Vyxeos liposomal

ANNEX I  
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  

1 



 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Vyxeos liposomal 44 mg/100 mg powder for concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE 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. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
Purple, lyophilised cake. 
 
 
4. CLINICAL PARTICULARS 
 
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: 
 

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 

 

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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). 
 

3 



 
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. 
 
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 discountinued in patients who 
develop signs or symptoms of cardiomyopathy, unless the benefits outweigh the risks (see section 
4.4). 
 
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]) or moderate (CrCL 30 mL/min to 59 mL/min) renal 
impairment. There is no experience with Vyxeos liposomal in patients with severe renal impairment 
(CrCL 15 mL/min to 29 mL/min) or end-stage renal disease. Vyxeos liposomal should only be used in 
patients with severe renal impairment if the benefits outweigh the risks (see sections 4.4 and 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 
The safety and efficacy of Vyxeos liposomal in children aged 0-18 years have not yet been 
established. No data are available. 
 
Method of administration 
Vyxeos liposomal is for intravenous use only. It must not be administered via an 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 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 
 

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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. 
 
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 1: 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). 
 

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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 or renal impairment may increase the risk of toxicity associated with daunorubicin and 
cytarabine. Evaluation of hepatic and renal 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, 
severe renal impairment (creatinine clearance less than 30 mL/min), or end stage renal disease. 
Vyxeos liposomal should only be used in patients with severe hepatic and/or renal 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. 
 

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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-drug 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 
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 to discontinue breast-feeding during Vyxeos liposomal therapy. 
 
Fertility 
Based on findings in animals, male fertility may be compromised by treatment with Vyxeos liposomal 
(see section 5.3). 
 

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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 2: 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) 

Common 
Headache (1.1) 

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System Organ Class ADRs/Frequency (%) Grade 3-5 ADRs/Frequency (%) 
Dizziness (23.2)  

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) 
 

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System Organ Class ADRs/Frequency (%) Grade 3-5 ADRs/Frequency (%) 
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 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). 
 
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. 
 
 

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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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: other antineoplastic agents, combinations of antineoplastic agents, ATC 
code: L01XY01. 
 
Mechanism of action 
Vyxeos liposomal is a liposomal formulation of a fixed combination of daunorubicin and cytarabine in 
a 1:5 molar ratio. The 1:5 molar ratio has been shown in vitro and in vivo to maximise synergistic 
antitumour activity in AML. 
 
Daunorubicin has antimitotic and cytotoxic activity, which is achieved by forming complexes with 
DNA, inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of 
gene expression, and producing DNA-damaging free radicals. 
 
Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase 
of cell division. Intracellularly, cytarabine is converted into cytarabine-5-triphosphate (ara-CTP), 
which is the active metabolite. The mechanism of action is not completely understood, but it appears 
that ara-CTP acts primarily through inhibition of DNA synthesis. Incorporation into DNA and RNA 
may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to proliferating mammalian 
cells in culture. 
 
Vyxeos liposomal liposomes exhibit a prolonged plasma half-life following intravenous infusion, with 
greater than 99% of the daunorubicin and cytarabine in the plasma remaining encapsulated within the 
liposomes. Vyxeos liposomal delivers a synergistic combination of daunorubicin and cytarabine to 
leukaemia cells for a prolonged period of time. Based on data in animals, Vyxeos liposomal liposomes 
accumulate and persist in high concentration in the bone marrow, where they are preferentially taken 
up intact by leukaemia cells in an active engulfment process. In leukaemia-bearing mice, the 
liposomes are taken up by leukaemia cells to a greater extent than by normal bone marrow cells. After 
internalisation, Vyxeos liposomal liposomes undergo degradation, releasing daunorubicin and 
cytarabine within the intracellular environment, enabling the medicinal products to exert their 
synergistic antineoplastic activity. 
 
Clinical efficacy and safety 
The efficacy of Vyxeos liposomal in the treatment of high risk AML was evaluated in 1 controlled 
study. 
 
Study 301 in patients with untreated high risk AML 
Study 301 was a Phase 3 randomised, multicentre, open-label, parallel-arm, superiority study which 
evaluated Vyxeos liposomal vs. a standard combination of cytarabine and daunorubicin (7+3) in 309 
patients between 60 to 75 years of age with untreated high risk AML. Patients with the following 
AML sub-types were included in the study: therapy-related AML (t-AML), myelodysplastic syndrome 
AML (MDS AML) and chronic myelomonocytic leukaemia AML (CMMoL AML) with documented 
history of MDS or CMMoL prior to transformation to AML, and de novo AML with karyotype 
changes characteristic of myelodysplasia, (per 2008 WHO criteria). 
 

