Drug Interaction:
Drug Interaction Studies
No formal drug interaction studies have been performed with ZEJULA.
In Vitro Studies
Inhibition of CYPs: Neither niraparib nor the major primary metabolite
M1 is an inhibitor of CYPA2,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.
Induction of CYPs: Neither niraparib nor M1 is a CYP3A4 inducer.
Niraparib weakly induces CYP1A2 in vitro.
Substrate of CYPs: Niraparib is a substrate of carboxylesterases
(CEs) and UDPglucuronosyltransferases (UGTs) in vivo.
Inhibition of transporter systems: Niraparib is a weak inhibitor
of BCRP, but does not inhibit P-gp or BSEP.
The M1 metabolite is not an inhibitor of P-gp, BCRP, or BESP.
Neither niraparib nor M1is an inhibitor of organic anion transport
polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation
transporter 1 (OCT1), organic anion transporter 1 (OAT1),
3 (OAT3), or organic cation transporter 2 (OCT2).
Substrate of transporter systems:
Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer
Resistance Protein (BCRP). Niraparib is not a substrate o
bile salt export pump (BSEP).
The M1 metabolite is not a substrate of P-gp, BCRP, or BESP.
Neither niraparib nor M1 is a substrate of organic anion transport
polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic
cation transporter 1 (OCT1), organic anion transporter 1 (OAT1),
3 (OAT3), or organic cation transporter 2 (OCT2).
Indication:
U.S. FDA APPROVED DRUGS DURING 2017
Sr.No- 10
Name of the Drug- Zejula
Active Ingredient- Niraparib Pharmacological Classification-
For themaintenance treatment of recurrent epitthelial ovarian,
fallopian tube or prime cancers
Date of Approval- 03-27-2017
(Ref- FDA approved List 2017) HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ZEJULA safely and effectively. See full prescribing information for
ZEJULA.
ZEJULATM (niraparib) capsules, for oral use
Initial U.S. Approval: 2017
INDICATIONS AND USAGE
ZEJULA is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated
for the maintenance treatment of adult patients with recurrent epithelial
ovarian, fallopian tube, or primary peritoneal cancer who are in a
complete or partial response to platinum-based chemotherapy.
Adverse Reaction:
ADVERSE REACTIONS
Most common adverse reactions (incidence .10%) are
thrombocytopenia, anemia, neutropenia, leukopenia, palpitations,
nausea, constipation, vomiting, abdominal pain/distention,
mucositis/stomatitis, diarrhea, dyspepsia, dry mouth, fatigue/asthenia,
decreased appetite, urinary tract infection.
AST/ALT elevation,myalgia, back pain, arthralgia, headache, dizziness,
dysgeusia,insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and
hypertension.
Contra-Indications:
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML):
MDS/AML occurred in patients exposed to ZEJULA, and some
cases were fatal.
Monitor patients for hematological toxicity and discontinue
if MDS/AML is confirmed
Bone Marrow Suppression:
Test complete blood counts weekly for the first month, monthly for the
next 11 months and periodically thereafter for clinically significant changes.
Cardiovascular Effects:
Monitor blood pressure and heart rate monthly for the first year and
periodically thereafter during treatment with ZEJULA.
Manage with antihypertensive medications as well as adjustment
of the ZEJULA dose, if necessary.
Embryo-Fetal Toxicity:
ZEJULA can cause fetal harm. Advise females of reproductive potential
of the potential risk to a fetus and to use effective contraception.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
ZEJULA is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated
for the maintenance treatment of adult patients with recurrent epithelial
ovarian, fallopian tube, or primary peritoneal cancer who are in a
complete or partial response to platinum-based chemotherapy.
DOSAGE AND ADMINISTRATION
Recommended dose is 300 mg taken once daily with or without
food.
Continue treatment until disease progression or unacceptable
adverse reaction.
For adverse reactions, consider interruption of treatment, dose
reduction, or dose discontinuation.
DOSAGE FORMS AND STRENGTHS
Capsules: 100 mg
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Advise patients to contact their healthcare provider if they experience
weakness, feeling tired, fever,weight loss, frequent infections,
bruising, bleeding easily, breathlessness, blood in urine or stool,
and/or laboratory findings of low blood cell counts, or a need
for blood transfusions.
This may be a sign of hematological toxicity or myelodysplastic
syndrome (MDS) or acute myeloid leukemia (AML) which has been
reported in patients treated with ZEJULA [see Warnings and Precautions
Bone Marrow Suppression
Advise patients that periodic monitoring of their blood counts is required.
Advise patients to contact their healthcare provider for new onset of bleeding,
fever, or symptoms of infection
Cardiovascular Effects
Advise patients to undergo monthly blood pressure and heart rate
monitoring for the first year of treatment and then periodically thereafter
and to contact their healthcare provider if blood pressure is elevated
Dosing Instructions
Inform patients on how to take ZEJULA .
ZEJULA should be taken once daily.
Instruct patients that if they miss a dose of ZEJULA, not to take an extra dose to
make up for the one that they missed.
They should take their next dose at the regularly scheduled time.
Each capsule should be swallowed whole.
ZEJULA may be taken with or without food.
Bedtime administration may be a potential method for managing nausea.
Embryo-Fetal Toxicity
Advise females to inform their healthcare provider if they are pregnant
or become pregnant.
Inform female patients of the risk to a fetus and potential loss of the pregnancy
Contraception
Advise females of reproductive potential to use effective contraception
during treatment with ZEJULA and for at least 6 months after receiving
the last dose..
Lactation
Advise patients not to breastfeed while taking ZEJULA and for 1 month
after the last dose.
Manufactured for: TESARO, Inc. 1000 Winter St., #3300, Waltham, MA 02451
ZEJULA is a trademark of TESARO, Inc.
All other trademarks referenced herein are the property of
their respective owners.
©2017 TESARO, Inc. All rights reserved. 117648
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes,
PARP-1 and PARP-2,which play a role in DNA repair. In vitro studies
have shown that niraparib-induced cytotoxicity may involve inhibition
of PARP enzymatic activity and increased formation of PARP-DNA complexes
resulting in DNA damage, apoptosis and cell death.
Increased niraparib-induced cytotoxicity was observed in tumor cell lines
with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth
in mouse xenograft models of human cancer cell lines with deficiencies
in BRCA1/2 and in human patient-derived xenograft tumor models with
homologous recombination deficiency that had either mutated or wild
type BRCA1/2.
2. Pharmacodynamics
The pharmacodynamic response of niraparib has not been characterized.
Cardiovascular Effects
Niraparib has the potential to cause effects on pulse rate and blood
pressure in patients receiving the recommended dose, which may be
related to pharmacological inhibition of the dopamine transporter
(DAT), norepinephrine transporter (NET) and serotonin transporter
(SERT)
.
3. Pharmacokinetics
Following a single-dose administration of 300 mg niraparib,
the mean (±SD) peak plasma concentration (Cmax) was 804 (± 403) ng/mL.
The systemic exposures (Cmax and AUC) of niraparib increased in a dose
proportional manner with daily doses ranging 30 mg (0.1 times the approved
recommended dosage) to 400 mg (1.3 times the approved recommended dosage).
The accumulation ratio of niraparib exposure following 21 days of repeated
daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg.
Absorption
The absolute bioavailability of niraparib is approximately 73%.
Following oral administration of niraparib, peak plasma concentration,
Cmax, is reached within 3 hours.
Concomitant administration of a high fat meal (800-1,000 calories
with approximately 50% of total caloric content of the meal from fat)
did not significantly affect the pharmacokinetics of niraparib.
Distribution
Niraparib is 83.0% bound to human plasma proteins. The average
(±SD) apparent volume of distribution (Vd/F) was 1220 (±1114) L.
