BESPONSA 1mg powder for concentrate for solution for infusion
Pfizer Limited
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Active ingredient
inotuzumab ozogamicin
Legal Category
POM: Prescription only medicine
BESPONSA 1 mg powder for concentrate for solution for infusion
Each vial contains 1 mg inotuzumab ozogamicin.
After reconstitution (see section 6.6), 1 mL of solution contains 0.25 mg inotuzumab ozogamicin.
Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of a recombinant humanised IgG4 kappa CD22-directed monoclonal antibody (produced in Chinese hamster ovary cells by recombinant DNA technology) that is covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide.
For the full list of excipients, see section 6.1.
Powder for concentrate for solution for infusion.
White to off-white, lyophilised cake or powder.
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).
Posology
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, additional cycles of treatment, up to a maximum of 6 cycles, may be administered. 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/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) for patients who do not achieve a CR/CRi. Subsequent cycles are 4 weeks in duration.
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Table 1. Dosing regimen for Cycle 1 and subsequent cycles depending on response to treatment
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Day 1
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Day 8a
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Day 15a
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Dosing regimen for Cycle 1
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All patients:
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Dose (mg/m2)
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0.8
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0.5
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0.5
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Cycle length
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21 daysb
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Dosing regimen for subsequent cycles depending on response to treatment
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Patients who have achieved a CRc or CRid:
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Dose (mg/m2)
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0.5
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0.5
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0.5
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Cycle length
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28 dayse
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Patients who have not achieved a CRc or CRid:
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Dose (mg/m2)
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0.8
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0.5
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0.5
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Cycle length
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28 dayse
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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.
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Dose modifications
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.
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Table 2. Dose modifications for haematological toxicities at the start of a treatment cycle (Day 1)
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Haematological toxicity
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Toxicity and dose modification(s)
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Levels prior to BESPONSA treatment:
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ANC was ≥ 1 × 109/L
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If ANC decreases, interrupt the next cycle of treatment until recovery of ANC to ≥ 1 × 109/L.
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Platelet count was ≥ 50 × 109/La
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If platelet count decreases, interrupt the next cycle of treatment until platelet count recovers to ≥ 50 × 109/La.
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ANC was < 1 × 109/L and/or platelet count was < 50 × 109/La
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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).
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Abbreviation: ANC=absolute neutrophil count.
a Platelet count used for dosing must be independent of blood transfusion.
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Table 3. Dose modifications for non-haematological toxicities at any time during treatment
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Non-haematological toxicity
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Dose modification(s)
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VOD/SOS or other severe liver toxicity
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Permanently discontinue treatment (see section 4.4).
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Total bilirubin > 1.5 × ULN and AST/ALT > 2.5 × ULN
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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).
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Infusion related reaction
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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).
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Grade ≥ 2a non-haematological toxicity (BESPONSA-related)
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Interrupt treatment until recovery to Grade 1 or pre-treatment grade levels prior to each dose.
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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.
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Table 4 shows the dose modification guidelines depending on the duration of dosing interruptions due to toxicity.
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Table 4. Dose modifications depending on duration of dosing interruption due to toxicity
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Duration of dosing interruption due to toxicity
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Dose modification(s)
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< 7 days (within a cycle)
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Interrupt the next dose (maintain a minimum of 6 days between doses).
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≥ 7 days
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Omit the next dose within the cycle.
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≥ 14 days
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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.
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> 28 days
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Consider permanent discontinuation of BESPONSA.
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Special populations
Elderly
No adjustment to the starting dose is required based on age (see section 5.2).
Hepatic impairment
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).
Renal impairment
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.
Paediatric population
The safety and efficacy of BESPONSA in children aged 0 to <18 years have not been established. No data are available.
Method of administration
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.
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Patients who have experienced prior confirmed severe or ongoing venoocclusive liver disease/sinusoidal obstruction syndrome (VOD/SOS).
- Patients with serious ongoing hepatic disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis).
