4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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, 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 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 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)

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.

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. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

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.

4.3. Contraindications

- 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).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hepatotoxicity, including 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 studies had undergone HSCT within the previous 4 months.

Patients with a history of liver disease should be carefully evaluated (e.g., ultrasound scan, viral hepatitis testing) prior to treatment with BESPONSA to exclude serious ongoing hepatic disease (see section 4.3).

Due to the risk of VOD/SOS, for patients proceeding to HSCT, the recommended duration of treatment with inotuzumab ozogamicin is 2 cycles; a third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles (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 during treatment and after HSCT (see section 5.1), 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, discontinuation of the infusion or administration of steroids and antihistamines should be considered (see section 4.2). For severe or life-threatening infusion reactions, treatment should be permanently discontinued (see section 4.2).

Tumour lysis syndrome (TLS)

In patients receiving inotuzumab ozogamicin, TLS, which may be life-threatening or fatal, was reported (see section 4.8).

Pre‑medication to reduce uric acid levels and hydration is recommended prior to dosing for patients with a high tumour burden (see section 4.2).

Patients should be monitored for signs and symptoms of TLS and treated according to standard medical practice.

QT interval prolongation

In patients receiving inotuzumab ozogamicin, QT interval prolongation was observed (see sections 4.8 and 5.2).

BESPONSA should be administered with caution in patients who have a history of, or predisposition to QT interval prolongation, who are taking medicinal products that are known to prolong QT interval (see section 4.5) and in patients with electrolyte disturbances. ECG and electrolytes should be obtained prior to the start of treatment and periodically monitored during treatment (see sections 4.8 and 5.2).

Increased amylase and lipase

In patients receiving inotuzumab ozogamicin, increases in amylase and lipase have been reported (see section 4.8).

Patients should be monitored for increases in amylase and lipase. Potential hepatobiliary disease should be evaluated and treated according to standard medical practice.

Immunisations

The safety of immunisation with live viral vaccines during or following BESPONSA therapy has not been studied. Vaccination with live viral vaccines is not recommended for at least 2 weeks prior to the start of BESPONSA treatment, during treatment, and until recovery of B lymphocytes following the last treatment cycle.

Excipients

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 mg inotuzumab ozogamicin, that is to say essentially 'sodium‑free'.

This medicinal product may be further prepared for administration with sodium-containing solutions (see sections 4.2 and 6.6) and this should be considered in relation to the total sodium from all sources that will be administered to the patient.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed (see section 5.2).

Based on in vitro data, coadministration of inotuzumab ozogamicin with inhibitors or inducers of cytochrome P450 (CYP) or uridine diphosphate‑glucuronosyltransferase (UGT) drug metabolising enzymes are unlikely to alter exposure to N-acetyl-gamma-calicheamicin dimethylhydrazide. In addition, inotuzumab ozogamicin and N‑acetyl‑gamma‑calicheamicin dimethylhydrazide are unlikely to alter the exposure of substrates of CYP enzymes, and N‑acetyl‑gamma‑calicheamicin dimethylhydrazide is unlikely to alter the exposure of substrates of UGT enzymes or major drug transporters.

In patients receiving inotuzumab ozogamicin, prolonged QT interval was observed (see section 4.4). Therefore, the concomitant use of inotuzumab ozogamicin with medicinal products known to prolong QT interval or to induce Torsades de Pointes should be carefully considered. The QT interval should be monitored in case of combinations of such medicinal products (see sections 4.4, 4.8, and 5.2).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should avoid becoming pregnant while receiving BESPONSA.

Women should use effective contraception during treatment with BESPONSA and for at least 8 months after the final dose. Men with female partners of childbearing potential should use effective contraception during treatment with BESPONSA and for at least 5 months after the final dose.

Pregnancy

There are no data in pregnant women using inotuzumab ozogamicin. Based on non‑clinical safety findings, inotuzumab ozogamicin can cause embryo‑foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see section 5.3).

BESPONSA must not be used during pregnancy unless the potential benefit to the mother outweighs the potential risks to the foetus. Pregnant women, or patients becoming pregnant while receiving inotuzumab ozogamicin, or treated male patients as partners of pregnant women, must be apprised of the potential hazard to the foetus.

Breast-feeding

There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breast-fed child, or the effects on milk production. Because of the potential for adverse reactions in breast-fed children, women must not breast‑feed during treatment with BESPONSA and for at least 2 months after the final dose (see section 5.3).

Fertility

Based on non-clinical findings, male and female fertility may be compromised by treatment with inotuzumab ozogamicin (see section 5.3). There is no information on fertility in patients. Both men and women must seek advice for fertility preservation before treatment.

4.7. Effects on ability to drive and use machines

BESPONSA has moderate influence on the ability to drive and use machines. Patients may experience fatigue during treatment with BESPONSA (see section 4.8). Therefore, caution is recommended when driving or operating machines.

4.8. Undesirable effects

Summary of the safety profile

The most common (≥ 20%) adverse reactions were thrombocytopenia (51%), neutropenia (49%), infection (48%), anaemia (36%), leukopenia (35%), fatigue (35%), haemorrhage (33%), pyrexia (32%), nausea (31%), headache (28%), febrile neutropenia (26%), increased transaminases (26%), abdominal pain (23%), increased gamma-glutamyltransferase (21%), and hyperbilirubinaemia (21%).

In patients who received BESPONSA, the most common (≥ 2%) serious adverse reactions were infection (23%), febrile neutropenia (11%), haemorrhage (5%), abdominal pain (3%), pyrexia (3%), VOD/SOS (2%), and fatigue (2%).

Tabulated list of adverse reactions

Table 5 shows the adverse reactions reported in patients with relapsed or refractory ALL who received BESPONSA.

The adverse reactions are presented by system organ class (SOC) and frequency categories, defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5. Adverse reactions reported in patients with relapsed or refractory B-cell precursor ALL who received BESPONSA

MedDRA System organ class

Very common

Common

Infections and infestations

Infection (48%)a (includes Sepsis and Bacteraemia [17%], Fungal infection [9%], Lower respiratory tract infection [12%)], Upper respiratory tract infection [12%], Bacterial infection [1%], Viral infection [7%], Gastrointestinal infection [4%], Skin infection [4%])

Blood and lymphatic system disorders

Febrile neutropenia (26%)

Neutropenia (49%)

Thrombocytopenia (51%)

Leukopenia (35%)

Lymphopenia (18%)

Anaemia (36%)

Pancytopeniab (2%)

Immune system disorders

Hypersensitivity (1%)

Metabolism and nutrition disorders

Decreased appetite (12%)

Tumour lysis syndrome (2%)

Hyperuricaemia (4%)

Nervous system disorders

Headache (28%)

Vascular disorders

Haemorrhagec (33%) (includes Central nervous system haemorrhage [1%], Upper gastrointestinal haemorrhage [6%], Lower gastrointestinal haemorrhage [4%], Epistaxis [15%])

Gastrointestinal disorders

Abdominal pain (23%)

Vomiting (15%)

Diarrhoea (17%)

Nausea (31%)

Stomatitis (13%)

Constipation (17%)

Ascites (4%)

Abdominal distension (6%)

Hepatobiliary disorders

Hyperbilirubinaemia (21%)

Increased transaminases (26%)

Increased GGT (21%)

VOD/SOS (3% [pre-HSCT]d)

General disorders and administration site conditions

Pyrexia (32%)

Fatigue (35%)

Chills (11%)

Investigations

Increased alkaline phosphatase (13%)

ECG QT prolonged (1%)

Increased amylase (5%)

Increased lipase (9%)

Injury, poisoning and procedural complications

Infusion related reaction (10%)

Adverse reactions included treatment-emergent, all-causality events that commenced on, or after Cycle 1 Day 1 within 42 days after the final dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT).

Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.

