Daunorubicin liposomal; cytarabine liposomal is a combination of daunorubicin and cytarabine in a 1:5 molar ratio encapsulated in liposomes. It is indicated for the treatment of adults and pediatric patients aged 1 year and older with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. 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 the daunorubicin/cytarabine liposomal formulation with other daunorubicin- or cytarabine-containing products. Severe and life-threatening bleeding events and hypersensitivity reactions have been reported.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
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
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-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.
Cardiotoxicity was reported in 20% of adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial; grade 3 or higher cardiotoxicity occurred in 9% of patients. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of daunorubicin liposomal; cytarabine liposomal; do not exceed the lifetime maximum cumulative anthracycline limit (e.g., 550 mg/m2 or 400 mg/m2 in patients who received mediastinum radiation). Prior to initiating induction therapy, obtain an electrocardiogram and assess cardiac function using a multi-gated radionuclide angiography (MUGA) scan or echocardiography (ECHO); thereafter, assess cardiac function via MUGA scan or ECHO before each consolidation cycle and as clinically indicated. Discontinue therapy in patients who develop impaired cardiac function unless the benefits outweigh the risks of therapy. In the clinical study, cardiotoxicity included the following terms: acute coronary syndrome, endocarditis, acute myocardial infarction (MI), angina pectoris, aortic valve incompetence, cardiac arrest, heart failure, congestive heart failure, heart murmur, cardiogenic shock, cardiomegaly, cardiomyopathy, diastolic dysfunction, atrium or ventricular dilatation, decreased ejection fraction, left ventricular dysfunction, mitral valve incompetence, pericardial effusion, pericarditis, and right ventricular hypertrophy.
Cardiac arrhythmias (30%; grade 3 or higher, 7%), hypotension including orthostatic hypotension (20%; grade 3 or higher, 5%), hypertension (18%; grade 3 or higher, 10%), and chest pain (unspecified) (17%; grade 3 or higher, 3%) were reported in adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial. In this trial, cardiac arrhythmias included the following terms: supraventricular tachycardia (SVT), atrial fibrillation, atrial flutter, atrial tachycardia, sinus tachycardia, AV block, bradycardia, right bundle-branch block, extrasystoles, cardiac arrest, and ventricular tachycardia.
Daunorubicin liposomal; cytarabine liposomal contains copper gluconate and may cause copper toxicity/overload, particularly in patients with Wilson's disease or other copper-related metabolic disorders. If daunorubicin liposomal; cytarabine liposomal is administered in these patients, consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity; perform serial neuropsychological examinations; and monitor total serum copper, serum nonceruloplasmin bound copper, and 24-hour urine copper levels. Discontinue therapy in patients who develop signs or symptoms of acute copper toxicity. Based on recommended dosing, the maximum total copper exposure is 106 mg/m2.
Bleeding events associated with prolonged severe low platelet counts have been reported with daunorubicin liposomal; cytarabine liposomal therapy. Monitor blood counts regularly until platelet counts recover; platelet transfusions may be necessary. Bleeding (70%; grade 3 or higher, 10%), epistaxis (36%), and petechiae (11%) were reported in adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial; fatal central nervous system/intracranial bleeding occurred in 2% of patients. Additionally, transfusion reactions were reported in 11% of patients (grade 3 or higher, 2%). In this trial, bleeding included the following terms: anal or rectal bleeding, blood blister, hematuria, hematoma, catheter-site bruise or bleeding, central nervous system bleeding, cerebral hemorrhage, coagulopathy, contusion, ecchymosis, hemorrhagic enterocolitis, epistaxis, GI bleeding, hematemesis, hematochezia, hemoptysis, intracranial bleeding, hemorrhoidal hemorrhage, lip/tongue/mouth/mucosal/gingival bleeding, melena, periorbital bleeding, pharyngeal bleeding, postprocedural bleeding, pulmonary alveolar hemorrhage, pulmonary bleeding, purpura, conjunctival/vitreous/scleral/retinal hemorrhage, subdural hematoma, urethral bleeding, and vaginal bleeding.
