Indications and Usage for Zejula
Zejula® is 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.
Zejula Dosage and AdministrationRecommended Dosage
The recommended dose of Zejula
as monotherapy is 300 mg (three 100 mg capsules) taken orally once daily.
Instruct patients to take
their dose of Zejula at approximately the same time each day. Each capsule
should be swallowed whole. Zejula may be taken with or without food. Bedtime
administration may be a potential method for managing nausea.
Patients should start
treatment with Zejula no later than 8 weeks after their most recent
platinum-containing regimen.
Zejula treatment should be
continued until disease progression or unacceptable toxicity.
In the case of a missed dose
of Zejula, instruct patients to take their next dose at its regularly scheduled
time. If a patient vomits or misses a dose of Zejula, an additional dose should
not be taken.
Dose Adjustments for Adverse
Reactions
To manage adverse reactions,
consider interruption of treatment, dose reduction, or dose discontinuation.
The recommended dose modifications for adverse reactions are listed in Tables
1, 2 and 3.
Table 1: Recommended dose modifications for adverse reactions
|
|
Dose level
|
Dose
|
|
*
If further dose reduction below 100 mg/day is
required, discontinue Zejula.
|
|
Starting dose
|
300 mg/day
(three 100 mg capsules)
|
|
First dose
reduction
|
200 mg/day (two
100 mg capsules)
|
|
Second dose
reduction
|
100 mg/day* (one 100 mg capsule)
|
Table 2: Dose modifications for
non-hematologic adverse reactions
|
|
*
CTCAE=Common Terminology Criteria for Adverse Events
|
|
Non-hematologic
CTCAE* ≥ Grade 3 adverse reaction where
prophylaxis is not considered feasible or adverse reaction persists despite
treatment
|
· Withhold
Zejula for a maximum of 28 days or until resolution of adverse reaction.
· Resume
Zejula at a reduced dose per Table 1. Up to 2 dose reductions are permitted.
|
|
CTCAE ≥ Grade 3
treatment-related adverse reaction lasting more than 28 days while patient is
administered Zejula 100 mg/day
|
Discontinue
medication.
|
Table 3: Dose modifications for
hematologic adverse reactions
|
|
*
If myelodysplastic syndrome or acute myeloid leukemia
(MDS/AML) is confirmed, discontinue Zejula [see Warnings and Precautions (5.1, 5.2)].
|
|
Monitor complete
blood counts weekly for the first month, monthly for the next 11 months of
treatment and periodically after this time [see Warnings and Precautions (5.1)].
|
|
Platelet count
<100,000/µL
|
First
occurrence:
· Withhold
Zejula for a maximum of 28 days and monitor blood counts weekly until
platelet counts return to ≥100,000/µL.
· Resume
Zejula at same or reduced dose per Table 1.
· If
platelet count is <75,000/µL, resume at a reduced dose.
|
|
Second
occurrence:
· Withhold
Zejula for a maximum of 28 days and monitor blood counts weekly until
platelet counts return to ≥100,000/µL.
· Resume
Zejula at a reduced dose per Table 1.
· Discontinue
Zejula if the platelet count has not returned to acceptable levels within 28
days of the dose interruption period, or if the patient has already undergone
dose reduction to 100 mg once daily.*
|
|
Neutrophil
<1,000/µL or Hemoglobin <8 g/dL
|
· Withhold
Zejula for a maximum of 28 days and monitor blood counts weekly until
neutrophil counts return to ≥1,500/µL or hemoglobin returns to ≥9 g/dL.
· Resume
Zejula at a reduced dose per Table 1.
· Discontinue
Zejula if neutrophils and/or hemoglobin have not returned to acceptable
levels within 28 days of the dose interruption period, or if the patient has
already undergone dose reduction to 100 mg once daily.*
|
|
Hematologic
adverse reaction requiring transfusion
|
· For
patients with platelet count ≤10,000/μL, platelet transfusion should be
considered. If there are other risk factors such as co-administration of
anticoagulation or antiplatelet drugs, consider interrupting these drugs
and/or transfusion at a higher platelet count.
· Resume
Zejula at a reduced dose.
|
Dosage Forms and Strengths
100 mg capsule having a white
body with "100 mg" printed in black ink, and a purple cap with
"Niraparib" printed in white ink.
