Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
BESPONSA is indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B cell precursor acute lymphoblastic leukaemia (ALL). Adult 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).
BESPONSA should be administered under the supervision of a physician experienced in the use of cancer therapy and in an environment where full resuscitation facilities are immediately available. When considering the use of BESPONSA as a treatment for relapsed or refractory B cell ALL, baseline CD22 positivity of >0% using a validated and sensitive assay is required prior to initiating treatment (see section 5.1).
For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count ≤10,000/mm³ is recommended prior to the first dose.
Pre-medication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing (see section 4.4).
For patients with a high tumour burden, pre-medication to reduce uric acid levels and hydration is recommended prior to dosing (see section 4.4).
Patients should be observed during, and for at least 1 hour after the end of infusion for symptoms of infusion related reactions (see section 4.4).
BESPONSA should be administered in 3- to 4-week cycles.
For patients proceeding to haematopoietic stem cell transplant (HSCT), the recommended duration of treatment is 2 cycles. A third cycle may be considered for those patients who do not achieve a complete remission (CR) or complete remission with incomplete haematological recovery (CRi) and minimal residual disease (MRD) negativity after 2 cycles (see section 4.4). For patients not proceeding to HSCT, a maximum of 6 cycles may be administered. Any patients who do not achieve a CR/CRi within 3 cycles should discontinue treatment.
Table 1 shows the recommended dosing regimens.
For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m² per cycle, given as 3 divided doses on Days 1 (0.8 mg/m²), 8 (0.5 mg/m²), and 15 (0.5 mg/m²). Cycle 1 is 3 weeks in duration but may be extended to 4 weeks if the patient achieves a CR or CRi, and/or to allow recovery from toxicity.
For subsequent cycles, the recommended total dose of BESPONSA is 1.5 mg/m² per cycle given as 3 divided doses on Days 1 (0.5 mg/m²), 8 (0.5 mg/m²), and 15 (0.5 mg/m²) for patients who achieve a CR/CRi or 1.8 mg/m 2 per cycle given as 3 divided doses on Days 1 (0.8 mg/m²), 8 (0.5 mg/m²), and 15 (0.5 mg/m²) for patients who do not achieve a CR/CRi. Subsequent cycles are 4 weeks in duration.
Table 1. Dosing regimen for Cycle 1 and subsequent cycles depending on response to treatment:
| Day 1 | Day 8a | Day 15a | |
|---|---|---|---|
| Dosing regimen for Cycle 1 | |||
| All patients: | |||
| Dose (mg/m²) | 0.8 | 0.5 | 0.5 |
| Cycle length | 21 daysb | ||
| Dosing regimen for subsequent cycles depending on response to treatment | |||
| Patients who have achieved a CRc or CRid: | |||
| Dose (mg/m²) | 0.5 | 0.5 | 0.5 |
| Cycle length | 28 dayse | ||
| Patients who have not achieved a CRc or CRid: | |||
| Dose (mg/m²) | 0.8 | 0.5 | 0.5 |
| Cycle length | 28 dayse | ||
Abbreviations: ANC=absolute neutrophil counts; CR=complete remission; CRi=complete remission with incomplete haematological recovery.
a +/- 2 days (maintain minimum of 6 days between doses).
b For patients who achieve a CR/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).
c CR is defined as <5% blasts in the bone marrow and the absence of peripheral blood leukaemic blasts, full recovery of peripheral blood counts (platelets ≥100 × 109/L and ANC ≥1 × 109/L) and resolution of any extramedullary disease.
d CRi is defined as <5% blasts in the bone marrow and the absence of peripheral blood leukaemic blasts, incomplete recovery of peripheral blood counts (platelets <100 × 109/L and/or ANC <1 × 109/L) and resolution of any extramedullary disease.
e 7-day treatment-free interval starting on Day 21.
Dose modification of BESPONSA may be required based on individual safety and tolerability (see section 4.4). Management of some adverse drug reactions may require dosing interruptions and/or dose reductions, or permanent discontinuation of BESPONSA (see sections 4.4 and 4.8). If the dose is reduced due to BESPONSA-related toxicity, the dose should not be re-escalated.
Table 2 and Table 3 show the dose modification guidelines for haematological and non-haematological toxicities, respectively. 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-haematological toxicities.
Table 2. Dose modifications for haematological toxicities at the start of a treatment cycle (Day 1):
| Haematological toxicity | Toxicity and dose modification(s) |
|---|---|
| Levels prior to BESPONSA treatment: | |
| ANC was ≥1 × 109/L | If ANC decreases, interrupt the next cycle of treatment until recovery of ANC to ≥1 × 109/L. |
| Platelet count was ≥50 × 109/La | If platelet count decreases, interrupt the next cycle of treatment until platelet count recovers to ≥50 × 109/La. |
| ANC was <1 × 109/L and/or platelet count was <50 × 109/La | If ANC and/or platelet count decreases, interrupt the next cycle of treatment until at least one of the following occurs: |
| ANC and platelet count recover to at least baseline levels for the prior cycle, or | |
| ANC recovers to ≥1 × 109/L and platelet count recovers to ≥50 × 109/La, 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). |
Abbreviation: ANC=absolute neutrophil count.
a Platelet count used for dosing must be independent of blood transfusion.
