Inotuzumab

Brand names: Besponsa
Drug class: Antineoplastic Agents

Usage of Inotuzumab

B-Cell Precursor Acute Lymphoblastic Leukemia

Treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (pre-B-ALL) (designated an orphan drug by FDA for treatment of pre-B-ALL).

Efficacy determined based on complete remission (CR) and complete remission with incomplete hematologic recovery (CRi) in an open-label, randomized phase 3 study (INO-VATE ALL) in patients with relapsed or refractory pre-B-ALL.

Relate drugs

How to use Inotuzumab

General

  • To minimize risk of infusion-related reactions, premedicate with a corticosteroid, antipyretic, and antihistamine prior to each Inotuzumab ozogamicin infusion. Observe patients for symptoms of infusion-related reactions during and for ≥1 hour after end of each infusion. (See Infusion-related Reactions under Cautions.)
  • If patient has circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, a corticosteroid, and/or vincristine until peripheral blast counts decrease to ≤10,000/mm3 is recommended prior to initial dose of inotuzumab ozogamicin.
  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.

    • Restricted Distribution

  • Obtain inotuzumab ozogamicin through a specialty pharmacy and specialty distributors. Consult Pfizer Oncology Together at 877-744-5675 or at for specific availability information.

    • Administration

    IV Administration

    For solution compatibility information, see Compatibility under Stability.

    Administer by IV infusion. Manufacturer recommends polyolefin, PVC (diethylhexylphthalate [DEHP] or non-DEHP), or polybutadiene administration sets with or without a filter. If a filter is used, use a polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-, or hydrophilic polysulfone (HPS)-based filter; do not use nylon or mixed cellulose ester (MCE) filters.

    Must be reconstituted and diluted prior to administration. Use within 8 hours following reconstitution (including infusion time). (See Storage under Stability.)

    Reconstitution

    Reconstitute vial containing 0.9 mg of inotuzumab ozogamicin with 4 mL of sterile water for injection to provide a solution containing 0.25 mg/mL. Gently swirl vial. Do not shake reconstituted solution.

    Reconstituted solution should be clear to opalescent, colorless to slightly yellow, and free of visible particulates.

    Dilution

    Dilute appropriate dose in a PVC (DEHP or non-DEHP), polyolefin, or ethylene vinyl acetate (EVA) infusion bag containing 0.9% sodium chloride injection to achieve a total volume of 50 mL. Mix the diluted solution by gentle inversion; do not shake.

    Rate of Administration

    Administer by IV infusion at a rate of 50 mL/hour for 1 hour.

    Dosage

    Adults

    B-Cell Precursor Acute Lymphoblastic Leukemia IV

    Cycle 1: 0.8 mg/m2 on day 1, followed by 0.5 mg/m2 on days 8 and 15 during a 3-week cycle. May extend duration of cycle to 4 weeks if CR or CRi is achieved and/or toxicity occurs.

    Subsequent cycles in patients who have not achieved CR or CRi: 0.8 mg/m2 on day 1, followed by 0.5 mg/m2 on days 8 and 15 during each 4-week cycle. Discontinue drug if CR or CRi is not achieved within 3 cycles.

    Subsequent cycles in patients who have achieved CR or CRi: 0.5 mg/m2 on days 1, 8, and 15 during each 4-week cycle.

    Duration of therapy should not exceed 6 cycles in patients who will not undergo HSCT. In patients undergoing HSCT following inotuzumab ozogamicin therapy, recommended duration of therapy is 2 cycles; however, may consider a third cycle if CR or CRi and minimal residual disease (MRD) negativity are not achieved within the first 2 cycles (cycles 1–2). (See Hepatotoxicity, including Hepatic VOD, under Cautions.)

    Dosage Modification for Toxicity

    Do not re-escalate dosage following dosage reductions for toxicity.

    Hematologic Toxicity IV

    Dose delays may be required if ANC and platelet counts have not recovered to recommended values prior to initiation of a new treatment cycle; dose delays within a treatment cycle (i.e., days 8 and/or 15) not necessary.

    For ANC <1000/mm3 in patients who have a baseline ANC of ≥1000/mm3, delay next cycle until ANC ≥1000/mm3. If prolonged treatment-related neutropenia (i.e., lasting >28 days) occurs, discontinue drug.

    For platelet count <50,000/mm3 in patients who have a baseline platelet count of ≥50,000/mm3, delay next cycle until platelet count ≥50,000/mm3. If prolonged treatment-related thrombocytopenia (i.e., lasting >28 days) occurs, discontinue drug.