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The study included 2 phases, 1) Treatment Phase during which patients received up to 2 induction and 
2 consolidation courses, and 2) a Follow-up Phase, which began 30 days after the last induction or 
consolidation course and continued for up to 5 years from randomisation. The number of inductions 
and consolidations a patient received depended upon Complete Response (CR) or Complete Response 
with incomplete recovery (CRi), which was confirmed by bone marrow assessment. In clinical studies 
only, Vyxeos liposomal 100 units/m2/day (equivalent to 44 mg/100 mg/m2) was administered 
intravenously over 90 minutes on days 1, 3, and 5 for the first induction and on days 1 and 3 for 
patients requiring a second induction. A second induction was highly recommended for patients who 
did not achieve a CR or CRi in the first induction course and was mandatory for patients achieving 
greater than 50% reduction in percent blasts. Post-remission therapy with haematopoietic stem cell 
transplantation (HSCT) was permitted either in place of or after consolidation chemotherapy. For 
consolidation courses, in clinical studies only, the Vyxeos liposomal dose was reduced to 65 
units/m2/day (equivalent to 29mg/65 mg/m2) on days 1 and 3. In the 7+3 arm, first induction consisted 
of cytarabine 100 mg/m2/day on days 1 to 7 by continuous infusion, and daunorubicin 60 mg/m2/day 
on days 1, 2, and 3 whereas second induction and consolidation cytarabine was dosed on days 1 to 5 
and daunorubicin on days 1 and 2. 
 
There were 153 patients randomised to Vyxeos liposomal and 156 patients randomised to the 7+3 
control arm. The randomised patients had a median age of 68 (range 60-75 years), 61% were male, 
and 88% had an ECOG performance status of 0-1. At baseline 20%  had t-AML, 54% had AML with 
an antecedent haematological disorder and 25% had de novo AML with myelodysplasia-related 
cytogenetic abnormalities; 34% had been treated previously with a hypomethylating agent for 
MDS;54%  had an adverse karyotype. 
The demographic and baseline disease characteristics were generally balanced between the study 
arms. FLT3 mutation was identified in 15% (43/279) of patients tested and NPM1 mutation was 
identified in 9% (25/283) patients tested. 
 
The primary endpoint was overall survival measured from the date of randomisation to death from any 
cause. Vyxeos liposomal demonstrated superiority in overall survival in the ITT population compared 
with the comparator 7+3 treatment regimen (Figure 1). The median survival for the Vyxeos liposomal 
treatment group was 9.56 months compared with 5.95 months for the 7+3 treatment group (Hazard 
Ratio = 0.69, 95% CI = 0.52, 0.90, two-sided log-rank test p = 0.005). 
 
The overall rate of HSCT was 34% (52/153) in the Vyxeos liposomal arm and 25% (39/156) on the 
control arm. 
 
Figure 1: Kaplan-Meier curve for overall survival, ITT population 

 

12 



 
 Table 4: Efficacy results for study 301 
 
 Vyxeos liposomal 

N=153 
7+3 

N=156 

Overall survival 

 Median survival, months (95% CI) 9.56 (6.60, 11.86) 5.95 (4.99, 7.75) 

 Hazard ratio (95% CI) 0.69 (0.52, 0.90) 

 p-value (2-sided) a 0.005 

Event free survival 

 Median survival, months (95% CI) 2.53 (2.07, 4.99) 1.31 (1.08, 1.64) 

 Hazard ratio (95% CI) 0.74 (0.58, 0.96) 

 p-value (2-sided) a 0.021 

Complete response rate 

 CR, n (%) 57 (37) 40 (26) 

 Odds ratio (95% CI) 1.69 (1.03, 2.78) 

 p-value (2-sided) b 0.040 

 CR + CRi, n (%) 73 (48) 52 (33) 

