Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
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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%:
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).
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.
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).
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).
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.
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).
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.
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.
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).
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.
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.
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).
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.
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.
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%).
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:
Very common: 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%])
Very common: Febrile neutropenia (26%), Neutropenia (49%), Thrombocytopenia (51%), Leukopenia (35%), Lymphopenia (18%), Anaemia (36%)
Common: Pancytopenia^b^ (2%)
Common: Hypersensitivity (1%)
Very common: Decreased appetite (12%)
Common: Tumour lysis syndrome (2%), Hyperuricaemia (4%)
Very common: Headache (28%)
Very common: Haemorrhagec (33%) (includes Central nervous system haemorrhage [1%], Upper gastrointestinal haemorrhage [6%], Lower gastrointestinal haemorrhage [4%], Epistaxis [15%])
Very common: Abdominal pain (23%), Vomiting (15%), Diarrhoea (17%), Nausea (31%), Stomatitis (13%), Constipation (17%)
Common: Ascites (4%), Abdominal distension (6%)
Very common: Hyperbilirubinaemia (21%), Increased transaminases (26%), Increased GGT (21%)
Common: Venoocclusive liver disease (sinusoidal obstruction syndrome) (3% [pre-HSCT]d)
Very common: Pyrexia (32%), Fatigue (35%), Chills (11%)
Very common: Increased alkaline phosphatase (13%)
Common: ECG QT prolonged (1%), Increased amylase (5%), Increased lipase (9%)
Very common: 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 alsoincludes 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.
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.
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.
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.
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 ¾ 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.
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.
In the pivotal study (N=164), TLS, which may be life-threatening or fatal, was reported in 4/164 (2%) patients. Grade ¾ 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.
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.
For periodic monitoring of ECG and electrolyte levels, see section 4.4.
In the pivotal study (N=164), increases in amylase and lipase were reported in 8 (5%) and 15 (9%) patients, respectively. Increases in Grade ≥3 amylase and lipase were reported in 3 (2%) and 7 (4%) patients, respectively.
For periodic monitoring of increased amylase and lipase, see section 4.4.
In clinical studies of 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 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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