BESPONSA

Inotuzumab ozogamicin is an antibody-drug conjugate consisting of a humanized IgG4 kappa CD22-targeting monoclonal antibody covalently attached to calicheamicin derivative, N-acetyl-gamma-calicheamicin dimethylhydrazide.

The antibody portion of the drug binds to CD22 receptors expressed on leukemic B cells and intracellularly releases N-acetyl-gamma-calicheamicin dimethylhydrazide, which produces cytotoxic effects.

Inotuzumab ozogamicin was first approved by the European Commission in June for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

A month later, inotuzumab ozogamicin was also approved by the FDA.

In the

US, inotuzumab ozogamicin is indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients one year and older.

In Europe, it is indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B cell precursor ALL.

Patients with

Philadelphia chromosome positive (Ph+) relapsed or refractory B cell precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor (TKI).

Inotuzumab ozogamicin is an antineoplastic agent that works to deplete CD22-positive leukemic cells.

In preclinical models, it arrested tumour growth and reduced the number of ALL cells.

In clinical trials, inotuzumab ozogamicin was shown to prolong the QT interval.

Inotuzumab ozogamicin is intended to be administered in cycles that each run for 3-4 weeks.

The mean

C max of inotuzumab ozogamicin was 308 ng/mL.

The mean simulated total

AUC per cycle was 100,000 ngxh/mL.

In patients with relapsed or refractory

ALL, steady-state drug concentration was achieved by Cycle 4.

Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4.

In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L. 7, 8.

In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction. 7, 8 In humans, N acetyl-gamma-calicheamicin dimethylhydrazide serum levels were typically below the limit of quantitation of 50 pg/mL; 7, 8 however, sporadic measurable levels of unconjugated calicheamicin up to 276 pg/mL occurred in some patients.

The antibody portion of the drug is thought to undergo proteolytic degradation into amino acids then recycled into other proteins.

In patients with relapsed or refractory

ALL, the terminal half-life was 12.3 days. 7, 8.

The pharmacokinetics of inotuzumab ozogamicin were well characterized by a 2-compartment model with linear and time-dependent clearance components.

The clearance of inotuzumab ozogamicin at steady state is 0.0333 L/h in patients with relapsed or refractory ALL. 7, 8.

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There is limited clinical experience regarding the acute toxicity of inotuzumab ozogamicin.

Overdoses may result in adverse reactions that are consistent with the reactions observed at the recommended therapeutic dose.

In the event of an overdose, drug infusion should be temporarily interrupted, and patients should be monitored for liver and hematological toxicities.

Re-initiation of the drug at the correct therapeutic dose should be considered when all toxicities have resolved.

• Administer by intravenous infusion only.

• Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions.

• Dosing regimens for Cycle and subsequent cycles, depending on the response to treatment, are shown below.

See full prescribing information for dosing details.

Day 1 Day 8 Day 15 Dosing regimen for Cycle 1 All patients: Dose 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 21 days For patients who achieve a CR or a CRi, and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21).

Dosing regimen for subsequent cycles depending on response to treatment Patients who have achieved a CR or CRi: Dose 0.5 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days Patients who have not achieved a CR or CRi: Dose 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days.

• See full prescribing information for instructions on reconstitution of lyophilized powder, and preparation and administration of reconstituted drug. 2.1 Recommended Dosage.

• Pre-medicate before each dose.

• For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m 2 per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m 2 ), Day 8 (0.5 mg/m 2 ), and Day 15 (0.5 mg/m 2 ).

Cycle is 3 weeks in duration, but may be extended to 4 weeks if the patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity.

• In patients who achieve a CR or CRi, the recommended total dose of BESPONSA is 1.5 mg/m 2 per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m 2 ), Day 8 (0.5 mg/m 2 ), and Day 15 (0.5 mg/m 2 ).

Subsequent cycles are 4 weeks in duration.

• In patients who do not achieve a CR or CRi, the recommended total dose of BESPONSA is 1.8 mg/m 2 per cycle given as 3 divided doses on Day 1 (0.8 mg/m 2 ), Day 8 (0.5 mg/m 2 ), and Day 15 (0.5 mg/m 2 ).

Patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment.

• For patients proceeding to hematopoietic stem cell transplant (HSCT), the recommended duration of treatment with BESPONSA is 2 cycles.

A third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles.

• For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered.

Table 1 shows the recommended dosing regimens.

Table 1.

Dosing Regimen for Cycle and Subsequent Cycles Depending on Response to Treatment Abbreviations: CR=complete remission; CRi=complete remission with incomplete hematologic recovery.

