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)

Induction

  • First cycle: (Daunorubicin 44 mg/m2 /cytarabine 100 mg/m2) liposome IV on days 1, 3 and 5
  • Second cycle
    • Only for patients failing to achieve a response with first induction cycle
    • May be administered 2-5 weeks after the first cycle if there was no unacceptable toxicity
    • (Daunorubicin 44 mg/m2/cytarabine 100 mg/m2) liposome IV on days 1 and 3 if needed

Consolidation

Consolidation: (Daunorubicin 29 mg/m2/cytarabine 65 mg/m2) liposome IV on days 1 and 3

Initiate first consolidation cycle 5-8 weeks after start of the last induction cycle

Dosage Modifications

Cardiotoxicity

  • Discontinue treatment in patients who exhibit impaired cardiac function unless benefit of continuing treatment outweighs risk

Hypersensitivity reactions

  • For hypersensitivity reactions of any grade/severity, interrupt infusion immediately and manage symptoms
  • Mild symptoms: Once resolved, reinitiate infusion at half the prior infusion rate; 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; treat symptoms according to standard of care; monitor until symptoms resolve

Renal impairment

  • Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
  • Severe (CrCl 15-29 mL/min) or end-stage renal disease: Not studied

Hepatic impairment

  • Bilirubin ≤3 mg/dL: No dosage adjustment necessary
  • Bilirubin >3 mg/dL: Not studied

Dosing Considerations

Monitoring parameters

  • Before initiating treatment
    • Assess cardiac function (electrocardiogram [ECG], multigated radionuclide angiography [MUGA] scan or echocardiography [ECHO])
    • Obtain baseline liver and renal function
    • Verify pregnancy status of females of reproductive potential
  • Each cycle
    • Cardiac function (MUGA, ECHO) before consolidation and as clinically required
    • Liver and renal function

Consolidation

  • Do not start until ANC >0.5 Gi/L and the platelet count >50 Gi/L in the absence of unacceptable toxicity

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 indicated for newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patient aged ≥1 year

Induction

  • First cycle: (Daunorubicin 44 mg/m2 /cytarabine 100 mg/m2) liposome IV on days 1, 3 and 5
  • Second cycle
    • Only for patients failing to achieve a response with first induction cycle
    • May be administered 2-5 weeks after the first cycle if there was no unacceptable toxicity
    • (Daunorubicin 44 mg/m2/cytarabine 100 mg/m2) liposome IV on days 1 and 3 if needed

Consolidation

Consolidation: (Daunorubicin 29 mg/m2/cytarabine 65 mg/m2) liposome IV on days 1 and 3

Initiate first consolidation cycle 5-8 weeks after start of the last induction cycle

Dosage Modifications

Cardiotoxicity

  • Discontinue treatment in patients who exhibit impaired cardiac function unless benefit of continuing treatment outweighs risk

Hypersensitivity reactions

  • For hypersensitivity reactions of any grade/severity, interrupt infusion immediately and manage symptoms
  • Mild symptoms: Once resolved, reinitiate infusion at half the prior infusion rate; 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; treat symptoms according to standard of care; monitor until symptoms resolve

Renal impairment

  • Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
  • Severe (CrCl 15-29 mL/min) or end-stage renal disease: Not studied

Hepatic impairment

  • Bilirubin ≤3 mg/dL: No dosage adjustment necessary
  • Bilirubin >3 mg/dL: Not studied

Dosing Considerations

Monitoring parameters

  • Before initiating treatment
    • Assess cardiac function (ECG, MUGA, or ECHO)
    • Obtain baseline liver and renal function
    • Verify pregnancy status of females of reproductive potential
  • Each cycle

    • Cardiac function (MUGA, ECHO) before consolidation and as clinically required
    • Liver and renal function

Consolidation

Do not start until ANC >0.5 Gi/L and the platelet count >50 Gi/L in the absence of unacceptable toxicity

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Interactions

Interaction Checker

and cytarabine/daunorubicin liposomal

No Results

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    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

            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/m2​

            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
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            Pregnancy & Lactation

            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.

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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

            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%)
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            Administration

            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
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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.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.