inotuzumab (Rx)

Brand and Other Names:Besponsa
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 0.9mg/vial

Acute Lymphoblastic Leukemia

Indicated for relapsed/refractory B-cell precursor acute lymphoblastic leukemia

See Dosing Considerations

Cycle 1 for all patients

  • Total dose of inotuzumab: 1.8 mg/m² per 21-day cycle, administered as 3 divided doses
  • Day 1: 0.8 mg/m²
  • Day 8 and 15: 0.5 mg/m²
  • Duration of cycle 1 is 21 days; may extend to 28 days (eg, 7-day treatment-free interval starting on day 21) if patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity
  • CR is defined as < 5% blasts in bone marrow and absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (platelets ≥ 100 × 10^9/L and absolute neutrophil counts [ANC] ≥ 1 × 10^9/L) and resolution of any extramedullary disease
  • CRi is defined as < 5% blasts in bone marrow and absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts (platelets < 100 × 10^9/L and/or ANC < 1 × 10^9/L) and resolution of any extramedullary disease

Patients who achieve a CR or CRi

  • Total dose of inotuzumab is 1.5 mg/m² per 28-day cycle, including a 7-day treatment-free interval starting on day 21, administered as 3 divided doses
  • Day 1, 8, and 15: 0.5 mg/m² IV

Patients who do not achieve a CR or CRi

  • Total dose of inotuzumab is 1.8 mg/m² per 28-day cycle, including a 7-day treatment-free interval starting on day 21 administered as 3 divided doses
  • Day 1: 0.8 mg/m² IV
  • Day 8 and 15: 0.5 mg/m² IV
  • Patients who do not achieve a CR or CRi ≤3 cycles should discontinue treatment

Dosage Modifications

Renal impairment

  • Mild to moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
  • End-stage renal disease (CrCl <30 mL/min) and/or hemodialysis: Safety and efficacy is not established

Hepatic impairment

  • Total bilirubin (≤1.5x ULN) and AST/ALT (≤2.5x ULN): No dosage adjustment necessary
  • Total bilirubin >1.5x ULN and/or AST/ALT >2.5x ULN: Limited safety information; caution with use

Doses within a treatment cycle (eg, Days 8 and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia but interruptions within a cycle are recommended for non-hematologic toxicities; if dose is reduced due to drug related toxicity, it must not be re-escalated

Hematologic toxicities

  • Baseline absolute neutrophil count (ANC) ≥1 × 10^9/L: If ANC decreases, then interrupt next cycle until ANC ≥1 × 10^9/L; discontinue inotuzumab if low ANC persists for >28 days and is considered an inotuzumab-related toxicity
  • Baseline platelet count >50 × 10^9; /L: If platelet count decreases, then interrupt next cycle if platelet count was ≥50 × 10^9 /L; discontinue inotuzumab if low platelet count persists >28 days and is considered an inotuzumab-related toxicity
  • Baseline ANC>1 × 10^9 /L and/or platelet count <50 × 10^9 /L
    • If ANC or platelet count decreases, then interrupt next cycle of treatment until at least one of following occurs:
    • ANC and platelet count recover to at least baseline levels for prior cycle
    • ANC recovers ≥1 × 10^9 /L and platelet count ≥50 × 10^9 /L
    • Stable/improved disease (based on most recent bone marrow assessment) and ANC and platelet count decrease is correlated to the underlying disease (not considered to be inotuzumab-related toxicity)

Nonhematologic toxicities

  • Venoocclusive disease (VOD) or other severe liver disease: Permanently discontinue
  • Nonhematologic toxicity grade 2 or higher: Interrupt treatment until recovery to
  • Total bilirubin >1.5x ULN and AST/ALT >2.5x ULN
    • Interrupt dosing until recovery of total bilirubin ≤1.5x ULN and AST/ALT ≤2.5x ULN prior to each dose unless due to Gilbert syndrome or hemolysis
    • Permanently discontinue treatment if total bilirubin does not recover ≤1.5x ULN or AST/ALT ≤2.5x ULN
  • Infusion-related reactions
    • Interrupt infusion and institute appropriate medical management; depending on severity of infusion-related reaction, consider discontinuation of infusion or administration of steroids and antihistamines
    • Severe or life-threatening infusion reactions: Permanently discontinue treatment
  • Dose modifications depending on dosing interruption
    • <7 days (within a cycle): Interrupt next dose (maintain a minimum of 6 days between doses)
    • ≥7 days: Omit next dose within current cycle
    • ≥14 days: Once adequate recovery is achieved, decrease total dose by 25% for subsequent cycle; if further dose modifications are required, decrease number of doses to 2 per cycle for subsequent cycles; if dosing modifications are not tolerated, then permanently discontinue treatment

Dosing Considerations

Premedication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing

Observe patient during and for at least 1 hr post infusion for infusion-related signs/symptoms

Prior to initial dose, in patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine is recommended to achieve a peripheral blast count ≤10,000/mm³

Patients proceeding to hematopoietic stem cell transplantation (HSCT): Duration of inotuzumab treatment is 2 cycles; patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles may consider a third cycle

Patients not proceeding to HSCT: Additional cycles may be administered; not to exceed 6 cycles

Safety and efficacy not established

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Interactions

Interaction Checker

and inotuzumab

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Thrombocytopenia (51%)

            Neutropenia (49%)

            Infection (48%)

            Neutropenia, grade 3 or higher (48%)

            Thrombocytopenia, grade 3 or higher (42%)

            Anemia (36%)

            Leukopenia (35%)

            Fatigue (35%)

            Hemorrhage (33%)

            Leukopenia, grade 3 or higher (33%)

            Pyrexia (32%)

            Nausea (31%)

            Headache (28%)

            Infection, grade 3 or higher (28%)

            Febrile neutropenia (26%)

            Transaminases increased (26%)

            Anemia, grade 3 or higher (24%)

            Abdominal pain (23%)

            Hyperbilirubinemia (21%)

            Gamma-glutamyltransferase increased (21%)

            Lymphopenia (18%)

            Diarrhea (17%)

            Constipation (16%)

            Lymphopenia, grade 3 or higher (16%)

            Vomiting (15%)

            Stomatitis (13%)

            Alkaline phosphatase increased (13%)

            Decreased appetite (12%)

            Chills (11%)

            1-10%

            Grade 3 or higher

            • Gamma-glutamyltransferase increased (10%)
            • Transaminases increased (7%)
            • Hemorrhage (5%)
            • Fatigue (5%)
            • Hyperbilirubinemia (5%)
            • Pyrexia (3%)
            • Abdominal pain (3%)
            • Headache (2%)
            • Alkaline phosphatase increased (2%)
            • Stomatitis (2%)
            • Nausea (2%)
            • Decreased appetite (1%)
            • Vomiting (1%)
            • Diarrhea (1%)
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            Warnings

            Black Box Warnings

            Hepatoxicity, including VOD

            • Hepatotoxicity, including fatal and life-threatening VOD (also known as sinusoidal obstruction syndrome) reported with relapsed or refractory acute lymphoblastic leukemia (ALL) who received inotuzumab
            • Risk of VOD was greater in patients who underwent HSCT after inotuzumab treatment; use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin level ≥ULN before HSCT were significantly associated with an increased risk of VOD
            • Other risk factors include ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of inotuzumab treatment cycles
            • Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of inotuzumab; permanently discontinue treatment if VOD occurs
            • If severe VOD occurs, treat according to standard medical practice

            Increased risk of post-HSCT nonrelapse mortality

            • Reports of higher post-HSCT nonrelapse mortality rate in patients receiving inotuzumab, resulting in a higher Day 100 post-HSCT mortality rate
            • In a clinical trial, the post-HSCT nonrelapse mortality rate was 31/79 (39%) and 8/35 (23%) in inotuzumab arm compared with the investigator’s choice of chemotherapy arm
            • In inotuzumab arm, the most common causes of post-HSCT nonrelapse mortality included VOD and infections
            • Monitor toxicities post-HSCT, including signs and symptoms of infection and VOD

            Contraindications

            None

            Cautions

            Hepatotoxicity, including VOD, reported; monitor closely for signs and symptoms of VOD (eg, increased total bilirubin, hepatomegaly, rapid weight gain, ascites) (see Black Box Warnings)

            Increase risk of posttransplant nonrelapse mortality (see Black Box Warnings)

            QT prolongation reported; caution with history of or predisposition to QT prolongation, currently taking medications known to prolong QT interval, or electrolyte disturbances; obtain baseline ECG and electrolytes levels; monitor periodically during treatment

            In animal studies, embryofetal harm may occur when administered to a pregnant woman (see Pregnancy)

            Myelosuppression

            • Risk of myelosuppression; complications, including infections and bleeding/hemorrhagic events, observed; monitor complete blood cell counts prior to initiating; monitor for signs/symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment; if necessary, administer prophylactic anti-infectives and use surveillance testing during and after treatment
            • Management of severe infection, bleeding/hemorrhage, or other effects of myelosuppression, including severe neutropenia or thrombocytopenia, may require dosing interruption, dose reduction, or permanent discontinuation

            Infusion-related reactions

            • Infusion-related reactions may occur; premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing
            • Monitor closely during and for at least 1 hr after the end of infusion for potential onset of infusion-related reactions (eg, fever, chills, rash, or breathing problems); interrupt infusion and institute appropriate medical management if an infusion-related reaction occurs
            • See Dosage Modifications
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            Pregnancy