Hematologic toxicity occurs with daunorubicin liposomal; cytarabine liposomal therapy. Monitor complete blood counts regularly until recovery. Assess blood counts prior to each consolidation cycle; do not begin consolidation until the absolute neutrophil count (ANC) recovers to greater than 0.5 X 109 cells/L and the platelet count recovers to greater than 50 X 109 cells/L in the absence of unacceptable toxicity. All patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal therapy (n = 153) in a randomized trial experienced severe anemia, neutropenia, and thrombocytopenia; febrile neutropenia (68%; grade 3 or higher, 66%) was also reported in this trial. Severe neutropenia (ANC less than 0.5 X 109 cells/L) lasting past cycle day 42 in the absence of active leukemia occurred in 17% and 10% of patients following the first induction and first consolidation cycles, respectively. Severe thrombocytopenia (less than 50 X 109 cells/L) lasting past cycle day 42 in the absence of active leukemia was reported in 28% and 25% of patients following the first induction and first consolidation cycles, respectively.
Nephrotoxicity has been reported with daunorubicin liposomal; cytarabine liposomal therapy. Prior to initiating induction therapy, evaluate renal function (e.g., serum creatinine/BUN levels); thereafter, assess renal function before each consolidation cycle and as clinically indicated. Renal insufficiency was reported in 11% of adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial; grade 3 or higher renal insufficiency occurred in 5% of patients. In this trial, renal insufficiency included the following terms: acute prerenal failure, renal failure (unspecified), acute renal failure, azotemia, oliguria, and chronic renal failure.
Hepatotoxicity has been reported with daunorubicin liposomal; cytarabine liposomal therapy. Prior to initiating induction therapy, evaluate liver function tests (LFTs) including bilirubin levels; thereafter, assess LFTs before each consolidation cycle and as clinically indicated. In a randomized trial, severe elevated hepatic enzymes (i.e., increased ALT levels) were reported in 5% and 0% of adult patients with acute myelogenous leukemia following daunorubicin liposomal; cytarabine liposomal as induction and consolidation therapy, respectively. Additionally, severe hyperbilirubinemia occurred in 6% and 2% of patients following induction and consolidation therapy, respectively.
Rash (unspecified) (54%; grade 3 and higher, 5%); catheter or device injection site reaction including discharge, erosion, erythema, inflammation, edema, pain, and rash (16%); and pruritus (15%) were reported in adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial. In this trial, rash included the following terms: dermatitis, atopic dermatitis, contact dermatitis, eczema, erythema nodosum, exfoliative rash, psoriasis, erythematous rash, follicular rash, maculopapular rash, pruritic rash, pustular rash, and skin exfoliation.
Nausea (47%; grade 3 and higher, 1%), diarrhea/colitis (45%; grade 3 and higher, 3%), mucositis (44%; grade 3 and higher, 1%), constipation (40%), abdominal pain (33%; grade 3 and higher, 2%), anorexia/decreased appetite (29%; grade 3 and higher, 1%), vomiting (24%), and hemorrhoids (11%) were reported in adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial. Additionally, dyspepsia occurred in less than 10% of patients who received induction or consolidation with daunorubicin liposomal; cytarabine liposomal. In this trial, diarrhea/colitis included the following terms: cecitis, enterocolitis, ileitis, neutropenic colitis, and enteritis; mucositis included the following terms: anal erosion, anorectal discomfort, duodenitis, peptic ulcer, esophageal ulceration, GI inflammation, gingival pain or swelling, gingivitis, glossodynia, laryngeal inflammation, oral ulceration of the lip or mouth, mucosal inflammation or ulceration, odynophagia, esophagitis, oral mucosa erosion/blistering/erythema, pharyngeal ulceration, proctalgia, proctitis, rectal ulcer, stomatitis, tongue ulceration, oropharyngeal pain or discomfort, oral pain, and pharyngeal erythema.
Musculoskeletal pain was reported in 38% of adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial; grade 3 or higher musculoskeletal pain occurred in 3% of patients. In this trial, musculoskeletal pain included the following terms: arthralgia, back pain, bone pain, coccydynia, limb discomfort, musculoskeletal chest pain, myalgia, neck pain, extremity pain, and jaw pain.
