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Safety profile in the Phase 3 trial1

Reported adverse reactions with VYXEOS were generally consistent with the known safety profile of 7+3a

Common adverse reactions (≥20% incidence in the VYXEOS arm) during the induction phase1

Adverse reaction All gradesb Grades 3 to 5b
VYXEOS
(n=153) n (%) 		7+3
(n=151) n (%) 		VYXEOS
(n=153) n (%) 		7+3
(n=151) n (%)
Hemorrhage 107 (70) 74 (49) 15 (10) 9 (6)
Febrile neutropenia 104 (68) 103 (68) 101 (66) 102 (68)
Rash 82 (54) 55 (36) 8 (5) 2 (1)
Edema 78 (51) 90 (60) 2 (2) 5 (3)
Nausea 72 (47) 79 (52) 1 (1) 1 (1)
Diarrhea/colitis 69 (45) 100 (66) 4 (3) 10 (7)
Mucositis 67 (44) 69 (46) 2 (1) 7 (5)
Constipation 61 (40) 57 (38) 0 0
Musculoskeletal pain 58 (38) 52 (34) 5 (3) 4 (3)
Abdominal pain 51 (33) 45 (30) 3 (2) 3 (2)
Cough 51 (33) 34 (23) 0 1 (1)
Headache 51 (33) 36 (24) 2 (1) 1 (1)
Dyspnea 49 (32) 51 (34) 17 (11) 15 (10)
Fatigue 49 (32) 58 (38) 8 (5) 8 (5)
Arrhythmia 46 (30) 41 (27) 10 (7) 7 (5)
Decreased appetite 44 (29) 57 (38) 2 (1) 5 (3)
Pneumonia (excluding fungal) 39 (26) 35 (23) 30 (20) 26 (17)
Sleep disorders 38 (25) 42 (28) 2 (1) 1 (1)
Bacteremia (excluding sepsis) 37 (24) 37 (25) 35 (23) 31 (21)
Vomiting 37 (24) 33 (22) 0 0
Chills 35 (23) 38 (25) 0 0
Hypotension 30 (20) 32 (21) 7 (5) 1 (1)
Non-conduction cardiotoxicity 31 (20) 27 (18) 13 (9) 15 (10)
Adverse reaction All gradesb
VYXEOS
(n=153) n (%) 		7+3
(n=151) n (%)
Hemorrhage 107 (70) 74 (49)
Febrile neutropenia 104 (68) 103 (68)
Rash 82 (54) 55 (36)
Edema 78 (51) 90 (60)
Nausea 72 (47) 79 (52)
Diarrhea/colitis 69 (45) 100 (66)
Mucositis 67 (44) 69 (46)
Constipation 61 (40) 57 (38)
Musculoskeletal pain 58 (38) 52 (34)
Abdominal pain 51 (33) 45 (30)
Cough 51 (33) 34 (23)
Headache 51 (33) 36 (24)
Dyspnea 49 (32) 51 (34)
Fatigue 49 (32) 58 (38)
Arrhythmia 46 (30) 41 (27)
Decreased appetite 44 (29) 57 (38)
Pneumonia (excluding fungal) 39 (26) 35 (23)
Sleep disorders 38 (25) 42 (28)
Bacteremia (excluding sepsis) 37 (24) 37 (25)
Vomiting 37 (24) 33 (22)
Chills 35 (23) 38 (25)
Hypotension 30 (20) 32 (21)
Non-conduction cardiotoxicity 31 (20) 27 (18)
Adverse reaction Grades 3 to 5b
VYXEOS
(n=153) n (%) 		7+3
(n=151) n (%)
Hemorrhage 15 (10) 9 (6)
Febrile neutropenia 101 (66) 102 (68)
Rash 8 (5) 2 (1)
Edema 2 (2) 5 (3)
Nausea 1 (1) 1 (1)
Diarrhea/colitis 4 (3) 10 (7)
Mucositis 2 (1) 7 (5)
Constipation 0 0
Musculoskeletal pain 5 (3) 4 (3)
Abdominal pain 3 (2) 3 (2)
Cough 0 1 (1)
Headache 2 (1) 1 (1)
Dyspnea 17 (11) 15 (10)
Fatigue 8 (5) 8 (5)
Arrhythmia 10 (7) 7 (5)
Decreased appetite 2 (1) 5 (3)
Pneumonia (excluding fungal) 30 (20) 26 (17)
Sleep disorders 2 (1) 1 (1)
Bacteremia (excluding sepsis) 35 (23) 31 (21)
Vomiting 0 0
Chills 0 0
Hypotension 7 (5) 1 (1)
Non-conduction cardiotoxicity 13 (9) 15 (10)

Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and 0.7% of patients in the control arm.1

Other adverse reactions that occurred in ≥10% of patients in the VYXEOS arm included: dizziness, fungal infection, hypertension, hypoxia, upper respiratory infections (excluding fungal), chest pain, pyrexia, catheter/device/injection site reaction, delirium, pleural effusion, anxiety, pruritus, sepsis (excluding fungal), hemorrhoids, petechiae, renal insufficiency, transfusion reactions, and visual impairment (except bleeding).1

Cytarabine 100 mg/m2 and daunorubicin 60 mg/m2.
Adverse reactions were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

INDICATION

VYXEOS (daunorubicin and cytarabine) liposome for injection 44 mg/100 mg is indicated for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

IMPORTANT SAFETY INFORMATION

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.

Contraindications

VYXEOS is contraindicated in patients with a history of serious hypersensitivity reactions to cytarabine, daunorubicin, or any component of the formulation.

Warning and Precautions

Hemorrhage

Serious or fatal hemorrhage events, including fatal CNS hemorrhages, associated with prolonged thrombocytopenia, have occurred with VYXEOS. The overall incidence (grade 1-5) of hemorrhagic events was 74% in the VYXEOS arm and 56% in 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 in 8% of patients in the control arm. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and in 0.7% of patients in the control arm. Monitor blood counts regularly and administer platelet transfusion support as required.

Cardiotoxicity

VYXEOS contains daunorubicin, which has a known risk of cardiotoxicity. This risk may be increased in patients with prior anthracycline therapy, preexisting cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs. Assess cardiac function prior to VYXEOS treatment and repeat prior to consolidation and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS is not recommended in patients with cardiac function that is less than normal.

Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit.

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 the symptoms, and monitor until symptoms resolve.

Copper Overload

VYXEOS contains copper. 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 during VYXEOS treatment in patients with Wilson’s disease or other copper-related metabolic disorders. Use only if the benefits outweigh the risks. Discontinue in patients with signs or symptoms of acute copper toxicity.

Tissue Necrosis

Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Do not administer by intramuscular or subcutaneous route.

Embryo-Fetal Toxicity

VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid becoming pregnant while taking VYXEOS. If VYXEOS is used during pregnancy or if the patient becomes pregnant while taking VYXEOS, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS.

MOST COMMON ADVERSE REACTIONS

The most common adverse reactions (incidence ≥25%) were hemorrhagic events (74%), febrile neutropenia (70%), rash (56%), edema (55%), nausea (49%), mucositis (48%), diarrhea (48%), constipation (42%), musculoskeletal pain (43%), fatigue (39%), abdominal pain (36%), dyspnea (36%), headache (35%), cough (35%), decreased appetite (33%), arrhythmia (31%), pneumonia (31%), bacteremia (29%), chills (27%), sleep disorders (26%), and vomiting (25%).

Please see full Prescribing Information, including BOXED Warning.

CNS=central nervous system.

Reference: 1. VYXEOS [package insert]. Palo Alto, CA: Jazz Pharmaceuticals.

INDICATION

VYXEOS (daunorubicin and cytarabine) liposome for injection 44 mg/100 mg is indicated for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

Important Safety Information

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.