KYMRIAH: Package Insert and Label Information

KYMRIAH- tisagenlecleucel injection, suspension
Novartis Pharmaceuticals Corporation

WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids [see Dosage and Administration (2.3, 2.4), Warnings and Precautions (5.1)].

  • Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed [see Warnings and Precautions (5.2)].

  • KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS [see Warnings and Precautions (5.3)].

1 INDICATION S AND USAGE

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

1.1 Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)

Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

1.2 Adult Relapsed or Refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL)

Adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.

Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.

2 DOSAGE AND ADMINISTRATION

For autologous use only. For intravenous use only.

2.1 Dosage in Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)

KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells.

Based on the patient weight reported at the time of leukapheresis:

- Patients 50 kg or less: administer 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight

- Patients above 50 kg: administer 0.1 to 2.5 x 108 CAR-positive viable T cells

2.2 Dosage in Adult Relapsed or Refractory (r/r) Diffuse Large B-cell lymphoma (DLBCL)

KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells.

— For adult patients: administer 0.6 to 6.0 x 108 CAR-positive viable T cells

2.3 Administration

Preparing Patient for KYMRIAH Administration with Lymphodepletion

— Confirm availability of KYMRIAH prior to starting the lymphodepleting regimen.

Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)

  • Lymphodepleting chemotherapy: Fludarabine (30 mg/m2 intravenous daily for 4 days) and cyclophosphamide (500 mg/m2 intravenous daily for 2 days starting with the first dose of fludarabine). Infuse KYMRIAH 2 to 14 days after completion of the lymphodepleting chemotherapy.

Adult Relapsed or Refractory (r/r) Diffuse Large B-cell lymphoma (DLBCL)

• Lymphodepleting chemotherapy: Fludarabine (25 mg/m2 i.v. daily for 3 days) and cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine).

• Alternate lymphodepleting chemotherapy: bendamustine 90 mg/m2 i.v. daily for 2 days if a patient experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen.

• Infuse KYMRIAH 2 to 11 days after completion of the lymphodepleting chemotherapy.

• Lymphodepleting chemotherapy may be omitted if a patient’s white blood cell (WBC) count is less than or equal to 1 x 109 /L within 1 week prior to KYMRIAH infusion.

Preparation of KYMRIAH for Infusion and Administration

Delay the infusion of KYMRIAH if a patient has unresolved serious adverse reactions (including pulmonary reactions, cardiac reactions, or hypotension) from preceding chemotherapies, active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden following lymphodepleting chemotherapy [see Warnings and Precautions (5.1)].

A KYMRIAH dose may be contained in up to three cryopreserved patient specific infusion bags. Verify the number of bags received for the dose of KYMRIAH with the Certificate of Conformance (CoC) and Certificate of Analysis (CoA). Coordinate the timing of thaw of KYMRIAH and infusion in the following manner. Confirm the infusion time in advance, and adjust the start time for thaw so that KYMRIAH is available for infusion when the recipient is ready. If more than one bag has been received for the treatment dose, thaw 1 bag at a time. Wait to thaw/infuse the next bag until it is determined that the previous bag is safely administered.

Preparation of KYMRIAH for Infusion

1. Ensure tocilizumab and emergency equipment are available prior to infusion and during the recovery period.

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

3. Confirm patient identity: Prior to KYMRIAH preparation, match the patient’s identity with the patient identifiers on each KYMRIAH infusion bag(s). KYMRIAH is for autologous use only. Employ universal precautions to avoid potential transmission of infectious diseases when handling the product.

Note: The patient identifier number may be preceded by the letters DIN or Aph ID.

Figure 1. KYMRIAH Infusion Bag

Note: The patient identifier number may be preceded by the letters DIN or Aph ID. Figure 1. KYMRIAH Infusion Bag
(click image for full-size original)

4. Inspect the infusion bag(s) for any breaks or cracks prior to thawing. If a bag is compromised, do not infuse the contents. Call Novartis at 1-844-4KYMRIAH.

