1 INDICATIONS AND USAGE

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

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 (gBRCAmut) 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-approved companion diagnostic for ZEJULA [see Dosage and Administration (2.1)].

5 WARNINGS AND PRECAUTIONS

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, MDS/AML occurred in 6 out of 484 (1.2%) patients treated with ZEJULA and in 3 out of 244 (1.2%) 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 3.7 months to 2.5 years.

In NOVA, of patients within the gBRCAmut 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)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Maintenance Treatment of Recurrent Germline BRCA-mutated Ovarian Cancer

Select patients for the maintenance treatment of recurrent ovarian cancer with ZEJULA based on the presence of deleterious or suspected deleterious germline BRCA mutations [see Clinical Studies (14.2)].

Information on FDA-approved tests for the detection of deleterious or suspected deleterious germline BRCA mutations for this indication is available at https://www.fda.gov/companiondiagnostics.

2.2 Recommended Dosage

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 tablet whole and not to chew, crush, or split ZEJULA prior to swallowing. ZEJULA may be taken with or without food. Bedtime administration may be a potential method for managing nausea.

In the case of a missed dose of ZEJULA, instruct patients to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose of ZEJULA, an additional dose should not be taken.

First-Line Maintenance Treatment of Advanced Ovarian Cancer

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For patients weighing <77 kg (<170 lbs) OR with a platelet count of <150,000/mcL, the recommended dosage is 200 mg taken orally once daily.

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For patients weighing ≥77 kg (≥170 lbs) AND who have a platelet count ≥150,000/mcL, the recommended dosage is 300 mg taken orally once daily.

For the maintenance treatment of advanced ovarian cancer, patients should start treatment with ZEJULA no later than 12 weeks after their most recent platinum-containing regimen.

Maintenance Treatment of Recurrent Germline BRCA-mutated Ovarian Cancer

The recommended dosage of ZEJULA is 300 mg taken orally once daily.

For the maintenance treatment of recurrent ovarian cancer, patients should start treatment with ZEJULA no later than 8 weeks after their most recent platinum-containing regimen.

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.

Withhold ZEJULA for a maximum of 28 days or until resolution of adverse reaction.

Resume ZEJULA at a reduced dose per Table 1.

Withhold ZEJULA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL.

Resume ZEJULA at same or reduced dose per Table 1.

If platelet count is <75,000/mcL, resume at a reduced dose.

Withhold ZEJULA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL.

Resume ZEJULA at a reduced dose per Table 1.

Discontinue ZEJULA if the platelet count has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg once daily.a

Withhold ZEJULA for a maximum of 28 days and monitor blood counts weekly until neutrophil counts return to ≥1,500/mcL or hemoglobin returns to ≥9 g/dL.

Resume ZEJULA at a reduced dose per Table 1.

Discontinue ZEJULA if neutrophils and/or hemoglobin have not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg once daily.a

For patients with platelet count ≤10,000/mcL, platelet transfusion should be considered. If there are other risk factors such as coadministration of anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or transfusion at a higher platelet count.

Resume ZEJULA at a reduced dose.

2.4 Dosage Adjustment for Hepatic Impairment

Moderate Hepatic Impairment

For 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)].

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 a 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 3 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 a trend toward reversibility of these findings 4 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 2 rhesus monkeys were 0.10 and 0.52.

16 HOW SUPPLIED/STORAGE AND HANDLING

ZEJULA is available as oval-shaped, film-coated tablets containing 100 mg, 200 mg, or 300 mg of niraparib free base.

ZEJULA 100-mg tablets are gray, debossed with “100” on one side and “Zejula” on the other side. Bottle of 30 tablets (NDC 0173-0909-13).

ZEJULA 200-mg tablets are blue, debossed with “200” on one side and “Zejula” on the other side. Bottle of 30 tablets (NDC 0173-0912-13).

ZEJULA 300-mg tablets are green, debossed with “300” on one side and “Zejula” on the other side. Bottle of 30 tablets (NDC 0173-0915-13).

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myelodysplastic Syndrome/Acute Myeloid Leukemia

Advise 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 a need for blood transfusions. This may be a 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 Suppression

Advise 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 Effects

Advise patients to undergo blood pressure and heart rate monitoring at least weekly for the first 2 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 Syndrome

Inform 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 Instructions

Inform patients on how to take ZEJULA [see Dosage and Administration (2.2)]. ZEJULA should be taken once daily. Instruct patients that if they miss a 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 tablet should be swallowed whole. ZEJULA may be taken with or without food. Bedtime administration may be a potential method for managing nausea.

Embryo-Fetal Toxicity

Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)].

Contraception

Advise females of reproductive potential to use effective contraception during treatment with ZEJULA and for 6 months after receiving the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise patients not to breastfeed while taking ZEJULA and for 1 month after the last dose [see Use in Specific Populations (8.2)].

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Manufactured for

GlaxoSmithKline

Durham, NC 27701

©2024 GSK group of companies or its licensor.

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