 Odds ratio (95% CI) 1.77 (1.11, 2.81) 

 p-value (2-sided) b 0.016 
Abbreviations: CI = Confidence interval; CR= Complete response; CRi= Complete response with incomplete 
recovery 
a p-value from stratified log rank test stratifying by age and AML sub-type 
b p-value from stratified Cochran-Mantel-Haenszel test stratified by age and AML sub-type 
 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Vyxeos liposomal in one or more subsets of the paediatric population in AML (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of daunorubicin and cytarabine administered as Vyxeos liposomal were 
investigated in adult patients who received a dose of daunorubicin 44 mg/m2 and cytarabine 100 
mg/m2 administered as a 90-minute intravenous infusion on days 1, 3, and 5. The pharmacokinetics of 
each medicinal product was based on total plasma concentrations (i.e., encapsulated plus 
unencapsulated medicinal product). Following the dose administered on day 5, the mean (% 
coefficient of variation [CV]) maximum plasma concentrations (Cmax) for daunorubicin was 26.0 
(32.7%) mcg/mL and cytarabine was 62.2 (33.7%) mcg/mL. The mean (%CV) area under the curve 
(AUC) during one dosing interval for daunorubicin was 637 (38.4%) mcg.h/mL and cytarabine was 
1900 (44.3%) mcg.h/mL. 
 
When daunorubicin and cytarabine are administered as components of Vyxeos liposomal, the 
liposomes appear to govern their tissue distribution and rates of elimination; therefore, while the non-
liposomal medicinal products have markedly different clearance (CL), volume of distribution (V), and 
terminal half-life (t1/2) Vyxeos liposomal causes these pharmacokinetic parameters to converge. 
 

13 



The accumulation ratio was 1.3 for daunorubicin and 1.4 for cytarabine. There was no evidence of 
time-dependent kinetics or major departures from dose proportionality over the range of 1.3 mg/3 mg 
per m2 to 59 mg/134 mg per m2 (0.03 to 1.3 times the approved recommended dosage). 
 
Distribution 
The volume of distribution (%CV) for daunorubicin is 6.6 L (36.8%) and cytarabine is 7.1 L (49.2%). 
Plasma protein binding was not evaluated. 
 
Metabolism and biotransformation 
Similar to non-liposomal daunorubicin and cytarabine, subsequent to release from Vyxeos liposomal 
liposomes, both daunorubicin and cytarabine are extensively metabolised in the body. Daunorubicin is 
mostly catalysed by hepatic and non-hepatic aldo-keto reductase and carbonyl reductase to the active 
metabolite daunorubicinol. Cytarabine is metabolised by cytidine deaminase to the inactive metabolite 
1-β (beta)-D-arabinofuranosyluracil (AraU). Unlike non-liposomal daunorubicin and cytarabine, 
which are quickly metabolised to the respective metabolites, daunorubicin and cytarabine after Vyxeos 
liposomal administration are free bases encapsulated in liposomes. Plasma concentration-time profiles 
obtained from 13 to 26 patients who received Vyxeos liposomal 100 units/m2 (equivalent to 44 mg/ m² 
of daunorubicin and 100 mg/m² of cytarabine).on days 1, 3, and 5 show the mean AUClast 
metabolite:parent ratio for daunorubicinol and AraU  were 1.79% and 3.22% to that for daunorubicin 
and cytarabine, respectively; which are lower than those typically reported for non-liposomal products, 
~40-60% for daunorubicinol:daunorubicin and ~80% for AraU:cytarabine. The lower percentages of 
metabolite:parent ratios after Vyxeos liposomal administration indicate that most of the total 
daunorubicin and cytarabine in the circulation is trapped inside the Vyxeos liposomal liposomes, 
where they are inaccessible to medicinal product-metabolising enzymes. 
 
Elimination 
Vyxeos liposomal exhibits a prolonged half-life (%CV) of 31.5 h (28.5%) for daunorubicin and 40.4 h 
(24.2%) for cytarabine with greater than 99% of the daunorubicin and cytarabine in the plasma 
remaining encapsulated within the liposomes. The clearance (%CV) is 0.16 L/h (53.3%) for 
daunorubicin and 0.13 L/h (60.2%) for cytarabine. 
 
Urinary excretion of daunorubicin and daunorubicinol accounts for 9% of the administered dose of 
daunorubicin, and urinary excretion of cytarabine and AraU accounts for 71% of the administered 
dose of cytarabine. 
 
Special populations 
Age, sex, race, body weight, body mass index, and white blood cell count do not have a clinically 
important effect on the exposure of total daunorubicin or cytarabine after adjusting dose by body 
surface area. 
 
Paediatric population 
Insufficient pharmacokinetic data were collected in paediatric patients to draw conclusions. 
 