5. Place the infusion bag inside a second, sterile bag in case of a leak and to protect ports from contamination.

6. Thaw each infusion bag one at a time at 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Remove bag from thawing device immediately; do not store product bag at 37°C. Once the infusion bag has been thawed and is at room temperature (20°C to 25°C), it should be infused within 30 minutes. Do not wash, spin down, and/or resuspend KYMRIAH in new media prior to infusion.

7. Inspect the contents of the thawed infusion bag for any visible cell clumps. If visible cell clumps remain, gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not infuse KYMRIAH if clumps are not dispersed, the infusion bag is damaged or leaking, or otherwise appears to be compromised. Call Novartis at 1-844-4KYMRIAH.

Administration

8. Confirm the patient’s identity with the patient identifiers on the infusion bag.

9. Administer KYMRIAH as an intravenous infusion at 10 mL to 20 mL per minute, adjusted as appropriate for smaller children and smaller volumes. The volume in the infusion bag ranges from 10 mL to 50 mL. Do NOT use a leukocyte-depleting filter. If more than one bag is being infused for the treatment dose, wait to thaw/infuse the next bag until it is determined that the previous bag is safely administered.

— Prime the tubing prior to infusion with normal saline.

— Infuse all contents of the infusion bag.

— Rinse the infusion bag with 10 mL to 30 mL normal saline while maintaining a closed tubing system to assure as many cells as possible are infused into the patient.

— Cells from all the bag(s) must be infused to complete a single dose

KYMRIAH contains human cells genetically modified with a lentivirus. Follow local biosafety guidelines applicable for handling and disposal of such products.

Monitoring

— Administer KYMRIAH at a certified healthcare facility.

— Monitor patients 2-3 times during the first week following KYMRIAH infusion at the certified healthcare facility for signs and symptoms of CRS and neurologic toxicities [see Warnings and Precautions (5.1, 5.2)].

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

2.4 Management of Severe Adverse Reactions

Cytokine Release Syndrome

Identify cytokine release syndrome (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.

Table 1. Treatment of CRS
CRS Severity Management
Prodromal Syndrome: Low-grade fever, fatigue, anorexiaObserve in person; exclude infection; administer antibiotics per local guidelines if neutropenic; provide symptomatic support.
CRS requiring mild intervention (one or more of the following):- High fever- Hypoxia — Mild hypotensionAdminister antipyretics, oxygen, intravenous fluids and/or low-dose vasopressors as needed.
CRS requiring moderate to aggressive intervention (one or more of the following):- Hemodynamic instability despite intravenous fluids and vasopressor support — Worsening respiratory distress, including pulmonary infiltrates increasing oxygen requirement including high-flow oxygen and/or need for mechanical ventilation — Rapid clinical deterioration• Administer high dose or multiple vasopressors, oxygen, mechanical ventilation and/or other supportive care as needed.• Administer tocilizumab- Patient weight less than 30 kg: 12 mg/kg intravenously over 1 hour- Patient weight greater than or equal to 30 kg: 8 mg/kg intravenously over 1 hour (maximum dose 800 mg)

Repeat tocilizumab as needed at a minimum interval of 8 hours if there is no clinical improvement.

If no response to second dose of tocilizumab, consider a third dose of tocilizumab or pursue alternative measures for treatment of CRS.

Limit to a maximum total of 4 tocilizumab doses.

3 DOSAGE FORMS AND STRENGTHS

Pediatric and Y oung A dult r/r B- c ell ALL (up to 25 years of age) : A single dose of KYMRIAH contains 0.2 to 5.0 x 106 CAR-positive viable T cells per kg of body weight for patients 50 kg and below or 0.1 to 2.5 x 108 CAR-positive viable T cells for patients above 50 kg, suspended in a single patient-specific infusion bag [see How Supplied/Storage and Handling (16)].

Adult r/r DLBCL: A single dose of KYMRIAH contains 0.6 to 6.0 x 108 CAR-positive viable T cells, which may be suspended in one or more patient-specific infusion bag(s) [see How Supplied/Storage and Handling (16)].