            Pregnancy

            Based on its mechanism of action and findings from animal studies, inotuzumab can cause embryofetal harm when administered to a pregnant woman; no available data for use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage

            If used during pregnancy, or if patient becomes pregnant while taking inotuzumab, advise patient of the potential risk to a fetus

            Animal data

            • In rat embryofetal development studies, inotuzumab ozogamicin caused embryofetal toxicity at maternal systemic exposures that were ≥0.4 times exposure in patients at maximum recommended dose, based on AUC; pregnant rats received daily IV doses of inotuzumab ozogamicin up to 0.36 mg/m² during organogenesis; embryofetal toxicities, including increased resorptions and fetal growth restriction, as evidenced by decreased live fetal weights and delayed skeletal ossification, were observed at ≥0.11 mg/m² (~2 times the exposure in patients at maximum recommended dose, based on AUC); fetal growth restriction also occurred at 0.04 mg/m² (~0.4 times the exposure in patients at the maximum recommended dose, based on AUC)

            Females and Males of Reproductive Potential

            • Based on findings in animals, inotuzumab may impair fertility in males and females of reproductive potential
            • Pregnancy testing
              • Verify the pregnancy status of females of reproductive potential prior to initiating inotuzumab
            • Contraception
              • Advise females of reproductive potential to avoid becoming pregnant while receiving inotuzumab
              • Advise females of reproductive potential to use effective contraception during treatment with inotuzumab and for at least 8 months after the last dose
              • Advise males with female partners of reproductive potential to use effective contraception during treatment with inotuzumab and for at least 5 months after the last dose

            Lactation

            Unknown if distributed in human breast milk

            No data on presence of inotuzumab ozogamicin or its metabolites in human milk, its effects on breastfed infant, or effects on milk production

            Because of potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with inotuzumab and for at least 2 months after the last dose

            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

            CD22-directed antibody-drug conjugate (ADC) recognizes human CD22; small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent that covalently attaches to antibody via a linker

            Nonclinical data suggest anticancer activity of inotuzumab ozogamicin is due to binding of ADC to CD22-expressing tumor cells, followed by internalization of ADC-CD22 complex, and ultimately activating N-acetyl-gamma-calicheamicin 19 dimethylhydrazide, which induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death

            Absorption

            Peak plasma concentration: 308 ng/mL

            AUC: 100,000 ng·h/mL

            Steady-state drug concentration was achieved by cycle 4

            Distribution

            Protein bound: 97%

            Vd: ~12 L

            Metabolism

            N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction

            Elimination

            Clearance, steady state: 0.0333 L/h

            Half-life: 12.3 days

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            Administration

            IV Compatibilities

            0.9% NaCl

            IV Preparation

            Reconstitute each vial with 4 mL of sterile water for injection; reconstituted concentration 0.25 mg/mL

            Gently swirl vial to aid dissolution

            Do not shake; inspect reconstituted solution for particulates and discoloration; reconstituted solution should be clear to opalescent, colorless to slightly yellow, and free of visible foreign matter

            Use reconstituted solution immediately or after being refrigerated (2-8°C; 36-46°F) for up to 4 hr

            Aseptically withdraw calculated amount from vial(s) using a syringe (see full prescribing information for calculation and further preparation information); discard any unused reconstituted solution left in vial

            Add reconstituted solution to an infusion container with 0.9% NaCl to a total volume of 50 mL

            Infusion container made of polyvinyl chloride (PVC), DEHP, non-DEHP-containing polyolefin (polypropylene and/or polyethylene), or ethylene vinyl acetate (EVA) is recommended

            Gently invert infusion container to mix diluted solution; do not shake

            IV Administration

            Filtration is not required: if diluted solution is filtered, polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-,or hydrophilic polysulfone (HPS)-based filters are recommended

            Do not use filters made of nylon or mixed cellulose ester (MCE)

            Administer diluted solution with 8 hr of reconstitution (from reconstitution through end of administration)

            Infuse diluted solution over 1 hr at a rate of 50 mL/hr at room temperature (20-25°C; 68-77°F)

            Infusion lines made of PVC, DEHP-, or non-DEHP-containing, polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended

            Do not mix or administer inotuzumab with other medicinal products

            Storage

            All formulations: Protect from light and do not freeze

            Lyophilized powder vial: Refrigerate (2-8°C; 36-46°F) vials and store in original carton

            Reconstituted vial: Refrigerate (2-8°C; 36-46°F) for up to 4 hr

            Diluted solution

            • After start of dilution: Store at room temperature (20-25°C; 68-77°F) for up to 4 hr or refrigerate (2-8°C; 36-46°F) for up to 3 hr

            During administration

            • Store in refrigerator (2-8°C; 36-46°F); allow it to equilibrate at room temperature (20-25°C; 68-77°F); maximum time from reconstitution through end of administration ≤8 hr
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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.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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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.