1)    First-Line Maintenance Treatment of Advanced Ovarian Cancer

ZEJULA is indicated for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.

2)    Maintenance Treatment of Recurrent Germline BRCA-mutated Ovarian Cancer

ZEJULA is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAmut) recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

A test is used by Your healthcare provider to determine whether you have BRCA-mutated ovarian cancer

4.2. Posology and Method of administration

4.2.1.     Patient Selection 

Maintenance Treatment of Recurrent Germline BRCA-mutated Ovarian Cancer

Select patients for the maintenance treatment of recurrent ovarian cancer with ZEJULA based on the presence of deleterious or suspected deleterious germline BRCA mutations [see Pre-Clinical Safety Data - Clinical Studies (5.3)].

4.2.2.      Recommended Dosage 

Continue treatment with ZEJULA until disease progression or unacceptable toxicity.

Instruct patients to take their dose of ZEJULA at approximately the same time each day. Advise patients to swallow each tablet whole and not to chew, crush, or split ZEJULA prior to swallowing. ZEJULA may be taken with or without food. Bedtime administration may be a potential method for managing nausea.

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.

First-Line Maintenance Treatment of Advanced Ovarian Cancer

·     For patients weighing <77 kg (<170 lbs) OR with a platelet count of <150,000/mcL, the recommended dosage is 200 mg taken orally once daily.

·     For patients weighing ³77 kg (³170 lbs) AND who have a platelet count ³150,000/mcL, the recommended dosage is 300 mg taken orally once daily.

For the maintenance treatment of advanced ovarian cancer, patients should start treatment with ZEJULA no later than 12 weeks after their most recent platinum-containing regimen.

Maintenance Treatment of Recurrent Germline BRCA-mutated Ovarian Cancer

The recommended dosage of ZEJULA is 300 mg taken orally once daily.

For the maintenance treatment of recurrent ovarian cancer, patients should start treatment with ZEJULA no later than 8 weeks after their most recent platinum-containing regimen.

4.2.3.      Dosage 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

^a If further dose reduction below 100 mg/day is required, discontinue Zejula.

Table 2. Dose Modifications for Non-Hematologic Adverse Reactions

CTCAE = Common Terminology Criteria for Adverse Events.

Table 3. Dose Modifications for Hematologic Adverse Reactions

^a If myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) is confirmed, discontinue ZEJULA [see Special Warnings and Precautions for Use (4.4.1, 4.4.2)].

4.2.4     Dosage Adjustment for Hepatic Impairment 

Moderate Hepatic Impairment

For patients with moderate hepatic impairment, reduce the starting dosage of ZEJULA to 200 mg once daily. Monitor patients for hematologic toxicity and reduce the dose further, if needed [see Posology and Method of administration (4.2.3), Specific Populations (4.8), Pharmacodynamic Properties (5.1.1)].

4.4.   Special Warnings and Precautions for Use

4.4.1.      Myelodysplastic Syndrome/Acute Myeloid Leukemia 

Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with a fatal outcome, have been reported in patients who received ZEJULA.

In PRIMA, MDS/AML occurred in 6 out of 484 (1.2%) patients treated with ZEJULA and in 3 out of 244 (1.2%) patients treated with placebo [see Undesirable effects (4.8.1)]. The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer therapy-related AML varied from 3.7 months to 2.5 years.

In NOVA, of patients within the gBRCAmut cohort, MDS/AML occurred in 10 out of 136 (7%) patients treated with ZEJULA and in 2 out of 65 (3%) patients treated with placebo [see Undesirable effects (4.8.1)]. The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer-therapy related AML varied from 3.6 months to 5.9 years.

All patients who developed secondary MDS/cancer-therapy–related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue ZEJULA if MDS/AML is confirmed.

4.4.2.      Bone Marrow Suppression 

Hematologic adverse reactions, including thrombocytopenia, anemia, neutropenia, and/or pancytopenia have been reported in patients treated with ZEJULA [see Undesirable effects (4.8)].

In PRIMA, the overall incidences of ≥Grade 3 thrombocytopenia, anemia, and neutropenia were reported in 39%, 31%, and 21%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 4%, 2%, and 2%, respectively, of patients. In patients who were administered a starting dose of ZEJULA based on baseline weight or platelet count, ≥Grade 3 thrombocytopenia, anemia, and neutropenia were reported in 22%, 23%, and 15%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 3%, 3%, and 2%, respectively, of patients.

In NOVA, ≥Grade 3 thrombocytopenia, anemia, and neutropenia were reported in 29%, 25%, and 20%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 3%, 1%, and 2%, respectively, 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 Posology and Method of administration (4.2.3)].

4.4.3.      Hypertension and Cardiovascular Effects 

Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA [see Undesirable effects (4.8)].

In PRIMA, Grade 3 to 4 hypertension occurred in 6% of patients treated with ZEJULA compared with 1% of placebo-treated patients with a median time from first dose to first onset of 43 days (range: 1 to 531 days) and with a median duration of 12 days (range: 1 to 61 days). There were no discontinuations due to hypertension.

In NOVA, Grade 3 to 4 hypertension occurred in 9% of patients treated with ZEJULA compared with 2% of placebo-treated patients with a median time from first dose to first onset of 77 days (range: 4 to 504 days) and with a median duration of 15 days (range: 1 to 86 days). Discontinuation due to hypertension occurred in <1% of patients.

Monitor blood pressure and heart rate at least weekly for the first 2 months, then 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 dose of ZEJULA, if necessary [see Posology and Method of administration (4.2.3), Pre-Clinical Safety Data (5.3.2)].

4.4.4.      Posterior Reversible Encephalopathy Syndrome 

Posterior reversible encephalopathy syndrome (PRES) occurred in 0.1% of 2,165 patients treated with ZEJULA in clinical trials and has also been described in postmarketing reports [see Undesirable effects (4.8.2)]. Signs and symptoms of PRES include seizure, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging.

Monitor all patients treated with ZEJULA for signs and symptoms of PRES. If PRES is suspected, promptly discontinue ZEJULA and administer appropriate treatment. The safety of reinitiating ZEJULA in patients previously experiencing PRES is not known.

4.4.5.      Embryo-Fetal Toxicity 

Based on its mechanism of action, ZEJULA can cause fetal harm when administered to a pregnant woman [see Pharmacodynamic Propertie (5.1.1)]. 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 Special Warnings and Precautions for Use (4.4.2), Pre-Clinical Safety Data (5.3.1)]. 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 Fertility, Pregnancy and Lactation (4.6.1, 4.6.3)].

None.

4.6.1.      Pregnancy 

Risk Summary

Based on its mechanism of action, ZEJULA can cause fetal harm when administered to pregnant women [see Pharmacodynamic Properties (5.1.1)]. 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 Special Warnings and Precautions for Use (4.4.2), Pre-Clinical Safety Data (5.3.1)]. 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.

4.6.2.      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 child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with ZEJULA and for 1 month after receiving the last dose.

4.6.3.      Females and Males of Reproductive Potential 

ZEJULA can cause fetal harm when administered to a pregnant woman [see Fertility, Pregnancy and Lactation (4.6.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with ZEJULA.

Contraception

Females: Advise females of reproductive potential to use effective contraception during treatment with ZEJULA and for 6 months following the last dose.

Infertility

Males: Based on animal studies, ZEJULA may impair fertility in males of reproductive potential [see Pre-Clinical Safety Data (5.3.1)].

Zejula may influence the ability to drive or use machines. Patients who take Zejula may experience asthenia, fatigue, difficulty concentrating, and dizziness. Patients who experience these symptoms should observe caution when driving or using machines.

4.8.  Undesirable effects

The following clinically significant adverse reactions are described elsewhere in the labeling:

·       MDS/AML [see Special Warnings and Precautions for Use (4.4.1)]

·       Bone marrow suppression [see Special Warnings and Precautions for Use (4.4.2)]

·       Hypertension and cardiovascular effects [see Special Warnings and Precautions for Use (4.4.3)]

·       Posterior reversible encephalopathy syndrome [see Special Warnings and Precautions for Use (4.4.4)]

4.8.1.      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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a pooled safety population of patients (n = 1,314) with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with ZEJULA monotherapy including PRIMA (n = 484), NOVA (n = 367), and another clinical trial (n = 463), the most common adverse reactions >10% were nausea (65%), thrombocytopenia (60%), anemia (56%), fatigue (55%), constipation (39%), musculoskeletal pain (36%), abdominal pain (35%), vomiting (33%), neutropenia (31%), decreased appetite (24%), leukopenia (24%), insomnia (23%), headache (23%), dyspnea (22%), rash (21%), diarrhea (18%), hypertension (17%), cough (16%), dizziness (14%), acute kidney injury (13%), urinary tract infection (12%), and hypomagnesemia (11%).

First-Line Maintenance Treatment of Advanced Ovarian Cancer

The safety of ZEJULA for the treatment of patients with advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was studied in the PRIMA trial, a placebo-controlled, double-blind study in which 728 patients received niraparib or placebo. Among patients who received ZEJULA, the median duration of treatment was 11.1 months (range: 0.03 to 29 months).

All Patients Receiving ZEJULA in PRIMA: Serious adverse reactions occurred in 32% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were thrombocytopenia (16%), anemia (6%), and small intestinal obstruction (2.9%). Fatal adverse reactions occurred in 0.4% of patients, including intestinal perforation and pleural effusion (1 patient each). MDS/AML occurred in 1.2% of patients receiving ZEJULA.

Permanent discontinuation due to adverse reactions occurred in 12% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >1% of patients who received ZEJULA included thrombocytopenia (3.7%), anemia (1.9%), and nausea and neutropenia (1.2% each).

Adverse reactions led to dose reduction or interruption in 80% of patients, most frequently from thrombocytopenia (56%), anemia (33%), and neutropenia (20%).

Table 4 and Table 5 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in all patients treated with ZEJULA in the PRIMA study.

Table 4. Adverse Reactions Reported in ≥10% of All Patients Receiving ZEJULA in PRIMA^a

AST/ALT = Aspartate transaminase/alanine aminotransferase.

^a All adverse reactions in the table consist of grouped preferred terms except for nausea, vomiting, decreased appetite, headache, and insomnia, which are single preferred terms.

^b Common Terminology Criteria for Adverse Events version 4.02.

^c Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia.

^d Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased.

^e Includes blood creatinine increased, blood urea increased, acute kidney injury, renal failure, and blood creatine increased.

Table 5. Abnormal Laboratory Findings in ≥25% of All Patients Receiving ZEJULA in PRIMA

Patients Receiving ZEJULA with Dose Based on Baseline Weight or Platelet Count in PRIMA: Among patients who received ZEJULA with the dose based on weight and platelet count, the median duration of treatment was 11 months (range: 1 day to 16 months).

Serious adverse reactions occurred in 27% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were anemia (8%), and thrombocytopenia (7%). No fatal adverse reactions occurred.

Permanent discontinuation due to adverse reactions occurred in 14% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >2% of patients who received ZEJULA included thrombocytopenia and anemia (3% each) and nausea (2.4%).

Adverse reactions led to dose reduction or interruption in 72% of patients, most frequently from thrombocytopenia (40%), anemia (23%), and neutropenia (15%).

Table 6 and Table 7 summarize adverse reactions and abnormal laboratory findings in the group of patients who received ZEJULA.

Table 6. Adverse Reactions Reported in ≥10% of Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA^a

^a All adverse reactions in the table consist of grouped preferred terms except for nausea, vomiting, decreased appetite, headache, and insomnia, which are single preferred terms.

^b Common Terminology Criteria for Adverse Events version 4.02.

^c Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia.

^d Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased.

^e Includes blood creatinine increased, blood urea increased, acute kidney injury, renal failure, and blood creatine increased.

Table 7. Abnormal Laboratory Findings in ≥25% of All Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA

Maintenance Treatment of Recurrent Germline BRCA-mutated Ovarian Cancer

The safety of monotherapy with ZEJULA 300 mg once daily has been studied in 136 patients with platinum-sensitive recurrent gBRCAmut ovarian, fallopian tube, and primary peritoneal cancer in the NOVA trial. The percentages of patients who experienced adverse reactions in NOVA that led to dose reduction and dose interruption were 79% and 68%, respectively, most frequently from thrombocytopenia (41% and 35%, respectively) and anemia (23% and 20%, respectively). The permanent discontinuation rate due to adverse reactions in NOVA was 13%. The median exposure to ZEJULA in these patients was 367 days.

Table 8 and Table 9 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with ZEJULA in the gBRCAmut cohort in NOVA.

Table 8. Adverse Reactions Reported in ≥10% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort

^a Common Terminology Criteria for Adverse Events version 4.02.

^b Includes platelet count decreased.

^c Includes hemoglobin decreased.

^d Includes neutrophil count decreased.

^e Includes asthenia, malaise, lethargy.

The following adverse reactions have been identified in ≥1 to <10% of the 136 patients receiving ZEJULA in the gBRCAmut cohort of the NOVA trial and not included in the table: palpitations (9%), mucositis/stomatitis (9%), MDS/AML (7%), tachycardia (7%), and bronchitis (4%).

Table 9. Abnormal Laboratory Findings in ≥25% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort

4.8.2.      Postmarketing Experience 

The following adverse reactions have been identified during postapproval use of ZEJULA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders

Pancytopenia.

Immune System Disorders

Hypersensitivity (including anaphylaxis).

Nervous System Disorders

Posterior reversible encephalopathy syndrome (PRES).

Psychiatric Disorders

Confusional state/disorientation, hallucination, cognitive impairment (e.g., memory impairment, concentration impairment).

Respiratory, Thoracic, and Mediastinal Disorders

Non-infectious pneumonitis.

Skin and Subcutaneous Tissue Disorders

Photosensitivity.

Vascular Disorders

Hypertensive crisis.

Special Populations:

Pediatric Use 

The safety and effectiveness of ZEJULA have not been established in pediatric patients.

Geriatric Use 

In PRIMA, 39% of patients were aged 65 years or older and 10% were aged 75 years or older. In NOVA, 35% of patients were aged 65 years or older and 8% were aged 75 years or older. 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 

For patients with moderate hepatic impairment, reduce the starting dosage of niraparib to 200 mg once daily [see Posology and Method of administration (4.2.4)]. Niraparib exposure increased in patients with moderate hepatic impairment [total bilirubin ≥1.5 x upper level of normal (ULN) to 3.0 x ULN and any aspartate transaminase (AST) level]. Monitor patients for hematologic toxicity and reduce the dose further, if needed [see Posology and Method of administration (4.2.3)].

For patients with mild hepatic impairment (total bilirubin <1.5 x ULN and any AST level or bilirubin ≤ULN and AST >ULN), no dose adjustment is needed.

The recommended dose of ZEJULA has not been established for patients with severe hepatic impairment (total bilirubin >3.0 x ULN and any AST level) [see Pharmacokinetic Properties (5.2)].

There is no specific treatment in the event of Zejula overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should provide general supportive measures and should treat symptomatically.

5.1.         Pharmacodynamic Properties

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 tablet contains 159.3 mg, 318.7 mg, or 478.0 mg of niraparib tosylate monohydrate equivalent to 100 mg, 200 mg, or 300 mg, respectively, of niraparib free base as the active ingredient. The inactive ingredients in the core tablet are crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and silicon dioxide. The film-coating consists of Opadry II Gray (100 mg), Opadry II Blue (200 mg), or Opadry II Green (300 mg).

5.1.1.     Mechanism of Action 

Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that 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 (HRD) that had either mutated or wild-type BRCA1/2.

5.1.2.     Pharmacodynamics 

The pharmacodynamic response of niraparib has not been characterized.

Hypertension and 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 Pre-Clinical Safety Data (5.3.2)].

In the PRIMA study, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at most on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 22.4 and 14.0 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.4 and 19.6 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 15.9 and 13.9 mmHg in the niraparib and placebo arms, respectively.

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 patients with cancer (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.

5.2.    Pharmacokinetic Properties

Following a single-dose administration of 300 mg niraparib, the mean (±SD) peak plasma concentration (C_max) was 804 (±403) ng/mL. The exposure (C_max and AUC) of niraparib increased in a dose-proportional manner with daily doses ranging from 30 mg (0.1 times the approved recommended dose) to 400 mg (1.3 times the approved recommended dose). The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2-fold for doses ranging from 30 to 400 mg.

Absorption

The absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, C_max, is reached within 3 hours.

Food Effect: Following a high-fat meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) in patients with solid tumors, the C_max of niraparib tablets increased by 11% and AUC_inf increased by 28%, as compared with fasted conditions.

Distribution

Niraparib is 83.0% bound to human plasma proteins. The average (±SD) apparent volume of distribution (Vd/F) was 1,220 (±1,114) L. In a population pharmacokinetic analysis, the Vd/F of niraparib was 1,074 L in patients with cancer.

Elimination

Following multiple daily doses of 300 mg of niraparib, the mean half-life (t_1/2) is 36 hours. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/h in patients with cancer.

Metabolism: Niraparib is metabolized 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), race/ethnicity, and mild to moderate renal impairment (CLcr ≥30 to 90 mL/min) had no clinically significant effect on the pharmacokinetics of niraparib.

The effect of severe renal impairment (CLcr <30 mL/min) or end-stage renal disease undergoing hemodialysis on the pharmacokinetics of niraparib is unknown.

Patients with Hepatic Impairment: Mild hepatic impairment (total bilirubin <1.5 x ULN and any AST level or bilirubin ≤ ULN and AST > ULN) had no clinically significant effect on the pharmacokinetics of niraparib.

In a trial of patients with moderate hepatic impairment (total bilirubin ≥1.5 x ULN to 3.0 x ULN and any AST level) (n = 8), niraparib AUC_inf was 1.56 (90% CI: 1.06 to 2.30) times higher compared with patients with normal hepatic function (n = 9) following administration of a single 300-mg dose. Niraparib dosage reduction is recommended for patients with moderate hepatic impairment [see Posology and Method of administration (4.2.4)]. Moderate hepatic impairment did not have an effect on niraparib C_max or on niraparib protein binding.

The effect of severe hepatic impairment (total bilirubin >3.0 x ULN and any AST level) on the pharmacokinetics of niraparib is unknown.

Drug Interaction Studies

No clinical drug interaction studies have been performed with ZEJULA.

In Vitro Studies: Inhibition of Cytochrome P450 (CYP) Enzymes: Neither niraparib nor the major primary metabolite M1 is an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

          Induction of CYP Enzymes: Neither niraparib nor M1 is a CYP3A4 inducer. Niraparib weakly induces CYP1A2 in vitro.

          Substrate of CYP Enzymes: Niraparib is a substrate of CEs and the resulting M1 is further metabolized through the formation of glucuronides in vivo.

          Inhibition of Uridine 5'-Diphospho-Glucuronosyltransferases (UGTs): Niraparib did not exhibit inhibitory effect against the UGT isoforms (UGT1A1, UGT1A4, UGT1A9, and UGT2B7) up to 200 microM in vitro. Therefore, the potential for a clinically relevant inhibition of UGTs by niraparib is minimal.

          Inhibition of Transporter Systems: Niraparib is a weak inhibitor of breast cancer resistance protein (BCRP), but does not inhibit P-glycoprotein (P-gp), bile salt export pump (BSEP), or multidrug resistance-associated protein 2 (MRP2).

Niraparib is an inhibitor of multidrug and toxin extrusion (MATE) 1 and 2 with IC₅₀ of 0.18 microM and ≤0.14 microM, respectively. Increased plasma concentrations of coadministered drugs that are substrates of these transporters (e.g., metformin) cannot be excluded.

The M1 metabolite is not an inhibitor of P-gp, BCRP, BSEP, MRP2, or MATE1 or 2. Neither niraparib nor M1 is an inhibitor of organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT1)1, organic anion transporter (OAT)1, OAT3, or OCT2.

          Substrate of Transporter Systems: Niraparib is a substrate of P-gp and BCRP. Niraparib is not a substrate of BSEP, MRP2, or MATE1 or 2. The M1 metabolite is not a substrate of P-gp, BCRP, BSEP, or MRP2. However, M1 is a substrate of MATE1 and 2. Neither niraparib nor M1 is a substrate of OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2.

5.3.         Pre-Clinical Safety Data

5.3.1.     Carcinogenesis, 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 (AUC_0-24h) at the recommended dose of 300 mg daily. There was a trend toward reversibility of these findings 4 weeks after dosing was stopped.

5.3.2.     Animal Toxicology and/or Pharmacology 

In vitro, niraparib bound to DAT, NET, and SERT and inhibited uptake of norepinephrine and dopamine in cells with IC₅₀ values that were lower than the C_min 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, central nervous system).

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% to 20%, 18% to 27%, and 19% to 25%, respectively, and increased range of heart rates of 2% to 11%, 4% to 17%, and 12% to 21%, respectively, above pre-dose levels. The unbound plasma concentrations of niraparib in dogs at these dose levels were approximately 0.5, 1.5, and 5.8 times the unbound C_max 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:plasma C_max ratios of niraparib administered at 10 mg/kg orally to 2 rhesus monkeys were 0.10 and 0.52.

Clinical Studies 

First-Line Maintenance Treatment of Advanced Ovarian Cancer 

PRIMA (NCT02655016) was a double-blind, placebo-controlled trial in which patients (N = 733) in complete or partial response to first-line platinum-based chemotherapy were randomized 2:1 to ZEJULA or matched placebo. Initially, the patients received a starting dosage of 300 mg once daily regardless of body weight or platelet count. The study was amended to include a starting dose of 200 mg for patients weighing <77 kg (<170 lbs) OR with a platelet count of <150,000/mcL or 300 mg for patients weighing ³77 kg (³170 lbs) AND who had a platelet count ³150,000/mcL.

Patients were randomized post-completion of first-line platinum-based chemotherapy plus surgery. Randomization was stratified by best response during the front-line platinum regimen (complete response vs. partial response), neoadjuvant chemotherapy (NACT) (yes vs. no), and HRD status (positive vs. negative or not determined). HRD status was determined using the FDA-approved Myriad myChoice CDx assay. HRD positive status included either tumor BRCA mutant (tBRCAm) or a genomic instability score (GIS) ≥42.

The major efficacy outcome measure, progression-free survival (PFS), was determined by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In some cases, criteria other than RECIST, such as clinical signs and symptoms and increasing CA-125, were also applied. Overall survival was an additional efficacy outcome measure. PFS testing was performed hierarchically: first in the homologous recombination (HR)-deficient (HRD positive) population, then in the overall population. The median age of 62 ranged from 32 to 85 years among patients randomized with ZEJULA and 33 to 88 years among patients randomized with placebo. Eighty-nine percent of all patients were White. Sixty-nine percent of patients randomized with ZEJULA and 71% of patients randomized with placebo had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 at study baseline. Approximately 45% of patients were enrolled in the U.S. or Canada. In the overall population, 65% of patients had stage III disease and 35% had stage IV disease. Sixty‑seven percent of the patients received NACT. Sixty-nine percent of the patients had a complete response to the first-line platinum-based chemotherapy. Approximately 35% (n = 258) of patients received a starting dose of 200 or 300 mg depending on baseline body weight and platelet count. Among those patients, 186 patients received a starting dose of 200 mg.

PRIMA demonstrated a statistically significant improvement in PFS for patients randomized to ZEJULA as compared with placebo in the HR-deficient and overall population (Table 10, Figure 1, and Figure 2).

Table 10. Efficacy Results – PRIMA (determined by BICR^a)

BICR = Blinded Independent Central Review, HR = Homologous Recombination, NE = not estimable.

^a Efficacy analysis was based on blinded independent central review.

^b Based on a stratified Cox proportional hazards model.

^c Based on a stratified log-rank test.

In exploratory subgroup analyses of patients who were administered a starting dose of ZEJULA or matched placebo based on baseline weight or platelet count, the hazard ratio for PFS was 0.39 (95% CI: 0.22, 0.72) in the HR-deficient subgroup (n = 130) and 0.68 (95% CI: 0.48, 0.97) in the overall population (n = 258).

Figure 1. Progression-Free Survival – PRIMA Patients with HR-Deficient Tumors (Intent-to-Treat Population, N = 373)

Figure 2. Progression-Free Survival – PRIMA Overall Population (Intent-to-Treat Population, N = 733)

At the time of the PFS analysis, overall survival data were immature, with 11% deaths in the overall population.

Maintenance Treatment of Recurrent Germline BRCA-mutated Ovarian Cancer 

NOVA (NCT01847274) 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. Treatment was continued until disease progression or unacceptable toxicity. All patients had received at least 2 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 1 of 2 cohorts based on the results of germline BRCA testing with Myriad BRACAnalysis CDx. Patients with deleterious or suspected deleterious germline BRCA mutations (gBRCAmut) 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 efficacy results are based on the gBRCAmut cohort only.

The major efficacy outcome measure, PFS, was determined primarily by central independent assessment per RECIST version 1.1. In some cases, criteria other than RECIST, such as clinical signs and symptoms and increasing CA-125, were also applied. Overall survival (OS) was an additional outcome measure.

For the gBRCAmut cohort, the median age of patients was 57 years among patients treated with ZEJULA and 58 years among patients treated with placebo. Eighty-eight percent of all patients were White. Sixty-six percent of patients receiving ZEJULA and 74% of patients receiving placebo had an ECOG PS 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 to 12 months since the penultimate platinum regimen. Twenty-four percent of those treated with ZEJULA and 26% treated with placebo had received prior bevacizumab therapy. Approximately 50% 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 (Table 11 and Figure 3).

Table 11. Efficacy Results – NOVA gBRCAmut Cohort (IRC Assessment^a)

IRC = Independent Review Committee, gBRCAmut = germline BRCA-mutated, NR = not reached.

^a Efficacy analysis was based on blinded central independent radiologic and clinical oncology review committee.

^b Based on a stratified Cox proportional hazards model.

^c Based on a stratified log-rank test.

Figure 3. Progression-Free Survival – NOVA gBRCAmut Cohort Based on IRC Assessment (N = 203)

gBRCAmut = germline BRCA-mutated, IRC = Independent Review Committee.

A final OS analysis was conducted after 154 events were observed. Exploratory OS results showed a HR of 0.85 (95% CI: 0.61, 1.20) in the gBRCAmut cohort with a median OS of 40.9 months (95% CI: 34.9, 52.9) for patients treated with ZEJULA and 38.1 months (95% CI: 27.6, 47.3) for patients on placebo.

6.1.           List of Excipients 

Tablet core Intragranular

Microcrystalline cellulose

Lactose monohydrate

Povidone

Crospovidone

Silicon dioxide 

Magnesium stearate

Tablet core Extragranular

Crospovidone

Silicon dioxide

Magnesium stearate

Tablet coat

Opadry II Gray

Not applicable.

Store below 30° C.

Store in the original package

oPA/aluminium/PVC/aluminium/vinyl/acrylic blisters in cartons of 84 × 1 and 56 × 1 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements