Besponsa

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
BESPONSA 1 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 1 mg inotuzumab ozogamicin.  
 
After reconstitution (see section 6.6), 1 mL of solution contains 0.25 mg inotuzumab ozogamicin. 
 
Inotuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of a recombinant humanised 
IgG4 kappa CD22-directed monoclonal antibody (produced in Chinese hamster ovary cells by 
recombinant DNA technology) that is covalently linked to N-acetyl-gamma-calicheamicin 
dimethylhydrazide.  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
White to off-white, lyophilised cake or powder. 
 
 
4. CLINICAL PARTICULARS 
 
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). 



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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. 
 



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Dose modifications 
 
Dose modification of BESPONSA may be required based on individual safety and tolerability (see 
section 4.4). Management of some adverse drug reactions may require dosing interruptions and/or 
dose reductions, or permanent discontinuation of BESPONSA (see sections 4.4 and 4.8). If the dose is 
reduced due to BESPONSA-related toxicity, the dose should not be re-escalated. 
 
Table 2 and Table 3 show the dose modification guidelines for haematological and 
non-haematological toxicities, respectively. BESPONSA doses within a treatment cycle (i.e. Days 8 
and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosing 
interruptions within a cycle are recommended for non-haematological toxicities.  
 

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.  



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Table 3.  Dose modifications for non-haematological toxicities at any time during treatment 
 
Non-haematological toxicity Dose modification(s) 
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. No 
data are available. 
 



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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 traceability of biological medicinal products, the trade name and the batch number 
of the administered product should be clearly recorded in the patient file. 
 
Hepatotoxicity, including venoocclusive liver disease/sinusoidal obstruction syndrome (VOD/SOS) 
 
Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD/SOS, was 
reported in patients with relapsed or refractory ALL receiving BESPONSA (see section 4.8). 
BESPONSA significantly increased the risk of VOD/SOS above that of standard chemotherapy 
regimens in this patient population. This risk was most marked in patients who underwent subsequent 
HSCT. 
 
In the following subgroups, the reported frequency of VOD/SOS post-HSCT was ≥ 50%: 

- Patients who received a HSCT conditioning regimen containing 2 alkylating agents; 
- Patients aged ≥ 65 years; and 
- Patients with a serum bilirubin ≥ ULN prior to HSCT. 

 
The use of HSCT conditioning regimens containing 2 alkylating agents should be avoided. The 
benefit/risk should be carefully considered before administering BESPONSA to patients in whom the 
future use of HSCT conditioning regimens containing 2 alkylating agents is likely unavoidable. 
 
In patients in whom the serum bilirubin is ≥ ULN prior to HSCT, HSCT post BESPONSA treatment 
should only be undertaken after careful consideration of the benefit/risk. If these patients do proceed to 
HSCT, signs and symptoms of VOD/SOS should be monitored closely (see section 4.2). 
 
Other patient factors that appear to be associated with an increased risk of VOD/SOS after HSCT 
include a prior HSCT, age ≥ 55 years, a history of liver disease and/or hepatitis before treatment, later 
salvage lines, and a greater number of treatment cycles. 
 
Careful consideration is required before administering BESPONSA to patients who have had a prior 
HSCT. No patients with relapsed or refractory ALL who were treated with BESPONSA in clinical 
trials had undergone HSCT within the previous 4 months. 
 
Patients with a history of liver disease should be carefully evaluated (e.g., ultrasound scan, viral 
hepatitis testing) prior to treatment with BESPONSA to exclude serious ongoing hepatic disease (see 
section 4.3).  



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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). 
 



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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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No formal clinical drug 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). 
 



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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 last dose. Men with female partners of childbearing potential should use effective 
contraception during treatment with BESPONSA and for at least 5 months after the last 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 fetus. 
 
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%).  
 



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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%) 

Venoocclusive liver disease 
(sinusoidal obstruction 
syndrome) (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%) 



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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 

 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 last 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; 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 Venoocclusive liver disease 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 venoocclusive liver disease/sinusoidal obstruction syndrome (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 last 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. 
 



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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%) patient, 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.   



13 

 
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 BESPONSA in patients with relapsed or refractory ALL, 7/236 (3%) patients 
tested positive for anti-inotuzumab ozogamicin antibodies. No patients tested positive for neutralising 
anti-inotuzumab ozogamicin antibodies. In patients who tested positive for anti-inotuzumab 
ozogamicin antibodies, no effect on clearance of BESPONSA was detected based on 
population-pharmacokinetic analysis. The number of patients was too small to assess the impact of 
anti-inotuzumab ozogamicin antibodies on efficacy and safety.  
 
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 national reporting system 
listed in Appendix V. 
 
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. 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other Antineoplastic agent, monoclonal antibodies, 
ATC code: L01XC26. 
 
Mechanism of action  
 
Inotuzumab ozogamicin is an ADC composed of a CD22-directed monoclonal antibody that is 
covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide. Inotuzumab is a humanised 
immunoglobulin class G subtype 4 (IgG4) antibody that specifically recognises human CD22. The 
small 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 ADC 
to CD22-expressing tumour cells, followed by internalisation of the ADC-CD22 complex, and the 
intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of 



14 

the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-stranded 
DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death. 
 
Clinical efficacy and safety 
 
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 ALL 
were evaluated in an open-label, international, multicentre, Phase 3 study (Study 1) in which patients 
were randomised to receive BESPONSA (N=164 [164 received treatment) or Investigator’s choice of 
chemotherapy (N=162 [143 received treatment]), specifically fludarabine plus cytarabine plus 
granulocyte 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+ relapsed 
or refractory B-cell CD22-positive precursor ALL.  
 
