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.
Adverse
Reaction
Pneumonia
(excluding fungal)
Sleep disorders
Bacteremia
(excluding sepsis)
Vomiting
Chills
Hypotension
Non-conduction
cardiotoxicity
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
Visual impairment
(except bleeding)
The safety of VYXEOS was determined in a randomized trial for adults with
newly-diagnosed t-AML or AML-MRC 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 2.
Table 2: Common Adverse Reactions (≥10% Incidence
in the VYXEOS arm) During the Induction Phase
Grades 3 to 5 a
All Grades a
Adverse
VYXEOS
7+3
VYXEOS
7+3
Reaction
N=153
N=151
N=153
N=151
n (%)
n (%)
n (%)
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)
All Grades a
VYXEOS
7+3
N=153
N=151
n (%)
n (%)
Grades 3 to 5 a
VYXEOS
7+3
N=153
N=151
n (%)
n (%)
39 (26) 35 (23) 30 (20) 26 (17)
38 (25) 42 (28) 2 (1) 1 (1)
37 (24) 37 (25) 35 (23) 31 (21)
37 (24)
35 (23)
30 (20) 33 (22)
38 (25)
32 (21) 0
0
7 (5) 0
0
1 (1)
31 (20) 27 (18) 13 (9) 15 (10)
27 (18)
27 (18)
28 (18)
28 (18) 26 (17)
19 (13)
22 (15)
31 (21) 1 (1)
11 (7)
15 (10)
19 (12) 0
9 (6)
8 (5)
23 (15)
28 (18) 19 (13) 4 (3) 1 (1)
26 (17)
26 (17) 22 (15)
23 (15) 5 (3)
1 (1) 0
2 (1)
24 (16) 15 (10) 0 0
24 (16)
24 (16)
21 (14)
23 (15) 33 (22)
25 (17)
16 (11)
14 (9) 4 (3)
3 (2)
0
0 9 (6)
2 (1)
0
0
17 (11) 20 (13) n/a n/a
16 (11)
17 (11)
17 (11)
17 (11) 12 (8)
17 (11)
17 (11)
16 (11) 0
0
7 (5)
3 (2) 0
0
7 (5)
1 (1)
16 (11) 8 (5) 0 0
Adverse reactions were graded using NCI CTCAE version 3.0.
a
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