Vyxeos liposomal (previously Vyxeos) · 4.6 Fertility, pregnancy and lactation · 1

HOS-217547 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most frequently occurring adverse reactions (ADRs) were hypersensitivity including rash (66.9%), febrile neutropenia (63.5%), oedema (52.3%), diarrhoea/colitis (49.9%), mucositis (49.9%), fatigue (46.4%), musculoskeletal pain (44.5%), abdominal pain (36.3%), decreased appetite (33.9%), cough (33.9%), headache (32.3%), chills (31.2%), arrhythmia (30.4%), pyrexia (29.6%), sleep disorders (25.1%), and hypotension (23.7%). The most serious and frequently occurring ADRs were infection (58.7%), cardiotoxicity (18.7%) and haemorrhage (13.1%). Tabulated list of adverse reactions ADRs have been included under the appropriate category in the table below according to the highest frequency observed in any of the main clinical studies. Frequencies 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. For classification of ADRs which occur at Grades 3-5, a comprehensive listing is available from the NCI at NCI CTCAE. Toxicity is graded as mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4), with specific parameters according to the organ system involved. Death (Grade 5) is used for some of the criteria to denote a fatality. Table 3: ADRs reported in clinical studies in patients treated with Vyxeos liposomal (n=375) System organ class ADRs/Frequency (%) Grade 3-5 ADRs/Frequency (%) Infections and infestations Very common Very common Infection (78.1) Infection (58.7) Blood and lymphatic Very common Very common system disorders Febrile neutropenia (63.5) Febrile neutropenia (62.4) Common Common Thrombocytopenia (4.5) Thrombocytopenia (3.7) Neutropenia (3.7) Neutropenia (3.5) Anaemia (3.2) Anaemia (2.1) Immune systems disorders Very common Common Hypersensitivity (including Hypersensitivity (including rash) rash) (66.9)

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HOS-217543 · has-contraindication-information · PDF-Seite 4

History of serious hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 4

HOS-217542 · has-indication-information · PDF-Seite 2

Vyxeos liposomal is indicated for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

HOS-217545 · has-interaction-information · PDF-Seite 7

No interaction studies have been performed with Vyxeos liposomal. The delivery of daunorubicin and cytarabine in the Vyxeos liposomal formulation is anticipated to reduce the possibility of interactions, because systemic free concentrations of daunorubicin and cytarabine are much lower than when administered as the non-liposomal formulation. Cardiotoxic agents Concurrent use of cardiotoxic agents may increase the risk of cardiotoxicity. Use of Vyxeos liposomal in patients who have previously received doxorubicin increases the risk of cardiotoxicity (see section 4.4). Do not administer Vyxeos liposomal in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Hepatotoxic agents Hepatotoxic medicinal products may impair liver function and increase the toxicity. Since daunorubicin is metabolised by the liver, changes in hepatic function induced by concomitant therapies may affect metabolism, pharmacokinetics, therapeutic efficacy, and/or the toxicity of Vyxeos liposomal (see section 5.2). Hepatic function should be monitored more frequently when Vyxeos liposomal is coadministered with hepatoxic agents.

HOS-217546 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential/Contraception in males and females To exclude pregnancy, women of childbearing potential should undergo pregnancy testing before initiation of Vyxeos liposomal. Both male patients with partners of childbearing potential and female patients should use effective contraception during treatment with Vyxeos liposomal and for 6 months following the last dose. Pregnancy There are no data on the use of Vyxeos liposomal in pregnant women. Based on results from animal studies and its mechanism of action, Vyxeos liposomal should not be used during pregnancy, unless the clinical condition of the woman requires treatment and justifies the potential risk to the foetus (see section 5.3). If the medicinal product is used during pregnancy, or if the patient becomes pregnant while receiving Vyxeos liposomal, the woman should be informed of the potential hazard to the foetus. In any case, cardiologic examination and a blood count are recommended in foetuses and newborns born to mothers who received treatment during pregnancy. Breast-feeding It is not known whether Vyxeos liposomal is excreted in human milk. Because of the potential for serious adverse reactions in breast-feeding children from Vyxeos liposomal, women should be advised not to breast-feed during Vyxeos liposomal therapy. 7 Fertility Based on findings in animals, male fertility may be compromised by treatment with Vyxeos liposomal (see section 5.3).

HOS-217544 · has-warning-information · PDF-Seite 5

Other daunorubicin and/or cytarabine-containing products Vyxeos liposomal must not be substituted or interchanged with other daunorubicin and/or cytarabine containing products. Due to substantial differences in the pharmacokinetic parameters, the dose and schedule recommendations for Vyxeos liposomal are different from those for daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. The medicinal product name and dose should be verified prior to administration to avoid dosing errors. Severe myelosuppression Severe myelosuppression (including fatal infections and haemorrhagic events) has been reported in patients after administration of a therapeutic dose of Vyxeos liposomal. Serious or fatal haemorrhagic events, including fatal central nervous system (CNS) haemorrhages, associated with severe thrombocytopenia, have occurred in patients treated with Vyxeos liposomal. Baseline assessment of blood counts should be obtained, and patients should be carefully monitored during treatment with Vyxeos liposomal for possible clinical complications due to myelosuppression. Due to the long plasma half-life of Vyxeos liposomal, time to recovery of ANC and platelets may be prolonged and require additional monitoring. Prophylactic anti-infectives (including anti-bacterial, anti-virals, anti-fungals) may be administered during the period of profound neutropenia until ANC returns to 500/μL or greater. If myelosuppressive complications occur, appropriate supportive measures should be used, e.g., anti-infectives, colony-stimulating factors, transfusions. Blood counts should be regularly monitored until recovery (see section 4.8). Cardiotoxicity Cardiotoxicity is a known risk of anthracycline treatment. Prior therapy with anthracyclines (including patients who have previously received the recommended maximum cumulative doses of doxorubicin or daunorubicin hydrochloride), pre-existing cardiac disease (including impaired cardiac function), previous radiotherapy of the mediastinum, or concomitant use of cardiotoxic products may increase the risk of daunorubicin-induced cardiac toxicity. In two single arm studies of 65 anthracycline pre-treated children with relapsed or refractory AML treated with a single induction cycle (Cycle 1) of Vyxeos liposomal, cardiac disorders (including sinus tachycardia, QT prolongation and ejection fraction decreased) were observed. Several other long-term studies of

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