Besponsa · 4.1 Therapeutic indications · 1

HOS-097697 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile in adult patients The most common (≥ 20%) adverse reactions in adult patients 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 9 transaminases (26%), abdominal pain (23%), increased gamma-glutamyltransferase (21%), and hyperbilirubinaemia (21%). In adult 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 adult 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 adult patients with relapsed or refractory B-cell precursor ALL who received BESPONSA MedDRA System organ class Very common Common Infections and infestations Infectiona (48%) (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

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HOS-097693 · has-contraindication-information · PDF-Seite 6

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Patients who have experienced prior confirmed severe or ongoing venoocclusive liver disease/sinusoidal obstruction syndrome (VOD/SOS). - Patients with serious ongoing hepatic disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis).

HOS-097692 · has-indication-information · PDF-Seite 2

BESPONSA is indicated as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia (ALL). 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). BESPONSA is indicated as monotherapy for paediatric patients 1 year and older with CD22-positive B-cell precursor ALL: in first relapse after allo-haematopoietic stem cell transplant (HSCT); after any first relapse in patients with Very High Risk (VHR) disease (see section 5.1); after a second or greater relapse; and in those with refractory disease. Patients with Philadelphia chromosome positive (Ph+) disease should have exhausted relevant BCR-ABL targeting treatment options.

HOS-097695 · has-interaction-information · PDF-Seite 8

No 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 8 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).

HOS-097696 · has-pregnancy-information · PDF-Seite 9

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 final dose. Men with female partners of childbearing potential should use effective contraception during treatment with BESPONSA and for at least 5 months after the final dose. Pregnancy There are no data in pregnant women using inotuzumab ozogamicin. Based on nonclinical 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 foetus. 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 nonclinical 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.

HOS-097694 · has-warning-information · PDF-Seite 6

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Hepatotoxicity, including 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 studies had undergone HSCT within the previous 4 months. 6 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 symptom

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