VYXEOS

Anthracyclines
Pyrimidine Analogs

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Moderate
Administer routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
Irritant

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Daunorubicin liposomal; cytarabine liposomal is available as a single-dose, preservative-free, lyophilized vial containing 44 mg of daunorubicin and 100 mg of cytarabine encapsulated in liposomes; it requires dilution prior to IV infusion administration.
If a dose is missed, administer daunorubicin liposomal; cytarabine liposomal as soon as possible and adjust the dosing schedule to maintain the treatment interval.
Reconstitution:
After calculating the number of vials needed for the dose, remove vials from the refrigerator and allow them to warm to room temperature for 30 minutes.
Using a sterile syringe, add 19 mL of Sterile Water for Injection to each vial for a final vial concentration of 2.2 mg of daunorubicin and 5 mg of cytarabine; immediately start a 5-minute timer.
Swirl the contents of the vial for 5 minutes and gently invert the vial every 30 seconds; do not heat, vortex, or shake vigorously.
Allow the reconstituted solution to rest for 15 minutes; the solution should be an opaque, purple, homogeneous dispersion that is free from visible particulates.
Storage of reconstituted vials: Dilute immediately or store in refrigerator (2 to 8 degrees C; 36 to 46 degrees F) for up to 4 hours.
Dilution:
Prior to dilution, gently invert each reconstituted vial 5 times.
Aseptically withdraw the appropriate amount (mL) from the reconstituted vials for the calculated dose using the formula: volume required (mL) = dose of daunorubicin (mg/m2) multiplied by the patient's BSA (m2) divided by 2.2 (mg/mL); discard any unused portion left in the vial.
Add the required volume to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
Gently invert the bag to mix the solution; the admixture solution should be a deep purple, translucent, homogeneous dispersion that is free from visible particulates.
Storage of admixture: Administer immediately or store in refrigerator (2 to 8 degrees C; 36 to 46 degrees F) for up to 4 hours. NOTE: If the reconstituted vial was stored for 4 hours; the diluted admixture must be used immediately and cannot be stored for an additional 4 hours.
Intravenous (IV) Infusion:
Confirm patency of the IV access prior to administration.
Administer the daunorubicin liposomal; cytarabine liposomal admixture as an IV infusion over 90 minutes via an infusion pump through a central venous catheter or a peripherally inserted central catheter.
If using an in-line membrane filter, ensure the minimum pore diameter of the filter is 15 micrometers or greater.
During the infusion, monitor patients for signs of drug extravasation.
Do not mix with or administer as an infusion with other drugs.
Following the infusion, flush the IV line with 0.9% Sodium Chloride Injection or 5% Dextrose Injection.

neutropenia / Delayed / 0-100.0
thrombocytopenia / Delayed / 0-100.0
anemia / Delayed / 0-100.0
erythema nodosum / Delayed / 0-54.0
enterocolitis / Delayed / 0-45.0
odynophagia / Delayed / 0-44.0
peptic ulcer / Delayed / 0-44.0
esophageal ulceration / Delayed / 0-44.0
acute respiratory distress syndrome (ARDS) / Early / 0-32.0
bronchospasm / Rapid / 0-32.0
cardiac arrest / Early / 0-30.0
atrial tachycardia / Early / 0-30.0
AV block / Early / 0-30.0
atrial fibrillation / Early / 0-30.0
bradycardia / Rapid / 0-30.0
atrial flutter / Early / 0-30.0
apnea / Delayed / 0-25.0
infection / Delayed / 0-23.0
pericarditis / Delayed / 0-20.0
cardiotoxicity / Delayed / 20.0-20.0
cardiomyopathy / Delayed / 0-20.0
pericardial effusion / Delayed / 0-20.0
heart failure / Delayed / 0-20.0
myocardial infarction / Delayed / 0-20.0
pleural effusion / Delayed / 0-16.0
hyponatremia / Delayed / 6.0-14.0
hypoxia / Early / 12.0-12.0
nephrotoxicity / Delayed / 0-11.0
renal failure (unspecified) / Delayed / 0-11.0
azotemia / Delayed / 0-11.0
oliguria / Early / 0-11.0
wheezing / Rapid / 0-11.0
uveitis / Delayed / 0-11.0
visual impairment / Early / 11.0-11.0
hypertension / Early / 10.0-10.0
bleeding / Early / 10.0-10.0
hearing loss / Delayed / 0-10.0
angina / Early / 0-9.0
hypokalemia / Delayed / 6.0-9.0
supraventricular tachycardia (SVT) / Early / 0-7.0
sinus tachycardia / Rapid / 0-7.0
bundle-branch block / Early / 0-7.0
candidiasis / Delayed / 0-7.0
hypoalbuminemia / Delayed / 2.0-7.0
hyperbilirubinemia / Delayed / 0-6.0
hypotension / Rapid / 5.0-5.0
orthostatic hypotension / Delayed / 0-5.0
elevated hepatic enzymes / Delayed / 0-5.0
maculopapular rash / Early / 0-5.0
rash / Early / 5.0-5.0
contact dermatitis / Delayed / 0-5.0
atopic dermatitis / Delayed / 0-5.0
psoriasis / Delayed / 0-5.0
fatigue / Early / 5.0-5.0
asthenia / Delayed / 5.0-5.0
chest pain (unspecified) / Early / 3.0-3.0
diarrhea / Early / 3.0-3.0
colitis / Delayed / 3.0-3.0
arthralgia / Delayed / 0-3.0
myalgia / Early / 0-3.0
bone pain / Delayed / 0-3.0
back pain / Delayed / 0-3.0
musculoskeletal pain / Early / 3.0-3.0
sinusitis / Delayed / 0-3.0
pharyngitis / Delayed / 0-3.0
rhinorrhea / Early / 0-3.0
nasal congestion / Early / 0-3.0
rhinitis / Early / 0-3.0
delirium / Early / 3.0-3.0
confusion / Early / 0-3.0
impaired cognition / Early / 0-3.0
abdominal pain / Early / 2.0-2.0
peripheral edema / Delayed / 0-2.0
edema / Delayed / 2.0-2.0
fluid retention / Delayed / 0-2.0
nausea / Early / 1.0-1.0
esophagitis / Delayed / 0-1.0
gingivitis / Delayed / 0-1.0
stomatitis / Delayed / 0-1.0
oral ulceration / Delayed / 0-1.0
proctitis / Delayed / 0-1.0
anorexia / Delayed / 1.0-1.0
fever / Early / 1.0-1.0
nightmares / Early / 0-1.0
insomnia / Early / 0-1.0
abnormal dreams / Early / 0-1.0
dizziness / Early / 1.0-1.0
headache / Early / 1.0-1.0
intracranial bleeding / Delayed / 2.0
retinal hemorrhage / Delayed / Incidence not known
coagulopathy / Delayed / Incidence not known
hematemesis / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
penile edema / Early / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

constipation / Delayed / 40.0-40.0
hemorrhoids / Delayed / 11.0-11.0
dyspnea / Early / 11.0-11.0
blurred vision / Early / 0-11.0
photophobia / Early / 0-11.0
photopsia / Delayed / 0-11.0
pneumonitis / Delayed / 0-10.0
hallucinations / Early / 0-10.0
conjunctivitis / Delayed / 0-10.0
hyperemia / Delayed / 0-10.0
copper toxicity / Delayed / Incidence not known
hemoptysis / Delayed / Incidence not known
melena / Delayed / Incidence not known
hematoma / Early / Incidence not known
hematuria / Delayed / Incidence not known
subdural hematoma / Early / Incidence not known
vaginal bleeding / Delayed / Incidence not known
infusion-related reactions / Rapid / Incidence not known

epistaxis / Delayed / 36.0-36.0
cough / Delayed / 33.0-33.0
vomiting / Early / 24.0-24.0
chills / Rapid / 23.0-23.0
injection site reaction / Rapid / 16.0-16.0
pruritus / Rapid / 15.0-15.0
anxiety / Delayed / 14.0-14.0
petechiae / Delayed / 11.0-11.0
photosensitivity / Delayed / 0-11.0
dyspepsia / Early / 0-10.0
ocular irritation / Rapid / 0-10.0
xerophthalmia / Early / 0-10.0
ocular pain / Early / 0-10.0
purpura / Delayed / Incidence not known
ecchymosis / Delayed / Incidence not known

Daunorubicin liposomal; cytarabine liposomal has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection; therefore, do not interchange or substitute the combination daunorubicin/cytarabine liposomal formulation (Vyxeos) with other daunorubicin- or cytarabine-containing products. Ensure correct formulation selection and dose prior to preparation and administration to avoid dosing errors.

VYXEOS

Rx

Liposomal combination of daunorubicin (an anthracycline topoisomerase inhibitor) and cytarabine (a nucleoside metabolic inhibitor)
Used for newly diagnosed therapy-related AML or AML with myelodysplasia-related changes in adults and pediatric patients aged 1 year and older
Severe bleeding events and hypersensitivity reactions have been reported

First induction, 44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV over 90 minutes on days 1, 3, and 5; patients who do not achieve a response may receive a second induction. Second induction (given 2 to 5 weeks after the first induction cycle), 44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV on days 1 and 3. Consolidation therapy (given 5 to 8 weeks after the start of the last induction), 29 mg/m2 daunorubicin liposomal and 65 mg/m2 cytarabine liposomal IV on days 1 and 3. Patients without disease progression or unacceptable toxicity should receive a second cycle of consolidation therapy given 5 to 8 weeks after the start of the previous consolidation. Calculate a patient's prior cumulative anthracycline exposure prior to each cycle of therapy. Administer antiemetic agents prior to each dose. Interrupt the infusion in patients who develop a hypersensitivity reaction; premedication with an antihistamine and/or corticosteroid may be necessary with subsequent doses.[62214] At a median follow-up of 20.7 months, the median overall survival time was significantly improved following treatment with a liposomal formulation of daunorubicin and cytarabine compared with standard daunorubicin and cytarabine therapy (9.56 months vs. 5.95 months; hazard ratio = 0.69; 95% CI, 0.52 to 0.9; p = 0.003) in patients aged 60 to 75 years (median age, 68 years) with newly diagnosed, high-risk, secondary acute myelogenous leukemia in a multicenter, randomized, phase 3 trial (n = 309). Significantly higher complete remission (CR) (37.3% vs. 25.6%; p = 0.016) and overall remission (CR plus CR with incomplete neutrophil or platelet recovery) (47.7% vs. 33.3%; p = 0.016) rates were achieved with liposomal daunorubicin and cytarabine therapy.[63536]

First induction, 44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV over 90 minutes on days 1, 3, and 5; patients who do not achieve a response may receive a second induction. Second induction (given 2 to 5 weeks after the first induction cycle), 44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV on days 1 and 3. Consolidation therapy (given 5 to 8 weeks after the start of the last induction), 29 mg/m2 daunorubicin liposomal and 65 mg/m2 cytarabine liposomal IV on days 1 and 3. Patients without disease progression or unacceptable toxicity should receive a second cycle of consolidation therapy given 5 to 8 weeks after the start of the previous consolidation. Calculate a patient's prior cumulative anthracycline exposure prior to each cycle of therapy. Administer antiemetic agents prior to each dose. Interrupt the infusion in patients who develop a hypersensitivity reaction; premedication with an antihistamine and/or corticosteroid may be necessary with subsequent doses. Evidence for the safety and effectiveness of daunorubicin liposomal; cytarabine liposomal in pediatric patients aged 1 and older is based on a study in adult patients and data from 2 single-arm trials that included patients 1 year to less than 2 years old (n = 7), 2 years to less than 12 years old (n = 33), and 12 to less than 17 years old (n = 13).

No dosage adjustment is necessary in patients with a bilirubin level of 3 mg/dL or less. Daunorubicin liposomal; cytarabine liposomal has not been evaluated in patients with bilirubin levels greater than 3 mg/dL.

No dosage adjustment is necessary in patients with mild (creatinine clearance (CrCl), 60 to 89 mL/min), moderate (CrCl, 30 to 59 mL/min), or severe (CrCl, 15 to 29 mL/min) renal impairment. Daunorubicin liposomal; cytarabine liposomal has not been evaluated in patients with end-stage renal disease on hemodialysis.

Amphotericin B lipid complex (ABLC): (Minor) Amphotericin B can reduce cell resistance to daunorubicin, thus enhancing its activity. Amphotericin B can alter cell membranes, which could otherwise impede daunorubicin's entry into the cell. How this may affect liposomal delivery of daunorubicin is not known.
Amphotericin B liposomal (LAmB): (Minor) Amphotericin B can reduce cell resistance to daunorubicin, thus enhancing its activity. Amphotericin B can alter cell membranes, which could otherwise impede daunorubicin's entry into the cell. How this may affect liposomal delivery of daunorubicin is not known.
Amphotericin B: (Minor) Amphotericin B can reduce cell resistance to daunorubicin, thus enhancing its activity. Amphotericin B can alter cell membranes, which could otherwise impede daunorubicin's entry into the cell. How this may affect liposomal delivery of daunorubicin is not known.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cyclophosphamide: (Moderate) Monitor for signs and symptoms of cardiac dysfunction if coadministration of cyclophosphamide with anthracyclines is necessary as there is an additive or potentially synergistic increase in the risk of cardiomyopathy.
Cyclosporine: (Major) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other immunosuppressants may result in additive effects. In addition, high doses of cyclosporine (starting at 16 mg/kg/day IV) may increase exposure to anthracyclines (e.g., daunorubicin) in cancer patients. Cyclosporine is a substrate and inhibitor of P-glycoprotein, an energy-dependent drug efflux pump encoded for by the multidrug resistance gene-1 (MDR1). Overexpression of this protein has been described as a mechanism of resistance to naturally-occurring (non-synthetic) chemotherapy agents. Cyclosporine can block MDR1-mediated resistance when given at much higher doses than those used in transplantation and may also enhance the efficacy of daunorubicin by inhibiting this protein. Valspodar is a cyclosporine analog with less renal and immunosuppressive effects than cyclosporine while retaining effects on MDR. The addition of cyclosporine or valspodar to daunorubicin therapy may result in increases in AUC for both daunorubicin and daunorubincinol possibly due to a decrease in clearance of parent drug, a decrease in metabolism of daunorubincinol, or an increase in intracellular daunorubicin concentrations.
Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. Digoxin can reduce the uptake of doxorubicin into cardiac tissue and thus temper the cardiomyopathy caused by doxorubicin. Digoxin can be used to treat congestive heart failure due to doxorubicin cardiomyopathy and may offer improvement to some patients, although angiotensin-converting enzyme inhibitors may be of greater benefit. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy. It is not known if digoxin has similar effects on doxorubicin liposomal.
Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and daunorubicin liposomal as coadministration may increase serum concentrations of daunorubicin and increase the risk of adverse effects. Daunorubicin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); glecaprevir is an inhibitor of P-gp and BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and daunorubicin liposomal as coadministration may increase serum concentrations of daunorubicin and increase the risk of adverse effects. Daunorubicin is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of P-gp and BCRP.
Lumacaftor; Ivacaftor: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of daunorubicin liposomal and lumacaftor; ivacaftor may alter daunorubicin liposomal exposure; caution and close monitoring are advised if these drugs are used together. Daunorubicin is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
Margetuximab: (Major) Avoid administration of anthracyclines during margetuximab therapy and for up to 4 months after the last dose of margetuximab due to the risk of increased cardiac dysfunction. If concomitant use is unavoidable, closely monitor cardiac function. This interaction has not been studied with margetuximab; however, clinical data from other HER2-directed antibodies warrants consideration.
Pertuzumab; Trastuzumab; Hyaluronidase: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Trastuzumab: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Trastuzumab; Hyaluronidase: (Major) Avoid coadministration of anthracyclines and trastuzumab products due to the risk of increased cardiac dysfunction; if possible, continue to avoid for up to 7 months after the last dose of trastuzumab. If concomitant use is unavoidable, carefully monitor cardiac function. Anthracycline treatment after therapy with trastuzumab product may increase the risk of cardiac dysfunction due to the long washout period of trastuzumab.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

VYXEOS Intravenous Inj Lipos: 44-100mg

44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV.

44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV.

44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV.

44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV.

Daunorubicin is an anthracycline topoisomerase inhibitor and cytarabine is a nucleoside metabolic inhibitor. The 1:5 molar ratio of daunorubicin to cytarabine in the combination daunorubicin liposomal; cytarabine liposomal product has demonstrated synergistic effects on promoting the death of leukemia cells in vitro and in mice. Liposomes degrade following cellular internalization and release daunorubicin and cytarabine. In studies in mice, liposomes penetrated leukemia cells to a greater extent than normal cells in the bone marrow. Daunorubicin binds with DNA and inhibits topoisomerase II and DNA polymerase activity resulting in altered regulation of gene expression and the formation of DNA-damaging free radicals. Cytarabine is a cell cycle phase-specific chemotherapy agent that affects cells in the S-phase of cell division; it inhibits DNA polymerase.

Daunorubicin liposomal; cytarabine liposomal is administered intravenously. For daunorubicin liposomal and cytarabine liposomal, respectively, the mean volumes of distribution (Vd) were 6.6 L (coefficient of variation (CV), 36.8%) and 7.1 L (CV, 49.2%), the terminal half-lives were 31.5 hours (CV, 28.5%) and 40.4 hours (CV, 24.2%), and the total body clearances were 0.16 L/hour (CV, 53.3%) and 0.13 L/hour (CV, 60.2%) in adult patients who received 44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV over 90 minutes on days 1, 3, and 5. Prior to being released from the liposome component, daunorubicin is catalyzed by aldoketo reductase and carbonyl reductase enzymes to the active metabolite daunorubicinol and cytarabine is metabolized by cytidine deaminase to the inactive metabolite 1-ß-D-arabinofuranosyluracil (AraU). After IV administration of daunorubicin liposomal; cytarabine liposomal, urinary excretion of daunorubicin and daunorubicinol accounts for 9% of the daunorubicin dose, and urinary excretion of cytarabine and AraU accounts for 71% of the cytarabine dose.

For daunorubicin liposomal and cytarabine liposomal, respectively, the mean Cmax values were 26 mcg/mL (coefficient of variation (CV), 32.7%) and 62.2 mcg/mL (CV, 33.7%) and the mean AUC values were 637 mcg x hour/mL (CV, 38.4%) and 1,900 mcg x hour/mL (CV, 44.3%) in adult patients who received 44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV over 90 minutes on days 1, 3, and 5. The accumulation ratio was 1.3 for daunorubicin and 1.4 for cytarabine.

Daunorubicin liposomal; cytarabine liposomal may cause fetal harm when administered during pregnancy, based on its mechanism of action and animal studies. Females of reproductive potential should avoid becoming pregnant while taking daunorubicin liposomal; cytarabine liposomal. Discuss the potential hazard to the fetus if this drug is used during pregnancy or if a patient becomes pregnant while taking it. There have been 4 case reports of major limb malformations in infants born to mothers who received cytarabine, alone or in combination with other agents, during the first trimester of pregnancy. Embryo-fetal toxicities have been observed in animal studies following daunorubicin and cytarabine administration during organogenesis starting at drug doses resulting in exposures of approximately 0.02-times the exposure in humans (at the recommended dose).

It is not known if daunorubicin, cytarabine, or their metabolites are secreted in human milk or if they have effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from daunorubicin liposomal; cytarabine liposomal, women should discontinue breast-feeding during therapy and for 2 weeks after the last dose.