cytarabine/daunorubicin liposomal (Rx)

Brand and Other Names:Vyxeos
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

cytarabine/daunorubicin liposomal

injection, lyophilized cake for reconstitution

  • (100mg/44mg)/vial
  • (5mg/2.2mg)/mL (following reconstitution)

Acute Myeloid Leukemia

Fixed-dose combination for newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC)

See Dosing Considerations

Induction

  • First cycle: Daunorubicin 44 mg/m² / Cytarabine 100 mg/m² liposome IV on days 1, 3 and 5
  • Second cycle: Daunorubicin 44 mg/m² / Cytarabine 100 mg/m² liposome IV on days 1 and 3 if needed; only for patients who do achieve remission with first induction cycle

Consolidation

  • Consolidation: Daunorubicin 29 mg/m² / Cytarabine 65 mg/m² liposome IV on days 1 and 3
  • Initiate the first consolidation cycle 5-8 weeks after the start of the last induction cycle

Dosage Modifications

Missed dose: Administer missed dose as soon as possible; adjust dosing schedule accordingly to maintain the treatment interval

Cardiotoxicity: Discontinue treatment in patients who exhibit impaired cardiac function unless the benefit of continuing treatment outweighs the risk

Hypersensitivity reactions

  • For hypersensitivity reactions of any grade/severity, interrupt infusion immediately and manage symptoms
  • Mild symptoms: Once symptoms resolve, reinitiate infusion at half the prior rate of infusion; consider premedication with antihistamines and/or corticosteroids for subsequent doses
  • Moderate symptoms: Do not reinitiate infusion; for subsequent doses, initiate infusion at same rate and premedicate with antihistamines and/or corticosteroids
  • Severe/life-threatening symptoms: Permanently discontinue treatment; treat symptoms according to standard of care; monitor patient until symptoms resolve

Renal impairment

  • Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment
  • Severe (CrCl 15-29 mL/min) or end-stage renal disease: Safety and efficacy not established

Hepatic impairment

  • Bilirubin ≤3 mg/dL: No dosage adjustment necessary
  • Bilirubin >3 mg/dL: Safety and efficacy not established

Dosing Considerations

Prior to initiating treatment, assess cardiac function and obtain baseline liver and renal function; monitor before each cycle

Premedicate with antiemetics before each treatment

Induction: Administer second cycle 2-5 weeks after first cycle if needed and there was no unacceptable toxicity

Consolidation

  • Do not start consolidation until ANC >0.5 Gi/L and the platelet count >50 Gi/L in the absence of unacceptable toxicity
  • Administer the second consolidation cycle 5-8 weeks after the start of the first consolidation cycle in patients who do not show disease progression or unacceptable toxicity

Pediatric Dosage & Indications

Safety and efficacy not established

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Interactions

Interaction Checker

and cytarabine/daunorubicin liposomal

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >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%)

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            Warnings

            Black Box Warnings

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

            Vyxeos has different dosage recommendations than daunorubicin, cytarabine, liposomal daunorubicin, and liposomal cytarabine

            Do not substitute other preparations of daunorubicin or cytarabine for Vyxeos Verify drug name and dose prior to preparation and administration to avoid dosing errors

            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
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            Pregnancy & Lactation

            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.

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            Pharmacology

            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)

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            Administration

            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

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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