Niraparib (Monograph)

Brand name: Zejula
Drug class: Antineoplastic Agents
- PARP Inhibitors
- Poly(ADP-ribose) Polymerase Inhibitors
VA class: AN900
Chemical name: 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide
Molecular formula: C₁₉H₂₀N₄OC₁₉H₂₀N₄O•C₇H₈O₃S
CAS number: 1038915-60-4

Medically reviewed by Drugs.com on Feb 25, 2023. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP).

Uses for Niraparib

Ovarian Cancer

Used as a single agent for the maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response following first-line platinum-based chemotherapy (designated an orphan drug by FDA for this use).

Used as a single agent for the maintenance treatment of adults with deleterious or suspected deleterious germline BRCA-mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response following platinum-based chemotherapy (designated an orphan drug by FDA for this use).

Niraparib was previously indicated for the treatment of adults with homologous recombination deficiency (HRD)-positive advanced ovarian, fallopian tube, or primary peritoneal cancer previously treated with 3 or more chemotherapy regimens; however, the manufacturer voluntarily withdrew this indication in September 2022 based on the totality of information indicating potential detrimental effect on overall survival with other PARP inhibitors in the ovarian cancer population.

Niraparib Dosage and Administration

General

Pretreatment Screening

• Complete blood cell count (CBC).

• Delay initiation until hematologic toxicity caused by previous chemotherapy resolves to grade 1 or less.

• Pregnancy testing for females of reproductive potential.

• Confirm presence of a confirmed or suspected deleterious BRCA mutation prior to initiation of niraparib therapy for maintenance treatment of recurrent germline BRCA-mutated ovarian cancer. Consult FDA website for list of FDA-approved or cleared companion diagnostic tests ([Web]). An FDA-approved test for the detection of deleterious or suspected deleterious germline BRCA mutations is not currently available.

Patient Monitoring

• CBC weekly for the first month of therapy, monthly for the next 11 months, and then periodically thereafter.

• BP and heart rate at least weekly for the first 2 months of therapy, then monthly for first year and periodically thereafter.

• Signs and symptoms of posterior reversible encephalopathy syndrome (e.g., seizure, headache, altered mental status, visual disturbance, cortical blindness with or without associated hypertension).

Administration

Oral Administration

Administer orally once daily without regard to meals at approximately the same time each day. Administration with a light meal or snack or at bedtime may help reduce nausea. American Society of Clinical Oncology (ASCO) states that if persistent nausea/vomiting, weight loss >5%, and/or reduction in performance status occurs, temporarily withhold therapy and reduce dosage in the absence of other etiology.

Swallow capsules whole; do not chew, crush, or split.

If a dose is missed or vomited, the next dose should be taken at the regularly scheduled time. Do not take an extra dose.

Dosage

Available as niraparib tosylate monohydrate; dosage expressed in terms of niraparib.

Adults

Ovarian Cancer

First-line Maintenance Treatment of Platinum-sensitive Advanced Ovarian Cancer

Oral

Recommended initial dose depends on body weight and platelet count.

If patient weighs <77 kg or has a platelet count <150,000/mm³: 200 mg (two 100-mg capsules) once daily.

If patient weighs ≥77 kg and has a platelet count ≥150,000/mm³: 300 mg (three 100-mg capsules) once daily.

Initiate therapy no later than 12 weeks following the most recent platinum-based chemotherapy regimen. Continue therapy until disease progression or unacceptable toxicity occurs.

Maintenance Treatment of Platinum-sensitive Germline BRCA-mutated Recurrent Ovarian Cancer

Oral

300 mg (three 100-mg capsules) once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Initiate therapy no later than 8 weeks following the most recent platinum-based chemotherapy regimen.

Dosage Modification for Toxicity

Oral

If adverse reactions occur, interruption of therapy and/or dosage reduction or discontinuance of niraparib therapy may be necessary.

If dosage reduction from an initial dose of 300 mg once daily is necessary, reduce dosage to 200 mg once daily. If the toxicity recurs on a dosage of 200 mg once daily, reduce dosage to 100 mg once daily. If the toxicity recurs on a dosage of 100 mg once daily, discontinue niraparib.

If dosage reduction from an initial dose of 200 mg once daily is necessary, reduce dosage to 100 mg once daily; if the toxicity recurs on this dose, discontinue niraparib.