Day 1 Day 8 +/.

• 2 days (maintain minimum of 6 days between doses).

Day 15 Dosing regimen for Cycle 1 All patients: Dose Dose is based on the patient's body surface area (m 2 ). 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 21 days For patients who achieve a CR or a CRi, and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21).

Dosing regimen for subsequent cycles depending on response to treatment Patients who have achieved a CR CR is defined as < 5% blasts in the bone marrow and the 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. or CRi CRi is defined as < 5% blasts in the bone marrow and the 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. : Dose 0.5 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days 7-day treatment-free interval starting on Day 21.

Patients who have not achieved a CR or CRi: Dose 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days 2.2 Recommended Pre-medications and Cytoreduction.

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

Patients should be observed during and for at least 1 hour after the end of infusion for symptoms of infusion related reactions.

• For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count of less than or equal to 10,000/mm is recommended prior to the first dose. 2.3 Dosage Modifications for Adverse Reactions Modify the dose of BESPONSA for toxicities.

BESPONSA doses within a treatment cycle (i.e., Days and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosing interruptions within a cycle are recommended for non-hematologic toxicities.

If the dose is reduced due to BESPONSA-related toxicity, the dose must not be re-escalated.

Table 2.

BESPONSA Dosage Modifications for Hematologic Toxicities Criteria BESPONSA Dosage Modification(s) Abbreviation: ANC=absolute neutrophil count.

If prior to BESPONSA treatment

ANC was greater than or equal to 1 × 10 9 /L If ANC decreases, then interrupt the next cycle of treatment until recovery of ANC to greater than or equal to 1 × 10 9 /L. Discontinue BESPONSA if low ANC persists for greater than 28 days and is suspected to be related to BESPONSA.

If prior to

BESPONSA treatment platelet count was greater than or equal to 50 × 10 9 /L Platelet count used for dosing should be independent of blood transfusion.

If platelet count decreases, then interrupt the next cycle of treatment until platelet count recovers to greater than or equal to 50 × 10 9 /L.

BESPONSA if low platelet count persists for greater than 28 days and is suspected to be related to BESPONSA.

• ANC and platelet counts recover to at least baseline levels for the prior cycle, or.

• ANC recovers to greater than or equal to 1 × 10 9 /L and platelet count recovers to greater than or equal to 50 × 10 9 /L, or.

• Stable or improved disease (based on most recent bone marrow assessment) and the ANC and platelet count decrease is considered to be due to the underlying disease (not considered to be BESPONSA-related toxicity).

Table 3.

BESPONSA Dosage Modifications for Non-hematologic Toxicities

Non-hematologic Toxicity Dosage Modification(s) Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal; VOD=veno‑occlusive disease.

VOD or other severe liver toxicity

Permanently discontinue treatment.

Total bilirubin greater than 1.5 × ULN and AST / ALT greater than 2.5 × ULN Interrupt dosing until recovery of total bilirubin to less than or equal to 1.5 × ULN and AST/ALT to less than or equal to 2.5 × ULN prior to each dose unless due to Gilbert's syndrome or hemolysis.

Permanently discontinue treatment if total bilirubin does not recover to less than or equal to 1.5 × ULN or AST/ALT does not recover to less than or equal to 2.5 × ULN.

Infusion related reaction

Interrupt the infusion and institute appropriate medical management.

Depending on the severity of the infusion related reaction, consider discontinuation of the infusion or administration of steroids and antihistamines.

For severe or life-threatening infusion reactions, permanently discontinue treatment.

Non-hematologic toxicity greater than or equal to Grade 2 Severity grade according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0.

Interrupt treatment until recovery to

Grade 1 or pre-treatment grade levels prior to each dose.

Table 4.

BESPONSA Dosage Modifications Depending on Duration of Dosing Interruption Due to Non-Hematologic Toxicity Toxicities Duration of Dose Interruption Due to Toxicity Dosage Modification(s) Less than 7 days (within a cycle) Interrupt the next dose (maintain a minimum of 6 days between doses).

Greater than or equal to 7 days Omit the next dose within the cycle.

Greater than or equal to 14 days Once adequate recovery is achieved, decrease the total dose by 25% for the subsequent cycle.

If further dose modification is required, 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.

Greater than 28 days Consider permanent discontinuation of treatment. 2.4 Instructions for Reconstitution, Dilution, and Administration Protect the reconstituted and diluted BESPONSA solutions from light.

Do not freeze the reconstituted or diluted solution.

