BESPONSA Powder for concentrate for solution for infusion Ref.[8985] Active ingredients: Inotuzumab ozogamicin

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 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/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.

Table 1. Dosing regimen in adults and paediatric patients for cycle 1 and subsequent cycles depending on response to treatment:

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 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.

Table 2. Dose modifications for haematological toxicities at the start of a treatment cycle (Day 1):

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:

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:

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 paediatric patients aged <1 year have not been established.

Method of administration

BESPONSA is for intravenous use. The infusion must be administered over 1 hour. To mitigate the risk of QT prolongation, the time of infusion should be increased to 1.5 hours in paediatric patients with a body weight <35 kg.

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.

Instructions for reconstitution, dilution, and administration

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.

Reconstitution:

• Calculate the dose (mg) and number of vials of BESPONSA required.
• Reconstitute each 1 mg vial with 4 mL of water for injection, to obtain a single-use solution of 0.25 mg/mL of BESPONSA.
• Gently swirl the vial to aid dissolution. Do not shake.
• Inspect the reconstituted solution for particulates and discolouration. The reconstituted solution must be clear to slightly cloudy, colourless, and essentially free of visible foreign matter. If particles or discolouration are observed, do not use.
• BESPONSA contains no bacteriostatic preservatives. The reconstituted solution must be used immediately. If the reconstituted solution cannot be used immediately, it may be stored in a refrigerator (2°C-8°C) for up to 4 hours. Protect from light and do not freeze.

Dilution:

• Withdraw the required volume of the reconstituted solution from the vial(s) needed to obtain the appropriate dose according to patient body surface area. Protect from light. Discard any unused reconstituted BESPONSA solution left in the vial.
• Dilute the reconstituted BESPONSA solution in sodium chloride 9 mg/mL (0.9%) solution for injection, in the appropriate infusion container per Table 10. Protect from light.

Table 10. Infusion container information:

• Gently invert the infusion container to mix the diluted solution. Do not shake.
• The diluted solution must be used immediately, 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.

Administration:

• If the diluted solution is stored in a refrigerator (2°C-8°C), it must be allowed to equilibrate at room temperature (20°C-25°C) for approximately 1 hour prior to administration.
• Filtration of the diluted solution is not required. However, if the diluted solution is filtered, polyethersulphone (PES)-, polyvinylidene fluoride (PVDF)-, or hydrophilic polysulphone (HPS)-based filters are recommended. Do not use filters made of nylon or mixed cellulose ester (MCE).
• Protect the intravenous bag from light using an ultraviolet light-blocking cover (i.e., amber, dark brown, or green bags or aluminium foil) during infusion. The infusion line does not need to be protected from light.
• Infuse the diluted solution for 1 hour at a rate of 50 mL/h at room temperature (20°C-25°C). Protect from light. Infusion lines made of PVC (DEHP or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended.
• For syringe infusions, a syringe pump and micro-bore IV tubing must be used.

Do not mix BESPONSA or administer as an infusion with other medicinal products.

Table 11 shows the storage times and conditions for reconstitution, dilution, and administration of BESPONSA.

Table 11. Storage times and conditions for reconstituted and diluted BESPONSA solution:

^a With ≤4 hours between reconstitution and dilution.

Disposal

BESPONSA is for single use only.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.