In a population pharmacokinetic analysis, the Vd/F of niraparib
was 1074 L in cancer patients.
Elimination
Following multiple daily doses of 300 mg niraparib, the mean half-life
(t1/2) is 36 hours. In a population pharmacokinetic analysis, the apparent
total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients.
Metabolism
Niraparib is metabolized primarily by carboxylesterases (CEs) to
form a major inactive metabolite, which subsequently undergoes
glucuronidation.
Excretion
Following administration of a single oral 300 mg dose of
radio-labeled niraparib, the average percent recovery of the administered
dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine, and
38.8% (range 28.3% to 47.0%) in feces.
In pooled samples collected over 6 days, unchanged niraparib
accounted for 11% and 19% of the administered dose recovered
in urine and feces, respectively.
Specific Populations
Age (18 to 65 years old), race/ethnicity, and mild to moderate renal
impairment had no clinically significant effect on the pharmacokinetics
of niraparib.
The effect of severe renal impairment or end-stage renal disease
undergoing hemodialysis on the pharmacokinetics of niraparib is unknown.
The effect of moderate or severe hepatic impairment on the
pharmacokinetics of niraparib is unknown.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1 Pregnancy
Risk Summary
Based on its mechanism of action, ZEJULA can cause fetal harm when
administered to pregnant women.There are no data regarding the use of ZEJULA in
pregnant women to inform the drug-associated risk.
ZEJULA has the potential to cause teratogenicity and/or embryo-fetal death
since niraparib is genotoxic and targets actively dividing cells in animals
and patients (e.g., bone marrow).
Due to the potential risk to a fetus based on its mechanism of action,
animal developmental and reproductive toxicology studies were not
conducted with niraparib. Apprise pregnant women of
the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated
population is unknown.
In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically recognized pregnancies
is 2% to 4% and 15% to 20%, respectively.
2. Lactation
Risk Summary
No data are available regarding the presence of niraparib or its metabolites
in human milk, or on its effects on the breastfed infant or milk production.
Because of the potential for serious adverse reactions in breastfed infants
from ZEJULA, advise a lactating woman not to breastfeed during
treatment with ZEJULA and for 1 month after receiving the final dose.
3. Females and Males of Reproductive Potential
Pregnancy Testing
ZEJULA can cause fetal harm when administered to a pregnant woman .
A pregnancy test is recommended for females of reproductive potential
prior to initiating ZEJULA treatment.
Contraception
Females
ZEJULA can cause fetal harm when administered to a pregnant woman .
Advise females of reproductive potential to use effective contraception
treatment with ZEJULA and for at least for 6 months following the last dose.
Infertility
Males
Based on animal studies, ZEJULA may impair fertility in males of
reproductive potential.
4. Pediatric Use
Safety and effectiveness of ZEJULA have not been established in
pediatric patients.
5. Geriatric Use
In Trial 1 (NOVA), 35% of patients were aged .65 years and 8%
were aged .75 years. No overall differences in safety and effectiveness
of ZEJULA were observed between these patients and younger patients
but greater sensitivity of some older individuals cannot be ruled out.
6. Renal Impairment
No dose adjustment is necessary for patients with mild (CLcr:60 to 89 mL/min)
to moderate (CLcr:30 to 59 mL/min) renal impairment.
The degree of renal impairment was determined by creatinine clearance
as estimated by the Cockcroft-Gault equation.
The safety of ZEJULA in patients with severe renal impairment or end
stage renal disease undergoing hemodialysis is unknown.
7. Hepatic Impairment
No dose adjustment is needed in patients with mild hepatic impairment
according to the National
Cancer Institute . Organ Dysfunction Working Group (NCI-ODWG) criteria.
The safety of ZEJULA in patients with moderate to severe hepatic
impairment is unknown.
OVERDOSAGE
There is no specific treatment in the event of ZEJULA overdose, and
symptoms of overdose are not established. In the event of an overdose,
healthcare practitioners should follow general supportive measure
and should treat symptomatically.
