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  • CLASSES

    Small Molecule Antineoplastic Poly (ADP-ribose) Polymerase (PARP) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral poly (ADP-ribose) polymerase (PARP) inhibitor
    Used for treatment of heavily pretreated advanced ovarian cancer with associated homologous recombination deficiency (HRD), or as maintenance therapy for platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer
    Hematologic toxicity has been commonly reported, as well as cases of myelodysplastic syndrome/acute myeloid leukemia; closely monitor complete blood counts

    COMMON BRAND NAMES

    ZEJULA

    HOW SUPPLIED

    ZEJULA Oral Cap: 100mg

    DOSAGE & INDICATIONS

    For the treatment of ovarian cancer.
    For the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
    Oral dosage
    Adults

    300 mg PO once daily until disease progression or unacceptable toxicity. Begin niraparib therapy no later than 8 weeks after the last platinum-containing regimen. In a randomized, double-blind, placebo-controlled clinical trial, patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received treatment with niraparib within 8 weeks of the last platinum-based therapy had significantly improved progression-free survival (PFS) as assessed by a blinded, independent central review committee (IRC) compared with placebo. Median PFS was significantly improved both in patients with germline BRCA mutations (gBRCAmut) (21 months vs. 5.5 months) as well as in patients without gBRCAmut (9.3 months vs. 3.9 months).

    For the treatment of advanced ovarian, fallopian tube, or primary peritoneal cancer in patients treated with 3 or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status, as defined by a deleterious or suspected deleterious BRCA mutation.
    NOTE: Select patients based on the presence of deleterious or suspected deleterious BRCA mutation. Information on FDA-approved tests for the detection of deleterious or suspected deleterious BRCA mutations is available at www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    300 mg PO once daily until disease progression or unacceptable toxicity. Niraparib was studied in a noncomparative trial of patients with homologous recombination deficiency (HRD) positive, advanced ovarian cancer after 3 or more prior lines of chemotherapy (QUADRA trial; n = 98); patients without BRCA mutations must have progressed at least 6 months after their last dose of platinum therapy. Patients with HRD positive status had either a BRCA mutation or GIS of 42 or higher. Treatment with niraparib resulted in an objective response rate of 24% in patients with HRD, all as partial responses, for a median duration of 8.3 months. In the subgroup of patients with BRCA-mutated ovarian cancer (n = 63), investigator-assessed ORR was 39% in those with platinum-sensitive disease (n = 18), 29% in those with platinum-resistant disease (n = 21), and 19% in those with platinum-refractory disease (n = 16).

    For the treatment of advanced ovarian, fallopian tube, or primary peritoneal cancer after treatment with 3 or more prior chemotherapy regimens, in patients whose cancer is associated with homologous recombination deficiency (HRD) positive status, as defined by genomic instability; patients must have progressed more than 6 months after response to the last platinum-based chemotherapy.
    NOTE: Select patients based on genomic instability score (GIS). Information on FDA-approved tests for genomic instability is available at www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    300 mg PO once daily until disease progression or unacceptable toxicity. Niraparib was studied in a noncomparative trial of patients with homologous recombination deficiency (HRD) positive, advanced ovarian cancer after 3 or more prior lines of chemotherapy (QUADRA trial; n = 98); patients without BRCA mutations must have progressed at least 6 months after their last dose of platinum therapy. Patients with HRD positive status had either a BRCA mutation or GIS of 42 or higher. Treatment with niraparib resulted in an objective response rate of 24% in patients with HRD, all as partial responses, for a median duration of 8.3 months. In the subgroup of patients with platinum-sensitive GIS-positive disease, without a BRCA mutation, investigator-assessed ORR was 20% (n = 35).

    For the first-line maintenance therapy of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in a complete or partial response to first-line platinum-based chemotherapy, as monotherapy.
    Oral dosage
    Adults weighing less than 77 kg OR with a platelet count less than 150,000 cells/mm3

    200 mg PO once daily until disease progression or unacceptable toxicity. Begin niraparib therapy no later than 12 weeks after the last platinum-containing regimen. In a double-blind, phase 3 clinical trial, patients with newly diagnosed, advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer with a response to first-line platinum-based chemotherapy were randomized to receive maintenance therapy with niraparib or placebo within 12 weeks after completion of chemotherapy. Patients receiving maintenance therapy with niraparib had significantly improved progression-free survival (PFS) compared with placebo (21.9 months vs. 10.4 months), irrespective of BRCA status. Overall survival was not significantly different at only 10.8% data maturity. Treatment had expected adverse reactions that were somewhat mitigated for lower dosing in patients with a baseline weight below 77 kg or platelet counts of less than 150,000 cells/mm3.

    Adults weighing more than 77 kg AND with a platelet count greater than 150,000 cells/mm3

    300 mg PO once daily until disease progression or unacceptable toxicity. Begin niraparib therapy no later than 12 weeks after the last platinum-containing regimen. In a double-blind, phase 3 clinical trial, patients with newly diagnosed, advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer with a response to first-line platinum-based chemotherapy were randomized to receive maintenance therapy with niraparib or placebo within 12 weeks after completion of chemotherapy. Patients receiving maintenance therapy with niraparib had significantly improved progression-free survival (PFS) compared with placebo (21.9 months vs. 10.4 months), irrespective of BRCA status. Overall survival was not significantly different at only 10.8% data maturity. Treatment had expected adverse reactions that were somewhat mitigated for lower dosing in patients with a baseline weight below 77 kg or platelet counts of less than 150,000 cells/mm3.

    MAXIMUM DOSAGE

    Adults

    300 mg PO once daily.

    Geriatric

    300 mg PO once daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage Adjustments for Baseline Hepatic Impairment:
    Mild hepatic impairment (total bilirubin less than 1.5 times upper level of normal (ULN) and any AST or bilirubin below the ULN and AST greater than ULN): No dosage adjustment is necessary.
    Moderate hepatic impairment (total bilirubin 1.5 to 3 times ULN and any AST): Reduce the starting dose of niraparib to 200 mg PO once daily; monitor patients for hematologic toxicity and reduce the dose further if needed.
    Severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST): The recommended dose of niraparib has not been established.
     
    Dosage Adjustments for Treatment-Related Hepatotoxicity:
    Grade 3 or higher elevation in liver function tests (total bilirubin greater than 3 times the upper limit of normal (ULN) or ALT/AST greater than 5 times ULN) where treatment is not considered feasible or adverse reaction persists despite treatment: Hold niraparib treatment for a maximum of 28 days. If resolution occurs within 28 days, restart therapy at a reduced dose (i.e., 300 mg to 200 mg; 200 mg to 100 mg). If grade 3 or higher hepatic dysfunction persists beyond 28 days or occurs at a daily dose of 100 mg, discontinue niraparib treatment.

    Renal Impairment

    Dosage Adjustments for Baseline Renal Insufficiency:
    Mild to moderate renal impairment (CrCl 30 to 89 mL/min): No dosage adjustment necessary.
    Severe renal impairment (CrCl less than 30 mL/min) or end-stage renal disease (ESRD) undergoing hemodialysis: The safety of niraparib treatment is unknown.
     
    Dosage Adjustments for Treatment-Related Nephrotoxicity:
    Grade 3 or higher nephrotoxicity (SCr greater than 3 times the upper limit of normal (ULN) or GFR less than 25% of the lower limit of normal (LLN)) where treatment is not considered feasible or adverse reaction persists despite treatment: Hold niraparib treatment for a maximum of 28 days. If resolution occurs within 28 days, restart therapy at a reduced dose (i.e., 300 mg to 200 mg; 200 mg to 100 mg). If grade 3 or higher renal dysfunction persists beyond 28 days or occurs at a daily dose of 100 mg, discontinue niraparib treatment.

    ADMINISTRATION

    Oral Administration

    Niraparib capsules may be taken with or without food.
    Swallow the capsules whole; do not chew, crush, split, or dissolve.
    Take capsules at the same time daily; bedtime administration may help alleviate nausea.
    If a dose is missed or the patient vomits, the next dose should be taken at the regularly scheduled time; do not take an additional dose.

    STORAGE

    ZEJULA:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Anemia, bone marrow suppression, neutropenia, thrombocytopenia

    Bone marrow suppression (neutropenia, anemia, and thrombocytopenia) has been reported in patients treated with niraparib in clinical trials. Do not start therapy with niraparib until patients have recovered from hematologic toxicity caused by previous chemotherapy (to grade 1 or less). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. An interruption of therapy and/or dose reduction or discontinuation of therapy may be necessary if hematologic toxicity occurs. If therapy is interrupted and hematologic toxicities do not resolve within 28 days, discontinue niraparib treatment and refer the patient to a hematologist for further evaluation, including bone marrow analysis and blood sample for cytogenetics.

    Leukemia, myelodysplastic syndrome (MDS), new primary malignancy

    A new primary malignancy, specifically myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) including some cases with fatal outcome, has been reported in patients treated with niraparib in clinical trials. The duration of niraparib treatment prior to diagnosis with MDS or AML ranged from less than 2 months to more than 4 years; all patients were also previously treated with platinum chemotherapy and/or DNA damaging agents including radiotherapy. Discontinue niraparib if a diagnosis of MDS or AML is confirmed.

    Cardiac arrhythmias, cardiac disease, heart failure, hypertension, hypertensive crisis

    Hypertension and hypertensive crisis have been reported in patients treated with niraparib in clinical trials. Use niraparib with caution and close monitoring in patients with pre-existing hypertension, cardiac disease, heart failure, or a history of cardiac arrhythmias. Monitor blood pressure and heart rate at least weekly for the first 2 months, then monthly for the first year of therapy, and periodically thereafter. Medically manage hypertension as appropriate; an interruption of therapy, dose adjustment, or discontinuation of therapy may be necessary.

    Encephalopathy

    Posterior Reversible Encephalopathy Syndrome (PRES) has occurred in patients treated with niraparib. Signs and symptoms include seizures, headache, visual disturbances or cortical blindness, and altered mental status. Monitor all patients treated with niraparib for signs and symptoms of PRES. Promptly discontinue niraparib therapy if PRES is suspected or diagnosed and administer appropriate treatment; this syndrome may be confirmed on magnetic resonance imaging. The safety of reinitiating niraparib in patients who previously experienced PRES is not known.

    Tartrazine dye hypersensitivity

    Niraparib contains tartrazine dye (FD&C yellow no. 5). Patients with tartrazine dye hypersensitivity who take niraparib may be at risk for developing allergic reactions (e.g., bronchial asthma). Tartrazine sensitivity frequently occurs in patients who also have aspirin hypersensitivity.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during niraparib treatment and for at least 6 months after the last dose. Based on its mechanism of action, niraparib can cause teratogenicity and/or embryo-fetal death when administered to pregnant women because it is genotoxic and targets actively dividing cells (e.g., bone marrow). Because of this potential risk, animal developmental and reproductive studies were not conducted.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during niraparib treatment. Niraparib can be teratogenic and cause embryo-fetal death if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with niraparib. Females of reproductive potential should undergo pregnancy testing prior to initiation of niraparib. Women who become pregnant while receiving niraparib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of niraparib on human fertility, reduced sperm, spermatids, and germ cells in epididymides and testes (male infertility) has been observed in animal studies at exposures approximately 0.012 to 0.3 times the human exposure of niraparib at the recommended dose; there was a trend toward reversibility 4 weeks after discontinuation of niraparib.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants, advise women to discontinue breast-feeding during niraparib treatment and for 1 month after the final dose. It is not known whether niraparib is present in human milk or if it has negative effects on milk production.

    ADVERSE REACTIONS

    Severe

    thrombocytopenia / Delayed / 21.0-39.0
    anemia / Delayed / 23.0-31.0
    neutropenia / Delayed / 13.0-21.0
    hypertension / Early / 9.0-12.0
    nausea / Early / 1.0-10.0
    elevated hepatic enzymes / Delayed / 0-8.0
    vomiting / Early / 0-8.0
    asthenia / Delayed / 0-8.0
    fatigue / Early / 3.0-8.0
    abdominal pain / Early / 0-7.0
    GI obstruction / Delayed / 0-7.0
    hyponatremia / Delayed / 0-6.0
    leukopenia / Delayed / 0-5.0
    constipation / Delayed / 0.8-5.0
    hyperglycemia / Delayed / 0-5.0
    musculoskeletal pain / Early / 0-3.0
    dyspnea / Early / 0.4-3.0
    infection / Delayed / 0.8-2.0
    anorexia / Delayed / 0.3-2.0
    hypoalbuminemia / Delayed / 0-2.0
    new primary malignancy / Delayed / 0.7-1.4
    headache / Early / 0.3-1.0
    insomnia / Early / 0-1.0
    hypomagnesemia / Delayed / 0-1.0
    renal failure (unspecified) / Delayed / 0-1.0
    back pain / Delayed / 0-0.8
    rash / Early / 0-0.5
    stomatitis / Delayed / 0-0.5
    anxiety / Delayed / 0-0.3
    xerostomia / Early / 0-0.3
    diarrhea / Early / 0-0.2
    leukemia / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    hypertensive crisis / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    pleural effusion / Delayed / Incidence not known

    Moderate

    palpitations / Early / 0-10.0
    sinus tachycardia / Rapid / 0-10.0
    depression / Delayed / 0-10.0
    conjunctivitis / Delayed / 0-10.0
    peripheral edema / Delayed / 0-10.0
    hypokalemia / Delayed / 0-10.0
    encephalopathy / Delayed / 0.1-0.1
    lymphopenia / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    impaired cognition / Early / Incidence not known
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known

    Mild

    pharyngitis / Delayed / 0-23.0
    dizziness / Early / 11.0-19.0
    dyspepsia / Early / 0-18.0
    cough / Delayed / 13.0-18.0
    epistaxis / Delayed / 0-10.0
    weight loss / Delayed / 1.0-10.0
    dysgeusia / Early / 0-10.0
    photosensitivity / Delayed / Incidence not known

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during niraparib treatment and for at least 6 months after the last dose. Based on its mechanism of action, niraparib can cause teratogenicity and/or embryo-fetal death when administered to pregnant women because it is genotoxic and targets actively dividing cells (e.g., bone marrow). Because of this potential risk, animal developmental and reproductive studies were not conducted.

    Due to the potential for serious adverse reactions in nursing infants, advise women to discontinue breast-feeding during niraparib treatment and for 1 month after the final dose. It is not known whether niraparib is present in human milk or if it has negative effects on milk production.

    MECHANISM OF ACTION

    Niraparib inhibits poly (ADP-ribose) polymerase (PARP) enzyme 1 (PARP1) and PARP enzyme 2 (PARP2). PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. In vitro, niraparib-induced cytotoxicity resulted in DNA damage, apoptosis and cell death due to increased formation of PARP-DNA complexes; cytotoxicity was observed in tumor cell lines irrespective of BRCA1/2 deficiencies. Niraparib decreased tumor growth in mouse xenograft models of human cancer with BCRA1/2 deficiencies and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2. Additionally, niraparib inhibits the uptake of norepinephrine and dopamine by binding to the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) in vitro in cells with IC50 values that were lower than the Cmin at steady state in patients receiving the recommended dose. Because of this, niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular or CNS).

    PHARMACOKINETICS

    Niraparib is administered orally. It is 83% bound to human plasma proteins, with an average apparent volume of distribution (Vd/F) of 1,220 +/- 1,114 L; in a population pharmacokinetic analysis, the Vd/F of niraparib in cancer patients was 1,074 L. After oral administration, niraparib crossed the blood-brain barrier in rats and monkeys; the CSF:plasma Cmax ratio was 0.1 and 0.52 when administered to two Rhesus monkeys at a dose of 10 mg/kg. Niraparib is metabolized by carboxylesterases to form a major inactive metabolite, which undergoes subsequent glucuronidation. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/hour in cancer patients; after multiple daily dosing, the mean half-life is 36 hours. The accumulation ratio of niraparib exposure following 21 days of repeated daily doses was approximately 2 fold for doses ranging from 30 mg to 400 mg. An average of 47.5% (range, 33.4% to 60.2%) of a single radio-labeled dose of niraparib was recovered over 21 days in urine, and 38.8% (range, 28.3% to 47%) in feces; unchanged drug accounted for 11% and 19% of the dose recovered in urine and feces, respectively.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: carboxylesterases, P-glycoprotein (P-gp), BCRP, CYP1A2, MATE1, MATE2
    Clinical drug interaction studies have not been conducted with niraparib. Niraparib is a substrate of carboxylesterases in vitro, and the resulting inactive metabolite is further metabolized through glucuronidation in vivo. Niraparib is also a substrate of P-gp and BCRP in vitro. In vitro, it is a weak BCRP inhibitor as well as a weak CYP1A2 inducer. Niraparib inhibits multidrug and toxin extrusion (MATE) 1 and 2 with IC50 of 0.18 microMolar and 0.14 microMolar or less, respectively; increased plasma concentrations of MATE1 or 2 substrates cannot be excluded.

    Oral Route

    The mean Cmax after administration of a single 300-mg dose of niraparib was 804 +/- 403 ng/mL, with a Tmax of 3 hours; both the Cmax and AUC increased in a dose proportional manner over a range of 30 mg to 400 mg. Absolute bioavailability (F) is approximately 73%. Administration with a high fat meal (800 to 1,000 calories with approximately 50% of caloric content from fat) did not significantly impact the pharmacokinetics of niraparib.