tisagenlecleucel (Rx)

Brand and Other Names:Kymriah
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

injection, suspension

  • Single-dose units contain specific amounts of T-cell depending on the patient’s body weight that are suspended in a patient-specific infusion bag
  • ≤50 kg: 0.2-5 x 10^6 CAR-positive viable T cells/kg
  • >50 kg: 0.1-2.5 x 10^8 CAR-positive viable T cells/kg
  • See the certificate of analysis (CoA) for actual cell count following individual preparation

Acute Lymphoblastic Leukemia

CD19-directed genetically modified autologous T-cell immunotherapy indicated for patients aged 25 years or younger with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse

One treatment course consists of fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by IV infusion of tisagenlecleucel

Lymphodepleting chemotherapy

  • Fludarabine 30 mg/m² IV qDay for 4 days
  • Cyclophosphamide 500 mg/m² IV qDay for 2 days starting with the first dose of fludarabine

Premedication

  • Premedicate with acetaminophen and diphenhydramine or another H1-antihistamine ~30-60 minutes before tisagenlecleucel infusion
  • Do not use corticosteroids at any time except in the case of a life-threatening emergency

Tisagenlecleucel IV infusion

  • Administer 2-14 days after completing lymphodepleting chemotherapy
  • ≤50 kg: 0.2-5 x 10^6 CAR-positive viable T cells/kg
  • >50 kg: 0.1-2.5 x 10^8 CAR-positive viable T cells/kg
  • Infuse autologously prepared, weight-based IV for individual patient at 10-20 mL/min
  • Do not use a leukocyte-depleting filter
  • Adjust infusion rate as appropriate for smaller children and smaller volumes
  • Also see Administration

Dosage Modifications

Cytokine release syndrome (CRS) management

  • Prodromal syndrome
    • Symptoms: Low-grade fever, fatigue, anorexia
    • Observe in person; exclude infection; administer antibiotics per local guidelines if neutropenic; provide symptomatic support
  • Overt CRS
    • 1 or more symptoms of the following: High fever, hypoxia, mild hypotension
    • Administer antipyretics, oxygen, IV fluids, and/or low-dose vasopressors as needed
  • Severe or life-threatening CRS
    • 1 or more symptoms of the following: Hemodynamic instability despite IV fluids and vasopressor support, and/or worsening respiratory distress (including pulmonary infiltrates, increasing oxygen requirement including high-flow oxygen, and/or need for mechanical ventilation), and/or rapid clinical deterioration
    • Administer high-dose or multiple vasopressors, oxygen, mechanical ventilation, and/or other supportive care as needed
    • Administer tocilizumab, weight <30 kg: 12 mg/kg IV infused over 1 hr
    • Administer tocilizumab, weight ≥30 kg: 8 mg/kg IV infused over 1 hr; not to exceed 800 mg/dose
  • Resistant CRS
    • Symptoms: No clinical improvement in 12-18 hr, or worsening at any time, despite prior management
    • Administer multiple vasopressors, oxygen, mechanical ventilation, and/or other supportive care as needed
    • Administer methylprednisolone 2 mg/kg IV initially, then 2 mg/kg/day until vasopressors and high-flow oxygen are no longer needed, then taper quickly
    • If no response to steroids within 24 hr, repeat administration of tocilizumab (see above dose)
    • If no response to the second dose of tocilizumab within 24 hr, consider a third dose of tocilizumab or pursue alternative measures for treatment of CRS

Dosing Considerations

For autologous use only

Dosage Forms & Strengths

injection, suspension

  • CD19-directed genetically modified autologous T-cell immunotherapy indicated for patients aged 25 years or younger with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse
  • Single-dose units contain specific amounts of T-cell depending on the patient’s body weight that are suspended in a patient-specific infusion bag
  • ≤50 kg: 0.2-5 x 10^6 CAR-positive viable T cells/kg
  • >50 kg: 0.1-2.5 x 10^8 CAR-positive viable T cells/kg
  • See the certificate of analysis (CoA) for actual cell count following individual preparation

Acute Lymphoblastic Leukemia

One treatment course consists of fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by IV infusion of tisagenlecleucel

Lymphodepleting chemotherapy

  • Fludarabine 30 mg/m² IV qDay for 4 days
  • Cyclophosphamide 500 mg/m² IV qDay for 2 days starting with the first dose of fludarabine

Premedication

  • Premedicate with acetaminophen and diphenhydramine or another H1-antihistamine ~30-60 minutes before tisagenlecleucel infusion
  • Do not use corticosteroids at any time except in the case of a life-threatening emergency

Tisagenlecleucel IV infusion

  • Administer 2-14 days after completing lymphodepleting chemotherapy
  • ≤50 kg: 0.2-5 x 10^6 CAR-positive viable T cells/kg
  • >50 kg: 0.1-2.5 x 10^8 CAR-positive viable T cells/kg
  • Infuse autologously prepared, weight-based IV for individual patient at 10-20 mL/min
  • Do not use a leukocyte-depleting filter
  • Adjust infusion rate as appropriate for smaller children and smaller volumes
  • Also see Administration

