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Niraparib

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Nov.14.2023

Niraparib

Indications/Dosage

Labeled

  • ovarian cancer

Off-Label

    † Off-label indication

    For the treatment of ovarian cancer

    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. Continue 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.[64715] [61835] [69856]

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

    300 mg PO once daily. Continue 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.[64715] [61835] [69856]

    for the maintenance treatment of patients with recurrent deleterious or suspected deleterious germline BRCA-mutated 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. Continue 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 (NOVA), patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomized to maintenance therapy with niraparib or placebo within 8 weeks of the last platinum-based therapy. Median progression-free survival was significantly improved in in the cohort of patients with germline BRCA mutations (gBRCAmut) (21 months vs. 5.5 months). Median overall survival was also significantly improved in the gBRCAmut cohort treated with niraparib compared with placebo (40.9 months vs. 38.1 months).[61835] [69856]

    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†

    Oral dosage

    Adults

    Dosage not available.

    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†

    Oral dosage

    Adults

    Dosage not available.

    Therapeutic Drug Monitoring

    Dosage Adjustments for Treatment-Related Toxicities:

     

    Non-hematologic adverse reactions

    • Persistent grade 3 or higher non-hematologic adverse reactions, despite treatment: Hold niraparib treatment for a maximum of 28 days. If resolution occurs within 28 days, reduce the dose of niraparib by 100 mg, and restart therapy. If a grade 3 or higher adverse reaction persists beyond 28 days or occurs at a daily dose of 100 mg, discontinue niraparib treatment.[61835][69856]

     

    Thrombocytopenia (platelet count (PLT) less than 100,000 cells/mm3)

    • First occurrence: Hold niraparib treatment for a maximum of 28 days and monitor blood counts weekly. For patients with PLT less than or equal to 10,000 cells/mm3, 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. If platelet counts rise to 100,000 cells/mm3 within 28 days, restart therapy at the same dose or alternately, reduce the dose by 100 mg. If platelet counts are less than 75,000 cells/mm3, resume therapy after reducing the dose by 100 mg. If thrombocytopenia occurs at a daily dose of 100 mg, discontinue therapy.
    • Second occurrence: Hold niraparib treatment for a maximum of 28 days and monitor blood counts weekly. For patients with PLT less than or equal to 10,000 cells/mm3, 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. If platelet counts rise to 100,000 cells/mm3 within 28 days, reduce the dose of niraparib by 100 mg, and restart therapy. If platelet counts have not risen to 100,000 cells/mm3 or higher within 28 days, or if thrombocytopenia occurs at a daily dose of 100 mg, discontinue therapy.[61835][69856]

     

    Neutropenia (absolute neutrophil count less than 1,000 cells/mm3)

    • Hold niraparib treatment for a maximum of 28 days and monitor blood counts weekly. If the ANC returns to greater than or equal to 1,500 cells/mm3 within 28 days, reduce the dose of niraparib by 100 mg, and restart therapy. If the ANC has not returned to an acceptable level within 28 days, or if neutropenia occurs at a daily dose of 100 mg, discontinue niraparib treatment.[61835][69856]

     

    Anemia (hemoglobin less than 8 g/dL)

    • Hold niraparib treatment for a maximum of 28 days and monitor blood counts weekly. If the hemoglobin returns to greater than or equal to 9 g/dL within 28 days, reduce the dose of niraparib by 100 mg, and restart therapy. If the hemoglobin has not returned to an acceptable level within 28 days, or if anemia occurs at a daily dose of 100 mg, discontinue niraparib treatment.[61835][69856]

     

    Myelodysplastic syndrome or acute myeloid leukemia (MDS/AML)

    • Discontinue niraparib treatment.[61835][69856]

    Maximum Dosage Limits

    • 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.

    Patients with Hepatic Impairment Dosing

    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.[61835][69856]

     

    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.[61835][69856]

    Patients with Renal Impairment Dosing

    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.[61835][69856]

     

    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.[61835][69856]
    † Off-label indication
    Revision Date: 11/14/2023, 09:14:57 PM

    References

    61835 - Zejula (niraparib) capsules package insert. Waltham, MA: TESARO, Inc.; 2023 Apr.64715 - Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. NEJM 2019. Epub ahead of print, doi: 10.1056/NEJMoa1910962.67996 - GlaxoSmithKline. Dear Healthcare Provider Letter (niraparib). September 14, 2022.69856 - Zejula (niraparib) tablets package insert. Durham, NC: GlaxoSmithKline; 2023 Apr.

    How Supplied

    Niraparib Oral capsule

    Zejula 100mg Capsule (69656-0103) (TESARO, Inc.) (off market)

    Niraparib Oral tablet

    Zejula 100mg Tablet (00173-0909) (GlaxoSmithKline Group of Companies) null

    Niraparib Oral tablet

    Zejula 200mg Tablet (00173-0912) (GlaxoSmithKline Group of Companies) null

    Niraparib Oral tablet

    Zejula 300mg Tablet (00173-0915) (GlaxoSmithKline Group of Companies) null

    Description/Classification

    Description

    Niraparib is an oral poly (ADP-ribose) polymerase (PARP) inhibitor. PARP enzymes are involved in normal cellular homeostasis, including DNA transcription, cell cycle regulation, and DNA repair. It is indicated as maintenance therapy in patients with advanced or recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer. Niraparib has been associated with hematologic toxicity; cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) have also been reported. Complete blood counts should be closely monitored.[61835][69856]

    Classifications

    • Antineoplastic and Immunomodulating Agents
      • Antineoplastics
        • Small Molecule Antineoplastic Poly (ADP-ribose) Polymerase (PARP) Inhibitors
    Revision Date: 11/14/2023, 09:17:25 PM

    References

    61835 - Zejula (niraparib) capsules package insert. Waltham, MA: TESARO, Inc.; 2023 Apr.69856 - Zejula (niraparib) tablets package insert. Durham, NC: GlaxoSmithKline; 2023 Apr.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    Emetic Risk

    • Moderate/High
    • Administer routine antiemetic prophylaxis prior to treatment.[67389]

    Route-Specific Administration

    Oral Administration

    • If switching from capsules to tablets, ensure patient understands the correct number of tablets to take for each dose.
    • Niraparib may be taken with or without food.
    • Swallow the tablets whole; do not chew, crush, split, or dissolve.
    • Take niraparib 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.[61835][69856]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
      Revision Date: 11/15/2023, 12:31:27 PM

      References

      61835 - Zejula (niraparib) capsules package insert. Waltham, MA: TESARO, Inc.; 2023 Apr.67389 - Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797.69856 - Zejula (niraparib) tablets package insert. Durham, NC: GlaxoSmithKline; 2023 Apr.

      Adverse Reactions

      Moderate

      • anemia
      • confusion
      • conjunctivitis
      • constipation
      • depression
      • dyspnea
      • elevated hepatic enzymes
      • encephalopathy
      • hallucinations
      • hyperglycemia
      • hypertension
      • hypokalemia
      • hypomagnesemia
      • impaired cognition
      • leukopenia
      • lymphopenia
      • memory impairment
      • neutropenia
      • palpitations
      • peripheral edema
      • pneumonitis
      • sinus tachycardia
      • stomatitis
      • thrombocytopenia

      Severe

      • anaphylactoid reactions
      • anemia
      • anorexia
      • anxiety
      • asthenia
      • back pain
      • constipation
      • dyspnea
      • elevated hepatic enzymes
      • fatigue
      • GI obstruction
      • GI perforation
      • headache
      • hyperglycemia
      • hypertension
      • hypertensive crisis
      • hypomagnesemia
      • infection
      • insomnia
      • leukemia
      • leukopenia
      • musculoskeletal pain
      • nausea
      • neutropenia
      • new primary malignancy
      • pleural effusion
      • rash
      • renal failure (unspecified)
      • stomatitis
      • thrombocytopenia
      • vomiting
      • xerostomia

      Mild

      • anorexia
      • anxiety
      • asthenia
      • back pain
      • cough
      • dizziness
      • dysgeusia
      • dyspepsia
      • epistaxis
      • fatigue
      • headache
      • infection
      • insomnia
      • lethargy
      • malaise
      • musculoskeletal pain
      • nausea
      • pharyngitis
      • photosensitivity
      • rash
      • vomiting
      • weight loss
      • xerostomia

      Neutropenia including neutropenic infection and neutropenic sepsis (30% to 42%; grade 3 or 4, 15% to 21%), and leukopenia including lymphopenia (17% to 28%; grade 3 or 4, 5%) have been reported in patients receiving niraparib as maintenance therapy in clinical trials; in the PRIMA trial, administering a starting dose of niraparib based on baseline weight or platelet count did not meaningfully decrease the incidence of neutropenia. Treatment with niraparib should not begin until hematological toxicity from previous chemotherapy recovers to grade 1 or less. Monitor complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter. An interruption of therapy may be necessary for an ANC less than 1,000 cells/mm3. Additional changes from baseline reported separately included decreased leukocytes (66% to 71%; grade 3 or 4, 6% to 9%), decreased neutrophils (53% to 66%; grade 3 or 4, 15% to 23%), and decreased lymphocytes (51% to 52%; grade 3 or 4, 5% to 7%). Pancytopenia has been reported in postmarketing experience with niraparib.[61835] [69856]

      Anemia occurred in 50% to 64% (grade 3 or 4, 23% to 33%) of patients receiving niraparib maintenance therapy in clinical trials. In patients receiving first-line maintenance therapy, the incidence of anemia (50% vs. 64%; grade 3 or 4, 23% vs. 31%) was slightly decreased when the dose of niraparib was based on the baseline weight or platelet count rather than a flat dose in all patients. A decrease in hemoglobin from baseline was also reported in 81% to 87% (grade 3 or 4, 21% to 32%) of patients. Treatment with niraparib should not begin until hematological toxicity from previous chemotherapy recovers to grade 1 or less. Monitor complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter. An interruption of therapy may be necessary for a hemoglobin less than 8 g/dL.[61835] [69856]

      Thrombocytopenia occurred in 54% to 71% (grade 3 or 4, 21% to 39%) of patients receiving niraparib maintenance therapy in clinical trials. In patients receiving first-line maintenance therapy, the incidence of grade 3 or 4 thrombocytopenia was slightly decreased when the dose of niraparib was based on the baseline weight or platelet count rather than a flat dose in all patients (21% vs. 39%). A decrease in platelet count from baseline occurred in 63% to 81% (grade 3 or 4, 18% to 38%) of patients. Treatment with niraparib should not begin until hematological toxicity from previous chemotherapy recovers to grade 1 or less. Monitor complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter. An interruption of therapy may be necessary for a platelet count less than 100,000 cells/mm3.[61835] [69856]

      New primary malignancy, specifically cases of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) including some with fatal outcomes, has been reported in patients treated with niraparib. Refer patients to a hematologist for further evaluation if MDS/AML is suspected. Discontinue niraparib if a diagnosis of MDS or AML is confirmed. MDS/AML occurred in 1.2% of patients receiving niraparib as first-line maintenance therapy for platinum-sensitive ovarian cancer (n = 484) compared with 1.2% of those who received placebo (n = 244) in 1 clinical trial. In another clinical trial, MDS/AML occurred in 7% of patients receiving niraparib maintenance for recurrent gBRCA mutated ovarian cancer (n = 136) compared with 3% of those who received placebo (n = 65). All patients had received prior chemotherapy with platinum agents, and some had also received other DNA damaging agents and radiotherapy. The duration of niraparib therapy prior to developing MDS/AML ranged from 3.6 months to more than 5.9 years.[61835] [69856]

      Elevated hepatic enzymes (AST/ALT) occurred in 10% to 14% of patients receiving niraparib maintenance therapy in clinical trials (grade 3 or 4, 3% to 4%). Increases from baseline in alkaline phosphatase (43% to 46%; grade 3 or 4, 0.7% to 1%), AST (31% to 35%; grade 3 or 4, 1%), and ALT (25% to 29%; grade 3 or 4, 0.7% to 2%) were also reported. Increased gamma-glutamyl transferase and alkaline phosphatase occurred in 1% to less than 10% of platinum-sensitive ovarian cancer patients receiving niraparib maintenance therapy in one clinical trial.[61835] [69856]

