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DAUNOrubicin and Cytarabine

Class: Antineoplastic Agents
Chemical Name: 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
Molecular Formula: C9H13N3O5C27H29NO10
CAS Number: 147-94-4
Brands: Vyxeos

Warning

Warning: Do Not Interchange With Other Daunorubicin and/or Cytarabine-containing Products1

See full prescribing information for complete boxed warning. 1

  • The fixed liposomal combination of daunorubicin and cytarabine has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors.1

Introduction

The fixed liposomal combination of daunorubicin and cytarabine is an antineoplastic agent.1

Uses for DAUNOrubicin and Cytarabine

Fixed liposomal combination of daunorubicin and cytarabine has the following uses:

Daunorubicin and cytarabine is a liposomal combination of daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitor, that is indicated for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).1

DAUNOrubicin and Cytarabine Dosage and Administration

General

The fixed liposomal combination of daunorubicin and cytarabine is available in the following dosage form(s) and strength(s):

For injection: 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes as a lyophilized cake in a single-dose vial for reconstitution.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Induction: daunorubicin and cytarabine (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) liposome via intravenous infusion over 90 minutes on days 1, 3, and 5 and on days 1 and 3 for subsequent cycles of induction, if needed.1

  • Consolidation: daunorubicin and cytarabine (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) liposome via intravenous infusion over 90 minutes on days 1 and 3.1

Cautions for DAUNOrubicin and Cytarabine

Contraindications

  • History of serious hypersensitivity to daunorubicin, cytarabine, or any components of the formulation.1

Warnings/Precautions

Do Not Interchange With Other Daunorubicin and/or Cytarabine-containing Products

Due to substantial differences in the pharmacokinetic parameters, the dose and schedule recommendations for the fixed liposomal combination of daunorubicin and cytarabine are different from those for daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors. Do not substitute other preparations of daunorubicin or cytarabine for the fixed liposomal combination of daunorubicin and cytarabine.1

Hemorrhage

Serious or fatal hemorrhage events, including fatal central nervous system (CNS) hemorrhages, associated with prolonged severe thrombocytopenia, have occurred in patients treated with the fixed liposomal combination of daunorubicin and cytarabine. In Study 1 (NCT01696084), the incidence of any grade hemorrhagic events during the entire treatment period was 74% of patients in the fixed liposomal combination of daunorubicin and cytarabine arm and 56% in the control arm (a standard combination of cytarabine and daunorubicin). The most frequently reported hemorrhagic event was epistaxis (36% in the fixed liposomal combination of daunorubicin and cytarabine arm and 18% in the control arm). Grade 3 or greater events occurred in 12% of the fixed liposomal combination of daunorubicin and cytarabine treated patients and 8% of patients treated with control. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the fixed liposomal combination of daunorubicin and cytarabine arm and in 0.7% of patients in the control arm. Monitor blood counts regularly until recovery and administer platelet transfusion support as required.1

Cardiotoxicity

The fixed liposomal combination of daunorubicin and cytarabine contains the anthracycline daunorubicin, which has a known risk of cardiotoxicity. Prior therapy with anthracyclines, pre-existing cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs may increase the risk of daunorubicin-induced cardiac toxicity. Prior to administering the fixed liposomal combination of daunorubicin and cytarabine, obtain an electrocardiogram (ECG) and assess cardiac function by multi-gated radionuclide angiography (MUGA) scan or echocardiography (ECHO). Repeat MUGA or ECHO determinations of left ventricular ejection fraction (LVEF) prior to consolidation with the fixed liposomal combination of daunorubicin and cytarabine and as clinically required. Discontinue the fixed liposomal combination of daunorubicin and cytarabine in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. Daunorubicin and cytarabine liposomal combination treatment is not recommended in patients with LVEF that is less than normal.1

Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum.1

Calculate the lifetime cumulative anthracycline exposure prior to each cycle of daunorubicin and cytarabine liposomal combination. Daunorubicin and cytarabine liposomal combination treatment is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit. The exposure to daunorubicin following each cycle of daunorubicin and cytarabine liposomal combination is shown in Table 1.1

Table 1: Cumulative Exposure of Daunorubicin per Cycle of Daunorubicin and Cytarabine Liposomal Combination

Therapy

Daunorubicin per Dose

Number of Doses per Cycle

Daunorubicin per Cycle

First Induction Cycle

44 mg/m2

3

132 mg/m2

Second Induction Cycle

44 mg/m2

2

88 mg/m2

Each Consolidation Cycle

29 mg/m2

2

58 mg/m2

Hypersensitivity Reactions

Serious or fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine. Monitor patients for hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, interrupt or slow the rate of infusion with the fixed liposomal combination of daunorubicin and cytarabine and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue the fixed liposomal combination of daunorubicin and cytarabine permanently, treat symptoms according to the standard of care, and monitor until symptoms resolve.1

Copper Overload

Reconstituted daunorubicin and cytarabine liposomal combination contains 5 mg/mL copper gluconate, of which 14% is elemental copper. There is no clinical experience with the fixed liposomal combination of daunorubicin and cytarabine in patients with Wilson’s disease or other copper-related metabolic disorders. The maximum theoretical total exposure of copper under the recommended daunorubicin and cytarabine liposomal combination dosing regimen is 106 mg/m2. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with the fixed liposomal combination of daunorubicin and cytarabine. Monitor total serum copper, serum non-ceruloplasmin bound copper, 24-hour urine copper levels and serial neuropsychological examinations in these patients. Use the fixed liposomal combination of daunorubicin and cytarabine in patients with Wilson’s disease only if the benefits outweigh the risks. Discontinue the fixed liposomal combination of daunorubicin and cytarabine in patients with signs or symptoms of acute copper toxicity.1

Tissue Necrosis

Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer the fixed liposomal combination of daunorubicin and cytarabine by the intravenous route only. Do not administer by intramuscular or subcutaneous route.1

Embryo-fetal Toxicity

Based on its mechanism of action and findings from animal studies with daunorubicin and cytarabine, the fixed liposomal combination of daunorubicin and cytarabine can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of the fixed liposomal combination of daunorubicin and cytarabine, daunorubicin, or cytarabine in pregnant women. Daunorubicin and cytarabine are reproductive and developmental toxicants in multiple species (mice, rats, and/or dogs), starting at a dose that was approximately 0.02 times the exposure in patients at the recommended human dose on an mg/m2 basis. Patients should be advised to avoid becoming pregnant while taking the fixed liposomal combination of daunorubicin and cytarabine. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of the fixed liposomal combination of daunorubicin and cytarabine.1

Specific Populations

Pregnancy

Risk Summary: Based on anecdotal data of cytarabine in pregnant women and results of studies of daunorubicin and cytarabine in animals, the fixed liposomal combination of daunorubicin and cytarabine can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of the fixed liposomal combination of daunorubicin and cytarabine, daunorubicin, or cytarabine in pregnant women. Daunorubicin and cytarabine are reproductive and developmental toxicants in multiple species (mice, rats, and/or dogs), starting at a dose that was approximately 0.02 times the exposure in patients at the recommended human dose on a mg/m2 basis. Patients should be advised to avoid becoming pregnant while taking daunorubicin and cytarabine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential harm to a fetus.1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.1

Human Data: Cytarabine can cause fetal harm if a pregnant woman is exposed to the drug. Four anecdotal cases of major limb malformations have been reported in infants after their mothers received intravenous cytarabine, alone or in combination with other agents, during the first trimester.1

Animal Data: A liposomal formulation of daunorubicin was administered to rats on gestation days 6 through 15 at 0.3, 1, or 2 mg/kg per day (about 0.04, 0.14, or 0.27 times the recommended human dose on a mg/m2 basis) and produced severe maternal toxicity and embryolethality at 2 mg/kg per day and was embryotoxic and caused fetal malformations (anophthalmia, microphthalmia, incomplete ossification) at 0.3 mg/kg per day. Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.1

Cytarabine was teratogenic in mice (cleft palate, phocomelia, deformed appendages, skeletal abnormalities) when doses ≥2 mg/kg per day were administered IP during the period of organogenesis (about 0.06 times the recommended human dose on a mg/m2 basis), and in rats (deformed appendages) when 20 mg/kg was administered as a single IP dose on day 12 of gestation (about 1.2 times the recommended human dose on a mg/m2 basis). Single IP doses of 50 mg/kg in rats (about 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.1

Cytarabine was embryotoxic in mice when administered during the period of organogenesis. Embryotoxicity was characterized by decreased fetal weight at 0.5 mg/kg per day (about 0.02 times the recommended human dose on a mg/m2 basis), and increased early and late resorptions and decreased live litter sizes at 8 mg/kg per day (about 0.24 times the recommended human dose on a mg/m2 basis).1

Lactation

There are no data on the presence of daunorubicin, cytarabine, or their metabolites in human milk, their effects on the breastfed infant, or their effects on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with the fixed liposomal combination of daunorubicin and cytarabine and for at least 2 weeks after the last dose.1

Females and Males of Reproductive Potential

The fixed liposomal combination of daunorubicin and cytarabine can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating the fixed liposomal combination of daunorubicin and cytarabine.1

Advise females of reproductive potential to use effective contraception during treatment with the fixed liposomal combination of daunorubicin and cytarabine and for at least 6 months after the last dose.1

Advise males with female partners of reproductive potential to use effective contraception during treatment with the fixed liposomal combination of daunorubicin and cytarabine and for at least 6 months after the last dose.1

Based on findings of daunorubicin and cytarabine in animals, male fertility may be compromised by treatment with the fixed liposomal combination of daunorubicin and cytarabine.1

Pediatric Use

Safety and effectiveness of the fixed liposomal combination of daunorubicin and cytarabine in pediatric patients have not been established.1

Geriatric Use

Of the 375 patients who received the fixed liposomal combination of daunorubicin and cytarabine (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) in clinical studies, 57% were 65 years and over. No overall differences in safety were observed between these patients and younger patients, with the exception of bleeding events, which occurred more frequently in patients 65 years and older compared to younger patients (77% vs. 59%).1

Renal Impairment

Dosage adjustment is not required for patients with mild (creatinine clearance [Clcr] 60 mL/min to 89 mL/min by Cockcroft Gault equation [C-G]) or moderate (Clcr 30 mL/min to 59 mL/min) renal impairment. Not studied in patients with severe renal impairment (Clcr 15 mL/min to 29 mL/min) or end-stage renal disease.1

Hepatic Impairment

Dosage adjustment is not required for patients with a bilirubin level less than or equal to 3 mg/dL. Not studied in patients with bilirubin level greater than 3 mg/dL.1

Common Adverse Effects

The most common adverse reactions (incidence ≥25%) were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Monitor cardiac function more frequently when coadministered with cardiotoxic agents.1

  • Monitor hepatic function more frequently when coadministered with hepatotoxic agents.1

Actions

Mechanism of Action

Daunorubicin and cytarabine liposome for injection is a liposomal formulation of daunorubicin and cytarabine at a fixed 1:5 molar ratio. The 1:5 molar ratio of daunorubicin:cytarabine has been shown to have synergistic effects at killing leukemia cells in vitro and in murine models. Daunorubicin has antimitotic and cytotoxic activity, which is achieved by forming complexes with DNA, inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of gene expression, and producing DNA-damaging free radicals. Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. Cytarabine acts primarily through inhibition of DNA polymerase. Based on animal data, the liposomes enter and persist in the bone marrow, where they are taken up intact by bone marrow cells. In leukemia-bearing mice, the liposomes are taken up by leukemia cells to a greater extent than by normal bone marrow cells. After cellular internalization, liposomes undergo degradation releasing cytarabine and daunorubicin within the intracellular environment.1

Advice to Patients

Hemorrhage

Inform patients of the risk of fatal bleeding. Advise patients of the need for periodic monitoring of blood counts and of the importance of keeping scheduled appointments for blood work and necessary transfusions. Advise patients to contact a healthcare provider for new onset fever or symptoms of infection or if they notice signs of bruising or bleeding.1

Cardiotoxicity

Advise patients to contact their healthcare provider if they develop symptoms of heart failure.1

Hypersensitivity Reactions

Inform patients of the risk of hypersensitivity reactions, including anaphylaxis. Describe the symptoms of hypersensitivity reactions, including anaphylaxis, and instruct the patient to seek medical attention immediately if they experience such symptoms.1

Embryo-Fetal Toxicity

The fixed liposomal combination of daunorubicin and cytarabine can cause fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of daunorubicin and cytarabine and to inform their healthcare provider of a known or suspected pregnancy before and during treatment.1

Lactation

Advise patients not to breastfeed during treatment with the fixed liposomal combination of daunorubicin and cytarabine and for at least 2 weeks after the last dose.1

Infertility

Advise males of reproductive potential that the fixed liposomal combination of daunorubicin and cytarabine may cause temporary or permanent infertility.1

Concomitant Medications

Advise patients to speak with their physicians about any other medication they are currently taking.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

DAUNOrubicin and Cytarabine Liposomal

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

100 mg cytarabine, 44 mg daunorubicin

Vyxeos

Jazz Pharmaceuticals Inc.

AHFS Drug Information. © Copyright 2017, Selected Revisions September 11, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Jazz Pharmaceuticals, Inc.. VYXEOS ((daunorubicin and cytarabine) liposome) INTRAVENOUS prescribing information. 2017 Aug.

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