The maximum time from reconstitution through the end of administration should be less than or equal to 8 hours, with less than or equal to 4 hours between reconstitution and dilution.

• BESPONSA is a hazardous drug.

Follow applicable special handling and disposal procedures. 1.

• Calculate the dose (mg) and number of vial(s) of BESPONSA required.

• Reconstitute each vial with 4 mL of Sterile Water for Injection, USP, to obtain a concentration of 0.25 mg/mL of BESPONSA that delivers 3.6 mL (0.9 mg).

• Gently swirl the vial to aid dissolution.

• Inspect the reconstituted solution for particulates and discoloration.

The reconstituted solution should be clear to opalescent, colorless to slightly yellow, and essentially free of visible foreign matter.

• See Table for storage times and conditions for the reconstituted solution.

• Withdraw the required volume of the reconstituted solution from the vial(s) needed to obtain the appropriate dose according to the patient’s body surface area.

Discard any unused reconstituted

BESPONSA solution left in the vial.

• Dilute the reconstituted BESPONSA solution in 0.9% Sodium Chloride Injection, USP, in the appropriate infusion container per Table 5: Table 5.

Infusion Container Information Infusion Bag Administration Syringe Administration.

• For calculated doses greater than or equal to 0.5 mg.

• Ensure a final prepared concentration of 0.01 mg/mL to 0.1 mg/mL in a total volume of 50 mL.

• For calculated doses less than 0.5 mg.

• Ensure a final prepared concentration of 0.025 mg/mL to 0.1 mg/mL in a total volume between 2 mL to 50 mL.

• Gently invert the infusion container to mix the diluted solution.

• See Table for storage times and conditions for the diluted solution.

• See Table for storage times and conditions for prior to and during administration of the diluted solution.

• For syringe infusions, a syringe pump and micro-bore IV tubing must be used.

• Filtration of the diluted solution is not required.

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 (MCE).

• Infuse the diluted solution as an intravenous infusion over one hour.

Flush the intravenous infusion line with 0.9% Sodium Chloride Injection, USP, to ensure the complete dose is administered.

Do not mix

BESPONSA or administer as an infusion with other medicinal products.

Table 6 shows the storage times and conditions for reconstitution, dilution, and administration of BESPONSA.

Table 6.

Storage Times and Conditions for

SUPPLIED/STORAGE AND HANDLING How Supplied BESPONSA (inotuzumab ozogamicin) for injection is supplied as a white to off-white lyophilized powder in a single-dose vial for reconstitution and further dilution.

Each vial delivers 0.9 mg inotuzumab ozogamicin.

Each carton (NDC 0008-0100-01) contains one single-dose vial.

Refrigerate (2-8°C; 36-46°F) BESPONSA vials and store in the original carton to protect from light.

Do not freeze.

BESPONSA is a hazardous drug.

Follow applicable special handling and disposal procedures.

Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman.

There are no available data on

BESPONSA use in pregnant women to inform a drug-associated risk.

In rat embryo-fetal development studies, inotuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were ≥ 0.4 times the exposure in patients at the maximum recommended dose, based on AUC.

Advise patients of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2–4% and 15–20%, respectively.

In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m 2 during the period of organogenesis.

Embryo-fetal toxicities including increased resorptions and fetal growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification were observed at ≥ 0.11 mg/m 2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC).

Fetal growth retardation also occurred at 0.04 mg/m 2 (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC).

In an embryo-fetal development study in rabbits, pregnant animals received daily intravenous doses up to 0.15 mg/m 2 (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis.

At a dose of 0.15 mg/m 2, slight maternal toxicity was observed in the absence of any effects on embryo‑fetal development.

The safety and effectiveness of

BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL have been established.

The use of

BESPONSA for this indication is supported by evidence of safety and effectiveness in Study WI203581 (ITCC-059) .

The study included patients in the following age groups: 2 patients 1 year to < 2 years old, 10 patients 2 years to < 6 years old, 20 patients 6 years to < 12 years old, and 20 patients 12 years to < 17 years old.

Compared to adults, pediatric patients had a higher incidence of liver test abnormalities; with grade 3-4 increases in AST, ALT, and total bilirubin in 21%, 21%, and 9%, respectively, in pediatric patients treated with BESPONSA compared to 4%, 4%, and 5% in adults.

BESPONSA in patients < 1 year of age with relapsed or refractory CD22-positive B-cell precursor ALL have not been established.

ALL trial, 30/164 patients (18%) treated with BESPONSA were ≥ 65 years of age.

No differences in responses were identified between older and younger patients.

Based on a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age.