Inaqovi · 4.1 Therapeutic indications · 1

HOS-100126 · has-adverse-reaction-information · PDF-Seite 9

Summary of safety profile The safety of Inaqovi was evaluated in one Phase 3 study (ASTX727-02-EU) where 80 AML patients received the medicinal product as monotherapy and a Phase 1/2 study (ASTX727-07) where 189 AML patients received Inaqovi in combination with venetoclax. The overall safety profile for Inaqovi is described below and also reflects the known safety profile of intravenous decitabine. Among the patients who received treatment in ASTX727-02-EU and ASTX727-07 studies, the most common adverse drug reactions (≥ 20%) including Grade ≥ 3 were thrombocytopaenia (ASTX727-02- EU) and febrile neutropenia (ASTX727-07). The most common serious adverse reactions (≥ 20%) were febrile neutropaenia, sepsis, and pneumonia. Deaths while on treatment occurred in 24% of patients. The most frequent adverse reactions resulting in death included pneumonia (8%), sepsis (3%) and central nervous system haemorrhage in the setting of thrombocytopaenia (3%). Tabulated list of adverse reactions The safety evaluation of adverse reactions is largely based on experience with Dacogen in patients with AML. The safety of Inaqovi in adult patients was evaluated in a safety population that included AML patients from the Phase 3 study (ASTX727-02-EU, N=80) and the phase 1/2 study with Inaqovi in combination with venetoclax (ASTX727-07, N=189). Table 3 lists adverse drug reactions associated with Inaqovi patients with AML monotherapy (N=80) or combination therapy with venetoclax (N=189), or that have been associated with intravenous decitabine, according to system organ class (SOC) in MedDRA. Within each SOC, the adverse drug reactions are ranked by frequency and then presented in order of decreasing seriousness. The corresponding frequency category for each adverse drug reaction is 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 available data). Table 3: Adverse drug reactions observed with Inaqovi, Inaqovi combined with venetoclax or with intravenous decitabine therapy in AML patients 9  AML monotherapy (N=80), AML combination therapy (N=189) or IV decitabine MedDRA SOC MedDRA Term a All CTCAE Grades CTCAE Grade 3-4

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HOS-100122 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Breast-feeding (see section 4.6).

HOS-100121 · has-indication-information · PDF-Seite 2

Inaqovi is indicated as monotherapy for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for standard induction chemotherapy. Inaqovi in combination with venetoclax is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for standard induction chemotherapy.

HOS-100124 · has-interaction-information · PDF-Seite 7

Effect of other medicinal products on Inaqovi Decitabine and cedazuridine are not substrates or inhibitors for cytochrome P450 (CYP450); thus interactions with CYP inhibitors or inducers are not expected. Cytidine deaminase inhibitors Because decitabine is a substrate for the cytidine deaminase (CDA) enzyme, which metabolises decitabine resulting in an inactive deaminated form, other medicinal products inhibiting CDA should be avoided, as co-administration may result in increased decitabine exposure. 7 Effect of Inaqovi on other medicinal products Medicinal products metabolised by cytidine deaminase Cedazuridine is an inhibitor of CDA and thereby increases the exposure of decitabine following oral administration. Concomitant administration of Inaqovi with medicinal products metabolised by CDA (i.e., cytarabine, gemcitabine, azacitidine) may result in increased systemic exposure with a potential for increased toxicity of these medicinal products. Co-administration of Inaqovi with medicinal products metabolised primarily by CDA should be avoided. Food Overall decitabine exposure has been shown to be reduced when decitabine is administered with a high- fat, high-calorie meal or a low fat, low-calorie meal (see section 4.2 and section 5.2).

HOS-100125 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential/Contraception in men and women Due to the genotoxic potential of decitabine (see section 5.3), women of childbearing potential must use effective contraceptive measures and avoid becoming pregnant while being treated with Inaqovi and for 6 months following completion of treatment. Men should use effective contraceptive measures and be advised to not father a child while receiving Inaqovi, and for 3 months following completion of treatment (see section 5.3). The use of decitabine and cedazuridine with hormonal contraceptives has not been studied. Pregnancy There are no or a limited amount of human data from the use of decitabine and cedazuridine in pregnant women. Based on the results of embryo-foetal toxicity studies conducted in animals (see section 5.3), Inaqovi may harm the foetus when administered to pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Inaqovi is not recommended during pregnancy and in women of childbearing potential not using effective contraception. A pregnancy test should be performed on all women of childbearing potential before treatment is started. If Inaqovi is used during pregnancy, or if a patient becomes pregnant while receiving this medicinal product, the patient should be apprised of the potential hazard to the foetus. Breast-feeding It is unknown whether decitabine, cedazuridine, or their metabolites are excreted in breast milk. A risk to the newborns/infants cannot be excluded. Inaqovi is contraindicated during breast-feeding (see section 4.3). 8 Fertility No human data on the effect of decitabine and cedazuridine on fertility are available. Ovarian and testicular toxicity, including mutagenicity, has been observed in repeat-dose toxicity studies in mice. Because of the possibility of infertility as a consequence of therapy, men should seek advice on conservation of sperm and female patients of childbearing potential should seek consultation regarding oocyte cryopreservation prior to initiating treatment. Before starting treatment or planning pregnancy, consider the above guidance (see section 5.3).

HOS-100123 · has-warning-information · PDF-Seite 6

Myelosuppression Fatal and serious myelosuppression can occur with treatment (see section 4.8). Complete blood cell counts must be obtained prior to the initiation of treatment, prior to each cycle, and as clinically indicated to monitor response and toxicity. Growth factors and anti-infective therapies must be administered for treatment or prophylaxis as appropriate. The next cycle must be delayed and resumed at the same or reduced dose as recommended (see sections 4.2 and 4.8). Patients must be monitored for signs and symptoms of infection and treated promptly. Tumour lysis syndrome For patients taking venetoclax, due to the risk of tumour lysis syndrome (TLS), refer to the venetoclax SmPC sections 4.2, 4.4 and 4.8 for additional information. Neutropaenia Supportive treatments include, administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropaenia according to institutional guidelines. For situations where administration must be delayed, see section 4.2. Respiratory, thoracic and mediastinal disorders Cases of interstitial lung disease (ILD) (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving intravenous decitabine. Patients with an acute onset or unexplained worsening of pulmonary symptoms must be carefully assessed to exclude ILD. If ILD is confirmed, appropriate treatment must be initiated (see section 4.8). Hepatic impairment Use in patients with hepatic impairment has not been established. Caution must be exercised in the administration of medicinal product to patients with hepatic impairment and in patients who develop signs or symptoms of hepatic impairment. Liver function tests must be performed prior to the initiation of therapy, prior to each treatment cycle, and as clinically indicated (see sections 4.2 and 5.2). 6 Renal impairment Use in patients with severe renal impairment has not been studied. Caution must be exercised in the administration of the medicinal product to patients with severe renal impairment (CrCl < 30 mL/min). Renal function tests must be performed prior to the initiation of therapy, prior to each treatment cycle, and as clinically indicated (see sections 4.2 and 5.2). Cardiac disease Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from clinical st

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