Dosage Modifications

Cytokine release syndrome (CRS) management

  • Prodromal syndrome
    • Symptoms: Low-grade fever, fatigue, anorexia
    • Observe in person; exclude infection; administer antibiotics per local guidelines if neutropenic; provide symptomatic support
  • Overt CRS
    • 1 or more symptoms of the following: High fever, hypoxia, mild hypotension
    • Administer antipyretics, oxygen, IV fluids, and/or low-dose vasopressors as needed
  • Severe or life-threatening CRS
    • 1 or more symptoms of the following: Hemodynamic instability despite IV fluids and vasopressor support, and/or worsening respiratory distress (including pulmonary infiltrates, increasing oxygen requirement including high-flow oxygen, and/or need for mechanical ventilation), and/or rapid clinical deterioration
    • Administer high-dose or multiple vasopressors, oxygen, mechanical ventilation, and/or other supportive care as needed
    • Administer tocilizumab, weight <30 kg: 12 mg/kg IV infused over 1 hr
    • Administer tocilizumab, weight ≥30 kg: 8 mg/kg IV infused over 1 hr; not to exceed 800 mg/dose
  • Resistant CRS
    • Symptoms: No clinical improvement in 12-18 hr, or worsening at any time, despite prior management
    • Administer multiple vasopressors, oxygen, mechanical ventilation, and/or other supportive care as needed
    • Administer methylprednisolone 2 mg/kg IV initially, then 2 mg/kg/day until vasopressors and high-flow oxygen are no longer needed, then taper quickly
    • If no response to steroids within 24 hr, repeat administration of tocilizumab (see above dose)
    • If no response to the second dose of tocilizumab within 24 hr, consider a third dose of tocilizumab or pursue alternative measures for treatment of CRS

Dosing Considerations

For autologous use only

Not indicated for patients aged >25 years

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Interactions

Interaction Checker

and tisagenlecleucel

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            Percentages include all grades unless otherwise noted

            >10%

            Cytokine release syndrome (79%)

            Cytokine release syndrome, grades 3-4 (49%)

            Hypogammaglobulinemia (43%)

            Infection, unspecified pathogen (41%)

            Pyrexia (40%)

            Prolonged neutropenia, Day 28 (40%)

            Decreased appetite (37%)

            Headache (37%)

            Encephalopathy (34%)

            Hypotension (31%)

            Increased AST, grades 3-4 (28%)

            Hypokalemia, grades 3-4 (27%)

            Prolonged thrombocytopenia, Day 28 (27%)

            Viral infection (26%)

            Tachycardia (26%)

            Nausea (26%)

            Diarrhea (26%)

            Vomiting (26%)

            Hypoxia (24%)

            Fatigue (22%)

            Acute kidney injury (22%)

            Hypotension, grades 3-4 (22%)

            Increased ALT, grades 3-4 (21%)

            Increased bilirubin, grades 3-4 (21%)

            Delirium (21%)

            Hypophosphatemia, grades 3-4 (19%)

            Hypertension (19%)

            Bacterial infection (19%)

            Cough (19%)

            Constipation (18%)

            Viral infection, grades 3-4 (18%)

            Hypoxia, grades 3-4 (18%)

            Prolonged neutropenia, Day 56 (17%)

            Infection, unspecified pathogen, grades 3-4 (16%)

            Hypofibrinogenemia with grades 3-4 CRS (16%)

            Abdominal pain (16%)

            Pain in extremity (16%)

            Pulmonary edema (16%)

            Decreased appetite, grades 3-4 (15%)

            Pyrexia, grades 3-4 (15%)

            Myalgia (15%)

            Fungal infection (13%)

            Anxiety (13%)

            Bacterial infection, grades 3-4 (13%)

            Acute kidney injury, grades 3-4 (13%)

            Prolonged thrombocytopenia, Day 56 (12%)

            Arthralgia (12%)

            Tachypnea (12%)

            1-10%

            Face edema (10%)

            Peripheral edema (10%)

            Chills (10%)

            Fluid overload (10%)

            Back pain (10%)

            Pleural effusion (10%)

            Nasal congestion (10%)

            Pulmonary edema, grades 3-4 (10%)

            Encephalopathy, grades 3-4 (10%)

            Fungal infection, grades 3-4 (7%)

            Blood and lymphatic system disorders: DIC (9%), histiocytosis lymphocytic hemophagocytosis (7%), coagulopathy (6%)

            Investigations: Blood creatinine increased (7%), aPTT prolonged (6%)

            Respiratory, thoracic, and mediastinal disorders: Respiratory distress (6%), respiratory failure (6%), acute RDS (4%)

            Cardiac disorders: Cardiac arrest (4%), cardiac failure (7%)

            Metabolism and nutrition disorders: Tumor lysis syndrome (6%)

            Vascular disorders: Capillary leak syndrome (3%)

            General disorders and administration site conditions: Multiple organ dysfunction syndrome (3%)

            Nervous System: Intracranial hemorrhage (1%), seizure (3%)

            Gastrointestinal disorders: Abdominal compartment syndrome (1%)