Traceability
In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient file.
Hepatotoxicity, including venoocclusive liver disease/sinusoidal obstruction syndrome (VOD/SOS)
Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD/SOS, was reported in patients with relapsed or refractory ALL receiving BESPONSA (see section 4.8). BESPONSA significantly increased the risk of VOD/SOS above that of standard chemotherapy regimens in this patient population. This risk was most marked in patients who underwent subsequent HSCT.
In the following subgroups, the reported frequency of VOD/SOS post-HSCT was ≥ 50%:
- Patients who received a HSCT conditioning regimen containing 2 alkylating agents;
- Patients aged ≥ 65 years; and
- Patients with a serum bilirubin ≥ ULN prior to HSCT.
The use of HSCT conditioning regimens containing 2 alkylating agents should be avoided. The benefit/risk should be carefully considered before administering BESPONSA to patients in whom the future use of HSCT conditioning regimens containing 2 alkylating agents is likely unavoidable.
In patients in whom the serum bilirubin is ≥ ULN prior to HSCT, HSCT post BESPONSA treatment should only be undertaken after careful consideration of the benefit/risk. If these patients do proceed to HSCT, signs and symptoms of VOD/SOS should be monitored closely (see section 4.2).
Other patient factors that appear to be associated with an increased risk of VOD/SOS after HSCT include a prior HSCT, age ≥ 55 years, a history of liver disease and/or hepatitis before treatment, later salvage lines, and a greater number of treatment cycles.
Careful consideration is required before administering BESPONSA to patients who have had a prior HSCT. No patients with relapsed or refractory ALL who were treated with BESPONSA in clinical trials had undergone HSCT within the previous 4 months.
Patients with a history of liver disease should be carefully eva luated (e.g., ultrasound scan, viral hepatitis testing) prior to treatment with BESPONSA to exclude serious ongoing hepatic disease (see section 4.3).
For patients proceeding to HSCT, the recommended duration of treatment is 2 cycles, with a maximum of 3 cycles, to reduce the risk of VOD/ SOS (see section 4.2).
Signs and symptoms of VOD/SOS should be monitored closely in all patients, especially post HSCT. Signs may include elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD/SOS. In all patients, liver tests should be monitored, including, ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of BESPONSA. For patients who develop abnormal liver tests, liver tests and clinical signs and symptoms of hepatotoxicity should be monitored more frequently. For patients who proceed to HSCT, liver tests should be monitored closely during the first month post-HSCT, then less frequently thereafter, according to standard medical practice. Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA (see section 4.2).
Treatment should be permanently discontinued if VOD/SOS occurs (see section 4.2). If severe VOD/SOS occurs, the patient should be treated according to standard medical practice.
Myelosuppression/cytopenias
In patients receiving inotuzumab ozogamicin, neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some of which were life-threatening, have been reported (see section 4.8).
In patients receiving inotuzumab ozogamicin, complications associated with neutropenia and thrombocytopenia (including infections and bleeding/haemorrhagic events, respectively) were reported in some patients (see section 4.8).
Complete blood counts should be monitored prior to each dose of BESPONSA and signs and symptoms of infection, bleeding/haemorrhage, and other effects of myelosuppression should be monitored during treatment. As appropriate, prophylactic anti-infectives should be administered and surveillance testing should be employed during and after treatment.
Management of severe infection, bleeding/haemorrhage and other effects of myelosuppression, including severe neutropenia or thrombocytopenia, may require a dosing interruption, dose reduction, or discontinuation of treatment (see section 4.2).
Infusion related reactions
In patients receiving inotuzumab ozogamicin, infusion related reactions were reported (see section 4.8).
Pre-medication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing (see section 4.2).
Patients should be monitored 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 hypotension, hot flush, or breathing problems. If an infusion related reaction occurs, the infusion should be interrupted and appropriate medical management should be instituted. Depending on the severity of the infusion related reaction, discont
