Contents

ZEJULA (niraparib) capsules

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}-2Hindazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1). The molecular formula is C₂₆H₃₀N₄O₅S and it has a molecular weight of 510.61 amu.

Niraparib tosylate monohydrate is a 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.

INDICATIONS AND USAGE

First-Line Maintenance Treatment of Advanced Ovarian Cancer: ZEJULA is indicated for the maintenance treatment of adult patients with advanced epithelialovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response tofirst-line platinum-based chemotherapy.

Maintenance Treatment of Recurrent Ovarian Cancer: ZEJULA is indicated for the maintenance treatment of adult patients with recurrent epithelialovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response toplatinum-based chemotherapy.

Mechanism of Action

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.

DOSAGE AND ADMINISTRATION

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 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

For patients weighing <77 kg (<170 lbs) OR with a 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 a 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 Cancer

The 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 8 weeks after their most recent platinum-containing regimen.

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.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia: Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with fataloutcome, have been reported in patients who received monotherapy with ZEJULA in clinicaltrials. In 1,785 patients treated with ZEJULA in clinical trials, MDS/AML occurred in 15patients (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.

Bone Marrow Suppression: Hematologic adverse reactions, including thrombocytopenia, anemia, neutropenia, and/orpancytopenia have been reported in patients treated with ZEJULA.

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.

Hypertension and Cardiovascular Effects: Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA.

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.

Posterior Reversible Encephalopathy Syndrome: Posterior reversible encephalopathy syndrome (PRES) occurred in 0.1% of 2,165 patients treatedwith ZEJULA in clinical trials and has also been described in postmarketing reports. 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.

Embryo-Fetal Toxicity: Based on its mechanism of action, ZEJULA can cause fetal harm when administered to apregnant woman. ZEJULA has the potential to causeteratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets activelydividing cells in animals and patients (e.g., bone marrow). 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.

Allergic Reactions to FD&C Yellow No. 5 (Tartrazine): ZEJULA capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on its mechanism of action, ZEJULA can cause fetal harm when administered to pregnantwomen. 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). 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.

Lactation: No data are available regarding the presence of niraparib or its metabolites in human milk, or onits effects on the breastfed child or milk production. Because of the potential for serious adversereactions in a breastfed child, advise a lactating woman not to breastfeed during treatment withZEJULA and for 1 month after receiving the final dose.

Females and Males of Reproductive Potential

ZEJULA can cause fetal harm when administered to a pregnant woman.

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 at least for 6 months following the last dose.

Infertility

Males: Based on animal studies, ZEJULA may impair fertility in males of reproductive potential.

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

Geriatric Use: In PRIMA, 39% of patients were aged 65 years or older and 10% were aged 75 years or older. InNOVA, 35% of patients were aged 65 years or older and 8% were aged 75 years or older. Nooverall differences in safety and effectiveness of ZEJULA were observed between these patientsand younger patients but greater sensitivity of some older individuals cannot be ruled out.

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 bycreatinine clearance as estimated by the Cockcroft-Gault equation. The safety of ZEJULA inpatients with severe renal impairment or end-stage renal disease undergoing hemodialysis isunknown.

Hepatic Impairment: For patients with moderate hepatic impairment, reduce the starting dosage of niraparib to 200 mgonce daily. Niraparib exposure increased in patients withmoderate hepatic impairment [total bilirubin ≥1.5 x upper level of normal (ULN) to 3.0 x ULNand any aspartate transaminase (AST) level].

Monitor patients for hematologic toxicity andreduce the dose further, if needed.

For patients with mild hepatic impairment (total bilirubin <1.5 x 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 x ULN and any AST level)

ZEJULA (niraparib) capsules

ZEJULA (niraparib) capsules