Inotuzumab ozogamicin

Hepatic Impairment Based on a population pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1.0–1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST less than or equal to ULN; n=611).

In patients with moderate (total bilirubin greater than 1.5–3 × ULN and AST any level; n=3) and severe hepatic impairment (total bilirubin greater than 3 × ULN and AST any level; n=1), inotuzumab ozogamicin clearance did not appear to be reduced [see Clinical Pharmacology ]. No adjustment to the starting dose is required when administering BESPONSA to patients with total bilirubin less than or equal to 1.5 × ULN and AST/ALT less than or equal to 2.5 × ULN [see Dosage and Administration ].

There is limited safety information available in patients with total bilirubin greater than 1.5 × ULN and/or AST/ALT greater than 2.5 × ULN prior to dosing. 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 Dosage and Administration , Warnings and Precautions ] .

Recommended Dosage

Pre-medicate before each dose [see Dosage and Administration ] .

Administer by intravenous infusion only.

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 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/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. OR

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 ). 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 ] .

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. [See table below.] (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

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 6 for 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: [See table below.]

Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE .

PROTECT FROM LIGHT.

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

See Table 6 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. [See table below.] Diluted Solution

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.