CD22 expression was assessed using flow cytometry based on bone marrow aspirate. In patients with 
an inadequate bone marrow aspirate sample, a peripheral blood sample was tested. Alternatively, 
CD22 expression was assessed using immunohistochemistry in patients with an inadequate bone 
marrow 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 prior 
induction chemotherapy regimens for ALL. Patients with Ph+ B-cell precursor ALL were required to 
have 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 adjudication 
committee (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 randomised 
patients and the analysis of OS, PFS, DoR, and HSCT rate was conducted in all 326 randomised 
patients.  
 
Among all 326 randomised patients (ITT population), 215 (66%) patients had received 1 prior 
treatment regimen and 108 (33%) patients had received 2 prior treatment regimens for ALL. The 
median 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 respect 
to 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 1 
prior 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 testing 
by both local and central laboratory. By central and local laboratory tests, 231/253 (91.3%) patients 
and 130/253 (51.4%) patients, respectively, had ≥ 70% CD22-positive leukaemic blasts at baseline.  
 



15 

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 

(N=109) 
HIDAC, FLAG, or 

MXN/Ara-C (N=109) 
CRa/CRib; n (%) [95% CI] 88 (80.7%) 

[72.1%-87.7%] 
32 (29.4%) 

[21.0%-38.8%] 
2-sided p-value < 0.0001 

CRa; n (%) [95% CI] 39 (35.8%) 
[26.8%-45.5%] 

19 (17.4%) 
[10.8%-25.9%] 

2-sided p-value = 0.0022 
CRib; n (%) [95% CI] 49 (45.0%) 

[35.4%-54.8%] 
13 (11.9%) 

[6.5%-19.5%] 
2-sided p-value < 0.0001 

MRD negativityc for patients achieving 
CR/CRi; rated (%) [95% CI] 

69/88 (78.4%) 
[68.4%-86.5%] 

9/32 (28.1%) 
[13.7%-46.7%] 

2-sided p-value < 0.0001 
 BESPONSA 

(N=164) 
HIDAC, FLAG, or 

MXN/Ara-C (N=162) 
Median OS; months [95% CI] 7.7 

[6.0 to 9.2] 
6.2 

[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 

[3.9-5.8] 
1.7 

[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 

[2.8 to 4.6] 
0.0 
[-,-] 

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 haematological 
recovery; DoR=duration of remission; EAC=Endpoint Adjudication Committee; FLAG=fludarabine + 
cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=haematopoietic stem 
cell transplant; ITT=intent-to-treat; MRD=minimal residual disease; MXN=mitoxantrone; N/n=number of 
patients; OS=overall survival; PFS=progression-free survival. 



16 

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 

  
a CR, per EAC, was 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. 

b CRi, per EAC, was defined as < 5% blasts in the bone marrow and the absence of peripheral blood 
leukaemic 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 bone 
marrow nucleated cells. 

d Rate was defined as number of patients who achieved MRD negativity divided by the total number of 
patients 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 to 
global deterioration of health status), and start of new induction therapy or post-therapy HSCT without 
achieving CR/CRi. 

f In the standard definition of PFS, defined as the time from date of randomisation to earliest date of the 
following 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’s 
assessment to the date of a PFS event or censoring date if no PFS event was documented. Analysis was 
based on the ITT population with patients without remission being given a duration of zero and considered 
an 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 additional 
patients 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 those 
seen 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 in 
the BESPONSA and Investigator’s choice of chemotherapy arm, respectively, who proceeded directly 
to HSCT. In those patients who proceeded directly to HSCT, there was a median gap of 4.8 weeks 
(range: 1-19 weeks) between the last dose of inotuzumab ozogamicin and HSCT. The OS 
improvement for BESPONSA versus Investigator’s choice of chemotherapy arm was seen in patients 
who underwent HSCT. Although there was a higher frequency of early deaths post-HSCT (at Day 
100) in the BESPONSA arm, there was evidence of a late survival benefit for BESPONSA. In patients 
who 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. At 
month 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 in 
the BESPONSA arm. 
 
BESPONSA improved OS versus Investigator’s choice of chemotherapy for all stratification factors 
including 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 prognostic 
factors (Ph-, no prior HSCT, ≥ 90% leukaemic blasts CD22-positive at baseline, no baseline peripheral 
blasts, and baseline haemoglobin ≥ 10 g/dL, based on exploratory analyses). Patients with 
mixed-lineage leukaemia (MLL) gene rearrangements, including t (4;11), that generally have lower 



17 

CD22 expression prior to treatment, had a worse OS outcome following treatment with BESPONSA 
or Investigator’s choice of chemotherapy.  
 
For patient-reported outcomes, most functioning and symptom scores were in favour of BESPONSA 
compared 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 (64.7 
versus 53.4, improvement grade small), physical functioning (75.0 versus 68.1, improvement grade 
small), 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 mean 
postbaseline scores (BESPONSA and Investigator’s choice, respectively) in global health 
status/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 favour 
of 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-5D 
index (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-cell 
precursor ALL.  
 
Of 93 screened patients, 72 patients were assigned to study drug and treated with BESPONSA. The 
median age was 45 years (range 20-79); 76.4% were Salvage status ≥ 2; 31.9% had received a prior 
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%]), and adverse 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 determined 
to 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 15 
of 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 the 
9 patients with Ph+ B-cell ALL, 1 patient had received 1 previous TKI and 1 patient had received no 
prior 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 



18 

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; 
rated (%) [95% CI] 

18/24 (75%) 
[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=confidence 
interval; 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.  
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
BESPONSA in 1 or more subsets of the paediatric population for the treatment of relapsed or 
refractory ALL (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
In patients with relapsed or refractory ALL treated with inotuzumab ozogamicin at the recommended 
starting dose of 1.8 mg/m2/cycle (see section 4.2), steady-state exposure was achieved by Cycle 4. The 
mean (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 steady 
state was 100 mcgh/mL (32.9). 
 
Distribution  
 
In vitro, the binding of the N-acetyl-gamma-calicheamicin dimethylhydrazide to human plasma 
proteins is approximately 97%. In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide is a 
substrate of P-glycoprotein (P-gp). In humans, the total volume of distribution of inotuzumab 
ozogamicin was approximately 12 L.  
 
Biotransformation 
 
In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolised via 
nonenzymatic reduction. In humans, serum N-acetyl-gamma-calicheamicin dimethylhydrazide levels 
were typically below the limit of quantitation (50 pg/mL), but sporadic measurable levels of 
unconjugated calicheamicin up to 276 pg/mL occurred in some patients.  
 
Elimination  
 
Inotuzumab ozogamicin pharmacokinetics were well characterised by a 2-compartment model with 
linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the 
clearance of inotuzumab ozogamicin at steady state was 0.0333 L/h, and the terminal elimination 
half-life (t½) at the end of Cycle 4 was approximately 12.3 days. Following administration of multiple 
doses, a 5.3 times accumulation of inotuzumab ozogamicin was observed between Cycles 1 and 4.  
 



19 

Based on a population pharmacokinetic analysis in 765 patients, body surface area was found to 
significantly affect inotuzumab ozogamicin disposition. The dose of inotuzumab ozogamicin is 
administered based on body surface area (see section 4.2). 
 
Age, race, and gender 
 
Based on a population pharmacokinetic analysis, age, race, and gender did not significantly affect 
inotuzumab ozogamicin disposition.   
 
Hepatic impairment 
 
No formal pharmacokinetic studies of inotuzumab ozogamicin have been conducted in patients with 
hepatic impairment.  
 
Based on a population pharmacokinetic analysis in 765 patients, the clearance of inotuzumab 
ozogamicin 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 with 
normal hepatic function (total bilirubin/AST ≤ ULN; n=611) (see section 4.2). In 3 patients with 
hepatic impairment defined by NCI ODWG category C (total bilirubin > 1.5-3 × ULN and AST any 
level) and 1 patient with hepatic impairment defined by NCI ODWG category D (total 
bilirubin > 3 × ULN and AST any level), inotuzumab ozogamicin clearance did not appear to be 
reduced. 
 
Renal impairment 
 
No formal pharmacokinetic studies of inotuzumab ozogamicin have been conducted in patients with 
renal impairment.  
 
Based on population pharmacokinetic analysis in 765 patients, the clearance of inotuzumab 
ozogamicin in patients with mild renal impairment (CLcr 60-89 mL/min; n=237), moderate renal 
impairment (CLcr 30-59 mL/min; n=122), or severe renal impairment (CLcr 15-29 mL/min; n=4) was 
similar 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). 
 
Cardiac electrophysiology 
 
Population pharmacokinetic/pharmacodynamic evaluation suggested a correlation between increasing 
inotuzumab ozogamicin serum concentrations and prolongation of QTc intervals in ALL and 
non-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), maximum 
increases 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%) and 
3/124 (2%) in the Investigator’s choice of chemotherapy arm, respectively. Increases in QTcF interval 
of > 450 msec and > 500 msec were observed in 26/162 (16%) and none of the patients in the 
inotuzumab ozogamicin arm versus 12/124 (10%) and 1/124 (1%) patients in the Investigator’s choice 
of chemotherapy arm, respectively (see section 4.8).  
 
5.3 Preclinical safety data 
 
Repeat-dose toxicity 
 
In animals, the primary target organs included the liver, bone marrow and lymphoid organs with 
associated haematological changes, kidney, and nervous system. Other observed changes included 
male and female reproductive organ effects (see below) and preneoplastic and neoplastic liver lesions 



20 

(see below). Most effects were reversible to partially reversible except for effects in the liver and 
nervous system. The relevance of the irreversible animal findings to humans is uncertain. 
 
Genotoxicity 
 
Inotuzumab ozogamicin was clastogenic in vivo in the bone marrow of male mice. This is consistent 
with the known induction of DNA breaks by calicheamicin. N-acetyl-gamma-calicheamicin 
dimethylhydrazide (the cytotoxic agent released from inotuzumab ozogamicin) was mutagenic in an in 
vitro bacterial reverse mutation (Ames) assay. 
 
Carcinogenicity 
 
Formal carcinogenicity studies have not been conducted with inotuzumab ozogamicin. In toxicity 
studies, rats developed oval cell hyperplasia, altered hepatocellular foci, and hepatocellular adenomas 
in the liver at approximately 0.3 times the human clinical exposure based on AUC. In 1 monkey, a 
focus of hepatocellular alteration was detected at approximately 3.1 times the human clinical exposure 
based on AUC at the end of the 26-week dosing period. The relevance of these animal findings to 
humans is uncertain. 
 
Reproductive toxicity 
 
Administration of inotuzumab ozogamicin to female rats at the maternally toxic dose (approximately 
2.3 times the human clinical exposure based on AUC) prior to mating and during the first week of 
gestation resulted in embryo-foetal toxicity, including increased resorptions and decreased viable 
embryos. 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 delayed 
skeletal ossification. Slight foetal growth retardation in rats also occurred at approximately 0.4 times 
the human clinical exposure based on AUC (see section 4.6). 
 
