Vyxeos liposomal now reimbursed in Belgium for patients with untreated high-risk AML

_{NAME. Vyxeos liposomal 44 mg/100 mg powder for concentrate for solution for infusion. COMPOSITION. Each vial contains 44 mg of daunorubicin and 100 mg of cytarabine. After reconstitution the solution contains 2.2 mg/mL daunorubicin and 5 mg/mL cytarabine encapsulated in liposomes in a fixed combination in a 1:5 molar ratio. INDICATIONS. Treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). POSOLOGY AND ADMINISTRATION. Should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic medicinal products. Vyxeos liposomal has a different posology than daunorubicin injection and cytarabine injection and it must not be interchanged with other daunorubicin and/or cytarabine containing products. Posology. Vyxeos liposomal dosing is based on the patient’s body surface area (BSA) according to the following schedule: 1st induction: daunorubicin 44 mg/m2 & cytarabine 100 mg/m2 on days 1, 3, and 5. 2nd induction: daunorubicin 44 mg/m2 & cytarabine 100 mg/m2 on days 1 and 3. Consolidation: daunorubicin 29 mg/m2 & cytarabine 65 mg/m2 on days 1 and 3. Dosing schedule for induction of remission. 44 mg/100 mg/m2, administered IV over 90 min: on days 1, 3, and 5 as the 1st course of induction therapy. On days 1 and 3 as subsequent course of induction therapy, if needed. A subsequent course of induction may be administered in patients who do not show disease progression or unacceptable toxicity. The attainment of a normal-appearing bone marrow may require more than 1 induction course. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction is required. Treatment should be continued as long as the patient continues to benefit or until disease progression up to maximum of 2 induction courses. Dosing schedule for consolidation. 1st consolidation cycle should be administered 5-8 weeks after the start of the last induction. The recommended dosing schedule of Vyxeos liposomal is 29 mg/65 mg/m2, administered IV over 90 min: on days 1 & 3 as subsequent courses of consolidation therapy, if needed. Consolidation therapy is recommended for patients achieving remission who have recovered to absolute neutrophil count (ANC) > 500/μL and the platelet count has recovered to greater than 50,000/μL in the absence of unacceptable toxicity. A subsequent course of consolidation may be administered in patients who do not show disease progression or unacceptable toxicity within the range of 5-8 weeks after the start of the 1st consolidation. Treatment should be continued as long as the patient continues to benefit or until disease progression, up to maximum of 2 consolidation courses. Dose adjustments during treatment. Patients should be monitored for haematologic response and toxicities. Dosing should be delayed or permanently discontinued, if necessary, as described below. Patients may be pre-medicated for nausea and vomiting. An anti-hyperuricemic therapy should be considered (e.g., allopurinol) prior to initiating Vyxeos liposomal. Hypersensitivity. For mild hypersensitivity symptoms (e.g., mild flushing, rash, pruritus), the treatment should be stopped, and the patient should be supervised, including monitoring of vital signs. The treatment should be restarted slowly once the symptoms have resolved, by halving the rate of infusion and IV diphenhydramine (20-25 mg) and IV dexamethasone (10 mg) should be given. For moderate hypersensitivity symptoms (e.g., moderate rash, flushing, mild dyspnoea, chest discomfort) the treatment should be stopped. IV diphenhydramine (20-25 mg or equivalent) and IV dexamethasone (10 mg) should be given. The infusion should not be restarted. When the patient is retreated, Vyxeos liposomal should be given at the same dose and rate and with premedication. For severe/life-threatening hypersensitivity symptoms (e.g., hypotension requiring vasopressor therapy, angioedema, respiratory distress requiring bronchodilation therapy, generalised urticaria), the treatment should be stopped. IV diphenhydramine (20-25 mg) and dexamethasone (10 mg) should be given, and an epinephrine (adrenaline) or bronchodilators should be added if indicated. Do not reinitiate infusion, and do not retreat. Treatment with Vyxeos liposomal should be permanently discontinued. Patients should be monitored until symptoms resolve. Missed dose. The dose should be administered as soon as possible and the dosing schedule adjusted accordingly, maintaining the treatment interval. Cardiotoxicity. Assessment of cardiac function prior to start of treatment is recommended, especially in patients with a high risk of cardiac toxicity. Vyxeos liposomal treatment should be discontinued in patients who develop signs or symptoms of cardiomyopathy, unless the benefits outweigh the risks. Special populations. Renal impairment. Dose adjustment is not required for patients with mild (creatinine clearance [CrCL] 60-89 mL/min by Cockcroft Gault equation [C-G]), moderate (CrCL 30-59 mL/min) or severe (CrCL<30 mL/min) renal impairment. No experience with Vyxeos liposomal in patients with end-stage renal disease managed with dialysis. Hepatic impairment. Dose adjustment is not required for patients with a bilirubin level less than or equal to 50 μmol/L. No experience with Vyxeos liposomal in patients with hepatic impairment resulting in a bilirubin level greater than 50 μmol/L. Vyxeos liposomal should only be used in patients with severe hepatic impairment if the benefits outweigh the risks. Elderly population. No dose adjustment is required in elderly patients (≥65 years). Paediatric population. Outside its authorised indications Vyxeos liposomal has been studied in paediatric and young adult patients aged 1-21 years with relapsed AML. Due to the limited size of these trials, it is not possible to conclude that the benefits of the use outweigh the risks. No recommendation on a posology can be made. Administration. Vyxeos liposomal is for IV use only. No administration via an IM, intrathecal, or SC route. Vyxeos liposomal is administered by IV infusion over a period of 90 min. Care should be taken to ensure there is no extravasation to prevent the risk of tissue necrosis. Contraindications. History of serious hypersensitivity to the active substances or to any of the excipients. Undesirable effects. Summary. 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%). List. 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). 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. ADRs reported in clinical studies in patients treated with Vyxeos liposomal (n=375). ADRs/Frequency (%). Infections and infestations. Very Common: Infection (78.1). Blood and lymphatic system disorders. Very Common: Febrile neutropenia (63.5). Common: thrombocytopenia (4.5), Neutropenia (3.7), Anaemia (3.2). Immune systems disorders. Very Common: Hypersensitivity (including rash) (66.9). Metabolism and nutrition disorders. Common: Tumour lysis syndrome (7.5). Psychiatric disorders. Very Common: Sleep disorders (25.1), Anxiety (17.3), Delirium (15.5). Nervous system disorders. Very Common: Headache (32.3), Dizziness (23.2). Eye disorders. Very Common: Visual impairment (10.4). Cardiac disorders. Very Common: Cardiotoxicity (72), Arrhythmiaa (30.4), Chest pain (17.6). Vascular disorders. Very Common: Haemorrhage (69.1), Hypotension (23.7), Hypertension (17.3). Respiratory, thoracic and mediastinal disorders. Very Common: Dyspnoea (36.5), Cough (33.9), Pleural effusion (13.9). Gastrointestinal disorders. Very Common: Nausea (51.7), Diarrhoea/colitis (49.9), Mucositis (49.9), Constipation (42.7), Abdominal pain (36.3), Decreased appetite (33.9), vomiting (27.7). Common: Dyspepsia (9.6). Skin and subcutaneous tissue disorders. Very Common: Pruritus (17.3), Hyperhidrosis (10.1). Common: Night sweats (8.3), Alopecia (3.2). Uncommon: Palmar-plantar erythrodysaesthesia syndrome (0.8). Musculoskeletal and connective tissue disorders. Very Common: Musculoskeletal pain (44.5). Renal and urinary disorders. Very Common: Renal insufficiency (10.4). General disorders and administration site conditions. Very Common: Oedema (52.3), Fatigue (46.4), Chills (31.2), Pyrexia (29.6). Grade 3-5 ADRs/Frequency (%). Infections and infestations. Very Common: Infection (58.7). Blood and lymphatic system disorders. Very Common: Febrile neutropenia (62.4). Common: Thrombocytopenia (3.7), Neutropenia (3.5), Anaemia (2.1). Immune systems disorders. Common: Hypersensitivity (including rash) (9.1). Metabolism and nutrition disorders. Common: Tumour lysis syndrome (2.7). Psychiatric disorders. Common: Delirium (2.4). Uncommon: Sleep disorders (0.5). Nervous system disorders. Common: Headache (1.1). Uncommon: Dizziness (0.8). Eye disorders. Uncommon: Visual impairment (0.3). Cardiac disorders. Very Common: Cardiotoxicity (18.7). Common: Arrhythmiaa (4.3), Chest pain (1.9). Vascular disorders. Very Common: Haemorrhage (13.1). Common: Hypertension (6.9), Hypotension (4.5). Respiratory, thoracic and mediastinal disorders. Very Common: Dyspnoea (13.1). Uncommon: Pleural effusion (0.8). Description of selected adverse reactions. Infections. Due to the neutropenia experienced with Vyxeos liposomal, infections of various types were very common ADRs. Pneumonia, sepsis and bacteriaemia were the most frequently seen serious infection ADRs in the clinical studies population. The incidence of infection events was 78.1%; the incidence of non-serious events of infections was 73.1%, the incidence of serious events of infections was 28.5%; the incidence of infections which led to discontinuation is 0.5%. The incidence of fatal infections was 6.9%. The fatal infections experienced were sepsis and pneumonia. Haemorrhage. Due to the thrombocytopenia experienced with Vyxeos liposomal a variety of haemorrhagic events were seen in clinical studies. The most common haemorrhagic event was epistaxis, and the majority of these were considered not serious (29.1%). The incidence of haemorrhage events is 69.1%; the incidence of non-serious events of haemorrhage was 67.2 %; the incidence of serious events of haemorrhage is 5.6%; the incidence of haemorrhage which led to discontinuation is 0. The incidence of fatal haemorrhage was 2.1%. Serious or fatal haemorrhagic events, including fatal central nervous system (CNS) haemorrhages, associated with severe thrombocytopenia were seen in patients treated with Vyxeos liposomal. Cardiotoxicity. Cardiotoxicities were seen in Vyxeos liposomal clinical studies. The most frequently reported serious ADRs were decreased ejection fraction and congestive cardiac failure. Cardiotoxicity is a known risk of anthracycline treatment. The incidence of all cardiotoxicity events was 72.0%; the incidence of non-serious events of cardiotoxicity was 68.5 %; the incidence of serious events of cardiotoxicity was 9.1%; the incidence of cardiotoxicity which led to discontinuation is 0.5%. Incidence of fatal cardiotoxicity events is 0.5%. Cardiac arrest was reported as a fatal event; the patient experienced thrombocytopenia and neutropenia which contributed to cardiac arrest. Hypersensitivity. Hypersensitivity reactions were very common ADRs in Vyxeos liposomal clinical studies. The most frequently reported hypersensitivity ADRs were rash and the majority of these were not serious (38.9%). The incidence of all hypersensitivity events was 66.9%; the incidence of non-serious events of hypersensitivity was 66.4 %, of which 38.9 % were rash; the incidence of serious events of hypersensitivity is 1.1%; the frequency of hypersensitivity which led to discontinuation is 0. The frequency of fatal hypersensitivity events was 0. Paediatric population. The safety profile of Vyxeos liposomal in 38 paediatric patients with relapsed AML in study AAML1421 appeared to be in general similar to that observed in the approved indication in adults with newly treated AML treated with Vyxeos liposomal (see section 4.2). However, adverse events in study AAML 1421 observed in paediatric patients that were different from or more severe than those seen in adults (acknowledging limitations of cross study comparisons) included rash maculo-papular (47.4%), electrocardiogram QT prolongation (28.9%), the early onset of cardiotoxicity (defined as > 10% decrease LVEF to final LVEF < 50% LVEF; 21.0%), severe hypokalaemia (13.2%), hyperglycaemia (7.9%) and ALT increased (7.9%). Hypertension was observed in 18.2% of these paediatric patients. No paediatric long-term safety data beyond the study duration (26 months) are available. There is, thus, no paediatric safety data to address the long-term cardiotoxicity of Vyxeos liposomal, including long-term cardiotoxicity when used at doses above the maximum life-time cumulative anthracycline dose. There are no data on the effects of Vyxeos liposomal treatment on growth and maturation. Reporting of suspected adverse reactions. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the FAGG Afd. Vigilantie, Galileelaan 5/03, 1210 BRUSSEL, www.eenbijwerkingmelden.be, e-mail: adr@fagg.be. MARKETING AUTHORISATION HOLDER. Jazz Pharmaceuticals Ireland Ltd 5th Floor, Waterloo Exchange Waterloo Road Dublin, D04 E5W7, Ireland. MARKETING AUTHORISATION NUMBER(S). EU/1/18/1308/001 1 vial, EU/1/18/1308/002 2 vials, EU/1/18/1308/003 5 vials. DATE OF REVISION OF THE TEXT. 11/2022. DELIVERY MODE. Medicinal prescription.}