Niraparib

ZEJULA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

• for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either: o a deleterious or suspected deleterious BRCA mutation, and/or o genomic instability. Select patients for therapy based on an FDA‑authorized companion diagnostic for ZEJULA. ( 1.1 , 2.1 )
• for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA -mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA‑authorized companion diagnostic for ZEJULA. ( 1.2 , 2.1 )

1.1 First-Line Maintenance Treatment of HRD-Positive Advanced Ovarian Cancer ZEJULA is indicated for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:

• a deleterious or suspected deleterious BRCA mutation, and/or
• genomic instability. Select patients for therapy based on an FDA ‑ authorized companion diagnostic for ZEJULA [see Dosage and Administration ( 2.1 )] .

1.2 Maintenance Treatment of Recurrent Germline BRCA -Mutated Ovarian Cancer ZEJULA is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA -mutated (g BRCA mut) recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Select patients for therapy based on an FDA‑authorized companion diagnostic for ZEJULA [see Dosage and Administration ( 2.1 )] .

• Tablets: 100-mg gray, oval-shaped, film-coated tablet debossed with “100” on one side and “Zejula” on the other side.
• Tablets: 200-mg blue, oval-shaped, film-coated tablet debossed with “200” on one side and “Zejula” on the other side.
• Tablets: 300-mg green, oval-shaped, film-coated tablet debossed with “300” on one side and “Zejula” on the other side. Tablets: 100 mg, 200 mg, 300 mg. ( 3 )

None. None. ( 4 )

• Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML occurred in patients exposed to ZEJULA, and some cases were fatal. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. ( 5.1 )
• Bone Marrow Suppression: Test complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter for clinically significant changes. ( 5.2 )
• Hypertension and Cardiovascular Effects: Monitor blood pressure and heart rate at least weekly for the first 2 months, then monthly for the first year and periodically thereafter during treatment with ZEJULA. Manage with antihypertensive medications and adjustment of the dose of ZEJULA, if necessary. ( 5.3 )
• Posterior Reversible Encephalopathy Syndrome (PRES): PRES has occurred in patients treated with ZEJULA. Discontinue ZEJULA if PRES is confirmed. ( 5.4 )
• Embryo-Fetal Toxicity: ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 )

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with a fatal outcome, have been reported in patients who received ZEJULA. In PRIMA, of patients within the HRD-positive population, MDS/AML occurred in 8 out of 245 (3.3%) patients treated with ZEJULA and in 3 out of 125 (2.4%) patients treated with placebo with a follow-up of 6.1 years [see Adverse Reactions ( 6.1 ) ] . The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer-therapy–related AML varied from 5.5 months to 5 years. In NOVA, of patients within the g BRCA mut cohort, MDS/AML occurred in 10 out of 136 (7%) patients treated with ZEJULA and in 2 out of 65 (3%) patients treated with placebo [see Adverse Reactions (6.1) ] . The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer-therapy–related AML varied from 3.6 months to 5.9 years. All patients who developed secondary MDS/cancer-therapy–related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue ZEJULA if MDS/AML is confirmed.

5.2 Bone Marrow Suppression Hematologic adverse reactions, including thrombocytopenia, anemia, neutropenia, and/or pancytopenia have been reported in patients treated with ZEJULA [see Adverse Reactions (6) ] . In PRIMA, the overall incidences of ≥Grade 3 thrombocytopenia, anemia, and neutropenia were reported in 39%, 31%, and 21%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 4%, 2%, and 2%, respectively, of patients. In patients who were administered a starting dose of ZEJULA based on baseline weight or platelet count, ≥Grade 3 thrombocytopenia, anemia, and neutropenia were reported in 22%, 23%, and 15%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 3%, 3%, and 2%, respectively, of patients. In NOVA, ≥Grade 3 thrombocytopenia, anemia, and neutropenia were reported in 29%, 25%, and 20%, respectively, of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred in 3%, 1%, and 2%, respectively, of patients. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration ( 2.3 )].

5.3 Hypertension and Cardiovascular Effects Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA [see Adverse Reactions (6) ] . In PRIMA, Grade 3 to 4 hypertension occurred in 6% of patients treated with ZEJULA compared with 1% of placebo-treated patients with a median time from first dose to first onset of 43 days (range: 1 to 531 days) and with a median duration of 12 days (range: 1 to 61 days). There were no discontinuations due to hypertension. In NOVA, Grade 3 to 4 hypertension occurred in 9% of patients treated with ZEJULA compared with 2% of placebo-treated patients with a median time from first dose to first onset of 77 days (range: 4 to 504 days) and with a median duration of 15 days (range: 1 to 86 days). Discontinuation due to hypertension occurred in <1% of patients. Monitor blood pressure and heart rate at least weekly for the first 2 months, then monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Medically manage hypertension with antihypertensive medications and adjustment of the dose of ZEJULA, if necessary [see Dosage and Administration ( 2.3 ), Nonclinical Toxicology ( 13.2 )] .

5.4 Posterior Reversible Encephalopathy Syndrome Posterior reversible encephalopathy syndrome (PRES) occurred in 0.1% of 2,165 patients treated with ZEJULA in clinical trials and has also been described in postmarketing reports [see Adverse Reactions ( 6.2 )]. Signs and symptoms of PRES include seizure, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging. Monitor all patients treated with ZEJULA for signs and symptoms of PRES. If PRES is suspected, promptly discontinue ZEJULA and administer appropriate treatment. The safety of reinitiating ZEJULA in patients previously experiencing PRES is not known.

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

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

• MDS/AML [see Warnings and Precautions ( 5.1 )]
• Bone marrow suppression [see Warnings and Precautions ( 5.2 )]
• Hypertension and cardiovascular effects [see Warnings and Precautions ( 5.3 )]
• Posterior reversible encephalopathy syndrome [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (incidence ≥10%) in patients who received ZEJULA were nausea, thrombocytopenia, anemia, fatigue, constipation, musculoskeletal pain, abdominal pain, vomiting, neutropenia, decreased appetite, leukopenia, insomnia, headache, dyspnea, rash, diarrhea, hypertension, cough, dizziness, acute kidney injury, urinary tract infection, and hypomagnesemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a pooled safety population of patients (n = 1,314) with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with ZEJULA monotherapy including PRIMA (n = 484), NOVA (n = 367), and another clinical trial (n = 463), the most common adverse reactions >10% were nausea (65%), thrombocytopenia (60%), anemia (56%), fatigue (55%), constipation (39%), musculoskeletal pain (36%), abdominal pain (35%), vomiting (33%), neutropenia (31%), decreased appetite (24%), leukopenia (24%), insomnia (23%), headache (23%), dyspnea (22%), rash (21%), diarrhea (18%), hypertension (17%), cough (16%), dizziness (14%), acute kidney injury (13%), urinary tract infection (12%), and hypomagnesemia (11%). First-Line Maintenance Treatment of HRD-Positive Advanced Ovarian Cancer The safety of ZEJULA for the treatment of patients with advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was studied in the PRIMA trial, a placebo-controlled, double-blind study in which 484 patients received ZEJULA. Among this population, 245 patients were HRD-positive and their median duration of treatment was 13 months (range: 3 days to 29 months). HRD-Positive Patients Receiving ZEJULA in PRIMA: Serious adverse reactions occurred in 30% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were thrombocytopenia (11%) and anemia (5%). Fatal adverse reactions occurred in 1.6% of patients, including AML (0.4%), cardiac arrest (0.4%), intestinal perforation (0.4%), and sudden death (0.4%). Permanent discontinuation due to adverse reactions occurred in 11% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >1% of patients who received ZEJULA included thrombocytopenia (3.7%), nausea (1.6%), and anemia (1.2%). Adverse reactions led to dose reduction or interruption in 79% of patients, most frequently (>10%) from thrombocytopenia (53%), anemia (32%), and neutropenia (19%). Tables 4 and 5 summarize the common adverse reactions and abnormal laboratory findings observed in the PRIMA trial. Table 4. Adverse Reactions Reported in ≥10% of HRD-Positive Patients Receiving ZEJULA in PRIMA a AST/ALT = Aspartate aminotransferase/alanine aminotransferase. a All adverse reactions in the table consist of grouped preferred terms except for nausea, vomiting, decreased appetite, headache, and insomnia, which are single preferred terms. b Common Terminology Criteria for Adverse Events version 4.02. c Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia. d Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased. e Includes blood creatinine increased, blood urea increased, acute kidney injury, and renal failure. Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 245) % Placebo (n = 125) % ZEJULA (n = 245) % Placebo (n = 125) % Blood and lymphatic system disorders Thrombocytopenia 66 4 38 0 Anemia 65 16 31 2 Neutropenia c 43 9 17 2 Leukopenia d 29 10 6

0.8 Gastrointestinal disorders Nausea 62 34 1 0 Constipation 40 26 1

0.8 Vomiting 23 14 2

0.8 General disorders and administration site conditions Fatigue 52 44 2 2 Musculoskeletal and connective tissue disorders Musculoskeletal pain 46 38 0.8 0 Nervous system disorders Headache 27 15 0.8 0 Dizziness 20 11 0 0 Psychiatric disorders Insomnia 25 16 0.4

0.8 Anxiety 12 6 0 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 21 15 0

0.8 Cough 20 14 0

0.8 Metabolism and nutrition disorders Decreased appetite 20 6 0.4 0 Vascular disorders Hypertension 20 8 7 2 Investigations AST/ALT elevation 14 8 3 0 Renal and urinary disorders Acute kidney injury e 13 3 0 0 Table 5. Abnormal Laboratory Findings in ≥25% of HRD-Positive Patients Receiving ZEJULA in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 245) % Placebo (n = 125) % ZEJULA (n = 245) % Placebo (n = 125) % Decreased hemoglobin 85 65 28 2 Decreased leukocytes 72 37 9 0 Decreased platelets 71 11 36 0 Decreased neutrophils 64 28 21 2 Increased glucose 62 57 3 4 Decreased lymphocytes 55 26 9 5 Increased alkaline phosphatase 48 19 2

0.8 Increased creatinine 40 24 0 0 Decreased magnesium 39 35 0.4 0 Increased aspartate aminotransferase 35 18 2

0.8 Increased alanine aminotransferase 32 19 2 2 Increased calcium 31 23 1 0 HRD-Positive Patients Receiving ZEJULA with Dose Based on Baseline Weight or Platelet Count in PRIMA: Among patients who received ZEJULA with the dose based on weight and platelet count (n = 86), the median duration of treatment was 12 months (range: 4 days to 16 months). Serious adverse reactions occurred in 24% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were anemia (9%) and thrombocytopenia (2%). Permanent discontinuation due to adverse reactions occurred in 11% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >2% of patients who received ZEJULA included nausea (3.5%). Adverse reactions led to dose reduction or interruption in 72% of patients, most frequently (>10%) from thrombocytopenia (35%), anemia (22%), and neutropenia (17%). Tables 6 and 7 summarize adverse reactions and abnormal laboratory findings observed in this group. Table 6. Adverse Reactions Reported in ≥10% of HRD-Positive Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA a a All adverse reactions in the table consist of grouped preferred terms except for nausea, vomiting, decreased appetite, headache, and insomnia, which are single preferred terms. b Common Terminology Criteria for Adverse Events version 4.02. c Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia. d Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased. e Includes blood creatinine increased, blood urea increased, acute kidney injury, and renal failure. Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 86) % Placebo (n = 42) % ZEJULA (n = 86) % Placebo (n = 42) % Blood and lymphatic system disorders Thrombocytopenia 51 2 16 0 Anemia 49 21 22 0 Neutropenia c 35 7 13 0 Leukopenia d 26 7 6 0 Gastrointestinal disorders Nausea 55 21 0 0 Constipation 26 29 1 2 Vomiting 16 17 0

2.4 General disorders and administration site conditions Fatigue 47 41 0 0 Nervous system disorders Headache 24 19 1 0 Dizziness 15 7 0 0 Psychiatric disorders Insomnia 21 19 0 0 Metabolism and nutrition disorders Decreased appetite 19 7 1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 20 12 0 2 Vascular disorders Hypertension 16 12 4 5 Renal and urinary disorders Acute kidney injury e 14 2 0 0 Table 7. […]

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, ZEJULA can cause fetal harm when administered to pregnant women [see Clinical Pharmacology ( 12.1 )] . There are no data regarding the use of ZEJULA in pregnant women to inform the drug-associated risk. ZEJULA has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions ( 5.2 ), Nonclinical Toxicology ( 13.1 )] . Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. Apprise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation Risk Summary No data are available regarding the presence of niraparib or its metabolites in human milk, or on its effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during treatment with ZEJULA and for 1 month after receiving the last dose.

8.3 Females and Males of Reproductive Potential ZEJULA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with ZEJULA. Contraception Females: Advise females of reproductive potential to use effective contraception during treatment with ZEJULA and for 6 months following the last dose. Infertility Males: Based on animal studies, ZEJULA may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1 )] .

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

8.5 Geriatric Use In PRIMA, 39% of patients were aged 65 years or older and 10% were aged 75 years or older. In NOVA, 35% of patients were aged 65 years or older and 8% were aged 75 years or older. No overall differences in safety and effectiveness of ZEJULA were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment For patients with moderate hepatic impairment, the recommended dosage of ZEJULA is 200 mg once daily, regardless of body weight or platelet count. Monitor patients for hematologic toxicity and reduce the dose, if needed [see Dosage and Administration ( 2.3 , 2.4 )] . Niraparib exposure increased in patients with moderate hepatic impairment (total bilirubin ≥1.5 to 3 x ULN and any AST level). For patients with mild hepatic impairment (total bilirubin <1.5 x ULN and any AST level or bilirubin ≤ULN and AST >ULN), no dosage modification is recommended. The effect of severe hepatic impairment (total bilirubin >3 x ULN and any AST level) on niraparib pharmacokinetics is unknown.

Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib‑induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2 . Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2 .