bosutinib (as monohydrate)

HOS-096080 · has-adverse-reaction-information · PDF-Seite 12

Summary of safety profile A total of 1 372 leukaemia adult patients received at least 1 dose of single-agent bosutinib. The median duration of therapy was 26.30 months (range: 0.03 to 170.49 months). These patients were either newly-diagnosed, with CP CML or were resistant or intolerant to prior therapy with chronic, accelerated, or blast phase CML or Ph+ acute lymphoblastic leukaemia (ALL). The safety analyses included data from a completed extension study. At least 1 adverse reaction of any toxicity grade was reported for 1,349 (98.3%) patients. The most frequent adverse reactions reported for  20% of patients were diarrhoea (80.4%), nausea (41.5%), abdominal pain (35.6%), thrombocytopenia (34.4%), vomiting (33.7%), rash (32.8%), ALT increased (28.0%), anaemia (27.2%), pyrexia (23.4%), AST increased (22.5%), fatigue (32.0%), and headache (20.3%). At least 1 Grade 3 or Grade 4 adverse reaction was reported for 943 (68.7%) patients. The Grade 3 or Grade 4 adverse reactions reported for  5% of patients were thrombocytopenia (19.7%), ALT increased (14.6%), neutropenia (10.6%), diarrhoea (10.6%), anaemia (10.3%), lipase increased (10.1%), AST increased (6.7%), and rash (5.0%). 12 Tabulated list of adverse reactions These adverse reactions are presented by system organ class and frequency. Frequency categories are defined as: 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 4 – Adverse reactions for bosutinib Infections and infestations Very common Nasopharyngitis Respiratory tract infectiona Common Influenzab Pneumoniac Bronchitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Tumour lysis syndrome** Blood and lymphatic system disorders Very common Thrombocytopeniad Anaemiae Neutropeniaf Common Leukopeniag Uncommon Febrile neutropenia Granulocytopenia Immune system disorders Common Drug hypersensitivity Uncommon Anaphylactic shock Metabolism and nutrition disorders Very common Decreased appetite Common

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HOS-096076 · has-contraindication-information · PDF-Seite 7

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hepatic impairment (see sections 5.1 and 5.2).

HOS-096075 · has-indication-information · PDF-Seite 3

Bosulif is indicated for the treatment of:  Adult and paediatric patients aged 6 years and older with newly-diagnosed (ND) chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML).  Adult and paediatric patients aged 6 years and older with CP Ph+ CML previously treated with one or more tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.  Adult patients with accelerated phase (AP), and blast phase (BP) Ph+ CML previously treated with one or more tyrosine kinase inhibitor(s) [TKI(s)] and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.

HOS-096078 · has-interaction-information · PDF-Seite 10

Effects of other medicinal products on bosutinib CYP3A inhibitors The concomitant use of bosutinib with strong CYP3A inhibitors (including, but not limited to itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, nefazodone, mibefradil, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, boceprevir, telaprevir, grapefruit products including grapefruit juice) or moderate CYP3A inhibitors (including, but not limited to fluconazole, ciprofloxacin, erythromycin, diltiazem, verapamil, amprenavir, atazanavir, darunavir/ritonavir, fosamprenavir, aprepitant, crizotinib, imatinib) should be avoided, as an increase in bosutinib plasma concentration will occur. Caution should be exercised if mild CYP3A inhibitors are used concomitantly with bosutinib. Selection of an alternate concomitant medicinal product with no or minimal CYP3A enzyme inhibition potential, if possible, is recommended. If a strong or moderate CYP3A inhibitor must be administered during bosutinib treatment, an interruption of bosutinib therapy or a dose reduction in bosutinib should be considered. In a study of 24 healthy subjects in whom 5 daily doses of 400 mg ketoconazole (a strong CYP3A inhibitor) were co-administered with a single dose of 100 mg bosutinib under fasting conditions, ketoconazole increased bosutinib Cmax by 5.2-fold, and bosutinib AUC in plasma by 8.6-fold, as compared with administration of bosutinib alone. In a study of 20 healthy subjects, in whom a single dose of 125 mg aprepitant (a moderate CYP3A inhibitor) was co-administered with a single dose of 500 mg bosutinib under fed conditions, aprepitant 10 increased bosutinib Cmax by 1.5-fold, and bosutinib AUC in plasma by 2.0-fold, as compared with administration of bosutinib alone. CYP3A inducers The concomitant use of bosutinib with strong CYP3A inducers (including, but not limited to carbamazepine, phenytoin, rifampicin, St. John’s Wort), or moderate CYP3A inducers (including, but not limited to bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided, as a decrease in bosutinib plasma concentration will occur. Based on the large reduction in bosutinib exposure that occurred when bosutinib was co-administered with rifampicin, increasing the dose of bosutinib when co-administering with strong or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of exposure. Caution is warrante

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HOS-096079 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential/contraception Women of childbearing potential should be advised to use effective contraception during treatment with bosutinib and for at least 1 month after the last dose and to avoid becoming pregnant while receiving bosutinib. In addition, the patient should be advised that vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption. Pregnancy There are limited amount of data in pregnant women from the use of bosutinib. Studies in animals have shown reproductive toxicity (see section 5.3). Bosutinib is not recommended for use during pregnancy, or in women of childbearing potential not using contraception. If bosutinib is used during pregnancy, or the patient becomes pregnant while taking bosutinib, she should be apprised of the potential hazard to the foetus. Breast-feeding It is unknown whether bosutinib and its metabolites are excreted in human milk. A study of [14C] radiolabelled bosutinib in rats demonstrated excretion of bosutinib-derived radioactivity in breast milk (see section 5.3). A potential risk to the breast-feeding infant cannot be excluded. Breast-feeding should be discontinued during treatment with bosutinib. Fertility Based on non-clinical findings, bosutinib has the potential to impair reproductive function and fertility in humans (see section 5.3). Men being treated with bosutinib are advised to seek advice on conservation of sperm prior to treatment because of the possibility of decreased fertility due to therapy with bosutinib.

HOS-096077 · has-warning-information · PDF-Seite 7

Liver function abnormalities Treatment with bosutinib in adult and paediatric patients is associated with elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]). Transaminase elevations generally occurred early in the course of treatment (of the patients who experienced transaminase elevations of any grade, > 80% experienced their first event within the first 3 months). Patients receiving bosutinib should have liver function tests prior to treatment initiation and monthly for the first 3 months of treatment, and as clinically indicated. Patients with transaminase elevations should be managed by withholding bosutinib temporarily (with consideration given to dose reduction after recovery to Grade 1 or baseline), and/or discontinuation of bosutinib. Elevations of transaminases, particularly in the setting of concomitant increases in bilirubin, may be an early indication of drug-induced liver injury and these patients should be managed appropriately (see sections 4.2 and 4.8). Diarrhoea and vomiting Treatment with bosutinib in adult and paediatric patients is associated with diarrhoea and vomiting; therefore, patients with recent or ongoing clinically significant gastrointestinal disorder should use this medicinal product with caution and only after a careful benefit-risk assessment as respective patients were excluded from the clinical studies. Patients with diarrhoea and vomiting should be managed using standard-of-care treatment, including an anti-diarrhoeal or antiemetic medicinal product and/or fluid replacement. In addition, diarrhoea and vomiting can also be managed by withholding bosutinib temporarily, dose reduction, and/or discontinuation of bosutinib (see sections 4.2 and 4.8). The antiemetic agent, domperidone, has the potential to increase QT interval (QTc) prolongation and to induce “torsade de pointes”- arrhythmias; therefore, co-administration with domperidone should be avoided. It should only be used, if other medicinal products are not efficacious. In these situations an individual benefit-risk assessment is mandatory and patients should be monitored for occurrence of QTc prolongation. Myelosuppression Treatment with bosutinib in adult and paediatric patients is associated with myelosuppression, defined as anaemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month and then monthly thereafter, or as clinically indicated. Myelosuppression

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