Elderly population 
The pharmacokinetics of Vyxeos liposomal in patients aged > 85 years has not yet been evaluated. No 
data are available. 
 
Hepatic impairment 
The pharmacokinetics of total daunorubicin and cytarabine were not altered in patients with bilirubin 
≤ 50 µmol/L. The pharmacokinetics in patients with bilirubin greater than 50 µmol/L is unknown. 
 
Renal impairment 
Based on a population pharmacokinetic analysis using data from clinical studies in patients, no 
significant difference in clearance of daunorubicin or cytarabine was observed in patients with 
pre-existing mild to moderate renal impairment (60 mL/min ≥ to ≤ 89 mL/min creatinine clearance 
[CrCL] for mild, and 30 mL/min ≥ to ≤ 59 mL/min creatinine clearance [CrCL] for moderate) 
compared to patients with baseline normal renal function (CrCL ≥ 90 mL/min). The potential effects 

14 



of severe renal impairment (CrCL 15 mL/min ≥ to ≤ 29 mL/min, C-G) and end-stage renal disease on 
the pharmacokinetics of daunorubicin and cytarabine administered as Vyxeos liposomal are unknown 
(see section 4.2). 
 
5.3 Preclinical safety data 
 
Repeat-dose toxicity of Vyxeos liposomal was tested in two-cycle intravenous infusion toxicity studies 
with 28-day recovery periods conducted in rats and dogs. Adverse effects of Vyxeos liposomal 
occurred at all tested dose levels (low to null safety margins as based on systemic exposures) and were 
generally consistent with those known for non-liposomal daunorubicin and/or cytarabine, comprising 
mainly findings of gastrointestinal and hematological toxicity. Although central nervous system (CNS) 
and cardiovascular system parameters were included in these studies, given the observed morbidity 
and mortality, there was insufficient information to arrive at an integrated assessment of safety 
pharmacology of Vyxeos liposomal. Vyxeos liposomal contains daunorubicin, which is known for its 
profound cardiotoxicity potential, and cytarabine, which is known to be associated with CNS 
toxicities. 
 
Carcinogenicity, mutagenicity, and reproductive toxicity studies have not been conducted with Vyxeos 
liposomal. 
 
While cytarabine is not a carcinogen, daunorubicin is a possible carcinogen, hence, Vyxeos liposomal 
may be associated with a carcinogenic potential. Both daunorubicin and cytarabine are genotoxic, 
therefore, Vyxeos liposomal may be associated with a genotoxic risk. 
 
A high incidence of mammary tumours was observed about 120 days after a single intravenous dose of 
daunorubicin in rats (at about 1.7 times the human dose on a mg/m2 basis). Daunorubicin was 
mutagenic in in vitro tests (Ames assay, V79 hamster cell assay), and clastogenic in vitro 
(CCRF-CEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow) tests. 
 
Cytarabine was mutagenic in in vitro tests and was clastogenic in vitro (chromosome aberrations and 
SCE in human leukocytes) and in vivo (chromosome aberrations and SCE assay in rodent bone 
marrow, mouse micronucleus assay). Cytarabine caused the transformation of hamster embryo cells 
and rat H43 cells in vitro. 
 
Cytarabine was clastogenic to meiotic cells. 
 
Both cytarabine and daunorubicin, tested separately, showed teratogenic and embryotoxic effects in 
animal studies. Furthermore, daunorubicin caused testicular atrophy and total aplasia of spermatocytes 
in the seminiferous tubules in dogs and cytarabine, sperm-head abnormalities in mice. A single dose of 
cytarabine in rats, administered on day 14 of gestation, reduced prenatal and postnatal brain size and 
caused permanent impairment of learning ability. 
 
Environmental Risk Assessment (ERA)   
Environmental risk assessment has shown that Vyxeos liposomal is not anticipated to have the 
potential to be persistent, bioaccumulative, or toxic to the environment. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Distearoylphosphatidylcholine 
Distearoylphosphatidylglycerol 
Cholesterol 
Copper gluconate 
Trolamine (for pH adjustment) 
Sucrose 

15 



 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vials 
2 years. 
 
Stability of reconstituted suspension in the vial 
Chemical and physical in-use stability has been demonstrated for 4 hours at 2°C to 8°C when kept in 
an upright position.  
From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes 
the risk of microbial contamination, the product should be used immediately.  
If not used immediately, in-use storage times and conditions are the responsibility of the user.  
 
