Daurismo · 4.4 Special warnings and precautions for use · 1

HOS-287469 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The overall safety profile of Daurismo is based on data from clinical studies, including Study 1 in 84 patients with AML (N=75) and high-risk MDS (N=9). The median exposure to Daurismo across the dataset was 75.5 days. The most frequently (≥ 20%) reported adverse reactions in patients receiving Daurismo were anaemia (45.2%), haemorrhages (45.2%), febrile neutropenia (35.7%), nausea (35.7%), decreased appetite (33.3%), fatigue (30.9%), muscle spasms (30.9%), thrombocytopenia (30.9%), pyrexia (29.7%), diarrhoea (28.5%), pneumonia (28.5%), dysgeusia (26.1%), oedema peripheral (26.1%), constipation (25%), abdominal pain (25%), rash (25%), dyspnoea (25%) vomiting (21.4%), and weight decreased (20.2%). The most frequently reported adverse reactions leading to dose reductions in patients receiving Daurismo were muscle spasms (4.7%), fatigue (3.5%), febrile neutropenia (3.5%), anaemia (2.3%), thrombocytopenia (2.3%), and electrocardiogram QT prolonged (2.3%). The most frequently reported adverse reactions leading to permanent discontinuation in patients receiving Daurismo were pneumonia (5.9%), febrile neutropenia (3.5%), and nausea (2.3%). Tabulated list of adverse reactions Table 6 presents adverse reactions reported with Daurismo. The adverse reactions are listed by system organ class and frequency category. Frequency categories are defined as: very common (≥ 1/10) and common (≥ 1/100 to < 1/10). Within each frequency grouping, adverse reactions are presented in decreasing order of all grade frequencies. 10 Table 6: Adverse reactions reported in clinical studies (N=84) All grades System organ class Preferred term Frequency All grades Grade ≥ 3 (%) (%) Infections and Pneumonia Very common 28.5 23.8 infestations Sepsis Common 5.9 5.9 Urinary tract Common 5.9 1.1 infection Blood and lymphatic Anaemia Very common

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HOS-287465 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-287464 · has-indication-information · PDF-Seite 2

Daurismo is indicated, in combination with low-dose cytarabine, for the treatment of newly diagnosed de novo or secondary acute myeloid leukaemia (AML) in adult patients who are not candidates for standard induction chemotherapy.

HOS-287467 · has-interaction-information · PDF-Seite 8

Effects of other medicinal products on the pharmacokinetics of glasdegib In vitro, CYP3A4 is responsible for the majority of glasdegib depletion and contributed to the formation of other minor oxidative metabolites, with CYP2C8 and UGT1A9 playing a minor role in the metabolism of glasdegib. Substances that may increase glasdegib plasma concentration CYP3A4 inhibitors Ketoconazole, a strong inhibitor of CYP3A4, dosed at 400 mg once daily for 7 days, increased the mean area under the curve (AUCinf) by ~2.4-fold and maximum plasma concentration (Cmax) by 40% of a single 200 mg oral dose of glasdegib in healthy subjects. Caution should be used when administering concomitantly with strong CYP3A4 inhibitors (e.g. boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, telaprevir, troleandomycin, voriconazole, ritonavir, grapefruit or grapefruit juice) as an increase in glasdegib plasma concentration may occur. If possible, alternate concomitant medicinal product with no or minimal CYP3A4 inhibition potential is recommended (see section 4.4). Gastric pH altering medicinal products Coadministration of a single 100 mg glasdegib dose under fasted condition with multiple doses of the proton-pump inhibitor (PPI), rabeprazole, resulted in no change in glasdegib plasma exposure (AUC inf ratio: 100.6%). Concomitant administration of glasdegib with acid-reducing agents (including PPIs, H2-receptor antagonists, and locally acting antacids) is permitted. Substances that may decrease glasdegib plasma concentration CYP3A4 inducers Rifampicin, a strong inducer of CYP3A4, administered at a dose of 600 mg once daily for 11 days, reduced the mean AUCinf by 70% and Cmax by 35% of a single 100 mg dose of glasdegib in healthy subjects. Concomitant use with strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John’s Wort) should be avoided, as this is likely to decrease glasdegib plasma concentrations. Simulations using physiologic-based pharmacokinetic modelling suggested that coadministration of efavirenz (a moderate inducer of CYP3A4) with glasdegib decreased glasdegib AUCinf by 55% and Cmax by 25%. Concomitant use of moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided as they may also reduce glasdegib plasma concentrations (see section 4.4). If concomitant use of moderate CYP3A4 inducers cannot be avoided, the dose of Daurismo should be increased (see sectio

