YESCARTA: Package Insert and Label Information

YESCARTA- axicabtagene ciloleucel suspension
Kite Pharma, Inc.

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA 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 fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.2)].
  • YESCARTA 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

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

1.1 Large B-cell Lymphoma

Adult patients with relapsed or refractory large B-cell lymphoma after two or more 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.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

1.2 Follicular Lymphoma

Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION

For autologous use only. For intravenous use only.

2.1 Dose

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

2.2 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.

Preparing Patient for YESCARTA Infusion

Confirm availability of YESCARTA prior to starting the lymphodepleting regimen.

Pre-treatment

  • Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously on the fifth, fourth, and third day before infusion of YESCARTA.

Premedication

  • Administer acetaminophen 650 mg PO and diphenhydramine 12.5 mg intravenously or PO 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 patient identity: Prior to YESCARTA preparation, match the patient’s identity with 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.
  • Once patient identification 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 at 1-844-454-KITE).
  • Place the infusion bag inside a second sterile bag 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.
  • Once thawed, YESCARTA may be stored at room temperature (20°C to 25°C) for up to 3 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 infusion of YESCARTA.
  • Confirm the patient’s identity matches the patient identifiers on the YESCARTA product bag.
  • Prime the tubing with normal saline prior to infusion.
  • Infuse the entire contents of the YESCARTA bag within 30 minutes by either gravity or a peristaltic pump. YESCARTA is stable at room temperature for up to 3 hours after thaw.
  • Gently agitate the product bag during YESCARTA infusion to prevent cell clumping.
  • After the entire content of the product bag is infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered.

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

Monitoring

  • Administer YESCARTA at a certified healthcare facility.
  • Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS and neurologic toxicities.
  • Instruct patients to remain within proximity of the certified healthcare facility for at least 4 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 Table 2 for management of neurologic toxicity.
Refer to tocilizumab Prescribing Information for details.
§
Alternate therapy includes (but is not limited to): anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG.
Grade 1 Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise). If symptoms (e.g., fever) not improving after 24 hours, consider managing as Grade 2. If not improving after 3 days, administer one dose of dexamethasone 10 mg intravenously.
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 orGrade 2 organ toxicity. Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).If no clinical improvement in the signs and symptoms of CRS after the first dose, repeat tocilizumab every 8 hours as needed.Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses.If improving, discontinue tocilizumab. Administer dexamethasone 10 mg intravenously once daily.If improving, manage as Grade 1 above and continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.If not improving, manage as appropriate grade below.
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 orGrade 3 organ toxicity or Grade 4 transaminitis. Per Grade 2.If improving, manage as appropriate grade above. Dexamethasone 10 mg intravenously three times a day. If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.If not improving, manage as Grade 4.
Grade 4 Life-threatening symptoms.Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD) orGrade 4 organ toxicity (excluding transaminitis). Per Grade 2.If improving, manage as appropriate grade above. Administer methylprednisolone 1000 mg intravenously once per day for 3 days.If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.If not improving, consider methylprednisolone 1000 mg 2-3 times a day or alternate therapy.§

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 levetiracetam for seizure prophylaxis for any grade of neurologic toxicities.

Table 2. Neurologic Toxicity Grading and Management Guidance
Grading Assessment * Concurrent CRS No Concurrent CRS
*
Severity based on Common Terminology Criteria for Adverse Events.
Alternate therapy includes (but is not limited to): anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG.
Grade 1 Administer tocilizumab per Table 1 for management of Grade 1 CRS.In addition, administer one dose of dexamethasone 10 mg intravenously.If not improving after 2 days, repeat dexamethasone 10 mg intravenously. Administer one dose of dexamethasone 10 mg intravenously.If not improving after 2 days, repeat dexamethasone 10 mg intravenously.
Consider levetiracetam for seizure prophylaxis.
Grade 2 Administer tocilizumab per Table 1 for management of Grade 2 CRS.In addition, administer dexamethasone 10 mg intravenously four times a day. If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.If not improving, manage as appropriate grade below. Administer dexamethasone 10 mg intravenously four times a day.If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate.If not improving, manage as appropriate grade below.
Consider levetiracetam for seizure prophylaxis.
Grade 3 Administer tocilizumab per Table 1 for management of Grade 2 CRS. In addition, administer methylprednisolone 1000 mg intravenously once daily. If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.If not improving, manage as Grade 4. Administer methylprednisolone 1000 mg intravenously once daily. If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.If not improving, manage as Grade 4.
Consider levetiracetam for seizure prophylaxis.
Grade 4 Administer tocilizumab per Table 1 for management of Grade 2 CRS. In addition, administer methylprednisolone 1000 mg intravenously twice per day.If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.If not improving, consider 1000 mg of methylprednisolone intravenously 3 times a day or alternate therapy. Administer methylprednisolone 1000 mg intravenously twice per day.If improving, manage as appropriate grade above and continue corticosteroids until the severity is Grade 1 or less, then taper as clinically appropriate.If not improving, consider 1000 mg of methylprednisolone intravenously 3 times a day or alternate therapy.
Consider levetiracetam for seizure prophylaxis.

3 DOSAGE FORMS AND STRENGTHS

YESCARTA is available as a cell suspension for infusion.

A single dose of YESCARTA contains 2 × 106 CAR-positive viable T cells per kg of body weight (or 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)].

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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