    If neutropenia or thrombocytopenia occurs in patients who have a baseline ANC <1000/mm3 and/or platelet count <50,000/mm3, delay next cycle until one of the following occurs: ANC and platelet count return to at least baseline values, ANC ≥1000/mm3 and platelet count ≥50,000/mm3, or assessment of bone marrow reveals stable or improved disease and neutropenia and thrombocytopenia are considered disease-related.

    Hepatotoxicity IV

    For serum ALT and/or AST concentrations >2.5 times the ULN or total bilirubin concentrations >1.5 times the ULN (except in patients with Gilbert’s syndrome or hemolysis), interrupt therapy until ALT and AST recover to ≤2.5 times the ULN and total bilirubin concentrations recover to ≤1.5 times the ULN. If therapy is withheld for <7 days, administer next dose upon resolution of toxicity; however, adjust administration schedule to maintain a minimum of 6 days between doses. If therapy is withheld for ≥7 days but <14 days, omit next dose. If therapy is withheld for ≥14 days, reduce dosage by 25% in subsequent cycles; if further dosage reduction is necessary, reduce frequency of administration in subsequent cycles from 3 to 2 doses per cycle. If dosage modification (dosage reduction or reduced frequency) is not tolerated or elevated ALT, AST, or total bilirubin concentrations persist for >28 days despite interruption of therapy, permanently discontinue drug.

    If hepatic VOD or other severe hepatotoxicity occurs, permanently discontinue drug.

    Infusion-related Reactions IV

    If infusion-related reactions occur, interrupt infusion or permanently discontinue drug and institute appropriate treatment and supportive care. Depending on severity (except for severe or life-threatening reactions), may consider discontinuance of infusion or continuation of infusion and administration of a corticosteroid and antihistamine.

    If severe or life-threatening infusion-related reactions occur, permanently discontinue drug.

    Other Nonhematologic Toxicity IV

    For grade 2 or greater nonhematologic toxicity (except for hepatotoxicity and infusion-related effects), interrupt therapy until toxicity returns to baseline or improves to grade 1. If therapy is withheld for <7 days, administer next dose upon resolution of toxicity; however, adjust administration schedule to maintain a minimum of 6 days between doses. If therapy is withheld for ≥7 days but <14 days, omit next dose. If therapy is withheld for ≥14 days, reduce dosage by 25% in subsequent cycles; if further dosage reduction is necessary, reduce frequency of inotuzumab ozogamicin in subsequent cycles from 3 to 2 doses per cycle. If dosage modification (dosage reduction or reduced frequency) is not tolerated or nonhematologic toxicity persists for >28 days despite interruption of therapy, permanently discontinue drug.

    Prescribing Limits

    Adults

    B-Cell Precursor Acute Lymphoblastic Leukemia IV

    Duration of therapy should not exceed 6 cycles in patients who will not undergo HSCT. In patients undergoing HSCT following inotuzumab ozogamicin therapy, duration of therapy should not exceed 2 cycles; however, may consider a third cycle if CR or CRi and minimal residual disease negativity are not achieved within the first 2 cycles (cycles 1–2). (See Hepatotoxicity, including Hepatic VOD, under Cautions.)

    Special Populations

    Hepatic Impairment

    Serum ALT/AST concentrations ≤2.5 times the ULN and total bilirubin concentrations ≤1.5 times the ULN: No initial dosage adjustment required. (See Special Populations under Pharmacokinetics.)

    Serum ALT/AST concentrations >2.5 times the ULN and/or total bilirubin concentrations >1.5 times the ULN: Limited data; no specific dosage recommendations.

    Renal Impairment

    Clcr 15–89 mL/minute: No specific dosage recommendations. (See Special Populations under Pharmacokinetics.)

    End-stage renal disease (including those receiving dialysis): Not studied; no specific dosage recommendations at this time.

    Geriatric Patients

    No initial dosage adjustment required.

    Warnings

    Contraindications

  • No known contraindications.

    • Warnings/Precautions

    Warnings

    Hepatotoxicity, including Hepatic VOD

    Hepatotoxicity, including severe, life-threatening, and sometimes fatal VOD (also known as sinusoidal obstruction syndrome) and liver function test abnormalities, reported in inotuzumab ozogamicin-treated patients. In the INO-VATE ALL study, hepatic VOD occurred more frequently in inotuzumab ozogamicin-treated patients who underwent HSCT following therapy with the drug than in those without HSCT. Most cases of hepatic VOD were grade 3 or worse. Median time to onset of hepatic VOD in patients who underwent HSCT: 15 days (range: 3–57 days). Among those who did not undergo HSCT, hepatic VOD reported up to 56 days following the last dose of the drug or during follow-up.