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HOS-287468 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/Contraception in males and females If Daurismo is used in women of childbearing potential, they should be advised to avoid becoming pregnant. The pregnancy status of female patients of childbearing potential should be verified prior to initiating treatment. If the patient becomes pregnant while taking Daurismo, the patient should be apprised of the potential hazard to the foetus. Based on its mechanism of action and findings from animal embryo-foetal developmental studies, Daurismo can cause foetal harm when administered to a pregnant woman. Women of childbearing potential who are receiving this medicinal product should always use effective contraception during treatment with Daurismo and for at least 30 days after the last dose. If a female patient becomes pregnant, or suspects a pregnancy, during treatment with Daurismo or during the 30 days after the last dose, she must notify her healthcare provider immediately (see section 4.4). Males Glasdegib may be present in semen. Male patients should not donate semen during treatment with Daurismo and for at least 30 days after the last dose. Male patients with female partners should be advised of the potential risk of exposure through semen and to always use effective contraception, including a condom (with spermicide, if available), even after a vasectomy, to avoid exposure of a pregnant partner or a female partner of childbearing potential during treatment with Daurismo and for at least 30 days after the last dose. Male patients must inform their healthcare provider immediately if their female partner becomes pregnant during treatment with Daurismo or during the 30 days after the last dose (see section 4.4). Pregnancy There are no data on the use of Daurismo in pregnant women. Based on its mechanism of action and findings in animal embryo-foetal developmental toxicity studies, glasdegib can cause foetal harm when administered to a pregnant woman (see section 5.3). Daurismo should not be used during pregnancy and in women of childbearing potential not using contraception (see section 4.4). 9 Breast-feeding No studies have been conducted in humans to assess the effect of glasdegib on milk production, its presence in breast milk, or its effects on the breast-fed child. It is unknown whether glasdegib and its metabolites are excreted in human milk. Given the potential for serious adverse reactions in breast-feeding child

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HOS-287466 · has-warning-information · PDF-Seite 6

Embryo-foetal toxicity Based on its mechanism of action and findings from animal embryo-foetal developmental toxicity studies, Daurismo can cause embryo-foetal death or severe birth defects when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus (see section 4.6). Daurismo should not be used during pregnancy and in women of childbearing potential not using contraception. The pregnancy status of female patients of childbearing potential should be verified prior to initiating treatment with Daurismo. Women of childbearing potential should be advised to always use effective contraception during treatment with Daurismo and for at least 30 days after the last dose (see section 4.6). Males Glasdegib may be present in semen. Male patients with female partners should be advised of the potential risk of exposure through semen and to always use effective contraception, including a condom (with spermicide, if available), even after vasectomy, to avoid exposure of a pregnant partner or a female partner of childbearing potential during treatment with Daurismo and for at least 30 days after the last dose (see section 4.6). 6 If a female patient or female partner of a male patient becomes pregnant, or suspects a pregnancy during treatment with Daurismo or during the 30 days after the last dose, they must inform their healthcare provider immediately (see section 4.6). Based on non-clinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation prior to initiating treatment with Daurismo (see section 4.6). QT interval prolongation In a randomised study (Study 1) of patients with AML and high-risk MDS (myelodysplastic syndrome) treated with Daurismo with low-dose cytarabine vs low-dose cytarabine alone, Grade 3/4 ECG QT prolonged was reported in 3.5% of patients treated with Daurismo with low-dose cytarabine compared to 2.4% of the patients treated with low-dose cytarabine alone. Electrolytes should be assessed prior to initiation of Daurismo, at least once weekly for the first month, and then once monthly for the duration of therapy. Electrolyte abnormalities should be corrected. Concomitant medicinal products should be assessed. For medicinal products that have known QT prolonging effects and/or strong CYP3A4 inhibitor potential, alternatives should be considered. ECGs s

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