Stability of diluted infusion solution 
Chemical and physical in-use stability has been demonstrated for 4 hours at 2°C to 8°C. 
From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes 
the risk of microbial contamination, the product should be used immediately.  
If not used immediately, in-use storage times and conditions are the responsibility of the user.  
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C). 
 
Keep the vial in the original carton in order to protect from light. Store in an upright position. 
 
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
50 mL vial (type 1 glass) with a stopper (chlorobutyl rubber), and an overseal (aluminium) containing 
44 mg daunorubicin and 100 mg cytarabine. 
 
Each pack contains either 1 vial, 2 vials or 5 vials. Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Vyxeos liposomal is a cytotoxic medicinal product. Applicable special handling and disposal 
procedures should be followed. The product is intended for single use only. Any unused product 
should be disposed of in accordance with local requirements for cytotoxic agents. 
 
Preparation instructions 
• Determine the dose and number of vials of Vyxeos liposomal based on the individual patient’s 

BSA as outlined in section 4.2. 
• Remove the appropriate number of vials of Vyxeos liposomal from the refrigerator and 

equilibrate to the room temperature (15°C to 30°C) for 30 minutes. 
• Then, reconstitute each vial with 19 mL of sterile water for injections using a 20 mL syringe, 

and immediately thereafter start a 5-minute timer. 
• Carefully swirl the contents of the vial for 5 minutes while gently inverting the vial every 

30 seconds. 
• Do not heat, vortex, or shake vigorously. 
• After reconstitution, let it rest for 15 minutes. 

16 



• The reconstituted product should be an opaque, purple, homogeneous dispersion, essentially 
free from visual particulates. 

• If the reconstituted product is not diluted into an infusion bag immediately, store in a 
refrigerator (2ºC to 8ºC) for up to 4 hours. 

• Calculate the volume of reconstituted Vyxeos liposomal required using the following formula: 
[volume required (mL) = dose of daunorubicin (mg/m2) x patient’s BSA (m2)/2.2 (mg/mL)]. 
The concentration of the reconstituted solution is 44 mg/20 mL (2.2 mg/mL) daunorubicin and 
100 mg/20 mL (5 mg/mL) cytarabine. 

• Gently invert each vial 5 times prior to withdrawing the concentrate for dilution. 
• Aseptically withdraw the calculated volume of reconstituted Vyxeos liposomal from the vial(s) 

with a sterile syringe and transfer it to an infusion bag containing 500 mL of sodium chloride 9 
mg/mL (0.9%) solution for injection, or 5% glucose. There may be residual product remaining 
in the vial. Discard unused portion. 

• Gently invert the bag to mix the solution. The dilution of the reconstituted product results in a 
deep purple, translucent, homogeneous dispersion. 

• If the diluted infusion solution is not used immediately, store in a refrigerator (2°C to 8°C) for 
up to 4 hours. 

• Gently invert the bag to mix the solution after refrigeration. 
 
Administration instructions 
• Do not mix Vyxeos liposomal with, or administer as an infusion with, other medicinal products. 
• Administer Vyxeos liposomal by constant intravenous infusion over 90 minutes via an infusion 

pump through a central venous catheter or a peripherally inserted central catheter. An in-line 
membrane filter may be used for the intravenous infusion of Vyxeos liposomal, provided the 
minimum pore diameter of the filter is greater than or equal to 15 µm. 

• Flush the line after administration with sodium chloride 9 mg/mL (0.9%) solution for injection. 
 
This medicinal product could have potential risk for the environment due to the cytotoxic and 
antimitotic activities, which could induce possible reproductive effects. All materials used for dilution 
and administration should be disposed of according to local procedures applicable to the discarding of 
antineoplastic agents. Any unused medicinal product or waste material should be disposed of in 
accordance with local requirements for cytotoxic agents.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Jazz Pharmaceuticals Ireland Ltd  
5th Floor 
Waterloo Exchange 
Waterloo Road 
Dublin  
D04 E5W7 
Ireland 
 
 
8. 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 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 23 August 2018 
 
 

17 



10. DATE OF REVISION OF THE TEXT 
 
10/2019 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 
  

18 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

19 



A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
Jazz Pharmaceuticals Ireland Limited 
5th Floor  
Waterloo Exchange 
Waterloo Road 
Dublin 
D04 E5W7 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

  

20 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  

21 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

22 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Vyxeos liposomal 44 mg/100 mg powder for concentrate for solution for infusion 
daunorubicin/cytarabine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
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 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: Distearoylphosphatidylcholine, distearoylphosphatidylglycerol, cholesterol, copper 
gluconate, trolamine, and sucrose. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
1 vial 
2 vials  
5 vials 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Intravenous use after dilution. 
 
