Inotuzumab

Inotuzumab is used for: Acute Lymphoblastic Leukemia

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

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

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)

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 Increase risk of posttransplant nonrelapse mortality 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

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

Side effects of Inotuzumab : >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%)

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