Abbreviations: ALL=acute lymphoblastic leukaemia; VOD/SOS= venoocclusive liver disease/sinusoidal obstruction syndrome; ECG=electrocardiogram; GGT=gamma‑glutamyltransferase; HSCT=haematopoietic stem cell transplant.

a Infection also includes other types of infection (11%). Note: patients may have had > 1 type of infection.

b Pancytopenia includes the following reported preferred terms: Bone marrow failure, Febrile bone marrow aplasia, and Pancytopenia.

c Haemorrhage also includes other types of haemorrhage (17%). Note: patients may have had > 1 type of haemorrhage.

d VOD/SOS includes 1 additional patient with VOD that occurred at Day 56 with no intervening HSCT. VOD/SOS was also reported in 18 patients after a subsequent HSCT.

Description of selected adverse reactions

Hepatotoxicity, including VOD/SOS

In the pivotal clinical study (N=164), VOD/SOS was reported in 23 (14%) patients including 5 (3%) patients during study therapy or in follow-up without an intervening HSCT. Among the 79 patients who proceeded to a subsequent HSCT (8 of whom received additional salvage therapy after treatment with BESPONSA before proceeding to HSCT), VOD/SOS was reported in 18 (23%) patients. Five of the 18 VOD/SOS events that occurred post-HSCT were fatal (see section 5.1).

VOD/SOS was reported up to 56 days after the final dose of inotuzumab ozogamicin without an intervening HSCT. The median time from HSCT to onset of VOD/SOS was 15 days (range: 3‑57 days). Of the 5 patients who experienced VOD/SOS during treatment with inotuzumab ozogamicin but without an intervening HSCT, 2 patients had also received an HSCT before BESPONSA treatment.

Among patients who proceeded to HSCT after BESPONSA treatment, VOD/SOS was reported in 5/11 (46%) patients who received an HSCT both prior to and after BESPONSA treatment and 13/68 (19%) patients who only received an HSCT after BESPONSA treatment.

Regarding other risk factors, VOD/ SOS was reported in 6/11 (55%) patients who received a HSCT conditioning regimen containing 2 alkylating agents and 9/53 (17%) patients who received a HSCT conditioning regimen containing 1 alkylating agent, 7/17 (41%) patients who were ≥ 55 years old and 11/62 (18%) patients who were < 55 years old, and 7/12 (58%) patients with a serum bilirubin ≥ ULN prior to HSCT and in 11/67 (16%) patients with a serum bilirubin < ULN prior to HSCT.

In the pivotal study (N=164), hyperbilirubinaemia and increased transaminases were reported in 35 (21%) and 43 (26%) patients, respectively. Grade ≥ 3 hyperbilirubinaemia and increased transaminases were reported in 9 (6%) and 11 (7%) patients, respectively. The median time to onset of hyperbilirubinaemia and increased transaminases was 73 days and 29 days, respectively.

For clinical management of hepatotoxicity, including VOD/SOS, see section 4.4.

Myelosuppression/cytopenias

In the pivotal study (N=164), thrombocytopenia and neutropenia were reported in 83 (51%) and 81 (49%) patients, respectively. Grade 3 thrombocytopenia and neutropenia were reported in 23 (14%) and 33 (20%) patients, respectively. Grade 4 thrombocytopenia and neutropenia were reported in 46 (28%) and 45 (27%) patients, respectively. Febrile neutropenia, which may be life-threatening, was reported in 43 (26%) patients.

For clinical management of myelosuppression/cytopenias, see section 4.4.

Infections

In the pivotal study (N=164), infections, including serious infections, some of which were life‑threatening or fatal, were reported in 79 (48%) patients. The frequencies of specific infections were: sepsis and bacteraemia (17%), lower respiratory tract infection (12%), upper respiratory tract infection (12%), fungal infection (9%), viral infection (7%), gastrointestinal infection (4%), skin infection (4%), and bacterial infection (1%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, were reported in 8 (5%) patients.

For clinical management of infections, see section 4.4.

Bleeding/haemorrhage

In the pivotal clinical study (N=164), bleeding/haemorrhagic events, mostly mild in severity, were reported in 54/ (33%) patients. The frequencies of specific bleeding/haemorrhagic events were: epistaxis (15%), upper gastrointestinal haemorrhage (6%), lower gastrointestinal haemorrhage (4%), and central nervous system (CNS) haemorrhage (1%). Grade 3/4 bleeding/haemorrhagic events were reported in 8/164 (5%) patients. One Grade 5 bleeding/haemorrhagic event (intra‑abdominal haemorrhage) was reported.

For clinical management of bleeding/haemorrhagic events, see section 4.4.

Infusion related reactions

In the pivotal study (N=164), infusion related reactions were reported in 17 (10%) patients. All events were Grade ≤ 2 in severity. Infusion related reactions generally occurred in Cycle 1 and shortly after the end of the inotuzumab ozogamicin infusion and resolved spontaneously or with medical management.

For clinical management of infusion related reactions, see section 4.4.

Tumour lysis syndrome (TLS)

In the pivotal study (N=164), TLS, which may be life-threatening or fatal, was reported in 4/164 (2%) patients. Grade 3/4 TLS was reported in 3 (2%) patients. TLS occurred shortly after the end of the inotuzumab ozogamicin infusion and resolved with medical management.

For clinical management of TLS, see section 4.4.

QT interval prolongation

In the pivotal study (N=164), maximum increases in QT interval corrected for heart rate using the Fridericia formula (QTcF) ≥ 30 msec and ≥ 60 msec from baseline were measured in 30/162 (19%) and 4/162 (3%) patients, respectively. An increase in QTcF interval of > 450 msec was observed in 26/162 (16%) patients. No patients had an increase in QTcF interval > 500 msec. Grade 2 QT interval prolongation was reported in 2/164 (1%) patients. No Grade ≥ 3 QT interval prolongation or events of Torsades de Pointes were reported.

For periodic monitoring of ECG and electrolyte levels, see section 4.4.

Increased amylase and lipase

In the pivotal study (N=164), increases in amylase and lipase were reported in 8 (5%) and 15 (9%) patients, respectively. Increases in Grade ≥ 3 amylase and lipase were reported in 3 (2%) and 7 (4%) patients, respectively.

For periodic monitoring of increased amylase and lipase, see section 4.4.

Immunogenicity

In clinical studies of inotuzumab ozogamicin in adult patients with relapsed or refractory ALL, 7/236 (3%) patients tested positive for anti-inotuzumab ozogamicin antibodies (ADA). No patients tested positive for neutralising ADA. In patients who tested positive for ADA, no effect on clearance of BESPONSA was detected based on population‑pharmacokinetic analysis. The number of patients with positive ADA was too small to assess the impact of ADA on efficacy and safety.

In clinical study ITCC-059 of inotuzumab ozogamicin in paediatric patients with relapsed or refractory ALL (N=51), the incidence of ADA against inotuzumab ozogamicin was 0%.

Paediatric population

BESPONSA has been evaluated in 53 paediatric patients ≥ 1 and < 18 years of age with relapsed or refractory CD22-positive B cell precursor ALL in Study ITCC-059 (see section 5.1).

The most common adverse reactions (> 30%) in the paediatric study ITCC-059 were thrombocytopenia (60%), pyrexia (52%), anaemia (48%), vomiting (48%) neutropenia (44%), infection (44%), haemorrhage (40%), febrile neutropenia (32%), nausea (32%), abdominal pain (32%) in the Phase 1 Cohort and pyrexia (46%), thrombocytopenia (43%), anaemia (43%), vomiting (43%), neutropenia (36%), leukopenia (36%), nausea (32%), infection (32%), transaminase increased (32%), and haemorrhage (32%) in the Phase 2 Cohort.

In the Phase 1 Cohort, 2/25 (8.0%) patients had VOD (neither received transplant) and 6/28 (21.4%) patients in the Phase 2 Cohort had VOD, with a post-HSCT VOD rate of 5/18 (27.8% [95% CI: 9.69 - 53.48]). In the Phase 1 Cohort, 8/25 patients (32%) and 18/28 (64%) in the Phase 2 Cohort had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 2/8 (25%) and 5/18 (28%) in the Phase 1 Cohort and the Phase 2 Cohort, respectively.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.