Table 5 Post-Baseline Laboratory Abnormalities by
CTCAE Grade in ≥ 5% of Patients and at Least 2%
Greater in the GAZYVA Treated Arm (Stage 1)
GAZYVA
+ Chlorambucil
n = 241
Investigations
Chlorambucil
n = 116
All
Grades
All
Grades
Grades % 3–4 % Grades % 3–4 %
Hematology
Neutropenia
78
48
53
27
Lymphopenia
80
40
9
3
Leukopenia
84
37
12
<1
Chemistry
Hypocalcemia
38
3
33
2
Hyperkalemia
33
5
18
3
Hyponatremia
30
8
12
3
AST
(SGOT increased)
29
1
16
0
Creatinine
increased
30
<1
20
2
ALT
(SGPT increased)
27
2
16
0
Hypoalbuminemia
23
<1
15
<1
Alkaline phosphatase 18
increased
0
11
0
Hypokalemia
1
5
<1
15
Table 6 Post-Baseline Laboratory Abnormalities by
CTCAE Grade in ≥ 5% of Patients and at Least 2%
Greater in the GAZYVA Treated Arm (Stage 2)
Investigations
GAZYVA
+ Chlorambucil
n = 336
Rituximab
+ Chlorambucil
n = 321
All
Grades
All
Grades
Grades % 3–4 % Grades % 3–4 %
Hematology
Neutropenia
76
46
69
41
Lymphopenia
80
39
50
16
Leukopenia
16
84
35
62
Thrombocytopenia 48
13
40
8
Anemia
39
10
37
10
Chemistry
Hypocalcemia
37
3
32
<1
Hyperkalemia
14
1
10
<1
Hyponatremia
26
7
18
2
AST
27
(SGOT increased)
2
21
<1
ALT
28
(SGPT increased)
2
21
1
Hypoalbuminemia 23
<1
16
<1
Infusion Reactions: The incidence of infusion reactions
was 65% with the first infusion of GAZYVA. The incidence
of Grade 3 or 4 infusion reactions was 20% with 7% of
patients discontinuing therapy. The incidence of reactions
with subsequent infusions was 3% with the second 1000
mg and < 1% thereafter. No Grade 3 or 4 infusion reactions
were reported beyond the first 1000 mg infused.
Of the first 53 patients receiving GAZYVA on the trial,
47 (89%) experienced an infusion reaction. After this
experience, study protocol modifications were made to
require pre-medication with a corticosteroid, antihistamine,
and acetaminophen. The first dose was also divided into
two infusions (100 mg on day 1 and 900 mg on day 2). For
the 140 patients for whom these mitigation measures were
implemented, 74 patients (53%) experienced a reaction
with the first 1000 mg (64 patients on day 1, 3 patients on
day 2, and 7 patients on both days) and < 3% thereafter [see
Dosage and Administration (2)].
Neutropenia: The incidence of neutropenia reported as an
adverse reaction was 38% in the GAZYVA treated arm and
32% in the rituximab treated arm, with the incidence of
serious adverse events being 1% and < 1%, respectively
(Table 4). Cases of late-onset neutropenia (occurring 28
days after completion of treatment or later) were 16% in the
GAZYVA treated arm and 12% in the rituximab treated arm.
(7%), with the incidence of Grade 3–4 events being 10%
and 3%, respectively (Table 4). The difference in incidences
between the treatment arms is driven by events occurring
during the first cycle. The incidence of thrombocytopenia (all
grades) in the first cycle were 11% in the GAZYVA and 3%
in the rituximab treated arms, with Grade 3–4 rates being
8% and 2%, respectively. Four percent of patients in the
GAZYVA treated arm experienced acute thrombocytopenia
(occurring within 24 hours after the GAZYVA infusion).
The overall incidence of hemorrhagic events and the number
of fatal hemorrhagic events were similar between the
treatment arms, with 3 in the rituximab and 4 in the GAZYVA
treated arms. However, all fatal hemorrhagic events in
patients treated with GAZYVA occurred in Cycle 1.
Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor
lysis syndrome was 2% in the GAZYVA treated arm versus
0% in the rituximab treated arm.
Musculoskeletal Disorders: Adverse events related to
musculoskeletal disorders (all events from the System
Organ Class), including pain, have been reported in the
GAZYVA treated arm with higher incidence than in the
rituximab treated arm (18% vs. 15%).
Liver Enzyme Elevations: Hepatic enzyme elevations have
occurred in patients who received GAZYVA in clinical trials
and had normal baseline hepatic enzyme levels (AST, ALT,
and ALP). The events occurred most frequently within 24-48
hours of the first infusion. In some patients, elevations in liver
enzymes were observed concurrently with infusion reactions
or tumor lysis syndrome. In the pivotal study, there was no
clinically meaningful difference in overall hepatotoxicity
adverse events between all arms (4% of patients in the
GAZYVA treated arm). Medications commonly used to
prevent infusion reactions (e.g., acetaminophen) may also
be implicated in these events. Monitor liver function tests
during treatment, especially during the first cycle. Consider
treatment interruption or discontinuation for hepatotoxicity.
6.2 Immunogenicity
Serum samples from patients with previously untreated
CLL were tested during and after treatment for antibodies
to GAZYVA. Of the GAZYVA treated patients, 7% (18/271)
tested positive for anti-GAZYVA antibodies at one or more
time points. Neutralizing activity of anti-GAZYVA antibodies
has not been assessed.
Immunogenicity data are highly dependent on the sensitivity
and specificity of the test methods used. Additionally, the
observed incidence of a positive result in a test method may
be influenced by several factors, including sample handling,
timing of sample collection, drug interference, concomitant
medication, and the underlying disease. Therefore,
comparison of the incidence of antibodies to GAZYVA
with the incidence of antibodies to other products may be
misleading. Clinical significance of anti-GAZYVA antibodies
is not known.
6.3 Additional Clinical Trial Experience
Worsening of Pre-existing Cardiac Conditions: Fatal cardiac
events have been reported in patients treated with GAZYVA.
7 DRUG INTERACTIONS
No formal drug interaction studies have been conducted
with GAZYVA.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies of
GAZYVA in pregnant women. Women of childbear