Dosage & Administration
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 days * | ||
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 | ||
Besponsa Prescribing Information
HEPATOTOXICITY, INCLUDING VOD
- •
- Hepatotoxicity, including fatal and life-threatening VOD occurred in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) who received BESPONSA. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin level ≥ upper limit of normal (ULN) before HSCT were 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.
- •
- Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA. Permanently discontinue treatment if VOD occurs. If severe VOD occurs, treat according to standard medical practice [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
INCREASED RISK OF POST-HSCT NON-RELAPSE MORTALITY
- •
- There was higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate [see Warnings and Precautions (5.2)].
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.
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/m2 per 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/m2 per 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/m2 per 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.
| Abbreviations: CR=complete remission; CRi=complete remission with incomplete hematologic recovery. | |||
| |||
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 days ‡ | ||
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 # | ||
Recommended Pre-medications and Cytoreduction
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- 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/mm3 is recommended prior to the first dose.
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)]
| 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/L * | 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:
|
| 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 2 * | Interrupt treatment until recovery to Grade 1 or pre-treatment grade levels prior to each dose. |
| 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. |
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.
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- 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:
Infusion Bag Administration | Syringe Administration |
|
|
- •
- 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.
| |
Storage Time and Conditions * | |
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.
Pregnancy
Risk Summary
Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)], 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 [see Data]. 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.
Data
Animal Data
In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m2 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/m2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m2 (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/m2 (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/m2, slight maternal toxicity was observed in the absence of any effects on embryo‑fetal development.
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.
Females and Males of Reproductive Potential
Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating BESPONSA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for 8 months after the last dose [see Nonclinical Toxicology (13.1)].
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for 5 months after the last dose [see Nonclinical Toxicology (13.1)].
Infertility
Females
Based on findings in animals, BESPONSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].
Males
Based on findings in animals, BESPONSA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].
Pediatric Use
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) [see Adverse Reactions (6.1), Clinical Studies (14.1)]. 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.
The safety and effectiveness of BESPONSA in patients < 1 year of age with relapsed or refractory CD22-positive B-cell precursor ALL have not been established.
Geriatric Use
In the INO-VATE 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 [see Clinical Pharmacology (12.3)].
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 (12.3)].
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 (2.3)]. 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 (2.3), Warnings and Precautions (5.1)].
None.