Vyxeos

(daunorubicin and cytarabine) liposome · Injection, Powder, Lyophilized, For Suspension · Intravenous

Prescription (Rx) Anthracycline Topoisomerase Inhibitor Nucleoside Metabolic Inhibitor

Boxed warning. WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS
• VYXEOS 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 [see Warnings and Precautions ( 5.1 )] . WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS See full prescribing information for complete boxed warning.
• VYXEOS 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 ( 5.1 ).

Uses

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

Dosage and administration

• Induction: VYXEOS (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 ) 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. ( 2.1 )
• Consolidation: VYXEOS (daunorubicin 29 mg/m 2 and cytarabine 65 mg/m 2 ) liposome via intravenous infusion over 90 minutes on days 1 and 3. ( 2.1 )
• See Full Prescribing Information for instructions on preparation and administration. ( 2.3 , 2.4 ) 2.1 Recommended Dosage A full VYXEOS course consists of 1-2 cycles of Induction and up to 2 cycles of Consolidation at the dose and schedule listed in Table 1. Prior to initiating each cycle of VYXEOS, calculate the prior cumulative anthracycline exposure for the patient [see Warnings and Precautions ( 5.3 )] . Administer prophylactic anti-emetics before treatment with VYXEOS. Table 1: Dose and Schedule for VYXEOS Cycle VYXEOS Dose and Schedule First Induction (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 ) liposome days 1, 3, and 5 Second Induction a (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 ) liposome days 1 and 3 Consolidation (daunorubicin 29 mg/m 2 and cytarabine 65 mg/m 2 ) liposome days 1 and 3 a Only for patients failing to achieve a response with the first induction cycle. For the first cycle of induction, the recommended dose of VYXEOS is (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 ) liposome administered via intravenous infusion over 90 minutes on days 1, 3, and 5. Prior to initiating induction, assess cardiac function and obtain liver and renal function studies. For patients who do not achieve remission with the first induction cycle, a second induction cycle may be administered 2 to 5 weeks after the first if there was no unacceptable toxicity with VYXEOS. The recommended dose for the second induction cycle of VYXEOS is (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 ) liposome administered via intravenous infusion over 90 minutes on days 1 and 3. Administer the first consolidation cycle 5 to 8 weeks after the start of the last induction. The recommended dose for each cycle of consolidation therapy is VYXEOS (daunorubicin 29 mg/m 2 and cytarabine 65 mg/m 2 ) liposome administered via intravenous infusion over 90 minutes on days 1 and 3. Assess cardiac function, complete blood counts, liver and renal function before each consolidation cycle. Do not start VYXEOS consolidation until the absolute neutrophil count recovers to greater than 0.5 Gi/L and the platelet count recovers to greater than 50 Gi/L in the absence of unacceptable toxicity. Administer the second consolidation cycle 5 to 8 weeks after the start of the first consolidation cycle in patients who do not show disease progression or unacceptable toxicity to VYXEOS. 2.2 Dosage Modification Missed Doses of VYXEOS If a planned dose of VYXEOS is missed, administer the dose as soon as possible and adjust the dosing schedule accordingly, maintaining the treatment interval. Hypersensitivity Reactions For hypersensitivity reactions of any grade/severity, interrupt VYXEOS infusion immediately and manage symptoms. Reduce the rate of infusion or discontinue treatment as outlined below [see Warnings and Precautions ( 5.4 )] .
• Mild symptoms: Once symptoms resolve, reinitiate infusion at half the prior rate of infusion. Consider premedication with antihistamines and/or corticosteroids for subsequent doses of VYXEOS.
• Moderate symptoms: Do not reinitiate infusion. For subsequent doses of VYXEOS, premedicate with antihistamines and/or corticosteroids prior to initiating infusion at same rate.
• Severe/life-threatening symptoms: Permanently discontinue VYXEOS treatment, treat according to the standard of care to manage symptoms, and monitor patient until symptoms resolve. Cardiotoxicity Discontinue VYXEOS in patients who exhibit impaired cardiac function unless the benefit of continuing treatment outweighs the risk [see Warnings and Precautions ( 5.3 )] . 2.3 Preparation and Handling Instructions VYXEOS is a hazardous drug. Follow applicable special handling and disposal procedures. 1 VYXEOS is supplied as a single-dose vial and does not contain any preservatives. Do not save any unused portions for later administration. Reconstitute and further dilute VYXEOS prior to intravenous infusion. Reconstitution:
• Calculate the VYXEOS dose based on daunorubicin and individual patient's body surface area (BSA).
• Calculate the number of vials of VYXEOS based on the daunorubicin dose.
• Remove the appropriate number of vials of VYXEOS from the refrigerator and equilibrate to the room temperature for 30 minutes.
• Then, reconstitute each vial with 19 mL of Sterile Water for Injection using a sterile syringe and immediately thereafter start a 5-minute timer.
• Carefully swirl the contents of the vial for 5 minutes while gently inverting the vial every 30 seconds.
• Do not heat, vortex, or shake vigorously.
• After reconstitution, let rest for 15 minutes.
• The reconstituted product should be an 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.
• Use the reconstituted solution immediately. If needed, store the reconstituted solution in the vial refrigerated at 2ºC to 8ºC (36°F to 46°F) for up to 4 hours. Note that the reconstituted product in the vial and the reconstituted product which has been diluted into an infusion solution are stable for a total of 4 hours (not 4 hours each) when stored at 2°C to 8°C. Dilution:
• Calculate the volume of reconstituted VYXEOS required using the following formula: [volume required (mL) = dose of daunorubicin (mg/m 2 ) X patient's BSA (m 2 ) ÷ 2.2 (mg/mL)]
• Gently invert each vial 5 times prior to withdrawing the reconstituted product for further dilution.

Dosage forms and strengths

3 DOSAGE FORMS AND STRENGTHS VYXEOS is a sterile, preservative-free, purple, lyophilized cake for reconstitution supplied in a single-dose clear glass vial as follows:
• For injection: 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes. For injection: 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes as a lyophilized cake in a single-dose vial for reconstitution. ( 3 )

Contraindications

The use of VYXEOS is contraindicated in patients with the following:
• History of serious hypersensitivity reaction to cytarabine, daunorubicin, or any component of the formulation [see Warnings and Precautions ( 5.4 )] .
• History of serious hypersensitivity to daunorubicin, cytarabine or any component of the formulation. ( 4 )

Warnings and precautions

• Hemorrhage: Serious or fatal hemorrhagic events with associated prolonged thrombocytopenia have occurred with VYXEOS. Monitor blood counts regularly until recovery. ( 5.2 )
• Cardiotoxicity: VYXEOS treatment is not recommended in patients with cardiac function that is less than normal. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of continuing treatment outweighs the risk. ( 2.2 , 5.3 )
• Hypersensitivity: If severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS, treat according to standard of care, and monitor until signs and symptoms resolve. ( 2.2 , 5.4 )
• Tissue Necrosis: Daunorubicin has been associated with local tissue necrosis at the site of drug extravasation. Confirm intravenous access before administration. ( 5.6 )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 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 VYXEOS 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 VYXEOS. 5.2 Hemorrhage Serious or fatal hemorrhage events, including fatal central nervous system (CNS) hemorrhages, associated with prolonged severe thrombocytopenia, have occurred in patients treated with VYXEOS. In Study 1 (NCT01696084), the incidence of any grade hemorrhagic events during the entire treatment period was 74% of patients on the VYXEOS arm and 56% on the control arm. The most frequently reported hemorrhagic event was epistaxis (36% in VYXEOS arm and 18% in control arm). Grade 3 or greater events occurred in 12% of VYXEOS treated patients and 8% of patients treated with 7+3. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients on the VYXEOS arm and in 0.7% of patients on the control arm. Monitor blood counts regularly until recovery and administer platelet transfusion support as required [see Adverse Reactions ( 6.1 )]. 5.3 Cardiotoxicity VYXEOS 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 VYXEOS, 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 VYXEOS and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS treatment is not recommended in patients with LVEF that is less than normal. Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m 2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m 2 ) in patients who received radiation therapy to the mediastinum. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS treatment is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit. The exposure to daunorubicin following each cycle of VYXEOS is shown in Table 2. Table 2: Cumulative Exposure of Daunorubicin per Cycle of VYXEOS Therapy Daunorubicin per Dose Number of Doses per Cycle Daunorubicin per Cycle First Induction Cycle 44 mg/m 2 3 132 mg/m 2 Second Induction Cycle 44 mg/m 2 2 88 mg/m 2 Each Consolidation Cycle 29 mg/m 2 2 58 mg/m 2 5.4 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 VYXEOS and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS permanently, treat symptoms according to the standard of care, and monitor until symptoms resolve [see Dosage and Administration ( 2.2 )] . 5.5 Copper Overload Reconstituted VYXEOS contains 5 mg/mL copper gluconate, of which 14% is elemental copper. There is no clinical experience with VYXEOS in patients with Wilson’s disease or other copper-related metabolic disorders. The maximum theoretical total exposure of copper under the recommended VYXEOS dosing regimen is 106 mg/m 2 [see Dosage and Administration ( 2.1 )] . Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with VYXEOS. Monitor total serum copper, serum non-ceruloplasmin bound copper, 24-hour urine copper levels and serial neuropsychological examinations in these patients. Use VYXEOS in patients with Wilson’s disease only if the benefits outweigh the risks. Discontinue VYXEOS in patients with signs or symptoms of acute copper toxicity. 5.6 Tissue Necrosis Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Confirm patency of the intravenous access before administration. Do not administer by the intramuscular or subcutaneous route.

Side effects

The following adverse reactions are discussed in greater detail in other sections of the labeling:
• Hemorrhage [see Warnings and Precautions ( 5.2 )]
• Cardiotoxicity [see Warnings and Precautions ( 5.3 )]
• Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )]
• Copper Overload [see Warnings and Precautions ( 5.5 )]
• Tissue Necrosis [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (incidence ≥ 25%) are 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VYXEOS was determined in a randomized trial for adults with newly diagnosed t‑AML or AML-MRC [see Clinical Studies ( 14 )] which included 153 patients treated with VYXEOS and 151 patients treated with a standard combination of cytarabine and daunorubicin (7+3). At study entry, patients were required to have a LVEF of at least 50% and a prior lifetime cumulative anthracycline exposure less than 368 mg/m 2 daunorubicin (or equivalent). On study, the median number of cycles administered was 2 (range, 1–4 cycles) on the VYXEOS arm and 1 (range, 1–4 cycles) on the control arm. The median cumulative daunorubicin dose was 189 mg/m 2 (range, 44–337 mg/m 2 ) on the VYXEOS arm and 186 mg/m 2 (range, 44–532 mg/m 2 ) on the control arm. Nine patients each on the VYXEOS arm (6%) and the control arm (6%) had a fatal adverse reaction on treatment or within 30 days of therapy that was not in the setting of progressive disease. Fatal adverse reactions on the VYXEOS arm included infection, CNS hemorrhage, and respiratory failure. Overall, all-cause day-30 mortality was 6% in the VYXEOS arm and 11% in the control arm. During the first 60 days of the study, 14% (21/153) of patients died in the VYXEOS arm vs. 21% (32/151) of patients in the 7+3 treatment group. The most common serious adverse reactions (incidence ≥ 5%) on the VYXEOS arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia and hemorrhage. Adverse reactions led to discontinuation of VYXEOS in 18% (28/153) of patients, and 13% (20/151) in the control arm. The adverse reactions leading to discontinuation on the VYXEOS arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage (GI and CNS), renal insufficiency, colitis, and generalized medical deterioration. The most common adverse reactions (incidence ≥ 25%) in patients on the VYXEOS arm 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. The incidences of common adverse drug reactions during the induction phase in Study 1 are presented in Table 3. Table 3: Common Adverse Reactions (≥ 10% Incidence in the VYXEOS arm) During the Induction Phase Adverse Reaction a All Grades b Grades 3 to 5 b VYXEOS N=153 n (%) 7+3 N=151 n (%) VYXEOS N=153 n (%) 7+3 N=151 n (%) Hemorrhage a 107 (70) 74 (49) 15 (10) 9 (6) Febrile Neutropenia 104 (68) 103 (68) 101 (66) 102 (68) Rash a 82 (54) 55 (36) 8 (5) 2 (1) Edema a 78 (51) 90 (60) 2 (2) 5 (3) Nausea 72 (47) 79 (52) 1 (1) 1 (1) Diarrhea/Colitis a 69 (45) 100 (66) 4 (3) 10 (7) Mucositis a 67 (44) 69 (46) 2 (1) 7 (5) Constipation 61 (40) 57 (38) 0 0 Musculoskeletal pain a 58 (38) 52 (34) 5 (3) 4 (3) Abdominal pain a 51 (33) 45 (30) 3 (2) 3 (2) Cough a 51 (33) 34 (23) 0 1 (1) Headache a 51 (33) 36 (24) 2 (1) 1 (1) Dyspnea a 49 (32) 51 (34) 17 (11) 15 (10) Fatigue a 49 (32) 58 (38) 8 (5) 8 (5) Arrhythmia a 46 (30) 41 (27) 10 (7) 7 (5) Decreased appetite 44 (29) 57 (38) 2 (1) 5 (3) Pneumonia (excluding fungal) a 39 (26) 35 (23) 30 (20) 26 (17) Sleep disorders a 38 (25) 42 (28) 2 (1) 1 (1) Bacteremia (excluding sepsis) a 37 (24) 37 (25) 35 (23) 31 (21) Vomiting a 37 (24) 33 (22) 0 0 Chills 35 (23) 38 (25) 0 0 Hypotension a 30 (20) 32 (21) 7 (5) 1 (1) Non-conduction cardiotoxicity a 31 (20) 27 (18) 13 (9) 15 (10) Dizziness a 27 (18) 26 (17) 1 (1) 0 Fungal infection a 27 (18) 19 (13) 11 (7) 9 (6) Hypertension a 28 (18) 22 (15) 15 (10) 8 (5) Hypoxia a 28 (18) 31 (21) 19 (12) 23 (15) Upper respiratory infections (excluding fungal) a 28 (18) 19 (13) 4 (3) 1 (1) Chest pain a 26 (17) 22 (15) 5 (3) 0 Pyrexia 26 (17) 23 (15) 1 (1) 2 (1) Catheter/device/injection site reaction a 24 (16) 15 (10) 0 0 Delirium a 24 (16) 33 (22) 4 (3) 9 (6) Pleural effusion 24 (16) 25 (17) 3 (2) 2 (1) Anxiety 21 (14) 16 (11) 0 0 Pruritus a 23 (15) 14 (9) 0 0 Sepsis (excluding fungal) a 17 (11) 20 (13) n/a Hemorrhoids 16 (11) 12 (8) 0 0 Petechiae 17 (11) 17 (11) 0 0 Renal insufficiency a 17 (11) 17 (11) 7 (5) 7 (5) Transfusion reactions a 17 (11) 16 (11) 3 (2) 1 (1) Visual impairment (except bleeding) a 16 (11) 8 (5) 0 0 a Grouped terms: Hemorrhage: Anal hemorrhage, Blood blister, Blood urine present, Breast hematoma, Catheter site bruise, Catheter site hemorrhage, Central nervous system hemorrhage, Cerebral hematoma, Cerebral hemorrhage, Coagulopathy, Conjunctival hemorrhage, Contusion, Ecchymosis, Enterocolitis hemorrhagic, Epistaxis, Gastric hemorrhage, Gastrointestinal hemorrhage, Gingival bleeding, Hematemesis, Hematochezia, Hematoma, Hematuria, Hemoptysis, Hemorrhage, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhage urinary tract, Hemorrhoidal hemorrhage, L…

Drug interactions

• Monitor cardiac function more frequently when coadministered with cardiotoxic agents. ( 7.1 )
• Monitor hepatic function more frequently when coadministered with hepatotoxic agents. ( 7.2 ) 7.1 Cardiotoxic Agents Concomitant use of cardiotoxic agents may increase the risk of cardiotoxicity. Assess cardiac function more frequently when VYXEOS is coadministered with cardiotoxic agents [see Warnings and Precautions ( 5.3 )]. 7.2 Hepatotoxic Agents Concomitant use with hepatotoxic agents may impair liver function and increase the toxicity of VYXEOS. Monitor hepatic function more frequently when VYXEOS is coadministered with hepatotoxic agents.

Use in specific populations

Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on anecdotal data of cytarabine in pregnant women and results of studies of daunorubicin and cytarabine in animals, VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VYXEOS, 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/m 2 basis [see Animal Data] . Patients should be advised to avoid becoming pregnant while taking VYXEOS. 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. 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. Data 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. Animal Data A liposomal formulation of daunorubicin was administered to rats on gestation days 6 through 15 at 0.3, 1.0, or 2.0 mg/kg/day (about 0.04, 0.14, or 0.27 the recommended human dose on a mg/m 2 basis) and produced severe maternal toxicity and embryolethality at 2.0 mg/kg/day and was embryotoxic and caused fetal malformations (anophthalmia, microphthalmia, incomplete ossification) at 0.3 mg/kg/day. Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes. Cytarabine was teratogenic in mice (cleft palate, phocomelia, deformed appendages, skeletal abnormalities) when doses ≥ 2 mg/kg/day were administered intraperitoneal (IP) during the period of organogenesis (about 0.06 times the recommended human dose on a mg/m 2 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/m 2 basis). Single IP doses of 50 mg/kg in rats (about 3 times the recommended human dose on a mg/m 2 basis) on day 14 of gestation reduced prenatal and postnatal brain size and permanent impairment of learning ability. Cytarabine was embryotoxic in mice when administered during the period of organogenesis. Embryotoxicity was characterized by decreased fetal weight at 0.5 mg/kg/day (about 0.02 times the recommended human dose on a mg/m 2 basis), and increased early and late resorptions and decreased live litter sizes at 8 mg/kg/day (about 0.24 times the recommended human dose on a mg/m 2 basis). 8.2 Lactation Risk Summary 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 VYXEOS and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential VYXEOS can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating VYXEOS. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with VYXEOS and for 6 months after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with VYXEOS and for 6 months after the last dose [see Nonclinical Toxicology ( 13.1 )]. Infertility Based on findings of daunorubicin and cytarabine in animals, male fertility may be compromised by treatment with VYXEOS [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use Newly Diagnosed t-AML or AML-MRC The safety and effectiveness of VYXEOS have been established in pediatric patients 1 year and older with newly diagnosed t-AML or AML-MRC. The use of VYXEOS for this indication is supported by evidence of effectiveness from an adequate and well-controlled study in adults with data on safety from two single-arm trials, which included patients in the following age groups: 7 patients 1 year to less than 2 years old, 33 patients 2 years to less than 12 years old, 13 patients 12 years old to less than 17 years old. The exposures of total daunorubicin and cytarabine observed in pediatric patients were within the values observed in adults given the same dose based on body surface area [ see Clinical Pharmacology ( 12.3 )] . No new safety signals were observed in pediatric patients in these two single-arm trials. No differences in safety were observed by age. The safety and effectiveness of VYXEOS in pediatric patients less than 1 year of age with newly diagnosed t-AML or AML-MRC have not been established. Newly Diagnosed de novo AML The safety and effectiveness of VYXEOS in pediatric patients with de novo AML were assessed but not established in an open-label, randomized study (NCT04293562) comparing VYXEOS plus gemtuzumab ozogamicin to standard chemotherapy plus gemtuzumab ozogamicin. The VYXEOS arm included 324 pediatric patients less than 17 years old. No new safety signals were identified in the pediatric patients treated with VYXEOS and gemtuzumab ozogamicin in this trial.

Pregnancy

8.1 Pregnancy Risk Summary Based on anecdotal data of cytarabine in pregnant women and results of studies of daunorubicin and cytarabine in animals, VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VYXEOS, 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/m 2 basis [see Animal Data] . Patients should be advised to avoid becoming pregnant while taking VYXEOS. 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. 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. Data 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. Animal Data A liposomal formulation of daunorubicin was administered to rats on gestation days 6 through 15 at 0.3, 1.0, or 2.0 mg/kg/day (about 0.04, 0.14, or 0.27 the recommended human dose on a mg/m 2 basis) and produced severe maternal toxicity and embryolethality at 2.0 mg/kg/day and was embryotoxic and caused fetal malformations (anophthalmia, microphthalmia, incomplete ossification) at 0.3 mg/kg/day. Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes. Cytarabine was teratogenic in mice (cleft palate, phocomelia, deformed appendages, skeletal abnormalities) when doses ≥ 2 mg/kg/day were administered intraperitoneal (IP) during the period of organogenesis (about 0.06 times the recommended human dose on a mg/m 2 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/m 2 basis). Single IP doses of 50 mg/kg in rats (about 3 times the recommended human dose on a mg/m 2 basis) on day 14 of gestation reduced prenatal and postnatal brain size and permanent impairment of learning ability. Cytarabine was embryotoxic in mice when administered during the period of organogenesis. Embryotoxicity was characterized by decreased fetal weight at 0.5 mg/kg/day (about 0.02 times the recommended human dose on a mg/m 2 basis), and increased early and late resorptions and decreased live litter sizes at 8 mg/kg/day (about 0.24 times the recommended human dose on a mg/m 2 basis).

Pediatric use

8.4 Pediatric Use Newly Diagnosed t-AML or AML-MRC The safety and effectiveness of VYXEOS have been established in pediatric patients 1 year and older with newly diagnosed t-AML or AML-MRC. The use of VYXEOS for this indication is supported by evidence of effectiveness from an adequate and well-controlled study in adults with data on safety from two single-arm trials, which included patients in the following age groups: 7 patients 1 year to less than 2 years old, 33 patients 2 years to less than 12 years old, 13 patients 12 years old to less than 17 years old. The exposures of total daunorubicin and cytarabine observed in pediatric patients were within the values observed in adults given the same dose based on body surface area [ see Clinical Pharmacology ( 12.3 )] . No new safety signals were observed in pediatric patients in these two single-arm trials. No differences in safety were observed by age. The safety and effectiveness of VYXEOS in pediatric patients less than 1 year of age with newly diagnosed t-AML or AML-MRC have not been established. Newly Diagnosed de novo AML The safety and effectiveness of VYXEOS in pediatric patients with de novo AML were assessed but not established in an open-label, randomized study (NCT04293562) comparing VYXEOS plus gemtuzumab ozogamicin to standard chemotherapy plus gemtuzumab ozogamicin. The VYXEOS arm included 324 pediatric patients less than 17 years old. No new safety signals were identified in the pediatric patients treated with VYXEOS and gemtuzumab ozogamicin in this trial.

Geriatric use

8.5 Geriatric Use Of the 375 patients who received VYXEOS (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 ) liposome 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%).

Description

(daunorubicin and cytarabine) liposome for injection is a combination of daunorubicin and cytarabine in a 1:5 molar ratio encapsulated in liposomes for intravenous administration. The liposome membrane is composed of distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), and cholesterol in a 7:2:1 molar ratio. Daunorubicin is an anthracycline topoisomerase inhibitor. The chemical name for daunorubicin is (1S,3S)-3-acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl-3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside; its molecular weight is 527.52. Daunorubicin has the following structural formula: Cytarabine is a nucleoside metabolic inhibitor. The chemical name of cytarabine is 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone; its molecular weight is 243.22. Cytarabine has the following structural formula: VYXEOS liposome for injection is supplied as a sterile, preservative-free, purple, lyophilized cake, in a single-dose vial. Each vial contains 44 mg daunorubicin and 100 mg cytarabine, and the following inactive ingredients: distearoylphosphatidylcholine 454 mg, distearoylphosphatidylglycerol 132 mg, cholesterol HP 32 mg, copper gluconate 100 mg, triethanolamine 4 mg, and sucrose 2054 mg. daunorubicin cytarabine

Mechanism of action

12.1 Mechanism of Action VYXEOS (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.

How supplied

How Supplied VYXEOS (daunorubicin and cytarabine) liposome for injection is supplied as a sterile, preservative-free, purple, lyophilized cake, in a single-dose vial. Each VYXEOS vial (NDC 68727-745-01) contains 44 mg daunorubicin and 100 mg cytarabine. NDC 68727-745-02: Carton containing 2 vials of VYXEOS Storage Store unreconstituted VYXEOS vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in an upright position. The vial should be stored in its original carton to protect from light. Handling and Disposal VYXEOS is a hazardous drug. Follow applicable special handling and disposal procedures. 1

Patient information

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 [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . Cardiotoxicity Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions ( 5.3 )] . 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 [see Warnings and Precautions ( 5.4 )] . Embryo-Fetal Toxicity VYXEOS 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 VYXEOS and to inform their healthcare provider of a known or suspected pregnancy before and during treatment with VYXEOS [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.1 ) and ( 8.3 )] . Lactation Advise patients not to breastfeed during treatment with VYXEOS and for 2 weeks after the last dose [see Use in Specific Populations ( 8.2 )] . Infertility Advise males of reproductive potential that VYXEOS may cause temporary or permanent infertility [see Use in Specific Populations ( 8.3 )] . Concomitant Medications Advise patients to speak with their physicians about any other medication they are currently taking [see Drug Interactions ( 7 )] . This product's label may have been updated. For full prescribing information, please visit labels.fda.gov. Distributed by: Jazz Pharmaceuticals, Inc. Palo Alto, CA 94306 Protected by U.S. Patent Nos. 7,238,367; 7,744,921; 7,850,990; 8,022,279; 8,092,828; 8,431,806; 8,518,437; 9,271,931; 10,028,912; 10,166,184; and 10,835,492 VYXEOS ® is a trademark of Jazz Pharmaceuticals plc or its subsidiaries. ©2025 Jazz Pharmaceuticals www.vyxeos.com

Label text from the FDA structured product label by Jazz Pharmaceuticals, Inc. (revised Jan 30, 2026). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Cytarabine in 1 product
Daunorubicin in 1 product

Vyxeos NDC products (1)

NDC	Strength & form	Labeler	Type
68727-745	Cytarabine 100 mg/20mL; Daunorubicin 44 mg/20mL Injection, Powder, Lyophilized, For Suspension	Jazz Pharmaceuticals, Inc.	NDA

Frequently asked questions

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Vyxeos is listed by 1 labeler in the FDA NDC directory, including Jazz Pharmaceuticals, Inc..