(Daunorubicin And Cytarabine) Liposome

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 )

2 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. • Aseptically withdraw the calculated volume of the reconstituted product from the vial(s) with a sterile syringe and transfer it to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. There may be residual product remaining in the vial. Discard unused portion. • Gently invert the bag to mix the solution. The dilution of the reconstituted product results in a deep purple, translucent, homogeneous dispersion, free from visible particulates. • If the diluted infusion solution is not used immediately, store in a refrigerator at 2ºC to 8ºC (36°F to 46°F) for up to 4 hours. If the reconstituted solution in the vial was stored for 4 hours, the diluted infusion solution must be used immediately and cannot be stored for an additional 4 hours. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Only solutions without visible particles should be used. 2.4 Administration Instructions • For intravenous use only. • Do not mix VYXEOS with or administer as an infusion with other drugs. • Administer VYXEOS by constant intravenous infusion over 90 minutes via an infusion pump through a central venous catheter or a peripherally inserted central catheter. An in-line membrane filter may be used for the intravenous infusion of Vyxeos, provided the minimum pore diameter of the filter is greater than or equal to 15 microns. • Flush the line after administration with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.

6 ADVERSE REACTIONS 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, Lip hematoma, Lip hemorrhage, Lower gastrointestinal hemorrhage, Melena, Mouth hemorrhage, Mucosal hemorrhage, Periorbital hematoma, Periorbital hemorrhage, Pharyngeal hematoma, Pharyngeal hemorrhage, Post procedural contusion, Post procedural hematoma, Post procedural hemorrhage, Pulmonary alveolar hemorrhage, Pulmonary hemorrhage, Purpura, Rectal hemorrhage, Retinal hemorrhage, Scleral hemorrhage, Scrotal hematoma, Skin ulcer hemorrhage, Small intestinal hemorrhage, Stomatitis hemorrhagic, Subdural hematoma, Subdural hemorrhage, Subgaleal hematoma, Tongue hemorrhage, Traumatic hematoma, Upper gastrointestinal hemorrhage, Urethral hemorrhage, Vaginal hemorrhage, Vessel puncture site hemorrhage, Vitreous hemorrhage; Rash: Dermatitis, Dermatitis acneiform, Dermatitis allergic, Dermatitis contact, Eczema, Erythema nodosum, Exfoliative rash, Psoriasis, Rash, Rash erythematous, Rash follicular, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Skin exfoliation; Edema: Face edema, Fluid overload, Fluid retention, Generalized edema, Localized edema, Edema, Edema peripheral, Penile edema, Scrotal edema, Swelling, Swelling face; Diarrhea/Colitis : Cecitis, Colitis, Diarrhea, Enterocolitis, Ileitis, Neutropenic colitis, Enteritis, Enterocolitis; Mucositis: Anal erosion, Anorectal discomfort, Duodenitis, Gastric ulcer, Gastrointestinal inflammation, Gingival pain, Gingival swelling, Gingivitis, Glossodynia, Laryngeal inflammation, Lip ulceration, Mouth ulceration, Mucosal inflammation, Mucosal ulceration, Odynophagia, Edema mouth, Esophageal ulcer, Esophagitis, Oral mucosa erosion, Oral mucosal blistering, Oral mucosal erythema, Pharyngeal ulceration, Proctalgia, Proctitis, Rectal ulcer, Stomatitis, Tongue ulceration, Oropharyngeal pain, Oral pain, Oropharyngeal discomfort, Pharyngeal erythema; Musculoskeletal pain: Arthralgia, Back pain, Bone pain, Coccydynia, Limb discomfort, Musculoskeletal chest pain, Musculoskeletal pain, Myalgia, Neck pain, Pain in extremity, Pain in jaw; Abdominal pain : Abdominal pain, Abdominal distension, Abdominal pain upper, Abdominal discomfort, Abdominal pain lower, Abdominal tenderness; Cough : Cough, Productive Cough; Headache : Headache, Sinus Headache; Dyspnea : Acute respiratory distress syndrome, Acute respiratory failure, Bronchospasm, Dyspnea, Dyspnea exertional, Respiratory distress, Respiratory failure, Wheezing; Fatigue : Fatigue, Asthenia; Arrhythmia : Arrhythmia, Arrhythmia supraventricular, Atrial fibrillation, Atrial flutter, Atrial tachycardia, Atrioventricular block first degree, Atrioventricular block second degree, Bradycardia, Bundle branch block right, Extrasystoles, Heart rate increased, Nodal arrhythmia, Nodal rhythm, Sinus arrest, Sinus arrhythmia, Sinus bradycardia, Sinus tachycardia, Supraventricular tachycardia, Tachycardia, Ventricular extrasystoles, Ventricular tachycardia; Pneumonia (excluding fungal): Lung consolidation, Lung infection, Lung infiltration, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia klebsiella, Pneumonia pseudomonas aeruginosa, Pneumonia viral; Sleep disorders: Abnormal dreams, Insomnia, Nightmare, Sleep apnea syndrome, Sleep disorder; Bacteremia (excluding sepsis) : Bacillus test positive, Bacteremia, Bacteroides bacteremia, Corynebacterium test positive, Enterobacter bacteremia, Enterococcal bacteremia, Enterococcus test positive, Escherichia bacteremia, Klebsiella bacteremia, Pseudomonal bacteremia, Pseudomonas test positive, Staphylococcal bacteremia, Staphylococcus test positive, Stomatococcus test positive, Streptococcal bacteremia, Streptococcus test positive, Escherichia test positive, Klebsiella test positive; Vomiting : Retching, Vomiting; Hypotension: Hypotension, Orthostatic hypotension; Non-conduction cardiotoxicity: Acute coronary syndrome, Acute endocarditis, Acute myocardial infarction, Angina pectoris, Aortic valve incompetence, Cardiac arrest, Cardiac failure, Cardiac failure congestive, Cardiac murmur, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, Cardiotoxicity, Cytotoxic cardiomyopathy, Diastolic dysfunction, Dilatation atrial, Dilatation ventricular, Ejection fraction decreased, Endocarditis, Left ventricular dysfunction, Mitral valve incompetence, Myocardial infarction, Pericardial effusion, Pericarditis, Restrictive cardiomyopathy, Right ventricular hypertrophy; Dizziness : Dizziness, Dizziness postural, Dizziness exertional; Fungal infection : Aspergillosis, Bronchopulmonary aspergillosis, Candida test positive, Candidiasis, Fungemia, Fungal infection, Fungal skin infection, Intertrigo candida, Lower respiratory tract infection fungal, Oral candidiasis, Pneumonia fungal, Pulmonary mycosis, Sinusitis fungal, Skin candida, Tinea cruris, Tinea infection, Vulvovaginal mycotic infection, Wound infection fungal, Zygomycosis, Mycotic aneurysm; Hypertension: Blood pressure increased, Hypertension; Hypoxia: Hypoxia, Oxygen saturation decreased; Upper respiratory infection (excluding fungal): Acute sinusitis, Chronic sinusitis, Increased upper airway secretion, Nasal congestion, Pharyngitis, Rhinitis, Rhinorrhea, Sinus congestion, Sinusitis, Sinusitis bacterial, Upper respiratory tract congestion, Upper respiratory tract infection, Upper-airway cough syndrome, Viral upper respiratory tract infection; Chest pain : Chest discomfort, Chest pain, Non-cardiac chest pain, Pleuritic pain; Catheter/device/injection site reaction : Catheter site discharge, Catheter site erosion, Catheter site erythema, Catheter site inflammation, Catheter site edema, Catheter site pain, Catheter site pruritus, Catheter site rash, Infusion site edema, Infusion site pain, Infusion site vesicles, Catheter site related reaction; Delirium : Cognitive disorder, Confusional state, Delirium; Pruritis : Anal pruritis, Ear pruritis, Pruritis, Pruritis generalized; Sepsis (excluding fungal): Enterobacter sepsis, Escherichia sepsis, Klebsiella sepsis, Neutropenic sepsis, Sepsis, Septic shock, Staphylococcal sepsis, Streptococcal sepsis, Urosepsis, Viral sepsis; Renal insufficiency: Acute prerenal failure, Azotemia, Oliguria, Renal failure, Renal failure acute, Renal failure chronic; Transfusion reactions : Allergic transfusion reaction, Febrile non-hemolytic transfusion reaction, Transfusion reaction; Visual impairment (except bleeding): Photophobia , Photopsia , Photosensitivity reaction , Retinal tear , Scintillating scotoma , Uveitis , Vision blurred , Visual acuity reduced , Visual impairment , Vitreous detachment , Vitreous floaters b Adverse reactions were graded using NCI CTCAE version 3.0. During the consolidation phase (both consolidation cycles pooled) the two most common adverse reactions on the VYXEOS arm are the same as those during induction, hemorrhagic events and febrile neutropenia. These occurred at lower rates in the pooled consolidation phase (43% and 29%, respectively), compared to the induction phase. All of the common adverse reactions (≥ 10% incidence in the VYXEOS arm) seen in the pooled consolidation phase were also seen in the induction phase. These occurred at lower incidence in the consolidation phase, with the exception of chills, dizziness and pyrexia, where the incidences were relatively similar across the induction and consolidation cycles. Other notable adverse drug reactions that occurred in less than 10% of patients treated with VYXEOS during induction or consolidation included: • Ear and labyrinth disorders: Deafness, Deafness unilateral • Eye Disorders: Eye conjunctivitis, Dry eye, Eye edema, Eye swelling, Eye irritation, Eye pain, Ocular discomfort, Ocular hyperemia, Periorbital edema, Scleral hyperemia • Gastrointestinal disorders: Dyspepsia • Psychiatric disorders: Hallucinations • Respiratory, thoracic and mediastinal disorders: Pneumonitis Laboratory Abnormalities All patients developed severe neutropenia, thrombocytopenia, and anemia. See Table 4 for the incidences of Grade 3 thrombocytopenia and Grade 4 neutropenia that were prolonged in the absence of active leukemia. Table 4: Prolonged Cytopenias for Patients in Study 1 Induction 1 Consolidation 1 b VYXEOS N=58 n (%) 7+3 N=34 n (%) VYXEOS N=48 n (%) 5+2 N=32 n (%) Prolonged thrombocytopenia a 16 (28) 4 (12) 12 (25) 5 (16) Prolonged neutropenia a 10 (17) 1 (3) 5 (10) 1 (3) a Platelets < 50 Gi/L or neutrophils < 0.5 Gi/L lasting past cycle day 42 in the absence of active leukemia. b Patients receiving at least 1 consolidation. Grade 3-4 chemistry abnormalities occurring in greater than 5% of VYXEOS treated patients in Study 1 are presented in Table 5. Table 5: Grade 3-4 a Chemistry Abnormalities ≥ 5% of VYXEOS Treated Patients in Study 1 Induction Consolidation VYXEOS N=153 n (%) 7+3 N=151 n (%) VYXEOS N=49 n (%) 5+2 N=32 n (%) Chemistry Abnormalities Hyponatremia 21 (14) 20 (13) 3 (6) 0 Hypokalemia 14 (9) 19 (13) 3 (6) 2 (6) Hypoalbuminemia 11 (7) 19 (13) 1 (2) 4 (13) Hyperbilirubinemia 9 (6) 6 (4) 1 (2) 1 (3) Alanine aminotransferase 7 (5) 8 (5) 0 1 (3) a Graded using NCI CTCAE version 3.0. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of VYXEOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Infusion-related reactions

12.3 Pharmacokinetics The pharmacokinetics of daunorubicin and cytarabine administered as VYXEOS were investigated in adult patients who received a dose of daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 administered as a 90-minute intravenous infusion on days 1, 3, and 5. The pharmacokinetics of each drug was based on total plasma concentrations (i.e., encapsulated plus unencapsulated drug). Following the dose administered on day 5, the mean (% coefficient of variation [CV]) maximum plasma concentration (C max ) for daunorubicin was 26.0 (32.7%) mcg/mL and cytarabine was 62.2 (33.7%) mcg/mL. The mean (%CV) area under the curve (AUC) during one dosing interval for daunorubicin was 637 (38.4%) mcg∙h/mL and cytarabine was 1900 (44.3%) mcg∙h/mL. The accumulation ratio was 1.3 for daunorubicin and 1.4 for cytarabine. There was no evidence of time-dependent kinetics or major departures from dose proportionality over the range of 1.3 mg/3 mg per m 2 to 59 mg/134 mg per m 2 (0.03 to 1.3 times the approved recommended dosage). Distribution The volume of distribution (%CV) for daunorubicin is 6.6 L (36.8%) and cytarabine is 7.1 L (49.2%). Plasma protein binding was not evaluated. Elimination VYXEOS exhibits a prolonged half-life (%CV) of 31.5 h (28.5%) for daunorubicin and 40.4 h (24.2%) for cytarabine with greater than 99% of the daunorubicin and cytarabine in the plasma remaining encapsulated within the liposomes. The clearance (%CV) is 0.16 L/h (53.3%) for daunorubicin and 0.13 L/h (60.2%) for cytarabine. Metabolism Subsequent to release from VYXEOS liposomes, daunorubicin is catalyzed by aldoketo reductase and carbonyl reductase enzymes to the active metabolite daunorubicinol. Cytarabine is metabolized by cytidine deaminase to the inactive metabolite 1-β-D-arabinofuranosyluracil (AraU). Excretion Urinary excretion of daunorubicin and daunorubicinol accounts for 9% of the administered dose of daunorubicin, and urinary excretion of cytarabine and AraU accounts for 71% of the administered dose of cytarabine. Specific Populations No clinically meaningful effects on the pharmacokinetics of daunorubicin and cytarabine were observed based on age (1 to 81 years), sex, race, body weight (9 to 156 kg), body mass index (14 to 48 kg/m 2 ), and white blood cell count (0.2 to 111 Gi/L) after adjusting dose by body surface area. Pediatric Patients 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. Geriatric Patients The exposures of total daunorubicin and cytarabine observed in patients aged > 65 years were within the values observed in patients aged 18 to 64 years given the same dose based on body surface area. Patients with Renal Impairment Comparing to patients with normal renal function (n=7, CLcr ≥ 90 mL/min), patients with moderate renal impairment (n=8, CLcr 30 to 59 mL/min) showed 8% and 6% decrease, respectively, in the mean AUC tau of total cytarabine and daunorubicin; patients with severe renal impairment (n=6, CLcr 15 to 29 mL/min) showed 0.4% increase and 3% decrease, respectively, in the mean AUC tau of cytarabine and daunorubicin in a dedicated study. There are no data in patients with end-stage renal disease managed with hemodialysis. Patients with Hepatic Impairment The pharmacokinetics of total cytarabine and daunorubicin were not altered in patients with bilirubin less than and equal to 3 mg/dL. The pharmacokinetics in patients with bilirubin greater than 3 mg/dL is unknown .