    Risk of hepatic VOD increased in patients who undergo HSCT following therapy with inotuzumab ozogamicin, those who receive conditioning regimens containing 2 alkylating agents, and those whose most recent total bilirubin concentration is at or above the ULN prior to HSCT. Other risk factors include ongoing or prior hepatic disease, history of HSCT, older age, heavily pretreated disease (i.e., later salvage line of therapy), and increased number of treatment cycles with inotuzumab ozogamicin. Patients who have experienced prior VOD or who have serious ongoing hepatic disease also are at increased risk for worsening of hepatic disease, including development of VOD, following therapy with the drug.

    Reduce treatment duration to 2 cycles in patients undergoing HSCT. (See B-Cell Precursor Acute Lymphoblastic Leukemia under Dosage and Administration.)

    Some experts recommend concurrent administration of drugs such as ursodiol to prevent development of hepatic VOD.

    Closely monitor for signs and symptoms of hepatic VOD (e.g., elevated total bilirubin concentrations, hepatomegaly, rapid weight gain, ascites, edema, jaundice).

    Assess liver function tests (i.e., ALT, AST, total bilirubin, alkaline phosphatase) prior to and following each dose of inotuzumab ozogamicin; additionally, closely monitor liver function tests for the first month following HSCT and then less frequently thereafter, according to standard clinical practice.

    If hepatotoxicity occurs, temporary interruption of therapy, dosage reduction, or drug discontinuance may be necessary. (See Hepatotoxicity under Dosage and Administration.)

    If hepatic VOD occurs, permanently discontinue drug. Supportive care, including maintaining adequate fluid balance, is recommended by some experts; continued administration of ursodiol also recommended. Defibrotide sodium may be used in the treatment of patients with hepatic VOD with renal or pulmonary compromise.

    Increased Risk of Post-transplant Non-relapse Mortality

    Increased mortality at day 100 post-HSCT in patients who underwent HSCT following inotuzumab ozogamicin therapy. Most common causes of post-HSCT non-relapse mortality were hepatic VOD and infectious complications.

    Closely monitor for manifestations of post-HSCT complications, including infection and hepatic VOD. (See Hepatotoxicity, including Hepatic VOD, under Cautions.)

    Other Warnings and Precautions

    Myelosuppression

    Neutropenia and thrombocytopenia, resulting in severe, life-threatening, and sometimes fatal complications (e.g., pneumonia, neutropenic sepsis, sepsis, septic shock, pseudomonal sepsis, hemorrhage), reported. Infectious complications associated with neutropenia occur frequently. Most common hemorrhagic event is epistaxis.

    Monitor CBC counts prior to each dose.

    Initiate prophylactic anti-infective therapy and employ surveillance testing during and following therapy as appropriate.

    Monitor for signs and symptoms of myelosuppression-related complications (e.g., infection, hemorrhage). If neutropenia, thrombocytopenia, or myelosuppression-related complications occur, temporary interruption of therapy, dosage reduction, or drug discontinuance may be necessary. (See Hematologic Toxicity under Dosage and Administration.)

    Infusion-related Reactions

    Infusion-related reactions reported, generally shortly after completion of the infusion during first treatment cycle. Infusion-related reactions resolve spontaneously or following medical intervention.

    Premedicate with a corticosteroid, antipyretic, and antihistamine prior to each dose.

    Closely monitor for manifestations of infusion-related reactions (e.g., fever, chills, rash, breathing difficulty) during and for ≥1 hour following completion of the infusion. If infusion-related reactions occur, temporary interruption of infusion or permanent discontinuance of the drug may be necessary along with appropriate treatment and supportive care. (See Infusion-related Reactions under Dosage and Administration.)

    Prolongation of QT Interval

    Prolongation of the QT interval reported.

    Use with caution in patients with a history of or predisposition for prolongation of the QTc interval, patients concurrently receiving other drugs known to prolong the QT interval, and patients with electrolyte abnormalities. (See Drugs that Prolong the QT Interval under Interactions.)

    Monitor ECGs and serum electrolytes prior to initiation of inotuzumab ozogamicin, following initiation of any drug known to prolong the QTc interval, and periodically during therapy as clinically indicated.

    Fetal/Neonatal Morbidity and Mortality

    Based on its mechanism of action and animal findings, may cause fetal harm. Embryofetal toxicity demonstrated in animals.

    Verify pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. Women of childbearing potential and men who are partners of such women should use effective contraceptive methods while receiving inotuzumab ozogamicin and for ≥8 and ≥5 months, respectively, after the drug is discontinued.

    If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

    Impairment of Fertility

    May impair male and female fertility.

    Immunogenicity

    Antibodies to inotuzumab ozogamicin reported. Clearance not affected by presence of antibodies. Neutralizing antibodies not reported.

    Specific Populations

    Pregnancy

    May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

    Confirm pregnancy status prior to initiating therapy.

    Lactation

    Not known whether inotuzumab ozogamicin or its metabolites are distributed into milk. Effects on nursing infants and milk production also unknown. Avoid breast-feeding during therapy and for ≥2 months after drug discontinuance.

    Pediatric Use

    Safety and efficacy not established.

    Geriatric Use

    In the INO-VATE ALL study, 18% of patients were ≥65 years of age. No differences in efficacy or safety relative to younger adults observed; however, thrombocytopenia, febrile neutropenia, and elevated concentrations of γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) occurred more frequently in geriatric patients.

    Older age is associated with an increased risk of developing hepatic VOD in inotuzumab ozogamicin-treated patients. (See Hepatotoxicity, including Hepatic VOD, under Cautions.)

    Pharmacokinetics do not appear to be substantially affected by patient age; initial dosage adjustment in geriatric patients not necessary. (See Special Populations under Pharmacokinetics.)

    Hepatic Impairment

    Clearance not affected by preexisting mild hepatic impairment.

    Limited data in patients with preexisting moderate or severe hepatic impairment; however, clearance did not appear to be reduced. (See Special Populations under Pharmacokinetics.)

    Renal Impairment

    Clearance not affected by renal impairment (Clcr 15–89 mL/minute). (See Special Populations under Pharmacokinetics.)

    Efficacy and safety in patients with end-stage renal disease (with or without hemodialysis) unknown.

    Common Adverse Effects

    Relapsed or refractory ALL: Thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, elevated ALT and/or AST concentrations, abdominal pain, elevated γ-glutamyltransferase concentrations, hyperbilirubinemia.

    What other drugs will affect Inotuzumab

    In vitro, N-acetyl-γ-calicheamicin dimethylhydrazide is primarily metabolized by nonenzymatic reduction. In vitro, inhibition of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 and UGT isoenzymes 1A1, 1A4, 1A6, 1A9, and 2B7 is unlikely at clinically relevant concentrations. In vitro, induction of CYP isoenzymes 1A2, 2B6, and 3A4 is unlikely at clinically relevant concentrations.

    N-acetyl-γ-calicheamicin dimethylhydrazide is a substrate of P-glycoprotein (P-gp). Unlikely to inhibit P-gp, breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1 or OAT3, organic cation transporter (OCT) 2, and organic anion transport protein (OATP) 1B1 and OATP1B3.

    In vitro, inotuzumab ozogamicin is unlikely to substantially inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 or induce CYP isoenzymes 1A2, 2B6, and 3A4 at clinically relevant concentrations.

    Drugs that Prolong the QT Interval

    Possible additive effects on corrected QT (QTc)-interval prolongation with drugs known to prolong the QT interval or cause torsades de pointes. Avoid concomitant use; discontinue use of such drugs or consider use of alternative drugs without QT-interval prolongation potential. If concomitant use cannot be avoided, monitor ECGs and serum electrolyte concentrations more frequently (i.e., prior to initiation of inotuzumab ozogamicin therapy, after initiation of any drug known to prolong the QTc interval, and periodically during therapy as clinically indicated). (See Prolongation of QT Interval under Cautions.)

    Hepatotoxic Drugs

    Because hepatic VOD and liver function test abnormalities are associated with inotuzumab ozogamicin therapy, some experts recommend avoiding concomitant therapy with other drugs known to cause hepatotoxicity in patients receiving inotuzumab ozogamicin and high-dose conditioning regimens with alkylating agents, if possible. (See Hepatotoxicity, including Hepatic VOD, under Cautions.)

    Specific Drugs

    Drug

    Interaction

    Comments

    Alkylating agents (e.g., Busulfan, melphalan, thiotepa)

    Increased risk of hepatic VOD in patients undergoing HSCT following therapy with inotuzumab ozogamicin, including those who received conditioning regimens containing 2 alkylating agents (see Hepatotoxicity, including Hepatic VOD, under Cautions)

    Avoid conditioning regimens containing 2 alkylating agents in patients undergoing HSCT following inotuzumab ozogamicin therapy

    Antifungals, azoles

    Possible increased risk of hepatotoxicity

    Some experts recommend avoiding concomitant use, if possible

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