BESPONSA 1mg powder for concentrate infusion solution medication leaflet

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 byrecombinant DNA technology) that is covalently linked to N-acetyl-gamma-calicheamicindimethylhydrazide.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

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 havefailed treatment with at least 1 tyrosine kinase inhibitor (TKI).

BESPONSA should be administered under the supervision of a physician experienced in the use ofcancer 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 initiatingtreatment (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 isrecommended 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 ofinfusion 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 oftreatment is 2 cycles. A third cycle may be considered for those patients who do not achieve acomplete remission (CR) or complete remission with incomplete haematological recovery (CRi) andminimal residual disease (MRD) negativity after 2 cycles (see section 4.4). For patients not proceedingto HSCT, a maximum of 6 cycles may be administered. Any patients who do not achieve a CR/CRiwithin 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 is3 weeks in duration but may be extended to 4 weeks if the patient achieves a CR or CRi, and/or toallow recovery from toxicity.

For subsequent cycles, the recommended total dose of BESPONSA is 1.5 mg/m2 per cycle given as3 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), and15 (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 totreatment

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 withincomplete 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 beextended 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, fullrecovery of peripheral blood counts (platelets ≥ 100 × 109/L and ANC ≥ 1 × 109/L) and resolution of anyextramedullary 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) andresolution 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 (seesection 4.4). Management of some adverse drug reactions may require dosing interruptions and/ordose reductions, or permanent discontinuation of BESPONSA (see sections 4.4 and 4.8). If the dose isreduced due to BESPONSA-related toxicity, the dose should not be re-escalated.

Table 2 and Table 3 show the dose modification guidelines for haematological andnon-haematological toxicities, respectively. BESPONSA doses within a treatment cycle (i.e. Days 8and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosinginterruptions 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 BESPONSAtreatment:

ANC was ≥ 1 × 109/L If ANC decreases, interrupt the next cycle of treatment untilrecovery of ANC to ≥ 1 × 109/L.

Platelet count was If platelet count decreases, interrupt the next cycle of treatment≥ 50 × 109/La until platelet count recovers to ≥ 50 × 109/La.

ANC was < 1 × 109/L and/or If ANC and/or platelet count decreases, interrupt the next cycleplatelet count was of treatment until at least one of the following occurs:< 50 × 109/La - ANC and platelet count recover to at least baseline levels forthe prior cycle, or

- ANC recovers to ≥ 1 × 109/L and platelet count recoversto ≥ 50 × 109/La, or

- Stable or improved disease (based on most recent bonemarrow assessment) and the ANC and platelet countdecrease 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 Permanently discontinue treatment (see section 4.4).toxicity

Total bilirubin > 1.5 × ULN and Interrupt the dosing until recovery of total bilirubin to

AST/ALT > 2.5 × ULN ≤ 1.5 × ULN and AST/ALT to ≤ 2.5 × ULN prior to each doseunless due to Gilbert’s disease or haemolysis. Permanentlydiscontinue 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 medicalmanagement. Depending on the severity of the infusion relatedreaction, consider discontinuation of the infusion oradministration of steroids and antihistamines. For severe orlife-threatening infusion reactions, permanently discontinuetreatment (see section 4.4).

Grade ≥ 2a non-haematological Interrupt treatment until recovery to Grade 1 or pre-treatmenttoxicity (BESPONSA-related) 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 dueto toxicity.

Table 4. Dose modifications depending on duration of dosing interruption due to toxicity

Duration of dosing Dose modification(s)interruption due to toxicity< 7 days (within a cycle) Interrupt the next dose (maintain a minimum of 6 daysbetween doses).≥ 7 days Omit the next dose within the cycle.≥ 14 days Once adequate recovery is achieved, decrease the total dose by25% for the subsequent cycle. If further dose modification isrequired, then reduce the number of doses to 2 per cycle forsubsequent cycles. If a 25% decrease in the total dose followedby a decrease to 2 doses per cycle is not tolerated, thenpermanently 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 totalbilirubin ≤ 1.5 × upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanineaminotransferase (ALT) ≤ 2.5 × ULN (see section 5.2). There is limited safety information available inpatients with total bilirubin > 1.5 × ULN and AST/ALT > 2.5 × ULN prior to dosing. Interrupt dosinguntil recovery of total bilirubin to ≤ 1.5 × ULN and AST/ALT to ≤ 2.5 × ULN prior to each doseunless due to Gilbert’s syndrome or haemolysis. Permanently discontinue treatment if total bilirubindoes not recover to ≤ 1.5 × ULN or AST/ALT does not recover to ≤ 2.5 × ULN (see Table 3 andsection 4.4).

No adjustment to the starting dose is required in patients with mild, moderate, or severe renalimpairment (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 inpatients with end-stage renal disease.

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 aposology can be made.

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 onreconstitution 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 liverdisease/sinusoidal obstruction syndrome (VOD/SOS).

- Patients with serious ongoing hepatic disease (e.g., cirrhosis, nodular regenerative hyperplasia,active hepatitis).

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

Hepatotoxicity, including VOD/SOS

Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD/SOS, wasreported 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 chemotherapyregimens 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. Thebenefit/risk should be carefully considered before administering BESPONSA to patients in whom thefuture 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 treatmentshould 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 HSCTinclude a prior HSCT, age ≥ 55 years, a history of liver disease and/or hepatitis before treatment, latersalvage 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 clinicalstudies had undergone HSCT within the previous 4 months.