See the CoA for actual cell count. The volume in the infusion bag ranges from 10 mL to 50 mL.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Cytokine Release Syndrome (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 54 (79%) of the 68 pediatric and young adult patients with r/r ALL and 78 (74%) of the 106 adult patients with r/r DLBCL receiving KYMRIAH, including ≥ Grade 3 (Penn grading system1) in 49% of patients with r/r ALL and in 23% of patients with r/r DLBCL. The median time to onset was 3 days (range: 1-51), and in only two patients was onset after Day 10. The median time to resolution of CRS was 8 days (range: 1-36).

Of the 54 patients with r/r ALL who had CRS, 27 (50%) received tocilizumab. Seven (13%) patients received two doses of tocilizumab, 3 (6%) patients received three doses of tocilizumab, and 14 (26%) patients received addition of corticosteroids (e.g., methylprednisolone). Of the 78 patients with r/r DLBCL who had CRS, 16 (21%) received systemic tocilizumab or corticosteroids. Six (8%) patients received a single dose of tocilizumab, 10 (13%) patients received two doses of tocilizumab, and 10 (13%) patients received corticosteroids in addition to tocilizumab. Two patients with r/r DLBCL received corticosteroids for CRS without concomitant tocilizumab, and two patients received corticosteroids for persistent neurotoxicity after resolution of CRS.

Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive leukemia, and one patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Of the 3 r/r DLBCL patients who died within 30 days of infusion, all had CRS in the setting of stable to progressive underlying disease, one of whom developed bowel necrosis. Among patients with CRS, key manifestations include fever (92% in r/r ALL and r/r DLBCL), hypotension (67% in r/r ALL; 47% in r/r DLBCL), hypoxia (20% in r/r ALL; 35% in r/r DLBCL) and tachycardia (30% in r/r ALL; 14% in r/r DLBCL). CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy.

Delay the infusion of KYMRIAH after lymphodepleting chemotherapy if the patient has unresolved serious adverse reactions from preceding chemotherapies (including pulmonary toxicity, cardiac toxicity, or hypotension), active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden [see Dosage and Administration (2.3)].

Ensure that two doses of tocilizumab are available on site prior to infusion of KYMRIAH. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with KYMRIAH. 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, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated [see Dosage and Administration (2.3, 2.4)].

Risk factors for severe CRS in the pediatric and young adult r/r B-cell ALL population are high pre-infusion tumor burden (greater than 50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes. Risk factors for developing severe CRS in adult r/r DLBCL are not known.

5.2 Neurological Toxicities

Neurological toxicities including severe or life-threatening reactions, occurred in 49 (72%) of the 68 patients with r/r ALL and 62 (58%) of the 106 patients with r/r DLBCL following treatment with KYMRIAH, including ≥ Grade 3 in 21% of patients with r/r ALL and 18% of patients with r/r DLBCL. Among patients who had a neurological toxicity, 88% occurred within 8 weeks following KYMRIAH infusion.

Median time to the first event was 6 days from infusion (range: 1-359), and the median duration was 6 days for patients with r/r ALL and 14 days for patients with r/r DLBCL. Resolution occurred within 3 weeks in 79% of patients with r/r ALL and 61% of patients with r/r DLBCL. Encephalopathy lasting up to 50 days was noted.

The onset of neurological toxicity can be concurrent with CRS, following resolution of CRS or in the absence of CRS.

The most common neurological toxicities observed with KYMRIAH include headache (37% in r/r ALL; 21% in r/r DLBCL), encephalopathy (34% in r/r ALL; 16% in r/r DLBCL), delirium (21% in r/r ALL; 6% in r/r DLBCL), anxiety (13% in r/r ALL; 9% in r/r DLBCL), sleep disorders (10% in r/r ALL; 9% in r/r DLBCL), dizziness (6% in r/r ALL; 11% in r/r DLBCL), tremor (9% in r/r ALL; 7% r/r DLBCL) and peripheral neuropathy (4% in r/r ALL; 8% in r/r DLBCL). Other manifestations included seizures, mutism and aphasia.

Monitor patients for neurological events and exclude other causes for neurological symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events.

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