on results of the population pharmacokinetic analysis, a trend for increased
adverse events was observed in patients with moderate hepatic impairment;
monitor these patients more closely for signs of toxicity during the initiation
and dose ramp-up phase. A recommended dose has not been determined
for patients with severe hepatic impairment.
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.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with venetoclax.
Venetoclax was not mutagenic in an in vitro bacterial mutagenicity (Ames)
assay, did not induce numerical or structural aberrations in an in vitro
chromosome aberration assay using human peripheral blood lymphocytes,
and was not clastogenic in an in vivo mouse bone marrow micronucleus
assay at doses up to 835 mg/kg. The M27 metabolite was negative for
genotoxic activity in in vitro Ames and chromosome aberration assays.
Fertility and early embryonic development studies were conducted in
male and female mice. These studies evaluate mating, fertilization, and
embryonic development through implantation. There were no effects of
venetoclax on estrus cycles, mating, fertility, corpora lutea, uterine implants
or live embryos per litter at dosages up to 600 mg/kg/day. However, a risk
to human male fertility exists based on testicular toxicity (germ cell loss)
observed in dogs at exposures as low as 0.5 times the human AUC exposure
at the recommend dose.
Animal Toxicology and/or Pharmacology
In dogs, venetoclax caused single-cell necrosis in various tissues, including
the gallbladder, exocrine pancreas, and stomach with no evidence of
disruption of tissue integrity or organ dysfunction; these findings were
minimal to mild in magnitude. Following a 4-week dosing period and
subsequent 4-week recovery period, minimal single-cell necrosis was still
present in some tissues and reversibility has not been assessed following
longer periods of dosing or recovery.
In addition, after approximately 3 months of daily dosing in dogs, venetoclax
caused progressive white discoloration of the hair coat, due to loss of
melanin pigment.
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication
Guide).
• Tumor Lysis Syndrome
Advise patients of the potential risk of TLS, particularly at treatment
initiation and during ramp-up phase, and to immediately report any signs
and symptoms associated with this event (fever, chills, nausea, vomiting,
confusion, shortness of breath, seizure, irregular heartbeat, dark or
cloudy urine, unusual tiredness, muscle pain, and/or joint discomfort) to
their doctor for evaluation [see Warnings and Precautions].
Advise patients to be adequately hydrated every day when taking
VENCLEXTA to reduce the risk of TLS. The recommended volume is 6 to
8 glasses (approximately 56 ounces total) of water each day. Patients
should drink water starting 2 days before and on the day of the first dose,
and every time the dose is increased.
Advise patients of the importance of keeping scheduled appointments for
blood work or other laboratory tests.
Advise patients that it may be necessary to take VENCLEXTA in the
presence of a doctor to allow monitoring for TLS.
• Neutropenia
Advise patients to contact their doctor immediately if they develop a
fever or any signs of infection. Advise patients of the need for periodic
monitoring of blood counts [see Warnings and Precautions].
• Drug Interactions
Advise patients to avoid consuming grapefruit products, Seville oranges,
or starfruit during treatment with VENCLEXTA. Advise patients that
VENCLEXTA may interact with some drugs; therefore, advise patients to
inform their doctor of the use of any prescription medication, over-the-
counter drugs, vitamins and herbal products [see Contraindications and
Drug Interactions].
• Immunizations
Advise patients to avoid vaccination with live vaccines because they may
not be safe or effective during treatment with VENCLEXTA [see Warnings
and Precautions].
• Pregnancy and Lactation
Advise women of the potential risk to the fetus and to avoid pregnancy
during treatment with VENCLEXTA. Advise female patients of reproductive
potential to use effective contraception during therapy and for at least
30 days after completing of therapy. Advise females to contact their
doctor if they become pregnant, or if pregnancy is suspected, during
treatment with VENCLEXTA. Also advise patients not to breastfeed while
taking VENCLEXTA [see Warnings and Precautions, and Use in Specific
Populations].
• Male Infertility
Advise patients of the possibility of infertility and possible use of
sperm banking for males of reproductive potential [see Use in Specific
Populations].
Instructions for Taking VENCLEXTA
Advise patients to take VENCLEXTA exactly as prescribed and not to
change their dose or to stop taking VENCLEXTA unless they are told to do
so by their doctor. Advise patients to take VENCLEXTA orally once daily,
at approximately the same time each day, according to their doctor’s
instructions and that the tablets