cytarabine/daunorubicin liposomal (Rx)

>10%

Hemorrhage, all grades (70%)

Febrile neutropenia, all grades (68%)

Febrile neutropenia, ≥grade 3 (66%)

Rash, all grades (54%)

Edema, all grades (51%)

Nausea, all grades (47%)

Diarrhea/colitis, all grades (45%)

Abdominal pain, all grades (33%)

Cough, all grades (33%)

Headache, all grades (33%)

Dyspnea, all grades (32%)

Fatigue, all grades (32%)

Arrhythmia, all grades (30%)

Decreased appetite, all grades (29%)

Prolonged thrombocytopenia, induction (28%)

Pneumonia (excluding fungal), all grades (26%)

Sleep disorders, all grades (25%)

Prolonged thrombocytopenia, consolidation cycle (25%)

Bacteremia (excluding sepsis), all grades (24%)

Vomiting, all grades (24%)

Chills, all grades (23%)

Bacteremia (excluding sepsis), grade ≥3 (23%)

Hypotension, all grades (20%)

Pneumonia (excluding fungal), grade ≥3 (20%)

Non conduction cardiotoxicity, all grades (20%)

Mucositis, all grades (44%)

Musculoskeletal pain, all grades (38%)

Dizziness, all grades (18%)

Fungal infection, all grades (18%)

Hypertension, all grades (18%)

Hypoxia, all grades (18%)

Upper respiratory tract infections (excluding fungal), all grades (18%)

Prolonged neutropenia, induction cycle (17%)

Chest pain, all grades (17%)

Pyrexia, all grades (17%)

Catheter/device/injection site reaction, all grades (16%)

Delirium, all grades (16%)

Pleural effusion, all grades (16%)

Pruritus, all grades (15%)

Anxiety, all grades (14%)

Hypoxia, grade ≥3 (13%)

Hemorrhoids, all grades (11%)

Petechiae, all grades (11%)

Renal insufficiency, all grades (11%)

Transfusion reactions, all grades (11%)

Visual impairment, all grades (11%)

Dyspnea (11%)

1-10%

Deafness (<10%)

Deafness unilateral (<10%)

Eye conjunctivitis (<10%)

Dry eye (<10%)

Eye edema (<10%)

Eye swelling (<10%)

Eye irritation (<10%)

Eye pain (<10%)

Periorbital edema (<10%)

Scleral hyperemia (<10%)

Dyspepsia (<10%)

Hallucinations (<10%)

Pneumonitis (<10%)

Prolonged neutropenia, consolidation (10%)

Hemorrhage, grade ≥3 (10%)

Hypertension, grade ≥3 (10%)

Non conduction cardiotoxicity, grade ≥3 (9%)

Arrhythmia, grade ≥3 (7%)

Fungal infection, grade ≥3 (7%)

Rash, grade ≥3 (5%)

Renal insufficiency, grade ≥3 (5%)

Upper respiratory tract infections (excluding fungal), grade ≥3 (3%)

Chest pain, grade ≥3 (3%)

Delirium, grade ≥3 (3%)

Edema, grade ≥3 (3%)

Diarrhea/colitis, grade ≥3 (3%)

Muscloskeletal pain, grade ≥3 (3%)

Abdominal pain, grade ≥3 (2%)

Pleural effusion, grade ≥3 (2%)

Transfusion reactions, grade ≥3 (2%)

Headache, grade ≥3 (1%)

Pyrexia, grade ≥3 (1%)

Nausea, grade ≥3 (1%)

Contraindications

Serious hypersensitivity to daunorubicin, cytarabine, or any component of the formulation

Cautions

Do not interchange with other daunorubicin- and/or cytarabine- containing products

Serious or fatal hemorrhage events may occur; monitor blood cell counts until recovery and administer platelet transfusion if needed

Reports of fatal hypersensitivity reactions (eg, anaphylactic reactions); monitor for hypersensitivity reactions

Severe local tissue necrosis at extravasation site has been associated with daunorubicin; confirm patency of intravenous access before administration; administer IV only; do not administer IM or SC

May cause embryofetal harm

Copper overload

• Reconstituted solution contains 5 mg/mL copper gluconate (14% elemental copper)
• Maximum theoretical total exposure of copper for dosing regimen is 106 mg/m²
• No clinical experience in patients with Wilson disease or other copper-related metabolic disorders; use only if benefits outweigh risks
• Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in treated patients with Wilson’s disease
• Monitor total serum copper, serum nonceruloplasmin bound copper, 24-hr urine copper levels, and serial neuropsychological examinations in these patients
• Discontinue if signs or symptoms of acute copper toxicity occurs

Cardiotoxicity

• Pre-existing cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs may increase the risk of daunorubicin induced cardiac toxicity
• Monitor as clinically required; discontinue in patients with impaired cardiac function unless benefit of treatment outweighs the risk
• Not recommended in patients with abnormal left ventricular ejection fraction
• Calculate lifetime cumulative anthracycline exposure before each cycle; total cumulative doses of nonliposomal daunorubicin > 550 mg/m² have been associated with an increased incidence of drug-induced congestive heart failure; tolerable limit appears lower (400 mg/m²) in patients who received radiation therapy to the mediastinum
• Not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit

• Cumulative exposure of daunorubicin

  • First induction cycle: Daunorubicin per dose 44 mg/m² for 3 doses; daunorubicin per cycle 132 m²
  • Second induction cycle: Daunorubicin per dose 44 mg/m² for 2 doses; daunorubicin per cycle 88 mg/m²
  • Each consolidation cycle: Daunorubicin per dose 29 mg/m² for 2 doses; daunorubicin per cycle 58 mg/m^2​

Drug interaction overview

• Cardiotoxic agents

  • Assess cardiac function more frequently
  • Coadministration with cardiotoxic agents may increase the risk of cardiotoxicity

• Hepatoxicity

  • Closely monitor hepatic function
  • Coadministration with hepatotoxic agents may impair liver function and increase toxicity

Pregnancy

Based on data of cytarabine in pregnant females and study results of daunorubicin and cytarabine in animals, embryofetal harm may occur when administered to pregnant females

There are no adequate and well-controlled studies of Vyxeos, daunorubicin, or cytarabine in pregnant females

Advise to avoid becoming pregnant during treatment

If used during pregnancy, or if patient becomes pregnant while taking this drug, apprise patient of the potential harm to a fetus

Verify pregnancy status of females of reproductive potential before initiating treatment

Animal data

• Daunorubicin and cytarabine are reproductive and developmental toxicants in multiple species (mice, rats, and/or dogs), starting dose was ~0.02x the exposure in patients at the recommended human dose on a mg/m2 basis

Contraception

• Females and males with female partners of reproductive potential: Use effective contraception during treatment and for at least 6 months after last dose

Infertility

• Based on findings of daunorubicin and cytarabine in animals, male fertility may be compromised by treatment

Lactation

There are no data on drug presence or its metabolites in human milk, effects on breastfed infants, or effects on milk production

Advise not to breastfeed during treatment and for at least 2 weeks after the last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Cytarabine and daunorubicin combination encapsulated within a nano scale liposome at a 5:1 molar ratio; selectively ingested by leukemic cells, enhancing efficacy and increasing therapeutic index

Cytarabine: Metabolite cytarabine-5'-triphosphate inhibits DNA polymerase during S phase

Daunorubicin: Anthracycline; intercalates between DNA base pairs, impairs topoisomerase II function, inhibits DNA polymerase activity, affects gene expression regulation, and produces DNA-damaging free radicals

Absorption

Peak plasma concentration

• Daunorubicin: 26 mcg/mL
• Cytarabine: 62.2 mcg/mL

AUC

• Daunorubicin: 637 mcg⋅h/mL
• Cytarabine: 1900 mcg⋅h/mL

Accumulation ratio

• Daunorubicin: 1.3
• Cytarabine: 1.4

Distribution

Vd

• Daunorubicin: 6.6 L
• Cytarabine: 7.1 L

Metabolism

Daunorubicin: Catalyzed by aldoketo reductase and carbonyl reductase enzymes to active metabolite daunorubicinol

Cytarabine: Metabolized by cytidine deaminase to inactive metabolite 1-β-D-arabinofuranosyluracil (AraU)

Elimination

Half-life

• Daunorubicin: 31.5 hr
• Cytarabine: 40.4 hr

Clearance

• Daunorubicin: 0.16 L/hr
• Cytarabine: 0.13 L/hr

Excretion

• Daunorubicin and daunorubicinol (metabolite): Urine (9%)
• Cytarabine and AraU (metabolite): Urine (71%)

IV Incompatibilities

Do not infuse with other drugs

IV Compatibilities

0.9% NaCl, D5W

IV Preparation

Reconstitution

• Remove appropriate number of vials from refrigerator; equilibrate vials to room temperature for 30 minutes
• Reconstitute each vial with 19 mL of sterile water and immediately swirl vial carefully for 5 minutes; gently inverting vial every 30 seconds, resulting concentration: daunorubicin 2.2 mg/cytarabine 5 mg per mL
• Do not heat, vortex, or shake vigorously
• After reconstitution, rest for 15 minutes; reconstituted product should be an opaque, purple, homogeneous dispersion with no visible particulates
• Gently invert each vial 5 times before further dilution
• If reconstituted product is not used immediately, refrigerate at 36-46°F (2-8ºC) for up to 4 hr

Further dilution

• Use the following formula to calculate volume of reconstituted product required: [volume required (mL) = dose of daunorubicin (mg/m) x patient’s BSA (m ) ÷ 2.2 (mg/mL)]
• Aseptically withdraw calculated volume of reconstituted product and transfer it to 500 mL of 0.9% NaCl or D5W; discard unused drug
• If not used immediately, refrigerate at 36-46°F (2-8ºC) for up to 4 hr
• Visually inspect diluted solutions for particulate matter and discoloration prior to administration

IV Administration

For IV use only

Do not mix with or infuse with other drugs

Infuse over 90 minutes via a central venous or peripherally inserted central catheter

Do not use inline filter

Flush line after administration with 0.9% NaCl or D5W

Storage

Cytotoxic drug

Follow applicable special handling and disposal procedures

Unopened vials

• Refrigerate at 36-46ºF (2-8ºC) in an upright position; store in original carton to protect from light
• Does not contain any preservatives; discard any unused portions

Reconstituted vials or diluted solutions

• Refrigerate at 36-46ºF (2-8ºC) for up to 4 hr if not used immediately