Contraindications
None.
Warnings and PrecautionsMyelodysplastic Syndrome/Acute
Myeloid Leukemia
Myelodysplastic Syndrome/Acute
Myeloid Leukemia (MDS/AML), including cases with fatal outcome, have been
reported in patients who received Zejula. In Trial 1 (NOVA), MDS/AML occurred
in 5 out of 367 (1.4%) of patients who received Zejula and in 2 out of 179
(1.1%) patients who received placebo. Overall, MDS/AML has been reported in 7
out of 751 (0.9%) patients treated with Zejula in clinical studies.
The duration of Zejula
treatment in patients prior to developing MDS/AML varied from <1 month to 2
years. All patients had received previous chemotherapy with platinum and some
had also received other DNA damaging agents and radiotherapy. Discontinue
Zejula if MDS/AML is confirmed.
Bone Marrow Suppression
Hematologic adverse reactions
(thrombocytopenia, anemia and neutropenia) have been reported in patients
treated with Zejula. Grade ≥3 thrombocytopenia, anemia and neutropenia were
reported, respectively, in 29%, 25%, and 20% of patients receiving Zejula.
Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred,
respectively, in 3%, 1%, and 2% of patients.
Do not start Zejula until
patients have recovered from hematological toxicity caused by previous chemotherapy
(≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly
for the next 11 months of treatment, and periodically after this time. If
hematological toxicities do not resolve within 28 days following interruption,
discontinue Zejula, and refer the patient to a hematologist for further
investigations, including bone marrow analysis and blood sample for
cytogenetics [see Dosage
and Administration (2.2)].
Cardiovascular Effects
Hypertension and hypertensive
crisis have been reported in patients treated with Zejula. Grade 3-4
hypertension occurred in 9% of Zejula treated patients compared to 2% of
placebo treated patients in Trial 1. Discontinuation due to hypertension
occurred in <1% of patients.
Monitor blood pressure and
heart rate monthly for the first year and periodically thereafter during
treatment with Zejula. Closely monitor patients with cardiovascular disorders,
especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Medically manage hypertension with antihypertensive medications and adjustment
of the Zejula dose, if necessary [see Dosage
and Administration (2.2) and Nonclinical Toxicology
(13.2)].
Embryo-Fetal Toxicity
Based on its mechanism of
action, Zejula can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology
(12.1)]. 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) [see Warnings
and Precautions (5.2) and Nonclinical Toxicology
(13.1)]. 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. Advise females of reproductive potential to use
effective contraception during treatment and for 6 months after the last dose
of Zejula [see Use in
Specific Populations (8.1, 8.3)].
Adverse Reactions
The following clinically
significant adverse reactions are described elsewhere in the labeling:
Myelodysplastic Syndrome/Acute Myeloid
Leukemia [see Warnings
and Precautions (5.1)]Bone Marrow Suppression [see Warnings
and Precautions (5.2)]Cardiovascular Effects [see Warnings
and Precautions (5.3)]Clinical Trials Experience
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.
The safety of Zejula
monotherapy 300 mg once daily has been studied in 367 patients with
platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal
cancer in Trial 1 (NOVA). Adverse reactions in Trial 1 led to dose reduction or
interruption in 69% of patients, most frequently from thrombocytopenia (41%)
and anemia (20%). The permanent discontinuation rate due to adverse reactions
in Trial 1 was 15%. The median exposure to Zejula in these patients was 250
days.
Table 4 and Table 5 summarize
the common adverse reactions and abnormal laboratory findings, respectively,
observed in patients treated with Zejula.
Table 4: Adverse Reactions Reported in ≥10% of Patients Receiving
Zejula
|
|
|
Grades 1-4*
|
Grades 3-4*
|
|
|
Zejula
N=367
%
|
Placebo
N=179
%
|
Zejula
N=367
%
|
Placebo
N=179
%
|
|
*
CTCAE=Common Terminology Criteria for Adverse Events
version 4.02
|
|
Blood and Lymphatic System Disorders
|
|
Thrombocytopenia
|
61
|
5
|
29
|
0.6
|
|
Anemia
|
50
|
7
|
25
|
0
|
|
Neutropenia
|
30
|
6
|
20
|
2
|
|
Leukopenia
|
17
|
8
|
5
|
0
|
|
Cardiac Disorders
|
|
Palpitations
|
10
|
2
|
0
|
0
|
|
Gastrointestinal Disorders
|
|
Nausea
|
74
|
35
|
3
|
1
|
|
Constipation
|
40
|
20
|
0.8
|
2
|
|
Vomiting
|
34
|
16
|
2
|
0.6
|
|
Abdominal
pain/distention
|
33
|
39
|
2
|
2
|
|
Mucositis/stomatitis
|
20
|
6
|
0.5
|
0
|
|
Diarrhea
|
20
|
21
|
0.3
|
1
|
|
Dyspepsia
|
18
|
12
|
0
|
0
|
|
Dry mouth
|
10
|
4
|
0.3
|
0
|
|
General Disorders and Administration Site Conditions
|
|
Fatigue/Asthenia
|
57
|
41
|
8
|
0.6
|
|
Metabolism and Nutrition Disorders
|
|
Decreased
appetite
|
25
|
15
|
0.3
|
0.6
|
|
Infections and Infestations
|
|
Urinary tract
infection
|
13
|
8
|
0.8
|
1
|
|
Investigations
|
|
|
|
|
|
AST/ ALT
elevation
|
10
|
5
|
4
|
2
|
|
Musculoskeletal and Connective Tissue Disorders
|
|
Myalgia
|
19
|
20
|
0.8
|
0.6
|
|
Back pain
|
18
|
12
|
0.8
|
0
|
|
Arthralgia
|
13
|
15
|
0.3
|
0.6
|
|
Nervous System Disorders
|
|
Headache
|
26
|
11
|
0.3
|
0
|
|
Dizziness
|
18
|
8
|
0
|
0
|
|
Dysgeusia
|
10
|
4
|
0
|
0
|
|
Psychiatric Disorders
|
|
Insomnia
|
27
|
8
|
0.3
|
0
|
|
Anxiety
|
11
|
7
|
0.3
|
0.6
|
|
Respiratory, Thoracic, and Mediastinal Disorders
|
|
Nasopharyngitis
|
23
|
14
|
0
|
0
|
|
Dyspnea
|
20
|
8
|
1
|
1
|
|
Cough
|
16
|
5
|
0
|
0
|
|
Skin and Subcutaneous Tissue Disorders
|
|
Rash
|
21
|
9
|
0.5
|
0
|
|
Vascular Disorders
|
|
Hypertension
|
20
|
5
|
9
|
2
|
Table 5: Abnormal Laboratory Findings in ≥25% of Patients Receiving
Zejula
|
|
|
Grades 1-4
|
Grades 3-4
|
|
|
Zejula
N=367
(%)
|
Placebo
N= 179
(%)
|
Zejula
N= 367
(%)
|
Placebo
N= 179
(%)
|
|
N=number of
patients; WBC=white blood cells; ALT=Alanine aminotransferase; AST=Aspartate
aminotransferase
|
|
Decrease in
hemoglobin
|
85
|
56
|
25
|
0.5
|
|
Decrease in
platelet count
|
72
|
21
|
35
|
0.5
|
|
Decrease in WBC
count
|
66
|
37
|
7
|
0.7
|
|
Decrease in
absolute neutrophil count
|
53
|
25
|
21
|
2
|
|
Increase in AST
|
36
|
23
|
1
|
0
|
|
Increase in ALT
|
28
|
15
|
1
|
2
|
The following adverse
reactions and laboratory abnormalities have been identified in ≥1 to <10% of
the 367 patients receiving Zejula in the NOVA trial and not included in the
table: tachycardia, peripheral edema, hypokalemia, bronchitis, conjunctivitis,
gamma-glutamyl transferase increased, blood creatinine increased, blood
alkaline phosphatase increased, weight decreased, depression, epistaxis.
USE IN SPECIFIC POPULATIONSPregnancy
Risk
Summary
Based on its mechanism of
action, Zejula can cause fetal harm when administered to pregnant women [see Clinical Pharmacology
(12.1)]. 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) [see Warnings
and Precautions (5.2) and Nonclinical Toxicology
(13.1)]. 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.
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.
Females and Males of
Reproductive Potential
Pregnancy
Testing
Zejula can cause fetal harm
when administered to a pregnant woman [see Use in
Specific Populations (8.1)].
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 [see Use in
Specific Populations (8.1)].
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 [see Nonclinical Toxicology
(13.1)].
Pediatric Use
Safety and effectiveness of
Zejula have not been established in pediatric patients.
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.
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.
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 measures and should treat symptomatically.
Zejula Description
Niraparib is an orally
available poly(ADP-ribose) polymerase (PARP) inhibitor.
The chemical name for
niraparib tosylate monohydrate is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole
7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1). The molecular formula
is C26H30N4O5S and it has a molecular
weight of 510.61 amu. The molecular structure is shown below:
Niraparib tosylate monohydrate
is a white to off-white, non-hygroscopic crystalline solid. Niraparib
solubility is pH independent below the pKa of 9.95, with an aqueous free base
solubility of 0.7 mg/mL to 1.1 mg/mL across the physiological pH range.
Each Zejula capsule contains
159.4 mg niraparib tosylate monohydrate equivalent to 100 mg niraparib free
base as the active ingredient. The inactive ingredients in the capsule fill are magnesium stearate and
lactose monohydrate. The capsule shell consists
of titanium dioxide, gelatin in the white capsule body; and FD&C Blue #1,
FD&C Red #3, FD&C Yellow #5 and gelatin in the purple capsule cap.
The black printing ink consists of
shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene
glycol, purified water, strong ammonia solution, potassium hydroxide and black
iron oxide. The white printing ink consists
of shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene
glycol, sodium hydroxide, povidone and titanium oxide.
Zejula - Clinical PharmacologyMechanism 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.
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) [see Nonclinical
Toxicology (13.2)].
In the NOVA study, mean pulse
rate and blood pressure increased over baseline in the niraparib arm relative
to the placebo arm at all on-study assessments. Mean greatest increases from
baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the
niraparib and placebo arms, respectively. Mean greatest increases from baseline
in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the
niraparib and placebo arms, respectively. Mean greatest increases from baseline
in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the
niraparib and placebo arms, respectively.
Cardiac
Electrophysiology
The potential for QTc
prolongation with niraparib was evaluated in a randomized, placebo-controlled
trial in cancer patients (367 patients on niraparib and 179 patients on
placebo). No large changes in the mean QTc interval (>20 ms) were detected
in the trial following the treatment of niraparib 300 mg once daily.
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 from 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.
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 CYP1A2,
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 UDP-glucuronosyltransferases
(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
BSEP. Neither niraparib nor M1 is 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 of bile
salt export pump (BSEP). The M1 metabolite is not a substrate of P-gp, BCRP, or
BSEP. 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).
Nonclinical ToxicologyCarcinogenesis, Mutagenesis,
Impairment of Fertility
Carcinogenicity studies have
not been conducted with niraparib.
Niraparib was clastogenic in
an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone
marrow micronucleus assay. This clastogenicity is consistent with genomic instability
resulting from the primary pharmacology of niraparib and indicates potential
for genotoxicity in humans. Niraparib was not mutagenic in a bacterial reverse
mutation assay (Ames) test.
Fertility studies in animals
have not been conducted with niraparib. In repeat-dose oral toxicity studies,
niraparib was administered daily for up to 3 months duration in rats and dogs.
Reduced sperm, spermatids and germ cells in epididymides and testes were
observed at doses ≥10 mg/kg and ≥1.5 mg/kg in rats and dogs, respectively.
These dose levels resulted in systemic exposures approximately 0.3 and 0.012
times, respectively, the human exposure (AUC0-24hr) at the recommended dose of
300 mg daily. There was a trend toward reversibility of these findings 4 weeks
after dosing was stopped.
Animal Toxicology and/or
Pharmacology
In vitro, niraparib bound to
the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin
transporter (SERT) and inhibited uptake of norepinephrine and dopamine in cells
with IC50values that were lower than the Cmin at steady-state in
patients receiving the recommended dose. Niraparib has the potential to cause
effects in patients related to inhibition of these transporters (e.g.,
cardiovascular or CNS).
