Inotuzumab (Monograph)

Brand name: Besponsa
Drug class: Antineoplastic Agents
- ADCs
- Antibody-drug Conjugates
Chemical name: Immunoglobulin G4 (anti-(human CD22 (antigen)) (human-mouse monoclonal G544 heavy chain), disulfide with human-mouse monoclonal G544 κ-chain, dimer, methyl [(1R,4Z,8S,13E)-8-[[2-O-[4-(acetylethylamino)-2,4-dideoxy-3-O-methyl-α-l-threo-pentopyranosyl]-4,6-dideoxy-4-[[[2,6-dideoxy-4-S-[4-[(6-deoxy-3-O-methyl-α-l-mannopyranosyl)oxy]-3-iodo-5,6-dimethoxy-2-methylbenzoyl]-4-thio-β-d-ribo-hexopyranosyl]oxy]amino]-β-d-glucopyranosyl]oxy]-13-[2-[[3-[[1-[4-(4-amino-4-oxobutoxy)phenyl]ethylidene]hydrazino]-1,1-dimethyl-3-oxopropyl]dithio]ethylidene]-1-hydroxy-11-oxobicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-10-yl]carbamate conjugate
Molecular formula: C₆₅₁₈H₁₀₀₀₂N₁₇₃₈O₂₀₃₆S₄₂
CAS number: 635715-01-4

Medically reviewed by Drugs.com on Oct 7, 2024. Written by ASHP.

Introduction

Antineoplastic agent; a CD22-directed antibody-drug conjugate consisting of a recombinant humanized IgG₄ kappa monoclonal antibody (inotuzumab) covalently linked to a cytotoxic calicheamicin derivative (N-acetyl-γ-calicheamicin).

Uses for 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.

Inotuzumab Dosage and Administration

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

Cl_cr 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.

Cautions for Inotuzumab

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 QT_c 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 QT_c 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 (Cl_cr 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.

Drug Interactions

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 (QT_c)-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 QT_c 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

Inotuzumab Pharmacokinetics

Absorption

Bioavailability

Mean peak plasma concentrations of inotuzumab ozogamicin increase with repeated exposure.

Plasma concentrations of unconjugated N-acetyl-γ-calicheamicin usually are undetectable.

Steady-state concentrations of inotuzumab ozogamicin attained by the fourth cycle of therapy; estimated systemic accumulation of the antibody-drug conjugate is 5.3-fold.

Distribution

Extent

Not known whether inotuzumab ozogamicin or its metabolites are distributed into milk.

Plasma Protein Binding

Calicheamicin derivative: Approximately 97%.

Elimination

Metabolism

N-acetyl-γ-calicheamicin dimethylhydrazide is primarily metabolized by nonenzymatic reduction in vitro.

Half-life

Antibody-drug conjugate: 12.3 days.

Special Populations

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration >1 times but not >1.5 times the ULN with any AST concentration) does not affect clearance.

Moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN with any AST concentration) does not appear to affect clearance, but data are limited.

Renal impairment (Cl_cr 15–89 mL/minute) does not affect clearance.

Age, gender, and race do not have clinically important effects on pharmacokinetics.

Stability

Storage

Parenteral

Powder for Injection

Unreconstituted drug: 2–8°C in original carton to protect from light. Do not freeze.

Reconstituted drug: 2–8°C for up to 4 hours. Protect from light. Do not freeze.

Diluted infusion solution: 20–25°C for up to 4 hours following dilution or 2–8°C for up to 3 hours following dilution. If refrigerated, allow approximately 1 hour for diluted infusion solution to equilibrate to room temperature. The maximum time from reconstitution through the end of administration should be ≤8 hours, and there should be ≤4 hours between reconstitution and dilution of the solution. Protect from light. Do not freeze.

Compatibility

Parenteral

Solution Compatibility

Actions

• Antibody-drug conjugate consisting of 3 components: a recombinant humanized IgG₄ kappa monoclonal antibody (inotuzumab) that is specific for human CD22; N-acetyl-γ-calicheamicin, a cytotoxic calicheamicin derivative that causes double-strand DNA breaks; and an acid-cleavable linker (dimethylhydrazide), which covalently attaches N-acetyl-γ-calicheamicin to inotuzumab. N-acetyl-γ-calicheamicin is a semisynthetic derivative of the microorganism Micromonospora echinospora subsp. calichensis. An average of approximately 6 molecules of N-acetyl-γ-calicheamicin are attached to each inotuzumab molecule (range: 2–8).

• The antibody portion of inotuzumab ozogamicin binds specifically to human CD22, which is expressed on the surface of malignant cells in greater than 90% of B-cell ALL cases, including B-cell precursor ALL. The resultant complex is internalized by the cell. N-acetyl-γ-calicheamicin is then released via hydrolytic cleavage of the linker and binds to DNA in the minor groove causing double-strand DNA breaks and subsequent cell cycle arrest and apoptosis.

Advice to Patients

• Risk of hepatotoxicity, including hepatic VOD and elevated serum aminotransferase (ALT and/or AST) concentrations. Importance of informing patients of the signs and symptoms of hepatic VOD (e.g., elevated serum bilirubin concentrations, rapid weight gain, abdominal swelling [which may be painful]) and advising them to seek immediate medical advice if such symptoms occur. Importance of informing patients to carefully consider the potential benefits and risks of inotuzumab ozogamicin treatment if they have a history of hepatic VOD or serious ongoing hepatic disease.

• Risk of treatment-related mortality following HSCT; most common causes are infectious complications or hepatic VOD. Importance of informing clinicians if signs and symptoms of infection occur.

• Risk of myelosuppression. Importance of reporting signs and symptoms of myelosuppression (e.g., infection, bleeding/hemorrhage).

• Risk of infusion-related reactions. Importance of informing clinician if symptoms of such reactions, including fever, chills, rash, or breathing difficulty, occur during infusion of inotuzumab ozogamicin.

• Risk of QT-interval prolongation. Importance of informing clinicians if syncope or feelings of dizziness or faintness occur.

• Risk of fetal harm. Necessity of advising women of childbearing potential and men who are partners of such women that they should use effective contraception while receiving the drug and for ≥8 and ≥5 months, respectively, after discontinuance of therapy. Importance of women informing clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

• Importance of advising women to avoid nursing during therapy and for ≥2 months after discontinuance of the drug.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., hepatic impairment, cardiovascular disease).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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