Inotuzumab ozogamicin interacts in the following cases:
The safety of immunisation with live viral vaccines during or following inotuzumab ozogamicin therapy has not been studied. Vaccination with live viral vaccines is not recommended for at least 2 weeks prior to the start of inotuzumab ozogamicin treatment, during treatment, and until recovery of B lymphocytes following the last treatment cycle.
In patients receiving inotuzumab ozogamicin, QT interval prolongation was observed.
Inotuzumab ozogamicin 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 and in patients with electrolyte disturbances. ECG and electrolytes should be obtained prior to the start of treatment and periodically monitored during treatment.
In patients receiving inotuzumab ozogamicin, increases in amylase and lipase have been reported.
Patients should be monitored for increases in amylase and lipase. Potential hepatobiliary disease should be evaluated and treated according to standard medical practice.
In patients receiving inotuzumab ozogamicin, TLS, which may be life-threatening or fatal, was reported.
Pre-medication to reduce uric acid levels and hydration is recommended prior to dosing for patients with a high tumour burden.
Patients should be monitored for signs and symptoms of TLS and 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.
In patients receiving inotuzumab ozogamicin, complications associated with neutropenia and thrombocytopenia (including infections and bleeding/haemorrhagic events, respectively) were reported in some patients.
Complete blood counts should be monitored prior to each dose of BESPONSA and signs and symptoms of infection during treatment and after HSCT, 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.
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.
Inotuzumab ozogamicin 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 inotuzumab ozogamicin and for at least 2 months after the final dose.
Women of childbearing potential should avoid becoming pregnant while receiving inotuzumab ozogamicin.
Women should use effective contraception during treatment with inotuzumab ozogamicin and for at least 8 months after the last dose. Men with female partners of childbearing potential should use effective contraception during treatment with inotuzumab ozogamicin and for at least 5 months after the last dose.
Based on non-clinical findings, male and female fertility may be compromised by treatment with inotuzumab ozogamicin. There is no information on fertility in patients. Both men and women must seek advice for fertility preservation before treatment.
Inotuzumab ozogamicin has moderate influence on the ability to drive and use machines. Patients may experience fatigue during treatment with inotuzumab ozogamicin. 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 inotuzumab ozogamicin, 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%).
The following list shows the adverse reactions reported in patients with relapsed or refractory ALL who received inotuzumab ozogamicin.
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.
Adverse reactions reported in patients with relapsed or refractory B-cell precursor ALL who received inotuzumab ozogamicin:
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: Pancytopeniab (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 inotuzumab ozogamicin, 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 inotuzumab ozogamicin 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.
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 inotuzumab ozogamicin treatment.
Among patients who proceeded to HSCT after inotuzumab ozogamicin treatment, VOD/SOS was reported in 5/11 (46%) patients who received an HSCT both prior to and after inotuzumab ozogamicin treatment and 13/68 (19%) patients who only received an HSCT after inotuzumab ozogamicin 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.
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.
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.
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.
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.
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.
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.
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.
In clinical studies of inotuzumab ozogamicin 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 inotuzumab ozogamicin 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.
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