      Nausea (52% to 77%; grade 3 or 4, 1% to 5%) and vomiting (17% to 40%; grade 3 or 4, 4% or less) were reported in patients receiving maintenance therapy for ovarian cancer with niraparib. Additionally, 17% to 18% of patients receiving niraparib maintenance therapy reported dyspepsia.[61835] [69856]

      Constipation occurred in 31% to 40% (grade 3 or 4, 0.7% to 1%) of patients with ovarian cancer receiving niraparib maintenance therapy in clinical trials. A small intestinal obstruction (GI obstruction) occurred in 2.9% of patients receiving maintenance therapy with niraparib for recurrent ovarian cancer; fatal GI perforation has also been reported.[61835] [69856]

      Niraparib has the potential to affect blood pressure in patients receiving the recommended dose, which may be related to inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Hypertension was reported in 17% to 21% (grade 3 or 4, 5% to 9%) of ovarian cancer patients receiving maintenance therapy in clinical trials. Hypertensive crisis has also been reported in patients treated with niraparib in clinical trials and in postmarketing experience. The mean blood pressure increased over baseline at most on-study assessments in patients treated with niraparib compared with placebo; the greatest increases were a mean of 24.4 to 24.5 mmHg systolic and 15.9 to 16.5 mmHg diastolic in the niraparib arm, versus 18.3 to 19.6 mmHg systolic and 11.6 to 13.9 mmHg diastolic in the placebo arm. Monitor blood pressure at least weekly for the first 2 months, then monthly for the first year and periodically thereafter. Medically manage hypertension with antihypertensive medications and niraparib dose adjustments, if necessary.[61835] [69856]

      Niraparib has the potential to affect heart rate in patients receiving the recommended dose, which may be related to inhibition of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Palpitations were reported in 9% to 10% of patients with platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer who received niraparib maintenance therapy in 2 randomized clinical trials. The mean heart rate increased over baseline at all on-study assessments in patients treated with niraparib compared with placebo; the greatest increases from baseline were a mean of 22.4 to 24.1 beats/minute in the niraparib arm and 14 to 15.8 beats/minute in the placebo arm. Sinus tachycardia was reported in 1% to less than 10% of niraparib-treated patients.[61835] [69856]

      Fatigue and/or asthenia has been reported in 48% to 61% (grade 3 or 4, 3% to 8%) of patients with ovarian cancer receiving niraparib as treatment or as maintenance therapy in clinical trials; in 1 study the term fatigue also included symptoms of general malaise and lethargy.[61835] [69856]

      Back pain occurred more often in patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer receiving niraparib maintenance therapy compared with those who received placebo (16% to 18% vs. 11% to 12%; grade 3 or 4, 0.7% to 0.8% vs. 0%) in 2 clinical trials. Musculoskeletal pain was reported in 39% (grade 3 or 4, 1%) of those receiving first-line maintenance therapy for ovarian cancer with niraparib.[61835] [69856]

      Headache (22% to 35%; grade 3 or 4, 0.3% to 1%) and dizziness (14% to 19%) were reported in patients with ovarian cancer receiving niraparib maintenance therapy in clinical trials.[61835] [69856]

      Anxiety occurred in 10% to 11% (grade 3 or 4, 0.3% to 0.7%) of patients with platinum-sensitive ovarian cancer receiving niraparib maintenance therapy compared with 7% to 11% (grade 3 or 4, 0.6% or less) of those receiving placebo in 2 randomized clinical trials; depression was also reported in 1% to less than 10% of patients in the niraparib arm of one of these trials.[61835] [69856]

      Insomnia was reported in 18% to 27% (grade 3 or 4, 1% or less) of patients receiving niraparib maintenance therapy in clinical trials.[61835] [69856]

      Dyspnea (17% to 22%; grade 3 or 4, 0.4% to 2%) and cough (16% to 18%) have been reported in patients with ovarian cancer who received niraparib maintenance therapy in clinical trials. Non-infectious pneumonitis has been reported in postmarketing experience with niraparib.[61835] [69856]

      Rash was reported in 10% to 21% (grade 3 or 4, 0.5% or less) of patients with platinum-sensitive ovarian cancer who received niraparib maintenance therapy in 2 clinical trials.[61835] [69856]

      Urinary tract infection (11% to 13%; grade 3 or 4, 0.8% or less) and naso-pharyngitis (13% to 23%) were reported in patients with platinum-sensitive ovarian cancer receiving niraparib maintenance therapy in 2 clinical trials; bronchitis (1% to less than 10%) and conjunctivitis (less than 10%) were additionally reported in these trials.[61835] [69856]

      Peripheral edema was reported in 1% to less than 10% of patients with recurrent, platinum-sensitive ovarian cancer receiving niraparib maintenance therapy in a randomized, double-blind, placebo-controlled clinical trial.[61835] [69856]

      Hypokalemia was reported in 1% to less than 10% of patients receiving maintenance therapy for recurrent, platinum-sensitive ovarian cancer with niraparib. Hypomagnesemia occurred in 36% to 44% (grade 3 or 4, 1% or less) of patients with ovarian cancer receiving niraparib as first-line maintenance therapy for platinum-sensitive ovarian cancer.[61835] [69856]

      Epistaxis was reported in 1% to less than 10% of patients with recurrent, platinum-sensitive ovarian cancer receiving niraparib maintenance therapy in a randomized, double-blind, placebo-controlled clinical trial.[61835] [69856]

      Anorexia or decreased appetite was reported in 19% to 25% (grade 3 or 4, 1% or less) of patients with ovarian cancer receiving niraparib maintenance therapy in clinical trials. Dysgeusia was also reported in 10% to 13% of patients receiving niraparib maintenance therapy for platinum-sensitive ovarian cancer. Weight loss occurred in less than 10% of patients with recurrent, platinum-sensitive ovarian cancer receiving niraparib maintenance therapy.[61835] [69856]

      Confusion, hallucinations, and impaired cognition (e.g., memory impairment, concentration impairment) have been reported with niraparib treatment in postmarketing experience.[61835] [69856]

      Grade 1 to 2 increases in serum creatinine occurred in 1% to less than 10% of patients with recurrent, platinum-sensitive ovarian cancer receiving niraparib maintenance therapy in a randomized clinical trial. The incidence was higher in patients with ovarian cancer receiving first-line maintenance therapy with niraparib (40% to 41%); acute kidney injury (AKI) was separately reported in 12% of niraparib-treated patients, with grade 3 or 4 AKI (renal failure (unspecified)) occurring in 0.2% to 1% of patients.[61835] [69856]

      Hypersensitivity to niraparib including anaphylaxis and anaphylactoid reactions has been reported in postmarketing experience with niraparib.[61835] [69856]

      Posterior reversible encephalopathy syndrome (PRES) occurred in 0.1% of patients treated with niraparib in clinical trials (n = 2,165) and has also been reported in postmarketing experience. Symptoms of PRES include seizures, headache, lethargy, confusion, blindness, altered consciousness, and/or other visual or neurological disturbances. Discontinue therapy if PRES is suspected or diagnosed; this syndrome may be confirmed on magnetic resonance imaging. The safety of restarting niraparib in patients who previously experienced PRES is unknown.[61835] [69856]

      Photosensitivity has been reported in postmarketing experience with niraparib.[61835] [69856]

      Mucositis/stomatitis was reported in 9% to 20% of patients receiving niraparib maintenance therapy for platinum-sensitive ovarian cancer (grade 3 or 4, 0.5% or less). Xerostomia was reported in 10% to 13% of these patients (grade 3 or 4, 0.3% to 0.7%).[61835] [69856]

      One patient who received first-line maintenance therapy for platinum-sensitive ovarian cancer with niraparib experienced a fatal pleural effusion.[61835] [69856]

      Hyperglycemia occurred in 63% to 66% (grade 3 or 4, 2% to 3%) of patients with ovarian cancer receiving niraparib as first-line maintenance therapy for platinum-sensitive ovarian cancer.[61835] [69856]

      Revision Date: 11/14/2023, 04:58:21 PM

      References

      61835 - Zejula (niraparib) capsules package insert. Waltham, MA: TESARO, Inc.; 2023 Apr.69856 - Zejula (niraparib) tablets package insert. Durham, NC: GlaxoSmithKline; 2023 Apr.

