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Table 8. New or Worsening Laboratory Abnormalities with VENCLEXTA
Reported in ≥40% (Any Grade) or ≥10% (Grade 3 or 4) of Patients
with AML Treated with VENCLEXTA in Combination with Azacitidine
or Decitabine
Laboratory
Abnormality
VENCLEXTA in
Combination with
Azacitidine
Any
Grade 3
Grade a
or 4 a
(%)
(%)
N = 67
N = 67
VENCLEXTA in
Combination with
Decitabine
Any
Grade 3
Grade a
or 4 a
(%)
(%)
N = 13
N = 13
Hematology
   Neutropenia
100
100
100
100
   Leukopenia
100
98
100
100
   Thrombocytopenia
91
78
83
83
   Lymphopenia
88
73
100
92
   Anemia
57
57
69
69
Chemistry
   Hyperglycemia
75
12
69
0
   Hypocalcemia
58
7
85
0
   Hypoalbuminemia
52
4
38
8
   Hypokalemia
49
7
46
0
   Hyponatremia
49
4
38
0
   Hypophosphatemia
46
15
23
8
   Hyperbilirubinemia
45
9
46
15
   Hypomagnesemia
21
0
54
8
a Includes laboratory abnormalities that were new or worsening, or
worsening from baseline unknown.
VENCLEXTA in Combination with Low-Dose Cytarabine
The most common adverse reactions (≥30%) of any grade were nausea,
thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea,
fatigue, constipation, and dyspnea.
Serious adverse reactions were reported in 95% of patients. The most
frequent serious adverse reactions (≥5%) were febrile neutropenia, sepsis
(excluding fungal), hemorrhage, pneumonia (excluding fungal), and
device-related infection.
The incidence of fatal adverse drug reactions was 4.9% within 30 days of
starting treatment with no reaction having an incidence of ≥2%.
Discontinuations due to adverse reactions occurred in 33% of patients.
The most frequent adverse reactions leading to drug discontinuation (≥2%)
were hemorrhage and sepsis (excluding fungal).
Dosage interruptions due to adverse reactions occurred in 52% of patients.
The most frequent adverse reactions leading to dose interruption (≥5%)
were thrombocytopenia, neutropenia, and febrile neutropenia.
Dosage reductions due to adverse reactions occurred in 8% of patients.
The most frequent adverse reaction leading to dose reduction (≥2%) was
thrombocytopenia.
Adverse reactions reported in patients with newly-diagnosed AML
receiving VENCLEXTA in combination with low-dose cytarabine are
presented in Table 9.
Table 9. Adverse Reactions Reported in ≥30% (Any Grade) or
≥5% (Grade ≥3) of Patients with AML Treated with VENCLEXTA in
Combination with Low-Dose Cytarabine
Any Grade Grade ≥3
(%)
(%)
N = 61
N = 61
a
59
59
Thrombocytopenia
a
46
46
Blood and lymphatic system Neutropenia
disorders
Febrile neutropenia
46
44
26
26
Anemia a
Nausea
64
2
Gastrointestinal disorders Diarrhea
44
3
Constipation
33
0
General disorders and
a
44
10
administration site
Fatigue
conditions
a
20
18
Sepsis
18
16
Pneumonia a
Infections and infestations Device related
13
11
infection
Urinary tract
8
7
infection
Metabolic and nutritional
Decreased
28
7
disorders
appetite a
Respiratory disorders
Dyspnea a
31
3
49
15
Hemorrhage a
21
7
Hypotension a
Vascular disorders
Hypertension
15
8
Adverse Reactions graded using NCI Common Terminology Criteria for
Adverse Events version 4.0.
a Includes multiple adverse reaction terms.
Body System
Adverse Reaction
Laboratory Abnormalities
Table 10 describes common laboratory abnormalities reported throughout
treatment that were new or worsening from baseline.
Table 10. New or Worsening Laboratory Abnormalities with
VENCLEXTA Reported in ≥40% (Any Grade) or ≥10% (Grade 3 or 4)
of Patients with AML Treated with VENCLEXTA in Combination with
Low-Dose Cytarabine
Laboratory Abnormality
All Grades a Grade 3 or 4 a
(%)
(%)
N = 61
N = 61
Hematology
   Thrombocytopenia
100
96
   Neutropenia
96
96
   Leukopenia
96
96
   Lymphopenia
93
66
   Anemia
61
59
Chemistry
   Hyperglycemia
85
8
   Hypocalcemia
79
16
   Hyponatremia
62
11
   Hyperbilirubinemia
57
3
   Hypoalbuminemia
59
5
   Hypokalemia
56
20
   Hypophosphatemia
51
21
   Hypomagnesemia
46
0
   Blood creatinine increased
46
3
   Blood bicarbonate decreased
41
0
a Includes laboratory abnormalities that were new or worsening, or
worsening from baseline unknown.
Tumor Lysis Syndrome
Tumor lysis syndrome is an important risk when initiating treatment in
patients with AML. The incidence of TLS was 3% (2/61) with VENCLEXTA
in combination with low-dose cytarabine with implementation of dose
ramp-up schedule in addition to standard prophylaxis and monitoring
measures. All events were laboratory TLS, and all patients were able to
reach the target dose.
DRUG INTERACTIONS
Effects of Other Drugs on VENCLEXTA
Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors
Concomitant use with a strong or moderate CYP3A inhibitor or a P-gp
inhibitor increases venetoclax C max and AUC inf , which may increase
VENCLEXTA toxicities, including the risk of TLS [see Warnings and
Precautions].
Concomitant use with a strong CYP3A inhibitor at initiation and during
the ramp-up phase in patients with CLL/SLL is contraindicated [see
Contraindications].
In patients with CLL/SLL taking a steady daily dosage (after ramp-up
phase), consider alternative medications or adjust VENCLEXTA dosage and
closely monitor for signs of VENCLEXTA toxicities.
In patients with AML, adjust VENCLEXTA dosage and closely monitor for
signs of VENCLEXTA toxicities.
Resume the VENCLEXTA dosage that was used prior to concomitant use
with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days
after discontinuation of the inhibitor.
Avoid grapefruit products, Seville oranges, and starfruit during treatment
with VENCLEXTA, as they contain inhibitors of CYP3A.
Strong or Moderate CYP3A Inducers
Concomitant use with a strong CYP3A inducer decreases venetoclax C max
and AUC inf , which may decrease VENCLEXTA efficacy. Avoid concomitant
use of VENCLEXTA with strong CYP3A inducers or moderate CYP3A
inducers.
Effect of VENCLEXTA on Other Drugs
Warfarin
Concomitant use of VENCLEXTA increases warfarin C max and AUC inf , which
may increase the risk of bleeding. Closely monitor international normalized
ratio (INR) in patients using warfarin concomitantly with VENCLEXTA.
P-gp Substrates
Concomitant use of VENCLEXTA increases C max and AUC inf of P-gp
substrates, which may increase toxicities of these substrates. Avoid
concomitant use of VENCLEXTA with a P-gp substrate. If a concomitant
use is unavoidable, separate dosing of the P-gp substrate at least 6 hours
before VENCLEXTA.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
There are no available data on VENCLEXTA use in pregnant women to
inform a drug-associated risk of major birth defects and miscarriage.
Based on toxicity observed in mice, VENCLEXTA may cause fetal harm
when administered to pregnant women. In mice, venetoclax was fetotoxic
at exposures 1.2 times the human clinical exposure based on AUC at a
human dose of 400 mg daily. If VENCLEXTA is used during pregnancy or if
the patient becomes pregnant while taking VENCLEXTA, the patient should
be apprised of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for
the indicated population is unknown. All pregnancies have a background
risk of birth defect, loss, or other adverse outcomes. The background risk
in the U.S. general population of major birth defects is 2% to 4% and of
miscarriage is 15% to 20% of clinically recognized pregnancies.
Data
Animal data
In embryo-fetal development studies, venetoclax was administered to
pregnant mice and rabbits during the period of organogenesis. In mice,
venetoclax was associated with increased post-implantation loss and
decreased fetal body weight at 150 mg/kg/day (maternal exposures
approximately 1.2 times the human AUC exposure at a dose of 400 mg
daily). No teratogenicity was observed in either the mouse or the rabbit.
Lactation
Risk Summary
There are no data on the presence of VENCLEXTA in human milk, the
effects of VENCLEXTA on the breastfed child, or the effects of VENCLEXTA
on milk production. Venetoclax was present in the milk when administered
to lactating rats (see Data).
Because many drugs are excreted in human milk and because the
potential for serious adverse reactions in a breastfed child from
VENCLEXTA is unknown, advise nursing women to discontinue
breastfeeding during treatment with VENCLEXTA.
Data
Animal Data
Venetoclax was administered (single dose; 150 mg/kg oral) to lactating
rats 8 to 10 days parturition. Venetoclax in milk was 1.6 times lower than
in plasma. Parent drug (venetoclax) represented the majority of the total
drug-related material in milk, with trace levels of three metabolites.
Females and Males of Reproductive Potential
VENCLEXTA may cause fetal harm [see Warnings and Precautions and Use
in Specific Populations].
Pregnancy Testing
Conduct pregnancy testing in females of reproductive potential before
initiation of VENCLEXTA [see Use in Specific Populations].
Contraception
Advise females of reproductive potential to use effective contraception
during treatment with VENCLEXTA and for at least 30 days after the last
dose [see Use in Specific Populations].
Infertility
Based on findings in animals, male fertility may be compromised by
treatment with VENCLEXTA.
Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
In a juvenile toxicology study, mice were administered venetoclax at 10,
30, or 100 mg/kg/day by oral gavage from 7 to 60 days of age. Clinical
signs of toxicity included decreased activity, dehydration, skin pallor, and
hunched posture at ≥30 mg/kg/day. In addition, mortality and body weight
effects occurred at 100 mg/kg/day. Other venetoclax-related effects were
reversible decreases in lymphocytes at ≥10 mg/kg/day; a dose of
10 mg/kg/day is approximately 0.06 times the clinical dose of 400 mg on a
mg/m 2 basis for a 20 kg child.
Geriatric Use
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Of the 352 patients with previously treated CLL/SLL evaluated for safety
from 3 open-label trials of VENCLEXTA monotherapy, 57% (201/352) were
≥65 years of age and 18% (62/352) were ≥75 years of age.
No clinically meaningful differences in safety and effectiveness were
observed between older and younger patients in the combination and
monotherapy studies.
Acute Myeloid Leukemia
Of the 67 patients treated with VENCLEXTA in combination with azacitidine
in the clinical trial, 96% were ≥65 years of age and 50% were ≥ 75 years
of age. Of the 13 patients treated with VENCLEXTA in combination with
decitabine in the clinical trial, 100% were ≥65 years of age and 26%
were ≥ 75 years of age. Of the 61 patients treated with VENCLEXTA in
combination with low-dose cytarabine, 97% were ≥65 years of age and
66% were ≥75 years of age.
The efficacy and safety data presented in the Adverse Reactions and
Clinical Studies sections were obtained from these patients [see Adverse
Reactions]. There are insufficient patient numbers to show differences in
safety and effectiveness between geriatric and younger patients.
Renal Impairment
Due to the increased risk of TLS, patients with reduced renal function
(CLcr <80 mL/min, calculated by Cockcroft-Gault formula) require more
intensive prophylaxis and monitoring to reduce the risk of TLS when
initiating treatment with VENCLEXTA [see Warnings and Precautions].
No dose adjustment is recommended for patients with mild or moderate
renal impairment (CLcr ≥ 30 mL/min). A recommended dose has not been
determined for patients with severe renal impairment (CLcr < 30 mL/min)
or patients on dialysis.
Hepatic Impairment
No dose adjustment is recommended for patients with mild (Child-Pugh A)
or moderate (Child-Pugh B) hepatic impairment.
Reduce the dose of VENCLEXTA for patients with severe hepatic
impairment (Child-Pugh C); monitor these patients more closely for signs
of toxicity.
OVERDOSAGE
There is no specific antidote for VENCLEXTA. For patients who experience
overdose, closely monitor and provide appropriate supportive treatment;
during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs
and symptoms of TLS along with other toxicities. Based on venetoclax
large volume of distribution and extensive protein binding, dialysis is
unlikely to result in significant removal of venetoclax.
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Marketed by:
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© 2019 AbbVie Inc.
© 2019 Genentech, Inc.
Ref: 03-B947 Revised: July, 2019
LAB-2815 MASTER
US-VENC-190294