLH/MAS reported to have CRS symptoms and neurologic events after infusion; administer HLH/MAS treatment per institutional standards

                    Infection risk

                    • 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
                    • Life-threatening and fatal opportunistic infections reported in immunosuppressed patients; consider possibility of rare infectious etiologies (eg, fungal and viral infections such as HHV-6 and progressive multifocal leukoencephalopathy) in patients with neurologic events; perform appropriate diagnostic procedures
                    • 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, and HIV in accordance with clinical guidelines before collection of cells for manufacturing

                    Neurologic effects

                    • Neurological toxicities, which may be severe or life-threatening, can occur following treatment
                    • 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

                    • 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 brexucabtagene autoleucel treatment, and until immune recovery afterwards
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                    Pregnancy & Lactation

                    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, brexucabtagene autoleucel is not recommended during pregnancy, and pregnancy after infusion should be discussed with the treating physician

                    Verify pregnancy status of females with reproductive potential; 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

                    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.

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                    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: 7-15 days

                    Peak plasma concentration, median: 102.4 cells/mcL (responsive patients); 12 cells/mcL (nonresponsive [NR] patients)

                    AUC (0-28d): 1487 cells/mcL⋅days (responsive patients); 169.5 cells/mcL⋅days (NR patients)

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                    Administration

                    IV Preparation

                    Confirm infusion time in advance, and adjust start time for thawing CAR-T cells to be 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 infusion bag

                    Inspect 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 37ºC using either a water bath or dry thaw method until there is no visible ice in the infusion bag

                    Gently mix contents of bag to disperse small clumps of cellular material; if visible cell clumps remain, continue to gently mix contents of bag

                    Do not wash, spin down, or resuspend in new media before IV infusion

                    Once thawed, stored at room temperature (20-25ºC) 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

                    Premedicate with acetaminophen PO and diphenhydramine PO or IV (or other H1 antihistamine) ~30-60 minutes; avoid prophylactic systemic corticosteroids, except in case of life-threatening emergency

                    Central venous access 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 ≤-238ºF (≤-150ºC) 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 68-77ºF (20-25ºC) for up to 3 hr
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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Formulary

                    FormularyPatient Discounts

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                    The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                    Tier Description
                    1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                    2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                    3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                    4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    NC NOT COVERED – Drugs that are not covered by the plan.
                    Code Definition
                    PA Prior Authorization
                    Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                    QL Quantity Limits
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                    Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.