Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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

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

Tabulated list of adverse reactions

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

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


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

MedDRA System organ class            Very common                            Common 
Infections and infestations          Infection (48%)a (includes Sepsis and Bacteraemia [17%],
Fungal infection [9%],
Lower respiratory tract infection
[12%], Upper respiratory tract infection [12%], Bacterial infection [1%], Viral infection
[7%], Gastrointestinal infection
[4%], Skin infection [4%])
Blood and lymphatic system           Febrile neutropenia (26%)              Pancytopeniab (2%) disorders                            Neutropenia (49%)
Thrombocytopenia (51%)
Leukopenia (35%)
Lymphopenia (18%)
Anaemia (36%)
Immune system disorders                                                     Hypersensitivity (1%) Metabolism and nutrition             Decreased appetite (12%)               Tumour lysis syndrome (2%) disorders                                                                   Hyperuricaemia (4%) Nervous system disorders             Headache (28%)
Vascular disorders                   Haemorrhagec (33%) (includes
Central nervous system haemorrhage [1%], Upper gastrointestinal haemorrhage
[6%], Lower gastrointestinal haemorrhage [4%], Epistaxis
[15%])
Gastrointestinal disorders           Abdominal pain (23%)                   Ascites (4%) Vomiting (15%)                         Abdominal distension (6%)
Diarrhoea (17%)
Nausea (31%)
Stomatitis (13%)
Constipation (17%)
Hepatobiliary disorders              Hyperbilirubinaemia (21%)              VOD/SOS (3% [pre- Increased transaminases (26%)          HSCT]d)
Increased GGT (21%)
General disorders and                Pyrexia (32%) administration site conditions       Fatigue (35%)
Chills (11%)
Investigations                       Increased alkaline phosphatase         ECG QT prolonged (1%) (13%)                                  Increased amylase (5%)
Increased lipase (9%)
Injury, poisoning and                Infusion- related reaction (10%) procedural complications
Adverse reactions included treatment-emergent, all-causality events that commenced on, or after Cycle 1 Day 1 within 42 days after the last final dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT).
Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.


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 
Abbreviations: ALL=acute lymphoblastic leukaemia; ; VOD/SOS= venoocclusive liver disease/sinusoidal obstruction syndrome, ECG=electrocardiogram; GGT=gamma-glutamyltransferase; HSCT=haematopoietic stem cell transplant.
a
Infection also includes other types of infection (11%). Note: patients may have had > 1 type of infection.
b
Pancytopenia includes the following reported preferred terms: Bone marrow failure, Febrile bone marrow aplasia, and Pancytopenia.
c
Haemorrhage also includes other types of haemorrhage (17%). Note: patients may have had > 1 type of haemorrhage.
d
VOD/SOS includes 1 additional patient with VOD that occurred at Day 56 with no intervening HSCT.
VOD/SOS was also reported in 18 patients after a subsequent HSCT.

Description of selected adverse reactions

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

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

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

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

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

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

Myelosuppression/cytopenias
In the pivotal study (N=164), thrombocytopenia and neutropenia were reported in 83 (51%) and 81 (49%) patients, respectively. Grade 3 thrombocytopenia and neutropenia were reported in 23 (14%) and 33 (20%) patients, respectively. Grade 4 thrombocytopenia and neutropenia were


reported in 46 (28%) and 45 (27%) patients, respectively. Febrile neutropenia, which may be life- threatening, was reported in 43 (26%) patients.

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

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

For clinical management of infections, see section 4.4.

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

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

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

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

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

For clinical management of TLS, see section 4.4.

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

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

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

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

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

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

Paediatric population

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

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

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


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic @moh.health.gov.il) or by email (adr@MOH.HEALTH.GOV.IL ).