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

Due to the risk of VOD/SOS, for patients proceeding to HSCT, the recommended duration oftreatment with inotuzumab ozogamicin is 2 cycles; a third cycle may be considered for those patientswho 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 weightgain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD/SOS. Inall patients, liver tests should be monitored, including, ALT, AST, total bilirubin, and alkalinephosphatase, prior to and following each dose of BESPONSA. For patients who develop abnormalliver tests, liver tests and clinical signs and symptoms of hepatotoxicity should be monitored morefrequently. For patients who proceed to HSCT, liver tests should be monitored closely during the firstmonth post-HSCT, then less frequently thereafter, according to standard medical practice. Elevation ofliver 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 beenreported (see section 4.8).

In patients receiving inotuzumab ozogamicin, complications associated with neutropenia andthrombocytopenia (including infections and bleeding/haemorrhagic events, respectively) werereported in some patients (see section 4.8).

Complete blood counts should be monitored prior to each dose of BESPONSA and signs andsymptoms of infection during treatment and after HSCT (see section 5.1), bleeding/haemorrhage, andother effects of myelosuppression should be monitored during treatment. As appropriate, prophylacticanti-infectives should be administered and surveillance testing should be employed during and aftertreatment.

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).

In patients receiving inotuzumab ozogamicin, infusion related reactions were reported (seesection 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 thepotential onset of infusion related reactions, including symptoms such as hypotension, hot flush, orbreathing problems. If an infusion related reaction occurs, the infusion should be interrupted andappropriate medical management should be instituted. Depending on the severity of the infusionrelated reaction, discontinuation of the infusion or administration of steroids and antihistamines shouldbe considered (see section 4.2). For severe or life-threatening infusion reactions, treatment should bepermanently discontinued (see section 4.2).

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

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

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

QT interval prolongation

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

BESPONSA should be administered with caution in patients who have a history of, or predispositionto 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 obtainedprior 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 (seesection 4.8).

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

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

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 sourcesthat will be administered to the patient.

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

Based on in vitro data, coadministration of inotuzumab ozogamicin with inhibitors or inducers ofcytochrome P450 (CYP) or uridine diphosphate-glucuronosyltransferase (UGT) drug metabolisingenzymes are unlikely to alter exposure to N-acetyl-gamma-calicheamicin dimethylhydrazide. Inaddition, inotuzumab ozogamicin and N-acetyl-gamma-calicheamicin dimethylhydrazide are unlikelyto alter the exposure of substrates of CYP enzymes, and N-acetyl-gamma-calicheamicindimethylhydrazide is unlikely to alter the exposure of substrates of UGT enzymes or major drugtransporters.

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 shouldbe monitored in case of combinations of such medicinal products (see sections 4.4, pct. 4.8, and 5.2).

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

Women should use effective contraception during treatment with BESPONSA and for at least8 months after the final dose. Men with female partners of childbearing potential should use effectivecontraception during treatment with BESPONSA and for at least 5 months after the final dose.

There are no data in pregnant women using inotuzumab ozogamicin. Based on non-clinical safetyfindings, inotuzumab ozogamicin can cause embryo-foetal harm when administered to a pregnantwoman. 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 outweighsthe potential risks to the foetus. Pregnant women, or patients becoming pregnant while receivinginotuzumab ozogamicin, or treated male patients as partners of pregnant women, must be apprised ofthe potential hazard to the fetus.

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

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

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

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 wereinfection (23%), febrile neutropenia (11%), haemorrhage (5%), abdominal pain (3%), pyrexia (3%),

VOD/SOS (2%), and fatigue (2%).

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, definedusing 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 beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder 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 Sepsisand Bacteraemia [17%],

Fungal infection [9%],

Lower respiratory tract infection[12%)], Upper respiratory tractinfection [12%], Bacterialinfection [1%], Viral infection[7%], Gastrointestinal infection[4%], Skin infection [4%])

Blood and lymphatic system Febrile neutropenia (26%) Pancytopeniab (2%)disorders Neutropenia (49%)

Thrombocytopenia (51%)

Leukopenia (35%)

Lymphopenia (18%)

Anaemia (36%)

Immune system disorders Hypersensitivity (1%)

Metabolism and nutrition Decreased appetite (12%) Tumour lysis syndrome (2%)disorders Hyperuricaemia (4%)

Nervous system disorders Headache (28%)

Vascular disorders Haemorrhagec (33%) (includes

Central nervous systemhaemorrhage [1%], Uppergastrointestinal haemorrhage[6%], Lower gastrointestinalhaemorrhage [4%], Epistaxis[15%])

Gastrointestinal disorders Abdominal pain (23%) Ascites (4%)

Vomiting (15%) Abdominal distension (6%)

Diarrhoea (17%)

Nausea (31%)

Stomatitis (13%)

Constipation (17%)

Hepatobiliary disorders Hyperbilirubinaemia (21%) VOD/SOS (3% [pre-HSCT]d)

Increased transaminases (26%)

Increased GGT (21%)

General disorders and Pyrexia (32%)administration site conditions Fatigue (35%)

Chills (11%)

Investigations Increased alkaline phosphatase ECG QT prolonged (1%)(13%) Increased amylase (5%)

Increased lipase (9%)

Injury, poisoning and Infusion related reaction (10%)procedural complications

Adverse reactions included treatment-emergent, all-causality events that commenced on, or after Cycle 1 Day 1within 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/sinusoidalobstruction syndrome; ECG=electrocardiogram; GGT=gamma-glutamyltransferase; HSCT=haematopoietic stemcell transplant.

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

ALL who received BESPONSA

MedDRA System organ class Very common Commona 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 marrowaplasia, and Pancytopenia.c Haemorrhage also includes other types of haemorrhage (17%). Note: patients may have had > 1 type ofhaemorrhage.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.

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 patientswho proceeded to a subsequent HSCT (8 of whom received additional salvage therapy after treatmentwith BESPONSA before proceeding to HSCT), VOD/SOS was reported in 18 (23%) patients. Five ofthe 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 anintervening 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 inotuzumabozogamicin 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 in5/11 (46%) patients who received an HSCT both prior to and after BESPONSA treatment and13/68 (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 HSCTconditioning regimen containing 2 alkylating agents and 9/53 (17%) patients who received a HSCTconditioning regimen containing 1 alkylating agent, 7/17 (41%) patients who were ≥ 55 years old and11/62 (18%) patients who were < 55 years old, and 7/12 (58%) patients with a serum bilirubin ≥ ULNprior 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 in35 (21%) and 43 (26%) patients, respectively. Grade ≥ 3 hyperbilirubinaemia and increasedtransaminases were reported in 9 (6%) and 11 (7%) patients, respectively. The median time to onset ofhyperbilirubinaemia 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%) and81 (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 in46 (28%) and 45 (27%) patients, respectively. Febrile neutropenia, which may be life-threatening, wasreported in 43 (26%) patients.

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

In the pivotal study (N=164), infections, including serious infections, some of which werelife-threatening or fatal, were reported in 79 (48%) patients. The frequencies of specific infectionswere: sepsis and bacteraemia (17%), lower respiratory tract infection (12%), upper respiratory tractinfection (12%), fungal infection (9%), viral infection (7%), gastrointestinal infection (4%), skininfection (4%), and bacterial infection (1%). Fatal infections, including pneumonia, neutropenicsepsis, 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, werereported 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 werereported in 8/164 (5%) patients. One Grade 5 bleeding/haemorrhagic event (intra-abdominalhaemorrhage) was reported.

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

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

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

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 theinotuzumab 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%) patient, respectively. An increase in QTcF interval of > 450 msec was observed in26/162 (16%) patients. No patients had an increase in QTcF interval > 500 msec. Grade 2 QT intervalprolongation 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.

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 patientstested positive for neutralising ADA. In patients who tested positive for ADA, no effect on clearanceof BESPONSA was detected based on population-pharmacokinetic analysis. The number of patientswith 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 orrefractory ALL (N=51), the incidence of ADA against inotuzumab ozogamicin was 0%.

BESPONSA has been evaluated in 53 paediatric patients ≥ 1 and < 18 years of age with relapsed orrefractory 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 werethrombocytopenia (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 afollow-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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical studies in patients with relapsed or refractory ALL, the maximum single and multiple dosesof inotuzumab ozogamicin were 0.8 mg/m2 and 1.8 mg/m2, respectively, per cycle, given as 3 divideddoses on Days 1 (0.8 mg/m2), 8 (0.5 mg/m2), and 15 (0.5 mg/m2) (see section 4.2). Overdoses mayresult in adverse reactions that are consistent with the reactions observed at the recommendedtherapeutic dose (see section 4.8).

In the event of an overdose, the infusion should be temporarily interrupted, and patients should bemonitored for liver and haematological toxicities (see section 4.2). Re-initiation of BESPONSA at thecorrect therapeutic dose should be considered when all toxicities have resolved.

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, monoclonal antibodiesand antibody drug conjugates, CD22 (Clusters of Differentiation 22) inhibitors, ATC code: L01FB01.

Inotuzumab ozogamicin is an ADC composed of a CD22-directed monoclonal antibody that iscovalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide. Inotuzumab is a humanisedimmunoglobulin class G subtype 4 (IgG4) antibody that specifically recognises human CD22. Thesmall molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic product.

N-acetyl-gamma-calicheamicin is covalently attached to the antibody via an acid-cleavable linker.

Nonclinical data suggest that the anticancer activity of BESPONSA is due to the binding of the ADCto CD22-expressing tumour cells, followed by internalisation of the ADC-CD22 complex, and theintracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage ofthe linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-stranded

DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

Patients with relapsed or refractory ALL who have received 1 or 2 prior treatment regimens for

ALL - Study 1

The safety and efficacy of BESPONSA in patients with relapsed or refractory CD22-positive ALLwere evaluated in an open-label, international, multicentre, Phase 3 study (Study 1) in which patientswere randomised to receive BESPONSA (N=164 [164 received treatment) or Investigator’s choice ofchemotherapy (N=162 [143 received treatment]), specifically fludarabine plus cytarabine plusgranulocyte colony-stimulating factor (FLAG) (N=102 [93 received treatment]),mitoxantrone/cytarabine (MXN/Ara-C) (N=38 [33 received treatment]), or high dose cytarabine(HIDAC) (N=22 [17 received treatment]).

