VYXEOS LIPOSOMAL Powder for concentrate for solution for infusion Ref.[51372] Active ingredients: Cytarabine Cytarabine and Daunorubicin Daunorubicin

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, colonystimulating 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 treatment with anthracycline/anthracenedione in children suggest that congestive cardiomyopathies with a latency of many years may occur (see section 4.8).

Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m² have been associated with an increased incidence of treatment-induced congestive heart failure. This limit appears lower (400 mg/m²) in patients who received radiation therapy to the mediastinum. The relationship between cumulative Vyxeos liposomal dose and the risk of cardiac toxicity has not been determined. Total cumulative exposure of daunorubicin has been described in the table below.

Table 2. Cumulative exposure of daunorubicin per course of Vyxeos liposomal:

A baseline cardiac evaluation with an electrocardiogram (ECG) and a multi-gated radionuclide angiography (MUGA) scan or an echocardiography (ECHO) is recommended, especially in patients with risk factors for increased cardiac toxicity. Cardiac function should be closely monitored.

Treatment with Vyxeos liposomal should be discontinued in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk (see sections 4.5 and 4.8).

Pregnancy warning/women of childbearing potential

Patients should be advised to avoid becoming pregnant while receiving Vyxeos liposomal. Male patients and women of childbearing potential must use an effective method of contraception during treatment and for 6 months following the last dose of Vyxeos liposomal (see section 4.6).

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine.

For moderate hypersensitivity symptoms (e.g., moderate rash, flushing, mild dyspnoea, chest discomfort) the treatment should be stopped. Intravenous diphenhydramine (20-25 mg or equivalent) and intravenous 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. Intravenous 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 (see sections 4.2 and 4.8).

Tissue necrosis

Daunorubicin has been associated with local tissue necrosis at the site of medicinal product extravasation. In clinical studies with Vyxeos liposomal, one event of extravasation occurred, but no necrosis was observed. Care should be taken to ensure that there is no extravasation of medicinal product when Vyxeos liposomal is administered. Vyxeos liposomal should be administered intravenously only. Do not administer via an intramuscular, intrathecal, or subcutaneous route (see section 4.2).

Evaluation of hepatic and renal function

Hepatic impairment may increase the risk of toxicity associated with daunorubicin and cytarabine. Evaluation of hepatic function using conventional clinical laboratory tests is recommended prior to administration of Vyxeos liposomal and periodically during treatment. There is no experience with Vyxeos liposomal in patients with baseline serum bilirubin greater than 50 µmol/L or end-stage renal disease managed with dialysis. Vyxeos liposomal should only be used in patients with severe hepatic impairment if the benefits outweigh the risks (see section 4.2).

Laboratory tests

Vyxeos liposomal may induce hyperuricemia secondary to rapid lysis of leukaemic cells. Blood uric acid levels should be monitored and appropriate therapy initiated in the event that hyperuricemia develops.

History of Wilson’s disease or other copper-related disorder

Each vial contains 100 mg of copper gluconate, which corresponds to 14 mg of elemental copper. Vyxeos liposomal should only be used in patients with a history of Wilson’s disease or other copperrelated disorder if the benefits outweigh the risks (see section 6.1). Discontinue Vyxeos liposomal in patients with signs or symptoms of acute copper toxicity.

Immunosuppressant effects / Increased susceptibility to infections

Administration of live or live-attenuated vaccines in patients that are immunocompromised by chemotherapeutic agents may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving Vyxeos liposomal. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Gastrointestinal mucositis and diarrhoea

It should be taken into consideration that the absorption of oral accompanying medicinal products may be considerably influenced by gastrointestinal mucositis and/or diarrhoea frequently occurring in association with intensive chemotherapy.

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.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should avoid becoming pregnant while receiving Vyxeos liposomal. Women of childbearing potential should use effective contraception while they or their male partner undergo treatment. Women of childbearing potential should not receive treatment until pregnancy is excluded.

Women of childbearing potential should undergo pregnancy testing before initiation of Vyxeos liposomal. Men with sexual partners of reproductive potential and women should use effective contraception during treatment and for 6 months following the last dose of Vyxeos liposomal.

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, mothers should be advised not to breast-feed during Vyxeos liposomal therapy.

Fertility

Based on findings in animals, male fertility may be compromised by treatment with Vyxeos liposomal (see section 5.3).

Vyxeos liposomal has minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported with the use of Vyxeos liposomal. Therefore, caution is recommended when driving or operating machines.

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):

^a Arrhythmia group terms includes atrial fibrillation, bradycardia, and the most commonly reported arrhythmia was tachycardia

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 (see section 4.4).

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 (see section 4.4).

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 (see section 4.4).

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 (see section 4.4).

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 national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.