VENCLEXTA ® (venetoclax tablets)
INDICATIONS AND USAGE
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
VENCLEXTA is indicated for the treatment of adult patients with chronic
lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Acute Myeloid Leukemia
VENCLEXTA is indicated in combination with azacitidine, or decitabine, or
low-dose cytarabine for the treatment of newly-diagnosed acute myeloid
leukemia (AML) in adults who are age 75 years or older, or who have
comorbidities that preclude use of intensive induction chemotherapy.
This indication is approved under accelerated approval based on response
rates. Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory trials.
CONTRAINDICATIONS
Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation
and during the ramp-up phase is contraindicated in patients with
CLL/SLL due to the potential for increased risk of tumor lysis syndrome
[see Drug Interactions].
WARNINGS AND PRECAUTIONS
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS), including fatal events and renal failure
requiring dialysis, has occurred in patients with high tumor burden when
treated with VENCLEXTA [see Adverse Reactions].
In patients with CLL who followed the current (5 week) dose ramp-up
and the TLS prophylaxis and monitoring measures, the rate of TLS
was 2% in the VENCLEXTA CLL monotherapy studies. The rate of TLS
remained consistent with VENCLEXTA in combination with obinutuzumab
or rituximab. With a 2 to 3 week dose ramp-up and higher starting dose
in patients with CLL/SLL, the TLS rate was 13% and included deaths and
renal failure [see Adverse Reactions].
VENCLEXTA can cause rapid reduction in tumor and thus poses a risk
for TLS at initiation and during the ramp-up phase. Changes in blood
chemistries consistent with TLS that require prompt management can
occur as early as 6 to 8 hours following the first dose of VENCLEXTA and
at each dose increase.
The risk of TLS is a continuum based on multiple factors, including tumor
burden and comorbidities. Reduced renal function further increases the
risk. Patients should be assessed for risk and should receive appropriate
prophylaxis for TLS, including hydration and anti-hyperuricemics. Monitor
blood chemistries and manage abnormalities promptly. Interrupt dosing if
needed. Employ more intensive measures (intravenous hydration, frequent
monitoring, hospitalization) as overall risk increases [see Use in Specific
Populations].
Concomitant use of VENCLEXTA with P-gp inhibitors or strong or moderate
CYP3A inhibitors increases venetoclax exposure, may increase the risk of
TLS at initiation and during ramp-up phase and requires VENCLEXTA dose
adjustment [see Drug Interactions].
Neutropenia
In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64%
of patients and Grade 4 neutropenia developed in 31% to 33% of patients
treated with VENCLEXTA in combination and monotherapy studies (see
Tables 2, 4, 6). Febrile neutropenia occurred in 4% to 6% of patients
treated with VENCLEXTA in combination and monotherapy studies [see
Adverse Reactions].
In patients with AML, baseline neutrophil counts worsened in 97% to
100% of patients treated with VENCLEXTA in combination with azacitidine
or decitabine or low-dose cytarabine. Neutropenia can recur with
subsequent cycles of therapy.
Monitor complete blood counts throughout the treatment period. Interrupt
dosing or reduce dose for severe neutropenia. Consider supportive
measures including antimicrobials for signs of infection and use of growth
factors (e.g., G-CSF).
Infections
Fatal and serious infections such as pneumonia and sepsis have occurred
in patients treated with VENCLEXTA [see Adverse Reactions]. Monitor
patients closely for signs and symptoms of infection and treat promptly.
Withhold VENCLEXTA for Grade 3 and higher infection.
Immunization
Do not administer live attenuated vaccines prior to, during, or after
treatment with VENCLEXTA until B-cell recovery occurs. The safety
and efficacy of immunization with live attenuated vaccines during or
following VENCLEXTA therapy have not been studied. Advise patients that
vaccinations may be less effective.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings in animals, VENCLEXTA
may cause embryo-fetal harm when administered to a pregnant woman.
In an embryo-fetal study conducted in mice, administration of venetoclax
to pregnant animals at exposures equivalent to that observed in patients at
a dose of 400 mg daily resulted in post-implantation loss and decreased
fetal weight. There are no adequate and well-controlled studies in
pregnant women using VENCLEXTA. Advise females of reproductive
potential to avoid pregnancy during treatment. If VENCLEXTA is used
during pregnancy or if the patient becomes pregnant while taking
VENCLEXTA, the patient should be apprised of the potential hazard to the
fetus [see Use in Specific Populations].
Increased Mortality in Patients with Multiple Myeloma when
VENCLEXTA is Added to Bortezomib and Dexamethasone
In a randomized trial (BELLINI; NCT02755597) in patients with relapsed
or refractory multiple myeloma, the addition of VENCLEXTA to bortezomib
plus dexamethasone, a use for which VENCLEXTA is not indicated, resulted
in increased mortality. Treatment of patients with multiple myeloma with
VENCLEXTA in combination with bortezomib plus dexamethasone is not
recommended outside of controlled clinical trials.
ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in
greater detail in other sections of the labeling:
• Tumor Lysis Syndrome [see Warnings and Precautions]
• Neutropenia [see Warnings and Precautions]
• Infections [see Warnings and Precautions]
Because clinical trials are conducted under widely variable conditions,
adverse event rates observed in clinical trials of a drug cannot be directly
compared with rates of clinical trials of another drug and may not reflect
the rates observed in practice.
PROFESSIONAL BRIEF SUMMARY
CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
Clinical Trial Experience with Chronic Lymphocytic Leukemia/Small
Lymphocytic Lymphoma
CLL14
The safety of VENCLEXTA in combination with obinutuzumab (VEN+G)
versus obinutuzumab in combination with chlorambucil (GClb) was
evaluated in a randomized, open-label, actively controlled trial in patients
with previously untreated CLL.
Patients randomized to the VEN+G arm were treated with VENCLEXTA
and obinutuzumab in combination for six cycles, then with VENCLEXTA as
monotherapy for an additional six cycles. Patients initiated the first dose
of the 5 week ramp-up for VENCLEXTA on Day 22 of Cycle 1 and once
completed, continued VENCLEXTA 400 mg once daily for a total of 12
cycles. The trial required a total Cumulative Illness Rating Scale (CIRS) >6
or CLcr <70 mL/min, hepatic transaminases and total bilirubin ≤2 times
upper limit of normal, and excluded patients with any individual
organ/system impairment score of 4 by CIRS except eye, ear, nose, and
throat organ system.
A total of 426 patients were treated (212 with VEN+G, 214 with GClb).
The median duration of exposure to VENCLEXTA was 10.5 months (range:
0 to 13.5 months). The median number of cycles was 6 for obinutuzumab
and 12 for chlorambucil.
In the VEN+G arm, fatal adverse reactions that occurred in the absence
of disease progression and with onset within 28 days of the last study
treatment were reported in 2% (4/212) of patients, most often from
infection. Serious adverse reactions were reported in 49% of patients in
the VEN+G arm, most often due to febrile neutropenia and pneumonia
(5% each).
In the VEN+G arm, adverse reactions led to treatment discontinuation in
16% of patients, dose reduction in 21%, and dose interruption in 74%.
In the VEN+G arm, neutropenia led to dose interruption of VENCLEXTA in
41% of patients, reduction in 13%, and discontinuation in 2%.
Table 1 and Table 2 present adverse reactions and laboratory
abnormalities identified in the CLL14 trial, respectively. The most common
(≥15%) adverse reactions observed with VEN+G were neutropenia,
diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.
Table 1. Common (≥10%) Adverse Reactions in Patients Treated
with VEN+G Grade 4 laboratory abnormalities developing in ≥2% of patients treated
with VEN+G include neutropenia (32%), leukopenia and lymphopenia
(10%), thrombocytopenia (8%), hypocalcemia (8%), hyperuricemia (7%),
blood creatinine increased (3%), hypercalcemia (3%), and hypokalemia
(2%).
MURANO
The safety of VENCLEXTA in combination with rituximab (VEN+R) versus
bendamustine in combination with rituximab (B+R), was evaluated in an
open-label randomized study, in patients with CLL who had received at
least one prior therapy.
Patients randomized to VEN+R completed the scheduled ramp-up
(5 weeks) and received VENCLEXTA 400 mg once daily in combination with
rituximab for 6 cycles followed by single agent VENCLEXTA for a total of
24 months after ramp-up. Patients randomized to B+R received 6 cycles
(28 days per cycle) for a total of 6 months.
At the time of analysis, the median duration of exposure was 22 months in
the VEN+R arm compared with 6 months in the B+R arm.
In the VEN+R arm, fatal adverse reactions that occurred in the absence of
disease progression and within 30 days of the last VENCLEXTA treatment
and/or 90 days of last rituximab were reported in 2% (4/194) of patients.
Serious adverse reactions were reported in 46% of patients in the VEN+R
arm, with most frequent (≥5%) being pneumonia (9%).
In the VEN+R arm, adverse reactions led to treatment discontinuation in
16% of patients, dose reduction in 15%, and dose interruption in 71%.
In the B+R arm, adverse reactions led to treatment discontinuation in
10% of patients, dose reduction in 15%, and dose interruption in 40%.
In the VEN+R arm, neutropenia led to dose interruption of VENCLEXTA in
46% of patients and discontinuation in 3%, and thrombocytopenia led to
discontinuation in 3% of patients.
Table 3 and Table 4 present adverse reactions and laboratory
abnormalities, respectively, identified in the MURANO trial. The MURANO
trial was not designed to demonstrate a statistically significant difference
in adverse reaction rates for VEN+R as compared with B+R, for any
specific adverse reaction or laboratory abnormality.
Table 3. Common (≥10%) Adverse Reactions Reported with ≥5%
Higher All-Grade or ≥2% Higher Grade ≥3 Incidence in Patients
Treated with VEN+R Compared with B+R
VENCLEXTA +
Obinutuzumab +
Obinutuzumab
Chlorambucil
(N = 212)
(N = 214)
All
All
Grade
≥3
≥3
Grades
Grades Grade
%
%
%
%
Blood & lymphatic system disorders
60
56
62
52
Neutropenia a
17
8
20
7
Anemia a
Gastrointestinal disorders
Diarrhea
28
4
15
1
Nausea
19
0
22
1
Constipation
13
0
9
0
Vomiting
10
1
8
1
General disorders and administration site conditions
21
2
23
1
Fatigue a
Infections and Infestations
Upper respiratory
17
1
17
1
tract infection a
a Includes multiple adverse reaction terms.
Other clinically important adverse reactions (all Grades) reported in <10%
of patients treated with VEN+G are presented below:
Blood & lymphatic system disorders: febrile neutropenia (6%)
Infection and infestations (all include multiple adverse reaction terms):
pneumonia (9%), urinary tract infection (6%), sepsis (4%)
Metabolism and nutrition disorder: tumor lysis syndrome (1%)
During treatment with single agent VENCLEXTA after completion of VEN+G
combination treatment, the most common all grade adverse reaction
(≥10% patients) reported was neutropenia (26%). The most common
grade ≥3 adverse reactions (≥2% patients) were neutropenia (23%), and
anemia (2%).
Table 2. New or Worsening Clinically Important Laboratory
Abnormalities Occurring at ≥10% in Patients Treated with VEN+G VENCLEXTA + Rituximab
Followed by Single Agent Bendamustine +
VENCLEXTA
Rituximab
(N = 194)
(N = 188)
All
All Grade ≥3
Grade ≥3
Adverse Reaction by
Grades
Grades
(%)
(%)
Body System
(%)
(%)
Blood & lymphatic system disorders
Neutropenia a
65
62
50
44
Gastrointestinal disorders
Diarrhea
40
3
17
1
Infections & infestations
Upper respiratory
39
2
23
2
tract infection a
Lower respiratory
18
2
10
2
tract infection a
Musculoskeletal and connective tissue disorders
19
1
13
0
Musculoskeletal pain a
Metabolism and nutrition disorders
Tumor lysis
3
3
1
1
syndrome
a Includes multiple adverse reaction terms.
Other adverse reactions (all grades) reported in ≥10% of patients in
the VEN+R arm in MURANO, and other important adverse reactions are
presented below:
Blood & lymphatic system disorders: anemia (16%), thrombocytopenia
(15%), febrile neutropenia (4%)
Gastrointestinal disorders: nausea (21%), constipation (14%), abdominal
pain (13%), mucositis (10%), vomiting (8%)
Respiratory disorders: cough (22%)
General disorders and administration site conditions: fatigue (22%),
pyrexia (15%)
Skin disorders: rash (13%)
Nervous system and psychiatric disorders: headache (11%), insomnia
(11%)
Infections & infestations: pneumonia (10%), sepsis (1%)
During treatment with single agent VENCLEXTA after completion of VEN+R
combination treatment, the most common all grade adverse reactions
(≥10% patients) reported were upper respiratory tract infection (21%),
diarrhea (19%), neutropenia (16%), and lower respiratory tract infections
(11%). The most common Grade 3 or 4 adverse reactions (≥2% patients)
were neutropenia (12%) and anemia (3%).
Laboratory Abnormalities
Table 4 describes common treatment-emergent laboratory abnormalities
identified in the MURANO trial.
Table 4. Common (≥10%) New or Worsening Laboratory
Abnormalities Occurring at ≥5% (Any Grade) or ≥2% (Grade 3 or 4)
Higher Incidence with VEN+R Compared with B+R
Adverse Reaction by
Body System
Laboratory
Abnormality a
VENCLEXTA +
Obinutuzumab +
Obinutuzumab
Chlorambucil
(N = 212)
(N = 214)
All
All
Grade
3
or
4
3 or 4
Grades
Grades Grade
(%)
(%)
(%)
(%)
Hematology
Leukopenia
90
46
89
41
Lymphopenia
87
57
87
51
Neutropenia
83
63
79
56
Thrombocytopenia
68
28
71
26
Anemia
53
15
46
11
Chemistry
Blood creatinine
80
6
74
2
increased
Hypocalcemia
67
9
58
4
Hyperkalemia
41
4
35
3
Hyperuricemia
38
38
38
38
a Includes laboratory abnormalities that were new or worsening, or with
worsening from baseline unknown.
Laboratory
Abnormality
Hematology
Leukopenia
Lymphopenia
Neutropenia
VENCLEXTA +
Rituximab
N=194
All
Grade 3
Grades a
or 4
(%)
(%)
89
87
86
46
56
64
Bendamustine +
Rituximab
N=188
All
Grade 3
Grades a
or 4
(%)
(%)
81
79
84
35
55
59