Intravenous administration of
niraparib to vagotomized dogs over 30 minutes at 1, 3 and 10 mg/kg resulted in
an increased range of arterial pressures of 13-20, 18-27 and 19-25% and
increased range of heart rates of 2-11, 4-17 and 12-21% above pre-dose levels,
respectively. The unbound plasma concentrations of niraparib in dogs at these
dose levels were approximately 0.7, 2 and 8 times the unbound Cmax at steady-state in
patients receiving the recommended dose.
In addition, niraparib crossed
the blood-brain barrier in rats and monkeys following oral administration. The
cerebrospinal fluid (CSF):plasma Cmax ratios of niraparib administered at 10 mg/kg orally to two
Rhesus monkeys were 0.10 and 0.52.
Clinical Studies
Trial 1 (NOVA) was a
double-blind, placebo-controlled trial in which patients (n=553) with
platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary
peritoneal cancer were randomized 2:1 to Zejula 300 mg orally daily or matched
placebo within 8 weeks of the last therapy. All patients had received at least two
prior platinum-containing regimens and were in response (complete or partial)
to their most recent platinum-based regimen.
Randomization was stratified
by time to progression after the penultimate platinum therapy (6 to <12
months and ≥12 months); use of bevacizumab in conjunction with the penultimate
or last platinum regimen (yes/no); and best response during the most recent
platinum regimen (complete response and partial response). Eligible patients
were assigned to one of two cohorts based on the results of the BRACAnalysis
CDx. Patients with deleterious or suspected deleterious germline BRCA mutations (gBRCAm) were assigned to the
germline BRCA mutated (gBRCAmut) cohort (n=203), and those without
germline BRCA mutations were
assigned to the non-gBRCAmut cohort (n=350).
The major efficacy outcome
measure, PFS (progression-free survival), was determined primarily by central
independent assessment per RECIST (Response Evaluation Criteria in Solid
Tumors, version 1.1). In some cases, criteria other than RECIST, such as
clinical signs and symptoms and increasing CA-125, were also applied.
The median age of patients
ranged from 57-64 years among patients treated with Zejula and 58-67 years
among patients treated with placebo. Eighty-six percent of all patients were
white. Sixty-seven percent of patients receiving Zejula and 69% of patients
receiving placebo had an ECOG of 0 at study baseline. Approximately 40% of
patients were enrolled in the U.S. or Canada and 51% of all patients were in
complete response to most recent platinum-based regimen, with 39% on both arms
with an interval of 6-12 months since the penultimate platinum regimen.
Twenty-six percent of those treated with Zejula and 31% treated with placebo
had received prior bevacizumab therapy. Approximately 40% of patients had 3 or
more lines of treatment.
The trial demonstrated a
statistically significant improvement in PFS for patients randomized to Zejula
as compared with placebo in the gBRCAmut
cohort and the non-gBRCAmut cohort (Table 6,
and Figures 1 and 2).
Table 6: Efficacy Results - Study 1 (IRC Assessment*, Intent-To-Treat Population)
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|
|
|
gBRCAmut
Cohort
|
non-gBRCAmut
Cohort
|
|
|
Zejula
(N=138)
|
Placebo (N=65)
|
Zejula
(N=234)
|
Placebo (N=116)
|
|
|
NR=Not Reached
|
|
|
*
efficacy
analysis was based on blinded central independent radiologic and clinical
oncology review committee (IRC).
†
based on a
stratified Cox proportional hazards model
‡
based on a stratified log-rank test
|
|
|
PFS Median in months (95% CI)
|
21.0
(12.9, NR)
|
5.5
(3.8, 7.2)
|
9.3
(7.2, 11.2)
|
3.9
(3.7, 5.5)
|
|
|
Hazard Ratio (HR)†
(95% CI)
|
0.26
(0.17, 0.41)
|
0.45
(0.34, 0.61)
|
|
|
p-value‡
|
<0.0001
|
<0.0001
|
|
Figure
1: Kaplan-Meier Plot for Progression-Free Survival in the gBRCAmut
Cohort Based on IRC Assessment (ITT Population, N=203)
Figure
2: Kaplan-Meier Plot for Progression-Free Survival in the Non-gBRCAmut
Cohort Overall Based on IRC Assessment (ITT Population, N=350)
At the time of the PFS
analysis, limited overall survival data were available with 17% deaths across
the two cohorts.
How Supplied/Storage and Handling
Zejula is available as
capsules having a white body printed with "100 mg" in black ink, and
a purple cap printed with "Niraparib" in white ink.
Each capsule contains 100 mg
of niraparib free base.
|
Zejula capsules
are packaged as 90-count bottles
|
NDC 69656-103-90
|
Store at 20°C to 25°C (68°F to
77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F) [see USP
Controlled Room Temperature].
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Patient Information).
MDS/AML
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 (5.1)].
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 [see Warnings
and Precautions (5.2)].
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 [see Warnings
and Precautions (5.3)].
Dosing
Instructions
Inform patients on how to take
Zejula [see Dosage
and Administration (2.1)]. 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 [see Warnings and
Precautions (5.4) and Use in
Specific Populations (8.1)].
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 [see Use in
Specific Populations (8.3)].
Lactation
Advise patients not to
breastfeed while taking Zejula and for 1 month after the last dose [see Use in Special
Populations (8.2)].
Manufactured for: TESARO, Inc.
1000 Winter St., Waltham, MA 02451
Zejula is a registered
trademark of TESARO, Inc. All other trademarks referenced herein are the
property of their respective owners.
©2017 TESARO, Inc. All rights
reserved.
118569
|
PATIENT INFORMATION
Zejula® (zuh-JOO-luh)
(niraparib)
capsules
|
|
This Patient
Information has been approved by the U.S. Food and Drug Administration. Issued:
August 2017
|
|
What is the most important information I should know about Zejula?
|
|
Zejula may cause serious side effects including:
Bone marrow problems called Myelodysplastic
Syndrome (MDS) or a type of cancer of the blood called Acute Myeloid
Leukemia (AML). Some
people who have ovarian cancer and who have received previous treatment
with chemotherapy or certain other medicines for their cancer have
developed MDS or AML during treatment with Zejula. MDS or AML may lead
to death. If you develop MDS or AML, your healthcare provider will stop
treatment with Zejula.
Symptoms of low blood cell counts (low red blood cells, low white blood
cells, and low platelets) are common during treatment with Zejula, but
can be a sign of serious bone marrow problems, including MDS or AML.
Symptoms may include:
|
|
|
|
o weakness
o feeling
tired
o weight
loss
o frequent
infections
|
o fever
o shortness
of breath
o blood
in urine or stool
o bruising
or bleeding more easily
|
|
Your healthcare provider will do blood tests to
check your blood cell counts:
· before
treatment with Zejula
· weekly
for the first month of treatment with Zejula
· every
month for the next 11 months, then as needed during treatment with Zejula
|
|
· High blood pressure. High blood pressure is common during treatment
with Zejula, and can become serious. Your healthcare provider will check your
blood pressure and heart rate monthly for the first year and as needed
thereafter during your treatment with Zejula.
|
|
See "What are the possible side effects of
Zejula?" for more information about side effects.
|
|
What is Zejula?
Zejula is a prescription medicine used for the maintenance treatment of
adults with ovarian cancer, fallopian tube cancer, or primary peritoneal
cancer, when the cancer comes back. Zejula is used after the cancer has
responded (complete or partial response) to treatment with platinum-based
chemotherapy.
It is not known if Zejula is safe and effective in children.
|
|
Before taking Zejula, tell your healthcare provider about all of your
medical conditions, including if you:
|
|
|
· have
heart problems.
· have
high blood pressure.
· are
pregnant or plan to become pregnant. Zejula can harm your unborn baby and may
cause loss of pregnancy (miscarriage).
If you are able to become pregnant,
your healthcare provider may perform a pregnancy test before you start
treatment with Zejula.Females who are able to become
pregnant should use effective birth control (contraception) during
treatment with Zejula and for 6 months after the last dose of Zejula.
Talk to your healthcare provider about birth control methods that may
be right for you.Tell your healthcare provider right
away if you become pregnant.
· are
breastfeeding or plan to breastfeed. It is not known if Zejula passes into
your breast milk. Do not breastfeed during treatment with Zejula and for 1
month after the last dose of Zejula. Talk to your healthcare provider about
the best way to feed your baby during this time.
|
|
Tell your healthcare provider about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
|
|
How should I take Zejula?
|
|
|
· Take
Zejula exactly as your healthcare provider tells you to.
