ZEJULA

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • MDS/AML [see Warnings and Precautions ( 5.1 )] • Bone marrow suppression [see Warnings and Precautions ( 5.2 )] • Hypertension and cardiovascular effects [see Warnings and Precautions ( 5.3 )] • Posterior reversible encephalopathy syndrome [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (incidence ≥10%) in patients who received ZEJULA were nausea, thrombocytopenia, anemia, fatigue, constipation, musculoskeletal pain, abdominal pain, vomiting, neutropenia, decreased appetite, leukopenia, insomnia, headache, dyspnea, rash, diarrhea, hypertension, cough, dizziness, acute kidney injury, urinary tract infection, and hypomagnesemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 484) % Placebo (n = 244) % ZEJULA (n = 484) % Placebo (n = 244) % Blood and lymphatic system disorders Thrombocytopenia 66 5 39 0.4 Anemia 64 18 31 2 Neutropenia c 42 8 21 1 Leukopenia d 28 9 5 0.4 Gastrointestinal disorders Nausea 57 28 1 1 Constipation 40 20 1 0.4 Vomiting 22 12 1 1 General disorders and administration site conditions Fatigue 51 41 3 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain 39 38 1 0 Nervous system disorders Headache 26 15 0.4 0 Dizziness 19 13 0 0.4 Psychiatric disorders Insomnia 25 15 1 0.4 Respiratory, thoracic, and mediastinal disorders Dyspnea 22 13 0.4 1 Cough 18 15 0 0.4 Metabolism and nutrition disorders Decreased appetite 19 8 1 0 Vascular disorders Hypertension 18 7 6 1 Investigations AST/ALT elevation 14 7 3 0.8 Renal and urinary disorders Acute kidney injury e 12 5 0.2 0 Table 5. Abnormal Laboratory Findings in ≥25% of All Patients Receiving ZEJULA in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 484) % Placebo (n = 244) % ZEJULA (n = 484) % Placebo (n = 244) % Decreased hemoglobin 87 66 29 1 Decreased platelets 74 13 37 0 Decreased leukocytes 71 36 9 0 Increased glucose 66 57 3 3 Decreased neutrophils 66 25 23 1 Decreased lymphocytes 51 29 7 3 Increased alkaline phosphatase 46 21 1 0 Increased creatinine 40 23 0 0 Decreased magnesium 36 34 1 0 Increased aspartate aminotransferase 35 17 1 0.4 Increased alanine aminotransferase 29 17 2 1 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. Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 169) % Placebo (n = 86) % ZEJULA (n = 169) % Placebo (n = 86) % Blood and lymphatic system disorders Thrombocytopenia 54 5 21 1 Anemia 50 28 23 1 Neutropenia c 36 8 15 1 Leukopenia d 28 11 5 0 Gastrointestinal disorders Nausea 53 21 1 0 Constipation 31 15 1 1 Vomiting 17 9 0 1 General disorders and administration site conditions Fatigue 48 36 3 0 Nervous system disorders Headache 22 17 1 0 Dizziness 14 13 0 0 Psychiatric disorders Insomnia 21 14 0 0 Metabolism and nutrition disorders Decreased appetite 19 5 1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 18 10 0 1 Vascular disorders Hypertension 17 9 5 2 Renal and urinary disorders Acute kidney injury e 12 5 1 0 Table 7. Abnormal Laboratory Findings in ≥25% of All Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 169) % Placebo (n = 86) % ZEJULA (n = 169) % Placebo (n = 86) % Decreased hemoglobin 81 70 21 0 Decreased leukocytes 70 36 6 0 Decreased platelets 63 15 18 0 Increased glucose 63 56 2 1 Decreased neutrophils 60 27 15 0 Decreased lymphocytes 52 30 5 4 Decreased magnesium 44 30 0 0 Increased alkaline phosphatase 43 17 1 0 Increased creatinine 41 22 0 0 Increased aspartate aminotransferase 31 19 1 0 Increased alanine aminotransferase 28 15 2 2 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 g BRCA mut 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 g BRCA mut 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. Adverse Reaction Grades 1-4 a Grades 3-4 a ZEJULA (n = 136) % Placebo (n = 65) % ZEJULA (n = 136) % Placebo (n = 65) % Gastrointestinal disorders Nausea 77 34 5 3 Vomiting 40 15 4 0 Constipation 38 18 0.7 2 Dyspepsia 17 12 0 0 Dry mouth 13 3 0.7 0 Blood and lymphatic system disorders Thrombocytopenia b 71 5 38 2 Anemia c 52 8 33 0 Neutropenia d 31 9 21 3 General disorders and administration site conditions Fatigue e 61 35 8 2 Nervous system disorders Headache 35 8 0.7 0 Dizziness 18 9 0 0 Dysgeusia 13 2 0 0 Metabolism and nutrition disorders Decreased appetite 22 14 0 0 Vascular disorders Hypertension 21 8 8 5 Psychiatric disorders Insomnia 18 6 0.7 0 Anxiety 10 11 0.7 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 17 5 2 0 Cough 16 2 0 0 Nasopharyngitis 13 5 0 0 Musculoskeletal and connective tissue disorders Back pain 16 11 0.7 0 Infections and infestations Urinary tract infection 11 9 0 2 Skin and subcutaneous tissue disorders Rash 10 2 0 0 The following adverse reactions have been identified in ≥1 to <10% of the 136 patients receiving ZEJULA in the g BRCA mut 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 Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 136) % Placebo (n = 65) % ZEJULA (n = 136) % Placebo (n = 65) % Decrease in hemoglobin 85 62 32 0 Decrease in platelet count 81 25 38 2 Decrease in white blood cell count 71 37 9 2 Decrease in absolute neutrophil count 56 34 23 3 Increase in aspartate aminotransferase 35 25 0.7 0 Increase in alanine aminotransferase 25 15 0.7 2 6.2 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.

4 CONTRAINDICATIONS None. None. ( 4 )

11 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 C 26 H 30 N 4 O 5 S 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 and gelatin in the white capsule body and FD&C Blue No. 1, FD&C Red No. 3, FD&C Yellow No. 5 (tartrazine), 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 dioxide. Chemical Structure

2 DOSAGE AND ADMINISTRATION • First-line maintenance treatment of advanced ovarian cancer: • For patients weighing <77 kg (<170 lbs) OR with a platelet count <150,000/mcL, the recommended dosage is 200 mg taken orally once daily. ( 2.2 ) • For patients weighing ≥77 kg (≥170 lbs) AND a platelet count ≥150,000/ mcL, the recommended dosage is 300 mg taken orally once daily. ( 2.2 ) • Maintenance treatment of recurrent germline BRCA-mutated ovarian cancer: The recommended dosage is 300 mg taken orally once daily. ( 2.2 ) • Continue treatment until disease progression or unacceptable toxicity. ( 2.2 ) • ZEJULA may be taken with or without food. ( 2.2 ) • For adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. ( 2.3 ) • For patients with moderate hepatic impairment, reduce the starting dosage of niraparib to 200 mg once daily. ( 2.4 ) 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 Clinical Studies ( 14.2 )] . Information on FDA-approved tests for the detection of deleterious or suspected deleterious germline BRCA mutations for this indication is available at https://www.fda.gov/companiondiagnostics . 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 capsule 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 (two 100-mg capsules) taken orally once daily. • For patients weighing ≥77 kg (≥170 lbs) AND who have a platelet count ≥150,000/mcL, the recommended dosage is 300 mg (three 100-mg capsules) 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 (three 100-mg capsules) 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. 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. Starting Dose Level 200 mg 300 mg First dose reduction 100 mg/day a (one 100-mg capsule) 200 mg/day (two 100-mg capsules) Second dose reduction Discontinue ZEJULA. 100 mg/day a (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 that persists despite medical management • Withhold ZEJULA for a maximum of 28 days or until resolution of adverse reaction. • Resume ZEJULA at a reduced dose per Table 1. CTCAE ≥Grade 3 treatment-related adverse reaction lasting more than 28 days while patient is administered ZEJULA 100 mg/day Discontinue ZEJULA. Table 3. Dose Modifications for Hematologic Adverse Reactions a 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/mcL First occurrence: • Withhold ZEJULA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL. • Resume ZEJULA at same or reduced dose per Table 1 . • If platelet count is <75,000/mcL, 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/mcL. • 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. a Neutrophil <1,000/mcL 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/mcL 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. a Hematologic adverse reaction requiring transfusion • For patients with platelet count ≤10,000/mcL, platelet transfusion should be considered. If there are other risk factors such as coadministration of anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or transfusion at a higher platelet count. • Resume ZEJULA at a reduced dose. 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 Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] .

1 INDICATIONS AND USAGE ZEJULA is a poly (ADP-ribose) polymerase (PARP) inhibitor 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. ( 1.1 ) • for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA -mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for ZEJULA. ( 1.2 , 2.1 ) 1.1 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. 1.2 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 (g BRCA mut) recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for ZEJULA [see Dosage and Administration ( 2.1 )] .

12 CLINICAL PHARMACOLOGY 12.1 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 . 12.2 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 Nonclinical Toxicology ( 13.2 )] . 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. 12.3 Pharmacokinetics 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: Concomitant administration of a high-fat meal (800 to 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 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 Dosage and Administration ( 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 IC 50 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.

12.1 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 .

12.2 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 Nonclinical Toxicology ( 13.2 )] . 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.

12.3 Pharmacokinetics 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: Concomitant administration of a high-fat meal (800 to 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 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 Dosage and Administration ( 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 IC 50 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.

20230426

24

3 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. Capsules: 100 mg ( 3 )

ZEJULA niraparib niraparib niraparib magnesium stearate lactose monohydrate titanium dioxide GELATIN, UNSPECIFIED FD&C Blue no. 1 FD&C Red no. 3 FD&C Yellow no. 5 100;mg;Niraparib

13.2 Animal Toxicology and/or Pharmacology In vitro, niraparib bound to DAT, NET, and SERT and inhibited uptake of norepinephrine and dopamine in cells with IC 50 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.

13.1 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.

13 NONCLINICAL TOXICOLOGY 13.1 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. 13.2 Animal Toxicology and/or Pharmacology In vitro, niraparib bound to DAT, NET, and SERT and inhibited uptake of norepinephrine and dopamine in cells with IC 50 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.

NDA208447

ZEJULA

niraparib

69656-103

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 69656-103-30 Zejula (niraparib) capsules 100 mg Rx only 30 capsules Each 100-mg capsule is equivalent to 159.4 mg of niraparib tosylate monohydrate. 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] Do not accept if membrane seal under cap is missing or broken. See prescribing information for dosage information. Keep out of reach of children. Contains FD&C Yellow No. 5 (tartrazine) as a color additive. Trademarks are owned by or licensed to the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC 27709 ©2021 GSK group of companies or its licensor. Rev.6/21 126929 Zejula 100 mg 30 count label

Indications and Usage ( 1.2 ) 4/2023 Indications and Usage, Treatment of Advanced Homologous Recombination Deficiency (HRD) Positive Ovarian Cancer after >3 Lines of Chemotherapy (1.3) - Removed 9/2022 Dosage and Administration ( 2.1 ) 4/2023 Dosage and Administration, Treatment of Advanced HRD Positive Ovarian Cancer (2.1) - Removed 9/2022 Warnings and Precautions ( 5.1 ) 12/2022 Warnings and Precautions ( 5.2 , 5.3 ) 9/2022

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelodysplastic Syndrome/Acute Myeloid Leukemia 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 MDS or 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 )] . Hypertension and Cardiovascular Effects Advise patients to undergo blood pressure and heart rate monitoring at least weekly for the first 2 months, then monthly for the first year of treatment and periodically thereafter. Advise patients to contact their healthcare provider if blood pressure is elevated [see Warnings and Precautions ( 5.3 )]. Posterior Reversible Encephalopathy Syndrome Inform patients that they are at risk of developing posterior reversible encephalopathy syndrome (PRES) that can present with signs and symptoms including seizure, headaches, altered mental status, or vision changes. Advise patients to contact their healthcare provider if they develop any of these signs or symptoms [see Warnings and Precautions ( 5.4 )]. Dosing Instructions Inform patients on how to take ZEJULA [see Dosage and Administration ( 2.2 )] . 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 ( 5.5 ), Use in Specific Populations ( 8.1 )] . Contraception Advise females of reproductive potential to use effective contraception during treatment with ZEJULA and for 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 Specific Populations ( 8.2 )] . Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) Advise patients that ZEJULA capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons or in patients who also have aspirin hypersensitivity [see Warnings and Precautions ( 5.6 )] . Trademarks are owned by or licensed to the GSK group of companies. Manufactured for GlaxoSmithKline Durham, NC 27701 ©2023 GSK group of companies or its licensor. ZJC:6PI

14 CLINICAL STUDIES 14.1 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 ≥77 kg (≥170 lbs) AND who had a platelet count ≥150,000/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 (t BRCA m) 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. HR-Deficient Population Overall Population ZEJULA (n = 247) Placebo (n = 126) ZEJULA (n = 487) Placebo (n = 246) Progression-free survival events, n (%) 81 (33) 73 (58) 232 (48) 155 (63) Progression-free survival median in months (95% CI) 21.9 (19.3, NE) 10.4 (8.1, 12.1) 13.8 (11.5, 14.9) 8.2 (7.3, 8.5) Hazard ratio b (95% CI) 0.43 (0.31, 0.59) 0.62 (0.50, 0.76) P value c <0.0001 <0.0001 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. Figure 1. Progression-Free Survival in Patients with HR-Deficient Tumors (Intent-to-Treat Population, n = 373) Figure 2. Progression-Free Survival in the Overall Population (Intent-to-Treat Population, n = 733) 14.2 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 (g BRCA mut) were assigned to the germline BRCA -mutated (g BRCA mut) cohort (n = 203), and those without germline BRCA mutations were assigned to the non-g BRCA mut cohort (n = 350). The efficacy results are based on the g BRCA mut 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 g BRCA mut 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 g BRCA mut cohort ( Table 11 and Figure 3 ). Table 11. Efficacy Results – NOVA gBRCAmut Cohort (IRC Assessment a ) IRC = Independent Review Committee, g BRCA mut = 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. ZEJULA (n = 138) Placebo (n = 65) Progression-free survival median in months (95% CI) 21.0 (12.9, NR) 5.5 (3.8, 7.2) Hazard ratio b (95% CI) 0.26 (0.17, 0.41) P value c <0.0001 Figure 3. Progression-Free Survival – NOVA gBRCAmut Cohort Based on IRC Assessment (N = 203) g BRCA mut = 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 g BRCA mut 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. Figure 3. Progression-Free Survival in the gBRCAmut Cohort Based on IRC Assessment (Intent-to-Treat Population, n = 203)

8.5 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.

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

8.1 Pregnancy 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 ), 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.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy 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 ), 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. 8.2 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. 8.3 Females and Males of Reproductive Potential ZEJULA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . 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 Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of ZEJULA have not been established in pediatric patients. 8.5 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. 8.6 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. 8.7 Hepatic Impairment For patients with moderate hepatic impairment, reduce the starting dosage of niraparib to 200 mg once daily [see Dosage and Administration ( 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 Dosage and Administration ( 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 Clinical Pharmacology ( 12.3 )] .

16 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 30-count bottles NDC 69656-103-30 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].

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].