Inotuzumab ozogamicin is considered to have the potential to impair reproductive function and 
fertility in men and women based on non-clinical findings (see section 4.6). In repeat dose toxicity 
studies 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 female 
reproductive organs in rats and monkeys was approximately 2.2 and 3.1 times the human clinical 
exposure based on AUC, respectively. In repeat dose toxicity studies in rats, male reproductive 
findings included testicular degeneration, associated with hypospermia, and prostatic and seminal 
vesicle atrophy. The NOAEL was not identified for the effects on male reproductive organs, which 
were observed at approximately 0.3 times the human clinical exposure based on AUC.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sucrose 
Polysorbate 80 
Sodium chloride 
Tromethamine 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products except those mentioned in section 6.6. 
 



21 

6.3 Shelf life 
 
Unopened vial 
 
5 years 
 
Reconstituted solution 
 
BESPONSA contains no bacteriostatic preservatives. The reconstituted solution must be used 
immediately. If the reconstituted solution cannot be used immediately, it may be stored for up to 
4 hours in a refrigerator (2 °C-8 °C). Protect from light and do not freeze.  
 
Diluted solution 
 
The diluted solution must be used immediately or stored at room temperature (20 °C-25 °C) or in a 
refrigerator (2 °C-8 °C). The maximum time from reconstitution through the end of administration 
should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution. Protect from light and do not 
freeze.  
 
6.4 Special precautions for storage 
 
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. 
 
6.5 Nature and contents of container  
 
Type I amber glass vial with chlorobutyl rubber stopper and crimp seal with flip off cap containing 
1 mg of powder.  
 
Each carton contains 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
Instructions for reconstitution, dilution, and administration 
 
Use appropriate aseptic technique for the reconstitution and dilution procedures. Inotuzumab 
ozogamicin (which has a density of 1.02 g/mL at 20°C/68°F) is light sensitive and should be protected 
from ultraviolet light during reconstitution, dilution, and administration. 
 
The maximum time from reconstitution through the end of administration should be ≤ 8 hours, with 
≤ 4 hours between reconstitution and dilution.  
 
Reconstitution 
 

• Calculate the dose (mg) and number of vials of BESPONSA required.  
• Reconstitute each 1 mg vial with 4 mL of water for injection, to obtain a single-use solution of 

0.25 mg/mL of BESPONSA.  
• Gently swirl the vial to aid dissolution. Do not shake.  
• Inspect the reconstituted solution for particulates and discolouration. The reconstituted 

solution must be clear to slightly cloudy, colourless, and essentially free of visible foreign 
matter. If particles or discolouration are observed, do not use. 

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



22 

 
Dilution 
 

• Calculate the required volume of the reconstituted solution needed to obtain the appropriate 
dose according to patient body surface area. Withdraw this amount from the vial(s) using a 
syringe. 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 be 
between 0.01 and 0.1 mg/mL. Protect from light. An infusion container made of polyvinyl 
chloride (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), or 

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

 
Administration 
 

• If the diluted solution is stored in a refrigerator (2 °C-8 °C), it must be allowed to equilibrate 
at room temperature (20 °C-25 °C) for approximately 1 hour prior to administration. 

• Filtration of the diluted solution is not required. However, if the diluted solution is filtered, 
polyethersulphone (PES)-, polyvinylidene fluoride (PVDF)-, or hydrophilic polysulphone 
(HPS)-based filters are recommended. Do not use filters made of nylon or mixed cellulose 
ester (MCE). 

• Protect the intravenous bag from light using an ultraviolet light-blocking cover (i.e., amber, 
dark brown, or green bags or aluminium foil) during infusion. The infusion line does not need 
to be protected from light. 

• Infuse the diluted solution for 1 hour at a rate of 50 mL/h at room temperature (20 °C-25 °C). 
Protect from light. Infusion lines made of PVC (DEHP or non-DEHP-containing), polyolefin 
(polypropylene and/or polyethylene), or polybutadiene are recommended. 

 
Do not mix BESPONSA or administer as an infusion with other medicinal products. 
 
Table 8 shows the storage times and conditions for reconstitution, dilution, and administration of 
BESPONSA. 
 

Table 8.  Storage times and conditions for reconstituted and diluted BESPONSA solution 
 

Maximum time from reconstitution through the end of administration ≤ 8 hoursa 
Reconstituted solution Diluted solution 

After start of dilution Administration 
Use reconstituted solution 
immediately or after being 
stored in a refrigerator 
(2 °C-8 °C) for up to 4 hours. 
Protect from light. Do not 
freeze. 

Use diluted solution 
immediately or after being 
stored at room temperature 
(20 °C-25 °C) or in a 
refrigerator (2 °C-8 °C). The 
maximum time from 
reconstitution through the end 
of administration should be  
≤ 8 hours, with ≤ 4 hours 
between reconstitution and 
dilution. Protect from light. Do 
not freeze. 

If the diluted solution is stored 
in a refrigerator (2 °C-8 °C), 
bring it to room temperature 
(20 °C-25 °C) for 
approximately 1 hour prior to 
administration. Administer 
diluted solution as a 1-hour 
infusion at a rate of 50 mL/h at 
room temperature 
(20 °C-25 °C). Protect from 
light. 

a With ≤ 4 hours between reconstitution and dilution. 
 



