1 INDICATIONS AND USAGE ZEJULA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated: • for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy 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 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • MDS/AML [see Warnings and Precautions ( 5.1 )] • Bone marrow suppression [see Warnings and Precautions ( 5.2 )] • Hypertension and cardiovascular effects [see Warnings and Precautions ( 5.3 )] • Posterior reversible encephalopathy syndrome [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (incidence ≥10%) in patients who received ZEJULA were nausea, thrombocytopenia, anemia, fatigue, constipation, musculoskeletal pain, abdominal pain, vomiting, neutropenia, decreased appetite, leukopenia, insomnia, headache, dyspnea, rash, diarrhea, hypertension, cough, dizziness, acute kidney injury, urinary tract infection, and hypomagnesemia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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

First-Line Maintenance Treatment of HRD-Positive Advanced Ovarian Cancer The safety of ZEJULA for the treatment of patients with advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was studied in the PRIMA trial, a placebo-controlled, double-blind study in which 484 patients received ZEJULA.

Among this population, 245 patients were HRD-positive and their median duration of treatment was 13 months (range: 3 days to 29 months).

HRD-Positive Patients Receiving ZEJULA in PRIMA: Serious adverse reactions occurred in 30% of patients receiving ZEJULA.

Serious adverse reactions in >2% of patients were thrombocytopenia (11%) and anemia (5%).

Fatal adverse reactions occurred in 1.6% of patients, including AML (0.4%), cardiac arrest (0.4%), intestinal perforation (0.4%), and sudden death (0.4%).

Permanent discontinuation due to adverse reactions occurred in 11% of patients who received ZEJULA.

Adverse reactions resulting in permanent discontinuation in >1% of patients who received ZEJULA included thrombocytopenia (3.7%), nausea (1.6%), and anemia (1.2%).

Adverse reactions led to dose reduction or interruption in 79% of patients, most frequently (>10%) from thrombocytopenia (53%), anemia (32%), and neutropenia (19%).

Tables 4 and 5 summarize the common adverse reactions and abnormal laboratory findings observed in the PRIMA trial.

Table 4.

Adverse Reactions Reported in ≥10% of HRD-Positive Patients Receiving ZEJULA in PRIMA a AST/ALT = Aspartate aminotransferase/alanine aminotransferase.

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

b Common Terminology Criteria for Adverse Events version 4.02.

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

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

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

Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 245) % Placebo (n = 125) % ZEJULA (n = 245) % Placebo (n = 125) % Blood and lymphatic system disorders Thrombocytopenia 66 4 38 0 Anemia 65 16 31 2 Neutropenia c 43 9 17 2 Leukopenia d 29 10 6 0.8 Gastrointestinal disorders Nausea 62 34 1 0 Constipation 40 26 1 0.8 Vomiting 23 14 2 0.8 General disorders and administration site conditions Fatigue 52 44 2 2 Musculoskeletal and connective tissue disorders Musculoskeletal pain 46 38 0.8 0 Nervous system disorders Headache 27 15 0.8 0 Dizziness 20 11 0 0 Psychiatric disorders Insomnia 25 16 0.4 0.8 Anxiety 12 6 0 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 21 15 0 0.8 Cough 20 14 0 0.8 Metabolism and nutrition disorders Decreased appetite 20 6 0.4 0 Vascular disorders Hypertension 20 8 7 2 Investigations AST/ALT elevation 14 8 3 0 Renal and urinary disorders Acute kidney injury e 13 3 0 0 Table 5.

Abnormal Laboratory Findings in ≥25% of HRD-Positive Patients Receiving ZEJULA in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 245) % Placebo (n = 125) % ZEJULA (n = 245) % Placebo (n = 125) % Decreased hemoglobin 85 65 28 2 Decreased leukocytes 72 37 9 0 Decreased platelets 71 11 36 0 Decreased neutrophils 64 28 21 2 Increased glucose 62 57 3 4 Decreased lymphocytes 55 26 9 5 Increased alkaline phosphatase 48 19 2 0.8 Increased creatinine 40 24 0 0 Decreased magnesium 39 35 0.4 0 Increased aspartate aminotransferase 35 18 2 0.8 Increased alanine aminotransferase 32 19 2 2 Increased calcium 31 23 1 0 HRD-Positive Patients Receiving ZEJULA with Dose Based on Baseline Weight or Platelet Count in PRIMA: Among patients who received ZEJULA with the dose based on weight and platelet count (n = 86), the median duration of treatment was 12 months (range: 4 days to 16 months).

Serious adverse reactions occurred in 24% of patients receiving ZEJULA.

Serious adverse reactions in >2% of patients were anemia (9%) and thrombocytopenia (2%).

Permanent discontinuation due to adverse reactions occurred in 11% of patients who received ZEJULA.

Adverse reactions resulting in permanent discontinuation in >2% of patients who received ZEJULA included nausea (3.5%).

Adverse reactions led to dose reduction or interruption in 72% of patients, most frequently (>10%) from thrombocytopenia (35%), anemia (22%), and neutropenia (17%).

Tables 6 and 7 summarize adverse reactions and abnormal laboratory findings observed in this group.

Table 6.

Adverse Reactions Reported in ≥10% of HRD-Positive Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA a a All adverse reactions in the table consist of grouped preferred terms except for nausea, vomiting, decreased appetite, headache, and insomnia, which are single preferred terms.

b Common Terminology Criteria for Adverse Events version 4.02.

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

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

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

Adverse Reaction Grades 1-4 b Grades 3-4 b ZEJULA (n = 86) % Placebo (n = 42) % ZEJULA (n = 86) % Placebo (n = 42) % Blood and lymphatic system disorders Thrombocytopenia 51 2 16 0 Anemia 49 21 22 0 Neutropenia c 35 7 13 0 Leukopenia d 26 7 6 0 Gastrointestinal disorders Nausea 55 21 0 0 Constipation 26 29 1 2 Vomiting 16 17 0 2.4 General disorders and administration site conditions Fatigue 47 41 0 0 Nervous system disorders Headache 24 19 1 0 Dizziness 15 7 0 0 Psychiatric disorders Insomnia 21 19 0 0 Metabolism and nutrition disorders Decreased appetite 19 7 1 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 20 12 0 2 Vascular disorders Hypertension 16 12 4 5 Renal and urinary disorders Acute kidney injury e 14 2 0 0 Table 7.

Abnormal Laboratory Findings in ≥25% of HRD-Positive Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 86) % Placebo (n = 42) % ZEJULA (n = 86) % Placebo (n = 42) % Decreased hemoglobin 74 67 21 0 Decreased leukocytes 70 36 6 0 Decreased platelets 58 17 14 0 Increased glucose 57 62 4 2 Decreased neutrophils 57 31 13 0 Decreased lymphocytes 55 24 6 5 Decreased magnesium 51 41 0 0 Increased alkaline phosphatase 42 12 2 0 Increased creatinine 42 24 0 0 Increased aspartate aminotransferase 31 21 2 0 Increased alanine aminotransferase 30 17 2 2 Increased calcium 29 36 0 0 Maintenance Treatment of Recurrent Germline BRCA -Mutated Ovarian Cancer The safety of monotherapy with ZEJULA 300 mg once daily has been studied in 136 patients with platinum-sensitive recurrent g BRCA mut ovarian, fallopian tube, and primary peritoneal cancer in the NOVA trial.

The percentages of patients who experienced adverse reactions in NOVA that led to dose reduction and dose interruption were 79% and 68%, respectively, most frequently from thrombocytopenia (41% and 35%, respectively) and anemia (23% and 20%, respectively).

The permanent discontinuation rate due to adverse reactions in NOVA was 13%.

The median exposure to ZEJULA in these patients was 367 days.

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

Table 8.

Adverse Reactions Reported in ≥10% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort g BRCA mut = Germline BRCA -mutated.

a Common Terminology Criteria for Adverse Events version 4.02.

b Includes platelet count decreased.

c Includes hemoglobin decreased.

d Includes neutrophil count decreased.

e Includes asthenia, malaise, and lethargy.

Adverse Reaction Grades 1-4 a Grades 3-4 a ZEJULA (n = 136) % Placebo (n = 65) % ZEJULA (n = 136) % Placebo (n = 65) % Gastrointestinal disorders Nausea 77 34 5 3 Vomiting 40 15 4 0 Constipation 38 18 0.7 2 Dyspepsia 17 12 0 0 Dry mouth 13 3 0.7 0 Blood and lymphatic system disorders Thrombocytopenia b 71 5 38 2 Anemia c 52 8 33 0 Neutropenia d 31 9 21 3 General disorders and administration site conditions Fatigue e 61 35 8 2 Nervous system disorders Headache 35 8 0.7 0 Dizziness 18 9 0 0 Dysgeusia 13 2 0 0 Metabolism and nutrition disorders Decreased appetite 22 14 0 0 Vascular disorders Hypertension 21 8 8 5 Psychiatric disorders Insomnia 18 6 0.7 0 Anxiety 10 11 0.7 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 17 5 2 0 Cough 16 2 0 0 Nasopharyngitis 13 5 0 0 Musculoskeletal and connective tissue disorders Back pain 16 11 0.7 0 Infections and infestations Urinary tract infection 11 9 0 2 Skin and subcutaneous tissue disorders Rash 10 2 0 0 The following adverse reactions have been identified in ≥1 to <10% of the 136 patients receiving ZEJULA in the g BRCA mut cohort of the NOVA trial and not included in the table: palpitations (9%), mucositis/stomatitis (9%), MDS/AML (7%), tachycardia (7%), and bronchitis (4%).

Table 9.

Abnormal Laboratory Findings in ≥25% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort g BRCA mut = Germline BRCA- mutated.

Abnormal Laboratory Finding Grades 1-4 Grades 3-4 ZEJULA (n = 136) % Placebo (n = 65) % ZEJULA (n = 136) % Placebo (n = 65) % Decrease in hemoglobin 85 62 32 0 Decrease in platelet count 81 25 38 2 Decrease in white blood cell count 71 37 9 2 Decrease in absolute neutrophil count 56 34 23 3 Increase in aspartate aminotransferase 35 25 0.7 0 Increase in alanine aminotransferase 25 15 0.7 2 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZEJULA.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders Pancytopenia.

Immune System Disorders Hypersensitivity (including anaphylaxis).

Nervous System Disorders Posterior reversible encephalopathy syndrome (PRES).

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

Respiratory, Thoracic, and Mediastinal Disorders Non-infectious pneumonitis.

Skin and Subcutaneous Tissue Disorders Photosensitivity.

Vascular Disorders Hypertensive crisis.