DAUNOrubicin and Cytarabine (Monograph)

Drug class: Antineoplastic Agents
Chemical name: 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
Molecular formula: C₉H₁₃N₃O₅C₂₇H₂₉NO₁₀
CAS number: 147-94-4

Medically reviewed by Drugs.com on Sep 21, 2023. Written by ASHP.

Introduction

Antineoplastic;¹ fixed combination of daunorubicin (an anthracycline) and cytarabine (an antimetabolite) coencapsulated in liposomes.¹

Uses for DAUNOrubicin and Cytarabine

Acute Myeloid Leukemia (AML)

Treatment of newly diagnosed therapy-related AML (t-AML; secondary AML) or AML with myelodysplasia-related changes (AML-MRC) in adults^{1 15} (designated an orphan drug by FDA for this use).²

May be used for remission induction as well as consolidation therapy.¹

Evidence supporting efficacy is based principally on a study performed in patients with high-risk AML (i.e., patients >60 years of age with t-AML or AML-MRC).^{1 7 15}

DAUNOrubicin and Cytarabine Dosage and Administration

General

• Not interchangeable with other daunorubicin and/or cytarabine preparations.¹ Confirm correct drug name, formulation, and dose prior to preparation and administration.¹ (See Boxed Warning.)

• Monitor cardiac, hepatic, and renal function prior to initiation of induction therapy and prior to each cycle of consolidation therapy.¹ Also monitor CBCs prior to each cycle of consolidation therapy; consolidation therapy should be withheld until neutrophil counts >500/mm³ and platelet counts >50,000/mm³.¹

• Calculate lifetime cumulative anthracycline exposure prior to each cycle of daunorubicin/cytarabine liposomal.¹ (See Cardiac Effects under Cautions.)

• Premedicate with an antiemetic agent.¹

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer only by IV infusion through a central venous line (e.g., central venous catheter or peripherally inserted central catheter [PICC]) using an infusion pump; do not use an inline filter.¹ Daunorubicin component may cause severe tissue necrosis if extravasation occurs; do not administer IM or sub-Q.¹

Following administration, flush IV line with 0.9% sodium chloride injection or 5% dextrose injection.¹

Must reconstitute commercially available powder for injection and further dilute prior to administration.¹ (See Storage under Stability.)

Do not mix with any other drug or administer any other drug simultaneously in the same IV line.¹

Reconstitution

Determine number of vials to reconstitute based on indicated dose of daunorubicin component.¹

Prior to reconstitution, allow vials to equilibrate to room temperature for 30 minutes.¹

Reconstitute vial containing 44 mg of daunorubicin and 100 mg of cytarabine with 19 mL of sterile water for injection to provide a colloidal dispersion containing 2.2 mg of daunorubicin and 5 mg of cytarabine per mL.^{1 15} Using a timer, swirl each vial for 5 minutes (gently invert every 30 seconds).¹ Do not heat, vortex, or vigorously shake.¹ Allow reconstituted drug to rest for 15 minutes; mix again with 5 gentle inversions prior to further dilution.¹

Reconstituted daunorubicin/cytarabine liposomal dispersion should be opaque, purple, homogeneous, and free of visible particulates.¹

Dilution

Further dilute reconstituted drug prior to IV infusion.¹

Dilute appropriate dose in an IV bag containing 500 mL of 0.9% sodium chloride injection or 5% dextrose injection.¹ Mix diluted solution by gently inverting IV bag.¹ (See Storage under Stability.)

Diluted solution should be a translucent, deep purple, homogeneous dispersion that is free of visible particulates.¹

Discard any unused portions of reconstituted and diluted solution.¹

Rate of Administration

Administer by IV infusion over 90 minutes.¹

Dosage

Available as a fixed-combination preparation containing a 1:5 molar ratio of daunorubicin to cytarabine coencapsulated in liposomes (daunorubicin/cytarabine liposomal).¹

Each single-dose vial contains 44 mg of daunorubicin and 100 mg of cytarabine coencapsulated in liposomes.¹

Calculate dosage of the fixed combination based on the daunorubicin component.¹

Adults

AML

IV

Complete course consists of 1–2 cycles of induction therapy and 1–2 cycles of consolidation therapy.¹

Induction therapy: Daunorubicin 44 mg/m² and cytarabine 100 mg/m² as the fixed liposomal combination on days 1, 3, and 5 of first induction cycle; if complete remission not achieved and unacceptable toxicity does not occur, may administer a second induction cycle 2–5 weeks after first induction cycle on days 1 and 3 at same dosage.¹

Consolidation therapy (administer 5–8 weeks from start of last induction cycle): Daunorubicin 29 mg/m² and cytarabine 65 mg/m² as the fixed liposomal combination on days 1 and 3; may administer second consolidation cycle 5–8 weeks following initiation of first consolidation cycle if disease progression or unacceptable toxicity does not occur.¹

If a dose is missed, administer as soon as possible.¹ Adjust dosage schedule accordingly to maintain treatment interval between cycles.¹

Dosage Modification for Toxicity

Hypersensitivity Reactions

If a mild hypersensitivity reaction occurs, immediately interrupt infusion and initiate supportive treatment; upon resolution of symptoms, reduce rate of infusion by 50%.¹ Consider premedication with an antihistamine and/or corticosteroid prior to subsequent infusions.¹

If a moderate hypersensitivity reaction occurs, immediately interrupt infusion and initiate supportive treatment; do not resume infusion upon resolution of symptoms.¹ For subsequent infusions, may administer at same rate following administration of a premedication regimen (i.e., antihistamine and/or corticosteroid).¹

If a severe or life-threatening hypersensitivity reaction occurs, permanently discontinue therapy.¹ Initiate supportive treatment and monitor patient.¹

Prescribing Limits

Adults

IV

With conventional daunorubicin, increased incidence of heart failure observed with total cumulative dosage >400–550 mg/m².¹ (See Cardiac Effects under Cautions.)

Special Populations

Hepatic Impairment

No dosage adjustment necessary in patients with serum bilirubin concentrations ≤3 mg/dL.¹

Renal Impairment

No dosage adjustment necessary in patients with mild or moderate renal impairment (Cl_cr 30–89 mL/minute).¹

Geriatric Patients

No specific dosage recommendations.¹

Cautions for DAUNOrubicin and Cytarabine

Contraindications

• History of serious hypersensitivity reactions to cytarabine, daunorubicin, or any component of the formulation.¹

Warnings/Precautions

Warnings

Lack of Interchangeability with Other Daunorubicin and Cytarabine Preparations

Do not substitute the fixed liposomal combination of daunorubicin and cytarabine (daunorubicin/cytarabine liposomal) with other daunorubicin and/or cytarabine preparations (e.g., daunorubicin hydrochloride injection, daunorubicin citrate liposomal injection, cytarabine injection, cytarabine liposomal injection).¹ (See Boxed Warning.)

Pharmacokinetic properties, formulation, and dosage of the fixed-combination liposomal preparation differ from those of single-entity preparations (including their liposomal and nonliposomal forms).¹

Confirm correct drug, dose, and formulation prior to preparation and administration.¹

Sensitivity Reactions

Hypersensitivity Reactions

Serious or fatal hypersensitivity reactions, including anaphylactic reactions, reported in patients receiving daunorubicin and cytarabine as single agents.¹

Monitor for manifestations of hypersensitivity reactions.¹ If a hypersensitivity reaction occurs, initiate appropriate treatment and supportive care.¹ Reduce infusion rate, temporarily interrupt infusion, or discontinue therapy based on severity of the reaction.¹ (See Dosage Modification for Toxicity under Dosage and Administration.) If a severe or life-threatening hypersensitivity reaction occurs, permanently discontinue therapy and monitor patient.¹

Other Warnings and Precautions

Hemorrhage

Serious or fatal hemorrhage associated with prolonged severe thrombocytopenia reported.¹ Fatal CNS hemorrhage in absence of disease progression reported rarely.¹ Most common hemorrhagic event was epistaxis.¹

If hemorrhage occurs, monitor CBCs until resolution.¹ Administer platelet transfusions if necessary.¹

Cardiac Effects

Daunorubicin/cytarabine liposomal contains the anthracycline daunorubicin, and cardiotoxicity is a known risk of anthracycline therapy.¹

Previous therapy with other anthracycline agents, preexisting heart disease, previous radiation therapy to the mediastinal region, or concomitant use of other cardiotoxic drugs may increase risk.¹ With conventional daunorubicin, increased incidence of heart failure observed with total cumulative dosage >550 mg/m² (or >400 mg/m² in patients who have received radiation therapy to the mediastinal region).¹

Calculate lifetime cumulative anthracycline exposure prior to each cycle.¹ Include any previous or concomitant therapy with other anthracycline agents, such as doxorubicin, or related compounds in calculation.³ Do not use in patients who have reached the maximum cumulative limit.¹

Obtain baseline ECG and assess cardiac function (including left ventricular ejection fraction [LVEF]) with echocardiogram or multigated radionuclide angiography (MUGA) prior to initiation of therapy; do not use in patients with baseline LVEF below limit of normal.¹ Repeat echocardiogram or MUGA prior to initiation of consolidation therapy and as clinically indicated.¹ Evaluate risk versus benefit of initiating or continuing therapy in patients with impaired cardiac function.¹

Copper Overload

Reconstituted daunorubicin/cytarabine liposomal contains 5 mg/mL of copper gluconate (14% of which is elemental copper).¹ Safety in patients with Wilson disease or other copper-related metabolic disorders not established.¹ Maximum theoretical total exposure of copper following induction and consolidation therapy is 106 mg/m².¹

In patients with Wilson disease, use only if potential benefit outweighs risk.¹ If used in such patients, monitor total serum copper, serum non-ceruloplasmin-bound copper, and 24-hour urine copper excretion and perform neuropyschological assessments periodically.¹ Consult with a clinician who has expertise in managing acute copper toxicity.¹ If manifestations of acute copper toxicity occur in any patient, discontinue therapy.¹

Local Effects

Extravasation of daunorubicin, a component of daunorubicin/cytarabine liposomal, can produce severe local tissue necrosis.¹ (See IV Administration under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on animal findings and anecdotal reports in pregnant women.¹

Liposomal daunorubicin and conventional cytarabine shown to be teratogenic, embryotoxic, and fetotoxic in animals.¹ Major limb malformations reported in infants of mothers exposed to IV cytarabine, alone or in combination with other agents, during first trimester.¹ (See Pregnancy under Cautions.)

Confirm pregnancy status prior to initiating therapy.¹ Avoid pregnancy during therapy.¹ Women of childbearing potential and men who are partners of such women should use effective contraceptive methods while receiving daunorubicin/cytarabine liposomal and for ≥6 months after the fixed combination is discontinued.¹ If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.¹

Impairment of Fertility

May impair male fertility.¹

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women; however, animal studies suggest possible fetal harm if used during pregnancy.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether daunorubicin, cytarabine, or their metabolites distribute into human milk.¹ Effects on nursing infants and milk production also unknown.¹ Discontinue nursing during therapy and for ≥2 weeks after drug discontinuance.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

In clinical trials, no overall differences in safety relative to younger adults observed; however, hemorrhagic events occurred more frequently in geriatric patients.¹

Hepatic Impairment

Pharmacokinetics of daunorubicin and cytarabine not altered in patients with serum bilirubin concentrations ≤3 mg/dL.^{1 15}

Data lacking in patients with serum bilirubin concentrations >3 mg/dL.^{1 15}

Renal Impairment

Pharmacokinetics of daunorubicin and cytarabine not altered in patients with mild or moderate renal impairment (Cl_cr 30–89 mL/minute).^{1 15}

Data lacking in patients with severe renal impairment (Cl_cr 15–29 mL/minute) or end-stage renal disease.^{1 15}

Common Adverse Effects

Induction therapy for newly diagnosed t-AML and AML-MRC: 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 non-conduction cardiotoxicity,¹ prolonged thrombocytopenia,¹ prolonged neutropenia,¹ hyponatremia.¹

Consolidation therapy for newly diagnosed t-AML and AML-MRC: Similar adverse effects to those reported during induction therapy, but at a lower incidence (except for chills, dizziness, and pyrexia).¹

Drug Interactions

Specific drug interaction studies not performed to date; however, interactions mediated by inhibitors or inducers of CYP isoenzymes or common transporters not likely based on available clinical data with other liposomal or nonliposomal cytarabine and daunorubicin preparations.¹⁵

Cardiotoxic Drugs

Possible increased risk of cardiotoxicity.¹ If concomitant use cannot be avoided, monitor cardiac function more frequently.¹

Hepatotoxic Drugs

Possible impairment of hepatic function and increased risk of toxicity.¹ If concomitant use cannot be avoided, monitor hepatic function more frequently.¹

DAUNOrubicin and Cytarabine Pharmacokinetics

Absorption

Bioavailability

Following administration as the fixed liposomal combination, pharmacokinetics of daunorubicin and cytarabine are dose proportional over the dose range of 1.3–59 mg/m² and 3–134 mg/m², respectively.¹

Following administration of the fixed liposomal combination by IV infusion over 90 minutes on days 1, 3, and 5 in adults, accumulation ratio of daunorubicin and cytarabine are 1.3 and 1.4, respectively.¹

Special Populations

Patients with serum bilirubin concentrations ≤3 mg/dL: Pharmacokinetics of either drug not substantially altered.¹ (See Hepatic Impairment under Cautions.)

Patients with mild or moderate renal impairment (Cl_cr 30–89 mL/minute): Pharmacokinetics of either drug not substantially altered.¹ (See Renal Impairment under Cautions.)

Age, gender, race, body weight, body mass index, and leukocyte count do not substantially affect systemic exposure of either drug.¹

Distribution

Extent

Not known whether daunorubicin or cytarabine is distributed into milk.¹

Elimination

Metabolism

Daunorubicin: Catalyzed by aldo-keto reductase and carbonyl reductase enzymes to active metabolite daunorubicinol.¹

Cytarabine: Metabolized by cytidine deaminase to inactive metabolite 1-β-d-arabinofuranosyluracil (ara-U, uracil arabinoside).¹

Elimination Route

Daunorubicin: Approximately 9% of a dose eliminated in urine as unchanged drug and daunorubicinol.¹

Cytarabine: Approximately 71% of a dose eliminated in urine as unchanged drug and 1-β-d-arabinofuranosyluracil.¹

Half-life

Daunorubicin: 31.5 hours (>99% of daunorubicin in plasma remaining encapsulated in liposomes).¹

Cytarabine: 40.4 hours (>99% of cytarabine in plasma remaining encapsulated in liposomes).¹

Stability

Storage

Parenteral

Powder for Injection

2–8ºC in original package to protect from light.¹

May store reconstituted drug at 2–8ºC for ≤4 hours.¹

May store diluted infusion solution at 2–8ºC for ≤4 hours.¹

Compatibility

Parenteral

Solution Compatibility

Actions

• Fixed combination of daunorubicin (an anthracycline) and cytarabine (an antimetabolite) coencapsulated in liposomes.¹

• Daunorubicin exhibits antimitotic and cytotoxic activity.^{1 3} Intercalates into DNA and inhibits topoisomerase II (by stabilizing the complex between this enzyme and DNA), resulting in single-strand and double-strand breaks in DNA.^{1 3} 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; cytotoxic effect occurs only during S phase of cell division.^{1 4} Appears to inhibit DNA polymerase.^{1 4}

• Liposomal delivery system employed to optimize therapeutic efficacy of the combination regimen; liposomes control release of the drug combination such that fixed synergistic drug ratios established in vitro are maintained in vivo following drug administration.^{1 7 8 10 11 12 14}

• Formulated in a fixed 1:5 daunorubicin to cytarabine molar ratio, which has been shown to provide the greatest synergistic effect with the least antagonism.^{1 7 8 10 11 13 14}

• In addition to maintaining favorable drug ratios in plasma, preclinical studies also indicate that liposomes penetrate and sustain high concentrations of the drugs at the tumor site (specifically the bone marrow).^{1 7 8 10 11 12 14}

Advice to Patients

• Risk of hemorrhage.¹ Importance of monitoring 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 ≥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 ≥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.)

Preparations

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.

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