daunorubicin/cytarabine liposomal

General

Pronunciation:
daw-noe-roo-bi-sin/sye-tare-a-been lyp-po-so-mal

Trade Name(s)

Vyxeos

Ther. Class.
antineoplastics

Pharm. Class.
anthracyclines
antimetabolites

Indications

Newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

Action

Daunorubicin– forms a complex with DNA, which subsequently inhibits DNA and RNA synthesis (cell-cycle phase-nonspecific) cytarabine– inhibits DNA synthesis by inhibiting DNA polymerase (cell-cycle S-phase–specific).

Therapeutic Effect(s):

Improved survival.

Pharmacokinetics

Daunorubicin

Absorption: IV administration results in complete bioavailability.

Distribution: Well distributed to tissues. Crosses the placenta.

Metabolism and Excretion: Extensively metabolized by the liver to an active metabolite with antineoplastic activity (daunorubicinol); 9% excreted as unchanged drug and active metabolite in urine.

Half-life: 31.5 hr.

Cytarabine

Absorption: IV administration results in complete availability.

Distribution: Well distributed to tissues. Crosses the placenta.

Metabolism and Excretion: Metabolized mostly by the liver to an inactive metabolite; 71% excreted as unchanged drug and inactive metabolite in urine.

Half-life: 40.4 hr.

TIME/ACTION PROFILE (plasma levels)

ROUTE	ONSET	PEAK	DURATION
IV	unknown	unknown	unknown

Contraindication/Precautions

Contraindicated in:

Hypersensitivity to daunorubucin, cytarabine, or any other component of the formulation;
Severe renal impairment or end-stage renal disease;
Bilirubin level >3 mg/dL;
OB: May cause fetal harm; avoid pregnancy;
Lactation: Avoid breast feeding.

Use Cautiously in:

Previous anthracycline therapy, underlying cardiovascular disease, history of radiation to mediastinum, or concomitant use of cardiotoxic drugs (↑ risk of cardiotoxicity);
Wilson's disease (↑ risk of copper toxicity; contains copper);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Geri: ↑ risk of bleeding in patients ≥65 yr;
Pedi: Safety and effectiveness not established.

Adverse Reactions/Side Effects

CNS: anxiety, delirium, dizziness, headache, sleep disorders, hallucinations

CV: CARDIOTOXICITY, arrhythmias, chest pain, hypertension, hypotension, peripheral edema

EENT: visual impairment, conjunctivitis, deafness, dry eye, eye edema

Derm: petechiae, pruritis, rash

F and E: hyponatremia, hypokalemia

GI: abdominal pain, constipation, ↓ appetite, diarrhea, hemorrhoids, mucositis, nausea, vomiting, dyspepsia, hyperbilirubinemia, ↑ liver enzymes

GU: renal impairment, ↓ fertility (males)

Hemat: ANEMIA, HEMORRHAGE, NEUTROPENIA, THROMBOCYTOPENIA

Local: phlebitis at IV site

Metabolic: hypoalbuminemia

MS: pain

Resp: RESPIRATORY FAILURE, cough, dyspnea, pleural effusion

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), INFECTION, chills, fatigue, fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Additive myelosuppression with other antineoplastics.
May ↓ antibody response to live-virus vaccines and ↑ the risk of adverse reactions.
↑ risk of cardiotoxicity when used with other cardiotoxic drugs.
↑ risk of hepatotoxicity with other hepatotoxic agents.

Route/Dosage

This product is NOT interchangeable with other products containing daunorubicin or cytarabine.

IV (Adults): First induction cycle– daunorubicin 44 mg/m² and cytarabine 100 mg/m² (liposomal) on Days 1, 3, and 5; if remission not achieved, proceed to second induction cycle 2–5 wk later. Second induction cycle (only for patients failing to achieve remission with first induction cycle)– daunorubicin 44 mg/m² and cytarabine 100 mg/m² (liposomal) on Days 1 and 3; First consolidation cycle– daunorubicin 29 mg/m² and cytarabine 65 mg/m² (liposomal) on Days 1 and 3 administered 5–8 wk after the start of the last induction cycle; Second consolidation cycle (only for patients who do not show disease progression or unacceptable toxicity after first consolidation cycle)– daunorubicin 29 mg/m² and cytarabine 65 mg/m² (liposomal) on Days 1 and 3 administered 5–8 wk after the start of the first consolidation cycle.

Availability

Lyophilized cake for injection (requires reconstitution and further dilution): daunorubicin 44 mg and cytarabine 100 mg/vial

Assessment

Obtain ECG and assess cardiac function by multi-gated radionuclide angiography (MUGA) scan or echocardiography (ECHO) before each consolidation cycle. Repeat MUGA or ECHO determinations of left ventricular ejection fraction (LVEF) prior to consolidation and as clinically required. Discontinue therapy in patients with impaired cardiac function unless benefit outweighs risk. Therapy is not recommended in patients with less than normal LVEF.
Monitor for signs and symptoms of hypersensitivity reactions (rash, dyspnea, swelling). If any level of symptoms occur, hold infusion and manage symptoms. If mild symptoms occur, when symptoms resolve, reinitiate infusion at half prior rate. Consider premedication with antihistamines and/or corticosteroids for subsequent doses. If moderate symptoms occur, do not reinitiate infusion. For subsequent doses, premedicate with antihistamines and/or corticosteroids prior to initiating infusion at same rate. If severe or life-threatening symptoms occur, permanently discontinue infusion. Monitor until symptoms resolve.
Monitor for signs and symptoms of hemorrhage (epistaxis, blood in emesis, urine or stool). Administer platelet transfusions as needed.
Assess IV site frequently for inflammation or infiltration. Instruct patient to notify nurse immediately if pain or irritation at injection site occurs. If extravasation occurs, infusion must be stopped and restarted in another vein to avoid damage to subcut tissue. Notify health care professional immediately. Daunorubicin is a vesicant. Standard treatments include local injections of steroids and application of ice compresses.

Lab Test Considerations: Verify pregnancy status before starting therapy.

Assess CBC with platelet count, liver and renal function before each consolidation cycle. Do not start consolidation until the absolute neutrophil count recovers to 500/mm³ and platelet count recovers to >50,000 mm/³ in the absence of unacceptable toxicity. Administer second consolidation cycle 5 to 8 wk after start of 1st consolidation cycle in patients who do not show disease progression or unacceptable toxicity.
May cause hyponatremia, hypokalemia, hypoalbuminemia, hyperbilirubinemia, and ↑ ALT.

Potential Diagnoses

Decreased cardiac output (Adverse Reaction)

Implementation

IV Administration

Vyxeos has different dose recommendations than daunorubicin, cytarabine, daunorubicin liposome, and cytarabine liposome. It is not interchangeable with any of these products. Verify drug name and dose prior to preparation and administration to avoid dosing errors.
High Alert: Fatalities have occurred with chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have second practitioner independently double-check original order, calculations, and infusion pump settings. Calculate lifetime cumulative anthracycline exposure prior to each cycle.
Solution should be prepared in a biologic cabinet. Wear gloves, gown, and mask while handling IV medication. Discard IV equipment in specially designated containers.
Pre-medicate with anti-emetics before infusion.
Allow vials to reach room temperature for 30 min before preparing. Reconstitute vial with 19 mL Sterile Water for injection; immediately after start a 5–min timer. Swirl contents for 5 min; gently invert every 30 seconds. Do not heat or shake. Reconstituted solution is opaque, purple, homogeneous dispersion, essentially free from visible particulates. After reconstitution (but before final dilution), each mL will contain 2.2 mg of daunorubicin and 5 mg of cytarabine. Gently invert each vial 5 times prior to withdrawing reconstituted solution for further dilution. If not diluted into infusion bag immediately, store in refrigerator for up to 4 hrs. Diluent: Withdraw dose and dilute further with 500 mL 0.9% NaCl or D5W.Discard unused portion. Invert bag to mix gently. Solution is deep purple, translucent, homogeneous dispersion, free from visible particulates; do not administer solutions that are discolored or contain particulate matter. Solution is stable for 4 hrs if refrigerated.
Rate: Infuse over 90 min through a central venous catheter or a peripherally inserted central catheter. Do not use an in-line filter. Flush line after administration with 0.9% NaCl or D5W.
Y-Site Incompatibility: Do not mix or infuse with other medications.

Patient/Family Teaching

Explain purpose of medication to patient. If a planned dose is missed, administer as soon as possible and adjust dosing schedule to maintain treatment interval.
Inform patients of risk of fatal bleeding. Advise of need for periodic monitoring of blood counts and importance of keeping scheduled appointments for blood work and necessary transfusions. Advise patients to contact a health care professional if new onset fever or symptoms of infection (sore throat, pain on urination, chills) or signs of bruising or bleeding occur.
Advise patient to notify health care professional immediately if signs and symptoms of HF (peripheral edema, dyspnea, rales/crackles, weight gain, jugular venous distention) or hypersensitivity reactions occur.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications during therapy.
Rep: Advise female patient to notify health care professional if pregnancy is planned or suspected or if breast feeding. Advise female and male patients with a partner with reproductive potential to use effective contraception during and for at least 6 months and to avoid breast feeding for at least 2 months following last dose. Inform male patients that fertility may be impaired.

Evaluation/Desired Outcomes