Niraparib

• First ‑ Line Maintenance Treatment of HRD ‑ Positive Advanced Ovarian Cancer: o 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 ) o 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, recommended dosage is 200 mg taken orally once daily. ( 2.4 )

2.1 Patient Selection First-Line Maintenance Treatment of HRD-Positive Advanced Ovarian Cancer Select patients for first-line maintenance treatment of advanced ovarian cancer with ZEJULA based on the presence of HRD defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability [see Clinical Studies ( 14.1 )] . Information on FDA ‑ authorized tests for the detection of HRD ‑ positive status for this indication is available at https://www.fda.gov/companiondiagnostics. 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‑authorized 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 and Administration 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 tablets 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 HRD-Positive 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 ≥77 kg (≥170 lbs) AND who have a platelet count ≥150,000/mcL, the recommended dosage is 300 mg taken orally once daily. For the maintenance treatment of advanced ovarian cancer, start 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, start ZEJULA no later than 8 weeks after their most recent platinum-containing regimen.

2.3 Dosage Modifications for Adverse Reactions To manage adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. The recommended dosage modifications for adverse reactions are listed in Tables 1 , 2 , and 3 . Table 1. Recommended Dosage 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 200 mg/day Second dose reduction Discontinue ZEJULA. 100 mg/day a Table 2. Dosage 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. Dosage 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 ( 5.2 )] . 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 per Table 1 .

2.4 Dosage Modifications for Hepatic Impairment For patients with moderate hepatic impairment (total bilirubin ≥1.5 to 3 x ULN and any AST level), the recommended dosage of ZEJULA is 200 mg once daily, regardless of body weight or platelet count [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . Monitor patients for hematologic toxicity and reduce the dose, if needed [see Dosage and Administration ( 2.3 )] .

5 WARNINGS AND PRECAUTIONS

• Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML occurred in patients exposed to ZEJULA, and some cases were fatal. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. ( 5.1 )
• Bone Marrow Suppression: Test complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter for clinically significant changes. ( 5.2 )
• Hypertension and Cardiovascular Effects: 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. Manage with antihypertensive medications and adjustment of the dose of ZEJULA, if necessary. ( 5.3 )
• Posterior Reversible Encephalopathy Syndrome (PRES): PRES has occurred in patients treated with ZEJULA. Discontinue ZEJULA if PRES is confirmed. ( 5.4 )
• Embryo-Fetal Toxicity: ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 )

5.1 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, of patients within the HRD-positive population, MDS/AML occurred in 8 out of 245 (3.3%) patients treated with ZEJULA and in 3 out of 125 (2.4%) patients treated with placebo with a follow-up of 6.1 years [see Adverse Reactions ( 6.1 ) ] . The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer-therapy–related AML varied from 5.5 months to 5 years. In NOVA, of patients within the g BRCA mut 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 Adverse Reactions (6.1) ] . 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.

5.2 Bone Marrow Suppression Hematologic adverse reactions, including thrombocytopenia, anemia, neutropenia, and/or pancytopenia have been reported in patients treated with ZEJULA [see Adverse Reactions (6) ] . 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 Dosage and Administration ( 2.3 )].

5.3 Hypertension and Cardiovascular Effects Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA [see Adverse Reactions (6) ] . 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 Dosage and Administration ( 2.3 ), Nonclinical Toxicology ( 13.2 )] .

5.4 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 Adverse Reactions ( 6.2 )]. 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.

5.5 Embryo-Fetal Toxicity Based on its mechanism of action, ZEJULA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . ZEJULA has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions ( 5.2 ), Nonclinical Toxicology ( 13.1 )] . Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of ZEJULA [see Use in Specific Populations ( 8.1 , 8.3 )] .

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 HRD-Positive 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 484 patients received ZEJULA. Among this population, 245 patients were HRD-positive and their median duration of treatment was 13 months (range: 3 days to 29 months). HRD-Positive Patients Receiving ZEJULA in PRIMA: Serious adverse reactions occurred in 30% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were thrombocytopenia (11%) and anemia (5%). Fatal adverse reactions occurred in 1.6% of patients, including AML (0.4%), cardiac arrest (0.4%), intestinal perforation (0.4%), and sudden death (0.4%). Permanent discontinuation due to adverse reactions occurred in 11% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >1% of patients who received ZEJULA included thrombocytopenia (3.7%), nausea (1.6%), and anemia (1.2%). Adverse reactions led to dose reduction or interruption in 79% of patients, most frequently (>10%) from thrombocytopenia (53%), anemia (32%), and neutropenia (19%). Tables 4 and 5 summarize the common adverse reactions and abnormal laboratory findings observed in the PRIMA trial. Table 4. Adverse Reactions Reported in ≥10% of HRD-Positive Patients Receiving ZEJULA in PRIMA a AST/ALT = Aspartate aminotransferase/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, and renal failure. Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 245) % Placebo (n = 125) % ZEJULA (n = 245) % Placebo (n = 125) % Blood and lymphatic system disorders Thrombocytopenia 66 4 38 0 Anemia 65 16 31 2 Neutropenia c 43 9 17 2 Leukopenia d 29 10 6 0.8 Gastrointestinal disorders Nausea 62 34 1 0 Constipation 40 26 1 0.8 Vomiting 23 14 2 0.8 General disorders and administration site conditions Fatigue 52 44 2 2 Musculoskeletal and connective tissue disorders Musculoskeletal pain 46 38 0.8 0 Nervous system disorders Headache 27 15 0.8 0 Dizziness 20 11 0 0 Psychiatric disorders Insomnia 25 16 0.4 0.8 Anxiety 12 6 0 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 21 15 0 0.8 Cough 20 14 0 0.8 Metabolism and nutrition disorders Decreased appetite 20 6 0.4 0 Vascular disorders Hypertension 20 8 7 2 Investigations AST/ALT elevation 14 8 3 0 Renal and urinary disorders Acute kidney injury e 13 3 0 0 Table 5. Abnormal Laboratory Findings in ≥25% of HRD-Positive Patients Receiving ZEJULA in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 245) % Placebo (n = 125) % ZEJULA (n = 245) % Placebo (n = 125) % Decreased hemoglobin 85 65 28 2 Decreased leukocytes 72 37 9 0 Decreased platelets 71 11 36 0 Decreased neutrophils 64 28 21 2 Increased glucose 62 57 3 4 Decreased lymphocytes 55 26 9 5 Increased alkaline phosphatase 48 19 2 0.8 Increased creatinine 40 24 0 0 Decreased magnesium 39 35 0.4 0 Increased aspartate aminotransferase 35 18 2 0.8 Increased alanine aminotransferase 32 19 2 2 Increased calcium 31 23 1 0 HRD-Positive 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 (n = 86), the median duration of treatment was 12 months (range: 4 days to 16 months). Serious adverse reactions occurred in 24% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were anemia (9%) and thrombocytopenia (2%). Permanent discontinuation due to adverse reactions occurred in 11% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >2% of patients who received ZEJULA included nausea (3.5%). Adverse reactions led to dose reduction or interruption in 72% of patients, most frequently (>10%) from thrombocytopenia (35%), anemia (22%), and neutropenia (17%). Tables 6 and 7 summarize adverse reactions and abnormal laboratory findings observed in this group. Table 6. Adverse Reactions Reported in ≥10% of HRD-Positive 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, and renal failure. Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 86) % Placebo (n = 42) % ZEJULA (n = 86) % Placebo (n = 42) % Blood and lymphatic system disorders Thrombocytopenia 51 2 16 0 Anemia 49 21 22 0 Neutropenia c 35 7 13 0 Leukopenia d 26 7 6 0 Gastrointestinal disorders Nausea 55 21 0 0 Constipation 26 29 1 2 Vomiting 16 17 0 2.4 General disorders and administration site conditions Fatigue 47 41 0 0 Nervous system disorders Headache 24 19 1 0 Dizziness 15 7 0 0 Psychiatric disorders Insomnia 21 19 0 0 Metabolism and nutrition disorders Decreased appetite 19 7 1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 20 12 0 2 Vascular disorders Hypertension 16 12 4 5 Renal and urinary disorders Acute kidney injury e 14 2 0 0 Table 7. Abnormal Laboratory Findings in ≥25% of HRD-Positive Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 86) % Placebo (n = 42) % ZEJULA (n = 86) % Placebo (n = 42) % Decreased hemoglobin 74 67 21 0 Decreased leukocytes 70 36 6 0 Decreased platelets 58 17 14 0 Increased glucose 57 62 4 2 Decreased neutrophils 57 31 13 0 Decreased lymphocytes 55 24 6 5 Decreased magnesium 51 41 0 0 Increased alkaline phosphatase 42 12 2 0 Increased creatinine 42 24 0 0 Increased aspartate aminotransferase 31 21 2 0 Increased alanine aminotransferase 30 17 2 2 Increased calcium 29 36 0 0 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 g BRCA mut = Germline BRCA -mutated. 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, and 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 g BRCA mut = Germline BRCA- mutated. 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.

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, norepinephrine transporter, and serotonin transporter [see Nonclinical Toxicology ( 13.2 )] . In PRIMA, 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 NOVA, 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 At the approved maximum recommended dose, a mean increase in the QTc interval >20 ms was not observed.

12.3 Pharmacokinetics Niraparib mean (±SD) maximum plasma concentration (C max ) is 603 (±343) ng/mL at the approved maximum recommended dose of 300 mg. Niraparib steady-state C max and AUC increased in a dose-proportional manner with daily doses ranging from 30 mg (0.15 times the approved minimum recommended dose) to 400 mg (1.3 times the approved maximum recommended dose). The accumulation of niraparib exposure is approximately 2-fold at the approved recommended doses. Absorption The absolute bioavailability of niraparib is approximately 73%. Time to maximum plasma concentration (T max ) is reached within 5 hours. Food Effect: Niraparib C max increased by 11% and AUC by 28%, following administration with a high-fat meal (800 to 1,000 calories, 50% fat). Distribution Niraparib is 83% bound to human plasma proteins. Niraparib mean (±SD) apparent (oral) volume of distribution (Vd/F) is 1,220 (±1,114) L. Elimination Niraparib apparent (oral) total clearance (CL/F) is 15.9 (±3.8) L/h and mean half-life (t 1/2 ) is 50 (±15) hours. Metabolism: Niraparib is metabolized by carboxylesterases to form a major inactive metabolite M1, which subsequently undergoes glucuronidation. Excretion: Following administration of a single oral dose of radio-labeled niraparib 300 mg, 48% of the dose was recovered in urine (11% unchanged) and 39% in feces (19% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of niraparib were observed based on age (18 to 65 years), race/ethnicity, and mild to moderate renal impairment (CLcr 30 to 90 mL/min). The effect of severe renal impairment (CLcr <30 mL/min) or end-stage renal disease undergoing hemodialysis on the pharmacokinetics of niraparib is unknown. 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. Niraparib AUC increased 1.6-fold in patients with moderate hepatic impairment (total bilirubin ≥1.5 to 3 x ULN and any AST level) with no effect on niraparib C max or protein binding. The effect of severe hepatic impairment (total bilirubin >3 x ULN and any AST level) on the pharmacokinetics of niraparib is unknown. Drug Interaction Studies In Vitro Studies: Cytochrome P450 ( CYP) Enzymes: Niraparib and M1 did not inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Niraparib and M1 do not induce CYP3A. Uridine 5'-Diphospho-Glucuronosyltransferases (UGTs): Niraparib did not inhibit UGT1A1, UGT1A4, UGT1A9, and UGT2B7. Transporters: Niraparib inhibits BCRP, MATE1, and MATE2K, but does not inhibit P-glycoprotein (P-gp), BSEP, or MRP2. M1 did not inhibit P‑gp, BCRP, BSEP, MRP2, MATE1 or MATE2K. Niraparib and M1 did not inhibit OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2. Niraparib is a substrate of P-gp and BCRP, but not of BSEP, MRP2, MATE1, MATE2K, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2. M1 is a substrate of MATE1 and MATE2K, but not of P-gp, BCRP, BSEP, MRP2, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2.