VENCLEXTA*
Manufacturer DetailsGENETECH INC
Compositions:
Venetoclax -mg tablets,
Venetoclax -mg tablets,
| Strength | Rate | Packing Style |
|---|---|---|
| mg | 0.00 | tablets |
List of Related Indications:
- Chronic lymphocytic leukemia -CLL
List Of Drugs:
- Venetoclax- Venclexta -@- (Nov 2016)- Anti-cancer
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
Avoid concomitant use of VENCLEXTA with moderate CYP3A inhibitors,
strong or moderate CYP3A inducers, P-gp inhibitors, or narrow therapeutic
index P-gp substrates.
If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the
VENCLEXTA dose by at least 50%.
If a strong CYP3A inhibitor must be used after the ramp-up phase, reduce
the VENCLEXTA dose by at least 75%.
If a narrow therapeutic index P-gp substrate must be used, it should be
taken at least 6 hours before VENCLEXTA.
Indication:
DRUG INNOVATION - NOVEL DRUG APPROVALS FOR 2016
No Drug Name Active Ingredient Approval Date FDA-Approved use
on Approval date
7. Veclexta Venetoclax 4/11/2016 For chronic lymphocytic leukemia
in patients with a specific
chromosomal abnormality
Press release Drug Trials Snapshot
Approved by FDA on 4/11/2016 (Ref- FDA approved List- 2016)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
VENCLEXTA safely and effectively.
See full prescribing information for VENCLEXTA.
VENCLEXTA (venetoclax) tablets, for oral use
Initial U.S. Approval: 2016
INDICATIONS AND USAGE
VENCLEXTA is a BCL-2 inhibitor indicated for the treatment of patients
with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected
by an FDA approved test, who have received at least one prior therapy.
This indication is approved under accelerated approval based on
overall response rate.
Continued approval for this indication may be contingent upon verification
and description of clinical benefit in a confirmatory trial.
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse reactions (=20%) were neutropenia, diarrhea,
nausea, anemia, upper respiratory tract infection, thrombocytopenia, and
fatigue.
Contra-Indications:
CONTRAINDICATIONS
Concomitant use of VENCLEXTA with strong inhibitors of CYP3A
at initiation and during ramp-up phase is contraindicated.
WARNINGS AND PRECAUTIONS
Tumor Lysis Syndrome (TLS): Anticipate TLS; assess risk in all patients.
Premedicate with anti-hyperuricemics and ensure adequate hydration
Employ more intensive measures (intravenous hydration, frequent
monitoring, hospitalization) as overall risk increases.
Neutropenia: Monitor blood counts and for signs of infection; manage as
medically appropriate.
Immunization: Do not administer live attenuated vaccines prior to, during,
or after VENCLEXTA treatment.
Embryo-Fetal Toxicity: May cause embryo-fetal harm.
Advise females of reproductive potential of the potential risk to a fetus
and to use effective contraception during treatment.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
VENCLEXTA is a BCL-2 inhibitor indicated for the treatment of patients
with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected
by an FDA approved test, who have received at least one prior therapy.
This indication is approved under accelerated approval based on
overall response rate.
Continued approval for this indication may be contingent upon verification
and description of clinical benefit in a confirmatory trial.
DOSAGE AND ADMINISTRATION
Initiate therapy with VENCLEXTA at 20 mg once daily for 7 days,
followed by a weekly ramp-up dosing schedule to the recommended
daily dose of 400 mg.
VENCLEXTA tablets should be taken orally once daily with a meal and water.
Do not chew, crush, or break tablets.
Perform prophylaxis for tumor lysis syndrome.
DOSAGE FORMS AND STRENGTHS
Tablets: 10 mg, 50 mg, 100 mg
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.
Patient Information:
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.
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.
.
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..
Immunizations
Advise patients to avoid vaccination with live vaccines because they may
not be safe or effective during treatment with VENCLEXTA.
.
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.
Male Infertility
Advise patients of the possibility of infertility and possible use of s
perm banking for males of reproductive potential..
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 should be swallowed whole with a meal and water
without being chewed, crushed, or broken.
Advise patients to keep VENCLEXTA in the original packaging during
the first 4 weeks of treatment, and not to transfer the tablets to a
different container.
Advise patients that if a dose of VENCLEXTA is missed by less than
8 hours, to take the missed dose right away and take the next dose
as usual. If a dose of VENCLEXTA is missed by more than 8 hours,
advise patients to wait and take the next dose at the usual time.
Advise patients not to take any additional dose that day if they
vomit after taking VENCLEXTA,and to take the next dose at the
usual time the following day.
Manufactured and Marketed by:
AbbVie Inc.
North Chicago, IL 60064
and Marketed by:
Genentech USA, Inc.
A Member of the Roche Group
South San Francisco, CA 94080-4990
Genentech, Inc.
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Venetoclax is a selective and orally bioavailable small-molecule inhibitor
of BCL-2, an antiapoptotic protein.
Overexpression of BCL-2 has been demonstrated in CLL cells where it
mediates tumor cell survival and has been associated with resistance
to chemotherapeutics.
Venetoclax helps restore the process of apoptosis by binding directly
to the BCL-2 protein,displacing pro-apoptotic proteins like BIM,
triggering mitochondrial outer membrane permeabilization and the activation
of caspases. In nonclinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2.
2. Pharmacokinetics
Absorption
Following multiple oral administrations under fed conditions, maximum plasma
concentration of venetoclax was reached 5-8 hours after dose.
Venetoclax steady state AUC increased proportionally over the dose range
of 150-800 mg.
Under low-fat meal conditions, venetoclax mean (± standard deviation)
steady state C max was 2.1 ± 1.1 µg/mL and AUC0-24 was 32.8 ± 16.9
µg•h/mL at the 400 mg once daily dose.
Food Effect
Administration with a low-fat meal increased venetoclax exposure by
approximately 3.4-fold and administration with a high-fat meal increased
venetoclax exposure by 5.1- to 5.3-fold compared to fasting conditions.
Venetoclax should be administered with a meal
Distribution
Venetoclax is highly bound to human plasma protein with unbound fraction
in plasma <0.01across a concentration range of 1-30 µM (0.87-26 µg/mL).
The mean blood-to-plasma ratio was0.57. The population estimate for
apparent volume of distribution (Vdss/F) of venetoclax ranged
from 256-321 L in patients.
Elimination
The population estimate for the terminal elimination half-life of venetoclax
was approximately 26 hours. The pharmacokinetics of venetoclax
does not change over time.
Metabolism
In vitro studies demonstrated that venetoclax is predominantly
metabolized by CYP3A4/5. M27 was identified as a major metabolite in
plasma with an inhibitory activity against BCL-2 that is at least 58-fold
lower than venetoclax in vitro.
Excretion
After single oral administration of 200 mg radiolabeled [14C]-venetoclax
dose to healthy subjects, >99.9% of the dose was recovered in feces
and <0.1% of the dose was excreted in urine within 9 days, indicating
that hepatic elimination is responsible for the clearance of venetoclax
from the systemic circulation.
Unchanged venetoclax accounted for 20.8% of the administered
radioactive dose excreted in feces.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Risk Summary
There are no available human data on the use of VENCLEXTA
in pregnant women. 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 the recommended 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 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.
2. 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.
Because many drugs are excreted in human milk and because the
potential for serious adverse reactions in breastfed infants from
VENCLEXTA is unknown, advise nursing women to discontinue
breastfeeding during treatment with VENCLEXTA.
3. Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
4.Geriatric Use
Of the 106 patients with previously treated CLL with 17p deletion who
were evaluated for efficacy, 57% were =65 years of age and 17%
were =75 years of age.
Of the 240 patients with previously treated CLL evaluated for safety
from 3 open-label trials, 58% were =65 years of age and 17%
were =75 years of age.
No overall differences in safety and effectiveness were observed
between older and younger patients.
5. Renal Impairment
Patients with reduced renal function (CrCl <80 mL/min) are at increased
risk of TLS. These patients may require more intensive prophylaxis
and monitoring to reduce the risk of TLS when initiating treatment with
VENCLEXTA.
No specific clinical trials have been conducted in subjects with renal
impairment. Less than 0.1% of radioactive VENCLEXTA dose was
detected in urine. No dose adjustment is needed for patients with mild
or moderate renal impairment (CrCl =30 mL/min) based on results of the
population pharmacokinetic analysis.
A recommended dose has not been determined for patients with severe
renal impairment (CrCl <30 mL/min) or patients on dialysis.
6. Hepatic Impairment
No specific clinical trials have been conducted in subjects with hepatic
impairment, however human mass balance study showed that venetoclax
undergoes hepatic elimination.
Although no dose adjustment is recommended in patients with mild or
moderate hepatic impairment based 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.
7. 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.
