Vyxeos Drug Information

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.

• 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

• 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.

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 . 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 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 . 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.

• 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 )