Eligible patients were ≥ 18 years of age with Philadelphia chromosome negative (Ph-) or Ph+ relapsedor refractory B-cell CD22-positive precursor ALL.

CD22 expression was assessed using flow cytometry based on bone marrow aspirate. In patients withan inadequate bone marrow aspirate sample, a peripheral blood sample was tested. Alternatively,

CD22 expression was assessed using immunohistochemistry in patients with an inadequate bonemarrow aspirate and insufficient circulating blasts.

In the clinical study, the sensitivity of some local tests was lower than the central laboratory test.

Therefore, only validated tests with demonstrated high sensitivity should be used.

All patients were required to have ≥ 5% bone marrow blasts and to have received 1 or 2 priorinduction chemotherapy regimens for ALL. Patients with Ph+ B-cell precursor ALL were required tohave failed treatment with at least 1 second or third generation TKI and standard chemotherapy.

Table 1 (see section 4.2) shows the dosing regimen used to treat patients.

The co-primary endpoints were CR/CRi, assessed by a blinded independent endpoint adjudicationcommittee (EAC), and overall survival (OS). The secondary endpoints included MRD negativity,duration of remission (DoR), HSCT rate, and progression-free survival (PFS).

The primary analysis of CR/CRi and MRD negativity was conducted in the initial 218 randomisedpatients and the analysis of OS, PFS, DoR, and HSCT rate was conducted in all 326 randomisedpatients.

Among all 326 randomised patients (ITT population), 215 (66%) patients had received 1 priortreatment regimen and 108 (33%) patients had received 2 prior treatment regimens for ALL. Themedian age was 47 years (range: 18-79 years), 206 (63%) patients had a duration of first remission< 12 months, and 55 (17%) patients had undergone an HSCT prior to receiving BESPONSA or

Investigator’s choice of chemotherapy. The 2 treatment groups were generally balanced with respectto the baseline demographics and disease characteristics. A total of 276 (85%) patients had Ph- ALL.

Of the 49 (15%) patients with Ph+ ALL, 4 patients did not receive a prior TKI, 28 patients received 1prior TKI, and 17 patients received 2 prior TKIs. Dasatinib was the most commonly received TKI(42 patients) followed by imatinib (24 patients).

Baseline characteristics were similar in the initial 218 patients randomised.

Of the 326 patients (ITT population), 253 patients had samples that were evaluable for CD22 testingby both local and central laboratory. By central and local laboratory tests, 231/253 (91.3%) patientsand 130/253 (51.4%) patients, respectively, had ≥ 70% CD22-positive leukaemic blasts at baseline.

Table 6 shows the efficacy results from this study.

Table 6. Study 1: Efficacy results in patients ≥ 18 years of age with relapsed or refractory

B-cell precursor ALL who received 1 or 2 prior treatment regimens for ALL

BESPONSA HIDAC, FLAG, or(N=109) MXN/Ara-C (N=109)

CRa/CRib; n (%) [95% CI] 88 (80.7%) 32 (29.4%)[72.1%-87.7%] [21.0%-38.8%]2-sided p-value < 0.0001

CRa; n (%) [95% CI] 39 (35.8%) 19 (17.4%)[26.8%-45.5%] [10.8%-25.9%]2-sided p-value = 0.0022

CRib; n (%) [95% CI] 49 (45.0%) 13 (11.9%)[35.4%-54.8%] [6.5%-19.5%]2-sided p-value < 0.0001

MRD negativityc for patients achieving 69/88 (78.4%) 9/32 (28.1%)

CR/CRi; rated (%) [95% CI] [68.4%-86.5%] [13.7%-46.7%]2-sided p-value < 0.0001

BESPONSA HIDAC, FLAG, or(N=164) MXN/Ara-C (N=162)

Median OS; months [95% CI] 7.7 6.2[6.0 to 9.2] [4.7 to 8.3]

Hazard ratio [95% CI] = 0.751 [0.588-0.959]2-sided p-value = 0.0210

Median PFSe, f; months [95% CI] 5.0 1.7[3.9-5.8] [1.4-2.1]

Hazard ratio [95% CI] = 0.450 [0.348-0.581]2-sided p-value < 0.0001

Median DoRg; months [95% CI] 3.7 0.0[2.8 to 4.6] [-,-]

Hazard ratio [95% CI] = 0.471 [0.366-0.606]2-sided p-value < 0.0001

Abbreviations: ALL=acute lymphoblastic leukaemia; ANC=absolute neutrophil counts; Ara-C=cytarabine;

CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete haematologicalrecovery; DoR=duration of remission; EAC=Endpoint Adjudication Committee; FLAG=fludarabine +cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=haematopoietic stemcell transplant; ITT=intent-to-treat; MRD=minimal residual disease; MXN=mitoxantrone; N/n=number ofpatients; OS=overall survival; PFS=progression-free survival.

