Introduction

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

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 (designated an orphan drug by FDA for this use).

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

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).

DAUNOrubicin and Cytarabine Dosage and Administration

General

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

• Monitor cardiac, hepatic, and renal function prior to initiation of induction therapy and prior to each cycle of consolidation therapy. 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.

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

• Premedicate with an antiemetic agent.

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

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. Daunorubicin component may cause severe tissue necrosis if extravasation occurs; do not administer IM or sub-Q.

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

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

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

Reconstitution

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

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

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. Using a timer, swirl each vial for 5 minutes (gently invert every 30 seconds). Do not heat, vortex, or vigorously shake. Allow reconstituted drug to rest for 15 minutes; mix again with 5 gentle inversions prior to further dilution.

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

Dilution

Further dilute reconstituted drug prior to IV infusion.

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

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

Discard any unused portions of reconstituted and diluted solution.

Rate of Administration

Administer by IV infusion over 90 minutes.

Dosage

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

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

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

Adults

AML

IV

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

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.

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.

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

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%. Consider premedication with an antihistamine and/or corticosteroid prior to subsequent infusions.

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

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

Prescribing Limits

Adults

IV

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

Special Populations

Hepatic Impairment

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

Renal Impairment

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

Geriatric Patients

No specific dosage recommendations.

Contraindications

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

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). (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).

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

Sensitivity Reactions

Hypersensitivity Reactions

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

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

Other Warnings and Precautions

Hemorrhage

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

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

Cardiac Effects

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

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. 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).

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

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. Repeat echocardiogram or MUGA prior to initiation of consolidation therapy and as clinically indicated. Evaluate risk versus benefit of initiating or continuing therapy in patients with impaired cardiac function.

Copper Overload

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

In patients with Wilson disease, use only if potential benefit outweighs risk. 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. Consult with a clinician who has expertise in managing acute copper toxicity. If manifestations of acute copper toxicity occur in any patient, discontinue therapy.

Local Effects

Extravasation of daunorubicin, a component of daunorubicin/cytarabine liposomal, can produce severe local tissue necrosis. (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.

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

Confirm pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. 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. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Impairment of Fertility

May impair male fertility.

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

Safety and efficacy not established.

Geriatric Use

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

Hepatic Impairment

Pharmacokinetics of daunorubicin and cytarabine not altered in patients with serum bilirubin concentrations ≤3 mg/dL.

Data lacking in patients with serum bilirubin concentrations >3 mg/dL.

Renal Impairment

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

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

Common Adverse Effects

Induction therapy for newly diagnosed t-AML and AML-MRC: Hemorrhage, febrile neutropenia, rash, edema, nausea, diarrhea/colitis, mucositis, constipation, musculoskeletal pain, abdominal pain, cough, headache, dyspnea, fatigue, arrhythmia, loss of appetite, pneumonia (excluding fungal pneumonia), sleep disorders, bacteremia (excluding sepsis), vomiting, chills, hypotension, non-conduction cardiotoxicity, prolonged thrombocytopenia, prolonged neutropenia, hyponatremia.

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).

General

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

• Monitor cardiac, hepatic, and renal function prior to initiation of induction therapy and prior to each cycle of consolidation therapy. 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.

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

• Premedicate with an antiemetic agent.

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

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. Daunorubicin component may cause severe tissue necrosis if extravasation occurs; do not administer IM or sub-Q.

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

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

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

Reconstitution

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

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

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. Using a timer, swirl each vial for 5 minutes (gently invert every 30 seconds). Do not heat, vortex, or vigorously shake. Allow reconstituted drug to rest for 15 minutes; mix again with 5 gentle inversions prior to further dilution.

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

Dilution

Further dilute reconstituted drug prior to IV infusion.

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

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

Discard any unused portions of reconstituted and diluted solution.

Rate of Administration

Administer by IV infusion over 90 minutes.

Dosage

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

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

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

Adults

AML

IV

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

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.

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.

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

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%. Consider premedication with an antihistamine and/or corticosteroid prior to subsequent infusions.

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

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

Prescribing Limits

Adults

IV

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

Special Populations

Hepatic Impairment

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

Renal Impairment

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

Geriatric Patients

No specific dosage recommendations.

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.

Cardiotoxic Drugs

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

Hepatotoxic Drugs

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