Hematologic Toxicity

Oral

If platelet count <100,000/mm³ occurs, interrupt niraparib for ≤28 days and monitor CBCs weekly until platelet counts return to ≥100,000/mm³. For first occurrence of platelet count <100,000/mm³, resume niraparib at same dosage or at a reduced dosage. For subsequent occurrences, reduce daily dosage; however, if a dosage of 100 mg once daily requires further reduction or platelet counts do not return to acceptable levels in ≤28 days of withholding drug, discontinue niraparib therapy. (See Myelodysplastic Syndrome [MDS]/Acute Myeloid Leukemia [AML] and also see Hematologic Effects under Cautions.)

If platelet count <75,000/mm³ occurs, interrupt niraparib for ≤28 days and monitor CBCs weekly until platelet counts ≥100,000/mm³. Upon resumption of therapy, reduce daily dosage. If dosage of 100 mg once daily requires further reduction or platelet counts do not return to acceptable levels in ≤28 days of withholding drug, discontinue niraparib therapy.

For platelet count ≤10,000/mm³, interrupt niraparib for ≤28 days and consider platelet transfusion. If there are other risk factors such as concomitant anticoagulants or antiplatelet agents, consider temporarily interrupting these drugs and/or platelet transfusion at a higher platelet count. Upon completion of platelet transfusion, monitor CBCs weekly for 1 month. May resume niraparib at a reduced dosage once platelet count reaches ≥100,000/mm³ and ≥7 days have elapsed since platelet transfusion. Upon resumption of therapy, monitor CBCs weekly for an additional month to ensure platelet count is stable.

For neutropenia (ANC <1,000/mm³) or anemia (hemoglobin concentration <8 g/dL), interrupt niraparib for ≤28 days and monitor CBCs weekly. Resume therapy when ANC ≥1,500/mm³ or hemoglobin concentrations ≥9 g/dL. Upon resumption of therapy, reduce daily dosage in 100-mg decrements. If ANC and/or hemoglobin concentrations do not return to acceptable levels in ≤28 days of withholding drug or if dosage has already been reduced to 100 mg once daily, discontinue niraparib therapy.

If MDS/AML is confirmed, discontinue niraparib therapy.

Nonhematologic Toxicity

Oral

If grade 3 or greater nonhematologic toxicity occurs and persists despite medical management, interrupt niraparib therapy until toxicity resolves, but for ≤28 days. Upon resumption of therapy, reduce daily dosage; however, if dosage of 100 mg once daily requires further reduction, discontinue niraparib therapy.

If prolonged grade 3 or greater nonhematologic toxicity (lasting >28 days) occurs on a dosage of 100 mg once daily, discontinue niraparib therapy.

Prescribing Limits

Adults

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

Oral

Dosages <100 mg once daily not recommended.

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration ≤ULN with AST >ULN, or total bilirubin >ULN, but <1.5 times the ULN with any AST): Dosage adjustment not necessary.

Moderate hepatic impairment (total bilirubin concentration 1.5–3 times ULN with any AST): Reduce initial dosage to 200 mg once daily.

Severe hepatic impairment (total bilirubin concentration >3 times the ULN): Not studied; no specific dosage recommendations at this time.

Renal Impairment

Mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr 30–59 mL/minute) renal impairment: Adjustment of initial dosage not necessary.

Severe renal impairment (Cl_cr <30 mL/minute) or end-stage renal disease requiring hemodialysis: Not studied; no specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Related/similar drugs

carboplatin, Avastin, cyclophosphamide, doxorubicin, cisplatin, bevacizumab, Lynparza

Cautions for Niraparib

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)

MDS and AML, including fatal cases, reported in 16 of 620 patients receiving niraparib versus 5 of 309 patients treated with placebo in clinical studies (PRIMA and NOVA). All patients with MDS/AML had received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents and radiotherapy. The duration of niraparib therapy in patients who developed MDS/AML ranged from 3.6 months to 5.9 years.

Monitor CBC weekly for the first month of therapy, monthly for the next 11 months, and then periodically thereafter. If MDS/AML is confirmed, discontinue niraparib.

Hematologic Effects

Hematologic adverse effects (e.g., thrombocytopenia, anemia, neutropenia) may occur.

Delay initiation of niraparib until hematologic toxicity caused by previous chemotherapy resolves to grade 1 or less. Monitor CBC weekly for the first month of therapy, monthly for the next 11 months, and then periodically thereafter. If hematologic toxicity occurs, temporary interruption of therapy, dosage adjustment, or discontinuance of niraparib may be necessary.

If hematologic toxicity develops and persists for >28 days following interruption of therapy, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample. (See Myelodysplastic Syndrome [MDS]/Acute Myeloid Leukemia [AML] under Cautions.)

Cardiovascular Effects

Hypertension and hypertensive crisis reported.

QT-interval prolongation effects not observed.

Monitor BP and heart rate at least weekly for the first 2 months of therapy, then monthly for first year and periodically thereafter. Closely monitor patients with cardiovascular disorders, particularly those with coronary insufficiency, cardiac arrhythmias, and/or hypertension. If hypertension occurs, manage with antihypertensive therapy and adjust dosage of niraparib, if necessary.

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome reported in clinical trials and postmarketing reports.

Monitor for signs and symptoms of posterior reversible encephalopathy syndrome, including seizure, headache, altered mental status, visual disturbance, and cortical blindness with or without associated hypertension. If posterior reversible encephalopathy syndrome is suspected, discontinue niraparib promptly, and initiate appropriate treatment. Confirm diagnosis of posterior reversible encephalopathy with brain imaging (preferably magnetic resonance imaging).

Safety of restarting niraparib in patients who previously experienced posterior reversible encephalopathy syndrome is not known.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action. May cause teratogenicity and/or embryofetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow).

Avoid pregnancy during therapy. Verify pregnancy status prior to starting therapy. Females of reproductive potential should use effective contraceptive methods while receiving niraparib and for ≥6 months after the drug is discontinued. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard and risk for loss of the pregnancy.

Sensitivity Reactions

Niraparib capsules contain the dye tartrazine (FD&C Yellow No. 5), which may cause allergic-type reactions including bronchial asthma in susceptible individuals. Although frequency of tartrazine sensitivity is low, frequently occurs in individuals with aspirin sensitivity.

Impairment of Fertility

Animal studies suggest niraparib may impair male fertility.

Specific Populations

Pregnancy

May cause fetal harm.

Verify pregnancy status prior to starting therapy.

Lactation

Not known whether niraparib or its metabolites distribute into human milk or if drug has any effect on milk production or breast-fed infant. Discontinue breast-feeding during therapy and for 1 month after drug is discontinued.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but possibility of increased sensitivity in certain geriatric patients cannot be ruled out.

Hepatic Impairment

Systemic exposure not affected by mild hepatic impairment; dosage adjustment not necessary.

Increased exposure observed in patients with moderate hepatic impairment; reduce initial dosage to 200 mg once daily.

Pharmacokinetics and safety not established in patients with severe hepatic impairment to date.

Renal Impairment

Systemic exposure not affected by mild or moderate renal impairment (Cl_cr 30–90 mL/minute); dosage adjustment not necessary.

Pharmacokinetics and safety not established in patients with severe renal impairment (Cl_cr <30 mL/minute) or end-stage renal disease requiring hemodialysis.

Common Adverse Effects

Adverse effects reported in ≥10% of patients receiving niraparib include 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.

Laboratory abnormalities: Anemia, thrombocytopenia, leukopenia, neutropenia, elevated AST or ALT concentrations.

Drug Interactions

Niraparib is a substrate of carboxylesterases and UGT in vivo. In vitro, niraparib is not an inhibitor of UGT1A1, UGT1A4, UGT1A9, or UGT2B7.

In vitro, neither niraparib nor its major metabolite (M1) is an inhibitor of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 or inducer of CYP3A4. Niraparib is a weak inducer of CYP1A2 in vitro.

In vitro, niraparib is an inhibitor of multidrug and toxin extrusion (MATE) 1 and 2. Niraparib is not a substrate of MATE1 or 2. M1 is a substrate, but not an inhibitor, of MATE1 and 2.

In vitro, niraparib is a substrate, but not an inhibitor, of P-glycoprotein (P-gp); also is a substrate and weak inhibitor of breast cancer resistance protein (BCRP). M1 is not a substrate or inhibitor of P-gp or BCRP in vitro.

In vitro, neither niraparib nor M1 is a substrate or inhibitor of multidrug resistance-associated protein (MRP) 2, bile salt export pump (BSEP), organic anion transport protein (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, and OAT3.

Drugs Affecting Gastric Acidity

Not specifically studied to date; however, clinically important pharmacokinetic interactions appear unlikely based on solubility data.

Drugs Affected by Transport Systems

Niraparib is an inhibitor of MATE1 and 2; therefore, increased plasma concentrations of coadministered drugs that are substrates of MATE1 or 2 cannot be excluded.

Specific Drugs

Niraparib Pharmacokinetics

Absorption

Bioavailability

AUC and peak plasma concentrations are dose proportional over a dosage range of 30–400 mg once daily; systemic accumulation is approximately twofold following repeated administration.

Following oral administration, peak plasma concentrations are attained within 3 hours.

Absolute oral bioavailability is approximately 73%.

Food

Administration with a high-fat meal (800–1000 calories with approximately 50% of calories from fat) does not substantially affect exposure (peak plasma concentrations decreased by approximately 22% and AUC increased by approximately 7%).

Special Populations

Mild hepatic impairment does not affect systemic exposure. In moderate hepatic impairment, AUC was 1.56 times higher than AUC observed in patients with normal hepatic function.

Distribution

Extent

Crosses the blood-brain barrier in animals.

Not known whether niraparib or its metabolites distribute into milk.

Plasma Protein Binding

83%.

Elimination

Metabolism

Metabolized to inactive metabolites (i.e., M1, M10) principally by amide hydrolysis followed by glucuronidation.

Elimination Route

Eliminated in urine (47.5%; 11% as unchanged drug) and feces (38.8%; 19% as unchanged drug).

Half-life

36 hours.

Special Populations

Mild or moderate renal impairment (Cl_cr 30–90 mL/minute) does not substantially affect pharmacokinetics.

Severe renal impairment (Cl_cr <30 mL/minute) and end-stage renal disease requiring hemodialysis: Effects on pharmacokinetics not evaluated.

Mild hepatic impairment does not substantially affect pharmacokinetics.

Moderate hepatic impairment: AUC is 1.56 times higher than AUC observed in patients with normal hepatic function.

Severe hepatic impairment: Effects on pharmacokinetics not studied.

Age (18–65 years of age), gender, and race/ethnicity do not substantially affect pharmacokinetics.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Actions

• Highly selective inhibitor of mammalian poly(ADP-ribose) polymerase (PARP) enzymes PARP-1 and PARP-2, which are involved in detection of DNA damage and DNA repair.

• Niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, which result in DNA damage, apoptosis, and cell death.

• Exhibits cytotoxicity in tumor cell lines with or without deficiencies in BRCA1/2.

• Reduces tumor growth in xenograft models of human cancer cell lines with BRCA1/2 deficiencies in mice and in patient-derived xenograft tumor models with homologous recombination deficiency (HRD) expressing either mutated or wild-type BRCA1/2.

Advice to Patients

Importance of instructing patients to read the manufacturer's patient information.

Importance of advising patients to take niraparib capsules once daily at approximately the same time each day, either with or without food, and to swallow the capsules whole. Importance of advising patients that administration of the drug at bedtime may help alleviate any nausea symptoms.

If a dose is missed or vomited, importance of advising patients not to take an extra dose and to take the next normal dose at the regularly scheduled time.

Risk of myelodysplastic syndrome and acute myeloid leukemia. Importance of informing clinician if weakness, fatigue, fever, weight loss, frequent infections, bruising, unusual bleeding (including hematuria or bloody stool), or shortness of breath occurs.

Risk of bone marrow suppression. Importance of periodic hematologic monitoring during niraparib therapy. Importance of informing clinician if new onset of bleeding, fever, or symptoms of infection occur.

Risk of adverse cardiovascular effects, including hypertension and increased heart rate. Importance of advising patients to undergo at least weekly blood pressure and heart rate monitoring during the first 2 months of treatment, followed by monthly monitoring during the first year of treatment and periodic monitoring thereafter. Importance of advising patients to contact their clinician if elevated blood pressure occurs.

Risk of posterior reversible encephalopathy syndrome. Importance of advising patients to contact their clinician if seizure, headaches, altered mental status, or vision changes occur.

Risk of fetal harm and pregnancy loss. Necessity of advising females of reproductive potential to avoid pregnancy and to use effective contraception while receiving niraparib and for at least 6 months following discontinuance of therapy. Importance of women informing clinicians immediately if they become pregnant during therapy or think they may be pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

Importance of advising women to avoid breast-feeding while receiving niraparib and for 1 month following discontinuance of therapy.

Importance of advising patients that niraparib capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in susceptible individuals or in those who also have aspirin hypersensitivity.

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease, including hypertension, coronary insufficiency, or cardiac arrhythmias).

Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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