Table 3. Dose modifications for non-haematological toxicities at any time during treatment:
| Non-haematological toxicity | Dose modification(s) |
|---|---|
| VOD/SOS or other severe liver toxicity | Permanently discontinue treatment (see section 4.4). |
| Total bilirubin >1.5 × ULN and AST/ALT >2.5 × ULN | Interrupt the dosing until recovery of total bilirubin to ≤ 1.5 × ULN and AST/ALT to ≤2.5 × ULN prior to each dose unless due to Gilbert’s disease or haemolysis. Permanently discontinue treatment if total bilirubin does not recover to ≤1.5 × ULN or AST/ALT does not recover to ≤2.5 × ULN (see section 4.4). |
| 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 section 4.4). |
| Grade ≥2a non-haematological toxicity (BESPONSA-related) | Interrupt treatment until recovery to Grade 1 or pre-treatment grade levels prior to each dose. |
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal; VOD/SOS=venoocclusive disease/sinusoidal obstruction syndrome.
a Severity grade according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0.
Table 4 shows the dose modification guidelines depending on the duration of dosing interruptions due to toxicity.
Table 4. Dose modifications depending on duration of dosing interruption due to toxicity:
| Duration of dosing interruption due to toxicity | Dose modification(s) |
|---|---|
| <7 days (within a cycle) | Interrupt the next dose (maintain a minimum of 6 days between doses). |
| ≥7 days | Omit the next dose within the cycle. |
| ≥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. |
| >28 days | Consider permanent discontinuation of BESPONSA. |
No adjustment to the starting dose is required based on age (see section 5.2).
No adjustment to the starting dose is required in patients with hepatic impairment defined by total bilirubin ≤1.5 × upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5 × ULN (see section 5.2). There is limited safety information available in patients with total bilirubin >1.5 × ULN and AST/ALT >2.5 × ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to ≤1.5 × ULN and AST/ALT to ≤2.5 × ULN prior to each dose unless due to Gilbert’s syndrome or haemolysis. Permanently discontinue treatment if total bilirubin does not recover to ≤1.5 × ULN or AST/ALT does not recover to ≤2.5 × ULN (see Table 3 and section 4.4).
No adjustment to the starting dose is required in patients with mild, moderate, or severe renal impairment (creatinine clearance [CLcr] 60-89 mL/min, 30-59 mL/min, or 15-29 mL/min, respectively) (see section 5.2). The safety and efficacy of BESPONSA have not been studied in patients with end-stage renal disease.
The safety and efficacy of BESPONSA in children aged 0 to <18 years have not been established. No data are available.
BESPONSA is for intravenous use. The infusion must be administered over 1 hour.
BESPONSA should not be administered as an intravenous push or bolus.
BESPONSA must be reconstituted and diluted before administration. For instructions on reconstitution and dilution of BESPONSA before administration, see section 6.6.
In clinical studies in patients with relapsed or refractory ALL, the maximum single and multiple doses of inotuzumab ozogamicin were 0.8 mg/m² and 1.8 mg/m², respectively, per cycle, given as 3 divided doses on Days 1 (0.8 mg/m²), 8 (0.5 mg/m²), and 15 (0.5 mg/m²) (see section 4.2). Overdoses may result in adverse reactions that are consistent with the reactions observed at the recommended therapeutic dose (see section 4.8).
In the event of an overdose, the infusion should be temporarily interrupted, and patients should be monitored for liver and haematological toxicities (see section 4.2). Re-initiation of BESPONSA at the correct therapeutic dose should be considered when all toxicities have resolved.
Unopened vial: 5 years.
Reconstituted solution: BESPONSA contains no bacteriostatic preservatives. The reconstituted solution must be used immediately. If the reconstituted solution cannot be used immediately, it may be stored for up to 4 hours in a refrigerator (2°C-8°C). Protect from light and do not freeze.
Diluted solution: The diluted solution must be used immediately or stored at room temperature (20°C-25°C) or in a refrigerator (2°C-8°C). The maximum time from reconstitution through the end of administration should be ≤8 hours, with ≤4 hours between reconstitution and dilution. Protect from light and do not freeze.
Store in a refrigerator (2°C-8°C).
Do not freeze.
Store in the original carton in order to protect from light.
For storage conditions after reconstitution and dilution, see section 6.3.
Type I amber glass vial with chlorobutyl rubber stopper and crimp seal with flip off cap containing 1 mg of powder.
Each carton contains 1 vial.
Use appropriate aseptic technique for the reconstitution and dilution procedures. Inotuzumab ozogamicin (which has a density of 1.02 g/mL at 20°C/68°F) is light sensitive and should be protected from ultraviolet light during reconstitution, dilution, and administration.
The maximum time from reconstitution through the end of administration should be ≤ 8 hours, with ≤4 hours between reconstitution and dilution.
Do not mix BESPONSA or administer as an infusion with other medicinal products.
Table 8 shows the storage times and conditions for reconstitution, dilution, and administration of BESPONSA.
Table 8. Storage times and conditions for reconstituted and diluted BESPONSA solution:
| ←Maximum time from reconstitution through the end of administration ≤8 hoursa→ | ||
|---|---|---|
| Reconstituted solution | Diluted solution | |
| After start of dilution | Administration | |
| Use reconstituted solution immediately or after being stored in a refrigerator (2°C-8°C) for up to 4 hours. Protect from light. Do not freeze. | Use diluted solution immediately or after being stored at room temperature (20°C-25°C) or in a refrigerator (2°C-8°C). The maximum time from reconstitution through the end of administration should be ≤8 hours, with ≤4 hours between reconstitution and dilution. Protect from light. Do not freeze. | If the diluted solution is stored in a refrigerator (2°C-8°C), bring it to room temperature (20°C-25°C) for approximately 1 hour prior to administration. Administer diluted solution as a 1-hour infusion at a rate of 50 mL/h at room temperature (20°C-25°C). Protect from light. |
a With ≤4 hours between reconstitution and dilution.
BESPONSA is for single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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