Daunorubicin/Cytarabine Liposomal

Vyxeos liposomal is a liposomal formulation of a fixed combination of daunorubicin and cytarabine in a 1:5 molar ratio. That ratio has been shown in vitro and in vivo to maximise synergistic antitumour activity in acute myeloid leukaemia (AML). Each vial holds 44 mg of daunorubicin and 100 mg of cytarabine, encapsulated in liposomes.

Mechanism of Action

• Daunorubicin: antimitotic and cytotoxic. It forms complexes with DNA, inhibits topoisomerase II and DNA polymerase activity, affects the regulation of gene expression and produces DNA-damaging free radicals.
• Cytarabine: a cell cycle phase-specific antineoplastic that acts only in the S phase of cell division. Inside cells it is converted to cytarabine-5-triphosphate (ara-CTP), the active metabolite, which acts mainly by inhibiting DNA synthesis. Incorporation into DNA and RNA may also contribute.
• Liposomal delivery: after infusion the liposomes stay in the circulation for a long time, with more than 99% of both drugs in plasma still encapsulated. In animals the liposomes build up and persist at high concentration in the bone marrow, where leukaemia cells take them up intact by an active engulfment process, to a greater extent than normal marrow cells in leukaemia-bearing mice. A synergistic combination thus reaches leukaemia cells over a prolonged period.

Pharmacokinetics

Values are for total plasma concentrations (encapsulated plus unencapsulated drug).

• Exposure: after the day 5 dose of daunorubicin 44 mg/m² and cytarabine 100 mg/m² given over 90 minutes, mean peak concentrations were 26.0 mcg/mL for daunorubicin and 62.2 mcg/mL for cytarabine; the AUC over one dosing interval was 637 and 1,900 mcg·h/mL respectively. The accumulation ratio was 1.3 and 1.4. Kinetics were not time-dependent and stayed roughly dose-proportional over the range studied.
• Distribution: volume of distribution 6.6 L for daunorubicin and 7.1 L for cytarabine; plasma protein binding was not evaluated. The liposomes govern tissue distribution and elimination, so the pharmacokinetic parameters of the two drugs converge.
• Metabolism: once released from the liposomes both drugs are extensively metabolised. Daunorubicin is converted mainly by aldo-keto reductase and carbonyl reductase to the active metabolite daunorubicinol; cytarabine is converted by cytidine deaminase to the inactive metabolite AraU. Metabolite-to-parent ratios were low (daunorubicinol 1.79%, AraU 3.22%) because most of the circulating drug is trapped inside the liposomes, out of reach of metabolising enzymes.
• Elimination: half-life 31.5 hours for daunorubicin and 40.4 hours for cytarabine; clearance 0.16 and 0.13 L/h. Urinary excretion accounts for 9% of the daunorubicin dose (as daunorubicin and daunorubicinol) and 71% of the cytarabine dose (as cytarabine and AraU).
• Special populations: no clinically meaningful effect of age (1 to 81 years), sex, race, body weight, body mass index or white cell count. Exposure in children after 59 mg/135 mg per m² was comparable to that in adults after 44 mg/100 mg per m². Clearance did not differ in mild, moderate or severe renal impairment; the effect of end-stage renal disease on dialysis is unknown. Kinetics were unchanged with bilirubin up to 50 μmol/L and are unknown above that. There are no data above 85 years.

• Newly diagnosed therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC), in adults.

• History of serious hypersensitivity to the active substances or to any of the excipients.

The most frequent reactions in the clinical studies (375 patients) were hypersensitivity including rash (66.9%), febrile neutropenia (63.5%), oedema (52.3%), diarrhoea/colitis and mucositis (49.9% each), fatigue (46.4%), musculoskeletal pain (44.5%), abdominal pain (36.3%), decreased appetite and cough (33.9% each), headache (32.3%), chills (31.2%), arrhythmia (30.4%), pyrexia (29.6%), sleep disorders (25.1%) and hypotension (23.7%). The most serious and frequent were infection (58.7%), cardiotoxicity (18.7%) and haemorrhage (13.1%). Each reaction is listed under the highest frequency seen in any of the main clinical studies.

Very common (≥1/10): infection; febrile neutropenia; hypersensitivity (including rash); sleep disorders, anxiety, delirium; headache, dizziness; visual impairment; cardiotoxicity, arrhythmia (most often tachycardia; also atrial fibrillation and bradycardia), chest pain; haemorrhage, hypotension, hypertension; dyspnoea, cough, pleural effusion; nausea, diarrhoea/colitis, mucositis, constipation, abdominal pain, decreased appetite, vomiting; pruritus, hyperhidrosis; musculoskeletal pain; renal failure; oedema, fatigue, chills, pyrexia.

Common (≥1/100 to <1/10): thrombocytopenia, neutropenia, anaemia; tumour lysis syndrome; dyspepsia; night sweats; alopecia.

Uncommon (≥1/1,000 to <1/100): palmar-plantar erythrodysaesthesia syndrome.

Among grade 3 to 5 reactions, febrile neutropenia (62.4%) and infection (58.7%) were the most frequent. Serious or fatal infections, haemorrhage (including fatal central nervous system haemorrhage with severe thrombocytopenia) and cardiotoxicity are the main serious risks (see Special Instructions).

No interaction studies have been performed. The liposomal delivery is expected to reduce the possibility of interactions, because free systemic concentrations of daunorubicin and cytarabine are much lower than with the non-liposomal forms.

• Cardiotoxic agents: concurrent use may increase the risk of cardiotoxicity, and earlier treatment with doxorubicin does too. It should not be combined with other cardiotoxic agents unless cardiac function is closely monitored.
• Hepatotoxic agents: may impair liver function and increase toxicity. Because daunorubicin is metabolised by the liver, changes in liver function may alter its metabolism, pharmacokinetics, efficacy and/or toxicity, so liver function is monitored more often.
• Live vaccines: avoid (see Special Instructions).
• Oral medicines: absorption can be considerably affected by gastrointestinal mucositis and/or diarrhoea.

Treatment is initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic medicinal products. Vyxeos liposomal has a different posology from daunorubicin injection and cytarabine injection, and it must not be interchanged with other daunorubicin and/or cytarabine containing products. Dosing is based on body surface area (BSA). It is for intravenous use only, as an infusion over 90 minutes.

Dose and Schedule

• First induction: daunorubicin 44 mg/m² and cytarabine 100 mg/m² on days 1, 3 and 5.
• Second induction, if needed: 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.

A further induction course may be given to patients with no disease progression or unacceptable toxicity; a normal-appearing bone marrow may need more than one induction course, and a bone marrow evaluation after recovery from the previous course decides whether another is needed. Treatment continues while the patient benefits or until disease progression, up to a maximum of 2 induction courses.

The first consolidation cycle is given 5 to 8 weeks after the start of the last induction. Consolidation is recommended for patients in remission whose absolute neutrophil count has recovered above 500/μL and platelet count above 50,000/μL, without unacceptable toxicity. A second consolidation course may be given 5 to 8 weeks after the start of the first, up to a maximum of 2 consolidation courses.

Dose Adjustments During Treatment

Patients are monitored for haematological response and toxicity, and dosing is delayed or permanently stopped when needed. Patients may be pre-medicated against nausea and vomiting, and anti-hyperuricaemic therapy (for example allopurinol) should be considered before starting.

• Mild hypersensitivity (for example mild flushing, rash, pruritus): stop the infusion and supervise the patient, including vital signs. Restart slowly once symptoms have resolved, at half the infusion rate, with intravenous diphenhydramine (20–25 mg) and intravenous dexamethasone (10 mg).
• Moderate hypersensitivity (for example moderate rash, flushing, mild dyspnoea, chest discomfort): stop, and give intravenous diphenhydramine (20–25 mg or equivalent) and dexamethasone (10 mg). Do not restart the infusion. On retreatment, give the same dose and rate with premedication.
• Severe or life-threatening hypersensitivity (for example hypotension needing vasopressors, angioedema, respiratory distress needing a bronchodilator, generalised urticaria): stop, give diphenhydramine and dexamethasone, and add adrenaline (epinephrine) or bronchodilators if indicated. Do not restart or retreat; treatment is permanently discontinued. Patients are monitored until symptoms resolve.
• Cardiotoxicity: cardiac function is assessed before starting, especially in high-risk patients. Treatment is stopped in patients who develop signs or symptoms of cardiomyopathy, unless the benefit outweighs the risk.
• Missed dose: give it as soon as possible and adjust the schedule accordingly, keeping the treatment interval.

Special Populations

• Renal impairment: no adjustment in mild (creatinine clearance 60–89 mL/min), moderate (30–59 mL/min) or severe (below 30 mL/min) impairment. There is no experience in end-stage renal disease on dialysis.
• Hepatic impairment: no adjustment when bilirubin is 50 μmol/L or less. There is no experience above 50 μmol/L; in severe hepatic impairment it is used only if the benefits outweigh the risks.
• Elderly (65 years and older): no dose adjustment.
• Children: not authorised. It has been studied outside its authorised indications in patients aged 1–21 years with relapsed AML, but the studies were too small to conclude that benefits outweigh risks, and in younger patients (under 22 years) with de novo AML safety and efficacy have not been established. No posology can be recommended.

Method of Administration

Intravenous infusion over 90 minutes only. It must not be given intramuscularly, intrathecally or subcutaneously. Care is taken to avoid extravasation, because of the risk of tissue necrosis. Reconstitution and dilution are described in section 6.6 of the SmPC.

Do Not Substitute for Other Products

Vyxeos liposomal must not be substituted or interchanged with other daunorubicin and/or cytarabine containing products. Because their pharmacokinetics differ substantially, its dose and schedule differ from those of conventional daunorubicin and cytarabine injections and of other liposomal products. The medicinal product name and dose must be verified before administration to avoid dosing errors.

Severe Myelosuppression

Severe myelosuppression, including fatal infections and haemorrhagic events, has been reported, as have serious or fatal haemorrhages (including fatal central nervous system haemorrhage) with severe thrombocytopenia. Blood counts are checked at baseline and patients are monitored closely. Because of the long plasma half-life, recovery of neutrophils and platelets may be prolonged and need extra monitoring. Prophylactic anti-bacterial, antiviral and antifungal medicines may be given during profound neutropenia until the neutrophil count is back to 500/μL or more. Complications are treated with supportive measures such as anti-infectives, colony-stimulating factors and transfusions, and blood counts are monitored until recovery.

Cardiotoxicity

Cardiotoxicity is a known risk of anthracyclines. The risk rises with earlier anthracycline treatment (including patients who reached the recommended maximum cumulative dose of doxorubicin or daunorubicin hydrochloride), existing heart disease or impaired cardiac function, earlier mediastinal radiotherapy and concurrent cardiotoxic medicines.

• With conventional daunorubicin, cumulative doses above 550 mg/m² (400 mg/m² after mediastinal radiotherapy) are linked with more treatment-induced congestive heart failure. The relationship between the cumulative Vyxeos liposomal dose and cardiac toxicity has not been determined.
• The daunorubicin given per course is 132 mg/m² for the first induction, 88 mg/m² for the second induction and 58 mg/m² for each consolidation.
• A baseline ECG and a MUGA scan or echocardiogram are recommended, especially with risk factors, and cardiac function is monitored closely. Treatment is stopped if cardiac function is impaired, unless the benefit outweighs the risk.
• In two single-arm studies in 65 anthracycline-pretreated children with relapsed or refractory AML, one induction cycle was followed by cardiac disorders (sinus tachycardia, QT prolongation, reduced ejection fraction). In children, congestive cardiomyopathy can appear after many years.

Hypersensitivity

Serious hypersensitivity reactions, including anaphylaxis, have been reported with daunorubicin and cytarabine. Treatment is stopped and managed by severity as set out under Administration and Dosage; after a severe or life-threatening reaction it is stopped permanently.

Tissue Necrosis

Daunorubicin can cause local tissue necrosis if it leaks from the vein. One extravasation occurred in the clinical studies, without necrosis. Care must be taken that none occurs, and the medicine is given intravenously only.

Liver, Kidney and Laboratory Monitoring

Hepatic impairment may raise the toxicity of daunorubicin and cytarabine, so liver function is evaluated before and periodically during treatment. There is no experience with a baseline bilirubin above 50 μmol/L or with end-stage renal disease on dialysis. Rapid lysis of leukaemic cells may cause hyperuricaemia, so blood uric acid is monitored and treated if it rises.

Copper and Wilson’s Disease

Each vial contains 100 mg of copper gluconate, equal to 14 mg of elemental copper. In patients with a history of Wilson’s disease or another copper-related disorder it is used only if the benefit outweighs the risk, and it is stopped if signs of acute copper toxicity appear.

Infections and Vaccines

Live or live-attenuated vaccines given to patients made immunocompromised by chemotherapy may cause serious or fatal infections, so live vaccines should be avoided. Killed or inactivated vaccines may be given, although the response may be weaker.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: women of childbearing potential have a pregnancy test before starting. Female patients, and male patients with partners of childbearing potential, should use effective contraception during treatment and for 6 months after the last dose.
• Pregnancy: there are no data in pregnant women. Based on animal studies and its mechanism of action, it should not be used in pregnancy unless the woman’s clinical condition requires treatment and justifies the potential risk to the foetus. If it is used, or pregnancy occurs during treatment, the woman is told of the hazard to the foetus; a cardiological examination and a blood count are recommended in foetuses and newborns of treated mothers.
• Breastfeeding: it is not known whether it passes into human milk. Because of the potential for serious adverse reactions in breastfed children, women are advised not to breastfeed during treatment.
• Fertility: findings in animals suggest that male fertility may be compromised.

Effect on Driving

Vyxeos liposomal has a minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported, so caution is advised when driving or operating machines.

Store unopened vials in a refrigerator at 2–8 °C, in the original carton to protect from light, in an upright position. It is a cold-chain product: it stays refrigerated from dispatch until it is prepared. For storage after reconstitution and dilution, see Shelf Life.

• Unopened vials: 4 years.
• Reconstituted suspension in the vial: chemical and physical in-use stability has been shown for 4 hours at 2–8 °C, kept upright.
• Diluted infusion solution: chemical and physical in-use stability has been shown for 4 hours at 2–8 °C.
• From a microbiological point of view, the product should be used immediately unless the method of reconstitution and dilution rules out the risk of contamination. Otherwise in-use storage times and conditions are the responsibility of the user. The SmPC gives further in-use details.

Prescription only (Rx). Treatment is initiated and monitored by a physician experienced in the use of chemotherapeutic medicinal products. Vyxeos liposomal is given as a 90-minute intravenous infusion, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C. It must not be substituted with other daunorubicin and/or cytarabine containing products, and the product name and dose are verified before administration. Packs hold 1, 2 or 5 vials; not all pack sizes may be marketed.