ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:oMDS/AML [see Warnings and Precautions (5.1)]oBone marrow suppression [see Warnings and Precautions (5.2)]oHypertension and cardiovascular effects [see Warnings and Precautions (5.3)]oPosterior reversible encephalopathy syndrome [see Warnings and Precautions (5.4)]. oMDS/AML [see Warnings and Precautions (5.1)]. oBone marrow suppression [see Warnings and Precautions (5.2)]. oHypertension and cardiovascular effects [see Warnings and Precautions (5.3)]. oPosterior 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 drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.The most common adverse reactions of all grades in >10% of 1,314 patients who received ZEJULA in the pooled PRIMA, NOVA, and QUADRA trials 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 CancerThe 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, 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).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 and Table 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 PRIMAa AST/ALT Aspartate transaminase/alanine aminotransferase. 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. Common Terminology Criteria for Adverse Events version 4.02. Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia. Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased. Includes blood creatinine increased, blood urea increased, acute kidney injury, renal failure, and blood creatine increased.Adverse ReactionGrades 1-4b Grades 3-4b ZEJULA(n 484)%Placebo(n 244)%ZEJULA(n 484)%Placebo(n 244)%Blood and lymphatic system disorders Thrombocytopenia665390.4 Anemia6418312 Neutropeniac 428211 Leukopeniad 28950.4Gastrointestinal disorders Nausea572811 Constipation402010.4 Vomiting221211General disorders and administration site conditions Fatigue514131Investigations AST/ALT elevation14730.8Metabolism and nutrition disorders Decreased appetite19810Musculoskeletal and connective tissue disorders Musculoskeletal pain393810Nervous system disorders Headache26150.40 Dizziness191300.4Psychiatric disorders Insomnia251510.4Renal and urinary disorders Acute kidney injurye 1250.20Respiratory, thoracic, and mediastinal disorders Dyspnea22130.41 Cough181500.4Vascular disorders Hypertension18761Table 5. Abnormal Laboratory Findings in >=25% of All Patients Receiving ZEJULA in PRIMAAbnormal Laboratory FindingGrades 1-4Grades 3-4ZEJULA(n 484)%Placebo(n 244)%ZEJULA(n 484)%Placebo(n 244)%Decreased hemoglobin8766291Decreased platelets7413370Decreased leukocytes713690Increased glucose665733Decreased neutrophils6625231Decreased lymphocytes512973Increased alkaline phosphatase462110Increased creatinine402300Decreased magnesium363410Increased aspartate aminotransferase351710.4Increased alanine aminotransferase291721Patients 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: 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 and Table 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 PRIMAa 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. Common Terminology Criteria for Adverse Events version 4.02. Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia. Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased. Includes blood creatinine increased, blood urea increased, acute kidney injury, renal failure, and blood creatine increased.Adverse ReactionGrades 1-4b Grades 3-4b ZEJULA(n 169)%Placebo(n 86)%ZEJULA(n 169)%Placebo(n 86)%Blood and lymphatic system disordersThrombocytopenia545211 Anemia5028231 Neutropeniac 368151 Leukopeniad 281150Gastrointestinal disorders Nausea532110 Constipation311511 Vomiting17901General disorders and administration site conditions Fatigue483630Metabolism and nutrition disorders Decreased appetite19510Nervous system disorders Headache221710 Dizziness141300Psychiatric disorders Insomnia211400Renal and urinary disorders Acute kidney injurye 12510Respiratory, thoracic, and mediastinal disorders Dyspnea181001Vascular disorders Hypertension17952Table 7. Abnormal Laboratory Findings in >=25% of All Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMAAbnormal Laboratory FindingGrades 1-4Grades 3-4ZEJULA(n 169)%Placebo(n 86)%ZEJULA(n 169)%Placebo(n 86)%Decreased hemoglobin8170210Decreased leukocytes703660Decreased platelets6315180Increased glucose635621Decreased neutrophils6027150Decreased lymphocytes523054Increased alkaline phosphatase431710Decreased magnesium443000Increased creatinine412200Increased aspartate aminotransferase311910Increased alanine aminotransferase281522Maintenance Treatment of Recurrent Ovarian CancerThe safety of monotherapy with ZEJULA 300 mg once daily has been studied in 367 patients with platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancer in the NOVA trial. Adverse reactions in NOVA led to dose reduction or interruption in 69% of patients, most frequently from thrombocytopenia (41%) and anemia (20%). The permanent discontinuation rate due to adverse reactions in NOVA was 15%. The median exposure to ZEJULA in these patients was 250 days.Table and Table summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with ZEJULA in NOVA.Table 8. Adverse Reactions Reported in >=10% of Patients Receiving ZEJULA in NOVAAST/ALT Aspartate transaminase/alanine aminotransferase. Common Terminology Criteria for Adverse Events version 4.02. Includes preferred terms of neutropenic infection, neutropenic sepsis, and febrile neutropenia.Adverse ReactionGrades 1-4a Grades 3-4a ZEJULA(n 367)%Placebo(n 179)%ZEJULA(n 367)%Placebo(n 179)%Blood and lymphatic system disorders Thrombocytopenia615290.6 Anemia507250 Neutropeniab 306202 Leukopenia17850Cardiac disorders Palpitations10200Gastrointestinal disorders Nausea743531 Constipation40200.82 Vomiting341620.6 Mucositis/stomatitis2060.50 Dyspepsia181200 Dry mouth1040.30General disorders and administration site conditions Fatigue/asthenia574180.6Metabolism and nutrition disorders Decreased appetite25150.30.6Infections and infestations Urinary tract infection1380.81Investigations AST/ALT elevation10542Musculoskeletal and connective tissue disorders Back pain18120.80Nervous system disorders Headache26110.30 Dizziness18800 Dysgeusia 10400Psychiatric disorders Insomnia2780.30 Anxiety1170.30.6Respiratory, thoracic, and mediastinal disorders Nasopharyngitis231400 Dyspnea20811 Cough16500Skin and subcutaneous tissue disorders Rash2190.50Vascular disorders Hypertension20592Table 9. Abnormal Laboratory Findings in >=25% of Patients Receiving ZEJULA in NOVAAbnormal Laboratory FindingGrades 1-4Grades 3-4ZEJULA(n 367)%Placebo(n 179)%ZEJULA(n 367)%Placebo(n 179)%Decrease in hemoglobin8556250.5Decrease in platelet count7221350.5Decrease in white blood cell count663770.7Decrease in absolute neutrophil count5325212Increase in aspartate aminotransferase362310Increase in alanine aminotransferase281512The following adverse reactions and laboratory abnormalities have been identified in >=1 to <10% of the 367 patients receiving ZEJULA in the NOVA trial and not included in the table: tachycardia, peripheral edema, hypokalemia, bronchitis, conjunctivitis, gamma-glutamyl transferase increased, blood creatinine increased, blood alkaline phosphatase increased, weight decreased, depression, and epistaxis.Treatment of Advanced Ovarian Cancer after or More ChemotherapiesThe safety of monotherapy with ZEJULA 300 mg once daily has been studied in QUADRA, single-arm study in 463 patients with recurrent high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with or more prior lines of therapy. The median duration of overall study treatment was months (range: 0.03 to 32 months). For the indicated QUADRA population, the median duration was months (range: 0.1 to 30 months).Fatal adverse reactions occurred in 2% of patients, including cardiac arrest.Serious adverse reactions occurred in 43% of patients receiving ZEJULA. Serious adverse reactions in >3% of patients were small intestinal obstruction (7%), vomiting (6%), nausea (5%), and abdominal pain (4%).Permanent discontinuation due to adverse reactions (Grade to 4) occurred in 21% of patients who received ZEJULA.Adverse reactions led to dose reduction or interruption in 73% of patients receiving ZEJULA. The most common adverse reactions (>5%) resulting in dose reduction or interruption of ZEJULA were thrombocytopenia (40%), anemia (21%), neutropenia (11%), nausea (13%), vomiting (11%), fatigue (9%), and abdominal pain (5%). Table 10 and Table 11 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with ZEJULA in QUADRA. Table 10. Adverse Reactions Reported in >=10% of Patients Receiving ZEJULA in QUADRAAST/ALT Aspartate transaminase/alanine aminotransferase. Common Terminology Criteria for Adverse Events version 4.02. Anemia includes events with preferred terms of anemia, hemoglobin decreased, anemia macrocytic, aplastic anemia, and normochromic normocytic anemia. Thrombocytopenia includes events with preferred terms of thrombocytopenia and platelet count decreased. Neutropenia includes events with preferred terms of neutropenia, neutrophil count decreased, neutropenic infection, and neutropenic sepsis.Adverse ReactionGrades 1-4a (n 463)%Grades 3-4a (n 463)%Blood and lymphatic system disorders Anemiab 5127 Thrombocytopeniac 5228 Neutropeniad 2013Gastrointestinal disorders Nausea6710 Vomiting448 Constipation365 Abdominal pain347 Diarrhea170.2General disorders and administration site conditions Fatigue567Infections and infestations Urinary tract infection152Investigations Blood alkaline phosphatase increased112 AST/ALT elevation111Metabolism and nutrition disorders Decreased appetite272Musculoskeletal and connective tissue disorders Musculoskeletal pain293Nervous system disorders Headache190.4 Dizziness110Psychiatric disorders Insomnia211Renal and urinary disorders Acute kidney injury171Respiratory, thoracic, and mediastinal disorders Dyspnea223 Cough130Vascular disorders Hypertension145Table 11. Abnormal Laboratory Findings in >=25% of Patients Receiving ZEJULA in QUADRAAbnormal Laboratory FindingGrades 1-4(n 463)%Grades 3-4(n 463)%Decreased hemoglobin8326Increased glucose665Decreased platelets6028Decreased lymphocytes5718Decreased leukocytes539Decreased magnesium461Increased alkaline phosphatase404Increased gamma glutamyl transferase408Increased creatinine360.4Decreased sodium346Decreased neutrophils3415Increased aspartate aminotransferase292Decreased albumin272. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of ZEJULA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic System DisordersPancytopenia.Immune System DisordersHypersensitivity (including anaphylaxis).Nervous System DisordersPosterior reversible encephalopathy syndrome (PRES).Psychiatric DisordersConfusional state/disorientation, hallucination, cognitive impairment (e.g., memory impairment, concentration impairment).Respiratory, Thoracic, and Mediastinal DisordersNon-infectious pneumonitis.Skin and Subcutaneous Tissue DisordersPhotosensitivity.Vascular DisordersHypertensive crisis.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

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 IC50 values that were lower than the Cmin at steady-state in patients receiving the recommended dose. Niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular, 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 Cmax at steady-state in patients receiving the recommended dose. In addition, niraparib crossed the blood-brain barrier in rats and monkeys following oral administration. The cerebrospinal fluid:plasma Cmax ratios of niraparib administered at 10 mg/kg orally to rhesus monkeys were 0.10 and 0.52.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 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 months duration in rats and dogs. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed at doses >=10 mg/kg and >=1.5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.3 and 0.012 times, respectively, the human exposure (AUC0-24h) at the recommended dose of 300 mg daily. There was trend toward reversibility of these findings weeks after dosing was stopped.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play 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 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 EffectsNiraparib 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 ElectrophysiologyThe potential for QTc prolongation with niraparib was evaluated in 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 single-dose administration of 300 mg niraparib, the mean (+-SD) peak plasma concentration (Cmax) was 804 (+-403) ng/mL. The exposure (Cmax and AUC) of niraparib increased in 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. AbsorptionThe absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, Cmax, is reached within hours.Concomitant administration of 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.DistributionNiraparib is 83.0% bound to human plasma proteins. The average (+-SD) apparent volume of distribution (Vd/F) was 1,220 (+-1,114) L. In population pharmacokinetic analysis, the Vd/F of niraparib was 1,074 in patients with cancer .EliminationFollowing multiple daily doses of 300 mg of niraparib, the mean half-life (t1/2) is 36 hours. In 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 major inactive metabolite, which subsequently undergoes glucuronidation. Excretion: Following administration of 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 days, unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively.Specific PopulationsAge (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 ULN and any AST level or bilirubin <= ULN and AST ULN) had no clinically significant effect on the pharmacokinetics of niraparib.In trial of patients with moderate hepatic impairment (total bilirubin >=1.5 ULN to 3.0 ULN and any AST level) (n 8), niraparib AUCinf was 1.56 (90% CI: 1.06 to 2.30) times higher compared with patients with normal hepatic function (n 9) following administration of 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 Cmax or on niraparib protein binding.The effect of severe hepatic impairment (total bilirubin >3.0 ULN and any AST level) on the pharmacokinetics of niraparib is unknown.Drug Interaction StudiesNo 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 CYP3A4 inducer. Niraparib weakly induces CYP1A2 in vitro. Substrate of CYP Enzymes: Niraparib is 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 clinically relevant inhibition of UGTs by niraparib is minimal. Inhibition of Transporter Systems: Niraparib is 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 (MRP2).Niraparib is an inhibitor of multidrug and toxin extrusion (MATE) and with IC50 of 0.18 microM and <=0.14 microM, respectively. Increased plasma concentrations of coadministered drugs that are substrates of these transporters (e.g., metformin) cannot be excluded.The M1 metabolite is not an inhibitor of P-gp, BCRP, BSEP, MRP2, or MATE1 or 2. Neither niraparib nor M1 is an inhibitor of organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT1)1, organic anion transporter (OAT)1, OAT3, or OCT2. Substrate of Transporter Systems: Niraparib is substrate of P-gp and BCRP. Niraparib is not substrate of BSEP, MRP2, or MATE1 or 2. The M1 metabolite is not substrate of P-gp, BCRP, BSEP, or MRP2. However, M1 is substrate of MATE1 and 2. Neither niraparib nor M1 is substrate of OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 First-Line Maintenance Treatment of Advanced Ovarian Cancer PRIMA (NCT02655016) was 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 starting dosage of 300 mg once daily regardless of body weight or platelet count. The study was amended to include starting dose of 200 mg for patients weighing <77 kg (<170 lbs) OR with platelet count of <150,000/mcL or 300 mg for patients weighing >=77 kg (>=170 lbs) AND who had 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 (tBRCAm) or 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 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 complete response to the first-line platinum-based chemotherapy. Approximately 35% (n 258) of patients received starting dose of 200 or 300 mg depending on baseline body weight and platelet count. Among those patients, 186 patients received starting dose of 200 mg.PRIMA demonstrated statistically significant improvement in PFS for patients randomized to ZEJULA as compared with placebo in the HR-deficient and overall population (Table 12, Figure 1, and Figure 2).Table 12. Efficacy Results-PRIMA (determined by BICRa)HR Homologous Recombination, NE not estimable. Efficacy analysis was based on blinded independent central review. Based on stratified Cox proportional hazards model. Based on stratified log-rank test.HR-Deficient PopulationOverall PopulationZEJULA(n 247)Placebo(n 126)ZEJULA(n 487)Placebo(n 246)Progression-free survival events, (%)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 ratiob (95% CI)0.43 (0.31, 0.59)0.62 (0.50, 0.76)P valuec <0.0001<0.0001In exploratory subgroup analyses of patients who were administered 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 in Patients with HR-Deficient Tumors (Intent-to-Treat Population, = 373)Figure 2. Progression-Free Survival in the Overall Population (Intent-to-Treat Population, = 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, = 373). Figure 2. Progression-Free Survival in the Overall Population (Intent-to-Treat Population, = 733). 14.2 Maintenance Treatment of Recurrent Ovarian Cancer. NOVA (NCT01847274) was 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 weeks of the last therapy. Treatment was continued until disease progression or unacceptable toxicity. All patients had received at least 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 of cohorts based on the results of the BRACAnalysis CDx. Patients with deleterious or suspected deleterious germline BRCA mutations (gBRCAm) were assigned to the germline BRCA-mutated (gBRCAmut) cohort (n 203), and those without germline BRCA mutations were assigned to the non-gBRCAmut cohort (n 350).The major efficacy outcome measure, PFS, 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.The median age of patients ranged from 57 to 64 years among patients treated with ZEJULA and 58 to 67 years among patients treated with placebo. Eighty-six percent of all patients were White. Sixty-seven percent of patients receiving ZEJULA and 69% of patients receiving placebo had an ECOG PS of 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 to 12 months since the penultimate platinum regimen. Twenty-six percent of those treated with ZEJULA and 31% treated with placebo had received prior bevacizumab therapy. Approximately 40% of patients had or more lines of treatment.The trial demonstrated statistically significant improvement in PFS for patients randomized to ZEJULA as compared with placebo in the gBRCAmut cohort and the non-gBRCAmut cohort (Table 13, Figure 3, and Figure 4).Table 13. Efficacy Results-NOVA (IRC Assessment,a Intent-to-Treat Population)IRC Independent Review Committee, gBRCAmut germline BRCA-mutated, NR not reached. Efficacy analysis was based on blinded central independent radiologic and clinical oncology review committee. Based on stratified Cox proportional hazards model. Based on stratified log-rank test.gBRCAmut Cohortnon-gBRCAmut CohortZEJULA(n 138)Placebo(n 65)ZEJULA(n 234)Placebo(n 116)Progression-free survival median in months (95% CI)21.0(12.9, NR)5.5(3.8, 7.2)9.3(7.2, 11.2)3.9(3.7, 5.5)Hazard ratiob (95% CI)0.26(0.17, 0.41)0.45(0.34, 0.61)P valuec <0.0001<0.0001Figure 3. Progression-Free Survival in the gBRCAmut Cohort Based on IRC Assessment (Intent-to-Treat Population, = 203)gBRCAmut germline BRCA-mutated, IRC Independent Review Committee.Figure 4. Progression-Free Survival in the Non-gBRCAmut Cohort Overall Based on IRC Assessment (Intent-to-Treat Population, = 350)gBRCAmut germline BRCA-mutated, IRC Independent Review Committee.At the time of the PFS analysis, limited overall survival data were available with 17% deaths across the cohorts.. Figure 3. Progression-Free Survival in the gBRCAmut Cohort Based on IRC (Intent-to-Treat Population, = 203). Figure 4. Progression-Free Survival in the Non-gBRCAmut Cohort Overall Based on IRC (Intent-to-Treat Population, = 350). 14.3 Treatment of Advanced Ovarian Cancer after or More Chemotherapies. The efficacy of ZEJULA was studied in 98 patients with advanced ovarian cancer with HRD positive tumors in the single-arm QUADRA (NCT02354586) trial. Patients were required to have been treated with or more prior lines of chemotherapy and those with prior exposure to PARP inhibitors were excluded. Patients were selected using clinical trial assay. Those without BRCA mutations must have progressed at least months after their last dose of platinum therapy. All patients received ZEJULA capsules at starting dosage of 300 mg once daily as monotherapy until disease progression or unacceptable toxicity.HRD positive status was determined using the Myriad myChoice CDx as either tBRCAm (n 63) and/or GIS >=42 (n 35). GIS is an algorithmic measurement of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions.The major efficacy outcome measures were objective response rate (ORR) and duration of response as assessed by the investigator according to RECIST v. 1.1.The median age of the patients was 63 years (range: 39 to 91 years), the majority were White (82%), and all had an ECOG PS of (59%) or (41%).The efficacy results for QUADRA are summarized in Table 14.Table 14. Efficacy Results-QUADRA (Investigator Assessment)NE not estimable. Homologous recombination deficiency (HRD) positive status is defined as tBRCA-mutated and/or genomic instability score >42. Confirmed response rate. The objective response rate as assessed by blinded independent central review was consistent.Efficacy ResultsHRD Positive Cohorta (N 98)Objective response rate (95% CI)b 24% (16, 34)Complete responses0%Partial responses24%Median duration of response in months (95% CI)8.3 (6.5, NE)For patients with tBRCAm ovarian cancer, investigator-assessed ORR was 39% (7/18; 95% CI: [17, 64]) in patients with platinum-sensitive disease, 29% (6/21; 95% CI: [11, 52]) in patients with platinum-resistant disease, and 19% (3/16; 95% CI: [4, 46]) in patients with platinum-refractory disease.For patients with platinum-sensitive GIS-positive disease (without BRCAmut) (n 35), investigator-assessed ORR was 20% (95% CI [8, 37]).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

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 C26H30N4O5S and it has molecular weight of 510.61 amu. The molecular structure is shown below:Niraparib tosylate monohydrate is 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. (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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oFirst-line maintenance treatment of advanced ovarian cancer:oFor patients weighing <77 kg (<170 lbs) OR with platelet count <150,000/mcL, the recommended dosage is 200 mg taken orally once daily. (2.2)oFor patients weighing >=77 kg (>=170 lbs) AND platelet count >=150,000/ mcL, the recommended dosage is 300 mg taken orally once daily. (2.2) oFor other indications: The recommended dosage is 300 mg taken orally once daily. (2.2)oContinue treatment until disease progression or unacceptable adverse reaction. (2.2)oZEJULA may be taken with or without food. (2.2) oFor adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. (2.3)oFor patients with moderate hepatic impairment, reduce the starting dosage of niraparib to 200 mg once daily. (2.4). oFirst-line maintenance treatment of advanced ovarian cancer:oFor patients weighing <77 kg (<170 lbs) OR with platelet count <150,000/mcL, the recommended dosage is 200 mg taken orally once daily. (2.2)oFor patients weighing >=77 kg (>=170 lbs) AND platelet count >=150,000/ mcL, the recommended dosage is 300 mg taken orally once daily. (2.2) oFor patients weighing <77 kg (<170 lbs) OR with platelet count <150,000/mcL, the recommended dosage is 200 mg taken orally once daily. (2.2). oFor patients weighing >=77 kg (>=170 lbs) AND platelet count >=150,000/ mcL, the recommended dosage is 300 mg taken orally once daily. (2.2) oFor other indications: The recommended dosage is 300 mg taken orally once daily. (2.2). oContinue treatment until disease progression or unacceptable adverse reaction. (2.2). oZEJULA may be taken with or without food. (2.2) oFor adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. (2.3). oFor patients with moderate hepatic impairment, reduce the starting dosage of niraparib to 200 mg once daily. (2.4). 2.1 Patient Selection for Treatment of Advanced Ovarian Cancer after or More Chemotherapies. Select patients for treatment of advanced ovarian cancer after or more chemotherapy regimens associated with HRD positive status based on either deleterious or suspected deleterious BRCA mutation and/or genomic instability score (GIS) [see Clinical Studies (14.3)].Information on FDA-approved tests for the detection of either deleterious or suspected deleterious BRCA mutation or genomic instability 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 potential method for managing nausea.In the case of missed dose of ZEJULA, instruct patients to take their next dose at its regularly scheduled time. If patient vomits or misses 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 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 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 Ovarian CancerThe 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 weeks after their most recent platinum-containing regimen.Treatment of Advanced Ovarian Cancer after or More ChemotherapiesThe recommended dosage of ZEJULA is 300 mg (three 100-mg capsules) taken orally once daily.. 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 Reactionsa If further dose reduction below 100 mg/day is required, discontinue ZEJULA.Starting Dose Level200 mg300 mgFirst dose reduction100 mg/daya (one 100-mg capsule)200 mg/day (two 100-mg capsules)Second dose reductionDiscontinue ZEJULA.100 mg/daya (one 100-mg capsule)Table 2. Dose Modifications for Non-Hematologic Adverse ReactionsCTCAE Common Terminology Criteria for Adverse Events.Non-hematologic CTCAE >=Grade adverse reaction that persists despite medical managementoWithhold ZEJULA for maximum of 28 days or until resolution of adverse reaction.oResume ZEJULA at reduced dose per Table 1.CTCAE >=Grade treatment-related adverse reaction lasting more than 28 days while patient is administered Zejula 100 mg/dayDiscontinue ZEJULA.Table 3. Dose Modifications for Hematologic Adverse Reactionsa 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/mcLFirst occurrence: oWithhold ZEJULA for maximum of 28 days and monitor blood counts weekly until platelet counts return to >=100,000/mcL.oResume ZEJULA at same or reduced dose per Table 1.oIf platelet count is <75,000/mcL, resume at reduced dose.Second occurrence:oWithhold ZEJULA for maximum of 28 days and monitor blood counts weekly until platelet counts return to >=100,000/mcL.oResume ZEJULA at reduced dose per Table 1.oDiscontinue 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/dLoWithhold ZEJULA for maximum of 28 days and monitor blood counts weekly until neutrophil counts return to >=1,500/mcL or hemoglobin returns to >=9 g/dL.oResume ZEJULA at reduced dose per Table 1.oDiscontinue 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.aHematologic adverse reaction requiring transfusionoFor 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 higher platelet count.oResume ZEJULA at reduced dose.. oWithhold ZEJULA for maximum of 28 days or until resolution of adverse reaction.. oResume ZEJULA at reduced dose per Table 1.. oWithhold ZEJULA for maximum of 28 days and monitor blood counts weekly until platelet counts return to >=100,000/mcL.. oResume ZEJULA at same or reduced dose per Table 1.. oIf platelet count is <75,000/mcL, resume at reduced dose.. oWithhold ZEJULA for maximum of 28 days and monitor blood counts weekly until platelet counts return to >=100,000/mcL.. oResume ZEJULA at reduced dose per Table 1.. oDiscontinue 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 oWithhold ZEJULA for maximum of 28 days and monitor blood counts weekly until neutrophil counts return to >=1,500/mcL or hemoglobin returns to >=9 g/dL.. oResume ZEJULA at reduced dose per Table 1.. oDiscontinue 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. oFor 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 higher platelet count.. oResume ZEJULA at reduced dose.. 2.4 Dosage Adjustment for Hepatic Impairment. Moderate Hepatic ImpairmentFor 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 100 mg capsule having white body with 100 mg printed in black ink, and purple cap with Niraparib printed in white ink.. Capsules: 100 mg (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. ZEJULA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating treatment with ZEJULA.ContraceptionFemales: Advise females of reproductive potential to use effective contraception during treatment with ZEJULA and for at least for months following the last dose.InfertilityMales: Based on animal studies, ZEJULA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

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.

HEPATIC IMPAIRMENT SUBSECTION.

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 upper level of normal (ULN) to 3.0 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 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 ULN and any AST level) [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. ZEJULA is available as capsules having white body printed with 100 mg in black ink, and purple cap printed with Niraparib in white ink.Each capsule contains 100 mg of niraparib free base.ZEJULA capsules are packaged as90-count bottles NDC 69656-103-9030-count bottles NDC 69656-103-30. Store at 20C to 25C (68F to 77F); excursions are permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ZEJULA is poly (ADP-ribose) polymerase (PARP) inhibitor indicated: ofor the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. (1.1) ofor the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. (1.2)ofor the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either: oa deleterious or suspected deleterious BRCA mutation, or ogenomic instability and who have progressed more than months after response to the last platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for ZEJULA. (1.3, 2.1). ofor the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. (1.1) ofor the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. (1.2). ofor the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either: oa deleterious or suspected deleterious BRCA mutation, or ogenomic instability and who have progressed more than months after response to the last platinum-based chemotherapy.. oa deleterious or suspected deleterious BRCA mutation, or ogenomic instability and who have progressed more than months after response to the last platinum-based chemotherapy.. Select patients for therapy based on an FDA-approved companion diagnostic for ZEJULA. (1.3, 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 complete or partial response to first-line platinum-based chemotherapy.. 1.2 Maintenance Treatment of Recurrent Ovarian Cancer. ZEJULA is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.. 1.3 Treatment of Advanced Ovarian Cancer after or More Chemotherapies. ZEJULA is indicated for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:oa deleterious or suspected deleterious BRCA mutation, orogenomic instability and who have progressed more than months after response to the last platinum-based chemotherapy [see Clinical Studies (14.3)].Select patients for therapy based on an FDA-approved companion diagnostic for ZEJULA.. oa deleterious or suspected deleterious BRCA mutation, or. ogenomic instability and who have progressed more than months after response to the last platinum-based chemotherapy [see Clinical Studies (14.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Myelodysplastic Syndrome/Acute Myeloid LeukemiaAdvise 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 need for blood transfusions. This may be 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 SuppressionAdvise 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 EffectsAdvise patients to undergo blood pressure and heart rate monitoring at least weekly for the first 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 SyndromeInform 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 InstructionsInform patients on how to take ZEJULA [see Dosage and Administration (2.2)]. ZEJULA should be taken once daily. Instruct patients that if they miss 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 potential method for managing nausea.Embryo-Fetal ToxicityAdvise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to fetus and potential loss of the pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)].ContraceptionAdvise females of reproductive potential to use effective contraception during treatment with ZEJULA and for at least months after receiving the last dose [see Use in Specific Populations (8.3)].LactationAdvise patients not to breastfeed while taking ZEJULA and for month after the last dose [see Use in Specific Populations (8.2)].Allergic Reactions to FD&C Yellow No. (Tartrazine)Advise patients that ZEJULA capsules contain FD&C Yellow No. (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 GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2021 GSK group of companies or its licensor.ZJC:2PI.

LACTATION SECTION.

8.2 Lactation. Risk SummaryNo 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 breastfed child, advise lactating woman not to breastfeed during treatment with ZEJULA and for month after receiving the final dose.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

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 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 months duration in rats and dogs. Reduced sperm, spermatids, and germ cells in epididymides and testes were observed at doses >=10 mg/kg and >=1.5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.3 and 0.012 times, respectively, the human exposure (AUC0-24h) at the recommended dose of 300 mg daily. There was trend toward reversibility of these findings 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 IC50 values that were lower than the Cmin at steady-state in patients receiving the recommended dose. Niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular, 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 Cmax at steady-state in patients receiving the recommended dose. In addition, niraparib crossed the blood-brain barrier in rats and monkeys following oral administration. The cerebrospinal fluid:plasma Cmax ratios of niraparib administered at 10 mg/kg orally to rhesus monkeys were 0.10 and 0.52.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 69656-103-30Zejula(niraparib)capsules100 mgRx only30 capsulesEach 100-mg capsule is equivalent to 159.4 mg of niraparib tosylate monohydrate.Store at 20C to 25C (68F to 77F); excursions are permitted between 15C to 30C (59F to 86F), [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. (tartrazine) as color additive.Trademarks are owned by or licensed to the GSK group of companies.GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2021 GSK group of companies or its licensor.Rev.6/21126929. Zejula 100 mg 30 count label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The pharmacodynamic response of niraparib has not been characterized.Hypertension and Cardiovascular EffectsNiraparib 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 ElectrophysiologyThe potential for QTc prolongation with niraparib was evaluated in 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following single-dose administration of 300 mg niraparib, the mean (+-SD) peak plasma concentration (Cmax) was 804 (+-403) ng/mL. The exposure (Cmax and AUC) of niraparib increased in 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. AbsorptionThe absolute bioavailability of niraparib is approximately 73%. Following oral administration of niraparib, peak plasma concentration, Cmax, is reached within hours.Concomitant administration of 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.DistributionNiraparib is 83.0% bound to human plasma proteins. The average (+-SD) apparent volume of distribution (Vd/F) was 1,220 (+-1,114) L. In population pharmacokinetic analysis, the Vd/F of niraparib was 1,074 in patients with cancer .EliminationFollowing multiple daily doses of 300 mg of niraparib, the mean half-life (t1/2) is 36 hours. In 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 major inactive metabolite, which subsequently undergoes glucuronidation. Excretion: Following administration of 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 days, unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively.Specific PopulationsAge (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 ULN and any AST level or bilirubin <= ULN and AST ULN) had no clinically significant effect on the pharmacokinetics of niraparib.In trial of patients with moderate hepatic impairment (total bilirubin >=1.5 ULN to 3.0 ULN and any AST level) (n 8), niraparib AUCinf was 1.56 (90% CI: 1.06 to 2.30) times higher compared with patients with normal hepatic function (n 9) following administration of 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 Cmax or on niraparib protein binding.The effect of severe hepatic impairment (total bilirubin >3.0 ULN and any AST level) on the pharmacokinetics of niraparib is unknown.Drug Interaction StudiesNo 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 CYP3A4 inducer. Niraparib weakly induces CYP1A2 in vitro. Substrate of CYP Enzymes: Niraparib is 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 clinically relevant inhibition of UGTs by niraparib is minimal. Inhibition of Transporter Systems: Niraparib is 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 (MRP2).Niraparib is an inhibitor of multidrug and toxin extrusion (MATE) and with IC50 of 0.18 microM and <=0.14 microM, respectively. Increased plasma concentrations of coadministered drugs that are substrates of these transporters (e.g., metformin) cannot be excluded.The M1 metabolite is not an inhibitor of P-gp, BCRP, BSEP, MRP2, or MATE1 or 2. Neither niraparib nor M1 is an inhibitor of organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT1)1, organic anion transporter (OAT)1, OAT3, or OCT2. Substrate of Transporter Systems: Niraparib is substrate of P-gp and BCRP. Niraparib is not substrate of BSEP, MRP2, or MATE1 or 2. The M1 metabolite is not substrate of P-gp, BCRP, BSEP, or MRP2. However, M1 is substrate of MATE1 and 2. Neither niraparib nor M1 is substrate of OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased 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 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 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.3, 2.4)3/2021Warnings and Precautions (5.2, 5.4, 5.6)3/2021.

RENAL IMPAIRMENT SUBSECTION.

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.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information ZEJULA (zuh-JOO-luh) (niraparib) capsulesWhat is the most important information should know about ZEJULAZEJULA may cause serious side effects including:oBone marrow problems called myelodysplastic syndrome (MDS) or type of cancer of the blood called acute myeloid leukemia (AML). Some people who have ovarian cancer and who have received previous treatment with chemotherapy or certain other medicines for their cancer have developed MDS or AML during treatment with ZEJULA. MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with ZEJULA.Symptoms of low blood cell counts (low red blood cells, low white blood cells, and low platelets) are common during treatment with ZEJULA, but can be sign of serious bone marrow problems, including MDS or AML. Symptoms may include:oweaknessofeeling tiredoweight lossofrequent infectionsofeveroshortness of breathoblood in urine or stoolobruising or bleeding more easilyYour healthcare provider will do blood tests to check your blood cell counts:obefore treatment with ZEJULA.oweekly for the first month of treatment with ZEJULA.oevery month for the next 11 months, then as needed during treatment with ZEJULA.oHigh blood pressure. High blood pressure is common during treatment with ZEJULA, and can become serious. Your healthcare provider will check your blood pressure and heart rate at least weekly for the first months, then monthly for the first year and as needed thereafter during your treatment with ZEJULA.oPosterior reversible encephalopathy syndrome (PRES). PRES is condition that affects the brain and may happen during treatment with ZEJULA. If you have headache, vision changes, confusion, or seizure with or without high blood pressure, please contact your healthcare provider.See What are the possible side effects of ZEJULA for more information about side effects.What is ZEJULAZEJULA is prescription medicine used for the:omaintenance treatment of adults with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. ZEJULA is used after the cancer has responded (complete or partial response) to treatment with platinum-based chemotherapy.omaintenance treatment of adults with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer that comes back. ZEJULA is used after the cancer has responded (complete or partial response) to treatment with platinum-based chemotherapy.otreatment of adults with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have been treated with or more prior types of chemotherapy and who have tumors with: oa certain BRCA gene mutation, or ogene mutation problems and who have progressed more than months after their last treatment with platinum-based chemotherapy.Your healthcare provider will perform test to make sure that ZEJULA is right for you. It is not known if ZEJULA is safe and effective in children.Before taking ZEJULA, tell your healthcare provider about all of your medical conditions, including if you:ohave heart problems.ohave liver problems.ohave high blood pressure.oare allergic to FD&C Yellow No. (tartrazine) or aspirin. ZEJULA capsules contain FD&C Yellow No. (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain people, especially people who also have an allergy to aspirin. oare pregnant or plan to become pregnant. ZEJULA can harm your unborn baby and may cause loss of pregnancy (miscarriage). oIf you are able to become pregnant, your healthcare provider may perform pregnancy test before you start treatment with ZEJULA.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with ZEJULA and for months after the last dose of ZEJULA. Talk to your healthcare provider about birth control methods that may be right for you.oTell your healthcare provider right away if you become pregnant.oare breastfeeding or plan to breastfeed. It is not known if ZEJULA passes into your breast milk. Do not breastfeed during treatment with ZEJULA and for month after the last dose of ZEJULA. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take ZEJULAoTake ZEJULA exactly as your healthcare provider tells you to.oTake ZEJULA time each day, at the same time each day.oZEJULA may be taken with or without food.oZEJULA capsules should be swallowed whole. Do not chew, crush, or split ZEJULA capsules before swallowing.oTaking ZEJULA at bedtime may help relieve any nausea symptoms you may have.oDo not stop taking ZEJULA without first talking with your healthcare provider.oIf you miss dose of ZEJULA, take your next dose at your scheduled time. Do not take an extra dose to make up for missed dose.oIf you vomit after taking dose of ZEJULA, do not take an extra dose. Take your next dose at your scheduled time.oIf you take too much ZEJULA, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of ZEJULAZEJULA may cause serious side effects, including:oSee What is the most important information should know about ZEJULAThe most common side effects of ZEJULA include:oheart not beating regularlyonauseaoconstipationovomitingopain in the stomach areaomouth soresodiarrheaoindigestion or heartburnodry mouthotirednessoloss of appetiteourinary tract infectionochanges in liver function or other blood testsopain in your muscles and backoheadacheodizzinessochange in the way food tastesotrouble sleepingoanxietyosore throatoshortness of breathocoughorashochanges in the amount or color of your urineYour healthcare provider may change your dose, temporarily stop treatment, or permanently stop treatment with ZEJULA if you have certain side effects.These are not all the possible side effects of ZEJULA. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ZEJULAStore ZEJULA at room temperature between 68 to 77F (20 to 25C). Keep ZEJULA and all medicines out of the reach of children. General information about the safe and effective use of ZEJULA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ZEJULA for condition for which it was not prescribed. Do not give ZEJULA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about ZEJULA that is written for health professionals.What are the ingredients in ZEJULAActive ingredient: niraparib.Inactive ingredients:Capsule fill: magnesium stearate and lactose monohydrate.Capsule shell: titanium dioxide and gelatin in the white capsule body and FD&C Blue No. 1, FD&C Red No. 3, FD&C Yellow No. (tartrazine), and gelatin in the purple capsule cap.The black printing ink: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and black iron oxide.The white printing ink: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, sodium hydroxide, povidone, and titanium dioxide.For more information about ZEJULA, call 1-888-825-5249.Trademarks are owned by or licensed to the GSK group of companies.Manufactured for:GlaxoSmithKline, Research Triangle Park, NC 27709 (C)2021 GSK group of companies or its licensor.ZJC:1PILThis Patient Information has been approved by the U.S. Food and Drug Administration Revised: March 2021. oBone marrow problems called myelodysplastic syndrome (MDS) or type of cancer of the blood called acute myeloid leukemia (AML). Some people who have ovarian cancer and who have received previous treatment with chemotherapy or certain other medicines for their cancer have developed MDS or AML during treatment with ZEJULA. MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with ZEJULA.Symptoms of low blood cell counts (low red blood cells, low white blood cells, and low platelets) are common during treatment with ZEJULA, but can be sign of serious bone marrow problems, including MDS or AML. Symptoms may include:. oweakness. ofeeling tired. oweight loss. ofrequent infections. ofever. oshortness of breath. oblood in urine or stool. obruising or bleeding more easily. obefore treatment with ZEJULA.. oweekly for the first month of treatment with ZEJULA.. oevery month for the next 11 months, then as needed during treatment with ZEJULA.. oHigh blood pressure. High blood pressure is common during treatment with ZEJULA, and can become serious. Your healthcare provider will check your blood pressure and heart rate at least weekly for the first months, then monthly for the first year and as needed thereafter during your treatment with ZEJULA.. oPosterior reversible encephalopathy syndrome (PRES). PRES is condition that affects the brain and may happen during treatment with ZEJULA. If you have headache, vision changes, confusion, or seizure with or without high blood pressure, please contact your healthcare provider.. omaintenance treatment of adults with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. ZEJULA is used after the cancer has responded (complete or partial response) to treatment with platinum-based chemotherapy.. omaintenance treatment of adults with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer that comes back. ZEJULA is used after the cancer has responded (complete or partial response) to treatment with platinum-based chemotherapy.. otreatment of adults with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have been treated with or more prior types of chemotherapy and who have tumors with: oa certain BRCA gene mutation, or ogene mutation problems and who have progressed more than months after their last treatment with platinum-based chemotherapy.. oa certain BRCA gene mutation, or ogene mutation problems and who have progressed more than months after their last treatment with platinum-based chemotherapy.. ohave heart problems.. ohave liver problems.. ohave high blood pressure.. oare allergic to FD&C Yellow No. (tartrazine) or aspirin. ZEJULA capsules contain FD&C Yellow No. (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain people, especially people who also have an allergy to aspirin. oare pregnant or plan to become pregnant. ZEJULA can harm your unborn baby and may cause loss of pregnancy (miscarriage). oIf you are able to become pregnant, your healthcare provider may perform pregnancy test before you start treatment with ZEJULA.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with ZEJULA and for months after the last dose of ZEJULA. Talk to your healthcare provider about birth control methods that may be right for you.oTell your healthcare provider right away if you become pregnant.. oIf you are able to become pregnant, your healthcare provider may perform pregnancy test before you start treatment with ZEJULA.. oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with ZEJULA and for months after the last dose of ZEJULA. Talk to your healthcare provider about birth control methods that may be right for you.. oTell your healthcare provider right away if you become pregnant.. oare breastfeeding or plan to breastfeed. It is not known if ZEJULA passes into your breast milk. Do not breastfeed during treatment with ZEJULA and for month after the last dose of ZEJULA. Talk to your healthcare provider about the best way to feed your baby during this time.. oTake ZEJULA exactly as your healthcare provider tells you to.. oTake ZEJULA time each day, at the same time each day.. oZEJULA may be taken with or without food.. oZEJULA capsules should be swallowed whole. Do not chew, crush, or split ZEJULA capsules before swallowing.. oTaking ZEJULA at bedtime may help relieve any nausea symptoms you may have.. oDo not stop taking ZEJULA without first talking with your healthcare provider.. oIf you miss dose of ZEJULA, take your next dose at your scheduled time. Do not take an extra dose to make up for missed dose.. oIf you vomit after taking dose of ZEJULA, do not take an extra dose. Take your next dose at your scheduled time.. oIf you take too much ZEJULA, call your healthcare provider or go to the nearest hospital emergency room right away.. oSee What is the most important information should know about ZEJULA. oheart not beating regularly. onausea. oconstipation. ovomiting. opain in the stomach area. omouth sores. odiarrhea. oindigestion or heartburn. odry mouth. otiredness. oloss of appetite. ourinary tract infection. ochanges in liver function or other blood tests. opain in your muscles and back. oheadache. odizziness. ochange in the way food tastes. otrouble sleeping. oanxiety. osore throat. oshortness of breath. ocough. orash. ochanges in the amount or color of your urine.

SPL UNCLASSIFIED SECTION.

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 complete or partial response to first-line platinum-based chemotherapy.

STORAGE AND HANDLING SECTION.

Store at 20C to 25C (68F to 77F); excursions are permitted between 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased 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 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 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 SummaryNo 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 breastfed child, advise lactating woman not to breastfeed during treatment with ZEJULA and for month after receiving the final dose.. 8.3 Females and Males of Reproductive Potential. ZEJULA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating treatment with ZEJULA.ContraceptionFemales: Advise females of reproductive potential to use effective contraception during treatment with ZEJULA and for at least for months following the last dose.InfertilityMales: 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 upper level of normal (ULN) to 3.0 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 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 ULN and any AST level) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oMyelodysplastic 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)oBone 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)oHypertension and Cardiovascular Effects: Monitor blood pressure and heart rate at least weekly for the first 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)oPosterior Reversible Encephalopathy Syndrome (PRES): PRES has occurred in patients treated with ZEJULA. Discontinue ZEJULA if PRES is confirmed. (5.4)oEmbryo-Fetal Toxicity: ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.5, 8.1, 8.3)oAllergic Reactions to FD&C Yellow No. (Tartrazine): Contains FD&C Yellow No. (tartrazine) as color additive, which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients. (5.6). oMyelodysplastic 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). oBone 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). oHypertension and Cardiovascular Effects: Monitor blood pressure and heart rate at least weekly for the first 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). oPosterior Reversible Encephalopathy Syndrome (PRES): PRES has occurred in patients treated with ZEJULA. Discontinue ZEJULA if PRES is confirmed. (5.4). oEmbryo-Fetal Toxicity: ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.5, 8.1, 8.3). oAllergic Reactions to FD&C Yellow No. (Tartrazine): Contains FD&C Yellow No. (tartrazine) as color additive, which may cause allergic-type reactions (including bronchial asthma) in certain susceptible patients. (5.6). 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia. Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with fatal outcome, have been reported in patients who received monotherapy with ZEJULA in clinical trials. In 1,785 patients treated with ZEJULA in clinical trials, MDS/AML occurred in 15 patients (0.8%).The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer therapy-related AML varied from 0.5 months to 4.9 years. All of these patients had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. 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 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 starting dose of ZEJULA based on baseline weight or platelet count, >=Grade 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 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.In QUADRA, >=Grade thrombocytopenia, anemia, and neutropenia were reported in 28%, 27%, and 13%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 4%, 2%, and 1%, 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 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.In PRIMA, Grade to hypertension occurred in 6% of patients treated with ZEJULA compared with 1% of placebo-treated patients with median time from first dose to first onset of 43 days (range: to 531 days) and with median duration of 12 days (range: to 61 days). There were no discontinuations due to hypertension.In NOVA, Grade to hypertension occurred in 9% of patients treated with ZEJULA compared with 2% of placebo-treated patients with median time from first dose to first onset of 77 days (range: to 504 days) and with median duration of 15 days (range: to 86 days). Discontinuation due to hypertension occurred in <1% of patients.In QUADRA, Grade to hypertension occurred in 5% of patients treated with ZEJULA with median time from first dose to first onset of 15 days (range: to 316 days) and with median duration of days (range: to 118 days). Discontinuation due to hypertension occurred in <0.2% of patients.Monitor blood pressure and heart rate at least weekly for the first 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. 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 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 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 fetus. Advise females of reproductive potential to use effective contraception during treatment and for months after the last dose of ZEJULA [see Use in Specific Populations (8.1, 8.3)].. 5.6 Allergic Reactions to FD&C Yellow No. (Tartrazine). ZEJULA capsules contain FD&C Yellow No. (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.