The fixed liposomal combination of daunorubicin and cytarabine (daunorubicin/cytarabine liposomal) contains 2 antineoplastic agents coencapsulated in liposomes; daunorubicin is an anthracycline and cytarabine is an antimetabolite.1
The fixed liposomal combination of daunorubicin and cytarabine (daunorubicin/cytarabine liposomal; Vyxeos®) is used for the treatment of newly diagnosed therapy-related acute myeloid leukemia (t-AML; secondary AML) or AML with myelodysplasia-related changes (AML-MRC).1, 15 Daunorubicin/cytarabine liposomal has been designated an orphan drug by FDA for the treatment of this cancer.2 Evidence supporting the use of daunorubicin/cytarabine liposomal is based principally on a study performed in a subset of patients with high-risk AML (i.e., patients older than 60 years of age with t-AML or AML-MRC).1, 7, 15 In these patients, daunorubicin/cytarabine liposomal induction therapy followed by use as consolidation therapy substantially prolonged survival compared with a standard combination of the 2 drugs.1
AML is generally regarded as a disease of the elderly with a median age at diagnosis of 67 years; however, patients older than 60 years of age usually have a poor prognosis due to unfavorable cytogenetics or poor compliance due to treatment-related adverse effects.5, 7, 260 The specific type of AML can also affect prognosis; t-AML and AML-MRC are subtypes that are less likely to respond to standard induction therapy with cytarabine and an anthracycline.5, 260 Several strategies (e.g., modified treatment intensity or duration of treatment, new formulations of standard drugs) have been employed to improve overall efficacy and tolerability of combination chemotherapy.6, 7, 15, 260
Combination chemotherapy is widely used in an effort to delay the emergence of resistance to antineoplastic agents and to obtain an additive or synergistic therapeutic effect with minimum toxicity;7, 8, 9 however, in vitro data indicate that the synergistic, additive, or antagonistic interaction of a drug combination is dependent on the ratio of the individual drugs in cancer cells.8, 9, 10 In vivo, maintenance of an optimal drug ratio is precluded by independent and dissimilar pharmacokinetics of individual drugs administered as conventional aqueous-based drug combinations.8, 10, 14 The rationale for use of a liposomal delivery system is to control the release of drug combinations such that fixed synergistic drug ratios established in vitro are maintained in vivo following drug administration; this strategy, known as “ratiometric dosing,” has been employed to optimize therapeutic efficacy of antineoplastic drug combinations including the combination of daunorubicin and cytarabine.1, 7, 8, 10, 11, 12, 14 (See Description.)
The current indication for daunorubicin/cytarabine liposomal is based principally on the results of a randomized, multicenter, open-label phase 3 trial in patients 60-75 years of age with newly diagnosed t-AML or AML-MRC.1, 7, 15 A total of 309 patients were randomized in a 1:1 ratio to receive induction and consolidation therapy with either daunorubicin/cytarabine liposomal or a standard combination of daunorubicin and cytarabine administered as single-entity preparations (standard combination therapy).1 Daunorubicin (44 mg/m2) in fixed combination with cytarabine (100 mg/m2) encapsulated in liposomes was administered by IV infusion on days 1, 3, and 5 during the first induction cycle and, if necessary, on days 1 and 3 during the second induction cycle.1 During consolidation therapy, daunorubicin (29 mg/m2) in fixed combination with cytarabine (65 mg/m2) encapsulated in liposomes was administered by IV infusion on days 1 and 3 for up to 2 cycles.1 Induction therapy with standard combination therapy consisted of daunorubicin 60 mg/m2 daily by IV infusion on days 1-3 and cytarabine 100 mg/m2 daily by continuous IV infusion on days 1-7 of the first induction cycle; if necessary, a second induction cycle consisting of daunorubicin 60 mg/m2 daily by IV infusion on days 1-2 and cytarabine 100 mg/m2 daily by continuous IV infusion on days 1-5 was administered.1 Consolidation therapy with standard combination therapy consisted of daunorubicin 60 mg/m2 daily by IV infusion on days 1-2 and cytarabine 100 mg/m2 daily by continuous IV infusion on days 1-5 for up to 2 cycles.1 In all patients, a second cycle of induction therapy was administered if a reduction in leukemic blast cells exceeding 50% was achieved and was strongly recommended if complete remission was not achieved.1, 15 Stem cell transplantation was permitted as consolidation therapy or post-consolidation therapy.1 The primary measure of efficacy was overall survival.1 In this trial, 100 or 97% of patients in the daunorubicin/cytarabine liposomal or standard combination therapy groups, respectively, received at least one cycle of induction therapy, and 32 or 21% of patients in the respective treatment groups received at least one cycle of consolidation therapy.1 Following initial complete remission, induction failure, or salvage therapy after relapse, 34% of daunorubicin/cytarabine liposomal-treated patients and 25% of those who received standard combination therapy underwent stem cell transplantation.1
The median age of patients enrolled in the study was 68 years (range: 60-75 years); 61% were male, 88% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 54% had AML with an antecedent hematologic disorder, 25% had de novo AML with myelodysplasia-related cytogenetic abnormalities, and 20% had t-AML.1 Approximately one-third of patients previously received a hypomethylating agent for myelodysplastic syndrome (MDS).1 Fms-like tyrosine kinase-3 (Flt-3) mutation was present in 43 of 279 patients (15%) evaluated for this mutation.1 In addition, nucleophosmin 1 (NPM1) mutation was present in 25 of 283 patients (9%) evaluated for this mutation.1 Baseline characteristics were generally balanced between treatment groups.1
At the time of analysis, patients receiving daunorubicin/cytarabine liposomal had a longer median overall survival (9.6 versus 5.9 months; hazard ratio: 0.69) than those receiving standard combination therapy.1 In addition, patients receiving the fixed-combination liposomal preparation had higher complete remission rates compared with those receiving the standard combination regimen (38 versus 26%).1
The commercially available fixed liposomal combination of daunorubicin and cytarabine (daunorubicin/cytarabine liposomal; Vyxeos®) is not interchangeable with other daunorubicin- and/or cytarabine-containing preparations.1 To avoid dosing errors, clinicians should confirm the drug name, formulation, and dose prior to preparation and administration.1 (See Lack of Interchangeability with Other Daunorubicin and Cytarabine Preparations under Warnings/Precautions: Warnings, in Cautions.)
Cardiac, hepatic, and renal function should be assessed prior to initiation of induction therapy and prior to each cycle of consolidation therapy.1 In addition, complete blood cell counts (CBCs) should be monitored prior to each cycle of consolidation therapy.1 The manufacturer states that consolidation therapy should not be administered until neutrophil counts exceed 500/mm3 and platelet counts exceed 50,000/mm3.1
Because daunorubicin/cytarabine liposomal contains the anthracycline daunorubicin, the lifetime cumulative anthracycline exposure should be calculated prior to each cycle; the fixed-combination preparation should not be used in patients who have reached the maximum cumulative limit.1 (See Cardiac Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Because nausea occurs frequently in patients receiving daunorubicin/cytarabine liposomal, premedication with an antiemetic agent should be administered prior to therapy.1
Reconstitution and Administration
Procedures for proper handling and disposal of antineoplastic drugs should be followed when preparing or administering daunorubicin/cytarabine liposomal.1
Daunorubicin/cytarabine liposomal is administered only by IV infusion over 90 minutes through a central venous line (e.g., central venous catheter or peripherally inserted central catheter [PICC]) using an infusion pump.1 Because the daunorubicin component may cause severe tissue necrosis if extravasation occurs, the fixed-combination preparation must not be given by IM or subcutaneous injection.1 (See Local Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) The manufacturer states that an inline filter should not be used.1 The infusion line should be flushed with 0.9% sodium chloride injection or 5% dextrose injection after the drug is administered.1
Unopened vials of daunorubicin/cytarabine liposomal powder for injection should be stored upright at 2-8°C in the original package for protection from light.1 Prior to administration, the lyophilized powder must be reconstituted and diluted using proper aseptic technique.1 The number of vials needed should be determined based on the indicated dose of the daunorubicin component.1 The vials should be removed from the refrigerator and allowed to come to room temperature for 30 minutes prior to reconstitution.1 The lyophilized powder is reconstituted by adding 19 mL of sterile water for injection to a vial labeled as containing 44 mg of daunorubicin and 100 mg of cytarabine to provide a colloidal dispersion containing 2.2 mg of daunorubicin and 5 mg of cytarabine per mL.1, 15 Using a timer, each vial should be swirled for 5 minutes, including gentle inversion every 30 seconds.1 The resulting dispersion should not be heated, vortexed, or shaken vigorously.1 The vials should be allowed to rest for 15 minutes and then gently inverted an additional 5 times prior to dilution.1 The reconstituted daunorubicin/cytarabine liposomal colloidal dispersion should be opaque, purple, homogeneous, and free of visible particulates.1 Following reconstitution, the drug may be diluted immediately for preparation of the final infusion solution or stored at 2-8°C for up to 4 hours.1
To prepare the final diluted daunorubicin/cytarabine liposomal solution for infusion, the required amount of reconstituted drug should be withdrawn from the vials and transferred to an infusion bag containing 500 mL of 0.9% sodium chloride injection or 5% dextrose injection.1 The diluted solution should be mixed by gentle inversion.1 The final diluted daunorubicin/cytarabine liposomal solution should be a translucent, deep purple, homogeneous dispersion that is free of visible particulates.1 The solution may be infused immediately or stored at 2-8°C for up to 4 hours.1
Daunorubicin/cytarabine liposomal solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit; the solution should not be used if particulate matter is present.1
Daunorubicin/cytarabine liposomal should not be admixed with or infused simultaneously with any other drug.1 Any unused portions in the vials or infusion bag should be discarded since the daunorubicin/cytarabine liposomal product contains no preservative.1
Daunorubicin/cytarabine liposomal is a fixed-combination preparation containing a 1:5 molar ratio of daunorubicin to cytarabine coencapsulated in liposomes.1 Each single-dose vial of daunorubicin/cytarabine liposomal contains 44 mg of daunorubicin and 100 mg of cytarabine coencapsulated in liposomes.1 Dosage of the fixed-combination preparation should be calculated based on the daunorubicin component.1
A complete course of daunorubicin/cytarabine liposomal therapy consists of 1-2 cycles of induction therapy and 1-2 cycles of consolidation therapy.1
The recommended adult dosage of daunorubicin/cytarabine liposomal as induction therapy for newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) is daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on days 1, 3, and 5; if complete remission is not achieved following the first induction cycle and the fixed drug combination is well tolerated, a second induction cycle may be administered 2-5 weeks after the first induction cycle on days 1 and 3 at the same dosage.1
Consolidation therapy should be administered 5-8 weeks after the start of the last induction cycle.1 (See Dosage and Administration: General.) The recommended adult dosage of daunorubicin/cytarabine liposomal as consolidation therapy is daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 on days 1 and 3; a second consolidation cycle should be administered 5-8 weeks following initiation of the first consolidation cycle in the absence of disease progression or unacceptable toxicity.1
If a dose of daunorubicin/cytarabine liposomal is missed, the dose should be administered as soon as possible.1 The schedule of administration should be adjusted to maintain the treatment interval between cycles.1
Dosage Modification for Toxicity
If mild hypersensitivity reactions occur, the daunorubicin/cytarabine liposomal infusion should be interrupted immediately and supportive treatment should be initiated; upon resolution of symptoms, the infusion may be resumed but the rate of infusion should be reduced by 50%.1 Premedication with an antihistamine and/or corticosteroid should be considered prior to subsequent infusions.1 (See Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.)
If moderate hypersensitivity reactions occur, the daunorubicin/cytarabine liposomal infusion should be interrupted immediately and supportive treatment should be initiated; the infusion should not be resumed upon resolution of symptoms.1 Subsequent infusions of daunorubicin/cytarabine liposomal may be administered at the same rate following administration of a premedication regimen (i.e., antihistamine and/or corticosteroid).1
If severe or life-threatening hypersensitivity reactions occur, daunorubicin/cytarabine liposomal therapy should be permanently discontinued.1 Supportive treatment should be initiated and the patient should be monitored until symptoms resolve.1
No adjustment of daunorubicin/cytarabine liposomal dosage is necessary in patients with serum bilirubin concentrations of 3 mg/dL or less.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
No adjustment of daunorubicin/cytarabine liposomal dosage is necessary in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
History of serious hypersensitivity reactions to cytarabine, daunorubicin, or any component of the formulation.1
Lack of Interchangeability with Other Daunorubicin and Cytarabine Preparations
The fixed liposomal combination of daunorubicin and cytarabine (daunorubicin/cytarabine liposomal) is not interchangeable with other daunorubicin- and/or cytarabine-containing preparations (e.g., daunorubicin hydrochloride injection, daunorubicin citrate liposomal injection, cytarabine injection, cytarabine liposomal injection).1 The pharmacokinetic properties of the fixed-combination liposomal preparation differ from those of the single-entity preparations of each drug (including their liposomal and nonliposomal forms), and dosage for each product is specific to the formulation.1 Clinicians should confirm the correct drug, formulation, and dosage prior to preparation and administration of daunorubicin/cytarabine liposomal.1
Serious or fatal hypersensitivity reactions, including anaphylactic reactions, have been reported in patients receiving daunorubicin and cytarabine as single agents.1
Patients should be monitored for manifestations of hypersensitivity reactions.1 If a hypersensitivity reaction occurs, appropriate treatment and supportive care should be initiated.1 Reduction in infusion rate, temporary interruption, or discontinuance of therapy may be required depending on the severity of the reaction.1 (See Hypersensitivity Reactions under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) If a severe or life-threatening hypersensitivity reaction occurs, daunorubicin/cytarabine liposomal should be permanently discontinued.1
Other Warnings and Precautions
Serious or fatal hemorrhage associated with prolonged severe thrombocytopenia has been reported in patients receiving daunorubicin/cytarabine liposomal.1 In the principal efficacy trial in patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC), hemorrhage occurred in 74% of patients receiving daunorubicin/cytarabine liposomal compared with 56% of those receiving a standard combination of daunorubicin and cytarabine.1 Grade 3 or greater hemorrhage was reported in 12% of patients receiving daunorubicin/cytarabine liposomal compared with 8% of those receiving standard combination therapy.1 Fatal CNS hemorrhage in the absence of disease progression occurred in 2% of patients receiving daunorubicin/cytarabine liposomal compared with 0.7% of those receiving standard combination therapy.1 The most common hemorrhagic event reported in the trial was epistaxis.1
If hemorrhage occurs, complete blood cell counts (CBCs) should be monitored until resolution and platelet transfusions should be administered if necessary.1
The daunorubicin component of daunorubicin/cytarabine liposomal is an anthracycline, and cardiotoxicity is a known risk of anthracycline therapy.1 Among patients receiving daunorubicin/cytarabine liposomal in the principal efficacy study, cardiotoxicity, including acute coronary syndrome, acute myocardial infarction, decreased left ventricular ejection fraction (LVEF), congestive heart failure, cardiac failure or arrest, cardiomyopathy, endocarditis, pericarditis, and valvular abnormalities, was reported in 20% of patients, which was comparable to the incidence of cardiotoxicity in patients receiving a standard combination of daunorubicin and cytarabine.1 Arrhythmias occurred in 30% of patients receiving the fixed-combination preparation.1 The cumulative dosage of daunorubicin/cytarabine liposomal administered in the study ranged from 44-337 mg/m2 (of daunorubicin).1 Patients with baseline LVEF less than 50% and a lifetime cumulative exposure of 368 mg/m2 or more of daunorubicin (or equivalent) were not included in the study.1
Factors that may increase the risk of daunorubicin-induced cardiotoxicity include previous therapy with other anthracycline agents, preexisting heart disease, previous radiation therapy to the mediastinal region, or concomitant use of other cardiotoxic drugs.1 With conventional daunorubicin, the incidence of heart failure increases with cumulative dosages exceeding 550 mg/m2 (or 400 mg/m2 in patients who have received radiation therapy to the mediastinal region).1 The lifetime cumulative anthracycline exposure should be calculated prior to each cycle of daunorubicin/cytarabine liposomal; the total cumulative dosage should include any previous or concomitant therapy with other anthracycline agents, such as doxorubicin, or related compounds.1, 3 Daunorubicin/cytarabine liposomal should not be used in patients who have reached the maximum cumulative limit.1
Cardiac function should be evaluated prior to initiating daunorubicin/cytarabine liposomal therapy; the assessment should include an ECG and baseline determination of LVEF with an echocardiogram or multigated radionuclide angiography (MUGA).1 Patients with baseline LVEF below the lower limit of normal should not receive daunorubicin/cytarabine liposomal therapy.1 A repeat echocardiogram or MUGA should be performed prior to initiation of consolidation therapy and as clinically indicated.1 Daunorubicin/cytarabine liposomal should be discontinued in patients with impaired cardiac function unless the potential benefits outweigh the risks.1
For additional information on the cardiotoxicity of daunorubicin, see Cautions: Cardiac Effects, in Daunorubicin Hydrochloride 10:00.
The reconstituted daunorubicin/cytarabine liposomal dispersion contains 5 mg/mL of copper gluconate (14% of which is elemental copper).1 Clinical studies of daunorubicin/cytarabine liposomal did not include patients with Wilson disease or other copper-related metabolic disorders.1 The maximum theoretical total exposure of copper based on the recommended dosage of daunorubicin/cytarabine liposomal for induction and consolidation therapy is 106 mg/m2.1
In patients with Wilson disease, daunorubicin/cytarabine liposomal should be used only if the potential benefit outweighs the risk.1 If the drug is used in such patients, total serum copper, serum non-ceruloplasmin-bound copper, and 24-hour urine copper excretion should be monitored and neuropyschological assessments should be performed periodically.1 Consultation with a clinician who has expertise in managing acute copper toxicity is recommended in patients with Wilson disease who are treated with daunorubicin/cytarabine liposomal.1 If manifestations of acute copper toxicity occur in any patient, daunorubicin/cytarabine liposomal therapy should be discontinued.1
Extravasation of daunorubicin, a component of daunorubicin/cytarabine liposomal, can produce severe local tissue necrosis.1 Daunorubicin/cytarabine liposomal must not be given by IM or subcutaneous injection.1
For additional information on the local effects of daunorubicin, see Cautions: Local Effects, in Daunorubicin Hydrochloride 10:00.
Fetal/Neonatal Morbidity and Mortality
Daunorubicin/cytarabine liposomal may cause fetal harm in humans based on animal findings and anecdotal reports with the individual drugs in pregnant women; liposomal daunorubicin and conventional cytarabine have been shown to be teratogenic, embryotoxic, and fetotoxic in animals.1 There are no adequate and well-controlled studies using the fixed liposomal combination of daunorubicin and cytarabine or the individual drugs in pregnant women; however, 4 cases of major limb malformations have been reported in infants of mothers who received IV cytarabine, alone or in combination with other agents, during the first trimester.1
Severe maternal toxicity and embryolethality have been demonstrated in animals receiving liposomal daunorubicin at doses approximately 0.3 times the recommended human dose on a mg/m2 basis, while embryofetal toxicity (e.g., abortion, reduced number of offspring per litter, decreased litter sizes) and fetal malformations (i.e., anophthalmia, microphthalmia, incomplete ossification) have been observed at doses approximately 0.04 times the recommended human dose on a mg/m2 basis.1 Abnormalities including cleft palate, phocomelia, deformed appendages, and skeletal abnormalities have been observed in the offspring of mice given intraperitoneal cytarabine during the period of organogenesis at doses approximately 0.06 times the recommended human dose on a mg/m2 basis.1 Deformed appendages or reduced prenatal and postnatal brain size and permanent impairment of learning ability have been observed in the offspring of rats given cytarabine during the gestational period as a single intraperitoneal dose equivalent to approximately 1.2 or 3 times, respectively, the recommended human dose on a mg/m2 basis.1 Embryofetal toxicity (i.e., decreased fetal weight, increased early or late resorptions) and decreased live litter sizes have been observed in animals receiving cytarabine at doses as low as approximately 0.02 times the recommended human dose on a mg/m2 basis.1
Pregnancy should be avoided during daunorubicin/cytarabine liposomal therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of therapy, and women of childbearing potential should be advised to use effective contraceptive methods during and for at least 6 months after discontinuance of the drug.1 In addition, men with female partners of childbearing potential should use effective methods of contraception during and for at least 6 months after discontinuance of the drug.1 Patients should be apprised of the potential hazard to the fetus if daunorubicin/cytarabine liposomal is used during pregnancy.1
Results of animal studies suggest that daunorubicin administered as a single agent may cause reversible or permanent impairment of male fertility.1 In these animal studies, degeneration of reproductive tissues (testicular degeneration) and total aplasia of spermatocytes were observed in male dogs given IV daunorubicin at doses approximately 0.12 times the recommended human dose on a mg/m2 basis.1
There are no available data regarding the effect of cytarabine on fertility to date; however, a dose-dependent increase in sperm-head abnormalities and chromosomal aberrations were observed in animals receiving intraperitoneal cytarabine.1
Daunorubicin/cytarabine liposomal may cause fetal harm if administered to pregnant women based on animal findings and anecdotal reports in pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
It is not known whether daunorubicin, cytarabine, or their metabolites are distributed into human milk.1 Because of the potential for serious adverse reactions to daunorubicin/cytarabine liposomal in nursing infants, women should be advised to discontinue nursing during and for at least 2 weeks after discontinuance of daunorubicin/cytarabine liposomal therapy.1 The effects of the fixed-combination preparation on nursing infants or on milk production are unknown.1
Safety and efficacy of daunorubicin/cytarabine liposomal have not been established in pediatric patients.1
In clinical trials, 57% of patients receiving daunorubicin/cytarabine liposomal were 65 years of age or older.1 No overall differences in safety were observed between geriatric patients and younger adults; however, hemorrhagic events occurred more frequently in geriatric patients compared with younger adults (77 versus 59%).1
Pharmacokinetics of total (encapsulated plus unencapsulated) daunorubicin and cytarabine were not altered following administration of the fixed liposomal combination in patients with serum bilirubin concentrations of 3 mg/dL or less.1, 15 Patients with serum bilirubin concentrations exceeding 3 mg/dL were not evaluated.1, 15
Pharmacokinetics of total (encapsulated plus unencapsulated) daunorubicin and cytarabine were not altered following administration of the fixed liposomal combination in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).1, 15 Patients with severe renal impairment (creatinine clearance of 15-29 mL/minute) or end-stage renal disease were not evaluated.1, 15
Adverse effects reported in 20% or more of adults receiving daunorubicin/cytarabine liposomal as induction therapy for newly diagnosed t-AML or AML-MRC include hemorrhage,1 febrile neutropenia,1 rash,1 edema,1 nausea,1 diarrhea/colitis,1 mucositis,1 constipation,1 musculoskeletal pain,1 abdominal pain,1 cough,1 headache,1 dyspnea,1 fatigue,1 arrhythmia,1 loss of appetite,1 pneumonia (excluding fungal pneumonia),1 sleep disorders,1 bacteremia (excluding sepsis),1 vomiting,1 chills,1 hypotension,1 and non-conduction cardiotoxicity.1 Similar adverse effects were observed with daunorubicin/cytarabine liposomal in the consolidation phase; however, adverse effects with the exception of chills, dizziness, and pyrexia were reported at a lower incidence during consolidation therapy.1
Laboratory abnormalities reported in 10% or more of patients with newly diagnosed t-AML and AML-MRC receiving daunorubicin/cytarabine liposomal during induction and consolidation therapy include prolonged (defined as persisting beyond 42 days in the absence of active leukemia) thrombocytopenia and neutropenia; however, hyponatremia also occurred in patients receiving daunorubicin/cytarabine liposomal during induction therapy.1
Specific drug interaction studies have not been performed to date with daunorubicin/cytarabine liposomal; however, interactions mediated by inhibitors or inducers of cytochrome P-450 (CYP) isoenzymes or common transporters are not likely based on available clinical data with other liposomal or nonliposomal cytarabine and daunorubicin preparations.15
Concomitant use of daunorubicin/cytarabine liposomal with other cardiotoxic drugs may increase the risk of cardiotoxicity.1 If concomitant use cannot be avoided, the manufacturer recommends more frequent assessment of cardiac function.1 (See Cardiac Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Concomitant use of daunorubicin/cytarabine liposomal with hepatotoxic drugs may cause hepatic impairment and increase the incidence of adverse effects.1 If concomitant use cannot be avoided, the manufacturer recommends more frequent monitoring of hepatic function.1
The fixed liposomal combination of daunorubicin and cytarabine (daunorubicin/cytarabine liposomal) contains 2 antineoplastic agents in a fixed molar ratio coencapsulated in liposomes.1 Daunorubicin is an anthracycline antineoplastic antibiotic produced by Streptomyces coeruleorubidus that exhibits antimitotic and cytotoxic activity.1, 3 The drug forms a complex with DNA by intercalation between base pairs.1, 3 By stabilizing the complex between DNA and topoisomerase II, daunorubicin inhibits the activity of this enzyme, resulting in single-strand and double-strand breaks in DNA.1, 3 Daunorubicin also may inhibit polymerase activity, affect regulation of gene expression, and be involved in free radical damage to DNA.1, 3 Cytarabine is a cycle-phase specific antineoplastic agent, inducing G1-phase arrest and preferentially killing cells in the S phase.1, 4 Although the exact mechanism(s) of action of cytarabine has not been fully elucidated, the drug appears to act primarily through inhibition of DNA polymerase.1, 4
In vitro studies indicate that efficacy of combination chemotherapy is dependent on the molar ratio of the component drugs.6 The fixed liposomal combination of daunorubicin and cytarabine is formulated in a 1:5 molar ratio, which has been shown to provide the greatest synergistic effect with the least antagonism.1, 7, 8, 10, 11, 13, 14 (See Uses: Acute Myeloid Leukemia.) The liposomes encapsulating the drug combination are composed of distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), and cholesterol in a molar ratio of 7:2:1.1 In addition to maintaining favorable drug ratios in the plasma after administration, preclinical studies also indicate that liposomes can penetrate and sustain higher concentrations of the drugs at the tumor site (specifically the bone marrow).1, 7, 8, 10, 11, 12, 14 Following administration of daunorubicin/cytarabine liposomal in leukemia-bearing mice, the liposomes are preferentially internalized by leukemic cells.1 Following cellular internalization and degradation of the liposomes, daunorubicin and cytarabine are released into the intracellular environment.1
Following IV infusion of daunorubicin/cytarabine liposomal over 90 minutes on days 1, 3, and 5 in adults, the accumulation ratio of daunorubicin and cytarabine is 1.3 and 1.4, respectively.1 The pharmacokinetics of the drugs are dose proportional over the dose range of 1.3-59 mg/m2 for daunorubicin and 3-134 mg/m2 for cytarabine.1 Following release from liposomes, daunorubicin is mainly catalyzed by aldo-keto reductase and carbonyl reductase enzymes to the active metabolite daunorubicinol, and cytarabine is metabolized by the enzyme cytidine deaminase to the inactive metabolite 1-β-d-arabinofuranosyluracil (ara-U, uracil arabinoside).1 Following administration of daunorubicin/cytarabine liposomal, approximately 9% of the daunorubicin dose is eliminated as unchanged drug and daunorubicinol in urine, and approximately 71% of the cytarabine dose is eliminated as unchanged drug and 1-β-d-arabinofuranosyluracil in urine.1 When administered as the daunorubicin/cytarabine liposomal combination, the half-lives of the drugs are prolonged (to 31.5 hours for daunorubicin and 40.4 hours for cytarabine) with more than 99% of daunorubicin and cytarabine in plasma remaining encapsulated in liposomes.1
Data from a population pharmacokinetic analysis indicate that age, gender, race, body weight, body mass index, and leukocyte count do not have clinically important effects on the systemic exposure of total daunorubicin or cytarabine.1
Risk of hemorrhage.1 Importance of monitoring complete blood cell counts (CBCs).1 Importance of contacting a clinician if manifestations of infection (e.g., fever), unusual bleeding, or bruising occurs.1
Risk of cardiotoxicity.1 Importance of informing clinicians if manifestations of heart failure occur.1
Risk of hypersensitivity reactions, including anaphylaxis.1 Importance of seeking immediate medical attention if manifestations of a hypersensitivity reaction or anaphylaxis occur.1
Risk of impaired fertility in men.1
Risk of fetal harm.1 Necessity of advising women of childbearing potential and men who are partners of such women that they should use an effective method of contraception while receiving the drug and for at least 6 months after discontinuance of therapy.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1
Importance of advising women to avoid breast-feeding while receiving the drug and for at least 2 weeks after discontinuance of therapy.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions October 1, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Jazz Pharmaceuticals, Inc. Vyxeos® (daunorubicin and cytarabine liposome) for injection prescribing information. Palo Alto, CA; 2017 Aug.
2. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2018 Mar 28. [Web]
3. West-Ward Pharmaceuticals. Daunorubicin hydrochloride injection prescribing information. Eatontown, NJ; 2015 May.
4. Mylan Instututional. Cytarabine injection prescribing information. Rockford, IL; 2013 Dec.
5. De Kouchkovsky I, Abdul-Hay M. 'Acute myeloid leukemia: a comprehensive review and 2016 update'. Blood Cancer J . 2016; 6:e441. [PubMed 27367478]
6. Lancet JE, Cortes JE, Hogge DE et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood . 2014; 123:3239-46. [PubMed 24687088]
7. Brunetti C, Anelli L, Zagaria A et al. CPX-351 in acute myeloid leukemia: can a new formulation maximize the efficacy of old compounds?. Expert Rev Hematol . 2017; 10:853-862. [PubMed 28814164]
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