Table 6. Study 1: Efficacy results in patients ≥ 18 years of age with relapsed or refractory

B-cell precursor ALL who received 1 or 2 prior treatment regimens for ALLa CR, per EAC, was defined as < 5% blasts in the bone marrow and the absence of peripheral bloodleukaemic blasts, full recovery of peripheral blood counts (platelets ≥ 100 × 109/L and ANC ≥ 1 × 109/L)and resolution of any extramedullary disease.

b CRi, per EAC, was defined as < 5% blasts in the bone marrow and the absence of peripheral bloodleukaemic blasts, partial recovery of peripheral blood counts (platelets < 100 × 109/L and/or ANC< 1 × 109/L) and resolution of any extramedullary disease.

c MRD negativity was defined by flow cytometry as leukaemic cells comprising < 1 × 10-4 (< 0.01%) of bonemarrow nucleated cells.

d Rate was defined as number of patients who achieved MRD negativity divided by the total number ofpatients who achieved CR/CRi per EAC.

e PFS was defined as the time from date of randomisation to earliest date of the following events: death,progressive disease (including objective progression, relapse from CR/CRi, treatment discontinuation due toglobal deterioration of health status), and start of new induction therapy or post-therapy HSCT withoutachieving CR/CRi.

f In the standard definition of PFS, defined as the time from date of randomisation to earliest date of thefollowing events: death, progressive disease (including objective progression and relapse from CR/CRi), the

HR was 0.568 (2-sided p-value=0.0002) and median PFS was 5.6 months and 3.7 months in the

BESPONSA and Investigator’s choice of chemotherapy arm, respectively.

g Duration of remission was defined as the time since first response of CRa or CRib per Investigator’sassessment to the date of a PFS event or censoring date if no PFS event was documented. Analysis wasbased on the ITT population with patients without remission being given a duration of zero and consideredan event.

Among the initial 218 randomised patients, 64/88 (73%) and 21/88 (24%) of responding patients per

EAC achieved a CR/CRi in Cycles 1 and 2, respectively, in the BESPONSA arm. No additionalpatients achieved CR/CRi after Cycle 3 in the BESPONSA arm.

CR/CRi and MRD negativity findings in the initial 218 randomised patients were consistent with thoseseen in all 326 randomised patients.

Among all 326 randomised patients, the survival probability at 24 months was 22.8% in the

BESPONSA arm and 10% in the Investigator’s choice of chemotherapy arm.

A total of 79/164 (48.2%) patients in the BESPONSA arm and 36/162 (22.2%) patients in the

Investigator’s choice of chemotherapy arm had a follow-up HSCT. This included 70 and 18 patients inthe BESPONSA and Investigator’s choice of chemotherapy arm, respectively, who proceeded directlyto HSCT. In those patients who proceeded directly to HSCT, there was a median gap of 4.8 weeks(range: 1-19 weeks) between the final dose of inotuzumab ozogamicin and HSCT. The OSimprovement for BESPONSA versus Investigator’s choice of chemotherapy arm was seen in patientswho underwent HSCT. Although there was a higher frequency of early deaths post-HSCT (at Day100) in the BESPONSA arm, there was evidence of a late survival benefit for BESPONSA. In patientswho underwent a follow-up HSCT, the median OS was 11.9 months (95% CI: 9.2, 20.6) for

BESPONSA versus 19.8 months (95% CI: 14.6, 26.7) for Investigator’s choice of chemotherapy. Atmonth 24, the survival probability was 38.0% (95% CI: 27.4, 48.5) versus 35.5% (95% CI: 20.1, 51.3)for BESPONSA and Investigator’s choice of chemotherapy, respectively. Furthermore, at month 24,the survival probability was 38.0% (95% CI: 27.4, 48.5) for patients who underwent a follow-up

HSCT compared to 8.0% (95% CI: 3.3, 15.3) for patients who did not undergo a follow-up HSCT inthe BESPONSA arm.

BESPONSA improved OS versus Investigator’s choice of chemotherapy for all stratification factorsincluding duration of first remission 12 months, Salvage 1 status, and age at randomisation< 55 years. There was also a trend for better OS with BESPONSA for patients with other prognosticfactors (Ph-, no prior HSCT,  90% leukaemic blasts CD22-positive at baseline, no baseline peripheralblasts, and baseline haemoglobin ≥ 10 g/dL, based on exploratory analyses). Patients withmixed-lineage leukaemia (MLL) gene rearrangements, including t (4;11), that generally have lower

CD22 expression prior to treatment, had a worse OS outcome following treatment with BESPONSAor Investigator’s choice of chemotherapy.

For patient-reported outcomes, most functioning and symptom scores were in favour of BESPONSAcompared to Investigator’s choice of chemotherapy. Patient-reported outcomes measured using the

European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire(EORTC QLQ-C30), were significantly better for BESPONSA by estimated mean postbaseline scores(BESPONSA and Investigator’s choice of chemotherapy, respectively) for role functioning (64.7versus 53.4, improvement grade small), physical functioning (75.0 versus 68.1, improvement gradesmall), social functioning (68.1 versus 59.8, improvement grade medium), and appetite loss(17.6 versus 26.3, improvement grade small) compared to Investigator’s choice of chemotherapy.

There was a trend in favour of BESPONSA, improvement grade small, for estimated meanpostbaseline scores (BESPONSA and Investigator’s choice, respectively) in global healthstatus/Quality of Life (QoL) (62.1 versus 57.8), cognitive functioning (85.3 versus 82.5), dyspnoea(14.7 versus 19.4), diarrhoea (5.9 versus 8.9), fatigue (35.0 versus 39.4). There was a trend in favourof BESPONSA for estimated mean postbaseline scores from the EuroQoL 5 Dimension (EQ-5D)questionnaire, (BESPONSA and Investigator’s choice of chemotherapy, respectively) for the EQ-5Dindex (0.80 versus 0.76, minimally important difference for cancer = 0.06).

Patients with relapsed or refractory ALL who have received 2 or more prior treatment regimens for

ALL - Study 2

The safety and efficacy of BESPONSA were evaluated in a single-arm, open-label, multicentre

Phase 1/2 study (Study 2). Eligible patients were ≥ 18 years of age with relapsed or refractory B-cellprecursor ALL.

Of 93 screened patients, 72 patients were assigned to study drug and treated with BESPONSA. Themedian age was 45 years (range: 20-79 years); 76.4% were Salvage status ≥ 2; 31.9% had received aprior HSCT and 22.2% were Ph+. The most common reasons for treatment discontinuation were:disease progression/relapse (30 [41.7%)], resistant disease (4 [5.6%]); HSCT (18 [25.0%]), andadverse events (13 [18.1%]).

In the Phase 1 portion of the study, 37 patients received BESPONSA at a total dose of 1.2 mg/m2(N=3), 1.6 mg/m2 (N=12), or 1.8 mg/m2 (N=22). The recommended BESPONSA dose was determinedto be 1.8 mg/m2/cycle administered at a dose of 0.8 mg/m2 on Day 1 and 0.5 mg/m2 on Days 8 and 15of a 28-day cycle with a dose reduction upon achieving CR/CRi.

In the Phase 2 portion of the study, patients had to have received at least 2 prior treatment regimens for

ALL and patients with Ph+ B-cell ALL had to have failed treatment with at least 1 TKI. Of the9 patients with Ph+ B-cell ALL, 1 patient had received 1 previous TKI and 1 patient had received noprior TKIs.

Table 7 shows the efficacy results from this study.

Table 7. Study 2: Efficacy results in patients ≥ 18 years of age with relapsed or refractory

B-cell precursor ALL who received 2 or more prior treatment regimens for ALL

BESPONSA(N=35)

CRa/CRib; n (%) [95% CI] 24 (68.6%)[50.7%-83.2%]

CRa; n (%) [95% CI] 10 (28.6%)[14.6%-46.3%]

CRib; n (%) [95% CI] 14 (40.0%)[23.9%-57.9%]

Median DoRf; months [95% CI] 2.2

Table 7. Study 2: Efficacy results in patients ≥ 18 years of age with relapsed or refractory

B-cell precursor ALL who received 2 or more prior treatment regimens for ALL

BESPONSA(N=35)[1.0 to 3.8]

MRD negativityc for patients achieving CR/CRi; 18/24 (75%)rated (%) [95% CI] [53.3%-90.2%]

Median PFSe; months [95% CI] 3.7[2.6 to 4.7]

Median OS; months [95% CI] 6.4[4.5 to 7.9]

Abbreviations: ALL=acute lymphoblastic leukaemia; ANC=absolute neutrophil counts; CI=confidenceinterval; CR=complete remission; CRi=complete remission with incomplete haematological recovery;

DoR=duration of remission; HSCT=haematopoietic stem cell transplant; MRD=minimal residual disease;

N/n=number of patients; OS=overall survival; PFS=progression-free survival.a, b, c, d, e, f For definition, see Table 6 (with the exception that CR/CRi was not per EAC for Study 2)

In the Phase 2 portion of the study, 8/35 (22.9%) patients had a follow-up HSCT.

Study ITCC-059 has been performed in compliance with the agreed Paediatric Investigation Plan (seesection 4.2 for information on paediatric use).

Study ITCC-059 was a Phase 1/2 multicentre, single-arm, open-label study conducted in 53 paediatricpatients ≥ 1 and < 18 years of age with relapsed or refractory CD22-positive B-cell precursor ALL toidentify a recommended Phase 2 Dose (Phase 1) and to further evaluate the efficacy, safety, andtolerability of the selected BESPONSA dose as a monotherapy agent (Phase 2). The study alsoevaluated the Pharmacokinetics and Pharmacodynamics of BESPONSA as monotherapy (see section5.2).

In the Phase 1 Cohort (N=25), two dose levels were examined (initial dose of 1.4 mg/m2 per cycle andan initial dose of 1.8 mg/m2 per cycle). In the Phase 2 Cohort (N=28), patients were treated at theinitial dose of 1.8 mg/m2 per cycle (0.8mg/m2 on Day 1, 0.5mg/m2 on Days 8 and 15) followed by adose reduction to 1.5mg/m2 per cycle for patients in remission. In both Cohorts, patients received amedian of 2 cycles of therapy (range: 1 to 4 cycles). In the Phase 1 Cohort, the median age was11 years (range: 1-16 years), and 52% of patients had second or greater relapsed B-cell precursor

ALL. In the Phase 2 Cohort, the median age was 7.5 years (range: 1-17 years), and 57% of patientshad second or greater relapsed B-cell precursor ALL.

Efficacy was evaluated on the basis of Objective Response Rate (ORR), defined as the rate of patientswith CR+CRp+CRi. In the Phase 1 Cohort, 20/25 (80%) patients had CR, the ORR was 80% (95% CI:59.3-93.2), and the median Duration of Response (DoR) was 8.0 months (95% CI: 3.9-13.9). In the

Phase 2 Cohort, 18/28 (64%) patients had CR, the ORR was 79% (95% CI: 59.0-91.7), and the DoRwas 7.6 months (95% CI: 3.3-NE). In the Phase 1 Cohort, 8/25 patients (32%) and 18/28 (64%) in the

Phase 2 Cohort had a follow-up HSCT.

