Besponsa (Inotuzumab Ozogamicin)

BESPONSA is indicated for the treatment of relapsed or refractory

• •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

  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)]

  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
  )

• •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
  )

For injection: 0.9 mg as a white to off-white lyophilized powder in a single-dose vial for reconstitution and further dilution.

Lactation: Advise not to breastfeed. (