            Immune system disorders: GVHD (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 (see Adverse Effects)
            • Median time to CRS onset was 3 days (range: 1-22 days)
            • Key manifestations of CRS include high fever, lower than normal blood pressure, and difficulty breathing, and may be associated with hepatic, renal, and cardiac dysfunction and coagulopathy
            • Risk factors for severe CRS are high preinfusion tumor burden (>50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes
            • Do not administer to patients with active infection or inflammatory disorders
            • Delay tisagenlecleucel administration after lymphodepleting chemotherapy if 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
            • Treat severe or life-threatening CRS with tocilizumab
              • Ensure that tocilizumab is available on site prior to tisagenlecleucel administration
              • Monitor for CRS signs or symptoms for at least 4 weeks after treatment
              • 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 headache, encephalopathy, delirium, anxiety, and tremor (also see Adverse Effects)
            • Other manifestations of neurological toxicities included disturbances in consciousness, disorientation, confusion, agitation, seizures, mutism, and aphasia
            • 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 KYMRIAH REMS
            • Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH
            • REMS requirements
              • Healthcare facilities that dispense and administer tisagenlecleucel 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 tisagenlecleucel IV infusion, if needed for treatment of CRS
              • Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer tisagenlecleucel 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 dextran 40 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 tisagenlecleucel; prolonged neutropenia has been associated with increased risk of infection; myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after tisagenlecleucel infusion or until CRS has resolved

            Hypogammaglobulinemia and agammaglobulinemia (IgG) can occur in patients with a complete remission (CR); monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines

            Secondary malignancies or recurrence of leukemia may occur; 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

            HIV and the lentivirus used to make tisagenlecleucel have limited, short spans of identical genetic material (RNA); therefore, some commercial HIV nucleic acid test (NAT) tests may yield false-positive results in patients who have received tisagenlecleucel

            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 2 weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel treatment, and until immune recovery afterwards
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            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

            Pregnant women who have received tisagenlecleucel may have hypogammaglobulinemia; assess immunoglobulin levels in newborns of treated mothers

            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 tisagenlecleucel

            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.

            more...
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            Pharmacology

            Mechanism of Action

            CD19-directed genetically modified autologous T-cell immunotherapy that involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells

            CAR is composed of a murine single-chain antibody fragment that recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta

            CD3 zeta component is critical for initiating T-cell activation and antitumor activity, while 4-1BB enhances expansion and persistence of tisagenlecleucel

            CAR transmits a signal to promote T-cell expansion owing to binding of CD19 expressed cells, activation, target cell elimination, and persistence of tisagenlecleucel cells

            Absorption

            Peak plasma concentration: 34,700 copies/mcg (responsive patients); 20,000 copies/mcg (nonresponsive [NR] patients)

            Peak plasma time: 9.91 days (responsive patients); 20 days (NR patients)

            AUC: 318,000 copies/mcg·day (responsive patients); 156,000 (NR patients)

            Peak plasma concentration and AUC were ~2-fold higher in CR/CRi patients compared with NR patients

            Distribution

            Tisagenlecleucel was present in blood as well as bone marrow and was measurable beyond 2 yr

            Blood to bone marrow partitioning suggested that tisagenlecleucel distribution in bone marrow was 44% of that present in blood at day 28, while at months 3 and 6 tisagenlecleucel distributed at 67% and 69%, respectively, indicating high distribution to bone marrow

            Elimination

            Half-life: 16.8 days (responsive patients); 2.52 days (NR patients)

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            Administration

            IV Preparation

            Confirm infusion time in advance, and adjust start time for thaw so that tisagenlecleucel is available for infusion when recipient is ready

            Ensure tocilizumab and emergency equipment are available prior to infusion and during the recovery period; premedicate patient; see Dosing

            Confirm patient identity prior to preparation, match the patient's identity with the patient identifiers on the tisagenlecleucel infusion bag; tisagenlecleucel 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 Novartis at 1-844-4KYMRIAH

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

            Remove bag from thawing device immediately; do not store product bag at 37°C

            Once thawed, stored at room temperature (20-25°C) for up to 30 minutes

            Do not wash, spin down, and/or resuspend tisagenlecleucel in new media prior to infusion; inspect contents of the thawed infusion bag for any visible cell clump; 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 tisagenlecleucel if clumps are not dispersed, the infusion bag is damaged or leaking, or otherwise appears to be compromised; if this occurs, contact Novartis at 1-844-4KYMRIAH

            IV Administration

            Administer IV infusion at 10-20 mL/min, adjusted as appropriate for smaller children and smaller volume

            Infusion bag volume ranges from 10-50 mL

            Do not use a leukocyte-depleting filter; prime tubing prior to infusion with 0.9% NaCl

            Infuse all contents of the infusion bag; rinse infusion bag with 10-30 mL 0.9% NaCl while maintaining a closed tubing system to assure as many cells as possible are infused into the patient

            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 ≤-148°F (≤-120°C) in a temperature-monitored system
            • 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 30 minutes
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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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            OR Other Restrictions
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