23 

Disposal  
 
BESPONSA is for single use only. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1200/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 June 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  

  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



25 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer(s) of the biological active substance(s)  

Wyeth Pharmaceutical Division of Wyeth Holdings LLC, 
401 North Middletown Road,  
Pearl River, New York (NY) 10965 
United States (USA) 
 

Name and address of the manufacturer(s) responsible for batch release 

Pfizer Ireland Pharmaceuticals 
Grange Castle Business Park 
Clondalkin 
Dublin 22 
Ireland 
 
Or 
 
Pfizer Service Company BVBA 
Hoge Wei 10 
B-1930, Zaventem 
Belgium 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

• Periodic safety update reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation. 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

• Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 



26 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



29 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON  

 
 

1. NAME OF MEDICINAL PRODUCT 
 
BESPONSA 1 mg powder for concentrate for solution for infusion 
inotuzumab ozogamicin  
 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 1 mg of inotuzumab ozogamicin. 
After reconstitution each vial contains 0.25 mg/mL of inotuzumab ozogamicin. 
 
 

3. LIST OF EXCIPIENTS 
 
Sucrose 
Polysorbate 80 
Sodium chloride 
Tromethamine 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion 
1 vial 
1 mg 
 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
IV infusion after reconstitution and dilution. 
For single use only. 
 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 

8. EXPIRY DATE 
 
EXP   
 
 



30 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
Do not freeze.  
Store in the original carton in order to protect from light. 
 
 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL 
PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL 
PRODUCTS, IF APPROPRIATE 

 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 

12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1200/001 
 
 

13. BATCH NUMBER 
 
Lot  
 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 

15. INSTRUCTIONS ON USE 
 
 

16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 
  



31 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING 
 
VIAL 

 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 

 
BESPONSA 1 mg Powder for concentrate  
inotuzumab ozogamicin  
For IV infusion after reconstitution and dilution. 
 
 

2. METHOD OF ADMINISTRATION 
 
Single use only. 
 
 

3. EXPIRY DATE 
 
EXP  
 
 

4. BATCH NUMBER 
 
Lot  
 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 

6. OTHER 
 
 
  



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



33 

Package leaflet: Information for the user 

BESPONSA 1 mg powder for concentrate for solution for infusion 
inotuzumab ozogamicin 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 

- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

What is in this leaflet 

1. What BESPONSA is and what it is used for 
2. What you need to know before you are given BESPONSA 
3. How BESPONSA is given 
4. Possible side effects 
5. How to store BESPONSA 
6. Contents of the pack and other information 
 
 
1. What BESPONSA is and what it is used for 
 
The active ingredient in BESPONSA is inotuzumab ozogamicin. This belongs to a group of medicines 
that target cancer cells. These medicines are called antineoplastic agents. 
 
BESPONSA is used to treat adults with acute lymphoblastic leukaemia. Acute lymphoblastic 
leukaemia is a cancer of blood where you have too many white blood cells. BESPONSA is intended 
for the treatment of acute lymphoblastic leukaemia for adult patients who have previously tried other 
treatments and for whom those treatments have failed. 
 
BESPONSA acts by attaching to cells with a protein called CD22. Lymphoblastic leukaemia cells 
have this protein. Once attached to the lymphoblastic leukaemia cells, the medicine delivers a 
substance into the cells that interferes with the cells’ DNA and eventually kills them. 
 
 
2. What you need to know before you are given BESPONSA   
 
Do not use BESPONSA if you:  
 

• are allergic to inotuzumab ozogamicin or any of the other ingredients of this medicine (listed 
in section 6). 

• have previously had severe venoocclusive disease (a condition in which the blood vessels in 
the liver become damaged and blocked by blood clots) which was confirmed or have ongoing 
venoocclusive disease. 

• have serious ongoing liver disease, e.g., cirrhosis (a condition in which the liver does not 
function properly due to long-term damage), nodular regenerative hyperplasia (a condition 
with signs and symptoms of portal hypertension that can be caused by chronic use of 
medicines), active hepatitis (a disease characterised by inflammation of the liver). 
 



34 

Warnings and precautions  
 
Talk to your doctor, pharmacist or nurse before using BESPONSA if you: 
 

• have a history of liver problems or liver diseases or if you have signs and symptoms of a 
serious condition called hepatic venoocclusive disease, a condition in which the blood vessels 
in the liver become damaged and blocked by blood clots. Venoocclusive disease may be fatal 
and is associated with rapid weight gain, pain in the upper right side of your abdomen (belly), 
increase in the size of the liver, build-up of fluid causing abdominal swelling, and blood tests 
showing increases in bilirubin and/or liver enzymes (that may result in yellowing of the skin 
or eyes). This condition may occur during treatment with BESPONSA or after subsequent 
treatment with a stem cell transplant. A stem cell transplant is a procedure to transplant 
another person’s stem cells (cells which develop into new blood cells) into your bloodstream. 
This procedure may take place if your disease responds completely to treatment.  

• have signs or symptoms of a low number of blood cells known as neutrophils (sometimes 
accompanied with fever), red blood cells, white blood cells, lymphocytes, or a low number of 
blood components known as platelets; these signs and symptoms include developing an 
infection or fever or bruising easily or getting frequent nose bleeds. 

• have signs and symptoms of an infusion related reaction, such as fever and chills or breathing 
problems during or shortly after the BESPONSA infusion. 

• have signs and symptoms of tumour lysis syndrome, which may be associated with symptoms 
in the stomach and intestines (for example, nausea, vomiting, diarrhoea), heart (for example, 
changes in the rhythm), kidney (for example, decreased urine, blood in urine), and nerves and 
muscles (for example, muscular spasms, weakness, cramps), during or shortly after the 
BESPONSA infusion.  

• have a history of, or tendency to have, QT interval prolongation (a change in electrical activity 
of the heart that can cause serious irregular heart rhythms), are taking medicines that are 
known to prolong QT interval, and/or have abnormal electrolyte (e.g., calcium, magnesium, 
potassium) levels.  

• have elevations in amylase or lipase enzymes that may be a sign of problems with your 
pancreas or liver and gallbladder or bile ducts. 

 
Tell your doctor, pharmacist or nurse immediately if you became pregnant during the period of 
treatment with BESPONSA and for up to 8 months after finishing treatment.  
 
Your doctor will take regular blood tests to monitor your blood counts during treatment with 
BESPONSA. See also section 4. 
  
During treatment, especially in the first few days after starting treatment, your white blood cell count 
may be severely lowered (neutropenia), which may be accompanied by fever (febrile neutropenia).  
 
During treatment, especially in the first few days after starting treatment, you may have raised liver 
enzymes. Your doctor will take regular blood tests to monitor your liver enzymes during treatment 
with BESPONSA.  
 
Treatment with BESPONSA may prolong QT interval (a change in electrical activity of the heart that 
can cause serious irregular heart rhythms). Your doctor will take an electrocardiogram (ECG) and 
blood tests to measure electrolytes (e.g., calcium, magnesium, potassium) before the first dose of 
BESPONSA and repeat these tests during treatment. See also section 4. 
 
Your doctor will also monitor for signs and symptoms of tumour lysis syndrome after you receive 
BESPONSA. See also section 4. 
 
Children and adolescents 
 
BESPONSA should not to be used in children and adolescents under 18 years of age because no data 
are available in this population. 



35 

Other medicines and BESPONSA 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes medicines obtained without a prescription and herbal medicines.  
 
Pregnancy, breast-feeding and fertility 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or nurse for advice before taking this medicine. 
 
Contraception  
 
You must avoid becoming pregnant or fathering a child. Women must use effective contraception 
during treatment and for at least 8 months after the last dose of treatment. Men must use effective 
contraception during treatment and for at least 5 months after the last dose of treatment.  
  
Pregnancy 
 
The effects of BESPONSA in pregnant women are not known, but based on its mechanism of action 
BESPONSA may harm your unborn baby. You should not use BESPONSA during pregnancy, unless 
your doctor thinks that it is the best medicine for you.  
 
Contact your doctor immediately if you or your partner becomes pregnant during the period of 
treatment with this medicine.  
 
Fertility 
 
Men and women should seek advice regarding fertility preservation before treatment. 
 
Breast-feeding 
 
If you need treatment with BESPONSA, you must stop breast-feeding during treatment and for at least 
2 months after treatment. Talk to your doctor. 
 
Driving and using machines 
 
If you feel unusually tired (this is a very common side effect of BESPONSA), you should not drive or 
use machines. 
 
 
3. How BESPONSA is given 
 
Always use this medicine exactly as your doctor, pharmacist, or nurse has told you. Check with your 
doctor, pharmacist or nurse if you are not sure. 
 
How BESPONSA is given 
 

• Your doctor will decide on the correct dose.  
• A doctor or nurse will give you BESPONSA through a drip in your vein (intravenous 

infusion) which will run for 1 hour. 
• Each dose is given weekly and each treatment cycle is 3 doses. 
• If the medicine works well and you are going to receive a stem cell transplant (see section 2), 

you may receive 2 cycles or a maximum of 3 cycles of treatment.  
• If the medicine works well, but you are not going to receive a stem cell transplant (see section 

2), you may receive up to a maximum of 6 cycles of treatment.  
• If you do not respond to the medicine within 3 cycles, your treatment will be stopped.  



36 

• Your doctor may change your dose, interrupt, or completely stop treatment with BESPONSA 
if you have certain side effects. 

• Your doctor may lower your dose based on your response to treatment. 
• Your doctor will do blood tests during the treatment to check for side effects and for response 

to treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or nurse. 
 
Medicines given before treatment with BESPONSA  
 
Before your treatment with BESPONSA, you will be given other medicines (pre-medications) to help 
reduce infusion reactions and other possible side effects. These may include corticosteroids (e.g., 
dexamethasone), antipyretics (medicines to reduce fever), and antihistamines (medicines to reduce 
allergic reactions).  
 
Before your treatment with BESPONSA, you may be given medicines and be hydrated to prevent 
tumour lysis syndrome from occurring. Tumour lysis syndrome is associated with a variety of 
symptoms in the stomach and intestines (for example, nausea, vomiting, diarrhoea), heart (for 
example, changes in the rhythm), kidney (for example, decreased urine, blood in urine), and nerves 
and muscles (for example, muscular spasms, weakness, cramps). 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of 
these side effects may be serious. 
 
Tell your doctor immediately if you have signs and symptoms of any of the following serious side 
effects: 
 

• infusion related reaction (see section 2); signs and symptoms include fever and chills or 
breathing problems during or shortly after the BESPONSA infusion. 

• venoocclusive liver disease (see section 2); signs and symptoms include rapid weight gain, 
pain in the upper right side of your abdomen, increase in the size of the liver, accumulation of 
fluid causing abdominal swelling, and increases in bilirubin and/or liver enzymes (that may 
result in yellowing of the skin or eyes). 

• low number of blood cells known as neutrophils, (sometimes accompanied with fever), red 
blood cells, white blood cells, lymphocytes, or low number of blood components known as 
platelets (see section 2); signs and symptoms include developing an infection or fever or 
bruising easily or getting nose bleeds on a regular basis. 

• tumour lysis syndrome (see section 2); this may be associated with a variety of symptoms in 
the stomach and intestines (for example, nausea, vomiting, diarrhoea), heart (for example, 
changes in the rhythm), kidney (for example, decreased urine, blood in urine), and nerves and 
muscles (for example, muscular spasms, weakness, cramps). 