For single use only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 

23 



EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
 
Keep the vial in the outer carton in order to protect from light. 
 
Store in an upright position. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Jazz Pharmaceuticals Ireland Ltd  
5th Floor 
Waterloo Exchange 
Waterloo Road 
Dublin  
D04 E5W7 
Ireland  
 
 
12. 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 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 

24 



 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
  

25 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Vyxeos liposomal 44 mg/100 mg powder for concentrate for solution for infusion 
daunorubicin/cytarabine 
Intravenous use after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
Cytotoxic 
 
  

26 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

27 



Package leaflet: Information for the patient 
 

Vyxeos liposomal 44 mg/100 mg powder for concentrate for solution for infusion 
daunorubicin and cytarabine 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Vyxeos liposomal is and what it is used for 
2. What you need to know before you are given Vyxeos liposomal 
3. How you are given Vyxeos liposomal 
4. Possible side effects 
5. How to store Vyxeos liposomal 
6. Contents of the pack and other information 
 
 
1. What Vyxeos liposomal is and what it is used for 
 
What Vyxeos liposomal is 
Vyxeos liposomal belongs to a group of medicines called ‘antineoplastics’ used in cancer. It contains 
two active substances, called ‘daunorubicin’ and ‘cytarabine’, in the form of tiny particles known as 
‘liposomes’. 
These active substances act in different ways to kill cancer cells by stopping them from growing and 
dividing. Packaging them in liposomes prolongs their action in the body and helps them to enter and 
kill the cancer cells.  
 
What Vyxeos liposomal is used for 
Vyxeos liposomal is used to treat patients with newly diagnosed acute myeloid leukaemia (a cancer of 
the white blood cells). It is given when the leukaemia was caused by previous treatments (known as 
therapy related acute myeloid leukaemia) or when there are certain changes in the bone marrow 
(known as acute myeloid leukaemia with “myelodysplasia-related changes”). 
 
 
2. What you need to know before you are given Vyxeos liposomal 
 
You must not be given Vyxeos liposomal 
• if you are allergic to the active substances (daunorubicin or cytarabine) or any of the other 

ingredients of this medicine (listed in section 6). 
 
Warnings and precautions 
Your doctor will monitor you during treatment. Talk to your doctor or nurse before you are given 
Vyxeos liposomal: 
• if you have low numbers of platelets, red or white blood cells in your blood (you will have a 

blood test before starting treatment). If this applies to you: 
- your doctor may also give you a medicine to help stop you getting an infection. 
- your doctor will also check you for infections during treatment. 

• if you have ever had a heart problem or heart attack, or you have previously taken 
‘anthracycline’ cancer medicines. If this applies to you, your doctor may check your heart 
before starting, and during treatment. 

28 



• if you think you might be pregnant. You should use an effective method of contraception to 
avoid getting (you or your partner) pregnant during the treatment, and for the next 6 months 
after your last dose. 

• if you have any allergic (hypersensitivity) reactions. Your doctor may pause or stop treatment, 
or slow the rate of your drip,  if any hypersensitivity occurs.  

• if you have had problems with your kidneys or liver. Your doctor will monitor you during 
treatment. 

• if you have ever had a condition known as Wilson’s disease or other copper-related disorder, as 
Vyxeos liposomal contains an ingredient known as 'copper gluconate'. 

• if you are to be given a vaccine. 
 

Your doctor will monitor you with regards to your general health during treatment and may also give 
you other medicines to support your treatment, either before or with Vyxeos liposomal. If any of the 
above apply to you (or you are not sure), talk to your doctor, pharmacist, or nurse before you are given 
Vyxeos liposomal. 
 
Children and adolescents 
Vyxeos liposomal is not recommended for use in children and adolescents under 18 years. 
 
Other medicines and Vyxeos liposomal 
Tell your doctor or nurse if you are using, have recently used or might use any other medicines. This is 
because Vyxeos liposomal may affect the way some other medicines work. Also, some other 
medicines may affect the way Vyxeos liposomal works. 
 
In particular, tell your doctor or nurse if you are taking any of the following medicines: 
• cancer medicines that can affect your heart, such as doxorubicin. 
• medicines that can affect your liver. 
 
Pregnancy and breast-feeding 
You should not use Vyxeos liposomal during pregnancy as it may be harmful to the baby. Use an 
effective method of contraception during and for 6 months after treatment. Tell your doctor straight 
away if you become pregnant during treatment.  
 
You should not breast-feed while you are receiving treatment with Vyxeos liposomal as it may be 
harmful to the baby. 
 
If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask 
your doctor for advice before you are given this medicine. 
 
Driving and using machines 
You may feel sleepy or dizzy after having Vyxeos liposomal. If this happens, do not drive or use any 
tools or machines. 
 
 
3. How you are given Vyxeos liposomal 
 
Vyxeos liposomal must be given to you by a doctor or nurse with experience in treating AML. 
• It is given to you as a drip (infusion) into a vein. 
• The infusion is given over one and a half hours (90 minutes). 
 
Your doctor or nurse will work out your dose of the medicine based on your weight and height. Your 
treatment will be given in ‘courses’. Each course is given as a separate infusion and can be given 
weeks apart.  
 
You will receive a first course of treatment and your doctor will decide if you will receive further 
courses of treatment depending on how you respond to treatment and any side effects you get. Your 
doctor will assess how you respond to treatment after each course. 

29 



 
• During your first course - you will have an infusion on days 1, 3, and 5. 
• On further courses - you will have an infusion on days 1 and 3. This can be repeated if 

necessary. 
 

 
While you are receiving treatment with Vyxeos liposomal your doctor will perform regular blood tests 
to assess how you respond to the treatment and to check it is well tolerated. Your doctor may also 
check your heart as Vyxeos liposomal may affect it. 
 
If you are given too much Vyxeos liposomal 
This medicine will be given to you in a hospital by a doctor or nurse. It is unlikely that you will be 
given too much, however, tell your doctor or nurse if you have any concerns. 
 
If you miss an appointment 
Contact your doctor or nurse as soon as possible. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects which may affect more than 1 in 10 people (very common) 
Vyxeos liposomal may reduce the number of white blood cells, which fight infection, and also the 
blood cells which help the blood to clot (platelets) leading to bleeding disorders such as nosebleeds 
and bruising. Vyxeos liposomal may also cause heart problems and damage to the heart muscle. 
 
Therefore you must tell your doctor immediately if you experience: 
• fever, chills, sore throat, cough, mouth ulcers or any other symptoms of infection 
• bleeding or bruising without injury 
• chest pain or leg pain 
• feeling short of breath. 
 
Tell your doctor immediately if you get any of the side effects listed above. 
 
Other side effects 
 
Very common side effects (may affect more than 1 in 10 people): 
• a fall in the number of platelets (cells that help blood to clot) which may cause bruising or 

bleeding 
• fever, often with other signs of infection, due to very low white blood cells (febrile neutropenia) 
• slow, fast, or irregular heartbeat, chest pain (which may be a sign of infection)  
• problems with your sight, blurred vision 
• pain or swelling of the tissue lining the digestive system (mucositis), or pain in the abdomen 

(belly), constipation, loss of appetite, diarrhoea, nausea (feeling sick) or vomiting 
• redness of skin, rashes, muscle aches, headache, bone pain, joint pain, tiredness, generalised 

swelling including swelling of your arms and legs 
• headache, dizziness, confusion, difficulty sleeping, anxiety 
• kidney failure 
• shortness of breath, cough, fluid in the lungs 
• itching 
• bleeding 
• increased blood pressure or a fall in blood pressure 
• chills, low body temperature, or high body temperature 

30 



• increased sweating 
 
Common side effects (may affect up to 1 in 10 people): 
• a fall in the number of red blood cells (anaemia) leading to tiredness and weakness   
• kidney failure and abnormal blood tests due to massive death of cancer cells (Tumour lysis 

syndrome). 
• stomach cramps or excessive gas 
• excessive sweating at night  
• hair loss 
 
Uncommon side effects (may affect up to 1 in 100 people): 
• numbness and rash in the hands and feet (palmar-plantar erythrodysaesthesia syndrome). 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Vyxeos liposomal 
 
• Keep this medicine out of the sight and reach of children. 
• Do not use this medicine after the expiry date which is stated on the carton and the vial after 

EXP. The expiry date refers to the last day of that month. 
• Store in a refrigerator (2°C to 8°C). 
• Keep the vial in the outer carton in order to protect from light. 
• Store in an upright position. 
• After reconstitution, the vials should be stored in a refrigerator (2°C to 8°C) for up to 4 hours in 

an upright position.  
• After dilution, the solution in infusion bags should be stored in a refrigerator (2°C to 8°C) for up 

to 4 hours. 
• Do not use this medicine if you notice any particles in the diluted solution. 
• Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away 

medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Vyxeos liposomal contains  
• The active substances are daunorubicin and cytarabine. Each 50 ml 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. 
• The other ingredients are distearoylphosphatidylcholine, distearoylphosphatidylglycerol, 

cholesterol, copper gluconate, trolamine and sucrose. 
 
