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Niraparib Tosylate

Class: Antineoplastic Agents
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
Brands: Zejula

Introduction

Antineoplastic agent; an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP).1

Uses for Niraparib Tosylate

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

Maintenance therapy of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients in complete or partial response following platinum-based chemotherapy1 2 (designated an orphan drug by FDA for this use).3

In the principal efficacy study (NOVA), niraparib maintenance therapy substantially prolonged progression-free survival in patients with platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer compared with placebo regardless of the presence or absence of germline BRCA mutations or homologous recombination deficiency (HRD) status.1 2

Niraparib Tosylate Dosage and Administration

General

  • Obtain CBC weekly for the first month of therapy, monthly for the next 11 months, and then periodically thereafter.1 (See Myelodysplastic Syndrome [MDS]/Acute Myeloid Leukemia [AML] under Cautions.)

Administration

Oral Administration

Administer orally once daily without regard to meals at approximately the same time each day.1 Administration at bedtime may help reduce nausea.1

Swallow capsules whole.1

Dosage

Available as niraparib tosylate monohydrate; dosage expressed in terms of niraparib.1

Adults

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Oral

As maintenance monotherapy, 300 mg (three 100-mg capsules) once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Initiate therapy no later than 8 weeks following the most recent platinum-based chemotherapy regimen.1 2

Dosage Modification for Toxicity
Oral

If adverse reactions occur, interruption of therapy and/or dosage reduction or discontinuance of niraparib therapy may be necessary.1

If dosage reduction from 300 mg once daily is necessary, reduce dosage to 200 mg once daily.1

If further dosage reduction is necessary, reduce dosage to 100 mg once daily.1

If the toxicity recurs, discontinue niraparib.1

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/mm3.1 For first occurrence of platelet count <100,000/mm3, resume niraparib at same dosage or reduce dosage to 200 mg once daily.1 For subsequent occurrences, reduce daily dosage in 100-mg decrements.1 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.1 (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/mm3.1 8 Upon resumption of therapy, reduce daily dosage in 100-mg decrements.1 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.1

For platelet count ≤10,000/mm3, interrupt niraparib for ≤28 days and consider platelet transfusion.1 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.1 8 Upon completion of platelet transfusion, monitor CBCs weekly for 1 month.8 May resume niraparib at a reduced dosage once platelet count reaches ≥100,000/mm3 and ≥7 days have elapsed since platelet transfusion.1 8 Upon resumption of therapy, monitor CBCs weekly for an additional month to ensure platelet count is stable.8

For neutropenia (ANC <1,000/mm3) or anemia (hemoglobin concentration <8 g/dL), interrupt niraparib for ≤28 days and monitor CBCs weekly.1 Resume therapy when ANC ≥1,500/mm3 or hemoglobin concentrations ≥9 g/dL.1 Upon resumption of therapy, reduce daily dosage in 100-mg decrements.1 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.1

If MDS/AML is confirmed, discontinue niraparib therapy.1

Nonhematologic Toxicity
Oral

If grade 3 or greater nonhematologic toxicity occurs when prophylaxis is not considered feasible or adverse reaction persists despite treatment, interrupt niraparib therapy until toxicity resolves, but for ≤28 days.1 8 Upon resumption of therapy, reduce daily dosage in 100-mg decrements.1 If dosage of 100 mg once daily requires further reduction, discontinue niraparib therapy.1

If prolonged grade 3 or greater nonhematologic toxicity (lasting >28 days) occurs on a dosage of 100 mg once daily, discontinue niraparib therapy.1

Prescribing Limits

Adults

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Oral

Dosages <100 mg once daily not recommended.1

Special Populations

Hepatic Impairment

Mild hepatic impairment: Dosage adjustment not necessary.1 4

Moderate or severe hepatic impairment: Limited data; no specific dosage recommendations at this time.1 4 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild (Clcr 60–89 mL/minute) or moderate (Clcr 30–59 mL/minute) renal impairment: Adjustment of initial dosage not necessary.1 4

Severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease requiring hemodialysis: Not studied; no specific dosage recommendations at this time.1 4 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Niraparib Tosylate

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

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

MDS and AML, including fatal cases, reported in <2% of niraparib-treated patients.1 All patients with MDS/AML had received previous chemotherapy with platinum-containing agents and some had received other DNA-damaging antineoplastic agents and radiotherapy.1 The duration of niraparib therapy in patients who developed MDS/AML ranged from <1 month to 2 years.1

Monitor CBCs during therapy.1 (See Hematologic Effects under Cautions.) If MDS/AML is confirmed, discontinue niraparib.1

Hematologic Effects

Hematologic adverse effects (e.g., thrombocytopenia, anemia, neutropenia) may occur.1

Delay initiation of niraparib until hematologic toxicity caused by previous chemotherapy resolves to grade 1 or less.1 Monitor CBC weekly for the first month of therapy, monthly for the next 11 months, and then periodically thereafter.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

If clinically important hematologic toxicity develops and persists for >4 weeks following interruption of therapy, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.1 (See Myelodysplastic Syndrome [MDS]/Acute Myeloid Leukemia [AML] under Cautions.)

Cardiovascular Effects

Hypertension and hypertensive crisis reported.1 Tachycardia and other cardiac arrhythmias, palpitations, and angina also have occurred.1 4

QT-interval prolongation effects not observed.1

Monitor BP and heart rate monthly for first year of therapy and periodically thereafter.1 Closely monitor patients with cardiovascular disorders, particularly those with coronary insufficiency, cardiac arrhythmias, and/or hypertension.1 If hypertension occurs, manage with antihypertensive therapy and adjust dosage of niraparib, if necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action.1 May cause teratogenicity and/or embryofetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow).1

Avoid pregnancy during therapy.1 Women of childbearing potential should use effective contraceptive methods while receiving niraparib and for ≥6 months after the drug is discontinued.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard and risk for loss of the pregnancy.1

Impairment of Fertility

Animal studies suggest niraparib may impair male fertility.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

In women of childbearing potential, manufacturer recommends a pregnancy test prior to initiating niraparib therapy.1

Lactation

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

Pediatric Use

Safety and efficacy not established.1

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.1

Hepatic Impairment

Systemic exposure not affected by mild hepatic impairment.4 (See Hepatic Impairment under Dosage and Administration.)

Pharmacokinetics and safety not established in patients with moderate to severe hepatic impairment to date.1 4

Renal Impairment

Systemic exposure not affected by mild or moderate renal impairment (Clcr 30–89 mL/minute).4 (See Renal Impairment under Dosage and Administration.)

Pharmacokinetics and safety not established in patients with severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease requiring hemodialysis.1

Common Adverse Effects

Adverse effects: Nausea,1 2 fatigue/asthenia,1 2 constipation,1 2 vomiting,1 2 abdominal pain and/or distension,1 2 insomnia,1 2 headache,1 2 decreased appetite,1 2 nasopharyngitis,1 2 rash,1 diarrhea,1 2 dyspnea,1 2 hypertension,1 2 mucositis/stomatitis,1 myalgia,1 back pain,1 2 dizziness,1 2 dyspepsia,1 2 cough,1 2 arthralgia,1 2 urinary tract infection,1 2 anxiety,1 dry mouth,1 dysgeusia,1 2 palpitations.1 2

Laboratory abnormalities: Anemia,1 2 thrombocytopenia,1 2 leukopenia,1 neutropenia,1 2 elevated AST or ALT concentrations.1

Interactions for Niraparib Tosylate

Niraparib is a substrate of carboxylesterases and UGT in vivo.1 4

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 CYP3A4.1 4 Niraparib is a weak inducer of CYP1A2 in vitro.1 4

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).1 M1 is not a substrate or inhibitor of P-gp or BCRP in vitro.1

In vitro, neither niraparib nor M1 is a substrate or inhibitor of bile salt export pump (BSEP), organic anion transport protein (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, and OAT3.1 4 8

Drugs Affecting Gastric Acidity

Not specifically studied to date; however, clinically important pharmacokinetic interactions appear unlikely based on solubility data.4

Specific Drugs

Drug

Interaction

Comments

Anticoagulants

Increased risk of adverse hematologic effects and hemorrhagic events1

Interruption of anticoagulant therapy may be required1 8 (see Dosage Modification for Toxicity under Dosage and Administration)

Antiplatelet agents

Increased risk of adverse hematologic effects and hemorrhagic events1

Interruption of antiplatelet therapy may be required1 8 (see Dosage Modification for Toxicity under Dosage and Administration)

Histamine H2-receptor antagonists

Clinically important interactions unlikely based on solubility data4

Proton-pump inhibitors

Clinically important interactions unlikely based on solubility data4

Niraparib Tosylate Pharmacokinetics

Absorption

Bioavailability

AUC and peak plasma concentrations are dose proportional over a dosage range of 30–400 mg once daily;1 6 systemic accumulation is approximately twofold following repeated administration.1

Following oral administration, peak plasma concentrations are attained within 3 hours.1 4 6

Absolute oral bioavailability is approximately 73%.1 4

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%).1 4

Special Populations

Mild hepatic impairment does not affect systemic exposure.4

Distribution

Extent

Crosses the blood-brain barrier in animals.1

Not known whether niraparib or its metabolites distribute into milk.1

Plasma Protein Binding

83%.1

Elimination

Metabolism

Metabolized to inactive metabolites (i.e., M1, M10) principally by amide hydrolysis followed by glucuronidation.1 4

Elimination Route

Eliminated in urine (47.5%; 11% as unchanged drug) and feces (38.8%; 19% as unchanged drug).1

Half-life

36 hours.1 6

Special Populations

Mild or moderate renal impairment (Clcr 30–89 mL/minute) does not substantially affect pharmacokinetics.1 4

Severe renal impairment (Clcr <30 mL/minute) and end-stage renal disease requiring hemodialysis: Effects on pharmacokinetics not evaluated.1

Mild hepatic impairment does not substantially affect pharmacokinetics.4

Moderate to severe hepatic impairment: Effects on pharmacokinetics not studied.1 4

Age (18–65 years of age), gender, and race/ethnicity do not substantially affect pharmacokinetics.1 4

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

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.1 2

  • 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.1

  • Exhibits cytotoxicity in tumor cell lines with or without deficiencies in BRCA1/2.1

  • 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 expressing either mutated or wild-type BRCA1/2.1 7

Advice to Patients

  • Importance of instructing patients to read the manufacturer's patient information.1

  • 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.1 Importance of advising patients that administration of the drug at bedtime may help alleviate any nausea symptoms.1

    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.1

  • Risk of MDS/AML.1 Importance of informing clinician if fatigue/asthenia, fever, weight loss, frequent infections, bruising, unusual bleeding (including hematuria or bloody stool), or shortness of breath occurs.1

  • Risk of bone marrow suppression.1 Importance of periodic hematologic monitoring during niraparib therapy.1 Importance of informing clinician if new onset of bleeding, fever, or symptoms of infection occur.1

  • Risk of adverse cardiovascular effects, including hypertension and increased heart rate.1 Importance of advising patients to undergo monthly BP and heart rate monitoring during the first year of treatment and periodically thereafter and to contact their clinician if elevated BP occurs.1

  • Risk of fetal harm and pregnancy loss.1 Necessity of advising women of childbearing potential to avoid pregnancy and to use effective contraception while receiving niraparib and for ≥6 months following discontinuance of therapy.1 Importance of women informing clinicians immediately if they become pregnant during therapy or think they may be pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

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

  • 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).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

Niraparib Tosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

100 mg (of niraparib)

Zejula

Tesaro

AHFS DI Essentials. © Copyright 2017, Selected Revisions October 2, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Tesaro, Inc. Zejula (niraparib tosylate) capsules prescribing information. Waltham, MA; 2017 Mar.

2. Mirza MR, Monk BJ, Herrstedt J et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016; 375:2154-64. [PubMed 27717299]

3. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2017 May 31.

4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208447Orig1s000: Multi-discipline review. From FDA website.

6. Sandhu SK, Schelman WR, Wilding G et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013; 14:882-92. [PubMed 23810788]

7. AlHilli MM, Becker MA, Weroha SJ et al. In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma. Gynecol Oncol. 2016; 143:379-88. [PubMed 27614696]

8. Tesaro, Inc. Waltham, MA: Personal communication.

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