• QT interval prolongation (see section 2); signs and symptoms include a change in electrical 
activity of the heart that can cause serious irregular heart rhythms. Tell your doctor if you have 
symptoms, such as dizziness, lightheadedness or fainting. 

 
Other side effects may include: 
 
Very common (may affect more than 1 in 10 people): 
 

• Infections 
• Reduced number of white blood cells which may result in general weakness and a tendency to 

develop infections 



37 

• Reduced number of lymphocytes (a type of white blood cells) which may result in a tendency 
to develop infections  

• Reduced number of red blood cells which may result in fatigue and shortness of breath 
• Decreased appetite 
• Headache 
• Bleeding 
• Pain in the abdomen 
• Vomiting 
• Diarrhoea 
• Nausea 
• Mouth inflammation 
• Constipation 
• Raised bilirubin level which may result in a yellowish colour in the skin, eyes, and other 

tissues 
• Fever  
• Chills 
• Fatigue 
• High levels of liver enzymes (which can be indicators of liver injury) in the blood 

 
Common (may affect up to 1 in 10 people): 
 

• Reduction in the number of various types of blood cells 
• Excess of uric acid in the blood  
• Excessive accumulation of fluid in the abdomen  
• Swelling of the abdomen 
• Changes in heart rhythm (may show on electrocardiogram) 
• Abnormally high levels of amylase (an enzyme needed for digestion and conversion of starch 

into sugars) in the blood 
• Abnormally high levels of lipase (an enzyme needed to process dietary fat) in the blood 
• Hypersensitivity 

 
Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects, you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store BESPONSA  
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the vial label and carton after EXP. 
The expiry date refers to the last day of that month.  
 
Unopened vial  
 
-  Store in a refrigerator (2 °C-8 °C).  
-  Store in the original carton in order to protect from light.  
-  Do not freeze.  
 
Reconstituted solution 
 
- Use immediately or store in a refrigerator (2 °C-8 °C) for up to 4 hours.  
- Protect from light. 



38 

- Do not freeze. 
 
Diluted solution  
 
-  Use immediately or store at room temperature (20 °C-25 °C) or in a refrigerator (2 °C-8 °C). The 

maximum time from reconstitution through the end of administration should be ≤ 8 hours, with ≤ 
4 hours between reconstitution and dilution.  

- Protect from light. 
- Do not freeze.  
 
This medicine should be inspected visually for particulate matter and discolouration prior to 
administration. If particles or discolouration are observed, do not use. 
 
Do not throw away any medicines via wastewater or household waste. Ask your doctor how to throw 
away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What BESPONSA contains  
 

• The active substance is inotuzumab ozogamicin. Each vial contains 1 mg inotuzumab 
ozogamicin. After reconstitution, 1 mL of solution contains 0.25 mg inotuzumab ozogamicin. 

• The other ingredients are sucrose, polysorbate 80, sodium chloride, and tromethamine. 
 
What BESPONSA looks like and contents of the pack 
 
BESPONSA is a powder for concentrate for solution for infusion.  
 
Each pack of BESPONSA contains: 
 

• 1 glass vial containing a white to off-white lyophilised cake or powder. 
 
Marketing Authorisation Holder 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
Manufacturer 
 
Pfizer Ireland Pharmaceuticals 
Grange Castle Business Park 
Clondalkin 
Dublin 22 
Ireland  
 
Or 
 
Pfizer Service Company BVBA 
Hoge Wei 10 
B-1930, Zaventem 
Belgium 
 
 



39 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

Belgique/België/Belgien 
Pfizer S.A. / N.V. 
Tél/Tel: +32 (0)2 554 62 11 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje 
Tel: + 370 52 51 4000 

България 
Пфайзер Люксембург САРЛ, Клон 
България 
Тел.: +359 2 970 4333 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél/Tel: +32 (0)2 554 62 11 

Česká republika 
Pfizer PFE, spol. s r.o. 
Tel: +420 283 004 111 

Magyarország 
Pfizer Kft. 
Tel: +36-1-488-37-00 

Danmark  
Pfizer ApS 
Tlf: +45 44 20 11 00 

Malta 
Vivian Corporation Ltd. 
Tel: +356 21344610 

Deutschland 
Pfizer Pharma GmbH 
Tel: +49 (0)30 550055 51000 

Nederland 
Pfizer bv 
Tel: +31 (0)10 406 43 01 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500 

Norge 
Pfizer Norge AS 
Tlf: +47 67 52 61 00 

Ελλάδα 
Pfizer Ελλάς A.E. 
Τηλ: +30 210 6785 800 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 

España 
Pfizer, S.L. 
Tel: +34 91 490 99 00 

Polska 
Pfizer Polska Sp. z o.o. 
Tel: +48 22 335 61 00 

France 
Pfizer 
Tel: +33 (0)1 58 07 34 40 

Portugal 
Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 
Tel: +351 21 423 5500 

Hrvatska 
Pfizer Croatia d.o.o. 
Tel: + 385 1 3908 777 

România 
Pfizer Romania S.R.L. 
Tel: +40 (0) 21 207 28 00 

Ireland 
Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free) 
+44 (0)1304 616161 
 

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana 
Tel: + 386 (0)1 52 11 400 

Ísland 
Icepharma hf. 
Sími: +354 540 8000 

Slovenská republika 
Pfizer Luxembourg SARL, organizačná zložka 
Tel: + 421 2 3355 5500 

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland 
Pfizer Oy 
Puh/Tel: +358 (0)9 43 00 40 

Κύπρος 
Pfizer Ελλάς Α.Ε. (Cyprus Branch) 
Τηλ: +357 22 817690 

Sverige 
Pfizer Innovations AB 
Tel: +46 (0)8 550-520 00 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā 
Tel: + 371 670 35 775 

United Kingdom 
Pfizer Limited 
Tel: +44 (0) 1304 616161 

 
This leaflet was last revised in  
 
Other sources of information 
 



40 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.  
This leaflet is available in all EU/EEA languages on the European Medicines Agency website.  
             

