What is mechanism of action?

mechanism of action is CD22-directed Antibody Interactions [MoA]

Besponsa

(Inotuzumab Ozogamicin)

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Dosage & Administration

* •Administer by intravenous infusion only. (2.1)
* •Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions. (

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

[see Warnings and Precautions (5.4)]

.
* •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/mm³is recommended prior to the first dose.

)
* •Dosing regimens for Cycle 1 and subsequent cycles, depending on the response to treatment, are shown below. See full prescribing information for dosing details. (

2. DOSAGE AND ADMINISTRATION

* •Administer by intravenous infusion only. (2.1)
* •Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions.
* •Dosing regimens for Cycle 1 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/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	21 daysFor 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/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	28 days
Patients who have not achieved a CR or CRi:
Dose	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
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

[see Dosage and Administration (2.2)]

.
* •Administer by intravenous infusion only.
* •For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m²per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m²), Day 8 (0.5 mg/m²), and Day 15 (0.5 mg/m²). Cycle 1 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.
* •For subsequent cycles:
* •In patients who achieve a CR or CRi, the recommended total dose of BESPONSA is 1.5 mg/m²per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m²), Day 8 (0.5 mg/m²), and Day 15 (0.5 mg/m²). Subsequent cycles are 4 weeks in duration.

OR
* •In patients who do not achieve a CR or CRi, the recommended total dose of BESPONSA is 1.8 mg/m²per cycle given as 3 divided doses on Day 1 (0.8 mg/m²), Day 8 (0.5 mg/m²), and Day 15 (0.5 mg/m²). Subsequent cycles are 4 weeks in duration. 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

[see Warnings and Precautions (5.1)]

.
* •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 1 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:
DoseDose is based on the patient's body surface area (m²).	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	21 daysFor 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 × 10⁹/L and absolute neutrophil counts [ANC] ≥ 1 × 10⁹/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 × 10⁹/L and/or ANC < 1 × 10⁹/L) and resolution of any extramedullary disease. :
Dose	0.5 mg/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	28 days7-day treatment-free interval starting on Day 21.
Patients who have not achieved a CR or CRi :
Dose	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	28 days

2.2 Recommended Pre-medications and Cytoreduction

[see Warnings and Precautions (5.4)]

2.3 Dosage Modifications for Adverse Reactions

Modify the dose of BESPONSA for toxicities (see Tables 2–4). BESPONSA doses within a treatment cycle (i.e., Days 8 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

[see Warnings and Precautions (5.3)]

* ⁹⁹

-
Criteria	BESPONSA Dosage Modification(s)
Abbreviation: ANC=absolute neutrophil count.
If prior to BESPONSA treatment ANC was greater than or equal to 1 × 10⁹/L	If ANC decreases, then interrupt the next cycle of treatment until recovery of ANC to greater than or equal to 1 × 10⁹/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 × 10⁹/LPlatelet 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 × 10⁹/L . Discontinue BESPONSA if low platelet count persists for greater than 28 days and is suspected to be related to BESPONSA.
If prior to BESPONSA treatment ANC was less than 1 × 10⁹/L and/or platelet count was less than 50 × 10⁹/L	If ANC or platelet count decreases, 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, orANC recovers to greater than or equal to 1 × 10/L and platelet count recovers to greater than or equal to 50 × 10/L, orStable 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 [see Warnings and Precautions (5.1)] .
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 [see Warnings and Precautions (5.1)] .
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 [see Warnings and Precautions (5.4)] .
Non-hematologic toxicity greater than or equal to Grade 2Severity 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.

Reconstitution

* •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.

DO NOT SHAKE

.
* •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 6for storage times and conditions for the reconstituted solution.

Dilution

* •

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:

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

Table 5. Infusion Container Information
Infusion Bag Administration	Syringe Administration
*
*

* •

Gently invert the infusion container to mix the diluted solution.

DO NOT SHAKE

* •

PROTECT FROM LIGHT.

* •

See Table 6for storage times and conditions for the diluted solution.

Administration

* •

See Table 6for 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 Reconstituted and Diluted BESPONSA Solution
	Storage Time and Conditions Maximum time from reconstitution through end of administration less than or equal to 8 hours with less than or equal to 4 hours between reconstitution and dilution.
Reconstituted Solution	*
Diluted Solution	*

BESPONSA contains no bacteriostatic preservatives. Use reconstituted solution immediately or store refrigerated at (2°C-8°C; 36°F-46°F) for up to 4 hours.PROTECT FROM LIGHT. DO NOT FREEZE.Use diluted solution immediately or store at room temperature (20°C-25°C; 68°F-77°F) or refrigerated (2°C-8°C; 36°F-46°F) for up to 6 hours.If the diluted solution is refrigerated (2°C-8°C; 36°F-46°F), allow it to equilibrate at room temperature (20°C-25°C; 68°F-77°F) for approximately 1 hour prior to administration.Administer diluted solution within 8 hours of reconstitution including the 1 hour equilibration and 1 hour infusion.PROTECT FROM LIGHT. DO NOT FREEZE.

)

	Day 1	Day 8	Day 15
Dosing regimen for Cycle 1
All patients:
Dose	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	21 daysFor 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/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	28 days
Patients who have not achieved a CR or CRi:
Dose	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	28 days

* •See full prescribing information for instructions on reconstitution of lyophilized powder, and preparation and administration of reconstituted drug. (

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.

Reconstitution

DO NOT SHAKE

Dilution

* •

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

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

Table 5. Infusion Container Information
Infusion Bag Administration	Syringe Administration
*
*

* •

Gently invert the infusion container to mix the diluted solution.

DO NOT SHAKE

* •

PROTECT FROM LIGHT.

* •

See Table 6for storage times and conditions for the diluted solution.

Administration

* •

See Table 6for 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.

* •

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 Reconstituted and Diluted BESPONSA Solution
	Storage Time and Conditions Maximum time from reconstitution through end of administration less than or equal to 8 hours with less than or equal to 4 hours between reconstitution and dilution.
Reconstituted Solution	*
Diluted Solution	*

)

Besponsa Prescribing Information

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.

DO NOT SHAKE

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 6for storage times and conditions for the reconstituted solution.

Dilution

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

•
Indications and Usage 1. INDICATIONS AND USAGE BESPONSA is indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older . BESPONSA is a CD22-directed antibody and cytotoxic drug conjugate indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older.	3/2024
Dosage and Administration, Instructions for Reconstitution, Dilution and Administration 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. Reconstitution :

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

Table 5. Infusion Container Information
Infusion Bag Administration	Syringe Administration

•
Gently invert the infusion container to mix the diluted solution.
DO NOT SHAKE
.
•
PROTECT FROM LIGHT.
•
See Table 6for storage times and conditions for the diluted solution.

Administration

•
See Table 6for 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.

BESPONSA contains no bacteriostatic preservatives. Use reconstituted solution immediately or store refrigerated at (2°C-8°C; 36°F-46°F) for up to 4 hours.

PROTECT FROM LIGHT. DO NOT FREEZE.Use diluted solution immediately or store at room temperature (20°C-25°C; 68°F-77°F) or refrigerated (2°C-8°C; 36°F-46°F) for up to 6 hours.

If the diluted solution is refrigerated (2°C-8°C; 36°F-46°F), allow it to equilibrate at room temperature (20°C-25°C; 68°F-77°F) for approximately 1 hour prior to administration.

Administer diluted solution within 8 hours of reconstitution including the 1 hour equilibration and 1 hour infusion.

PROTECT FROM LIGHT. DO NOT FREEZE.

Table 6. Storage Times and Conditions for Reconstituted and Diluted BESPONSA Solution
	Storage Time and Conditions Maximum time from reconstitution through end of administration less than or equal to 8 hours with less than or equal to 4 hours between reconstitution and dilution.
Reconstituted Solution
Diluted Solution

3/2024

Warnings and Precautions, Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)

5.1 Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)

BESPONSA can cause hepatotoxicity, including VOD. In adult patients in the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD occurred in 23/164 patients (14%) in the BESPONSA arm during or following treatment or following a HSCT after completion of treatment. VOD occurred up to 56 days after the final dose during treatment or during follow-up without an intervening HSCT. The median time from subsequent HSCT to onset of VOD was 15 days (range: 3-57 days).

In the BESPONSA arm, among the 79 patients who proceeded to a subsequent HSCT, VOD occurred in 18/79 patients (23%), and among all 164 patients treated, VOD occurred in 5/164 patients (3%) during study therapy or in follow-up without an intervening HSCT.

The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing 2 alkylating agents (e.g., busulfan in combination with other alkylating agents) and last total bilirubin level greater than or equal to the ULN before HSCT are significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of BESPONSA treatment cycles. Patients who have experienced prior VOD or have serious ongoing hepatic liver disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis) are at an increased risk for worsening of liver disease, including developing VOD, following treatment with BESPONSA.

In Study WI203581 (ITCC-059) VOD occurred in 8/53 (15%) of pediatric patients treated with single agent BESPONSA. Among the 26 pediatric patients who underwent HSCT, VOD occurred in 5 (19%) patients

[see Adverse Reactions (6.1)]

Monitor closely for signs and symptoms of VOD including elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Due to the risk of VOD, for patients proceeding to HSCT, the recommended duration of treatment with BESPONSA is 2 cycles; a third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles

[see Dosage and Administration (2.1)]

. For patients who proceed to HSCT, monitor liver tests at least weekly during the first month post-HSCT, then less frequently thereafter, according to standard medical practice.

In adult patients in the INO-VATE ALL trial, increases in liver test abnormalities occurred. Grade 3 or 4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively.

In pediatric patients in Study WI203581 (ITCC-059), liver test abnormalities occurred, with Grade 3 or 4 increases in AST, ALT, and blood bilirubin in 11/53 (21%), 11/53 (21%), and 5/53 (9%) of patients, respectively

[see Adverse Reactions (6.1)]

In all patients, monitor liver tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of BESPONSA. Based on elevations of liver tests withhold, reduce dose, or permanently discontinue BESPONSA

[see Dosage and Administration (2.3)]

3/2024

Warnings and Precautions, Increased Risk of Post-Transplant Non-Relapse Mortality

5.2 Increased Risk of Post-Transplant Non-Relapse Mortality

In adult patients in the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared to the Investigator's choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate.

Overall, 79/164 patients (48%) in the BESPONSA arm and 35/162 patients (22%) in the Investigator's choice of chemotherapy arm had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 31/79 (39%) and 8/35 (23%) in the BESPONSA arm compared to the Investigator's choice of chemotherapy arm, respectively.

In the BESPONSA arm, the most common causes of post-HSCT non-relapse mortality included VOD and infections. Five of the 18 VOD events that occurred post-HSCT were fatal. In the BESPONSA arm, among patients with ongoing VOD at time of death, 6 patients died due to multiorgan failure (MOF) or infection (3 patients died due to MOF, 2 patients died due to infection, and 1 patient died due to MOF and infection).

In pediatric patients in Study WI203581 (ITCC-059), 26/53 patients (49%) had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 7/26 (27%).

Monitor for toxicities post-HSCT, including signs and symptoms of infection and VOD

[see Warnings and Precautions (5.1, 5.3)]

3/2024

Warnings and Precautions, Myelosuppression

5.3 Myelosuppression

BESPONSA can cause myelosuppression, including thrombocytopenia and neutropenia

[see Adverse Reactions (6.1)]

In adult patients in the INO-VATE ALL trial, thrombocytopenia and neutropenia occurred in 83/164 patients (51%) and 81/164 patients (49%), respectively. Grade 3 thrombocytopenia and neutropenia occurred in 23/164 patients (14%) and 33/164 patients (20%), respectively. Grade 4 thrombocytopenia and neutropenia occurred in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia, which may be life-threatening, occurred in 43/164 patients (26%). For patients who were in CR or CRi at the end of treatment, the recovery of platelet counts to > 50,000/mm³was later than 45 days after the final dose in 15/164 patients (9%) who received BESPONSA and 3/162 patients (2%) who received Investigator's choice of chemotherapy.

Complications associated with myelosuppression (including infections and bleeding/hemorrhage) occurred in patients receiving BESPONSA

[see Adverse Reactions (6.1)]

. Infections, including serious infections, some of which were life-threatening or fatal, occurred in 79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, occurred in 8/164 patients (5%). Bacterial, viral, and fungal infections occurred.

Hemorrhage occurred in 54/164 patients (33%). Grade 3 or 4 hemorrhage occurred in 8/164 patients (5%), including a fatality in 1/164 patients (1%) (intra-abdominal hemorrhage). The most common type of hemorrhage was epistaxis which occurred in 24/164 patients (15%).

In pediatric patients in Study WI203581 (ITCC-059), Grade 3 or 4 thrombocytopenia occurred in 24/53 (45%) patients. Grade 3 or 4 neutropenia occurred in 21/53 (40%) patients. Infections occurred in 23/53 (43%) patients, and hemorrhage occurred in 22/53 (42%) patients. The most common types of hemorrhage were hematoma in 8/53 (15%), mouth hemorrhage in 6/53 (11%), and epistaxis in 6/53 (11%) patients

[see Adverse Reactions (6.1)]

Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment with BESPONSA. As appropriate, administer prophylactic anti-infectives and employ surveillance testing during and after treatment with BESPONSA. Based on the severity of myelosuppression, reduce dose, temporarily withhold, or permanently discontinue BESPONSA

[see Dosage and Administration (2.3)].

3/2024

Warnings and Precautions, Infusion Related Reactions

5.4 Infusion Related Reactions

BESPONSA can cause infusion related reactions. In adult patients in the INO-VATE ALL trial, infusion related reactions occurred in patients who received BESPONSA. Infusion related reactions (all Grade 2) occurred in 4/164 patients (2%)

[see Adverse Reactions (6.1)]

. Infusion related reactions generally occurred in Cycle 1 shortly after the end of the BESPONSA infusion and resolved spontaneously or with medical management.

In pediatric patients in Study WI203581 (ITCC-059), infusion related reactions occurred in 4/53 (8%) patients

[see Adverse Reactions (6.1)]

Premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing

[see Dosage and Administration (2.2)]

Monitor patients closely during and for at least 1 hour after the end of infusion for the potential onset of infusion related reactions, including symptoms such as fever, chills, rash, or breathing problems. Interrupt infusion and institute appropriate medical management if an infusion related reaction occurs. 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 BESPONSA

[see Dosage and Administration (2.3)]

3/2024

Warnings and Precautions, QT Interval Prolongation

5.5 QT Interval Prolongation

BESPONSA can cause QT interval prolongation. In adult patients in the INO-VATE ALL trial, increases in QT interval corrected for heart rate using Fridericia’s formula (QTcF) of ≥ to 60 msec from baseline occurred in 4/162 patients (3%). Grade 2 QT prolongation was reported in 2/164 patients (1%)

[see Adverse Reactions (6.1)and Clinical Pharmacology (12.2)]

In pediatric patients in Study WI203581 (ITCC-059), increases in QTcF of > 60 msec from baseline occurred in 7/49 (14%) patients. 3/52 (6%) of patients had QTcF values > 500 msec

[see Adverse Reactions (6.1)]

Administer BESPONSA with caution in patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval

[see Drug Interactions (7)]

, and in patients with electrolyte disturbances

[see Drug Interactions (7)].

Obtain electrocardiograms (ECGs) and electrolytes prior to the start of treatment, after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment

[see Drug Interactions (7), Clinical Pharmacology (12.2)]

3/2024

•Administer by intravenous infusion only. (2.1)
•Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions. (
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
  [see Warnings and Precautions (5.4)]
  .
- •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/mm³is recommended prior to the first dose.
)

•Dosing regimens for Cycle 1 and subsequent cycles, depending on the response to treatment, are shown below. See full prescribing information for dosing details. (

2. DOSAGE AND ADMINISTRATION

•Administer by intravenous infusion only. (2.1)
•Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions.
•Dosing regimens for Cycle 1 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/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	21 daysFor 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/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	28 days
Patients who have not achieved a CR or CRi:
Dose	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
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
[see Dosage and Administration (2.2)]
.
•Administer by intravenous infusion only.
•For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m²per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m²), Day 8 (0.5 mg/m²), and Day 15 (0.5 mg/m²). Cycle 1 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.
•For subsequent cycles:
- •In patients who achieve a CR or CRi, the recommended total dose of BESPONSA is 1.5 mg/m²per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m²), Day 8 (0.5 mg/m²), and Day 15 (0.5 mg/m²). Subsequent cycles are 4 weeks in duration.
  
  OR
- •In patients who do not achieve a CR or CRi, the recommended total dose of BESPONSA is 1.8 mg/m²per cycle given as 3 divided doses on Day 1 (0.8 mg/m²), Day 8 (0.5 mg/m²), and Day 15 (0.5 mg/m²). Subsequent cycles are 4 weeks in duration. 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
[see Warnings and Precautions (5.1)]
.
•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 1 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:
DoseDose is based on the patient's body surface area (m²).	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	21 daysFor 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 × 10⁹/L and absolute neutrophil counts [ANC] ≥ 1 × 10⁹/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 × 10⁹/L and/or ANC < 1 × 10⁹/L) and resolution of any extramedullary disease. :
Dose	0.5 mg/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	28 days7-day treatment-free interval starting on Day 21.
Patients who have not achieved a CR or CRi :
Dose	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
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
[see Warnings and Precautions (5.4)]
.
•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/mm³is recommended prior to the first dose.

2.3 Dosage Modifications for Adverse Reactions

Table 2. BESPONSA Dosage Modifications for Hematologic Toxicities

[see Warnings and Precautions (5.3)]

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

ANC recovers to greater than or equal to 1 × 10⁹/L and platelet count recovers to greater than or equal to 50 × 10⁹/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).

-
Criteria	BESPONSA Dosage Modification(s)
Abbreviation: ANC=absolute neutrophil count.
If prior to BESPONSA treatment ANC was greater than or equal to 1 × 10⁹/L	If ANC decreases, then interrupt the next cycle of treatment until recovery of ANC to greater than or equal to 1 × 10⁹/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 × 10⁹/LPlatelet 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 × 10⁹/L . Discontinue BESPONSA if low platelet count persists for greater than 28 days and is suspected to be related to BESPONSA.
If prior to BESPONSA treatment ANC was less than 1 × 10⁹/L and/or platelet count was less than 50 × 10⁹/L	If ANC or platelet count decreases, then interrupt the next cycle of treatment until at least one of the following occurs:

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 [see Warnings and Precautions (5.1)] .
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 [see Warnings and Precautions (5.1)] .
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 [see Warnings and Precautions (5.4)] .
Non-hematologic toxicity greater than or equal to Grade 2Severity 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.

Reconstitution

•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.
DO NOT SHAKE
.
•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 6for storage times and conditions for the reconstituted solution.

Dilution

•
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:

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

Table 5. Infusion Container Information
Infusion Bag Administration	Syringe Administration

•
Gently invert the infusion container to mix the diluted solution.
DO NOT SHAKE
.
•
PROTECT FROM LIGHT.
•
See Table 6for storage times and conditions for the diluted solution.

Administration

•
See Table 6for 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.

BESPONSA contains no bacteriostatic preservatives. Use reconstituted solution immediately or store refrigerated at (2°C-8°C; 36°F-46°F) for up to 4 hours.

PROTECT FROM LIGHT. DO NOT FREEZE.Use diluted solution immediately or store at room temperature (20°C-25°C; 68°F-77°F) or refrigerated (2°C-8°C; 36°F-46°F) for up to 6 hours.

If the diluted solution is refrigerated (2°C-8°C; 36°F-46°F), allow it to equilibrate at room temperature (20°C-25°C; 68°F-77°F) for approximately 1 hour prior to administration.

Administer diluted solution within 8 hours of reconstitution including the 1 hour equilibration and 1 hour infusion.

PROTECT FROM LIGHT. DO NOT FREEZE.

Table 6. Storage Times and Conditions for Reconstituted and Diluted BESPONSA Solution
	Storage Time and Conditions Maximum time from reconstitution through end of administration less than or equal to 8 hours with less than or equal to 4 hours between reconstitution and dilution.
Reconstituted Solution
Diluted Solution

)

	Day 1	Day 8	Day 15
Dosing regimen for Cycle 1
All patients:
Dose	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	21 daysFor 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/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	28 days
Patients who have not achieved a CR or CRi:
Dose	0.8 mg/m²	0.5 mg/m²	0.5 mg/m²
Cycle length	28 days

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

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.

Reconstitution

•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.
DO NOT SHAKE
.
•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 6for storage times and conditions for the reconstituted solution.

Dilution

•
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:

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

Table 5. Infusion Container Information
Infusion Bag Administration	Syringe Administration

•
Gently invert the infusion container to mix the diluted solution.
DO NOT SHAKE
.
•
PROTECT FROM LIGHT.
•
See Table 6for storage times and conditions for the diluted solution.

Administration

•
See Table 6for 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.

BESPONSA contains no bacteriostatic preservatives. Use reconstituted solution immediately or store refrigerated at (2°C-8°C; 36°F-46°F) for up to 4 hours.

PROTECT FROM LIGHT. DO NOT FREEZE.Use diluted solution immediately or store at room temperature (20°C-25°C; 68°F-77°F) or refrigerated (2°C-8°C; 36°F-46°F) for up to 6 hours.

If the diluted solution is refrigerated (2°C-8°C; 36°F-46°F), allow it to equilibrate at room temperature (20°C-25°C; 68°F-77°F) for approximately 1 hour prior to administration.

Administer diluted solution within 8 hours of reconstitution including the 1 hour equilibration and 1 hour infusion.

PROTECT FROM LIGHT. DO NOT FREEZE.

Table 6. Storage Times and Conditions for Reconstituted and Diluted BESPONSA Solution
	Storage Time and Conditions Maximum time from reconstitution through end of administration less than or equal to 8 hours with less than or equal to 4 hours between reconstitution and dilution.
Reconstituted Solution
Diluted Solution

)

Lactation: Advise not to breastfeed. (

8.2 Lactation

Risk Summary

There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with BESPONSA and for 2 months after the last dose.

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