· Take
Zejula 1 time each day, at the same time each day.
· Zejula
may be taken with or without food.
· Zejula
capsules should be swallowed whole.
· Taking
Zejula at bedtime may help relieve any nausea symptoms you may have.
· Do
not stop taking Zejula without first talking with your healthcare provider.
· If
you miss a dose of Zejula, take your next dose at your scheduled time. Do not
take an extra dose to make up for a missed dose.
· If
you vomit after taking a dose of Zejula, do not take an extra dose. Take your
next dose at your scheduled time.
· If
you take too much Zejula, call your healthcare provider or go to the nearest
hospital emergency room right away.
|
|
What are the possible side effects of
Zejula?
Zejula can cause serious side effects, including:
|
|
|
· See "What is the most important information
I should know about Zejula?"
|
|
The most common
side effects of Zejula include:
|
|
· heart
not beating regularly
· nausea
· constipation
· vomiting
· pain
in the stomach area
· mouth
sores
· diarrhea
· indigestion
or heartburn
· dry
mouth
· tiredness
· loss
of appetite
· urinary
tract infection
|
· changes
in liver function blood tests
· pain
in your joints, muscles, and back
· headache
· dizziness
· change
in the way food tastes
· trouble
sleeping
· anxiety
· sore
throat
· shortness
of breath
· cough
· rash
|
|
Your healthcare
provider may change your dose, temporarily stop, or permanently stop
treatment with Zejula, if you have certain side effects.
These are not all the possible side effects of Zejula. For more information,
ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.
|
|
How should I store Zejula?
Store Zejula at room temperature between 68° to 77°F (20° to 25°C).
Keep Zejula and all medicines out of the reach of
children.
|
|
General information about the safe and effective use of Zejula.
Medicines are sometimes prescribed for purposes other than those listed in a
Patient Information leaflet. Do not use Zejula for a condition for which it
was not prescribed. Do not give Zejula to other people, even if they have the
same symptoms that you have. It may harm them. You can ask your healthcare
provider or pharmacist for information about Zejula that is written for
health professionals.
|
|
What are the ingredients in Zejula?
Active ingredient: niraparib
Inactive ingredients:
Capsule fill: magnesium stearate and lactose monohydrate
Capsule shell: titanium dioxide and gelatin in the white capsule body and
FD&C Blue #1, FD&C Red #3, FD&C Yellow #5 and gelatin in the
purple capsule cap.
The black printing ink: shellac, dehydrated alcohol, isopropyl alcohol, butyl
alcohol, propylene glycol, purified water, strong ammonia solution, potassium
hydroxide and black iron oxide.
The white printing ink: shellac, dehydrated alcohol, isopropyl alcohol, butyl
alcohol, propylene glycol, sodium hydroxide, povidone and titanium oxide.
Manufactured for: TESARO, Inc. 1000 Winter St., Waltham, MA 02451
Zejula is a registered trademark of TESARO, Inc. All other trademarks
referenced herein are the property of their respective owners. ©2017 TESARO,
Inc. All rights reserved.
118569
For more information, call 1-844-483-7276 or go to www.tesarobio.com
|
PRINCIPAL DISPLAY PANEL - 100 mg Capsule Bottle Label
NDC 69656-103-90
Rx only
Zejula®
niraparib
capsules
100 mg
90
capsules
TESARO™
118388
|
Zejula niraparib capsule
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:69656-103
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active
Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
niraparib (niraparib)
|
niraparib
|
100 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
magnesium stearate
|
|
|
lactose monohydrate
|
|
|
titanium dioxide
|
|
|
gelatin hydrolysate (porcine skin, mw 3000)
|
|
|
FD&C Blue no. 1
|
|
|
erythrosine sodium anhydrous
|
|
|
FD&C Yellow no. 5
|
|
|
|
Product
Characteristics
|
|
Color
|
WHITE, PURPLE
|
Score
|
no score
|
|
Shape
|
CAPSULE
|
Size
|
22mm
|
|
Flavor
|
|
Imprint Code
|
100;mg;Niraparib
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:69656-103-90
|
90 CAPSULE in 1
BOTTLE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA208447
|
03/27/2017
|
|
|
|
Labeler - TESARO, Inc. (963385559)
|
Revised:
08/2017
TESARO, Inc.