The following information is intended for healthcare professionals only. For full information on 
dosage and dose modifications please refer to the Summary of Product Characteristics. 
 
Method of administration 
 
BESPONSA is for intravenous use. The infusion must be administered over 1 hour. 
 
Do not administer BESPONSA as an intravenous push or bolus.  
 
BESPONSA must be reconstituted and diluted before administration. 
 
BESPONSA should be administered in 3- to 4-week cycles.  
 
For patients proceeding to a 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 
CR/CRi and MRD negativity after 2 cycles. 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 (see Summary of Product Characteristics section 4.2). 
 
The table below shows the recommended dosing regimens. 
 
For the first cycle, the recommended total dose for all patients is 1.8 mg/m2 per cycle, administered 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 is 1.5 mg/m2 per cycle administered 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.  
 

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 a 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). 



41 

Dosing regimen for Cycle 1 and subsequent cycles depending on response to treatment  
 

 Day 1 Day 8a Day 15a 
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. 
 
Instructions for reconstitution, dilution, and administration 
 
Use appropriate aseptic technique for the reconstitution and dilution procedures. Inotuzumab 
ozogamicin (which has a density of 1.02 g/mL at 20 °C/68 °F) is light sensitive and should be 
protected from ultraviolet light during reconstitution, dilution, and administration. 
 
The maximum time from reconstitution through the end of administration should be ≤ 8 hours, with ≤ 
4 hours between reconstitution and dilution.  
 
Reconstitution:  
 

• Calculate the dose (mg) and number of vials of BESPONSA required.  
• Reconstitute each 1 mg vial with 4 mL of water for injection, to obtain a single-use solution of 

0.25 mg/mL of BESPONSA.  
• Gently swirl the vial to aid dissolution. Do not shake.  
• Inspect the reconstituted solution for particulates and discolouration. The reconstituted 

solution must be clear to slightly cloudy, colourless, and essentially free of visible foreign 
matter. If particles or discolouration are observed, do not use. 

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

 
Dilution:  
 

• Calculate the required volume of the reconstituted solution needed to obtain the appropriate 
dose according to patient body surface area. Withdraw this amount from the vial(s) using a 
syringe. 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 be 
between 0.01 and 0.1 mg/mL. Protect from light. An infusion container made of polyvinyl 
chloride (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) or 

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

 
Administration: 
 

• If the diluted solution is stored in a refrigerator (2 °C-8 °C), it must be allowed to equilibrate 
at room temperature (20 °C-25 °C) for approximately 1 hour prior to administration. 

• Filtration of the diluted solution is not required. However, if the diluted solution is filtered, 
polyethersulphone (PES)-, polyvinylidene fluoride (PVDF)-, or hydrophilic polysulphone 
(HPS)-based filters are recommended. Do not use filters made of nylon or mixed cellulose 
ester (MCE). 



42 

• Protect the intravenous bag from light using an ultraviolet light-blocking cover (i.e., amber, 
dark brown, or green bags or aluminium foil) during infusion. The infusion line does not need 
to be protected from light. 

• Infuse the diluted solution for 1 hour at a rate of 50 mL/h at room temperature (20 °C-25 °C). 
Protect from light. Infusion lines made of PVC (DEHP or non-DEHP-containing), polyolefin 
(polypropylene and/or polyethylene), or polybutadiene are recommended. 

 
Do not mix BESPONSA or administer as an infusion with other medicinal products. 
 
The storage times and conditions for reconstitution, dilution, and administration of BESPONSA are 
shown below. 
 

Storage times and conditions for reconstituted and diluted BESPONSA solution 
 

Maximum time from reconstitution through the end of administration ≤ 8 hoursa 
Reconstituted solution Diluted solution 

After start of dilution Administration 
Use reconstituted solution 
immediately or after being 
stored in a refrigerator 
(2 °C-8 °C) for up to 4 hours. 
Protect from light. Do not 
freeze. 

Use diluted solution 
immediately or after being 
stored at room temperature 
(20 °C-25 °C) or in a 
refrigerator (2 °C-8 °C). The 
maximum time from 
reconstitution through the end 
of administration should be  
≤ 8 hours, with ≤ 4 hours 
between reconstitution and 
dilution. Protect from light. 
Do not freeze. 

If the diluted solution is stored 
in a refrigerator (2 °C-8 °C), 
bring it to room temperature 
(20 °C-25 °C) for 
approximately 1 hour prior to 
administration. Administer 
diluted solution as a 1-hour 
infusion at a rate of 50 mL/h at 
room temperature 
(20 °C-25 °C). Protect from 
light. 

a With ≤4 hours between reconstitution and dilution. 
 
Storage conditions and shelf life  
 
Unopened vials 
 
5 years 
 
Reconstituted solution 
 
BESPONSA contains no bacteriostatic preservatives. The reconstituted solution must be used 
immediately. If the reconstituted solution cannot be used immediately, it may be stored in a 
refrigerator (2 °C-8 °C) for up to 4 hours. Protect from light and do not freeze.  
 
Diluted solution 
 
The diluted solution must be used immediately or stored at room temperature (20 °C-25 °C) or in a 
refrigerator (2 °C-8 °C). The maximum time from reconstitution through the end of administration 
should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution. Protect from light and do not 
freeze.  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET