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)]

6.1 Clinical Trials Experience

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

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

First-Line Maintenance Treatment of Advanced Ovarian Cancer

The safety of ZEJULA for the treatment of patients with advanced ovarian cancer following first-line treatment with platinum-based chemotherapy was studied in the PRIMA trial, a placebo-controlled, double-blind study in which 728 patients received niraparib or placebo. Among patients who received ZEJULA, the median duration of treatment was 11.1 months (range: 0.03 to 29 months).

All Patients Receiving ZEJULA in PRIMA: Serious adverse reactions occurred in 32% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were thrombocytopenia (16%), anemia (6%), and small intestinal obstruction (2.9%). Fatal adverse reactions occurred in 0.4% of patients, including intestinal perforation and pleural effusion (1 patient each). MDS/AML occurred in 1.2% of patients receiving ZEJULA.

Permanent discontinuation due to adverse reactions occurred in 12% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >1% of patients who received ZEJULA included thrombocytopenia (3.7%), anemia (1.9%), and nausea and neutropenia (1.2% each).

Adverse reactions led to dose reduction or interruption in 80% of patients, most frequently from thrombocytopenia (56%), anemia (33%), and neutropenia (20%).

Table 4 and Table 5 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in all patients treated with ZEJULA in the PRIMA study.

Table 4. Adverse Reactions Reported in ≥10% of All Patients Receiving ZEJULA in PRIMAa
AST/ALT = Aspartate transaminase/alanine aminotransferase. a All adverse reactions in the table consist of grouped preferred terms except for nausea, vomiting, decreased appetite, headache, and insomnia, which are single preferred terms. b Common Terminology Criteria for Adverse Events version 4.02. c Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia. d Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased. e Includes blood creatinine increased, blood urea increased, acute kidney injury, renal failure, and blood creatine increased.
Adverse Reaction	Grades 1-4b		Grades 3-4b
Adverse Reaction	ZEJULA (n = 484) %	Placebo (n = 244) %	ZEJULA (n = 484) %	Placebo (n = 244) %
Blood and lymphatic system disorders
Thrombocytopenia	66	5	39	0.4
Anemia	64	18	31	2
Neutropeniac	42	8	21	1
Leukopeniad	28	9	5	0.4
Gastrointestinal disorders
Nausea	57	28	1	1
Constipation	40	20	1	0.4
Vomiting	22	12	1	1
General disorders and administration site conditions
Fatigue	51	41	3	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	39	38	1	0
Nervous system disorders
Headache	26	15	0.4	0
Dizziness	19	13	0	0.4
Psychiatric disorders
Insomnia	25	15	1	0.4
Respiratory, thoracic, and mediastinal disorders
Dyspnea	22	13	0.4	1
Cough	18	15	0	0.4
Metabolism and nutrition disorders
Decreased appetite	19	8	1	0
Vascular disorders
Hypertension	18	7	6	1
Investigations
AST/ALT elevation	14	7	3	0.8
Renal and urinary disorders
Acute kidney injurye	12	5	0.2	0

Table 5. Abnormal Laboratory Findings in ≥25% of All Patients Receiving ZEJULA in PRIMA
Abnormal Laboratory Finding	Grades 1-4		Grades 3-4
Abnormal Laboratory Finding	ZEJULA (n = 484) %	Placebo (n = 244) %	ZEJULA (n = 484) %	Placebo (n = 244) %
Decreased hemoglobin	87	66	29	1
Decreased platelets	74	13	37	0
Decreased leukocytes	71	36	9	0
Increased glucose	66	57	3	3
Decreased neutrophils	66	25	23	1
Decreased lymphocytes	51	29	7	3
Increased alkaline phosphatase	46	21	1	0
Increased creatinine	40	23	0	0
Decreased magnesium	36	34	1	0
Increased aspartate aminotransferase	35	17	1	0.4
Increased alanine aminotransferase	29	17	2	1

Patients Receiving ZEJULA with Dose Based on Baseline Weight or Platelet Count in PRIMA: Among patients who received ZEJULA with the dose based on weight and platelet count, the median duration of treatment was 11 months (range: 1 day to 16 months).

Serious adverse reactions occurred in 27% of patients receiving ZEJULA. Serious adverse reactions in >2% of patients were anemia (8%), and thrombocytopenia (7%). No fatal adverse reactions occurred.

Permanent discontinuation due to adverse reactions occurred in 14% of patients who received ZEJULA. Adverse reactions resulting in permanent discontinuation in >2% of patients who received ZEJULA included thrombocytopenia and anemia (3% each) and nausea (2.4%).

Adverse reactions led to dose reduction or interruption in 72% of patients, most frequently from thrombocytopenia (40%), anemia (23%), and neutropenia (15%).

Table 6 and Table 7 summarize adverse reactions and abnormal laboratory findings in the group of patients who received ZEJULA.

Table 6. Adverse Reactions Reported in ≥10% of Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMAa
a All adverse reactions in the table consist of grouped preferred terms except for nausea, vomiting, decreased appetite, headache, and insomnia, which are single preferred terms. b Common Terminology Criteria for Adverse Events version 4.02. c Includes neutropenia, neutropenic infection, neutropenic sepsis, and febrile neutropenia. d Includes leukopenia, lymphocyte count decreased, lymphopenia, and white blood cell count decreased. e Includes blood creatinine increased, blood urea increased, acute kidney injury, renal failure, and blood creatine increased.
Adverse Reaction	Grades 1-4b		Grades 3-4b
Adverse Reaction	ZEJULA (n = 169) %	Placebo (n = 86) %	ZEJULA (n = 169) %	Placebo (n = 86) %
Blood and lymphatic system disorders
Thrombocytopenia	54	5	21	1
Anemia	50	28	23	1
Neutropeniac	36	8	15	1
Leukopeniad	28	11	5	0
Gastrointestinal disorders
Nausea	53	21	1	0
Constipation	31	15	1	1
Vomiting	17	9	0	1
General disorders and administration site conditions
Fatigue	48	36	3	0
Nervous system disorders
Headache	22	17	1	0
Dizziness	14	13	0	0
Psychiatric disorders
Insomnia	21	14	0	0
Metabolism and nutrition disorders
Decreased appetite	19	5	1	0
Respiratory, thoracic, and mediastinal disorders
Dyspnea	18	10	0	1
Vascular disorders
Hypertension	17	9	5	2
Renal and urinary disorders
Acute kidney injurye	12	5	1	0

Table 7. Abnormal Laboratory Findings in ≥25% of All Patients Receiving ZEJULA Based on Baseline Weight or Platelet Count in PRIMA
Abnormal Laboratory Finding	Grades 1-4		Grades 3-4
Abnormal Laboratory Finding	ZEJULA (n = 169) %	Placebo (n = 86) %	ZEJULA (n = 169) %	Placebo (n = 86) %
Decreased hemoglobin	81	70	21	0
Decreased leukocytes	70	36	6	0
Decreased platelets	63	15	18	0
Increased glucose	63	56	2	1
Decreased neutrophils	60	27	15	0
Decreased lymphocytes	52	30	5	4
Decreased magnesium	44	30	0	0
Increased alkaline phosphatase	43	17	1	0
Increased creatinine	41	22	0	0
Increased aspartate aminotransferase	31	19	1	0
Increased alanine aminotransferase	28	15	2	2

Maintenance Treatment of Recurrent Germline BRCA-mutated Ovarian Cancer

The safety of monotherapy with ZEJULA 300 mg once daily has been studied in 136 patients with platinum-sensitive recurrent gBRCAmut 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 gBRCAmut cohort in NOVA.

Table 8. Adverse Reactions Reported in ≥10% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort
a Common Terminology Criteria for Adverse Events version 4.02. b Includes platelet count decreased. c Includes hemoglobin decreased. d Includes neutrophil count decreased. e Includes asthenia, malaise, lethargy.
Adverse Reaction	Grades 1-4a		Grades 3-4a
Adverse Reaction	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
Thrombocytopeniab	71	5	38	2
Anemiac	52	8	33	0
Neutropeniad	31	9	21	3
General disorders and administration site conditions
Fatiguee	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 gBRCAmut cohort of the NOVA trial and not included in the table: palpitations (9%), mucositis/stomatitis (9%), MDS/AML (7%), tachycardia (7%), and bronchitis (4%).

Table 9. Abnormal Laboratory Findings in ≥25% of Patients Receiving ZEJULA in NOVA gBRCAmut Cohort
Abnormal Laboratory Finding	Grades 1-4		Grades 3-4
Abnormal Laboratory Finding	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.