Leaflet VYXEOS LIPOSOMAL 44mg/100mg 44mg+100mg powder for concentrate infusion solution

Vyxeos liposomal 44 mg/100 mg powder for concentrate for solution for infusion.

Each vial of powder for concentrate for solution for infusion contains 44 mg of daunorubicin and100 mg of cytarabine.

After reconstitution, the solution contains 2.2 mg/mL daunorubicin and 5 mg/mL cytarabineencapsulated in liposomes in a fixed combination in a 1:5 molar ratio.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

Purple, lyophilised cake.

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

Vyxeos liposomal treatment should be initiated and monitored under the supervision of a physicianexperienced in the use of chemotherapeutic medicinal products.

Vyxeos liposomal has a different posology than daunorubicin injection and cytarabine injection and itmust not be interchanged with other daunorubicin and/or cytarabine containing products (see section4.4).

Vyxeos liposomal dosing is based on the patient’s body surface area (BSA) according to the followingschedule:

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

The recommended dosing schedule of Vyxeos liposomal 44 mg/100 mg/m2, administeredintravenously 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 diseaseprogression or unacceptable toxicity. The attainment of a normal-appearing bone marrow may requiremore than one induction course. Evaluation of the bone marrow following recovery from the previouscourse of induction therapy determines whether a further course of induction is required. Treatmentshould be continued as long as the patient continues to benefit or until disease progression up tomaximum of 2 induction courses.

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, administeredintravenously 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 toabsolute neutrophil count (ANC) > 500/µL and the platelet count has recovered to greater than50,000/µL in the absence of unacceptable toxicity. A subsequent course of consolidation may beadministered in patients who do not show disease progression or unacceptable toxicity within therange of 5 to 8 weeks after the start of the first consolidation. Treatment should be continued as longas the patient continues to benefit or until disease progression, up to maximum of 2 consolidationcourses.

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 beconsidered (e.g., allopurinol) prior to initiating Vyxeos liposomal.

For mild hypersensitivity symptoms (e.g., mild flushing, rash, pruritus), the treatment should bestopped, and the patient should be supervised, including monitoring of vital signs. The treatmentshould be restarted slowly once the symptoms have resolved, by halving the rate of infusion andintravenous diphenhydramine (20-25 mg) and intravenous dexamethasone (10 mg) should be given.

For moderate hypersensitivity symptoms (e.g., moderate rash, flushing, mild dyspnoea, chestdiscomfort) 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. Whenthe patient is retreated, Vyxeos liposomal should be given at the same dose and rate and withpremedication.

For severe/life-threatening hypersensitivity symptoms (e.g., hypotension requiring vasopressortherapy, angioedema, respiratory distress requiring bronchodilation therapy, generalised urticaria), thetreatment 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. Donot reinitiate infusion, and do not retreat. Treatment with Vyxeos liposomal should be permanentlydiscontinued. Patients should be monitored until symptoms resolve (see sections 4.4 and 4.8).

Assessment of cardiac function prior to start of treatment is recommended, especially in patients witha high risk of cardiac toxicity. Vyxeos liposomal treatment should be discontinued in patients whodevelop signs or symptoms of cardiomyopathy, unless the benefits outweigh the risks (seesection 4.4).

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

Dose adjustment is not required for patients with mild (creatinine clearance [CrCL] 60 mL/min to89 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 withend-stage renal disease managed with dialysis. (See section 5.2).

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 abilirubin level greater than 50 µmol/L. Vyxeos liposomal should only be used in patients with severehepatic impairment if the benefits outweigh the risks (see section 4.4).

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

Outside its authorised indications Vyxeos liposomal has been studied in paediatric and young adultpatients aged 1-21 years with relapsed AML. Due to the limited size of these studies, it is not possibleto 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 posologycan be made.

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 betaken 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, seesection 6.6.

History of serious hypersensitivity to the active substances or to any of the excipients listed insection 6.1.

Vyxeos liposomal must not be substituted or interchanged with other daunorubicin and/or cytarabinecontaining products. Due to substantial differences in the pharmacokinetic parameters, the dose andschedule recommendations for Vyxeos liposomal are different from those for daunorubicinhydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabineliposome injection. The medicinal product name and dose should be verified prior to administration toavoid dosing errors.

Severe myelosuppression (including fatal infections and haemorrhagic events) has been reported inpatients after administration of a therapeutic dose of Vyxeos liposomal. Serious or fatal haemorrhagicevents, including fatal central nervous system (CNS) haemorrhages, associated with severethrombocytopenia, have occurred in patients treated with Vyxeos liposomal. Baseline assessment ofblood 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 plasmahalf-life of Vyxeos liposomal, time to recovery of ANC and platelets may be prolonged and requireadditional monitoring.

Prophylactic anti-infectives (including anti-bacterial, anti-virals, anti-fungals) may be administeredduring the period of profound neutropenia until ANC returns to 500/μL or greater. If myelosuppressivecomplications 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 is a known risk of anthracycline treatment. Prior therapy with anthracyclines (includingpatients who have previously received the recommended maximum cumulative doses of doxorubicinor daunorubicin hydrochloride), pre-existing cardiac disease (including impaired cardiac function),previous radiotherapy of the mediastinum, or concomitant use of cardiotoxic products may increasethe risk of daunorubicin-induced cardiac toxicity.

In two single arm studies of 65 anthracycline pre-treated children with relapsed or refractory AMLtreated with a single induction cycle (Cycle 1) of Vyxeos liposomal, cardiac disorders (including sinustachycardia, QT prolongation and ejection fraction decreased) were observed. Several other long-termstudies of treatment with anthracycline/anthracenedione in children suggest that congestivecardiomyopathies 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 associatedwith 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 betweencumulative Vyxeos liposomal dose and the risk of cardiac toxicity has not been determined. Totalcumulative exposure of daunorubicin has been described in the table below.

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

Therapy Daunorubicin Number of doses Daunorubicin perper dose per course 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 radionuclideangiography (MUGA) scan or an echocardiography (ECHO) is recommended, especially in patientswith risk factors for increased cardiac toxicity. Cardiac function should be closely monitored.

Treatment with Vyxeos liposomal should be discontinued in patients with impaired cardiac functionunless 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 andfemale patients of childbearing potential must use an effective method of contraception duringtreatment and for 6 months following the last dose of Vyxeos liposomal (see section 4.6).

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

For moderate hypersensitivity symptoms (e.g., moderate rash, flushing, mild dyspnoea, chestdiscomfort) 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. Whenthe patient is retreated, Vyxeos liposomal should be given at the same dose and rate and withpremedication.

For severe/life-threatening hypersensitivity symptoms (e.g., hypotension requiring vasopressortherapy, angioedema, respiratory distress requiring bronchodilation therapy, generalised urticaria), thetreatment 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 Vyxeosliposomal should be permanently discontinued. Patients should be monitored until symptoms resolve(see sections 4.2 and 4.8).

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

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 toadministration 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 renaldisease managed with dialysis. Vyxeos liposomal should only be used in patients with severe hepaticimpairment if the benefits outweigh the risks (see section 4.2).

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

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 othercopper-related disorder if the benefits outweigh the risks (see section 6.1). Discontinue Vyxeosliposomal in patients with signs or symptoms of acute copper toxicity.

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

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

No interaction studies have been performed with Vyxeos liposomal. The delivery of daunorubicin andcytarabine 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 whenadministered as the non-liposomal formulation.

Concurrent use of cardiotoxic agents may increase the risk of cardiotoxicity. Use of Vyxeos liposomalin patients who have previously received doxorubicin increases the risk of cardiotoxicity (see section4.4). Do not administer Vyxeos liposomal in combination with other cardiotoxic agents unless thepatient's cardiac function is closely monitored.

Hepatotoxic medicinal products may impair liver function and increase the toxicity. Sincedaunorubicin is metabolised by the liver, changes in hepatic function induced by concomitanttherapies may affect metabolism, pharmacokinetics, therapeutic efficacy, and/or the toxicity of Vyxeosliposomal (see section 5.2). Hepatic function should be monitored more frequently when Vyxeosliposomal is coadministered with hepatoxic agents.

To exclude pregnancy, women of childbearing potential should undergo pregnancy testing beforeinitiation of Vyxeos liposomal. Both male patients with partners of childbearing potential and femalepatients should use effective contraception during treatment with Vyxeos liposomal and for 6 monthsfollowing the last dose.

There are no data on the use of Vyxeos liposomal in pregnant women. Based on results from animalstudies and its mechanism of action, Vyxeos liposomal should not be used during pregnancy, unlessthe clinical condition of the woman requires treatment and justifies the potential risk to the foetus (seesection 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 tomothers who received treatment during pregnancy.

It is not known whether Vyxeos liposomal is excreted in human milk. Because of the potential forserious adverse reactions in breast-feeding children from Vyxeos liposomal, women should be advisednot to breast-feed during Vyxeos liposomal therapy.

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

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

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%), sleepdisorders (25.1%), and hypotension (23.7%).

The most serious and frequently occurring ADRs were infection (58.7%), cardiotoxicity (18.7%) andhaemorrhage (13.1%).

ADRs have been included under the appropriate category in the table below according to the highestfrequency 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 000to < 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), orlife-threatening (Grade 4), with specific parameters according to the organ system involved. Death(Grade 5) is used for some of the criteria to denote a fatality.

Table 3: ADRs reported in clinical studies in patients treated with Vyxeos liposomal (n=375)

System organ class ADRs/Frequency (%) Grade 3-5 ADRs/Frequency (%)

Infections and infestations Very common Very common

Infection (78.1) Infection (58.7)

Blood and lymphatic Very common Very commonsystem disorders Febrile neutropenia (63.5) Febrile neutropenia (62.4)

Common Common

Thrombocytopenia (4.5) Thrombocytopenia (3.7)

Neutropenia (3.7) Neutropenia (3.5)

Anaemia (3.2) Anaemia (2.1)

Immune systems disorders Very common Common

Hypersensitivity (including Hypersensitivity (including rash)rash) (66.9) (9.1)

Metabolism and nutrition Common Commondisorders Tumour lysis syndrome (7.5) Tumour lysis syndrome (2.7)

Psychiatric disorders Very common Common

Sleep disorders (25.1) Delirium (2.4)

Anxiety (17.3)

Delirium (15.5) Uncommon

Sleep disorders (0.5)

Nervous system disorders Very common Common

Headache (32.3) Headache (1.1)

Dizziness (23.2)

Uncommon

Dizziness (0.8)

Eye disorders Very common Uncommon

Visual impairment (10.4) Visual impairment (0.3)

Cardiac disorders Very common Very common

Cardiotoxicity (72) Cardiotoxicity (18.7)

Arrhythmiaa (30.4)

Chest pain (17.6) Common

Arrhythmiaa (4.3)

Chest pain (1.9)

Vascular disorders Very common Very common

Haemorrhage (69.1) Haemorrhage (13.1)

Hypotension (23.7)

Hypertension (17.3) Common

Hypertension (6.9)

Hypotension (4.5)

Respiratory, thoracic and Very common Very commonmediastinal disorders Dyspnoea (36.5) Dyspnoea (13.1)

Cough (33.9)

Pleural effusion (13.9) Uncommon

Pleural effusion (0.8)

System organ class ADRs/Frequency (%) Grade 3-5 ADRs/Frequency (%)

Gastrointestinal disorders Very common Common

Nausea (51.7) Diarrhoea/colitis (6.1)

Diarrhoea/colitis (49.9) Abdominal pain (2.9)

Mucositis (49.9) Mucositis (2.1)

Constipation (42.7) Decreased appetite (1.6)

Abdominal pain (36.3) Constipation (1.1)

Decreased appetite (33.9) Nausea (1.1)

Vomiting (27.7)

Uncommon

Common Dyspepsia (0.5)

Dyspepsia (9.6) Vomiting (0.3)

Skin and subcutaneous Very common Uncommontissue disorders Pruritus (17.3) Hyperhidrosis (0.3)

Hyperhidrosis (10.1)

Common

Night sweats (8.3)

Alopecia (3.2)

Uncommon

Palmar-plantarerythrodysaesthesia syndrome(0.8)

Musculoskeletal and Very common Commonconnective tissue disorders Musculoskeletal pain (44.5) Musculoskeletal pain (5.1)

Renal and urinary Very common Commondisorders Renal insufficiency (10.4) Renal insufficiency (6.4)

General disorders and Very common Very commonadministration site Oedema (52.3) Fatigue (10.4)conditions Fatigue (46.4)

Chills (31.2) Common

Pyrexia (29.6) Pyrexia (3.2)

Oedema (2.7)

Uncommon

Chills (0.3)a Arrhythmia group terms includes atrial fibrillation, bradycardia, and the most commonly reported arrhythmiawas tachycardia

Due to the neutropenia experienced with Vyxeos liposomal, infections of various types were verycommon 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 ofnon-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 was6.9%. The fatal infections experienced were sepsis and pneumonia (see section 4.4).

Due to the thrombocytopenia experienced with Vyxeos liposomal a variety of haemorrhagic eventswere seen in clinical studies. The most common haemorrhagic event was epistaxis, and the majority ofthese were considered not serious (29.1%). The incidence of haemorrhage events is 69.1%; theincidence of non-serious events of haemorrhage was 67.2 %; the incidence of serious events ofhaemorrhage is 5.6%; the incidence of haemorrhage which led to discontinuation is 0. The incidenceof fatal haemorrhage was 2.1%. Serious or fatal haemorrhagic events, including fatal central nervoussystem (CNS) haemorrhages, associated with severe thrombocytopenia were seen in patients treatedwith Vyxeos liposomal (see section 4.4).

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 riskof anthracycline treatment. The incidence of all cardiotoxicity events was 72.0%; the incidence ofnon-serious events of cardiotoxicity was 68.5 %; the incidence of serious events of cardiotoxicity was9.1%; the incidence of cardiotoxicity which led to discontinuation is 0.5%. Incidence of fatalcardiotoxicity events is 0.5%. Cardiac arrest was reported as a fatal event; the patient experiencedthrombocytopenia and neutropenia which contributed to cardiac arrest (see section 4.4).

Hypersensitivity reactions were very common ADRs in Vyxeos liposomal clinical studies. The mostfrequently 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 eventsof hypersensitivity was 66.4 %, of which 38.9 % were rash; the incidence of serious events ofhypersensitivity is 1.1%; the frequency of hypersensitivity which led to discontinuation is 0. Thefrequency of fatal hypersensitivity events was 0 (see section 4.4).

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 adultswith newly treated AML treated with Vyxeos liposomal (see section 4.2). However, adverse reactionsin study AAML 1421 observed in paediatric patients that were different from or more severe thanthose 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% ofthese 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, includinglong-term cardiotoxicity when used at doses above the maximum life-time cumulative anthracyclinedose. There are no data on the effects of Vyxeos liposomal treatment on growth and maturation.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 supportivetreatment (incuding anti-infectives, blood and platelet transfusions, colony-stimulating factors, andintensive care as needed) should be provided until the patient recovers. Observe the patient carefullyover time for signs of cardiotoxicity and provide appropriate supportive therapy as clinically indicated.

Pharmacotherapeutic group: other antineoplastic agents, combinations of antineoplastic agents,cytarabine and daunorubicin, ATC code: L01XY01.

Vyxeos liposomal is a liposomal formulation of a fixed combination of daunorubicin and cytarabine ina 1:5 molar ratio. The 1:5 molar ratio has been shown in vitro and in vivo to maximise synergisticantitumour 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 ofgene expression, and producing DNA-damaging free radicals.

Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phaseof 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 appearsthat ara-CTP acts primarily through inhibition of DNA synthesis. Incorporation into DNA and RNAmay also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to proliferating mammaliancells in culture.

Vyxeos liposomal liposomes exhibit a prolonged plasma half-life following intravenous infusion, withgreater than 99% of the daunorubicin and cytarabine in the plasma remaining encapsulated within theliposomes. Vyxeos liposomal delivers a synergistic combination of daunorubicin and cytarabine toleukaemia cells for a prolonged period of time. Based on data in animals, Vyxeos liposomal liposomesaccumulate and persist in high concentration in the bone marrow, where they are preferentially takenup intact by leukaemia cells in an active engulfment process. In leukaemia-bearing mice, theliposomes are taken up by leukaemia cells to a greater extent than by normal bone marrow cells. Afterinternalisation, Vyxeos liposomal liposomes undergo degradation, releasing daunorubicin andcytarabine within the intracellular environment, enabling the medicinal products to exert theirsynergistic antineoplastic activity.

The efficacy of Vyxeos liposomal in adults for the treatment of newly diagnosed AML was evaluatedin a single controlled clinical study (Study 301) and the efficacy of Vyxeos liposomal in paediatricpatients for the treatment of relapsed AML was evaluated in a single clinical study AAML 1421.

Study 301 in patients with untreated high-risk AML

Study 301 was a Phase 3 randomised, multicentre, open-label, parallel-arm, superiority study whichevaluated Vyxeos liposomal vs. a standard combination of cytarabine and daunorubicin (7+3) in 309patients 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 documentedhistory of MDS or CMMoL prior to transformation to AML, and de novo AML with karyotypechanges characteristic of myelodysplasia, (per 2008 WHO criteria).

The study included 2 phases, 1) Treatment Phase during which patients received up to 2 induction and2 consolidation courses, and 2) a Follow-up Phase, which began 30 days after the last induction orconsolidation course and continued for up to 5 years from randomisation. The number of inductionsand consolidations a patient received depended upon complete response (CR) or complete responsewith incomplete recovery (CRi), which was confirmed by bone marrow assessment. In clinical studiesonly, Vyxeos liposomal 100 units/m2/day (equivalent to 44 mg/100 mg/m2) was administeredintravenously over 90 minutes on days 1, 3, and 5 for the first induction and on days 1 and 3 forpatients requiring a second induction. A second induction was highly recommended for patients whodid not achieve a CR or CRi in the first induction course and was mandatory for patients achievinggreater than 50% reduction in percent blasts. Post-remission therapy with haematopoietic stem celltransplantation (HSCT) was permitted either in place of or after consolidation chemotherapy. Forconsolidation courses, in clinical studies only, the Vyxeos liposomal dose was reduced to 65units/m2/day (equivalent to 29 mg/65 mg/m2) on days 1 and 3. In the 7+3 arm, first induction consistedof cytarabine 100 mg/m2/day on days 1 to 7 by continuous infusion, and daunorubicin 60 mg/m2/dayon days 1, 2, and 3 whereas second induction and consolidation cytarabine was dosed on days 1 to 5and daunorubicin on days 1 and 2.

There were 153 patients randomised to Vyxeos liposomal and 156 patients randomised to the 7+3control 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 withan antecedent haematological disorder and 25% had de novo AML with myelodysplasia-relatedcytogenetic 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 studyarms. FLT3 mutation was identified in 15% (43/279) of patients tested and NPM1 mutation wasidentified in 9% (25/283) patients tested.

The primary endpoint was overall survival measured from the date of randomisation to death from anycause. Vyxeos liposomal demonstrated superiority in overall survival in the ITT population comparedwith the comparator 7+3 treatment regimen (Figure 1). The median survival for the Vyxeos liposomaltreatment 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 thecontrol arm.

Figure 1: Kaplan-Meier curve for overall survival, ITT population

Table 4: Efficacy results for study 301

Vyxeos liposomal 7+3

N=153 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 incompleterecoverya p-value from stratified log rank test stratifying by age and AML sub-typeb p-value from stratified Cochran-Mantel-Haenszel test stratified by age and AML sub-type60 Month Follow-up

The 60 month overall survival rate was higher for the Vyxeos liposomal treatment arm (18%) versusthe 7+3 treatment arm (8%); the hazard ratio was 0.70, 95% CI= 0.55, 0.91.

Relapsed AML

The efficacy of Vyxeos liposomal as a single agent was evaluated in a phase 1/2, single-arm study(AAML 1421) conducted to evaluate safety and efficacy of Vyxeos liposomal in 38 paediatric andyoung adult patients aged 1-21 years with AML in first relapse. Study treatment consisted of oneinduction cycle of Vyxeos liposomal 59 mg/135 mg/m2 administered intravenously over 90 minuteson Days 1, 3, and 5 followed by fludarabine, cytarabine, and G-CSF (FLAG) for cycle 2. The medianage of patients was 11 years (range, 1-21 years). Eight (21%) of the patients were between 18 and 21years; Patients who received > 450 mg/m2 daunorubicin equivalents were excluded from the study.

The primary endpoint was overall response rate (defined as CR or CRp) after Vyxeos liposomal(Cycle 1) followed by FLAG (Cycle 2). The overall response rate was 68% (90% Clopper-Pearson CI53% to 80%). After cycle 1, 16 (43%) patients had a treatment response of CR + CRp, including14 (38%) patients who achieved CR, and based on the 7 subjects with relapse data available themedian duration of CR was 284 days.

The pharmacokinetics of daunorubicin and cytarabine administered as Vyxeos liposomal wereinvestigated in adult patients who received a dose of daunorubicin 44 mg/m2 and cytarabine100 mg/m2 administered as a 90-minute intravenous infusion on days 1, 3, and 5. Thepharmacokinetics of each medicinal product was based on total plasma concentrations (i.e.,encapsulated plus unencapsulated medicinal product). Following the dose administered on day 5, themean (% coefficient of variation [CV]) maximum plasma concentrations (Cmax) for daunorubicin was26.0 (32.7%) mcg/mL and cytarabine was 62.2 (33.7%) mcg/mL. The mean (%CV) area under thecurve (AUC) during one dosing interval for daunorubicin was 637 (38.4%) mcg.h/mL and cytarabinewas 1900 (44.3%) mcg.h/mL.

When daunorubicin and cytarabine are administered as components of Vyxeos liposomal, theliposomes appear to govern their tissue distribution and rates of elimination; therefore, while thenon-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.

The accumulation ratio was 1.3 for daunorubicin and 1.4 for cytarabine. There was no evidence oftime-dependent kinetics or major departures from dose proportionality over the range of 1.3 mg/3 mgper m2 to 59 mg/134 mg per m2 (0.03 to 1.3 times the approved recommended dose).

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.

Similar to non-liposomal daunorubicin and cytarabine, subsequent to release from Vyxeos liposomalliposomes, both daunorubicin and cytarabine are extensively metabolised in the body. Daunorubicin ismostly catalysed by hepatic and non-hepatic aldo-keto reductase and carbonyl reductase to the activemetabolite daunorubicinol. Cytarabine is metabolised by cytidine deaminase to the inactive metabolite1-β (beta)-D-arabinofuranosyluracil (AraU). Unlike non-liposomal daunorubicin and cytarabine,which are quickly metabolised to the respective metabolites, daunorubicin and cytarabine after Vyxeosliposomal administration are free bases encapsulated in liposomes. Plasma concentration-time profilesobtained from 13 to 26 patients who received Vyxeos liposomal 100 units/m2 (equivalent to 44 mg/ m²of daunorubicin and 100 mg/m² of cytarabine) on days 1, 3, and 5 show the mean AUClastmetabolite:parent ratio for daunorubicinol and AraU were 1.79% and 3.22% to that for daunorubicinand 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 ofmetabolite:parent ratios after Vyxeos liposomal administration indicate that most of the totaldaunorubicin and cytarabine in the circulation is trapped inside the Vyxeos liposomal liposomes,where they are inaccessible to medicinal product-metabolising enzymes.

Vyxeos liposomal exhibits a prolonged half-life (%CV) of 31.5 h (28.5%) for daunorubicin and40.4 h (24.2%) for cytarabine with greater than 99% of the daunorubicin and cytarabine in the plasmaremaining encapsulated within the liposomes. The clearance (%CV) is 0.16 L/h (53.3%) fordaunorubicin and 0.13 L/h (60.2%) for cytarabine.

Urinary excretion of daunorubicin and daunorubicinol accounts for 9% of the administered dose ofdaunorubicin, and urinary excretion of cytarabine and AraU accounts for 71% of the administereddose of cytarabine.

In a population pharmacokinetic analysis, no clinically meaningful effects on clearance and volumeparameters of daunorubicin and cytarabine by age (1 to 81 years), sex, race, body weight, body massindex, and white blood cell count were observed.

The dose-normalised mean exposures of total daunorubicin and cytarabine observed in paediatricpatients after 59 mg/135 mg/m2 were comparable to those of daunorubicin and cytarabine after44 mg/100 mg/m2 in adults.

The pharmacokinetics of Vyxeos liposomal in patients aged > 85 years has not yet been evaluated. Nodata are available.

Based on a dedicated study to evaluate the impact of moderate to severe renal impairment on thepharmacokinetics of Vyxeos liposomal and a population pharmacokinetic analysis using data fromclinical studies in patients with mild to moderate renal impairment, no significant difference inclearance of daunorubicin or cytarabine was observed in patients with pre-existing mild, moderate orsevere renal impairment compared to patients with baseline normal renal function. The potentialeffects of end-stage renal disease managed with dialysis on the pharmacokinetics of daunorubicin andcytarabine administered as Vyxeos liposomal are unknown (see section 4.2).

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.

The repeat-dose toxicity of Vyxeos liposomal was tested in two-cycle intravenous infusion toxicitystudies with 28-day recovery periods conducted in rats and dogs. Adverse effects of Vyxeos liposomaloccurred at all dose levels (low to no safety margins as based on systemic exposures) and weregenerally consistent with those documented for non-liposomal daunorubicin and/or cytarabine,comprising mainly gastrointestinal and hematological findings. Although central nervous system(CNS) and cardiovascular system parameters were included in these studies, given the observedmorbidity and mortality, there was insufficient information to conduct an integrated assessment of thesafety pharmacology of Vyxeos liposomal.

Genotoxicity, carcinogenicity, and reproductive and developmental toxicity studies have not beenconducted with Vyxeos liposomal. However studies are available with the single agents.

Cytarabine or its active metabolite Ara-C was mutagenic (bacterial mutagenicity assay) andclastogenic in vitro (chromosome aberrations and sister-chromatid exchanges (SCE) in humanleukocytes) and in vivo (chromosome aberrations and SCE assay in rodent). Cytarabine caused thetransformation of hamster embryo cells and rat H43 cells in vitro and was clastogenic to meiotic cells.

Daunorubicin was mutagenic (bacterial mutagenicity assay, V79 hamster cell assay), and clastogenicin vitro (CCRF-CEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow).

Studies with cytarabine were not identified. Published data with Ara-C, the active metabolite ofcytarabine, did not provide evidence of carcinogenicity. Published data with daunorubicin suggestpossible tumorigenicity in rats after a single dose of 5 or 10 mg/kg (0.68 to 1.4 times the RHD basedon mg/m2). The IARC Working Group (IARC 2000) classified daunorubicin in Group 2B (possiblycarcinogenic to humans).

Cytarabine was embryotoxic in mice and teratogenic in mice and rats when administered duringorganogenesis. Cytarabine also caused sperm-head abnormalities in mice and impairedspermatogenesis in rats. 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.

Daunorubicin was embryotoxic and caused fetal malformations when given during the period oforganogenesis in rats. Daunorubicin caused testicular atrophy and total aplasia of spermatocytes in theseminiferous tubules in dogs.

Environmental risk assessment has shown that Vyxeos liposomal is not anticipated to have thepotential to be persistent, bioaccumulative, or toxic to the environment.

Distearoylphosphatidylcholine

Distearoylphosphatidylglycerol

Cholesterol

Copper gluconate

Trolamine (for pH adjustment)

Sucrose

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

Unopened vials4 years.

Chemical and physical in-use stability has been demonstrated for 4 hours at 2 °C to 8 °C when kept inan upright position.

From a microbiological point of view, unless the method of opening/reconstitution/dilution precludesthe 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.

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 precludesthe 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.

The maximum combined storage time for reconstituted product in the vial and reconstituted productdiluted into an infusion bag is up to 4 hours at 2 °C to 8 °C.

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.

50 mL vial (type 1 glass) with a stopper (chlorobutyl rubber), and an overseal (aluminium) containing44 mg daunorubicin and 100 mg cytarabine.

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

Vyxeos liposomal is a cytotoxic medicinal product. Applicable special handling and disposalprocedures should be followed. The product is intended for single use only.

* 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 andequilibrate 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 every30 seconds.

* Do not heat, vortex, or shake vigorously.

* After reconstitution, let it rest for 15 minutes.

* The reconstituted product should be an opaque, purple, homogeneous dispersion, essentiallyfree from visual particulates.

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

* Following the storage of reconstituted product in the vial for up to 4 hours at 2 °C to 8 °C in anupright position, the reconstituted product must immediately be diluted into an infusion solutionand run for the 90-minute infusion time.o Reconstituted product in the vial and reconstituted product which has been diluted into aninfusion solution are stable for a maximum combined storage time of up to 4 hours whenstored at 2 °C to 8 °C, The 4-hour stability period for the reconstituted product in the vialdoes not allow for an additional 4-hour stability period after the appropriate dose from thereconstituted vial is diluted into the infusion solution.

o The 4-hour stability period when reconstituted product diluted into the infusion bag isstored at 2 °C to 8 °C does not include the time required for reconstitution or the 90-minute infusion time.

o The diluted infusion solution must be immediately infused for the 90-minute infusion timefollowing the up to 4-hour stability period.

* 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 and100 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 chloride9 mg/mL (0.9%) solution for injection, or 5% glucose. There may be residual product remainingin the vial. Discard unused portion.

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

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

* Gently invert the bag to mix the solution after refrigeration.

* 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 infusionpump through a central venous catheter or a peripherally inserted central catheter. An in-linemembrane filter may be used for the intravenous infusion of Vyxeos liposomal, provided theminimum 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 andantimitotic activities, which could induce possible reproductive effects. All materials used for dilutionand administration should be disposed of according to local procedures applicable to the discarding ofantineoplastic agents. Any unused medicinal product or waste material should be disposed of inaccordance with local requirements for cytotoxic agents.

Jazz Pharmaceuticals Ireland Ltd5th Floor

Waterloo Exchange

Waterloo Road

Dublin

D04 E5W7

Ireland

EU/1/18/1308/001 1 vial

EU/1/18/1308/002 2 vials

EU/1/18/1308/003 5 vials

Date of first authorisation: 23 August 2018

Date of latest renewal: 05 June 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu