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 (see Dosing Modifications)

Copper overload may occur; reconstituted cytarabine/daunorubicin liposomal contains 5 mg/mL copper gluconate (14% elemental copper); maximum theoretical total exposure of copper for dosing regimen is 106 mg/m²; monitor plasma and urine copper levels and serial neuropsychological examinations; consult in managing acute copper toxicity in Wilson disease

Severe local tissue necrosis at extravasation site has been associated with daunorubicin; administer IV only; do not administer IM or SC

May cause embryo fetal harm when administered to a pregnant woman

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; obtain an electrocardiogram (ECG) and assess cardiac function by multigated radionuclide angiography (MUGA) scan or echocardiography (ECHO) prior to initiating Vyxeos; monitor as clinically required; discontinue Vyxeos in patients with impaired cardiac function unless benefit of treatment outweighs the risk
• Not recommended in patients with abnormal left ventricular ejection fraction

• Cumulative exposure of daunorubicin

  • Cumulative dosage that exceeds 400-550 mg/m² in adults may result in severe and potentially fatal myocardial toxicity, including congestive heart failure; this may occur during therapy or several months to years after therapy
  • 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/m²

Advise to avoid becoming pregnant while taking cytarabine/daunorubicin liposomal

May cause embryofetal harm when administered to a pregnant woman; no well controlled studies of Vyxeos, daunorubicin, or cytarabine in pregnant woman

Verify the pregnancy status of females of reproductive potential prior to initiating cytarabine/daunorubicin liposomal

Based on animal data, male fertility may be compromised by cytarabine/daunorubicin liposomal treatment

In humans, cytarabine can cause fetal harm if a pregnant woman is exposed; 4 reported cases reported of major limb malformations in infants after mothers received IV cytarabine alone or in combination with other agents in the first trimester

Animal data

• Liposomal daunorubicin in rats in gestation days 6-15 at 0.3, 1, or 2 mg/kg/day (~ 0.04, 0.14, or 0.27 times the recommended human dose on a mg/m² basis) produced severe maternal toxicity and embryo lethality at 2 mg/kg/day and embryotoxicity and fetal malformations (anophthalmia, microphthalmia, incomplete ossification) at 0.3 mg/kg/day; embryotoxicity was defined as increased embryofetal death, reduced numbers of litters, and reduced litter sizes
• Cytarabine was teratogenic, when doses ≥2 mg/kg/day were administered IP during the period of organogenesis (~ 0.06 times the recommended human dose on a mg/m² basis) in mice (cleft palate, phocomelia, deformed appendages, skeletal abnormalities); single 20 mg/kg (~1.2 times the recommended human dose on a mg/m² basis) IP dose administered and in rats (deformed appendages) on day 12 of gestation; single IP doses of 50 mg/kg in rats (~3 times the recommended human dose on a mg/m² basis) on day 14 of gestation reduced prenatal and postnatal brain size and permanent impairment of learning ability
• Embryotoxicity was characterized by decreased fetal weight at 0.5 mg/kg/day (~ 0.02 times the recommended human dose on mg/m² basis), and increased early and late resorptions and decreased live litter sizes at 8 mg/kg/day (~ 0.24 times the recommended human dose on mg/m² basis)

Contraception

• Advise females and males with female partners of reproductive potential to use effective contraception during treatment and for at least 6 months after last dose

Lactation

There are no data on the presence of Vyxeos or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production

Owing to the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed during Vyxeos 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

Distribution

Vd: 6.6 L (daunorubicin); 7.1 L (cytarabine)

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: 31.5 hr (daunorubicin); 40.4 hr (cytarabine)

Clearance: 0.16 L/hr (daunorubicin); 0.13 L/hr (cytarabine)

Excretion: Urine 9% (daunorubicin); 71% (cytarabine)

IV Compatibilities

0.9% NaCl, D5W

IV Preparation

Remove the 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; each mL contains daunorubicin 2.2 mg/cytarabine 5 mg

Do not heat, vortex, or shake vigorously

After reconstitution, let rest for 15 minutes; reconstituted product should be an opaque, purple, homogeneous dispersion with no visible particulates

Gently invert each vial 5 times prior to withdrawing the reconstituted product for further dilution If the reconstituted product is not diluted into an infusion bag immediately, store in refrigerator at 36-46°F (2-8ºC) for up to 4 hr

Aseptically withdraw calculated volume of the reconstituted product and transfer it to 500 mL of 0.9% NaCl or D5W (see full prescribing information for calculation and further preparation information)

Discard unused portion

Diluted infusion solutions not used immediately should be stored in the refrigerator 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 intravenous 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

Unreconstituted vial: Store in a refrigerator at 36-46°F (2-8°C) in an upright position; vial should be stored in its original carton to protect from light

Reconstituted or diluted solutions: May store refrigerated at 36-46°F (2-8°C) for up to 4 hr if not used immediately