Cough (33%), dyspnea (32%; grade 3 and higher, 11%), hypoxia or decreased oxygen saturation level (18%; grade 3 and higher, 12%), and pleural effusion (16%; grade 3 and higher, 2%) were reported in adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial. Additionally, pneumonitis occurred in less than 10% of patients who received induction or consolidation with daunorubicin liposomal; cytarabine liposomal. In this trial, dyspnea included the following terms: acute respiratory distress syndrome (ARDS), acute respiratory failure, bronchospasm, exertional dyspnea, respiratory distress, respiratory failure, and wheezing.
Infection such as pneumonia (26%; grade 3 and higher, 20%), bacteremia (24%; grade 3 and higher, 23%), fungal infection including oral and skin candidiasis (18%; grade 3 and higher, 7%), upper respiratory infection (18%; grade 3 and higher, 3%), and sepsis including neutropenic sepsis (11%) was reported in adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial. In this trial, upper respiratory infection included the following terms: acute and chronic sinusitis, increased upper airway secretion, nasal congestion, pharyngitis, rhinitis, rhinorrhea, sinus congestion, upper respiratory tract congestion, and upper-airway cough syndrome.
Fever (17%; grade 3 and higher, 1%) and chills (23%) were reported in adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial.
Edema was reported in 51% of adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial; grade 3 or higher edema occurred in 2% of patients. In this trial, edema included the following terms: face edema, fluid overload, fluid retention, peripheral edema, penile edema, scrotal edema, swelling, and face swelling.
Sleep disorders (25%; grade 3 and higher, 1%), delirium (16%; grade 3 and higher, 3%), and anxiety (14%) were reported in adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial. Additionally, hallucinations occurred in less than 10% of patients who received induction or consolidation with daunorubicin liposomal; cytarabine liposomal. In this trial, delirium included the following terms: cognitive disorder/impaired cognition and confusion; sleep disorders included the following terms: abnormal dreams, insomnia, nightmares, and sleep apnea syndrome.
Visual impairment was reported in 11% of adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial. Additionally, conjunctivitis, xerophthalmia, eye edema or swelling, ocular irritation, ocular pain or discomfort, ocular or scleral hyperemia, and periorbital edema each occurred in less than 10% of patients who received induction or consolidation with daunorubicin liposomal; cytarabine liposomal. In this trial, visual impairment included the following terms: photophobia, photopsia, photosensitivity reaction, retinal tear, scintillating scotoma, uveitis, blurred vision, reduced visual acuity, vitreous detachment, and vitreous floaters.
Fatigue/asthenia occurred in 32% of adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial; grade 3 or higher fatigue/asthenia occurred in 5% of patients.
Hearing loss/deafness occurred in less than 10% of patients with acute myelogenous leukemia who received induction or consolidation with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial.
Dizziness (18%; grade 3 and higher, 1%) and headache (33%; grade 3 and higher, 1%) were reported in adult patients with acute myelogenous leukemia who received induction therapy with daunorubicin liposomal; cytarabine liposomal (n = 153) in a randomized trial.
Grade 3 or 4 hyponatremia (14%), hypokalemia (9%), and hypoalbuminemia (7%) were reported in adult patients with acute myelogenous leukemia following daunorubicin liposomal; cytarabine liposomal induction therapy (n = 153) in a randomized trial. Additionally, grade 3 or 4 hyponatremia (6%), hypokalemia (6%), and hypoalbuminemia (2%) were reported in patients following daunorubicin liposomal; cytarabine liposomal consolidation therapy.
Serious or fatal hypersensitivity reactions, including anaphylactoid reactions, have occurred with daunorubicin and cytarabine therapy. Additionally, infusion-related reactions have been reported in postmarketing surveillance of daunorubicin liposomal; cytarabine liposomal. Monitor patients for hypersensitivity reactions, including infusion-related reactions. Interrupt or slow the infusion rate in patients who develop a mild or moderate reaction; premedication with an antihistamine and/or corticosteroid may be necessary with subsequent doses. Permanently discontinue daunorubicin liposomal; cytarabine liposomal for severe or life-threatening reactions; provide symptomatic treatment and monitor patients until the symptoms resolve.
Use of daunorubicin liposomal; cytarabine liposomal is contraindicated in patients with a history of serious hypersensitivity reaction to cytarabine, daunorubicin (or anthracycline hypersensitivity), or any component of the formulation. Serious or fatal hypersensitivity reactions, including anaphylactoid reactions, have been reported with daunorubicin and cytarabine. Monitor patients for hypersensitivity reactions, including infusion-related reactions. Interrupt or slow the infusion rate in patients who develop a mild or moderate reaction; premedication with an antihistamine and/or corticosteroid may be necessary with subsequent doses. Permanently discontinue daunorubicin liposomal; cytarabine liposomal for severe or life-threatening reactions; provide symptomatic treatment and monitor patients until the symptoms resolve.
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.
Daunorubicin liposomal; cytarabine liposomal contains copper gluconate and may cause copper toxicity/overload; therefore, perform a risk/benefit analysis prior to administering this therapy in patients with Wilson's disease or other copper-related metabolic disorders. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity; perform serial neuropsychological examinations; and monitor total serum copper, serum nonceruloplasmin bound copper, and 24-hour urine copper levels if daunorubicin liposomal; cytarabine liposomal is initiated in these patients. Discontinue therapy in patients who develop signs or symptoms of acute copper toxicity. Based on recommended dosing, the maximum total copper exposure is 106 mg/m2.
Daunorubicin is an anthracycline and cardiotoxicity (e.g., congestive heart failure) may occur with daunorubicin liposomal; cytarabine liposomal therapy; therefore, it is not recommended in patients who have reached the lifetime maximum cumulative anthracycline limit (e.g., 550 mg/m2 or 400 mg/m2 in patients who received mediastinum radiation) or in patients with a left ventricular ejection fraction that is less than normal. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of daunorubicin liposomal; cytarabine liposomal. Prior to initiating induction therapy, obtain an electrocardiogram and assess cardiac function using a multi-gated radionuclide angiography (MUGA) scan or echocardiography (ECHO); thereafter, assess cardiac function via MUGA scan or ECHO before each consolidation cycle and as clinically indicated. Discontinue therapy in patients who develop impaired cardiac function unless the benefits outweigh the risks of therapy. Patients with prior anthracycline exposure, pre-existing cardiac disease, or prior radiation therapy to the mediastinum, or patients receiving concomitant cardiotoxic drugs have an increased risk of developing cardiotoxicity; assess cardiac function more frequently if daunorubicin liposomal; cytarabine liposomal is coadministered with cardiotoxic agents.
Serious or fatal bleeding events (e.g., central nervous system/intracranial bleeding) associated with prolonged low platelet counts have been reported with daunorubicin liposomal; cytarabine liposomal therapy. Monitor blood counts regularly until platelet counts recover; platelet transfusions may be necessary. In clinical studies, bleeding events occurred more often in geriatric patients aged 65 years and older who received daunorubicin liposomal; cytarabine liposomal compared with younger patients (77% vs. 59%).
Prolonged neutropenia and thrombocytopenia have been reported with daunorubicin liposomal; cytarabine liposomal therapy. Monitor complete blood counts regularly until recovery. Additionally, assess complete blood counts prior to each consolidation cycle; do not begin consolidation until the absolute neutrophil count recovers to greater than 0.5 X 109 cells/L and the platelet count recovers to greater 50 X 109 cells/L in the absence of unacceptable toxicity.
Hepatotoxicity (e.g., elevated hepatic enzymes, hyperbilirubinemia) has been reported with daunorubicin liposomal; cytarabine liposomal therapy; therefore, use it with caution in patients with hepatic disease or impairment. Prior to initiating induction therapy, evaluate liver function tests (LFTs) including bilirubin levels; thereafter, assess LFTs before each consolidation cycle and as clinically indicated. Patients receiving concomitant hepatotoxic drugs may have an increased risk of impaired liver function and toxicity; assess LFTs more frequently if daunorubicin liposomal; cytarabine liposomal is coadministered with hepatotoxic agents.
Renal impairment (e.g., azotemia, oliguria, renal failure) has been reported with daunorubicin liposomal; cytarabine liposomal therapy; therefore, use it with caution in patients with renal disease or impairment. Prior to initiating induction therapy, evaluate renal function (e.g., serum creatinine/BUN levels); thereafter, assess renal function before each consolidation cycle and as clinically indicated.
Daunorubicin may cause severe local tissue necrosis at the infusion site; monitor patients for signs of drug extravasation with daunorubicin liposomal; cytarabine liposomal therapy. Confirm patency of the IV access prior to administration. Intramuscular administration and subcutaneous administration are not recommended.
