Inotuzumab Ozogamicin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Besponsa: 0.9 mg (1 ea) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Inotuzumab ozogamicin is a humanized CD22-directed monoclonal antibody-drug conjugate which is composed of the IgG4 kappa antibody inotuzumab (which is specific for human CD22), a calicheamicin component (a cytotoxic agent that causes double-stranded DNA breaks), and an acid-cleavable linker that covalently binds the calicheamicin to inotuzumab. After the antibody-drug conjugate binds to CD22, the CD22-conjugate complex is internalized, and releases calicheamicin. Calicheamicin binds to the minor groove of DNA to induce double strand cleavage and subsequent cell cycle arrest and apoptosis (Kantarjian 2016).

Pharmacokinetics/Pharmacodynamics

Distribution

~12 L

Metabolism

Calicheamicin: Primarily via nonenzymatic reduction

Excretion

Clearance (steady state): 0.0333 L/hour

Half-Life Elimination

12.3 days

Protein Binding

Calicheamicin: ~97% bound to human plasma proteins

Use: Labeled Indications

Acute lymphoblastic leukemia (relapsed/refractory): Treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to inotuzumab or any component of the formulation.

Dosage and Administration

Dosing: Adult

Acute lymphoblastic leukemia, B-cell precursor (relapsed/refractory):IV: Premedication is recommended prior to dosing. Prior to the first dose, cytoreduction to a peripheral blast count of ≤10,000/mm³ with a combination of hydroxyurea, steroids, and/or vincristine is recommended for patients with circulating lymphoblasts.

Cycle 1: 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15 of a 21-day treatment cycle (total dose/cycle 1: 1.8 mg/m²); treatment cycle may be extended to 4 weeks if complete remission (CR) is achieved, or CR with incomplete hematologic recovery (CRi) and/or to allow for recovery from toxicity.

Subsequent cycles:

Patients who achieve CR or CRi: 0.5 mg/m² on days 1, 8 and 15 of a 28-day treatment cycle (total dose/cycle: 1.5 mg/m²)

Patients who do NOT achieve CR or CRi: 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15 of a 28-day treatment cycle (total dose/cycle: 1.8 mg/m²); if CR or CRi is not achieved within 3 cycles, discontinue treatment.

Treatment duration: The recommended duration of treatment is 2 cycles for patients proceeding to hematopoietic stem cell transplant (HSCT); may consider a third cycle in patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles. For patients not proceeding to HSCT, may continue treatment for a maximum of up to 6 cycles.

Premedication: A corticosteroid, an antipyretic, and an antihistamine are recommended prior to dosing (observe for symptoms of infusion reaction during and for at least 1 hour after the end of the infusion).

Note: Doses on days 8 and 15 may be varied by ±2 days (maintain a minimum of 6 days between doses). CR is defined as <5% blasts in bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (platelets ≥100,000/mm³ and ANC ≥1,000/mm³) and resolution of any extramedullary disease. CRi is defined as <5% blasts in bone marrow and the absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts (platelets <100,000/mm³ and/or ANC <1,000/mm³) and resolution of any extramedullary disease.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Modify the inotuzumab ozogamicin dose for toxicities; doses within a treatment cycle (eg, day 8 and/or day 15 doses) do not need to be interrupted due to neutropenia or thrombocytopenia; however, dosing interruptions within a cycle are recommended for nonhematologic toxicities. If a dose is reduced due to toxicity, do not re-escalate the dose.

Hematologic toxicity:

Note: Platelet count used for dosage modification should be independent of transfusion.

If ANC decreases, and the ANC prior to inotuzumab ozogamicin treatment was ≥1,000/mm³, interrupt the next cycle of treatment until ANC recovers to ≥1,000/mm³. Discontinue inotuzumab ozogamicin if low ANC persists for >28 days and is suspected to be related to inotuzumab ozogamicin.

If platelet count decreases, and the platelet count prior to inotuzumab ozogamicin treatment was ≥50,000/mm³, interrupt the next cycle of treatment until platelets recover to ≥50,000/mm³. Discontinue inotuzumab ozogamicin if low platelets persist for >28 days and is suspected to be related to inotuzumab ozogamicin.

If ANC or platelet counts decrease and ANC <1,000/mm³ and/or platelet count was <50,000/mm³ prior to inotuzumab ozogamicin treatment, then interrupt the next cycle of treatment until at least one of the following occurs:

- ANC and platelet counts recover to at least baseline levels for the prior cycle or

- ANC recovers to ≥1,000/mm³ and platelet count recovers to ≥50,000/mm³or

- Based on most recent bone marrow assessment, disease is stable or improved and the ANC and platelet count decrease is considered to be due to underlying disease (not considered to be an inotuzumab ozogamicin-related toxicity).

Nonhematologic toxicity:

Dose modifications depending on duration of treatment interruption due to nonhematologic toxicity:

If interruption is <7 days (within a cycle): Interrupt the next dose (maintain a minimum of 6 days between doses).

If interruption is ≥7 days: Omit the next dose within the cycle.

If interruption is ≥14 days: Once recovery is adequate, decrease the total inotuzumab ozogamicin dose by 25% for the subsequent cycle. If further dose modification is necessary, then reduce the number of doses to 2 per cycle for subsequent cycles. If a 25% decrease in the total dose followed by a decrease to 2 doses per cycle is not tolerated, then permanently discontinue treatment.

If interruption is >28 days: Consider permanently discontinuing.

Hepatotoxicity: Refer to Dosing: Hepatic Impairment.

Infusion reaction: Interrupt infusion and institute appropriate medical management; depending on the severity of the reaction, consider discontinuing the infusion or administer steroids and antihistamines. For severe or life-threatening infusion reactions, discontinue permanently.

Other nonhematologic toxicity ≥ grade 2: Interrupt treatment until recovery to grade 1 or pretreatment grade levels prior to each dose.

Reconstitution

Reconstitute each vial with 4 mL of SWFI to a concentration of 0.25 mg/mL; gently swirl to dissolve. Do not shake. Inspect reconstituted solution for particulates or discoloration; reconstituted solution should be clear to opalescent, colorless to slightly yellow, and free of visible foreign matter. Each vial delivers 3.6 mL (0.9 mg). Calculate required volume and add reconstituted solution to an infusion container with NS to a total volume of 50 mL. Infusion containers made of polyvinyl chloride (PVC; DEHP-or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or ethylene vinyl acetate (EVA) are recommended. Gently invert to mix (do not shake).

Administration

IV: Infuse over 1 hour (at a rate of 50 mL/hour). If refrigerated, allow to reach room temperature for ~1 hour prior to administration. Infuse at room temperature and protect from light during infusion. Infusion sets made of PVC (DEHP-or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended for administration. An inline filter is not required during administration; however, if the 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). Do not mix or administer with other medications.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Store vials in original carton to protect from light. Protect from light following reconstitution and dilution for infusion and do not freeze. Reconstituted solutions may be used immediately or after being refrigerated for up to 4 hours. Solutions diluted for infusion may be used immediately, after storage at room temperature for up to 4 hours, or after being refrigerated for up to 3 hours. The maximum time from reconstitution to the end of the infusion should be ≤8 hours, with ≤4 hours between reconstitution and dilution. If refrigerated, allow solutions diluted for infusion to reach room temperature for ~1 hour prior to administration.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Chloroquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Gadobenate Dimeglumine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Halofantrine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Haloperidol: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lofexidine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Lofexidine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Midostaurin: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ondansetron: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Pentamidine (Systemic): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Piperaquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Piperaquine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Probucol: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Probucol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Pimozide. Monitor therapy

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Chloroquine; Clofazimine; Domperidone; Gadobenate Dimeglumine; Halofantrine; Lofexidine; Midostaurin; Piperaquine; Probucol; Sodium Stibogluconate. Monitor therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Sodium Stibogluconate: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Sodium Stibogluconate. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (35%), headache (28%), chills (11%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (21% to 67%), hyperuricemia (4% to 16%)

Gastrointestinal: Increased serum lipase (9% to 32%), nausea (31%), abdominal pain (23%), diarrhea (17%), constipation (16%), vomiting (15%), increased serum amylase (5% to 15%), stomatitis (13%), decreased appetite (12%)

Hematologic & oncologic: Thrombocytopenia (51%; grade 3: 14%; grade 4: 28%), neutropenia (49%; grade 3: 20% to 49%; grade 4: 27%), anemia (36%; grade ≥3%: 24%), leukopenia (35%; grade ≥3: 33%), hemorrhage (grade ≥3: 5% to 33%), febrile neutropenia (26%; grade ≥3: 26%), lymphocytopenia (18%; grade ≥3: 16%)

Hepatic: Increased serum AST (71%), increased serum alkaline phosphatase (13% to 57%), increased serum ALT (49%), increased serum transaminases (26%), hepatic veno-occlusive disease (≤23%), hyperbilirubinemia (21%), hepatotoxicity (14%)

Infection: Infection (48%)

Respiratory: Epistaxis (15%)

Miscellaneous: Fever (32%)

1% to 10%:

Cardiovascular: Prolonged Q-T interval on ECG (1%)

Gastrointestinal: Abdominal distention (6%)

Hematologic & oncologic: Bone marrow failure (2%; includes bone marrow failure, febrile bone marrow aplasia), tumor lysis syndrome (2%)

Hepatic: Ascites (4%)

Immunologic: Antibody development (anti-inotuzumab antibodies: 3%)

Miscellaneous: Infusion related reaction (2%; grade 2: 2%; includes hypersensitivity)

Frequency not defined: Infection: Bacterial infection, fungal infection, viral infection

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Hematologic toxicity, including thrombocytopenia and neutropenia commonly occur (including grades 3 and 4). Neutropenic fever occurred in over one-fourth of patients; may be life-threatening. For patients who were in complete remission (CR) or CR with incomplete hematologic recovery (CRi) at the end of treatment, the time to platelet recovery (>50,000/mm³) was >45 days after the last dose in some patients. Complications associated with myelosuppression (including infections and bleeding/hemorrhagic events) have been observed. Monitor complete blood counts prior to each dose and monitor for signs and symptoms of effects of myelosuppression during treatment; may require treatment interruption, dose reduction, or permanent discontinuation.

• Hemorrhage: Hemorrhagic events associated with thrombocytopenia have been reported, including grades 3 or 4 hemorrhagic events and one grade 5 (fatal) intra-abdominal hemorrhage. The most common hemorrhagic event was epistaxis. Monitor for signs and symptoms of bleeding/hemorrhage during treatment; may require treatment interruption, dose reduction, or permanent discontinuation.

• Hepatotoxicity: [US Boxed Warning]: Hepatotoxicity, including severe, life-threatening, and sometimes fatal sinusoidal obstructions syndrome (formerly called veno-occlusive disease [VOD]) has occurred in patients with relapsed or refractory acute lymphoblastic leukemia who received inotuzumab ozogamicin. The risk of VOD was greater in patients who received a hematopoietic stem cell transplant (HSCT) following inotuzumab ozogamicin treatment. The use of HSCT conditioning regimens containing 2 alkylating agents (eg, busulfan in combination with other alkylating agents) and a total bilirubin level ≥ upper limit of normal before HSCT were significantly associated with increasing the risk of VOD. Other risk factors for VOD associated with inotuzumab ozogamicin included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a higher number of inotuzumab ozogamicin treatment cycles. Liver function test elevations may require treatment interruption, dose reduction, or permanent discontinuation; discontinue permanently if VOD occurs. Patients with a history of VOD or who have serious ongoing hepatic liver disease (eg, cirrhosis, idiopathic noncirrhotic portal hypertension [including nodular regenerative hyperplasia], active hepatitis) are at an increased risk for worsening of liver disease, including developing VOD, following inotuzumab ozogamicin therapy. VOD was reported up to 56 days after the last dose during treatment or during follow-up without an intervening HSCT. For patients receiving HSCT after inotuzumab ozogamicin, the median time to onset of VOD was 15 days (range: 3 to 57 days). Due to the VOD risk, the recommended treatment duration with inotuzumab ozogamicin is 2 cycles in patients proceeding to HSCT; an additional cycle may be considered for patients not in CR or CRi and MRD negativity after 2 cycles. For patients not proceeding to HSCT, the recommended maximum is 6 cycles. Monitor closely for signs and symptoms of VOD (eg, total bilirubin elevations, hepatomegaly [may be painful], rapid weight gain, and ascites). For patients who proceed to HSCT, monitor liver tests closely during the first month post-HSCT. Utilize standard medical management for severe VOD. Other hepatotoxicity events have been reported, including grades 3 and 4 AST, ALT, and total bilirubin elevations. Monitor liver function tests (ALT, AST, total bilirubin, and alkaline phosphatase) prior to and following each inotuzumab ozogamicin dose in all patients. Elevations of liver function tests may require dosing interruption, dose reduction, or permanent discontinuation of inotuzumab ozogamicin.

• Hypersensitivity: Hypersensitivity reactions have been reported.

• Infections: Infections, including serious infections (some life-threatening or fatal), were reported in nearly half of patients treated with inotuzumab ozogamicin. Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, have been reported; bacterial, viral, and fungal infections occurred. Monitor for signs and symptoms of infection during treatment. Administer prophylactic anti-infectives and employ surveillance testing during and after treatment. Severe infection may require treatment interruption, dose reduction, or permanent discontinuation.

• Infusion reactions: Grade 2 infusion related reactions were reported with inotuzumab ozogamicin administration in a small percentage of patients. Infusion reactions (eg, fever, chills, rash, dyspnea) usually occurred in cycle 1 shortly after the end of the infusion and resolved spontaneously or with medical management. Premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing. Monitor closely during the infusion and for at least 1 hour after the end of the infusion for potential reactions. If an infusion reaction occurs, interrupt infusion and manage appropriately. Depending on the severity, consider discontinuing the infusion or administering corticosteroids and antihistamines. Permanently discontinue if a severe or life-threatening infusion reaction occurs.

• QT prolongation: Increases in the corrected QT interval of ≥60 msec from baseline were observed in a small number of patients (including grade 2 prolongation in some patients), although none had QTcF values greater than 500 msec. There were no ≥ grade 3 QT prolongations or cases of torsades de pointes reported. Use inotuzumab ozogamicin with caution in patients with a history of (or predisposition for) QTc prolongation, patients taking drugs known to prolong the QT interval, and/or in patients with electrolyte abnormalities. Obtain ECG and electrolytes prior to treatment initiation, after initiation of any drug known to prolong QTc, and periodically as clinically indicated during treatment.

Disease related concerns:

• Hematopoietic stem cell transplant: [US Boxed Warning]: A higher post-HSCT non-relapse mortality rate was observed in patients who received inotuzumab ozogamicin, resulting in a higher Day 100 post-HSCT mortality rate. The most common causes of post-HSCT non-relapse mortality included VOD and/or infection. Among patients with ongoing VOD, multiorgan failure or infection resulting in fatality occurred. Monitor closely for toxicities post-HSCT, including signs/symptoms of infection and VOD.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Monitoring Parameters

Complete blood counts (prior to each dose), liver function tests including ALT, AST, total bilirubin, and alkaline phosphatase (prior to and following each dose); for patients who proceed to HSCT, monitor liver function tests closely during the first month post-HSCT, then less frequently thereafter, according to standard medical practice; electrolytes (prior to treatment initiation, after initiation of any drug known to prolong QTc, and periodically as clinically indicated during treatment), pregnancy status (prior to treatment in females of reproductive potential). Obtain ECG (prior to treatment initiation, after initiation of any drug known to prolong QTc, and periodically as clinically indicated during treatment).

Monitor closely for signs and symptoms of VOD (eg, hepatomegaly with or without pain, rapid weight gain, ascites); monitor for signs/symptoms of effects of myelosuppression (bleeding, hemorrhage, infection) during treatment; monitor closely during the infusion and for at least 1 hour after the end of the infusion for the potential infusion reactions.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and information from animal reproduction studies, inotuzumab ozogamicin may be expected to cause adverse events if used during pregnancy. Pregnancy status should be evaluated prior to therapy. Women of reproductive potential should use effective contraception during therapy and for at least 8 months after the last dose. Effective contraception should also be used for at least 5 months after the last dose when treating males who have female partners of reproductive potential.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.

Frequently reported side effects of this drug

• Headache
• Nausea
• Vomiting
• Abdominal pain
• Lack of appetite
• Diarrhea
• Constipation
• Mouth irritation
• Mouth sores

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Infection
• Infusion reaction
• Severe loss of strength and energy
• Dizziness
• Passing out
• Fast heartbeat
• Abnormal heartbeat
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.