TECARTUS: Package Insert and Label Information

TECARTUS- brexucabtagene autoleucel suspension
Kite Pharma, Inc.

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

  • Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred in patients receiving TECARTUS. Do not administer TECARTUS to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)] .
  • Neurologic toxicities, including life-threatening reactions, occurred in patients receiving TECARTUS, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with TECARTUS. Provide supportive care and/or corticosteroids, as needed [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.2)] .
  • TECARTUS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program [see Warnings and Precautions (5.3)] .

1 INDICATIONS AND USAGE

TECARTUS is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

1.1 Mantle Cell Lymphoma

Adult patients with relapsed or refractory mantle cell lymphoma (MCL).

This indication is approved under accelerated approval based on overall response rate and durability of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

1.2 Acute Lymphoblastic Leukemia

Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

2 DOSAGE AND ADMINISTRATION

For autologous use only. For intravenous use only.

Each single infusion bag of TECARTUS contains a suspension of chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL.

2.1 Dose

Recommended Dosage for MCL

The target dose is 2 × 106 CAR-positive viable T cells per kg body weight, with a maximum of 2 × 108 CAR-positive viable T cells.

Recommended Dosage for ALL

The target dose is 1 × 106 CAR-positive viable T cells per kg body weight, with a maximum of 1 × 108 CAR-positive viable T cells.

2.2 Administration

TECARTUS is for autologous use only. The patient’s identity must match the patient identifiers on the TECARTUS cassette and infusion bag. Do not infuse TECARTUS if the information on the patient-specific label does not match the intended patient.

Preparing Patient for TECARTUS Infusion

Confirm availability of TECARTUS prior to starting the lymphodepleting chemotherapy regimen.

Pre-treatment

  • MCL: Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously on each of the fifth, fourth, and third day before infusion of TECARTUS.
  • ALL: Administer a lymphodepleting chemotherapy regimen of fludarabine 25 mg/m2 intravenously over 30 minutes on the fourth, third, and second day and administer cyclophosphamide 900 mg/m2 over 60 minutes on the second day before infusion of TECARTUS.

Premedication

  • Premedicate with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to TECARTUS infusion.
  • Avoid prophylactic use of systemic corticosteroids as it may interfere with the activity of TECARTUS.

Preparation of TECARTUS for infusion

Coordinate the timing of TECARTUS thaw and infusion. Confirm the infusion time in advance, and adjust the start time of TECARTUS thaw such that TECARTUS will be available for infusion when the patient is ready.

  • Confirm patient identity: Prior to TECARTUS preparation, match the patient’s identity with the patient identifiers on the TECARTUS cassette.
  • Do not remove the TECARTUS infusion bag from the cassette if the patient information on the cassette label does not match the intended patient.
  • Once patient identity is confirmed, remove the TECARTUS infusion bag from the cassette and check that the patient information on the cassette label matches the patient information on the bag label.
  • Inspect the infusion 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 at 1-844-454-KITE).
  • Place the infusion bag inside a second sterile bag per local guidelines.
  • Thaw the infusion bag 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 TECARTUS in new media prior to infusion.
  • Once thawed, TECARTUS should be administered within 30 minutes but may be stored at room temperature (20°C to 25°C) for up to three hours.

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 administration of TECARTUS.
  • Confirm that the patient’s identity matches the patient identifiers on the TECARTUS infusion bag.
  • Prime the tubing with normal saline prior to infusion.
  • Infuse the entire contents of the TECARTUS bag within 30 minutes by either gravity or a peristaltic pump. TECARTUS is stable at room temperature for up to three hours after thaw.
  • Gently agitate the TECARTUS bag during infusion to prevent cell clumping.
  • After the entire contents of the TECARTUS bag are infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered.

TECARTUS contains human blood cells that are genetically modified with replication-incompetent retroviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal of TECARTUS to avoid potential transmission of infectious diseases.

Monitoring

  • Administer TECARTUS at a certified healthcare facility.
  • Monitor patients at the certified healthcare facility daily for at least seven days for patients with MCL and at least 14 days for patients with ALL following infusion for signs and symptoms of Cytokine Release Syndrome (CRS) and neurologic events.
  • Instruct patients to remain within proximity of the certified healthcare facility for at least four weeks following infusion.

2.3 Management of Severe Adverse Reactions

Cytokine Release Syndrome

Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1. Patients who experience Grade 2 or higher CRS (e.g., 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. For severe or life-threatening CRS, consider intensive care supportive therapy.

Table 1. CRS Grading and Management Guidance
CRS Grade * Tocilizumab Corticosteroids
*
Lee et al. 2014.
Refer to tocilizumab Prescribing Information for details.
Refer to Table 2 for management of neurologic toxicity.
Grade 1 Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise). If not improving after 24 hours, administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg). Not applicable.
Grade 2 Symptoms require and respond to moderate intervention.Oxygen requirement less than 40% FiO2 or hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity. Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses if no clinical improvement in the signs and symptoms of CRS.If improving, discontinue tocilizumab. Manage per Grade 3 if no improvement within 24 hours after starting tocilizumab.If improving, taper corticosteroids.
Grade 3 Symptoms require and respond to aggressive intervention.Oxygen requirement greater than or equal to 40% FiO2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis. Per Grade 2If improving, discontinue tocilizumab. Administer methylprednisolone 1 mg/kg intravenously twice daily or equivalent dexamethasone (e.g., 10 mg intravenously every 6 hours) until Grade 1, then taper corticosteroids.If improving, manage as Grade 2.If not improving, manage as Grade 4.
Grade 4 Life-threatening symptoms.Requirements for ventilator support or continuous veno-venous hemodialysis (CVVHD), or Grade 4 organ toxicity (excluding transaminitis). Per Grade 2If improving, discontinue tocilizumab. Administer methylprednisolone 1000 mg intravenously per day for 3 days.If improving, taper corticosteroids, and manage as Grade 3.If not improving, consider alternate immunosuppressants.

Neurologic Toxicity

Monitor patients for signs and symptoms of neurologic toxicities (Table 2). Rule out other causes of neurologic symptoms. Patients who experience Grade 2 or higher neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. Consider non-sedating anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis for any Grade 2 or higher neurologic toxicities.

Table 2. Neurologic Toxicity Grading and Management Guidance
Neurologic Event * Concurrent CRS No Concurrent CRS
Abbreviation: ADLs, activities of daily living.
*
Severity based on Common Terminology Criteria for Adverse Events.
Grade 1 Examples include:Somnolence – mild drowsiness or sleepinessConfusion – mild disorientationEncephalopathy – mild limiting of ADLsDysphasia – not impairing ability to communicate Administer tocilizumab per Table 1 for management of Grade 1 CRS. Supportive care.
Grade 2 Examples include:Somnolence – moderate limiting instrumental ADLsConfusion – moderate disorientationEncephalopathy – limiting instrumental ADLsDysphasia moderate impairing ability to communicate spontaneouslySeizure(s) Administer tocilizumab per Table 1 for management of Grade 2 CRS.If not improving within 24 hours after starting tocilizumab, administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less, then taper corticosteroids.If improving, discontinue tocilizumab.If still not improving, manage as Grade 3. Administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less.If improving, taper corticosteroids.
Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 3 Examples include:Somnolence – obtundation or stuporConfusion – severe disorientationEncephalopathy – limiting self-care ADLsDysphasia – severe receptive or expressive characteristics, impairing ability to read, write, or communicate intelligibly Administer tocilizumab per Table 1 for management of Grade 2 CRS.In addition, administer dexamethasone 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids.If improving, discontinue tocilizumab and manage as Grade 2.If still not improving, manage as Grade 4. Administer dexamethasone 10 mg intravenously every 6 hours.Continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids.If not improving, manage as Grade 4.
Consider non-sedating anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 4 Life-threatening consequencesUrgent intervention indicatedRequirement for mechanical ventilationConsider cerebral edema Administer tocilizumab per Table 1 for management of Grade 2 CRS.Administer methylprednisolone 1000 mg intravenously per day with first dose of tocilizumab and continue methylprednisolone 1000 mg intravenously per day for 2 more days.If improving, then manage as Grade 3.If not improving, consider alternate immunosuppressants. Administer methylprednisolone 1000 mg intravenously per day for 3 days.If improving, then manage as Grade 3.If not improving, consider alternate immunosuppressants.
Consider non-sedating anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

3 DOSAGE FORMS AND STRENGTHS

TECARTUS is available as a cell suspension for infusion.

  • MCL: A single dose of TECARTUS contains 2 × 106 CAR-positive viable T cells per kg of body weight [maximum of 2 × 108 CAR-positive viable T cells (for patients 100 kg and above)] in approximately 68 mL suspension in an infusion bag [see How Supplied/Storage and Handling (16)].
  • ALL: A single dose of TECARTUS contains 1 × 106 CAR-positive viable T cells per kg of body weight [maximum of 1 × 108 CAR-positive viable T cells (for patients 100 kg and above)] in approximately 68 mL suspension in an infusion bag [see How Supplied/Storage and Handling (16)].

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Cytokine Release Syndrome

CRS, including fatal or life-threatening reactions, occurred following treatment with TECARTUS. CRS occurred in 91% (75/82) of patients with MCL, including ≥ Grade 3 (Lee grading system1) CRS in 18% of patients. Among the patients with MCL who died after receiving TECARTUS, one patient had a fatal CRS event. The median time to onset of CRS was three days (range: 1 to 13 days) and the median duration of CRS was ten days (range: 1 to 50 days) for patients with MCL. CRS occurred in 92% (72/78) of patients with ALL, including ≥ Grade 3 (Lee grading system1) CRS in 26% of patients. Three patients with ALL had ongoing CRS events at the time of death. The median time to onset of CRS was five days (range: 1 to 12 days) and the median duration of CRS was eight days (range: 2 to 63 days) for patients with ALL.

The incidence of CRS (first occurrence) within the first seven days after TECARTUS infusion was 83% (68/82) in patients with MCL and 90% (70/78) in patients with ALL. In all patients combined (MCL/ALL), the incidence of first CRS (first occurrence) within the first seven days after TECARTUS infusion was 86% (138/160).

Among patients with CRS, the key manifestations (>10%) were similar in MCL and ALL and included fever (93%), hypotension (62%), tachycardia (59%), chills (32%), hypoxia (31%), headache (21%), fatigue (20%), and nausea (13%). Serious events associated with CRS in MCL and ALL combined (≥ 2%) included hypotension, fever, hypoxia, tachycardia, and dyspnea [see Adverse Reactions (6)].

Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of TECARTUS. Monitor patients daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for four weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)]. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated [see Dosage and Administration (2.3)].

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