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).
Counsel patients about the reproductive risk and contraception requirements during daunorubicin liposomal; cytarabine liposomal treatment. Pregnancy testing prior to starting daunorubicin liposomal; cytarabine liposomal therapy is recommended for females of reproductive potential. These patients should avoid pregnancy and use effective contraception during therapy and for 6 months after the last dose. Due to the risk of male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during and for 6 months after therapy. Based on information from animal studies, infertility may occur in male patients.
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.
For the treatment of acute myelogenous leukemia (AML):
NOTE: Daunorubicin liposomal;cytarabine liposomal has been designated as an orphan drug by the FDA for the treatment of AML.
-for the treatment of newly diagnosed therapy-related AML or AML with myelodysplasia-related changes:
Intravenous dosage:
Adults: 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. 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.
Children and Adolescents: 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).
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Hypersensitivity reactions
Mild symptoms: hold the infusion until symptoms resolve; resume the infusion at half the rate at which the reaction occurred. Consider premedicating patients with an antihistamine and/or corticosteroid prior to subsequent doses of daunorubicin liposomal; cytarabine liposomal.
Moderate symptoms: stop the infusion; do not complete the dose. For subsequent doses, premedicate patients with an antihistamine and/or corticosteroid and administer the daunorubicin liposomal; cytarabine liposomal infusion at the previous rate.
Severe or life-threatening symptoms: permanently discontinue daunorubicin liposomal; cytarabine liposomal therapy. Manage reaction according to current standard of care; monitor patients until the symptoms resolve.
Maximum Dosage Limits:
-Adults
44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV.
-Geriatric
44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV.
-Adolescents
44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV.
-Children
44 mg/m2 daunorubicin liposomal and 100 mg/m2 cytarabine liposomal IV.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
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.
*non-FDA-approved indication
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
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-B-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.
-Route-Specific Pharmacokinetics
Intravenous Route
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.
-Special Populations
Hepatic Impairment
No alterations in the pharmacokinetic (PK) parameters of total daunorubicin and cytarabine were observed in patients with bilirubin levels of 3 mg/dL or less. The PK values of daunorubicin and cytarabine have not been evaluated in patients with bilirubin levels greater than 3 mg/dL.
Renal Impairment
In a pharmacokinetic (PK) study, decreased daunorubicin liposomal; cytarabine liposomal exposure was not clinically significant in patients with moderate (n = 8; creatinine clearance (CrCl), 30 to 59 mL/min) or severe (n = 6; CrCl, 15 to 29 mL/min) renal impairment compared with patients who had normal renal function (n = 7; CrCl, 90 mL/min or more). The mean AUC(tau) values for daunorubicin decreased by 6% and 3% in patients with moderate and severe renal impairment, respectively. The mean AUC(tau) values for cytarabine decreased by 8% in patients with moderate renal impairment and increased by 0.4% in patients with severe renal impairment. The PK values of daunorubicin and cytarabine have not been evaluated in patients with end-stage renal disease on hemodialysis.
Pediatrics
The total daunorubicin and cytarabine exposure values were similar in pediatric patients compared with adults following the same dose based on body surface area.
Geriatric
Age (up to 81 years) does not have a clinically meaningful impact on the pharmacokinetic parameters of daunorubicin and cytarabine after adjusting for body surface area (BSA). The total daunorubicin and cytarabine exposure values were similar in patients 65 years and older compared with younger patients (18 to 64 years) following the same dose based on BSA.
Gender Differences
Gender does not have a clinically meaningful impact on the pharmacokinetic parameters of daunorubicin and cytarabine after adjusting for body surface area.
Ethnic Differences
Ethnicity/Race does not have a clinically meaningful impact on the pharmacokinetic parameters of daunorubicin and cytarabine.
Obesity
Body weight (range, 9 to 156 kg) or body mass index (14 to 48 kg/m2) does not have a clinically meaningful impact on the pharmacokinetic parameters of daunorubicin and cytarabine after adjusting for body surface area.
Other
White blood cell counts
White blood cell counts (0.2 to 111 X 109 cells/L) do not have a clinically meaningful impact on the pharmacokinetic parameters of daunorubicin and cytarabine.