What Vyxeos liposomal looks like and contents of the pack 
Vyxeos liposomal is a purple powder for concentrate for solution for infusion supplied in a glass vial.  

Each pack contains 1 vial, 2 vials or 5 vials. Not all pack sizes may be marketed. 

 
Marketing Authorisation Holder and Manufacturer 
 
Jazz Pharmaceuticals Ireland Ltd  
5th Floor 

31 



Waterloo Exchange 
Waterloo Road 
Dublin 
D04 E5W7 
Ireland 
 
Tel: +44 8450305089  
Email: medinfo-int@jazzpharma.com 
 
This leaflet was last revised in October 2019 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
 
 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
Vyxeos liposomal is a cytotoxic medicinal product. Applicable special handling and disposal 
procedures should be followed. The product is intended for single use only. It does not contain any 
preservatives. Unused portions should not be saved for later administration. 
 
Preparation instructions 
• Determine the dose and number of vials of Vyxeos liposomal based on the individual patient’s 

BSA as outlined in section 4.2. 
• Remove the appropriate number of vials of Vyxeos liposomal from the refrigerator and 

equilibrate to the room temperature (15°C to 30°C) for 30 minutes. 
• Then, reconstitute each vial with 19 mL of sterile water for injections using a 20 mL syringe 

and immediately thereafter start a 5-minute timer. 
• Carefully swirl the contents of the vial for 5 minutes while gently inverting the vial every 

30 seconds. 
• Do not heat, vortex, or shake vigorously. 
• After reconstitution, let rest for 15 minutes. 
• The reconstituted product should be an opaque, purple, homogeneous dispersion, essentially 

free from visual particulates. 
• If the reconstituted product is not diluted into an infusion bag immediately, store in a 

refrigerator (2ºC to 8ºC) for up to 4 hours. 
• Calculate the volume of reconstituted Vyxeos liposomal required using the following formula: 

[volume required (mL) = dose of daunorubicin (mg/m2) x patient’s BSA (m2)/2.2 (mg/mL)]. 
The concentration of the reconstituted solution is 44 mg/20 mL (2.2 mg/mL) daunorubicin and 
100 mg/20 mL (5 mg/mL) cytarabine. 

• Gently invert each vial 5 times prior to withdrawing the concentrate for dilution. 
• Aseptically withdraw the calculated volume of reconstituted Vyxeos liposomal from the vial(s) 

with a sterile syringe and transfer it to an infusion bag containing 500 mL of sodium chloride 9 
mg/mL (0.9%) solution for injection, or 5% glucose. There may be residual product remaining 
in the vial. Discard unused portion. 

• Gently invert the bag to mix the solution. The dilution of the reconstituted product results in a 
deep purple, translucent, homogeneous dispersion. 

• If the diluted infusion solution is not used immediately, store in a refrigerator (2°C to 8°C) for 
up to 4 hours. 

• Gently invert the bag to mix the solution after refrigeration 
 

32 



Administration instructions 
• Do not mix Vyxeos liposomal with, or administer as an infusion with, other medicinal products. 
• Administer Vyxeos liposomal by constant intravenous infusion over 90 minutes via an infusion 

pump through a central venous catheter or a peripherally inserted central catheter. An in-line 
membrane filter may be used for the intravenous infusion of Vyxeos liposomal, provided the 
minimum pore diameter of the filter is greater than or equal to 15 µm. 

• Flush the line after administration with sodium chloride 9 mg/mL (0.9%) solution for injection. 
 
Disposal 
This medicinal product could have potential risk for the environment due to the cytotoxic and 
antimitotic activities, which could induce possible reproductive effects. All materials used for dilution 
and administration should be disposed of according to local procedures applicable to the discarding of 
antineoplastic agents. Any unused medicinal product or waste material should be disposed of in 
accordance with local requirements for cytotoxic agents. 

33 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET