4.1. Therapeutic indications

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).

4.2. Posology and method of administration

Vyxeos liposomal treatment 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 (see section 4.4).

Posology

Vyxeos liposomal dosing is based on the patient's body surface area (BSA) according to the following schedule:

Table 1: Dose and schedule for Vyxeos liposomal

Therapy

Dosing schedule

First induction

daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on days 1, 3, and 5

Second induction

daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on days 1 and 3

Consolidation

daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 on days 1 and 3

Recommended dosing schedule for induction of remission

The recommended dosing schedule of Vyxeos liposomal 44 mg/100 mg/m2, administered intravenously over 90 minutes:

• on days 1, 3, and 5 as the first 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 one 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.

Recommended dosing schedule for consolidation

The first consolidation cycle should be administered 5 to 8 weeks after the start of the last induction.

The recommended dosing schedule of Vyxeos liposomal is 29 mg/65 mg/m2, administered intravenously over 90 minutes:

• on days 1 and 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 to 8 weeks after the start of the first consolidation. Treatment should be continued as long as the patient continues to benefit or until disease progression, up to maximum of 2 consolidation courses.

Recommended 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 intravenous diphenhydramine (20-25 mg) and intravenous dexamethasone (10 mg) should be given.

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 4.4 and 4.8).

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 (see section 4.4).

Missed dose

If a planned dose of Vyxeos liposomal is missed, the dose should be administered as soon as possible and the dosing schedule adjusted accordingly, maintaining the treatment interval.

Special populations

Renal impairment

Dose adjustment is not required for patients with mild (creatinine clearance [CrCL] 60 mL/min to 89 mL/min by Cockcroft Gault equation [C-G]), moderate (CrCL 30 mL/min to 59 mL/min) or severe (CrCL<30 mL/min) renal impairment. There is no experience with Vyxeos liposomal in patients with end-stage renal disease managed with dialysis (see section 5.2).

Hepatic impairment

Dose adjustment is not required for patients with a bilirubin level less than or equal to 50 µmol/L. There is 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 (see section 4.4).

Elderly population

No dose adjustment is required in elderly patients (≥65 years) (see section 5.2).

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 studies, it is not possible to conclude that the benefits of the use outweigh the risks.

Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

Vyxeos liposomal is for intravenous use only. It must not be administered via intramuscular, intrathecal, or subcutaneous route.

Vyxeos liposomal is administered by intravenous infusion over a period of 90 minutes. Care should be taken to ensure there is no extravasation to prevent the risk of tissue necrosis.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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 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

Therapy

Daunorubicin per dose

Number of doses per course

Daunorubicin per course

First induction

44 mg/m2

3

132 mg/m2

Second induction

44 mg/m2

2

88 mg/m2

Each consolidation

29 mg/m2

2

58 mg/m2

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).

Contraception and Pregnancy

Patients should be advised to avoid becoming pregnant while receiving Vyxeos liposomal. Male and female patients 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. Infusion should not be reinitiated, and retreatment should not be attempted. 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 copper-related 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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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.

Fertility

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

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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

Infection (78.1)

Very common

Infection (58.7)

Blood and lymphatic system disorders

Very common

Febrile neutropenia (63.5)

Common

Thrombocytopenia (4.5)

Neutropenia (3.7)

Anaemia (3.2)

Very common

Febrile neutropenia (62.4)

Common

Thrombocytopenia (3.7)

Neutropenia (3.5)

Anaemia (2.1)

Immune systems disorders

Very common

Hypersensitivity (including rash) (66.9)

Common

Hypersensitivity (including rash) (9.1)

Metabolism and nutrition disorders

Common

Tumour lysis syndrome (7.5)

Common

Tumour lysis syndrome (2.7)

Psychiatric disorders

Very common

Sleep disorders (25.1)

Anxiety (17.3)

Delirium (15.5)

Common

Delirium (2.4)

Uncommon

Sleep disorders (0.5)

Nervous system disorders

Very common

Headache (32.3)

Dizziness (23.2)

Common

Headache (1.1)

Uncommon

Dizziness (0.8)

Eye disorders

Very common

Visual impairment (10.4)

Uncommon

Visual impairment (0.3)

Cardiac disorders

Very common

Cardiotoxicity (72)

Arrhythmiaa (30.4)

Chest pain (17.6)

Very common

Cardiotoxicity (18.7)

Common

Arrhythmiaa (4.3)

Chest pain (1.9)

Vascular disorders

Very common

Haemorrhage (69.1)

Hypotension (23.7)

Hypertension (17.3)

Very common

Haemorrhage (13.1)

Common

Hypertension (6.9)

Hypotension (4.5)

Respiratory, thoracic and mediastinal disorders

Very common

Dyspnoea (36.5)

Cough (33.9)

Pleural effusion (13.9)

Very common

Dyspnoea (13.1)

Uncommon

Pleural effusion (0.8)

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)

Common

Diarrhoea/colitis (6.1)

Abdominal pain (2.9)

Mucositis (2.1)

Decreased appetite (1.6)

Constipation (1.1)

Nausea (1.1)

Uncommon

Dyspepsia (0.5)

Vomiting (0.3)

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)

Uncommon

Hyperhidrosis (0.3)

Musculoskeletal and connective tissue disorders

Very common

Musculoskeletal pain (44.5)

Common

Musculoskeletal pain (5.1)

Renal and urinary disorders

Very common

Renal insufficiency (10.4)

Common

Renal insufficiency (6.4)

General disorders and administration site conditions

Very common

Oedema (52.3)

Fatigue (46.4)

Chills (31.2)

Pyrexia (29.6)

Very common

Fatigue (10.4)

Common

Pyrexia (3.2)

Oedema (2.7)

Uncommon

Chills (0.3)

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 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, ADRs 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

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is no specific experience in the management of overdose in patients. If overdose occurs, exacerbation of adverse reactions associated with Vyxeos liposomal are expected and supportive treatment (incuding anti-infectives, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) should be provided until the patient recovers. Observe the patient carefully over time for signs of cardiotoxicity and provide appropriate supportive therapy as clinically indicated.