In patients with relapsed or refractory ALL treated with inotuzumab ozogamicin at the recommendedstarting dose of 1.8 mg/m2/cycle (see section 4.2), steady-state exposure was achieved by Cycle 4. Themean (SD) maximum serum concentration (Cmax) of inotuzumab ozogamicin was 308 ng/mL (362).

The mean (SD) simulated total area under the concentration-time curve (AUC) per cycle at steadystate was 100 mcg●h/mL (32.9).

In vitro, the binding of the N-acetyl-gamma-calicheamicin dimethylhydrazide to human plasmaproteins is approximately 97%. In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide is asubstrate of P-glycoprotein (P-gp). In humans, the total volume of distribution of inotuzumabozogamicin was approximately 12 L.

In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolised vianonenzymatic reduction. In humans, serum N-acetyl-gamma-calicheamicin dimethylhydrazide levelswere typically below the limit of quantitation (50 pg/mL), but sporadic measurable levels ofunconjugated calicheamicin up to 276 pg/mL occurred in some patients.

Inotuzumab ozogamicin pharmacokinetics were well characterised by a 2-compartment model withlinear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, theclearance of inotuzumab ozogamicin at steady state was 0.0333 L/h, and the terminal eliminationhalf-life (t½) at the end of Cycle 4 was approximately 12.3 days. Following administration of multipledoses, a 5.3 times accumulation of inotuzumab ozogamicin was observed between Cycles 1 and 4.

Based on a population pharmacokinetic analysis in 765 patients, body surface area was found tosignificantly affect inotuzumab ozogamicin disposition. The dose of inotuzumab ozogamicin isadministered based on body surface area (see section 4.2).

Pharmacokinetics in specific groups of subjects or patients

Age, race and gender

Based on a population pharmacokinetic analysis, age, race and gender did not significantly affectinotuzumab ozogamicin disposition.

No formal pharmacokinetic studies of inotuzumab ozogamicin have been conducted in patients withhepatic impairment.

Based on a population pharmacokinetic analysis in 765 patients, the clearance of inotuzumabozogamicin in patients with hepatic impairment defined by National Cancer Institute Organ

Dysfunction Working Group (NCI ODWG) category B1 (total bilirubin ≤ ULN and AST > ULN;

N=133) or B2 (total bilirubin > 1.0-1.5 × ULN and AST any level; N=17) was similar to patients withnormal hepatic function (total bilirubin/AST ≤ ULN; N=611) (see section 4.2). In 3 patients withhepatic impairment defined by NCI ODWG category C (total bilirubin > 1.5-3 × ULN and AST anylevel) and 1 patient with hepatic impairment defined by NCI ODWG category D (totalbilirubin > 3 × ULN and AST any level), inotuzumab ozogamicin clearance did not appear to bereduced.

No formal pharmacokinetic studies of inotuzumab ozogamicin have been conducted in patients withrenal impairment.

Based on population pharmacokinetic analysis in 765 patients, the clearance of inotuzumabozogamicin in patients with mild renal impairment (CLcr 60-89 mL/min; N=237), moderate renalimpairment (CLcr 30-59 mL/min; N=122), or severe renal impairment (CLcr 15-29 mL/min; N=4) wassimilar to patients with normal renal function (CLcr ≥ 90 mL/min; N=402) (see section 4.2).

Inotuzumab ozogamicin has not been studied in patients with end-stage renal disease (see section 4.2).

At the adult recommended dose, the median exposure in paediatric patients with ALL (aged ≥1 and< 18 years) was 25% higher than those in adults. The clinical relevance of the increased exposure isunknown.

Population pharmacokinetic/pharmacodynamic evaluation suggested a correlation between increasinginotuzumab ozogamicin serum concentrations and prolongation of QTc intervals in ALL andnon-Hodgkin’s lymphoma (NHL) patients. The median (upper bound of the 95% CI) for the change in

QTcF at a supratherapeutic Cmax concentration was 3.87 msec (7.54 msec).

In a randomised clinical study in patients with relapsed or refractory ALL (Study 1), maximumincreases in QTcF interval of  30 msec and ≥ 60 msec from baseline were measured in 30/162 (19%)and 4/162 (3%) patients in the inotuzumab ozogamicin arm, respectively, versus18/124 (15%) and3/124 (2%) in the Investigator’s choice of chemotherapy arm, respectively. Increases in QTcF intervalof > 450 msec and > 500 msec were observed in 26/162 (16%) and none of the patients in theinotuzumab ozogamicin arm versus 12/124 (10%) and 1/124 (1%) patients in the Investigator’s choiceof chemotherapy arm, respectively (see section 4.8).

In animals, the primary target organs included the liver, bone marrow and lymphoid organs withassociated haematological changes, kidney, and nervous system. Other observed changes includedmale and female reproductive organ effects (see below) and preneoplastic and neoplastic liver lesions(see below). Most effects were reversible to partially reversible except for effects in the liver andnervous system. The relevance of the irreversible animal findings to humans is uncertain.

Inotuzumab ozogamicin was clastogenic in vivo in the bone marrow of male mice. This is consistentwith the known induction of DNA breaks by calicheamicin. N-acetyl-gamma-calicheamicindimethylhydrazide (the cytotoxic agent released from inotuzumab ozogamicin) was mutagenic in anin vitro bacterial reverse mutation (Ames) assay.

Carcinogenic potential

Formal carcinogenicity studies have not been conducted with inotuzumab ozogamicin. In toxicitystudies, rats developed oval cell hyperplasia, altered hepatocellular foci, and hepatocellular adenomasin the liver at approximately 0.3 times the human clinical exposure based on AUC. In 1 monkey, afocus of hepatocellular alteration was detected at approximately 3.1 times the human clinical exposurebased on AUC at the end of the 26-week dosing period. The relevance of these animal findings tohumans is uncertain.

Administration of inotuzumab ozogamicin to female rats at the maternally toxic dose (approximately2.3 times the human clinical exposure based on AUC) prior to mating and during the first week ofgestation resulted in embryo-foetal toxicity, including increased resorptions and decreased viableembryos. The maternally toxic dose (approximately 2.3 times the human clinical exposure based on

AUC) also resulted in foetal growth retardation, including decreased foetal weights and delayedskeletal ossification. Slight foetal growth retardation in rats also occurred at approximately 0.4 timesthe human clinical exposure based on AUC (see section 4.6).

Inotuzumab ozogamicin is considered to have the potential to impair reproductive function andfertility in men and women based on non-clinical findings (see section 4.6). In repeat dose toxicitystudies in rats and monkeys, female reproductive findings included atrophy of ovaries, uterus, vagina,and mammary gland. The no observed adverse effect level (NOAEL) for the effects on femalereproductive organs in rats and monkeys was approximately 2.2 and 3.1 times the human clinicalexposure based on AUC, respectively. In repeat dose toxicity studies in rats, male reproductivefindings included testicular degeneration, associated with hypospermia, and prostatic and seminalvesicle atrophy. The NOAEL was not identified for the effects on male reproductive organs, whichwere observed at approximately 0.3 times the human clinical exposure based on AUC.

Sucrose

Polysorbate 80

Sodium chloride

Tromethamine

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

Unopened vial5 years.

BESPONSA contains no bacteriostatic preservatives. The reconstituted solution must be usedimmediately. If the reconstituted solution cannot be used immediately, it may be stored for up to4 hours in a refrigerator (2 °C-8 °C). Protect from light and do not freeze.

The diluted solution must be used immediately or stored at room temperature (20 °C-25 °C) or in arefrigerator (2 °C-8 °C). The maximum time from reconstitution through the end of administrationshould be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution. Protect from light and do notfreeze.

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 containing1 mg of powder.

Each carton contains 1 vial.

Instructions for reconstitution, dilution, and administration

Use appropriate aseptic technique for the reconstitution and dilution procedures. Inotuzumabozogamicin (which has a density of 1.02 g/mL at 20°C) is light sensitive and should be protected fromultraviolet 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.

- 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 of0.25 mg/mL of BESPONSA.

- Gently swirl the vial to aid dissolution. Do not shake.

- Inspect the reconstituted solution for particulates and discolouration. The reconstitutedsolution must be clear to slightly cloudy, colourless, and essentially free of visible foreignmatter. If particles or discolouration are observed, do not use.

- BESPONSA contains no bacteriostatic preservatives. The reconstituted solution must be usedimmediately. If the reconstituted solution cannot be used immediately, it may be stored in arefrigerator (2 °C-8 °C) for up to 4 hours. Protect from light and do not freeze.

- Calculate the required volume of the reconstituted solution needed to obtain the appropriatedose according to patient body surface area. Withdraw this amount from the vial(s) using asyringe. Protect from light. Discard any unused reconstituted solution left in the vial.

- Add the reconstituted solution to an infusion container with sodium chloride 9 mg/mL (0.9%)solution for injection, to a total nominal volume of 50 mL. The final concentration should bebetween 0.01 and 0.1 mg/mL. Protect from light. An infusion container made of polyvinylchloride (PVC) (di(2-ethylhexyl)phthalate [DEHP]- or non-DEHP-containing), polyolefin(polypropylene and/or polyethylene), or ethylene vinyl acetate (EVA) is recommended.

- 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), orin a refrigerator (2 °C-8 °C). The maximum time from reconstitution through the end ofadministration should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution. Protectfrom light and do not freeze.

- If the diluted solution is stored in a refrigerator (2 °C-8 °C), it must be allowed to equilibrateat 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 celluloseester (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 needto 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.

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 Use diluted solution If the diluted solution is storedimmediately or after being immediately or after being in a refrigerator (2 °C-8 °C),stored in a refrigerator stored at room temperature bring it to room temperature(2 °C-8 °C) for up to 4 hours. (20 °C-25 °C) or in a (20 °C-25 °C) for

Protect from light. Do not refrigerator (2 °C-8 °C). The approximately 1 hour prior tofreeze. maximum time from administration. Administerreconstitution through the end diluted solution as a 1-hourof administration should be infusion at a rate of 50 mL/h at≤ 8 hours, with ≤ 4 hours room temperaturebetween reconstitution and (20 °C-25 °C). Protect fromdilution. Protect from light. Do light.not freeze.

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 localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/17/1200/001

Date of first authorisation: 29 June 2017

Date of latest renewal: 16 February 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.