      Contraindications/Precautions

      Absolute contraindications are italicized.

      • anemia
      • bone marrow suppression
      • breast-feeding
      • cardiac arrhythmias
      • cardiac disease
      • contraception requirements
      • encephalopathy
      • heart failure
      • hypertension
      • hypertensive crisis
      • infertility
      • leukemia
      • myelodysplastic syndrome (MDS)
      • neutropenia
      • new primary malignancy
      • pregnancy
      • pregnancy testing
      • reproductive risk
      • salicylate hypersensitivity
      • tartrazine dye hypersensitivity
      • 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.[61835] [69856]

      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 3.6 months to 5.9 years; all patients were also previously treated with platinum chemotherapy and/or DNA damaging agents including radiotherapy. Refer patients to a hematologist for further evaluation if MDS/AML is suspected. Discontinue niraparib if a diagnosis of MDS or AML is confirmed.[61835] [69856]

      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.[61835] [69856]

      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.[61835] [69856]

      Niraparib capsules contain tartrazine dye (FD&C yellow no. 5). Patients with tartrazine dye hypersensitivity who take niraparib capsules may be at risk for developing allergic reactions (e.g., bronchial asthma). Tartrazine sensitivity frequently occurs in patients who also have aspirin hypersensitivity (salicylate hypersensitivity).[61835] [69856]

      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.[61835] [69856]

      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.[61835] [69856]

      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.[61835] [69856]

      Revision Date: 11/14/2023, 06:10:30 PM

      References

      61835 - Zejula (niraparib) capsules package insert. Waltham, MA: TESARO, Inc.; 2023 Apr.69856 - Zejula (niraparib) tablets package insert. Durham, NC: GlaxoSmithKline; 2023 Apr.

      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).[61835][69856]

      Revision Date: 11/14/2023, 09:19:05 PM

      References

      61835 - Zejula (niraparib) capsules package insert. Waltham, MA: TESARO, Inc.; 2023 Apr.69856 - Zejula (niraparib) tablets package insert. Durham, NC: GlaxoSmithKline; 2023 Apr.

      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.[61835][69856]

       

      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.[61835][69856]

      Route-Specific Pharmacokinetics

      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 capsules; the Cmax and AUC of niraparib tablets increased by 11% and 28%, respectively.[61835][69856]

      Special Populations

      Hepatic Impairment

      Mild hepatic impairment (total bilirubin less than 1.5 times the upper limit of normal (ULN) and any AST; or bilirubin less than or equal to ULN and AST greater than ULN) had no clinically significant effect on the pharmacokinetics of niraparib. The AUC of niraparib was 1.56 times higher in patients with moderate hepatic impairment (total bilirubin 1.5 to 3 times ULN and any AST; n = 8) compared to patients with normal hepatic function (n = 9) in a clinical trial; moderate hepatic impairment did not have an effect on the Cmax of niraparib or on niraparib protein binding. The effect of severe hepatic impairment (total bilirubin greater than 3.0 times ULN and any AST) on the pharmacokinetics of niraparib is unknown.[61835][69856]

      Renal Impairment

      Mild to moderate renal impairment had no clinically significant effect on the pharmacokinetics of niraparib. The effect of severe renal impairment or end-stage renal disease undergoing hemodialysis is unknown.[61835][69856]

      Ethnic Differences

      Ethnicity had no clinically significant effect on the pharmacokinetics of niraparib.[61835][69856]

      Revision Date: 11/14/2023, 09:40:44 PM

      References

      61835 - Zejula (niraparib) capsules package insert. Waltham, MA: TESARO, Inc.; 2023 Apr.69856 - Zejula (niraparib) tablets package insert. Durham, NC: GlaxoSmithKline; 2023 Apr.

      Pregnancy/Breast-feeding

      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.[61835] [69856]

      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.[61835] [69856]

      Revision Date: 11/14/2023, 06:10:30 PM

      References

      61835 - Zejula (niraparib) capsules package insert. Waltham, MA: TESARO, Inc.; 2023 Apr.69856 - Zejula (niraparib) tablets package insert. Durham, NC: GlaxoSmithKline; 2023 Apr.

      Interactions

      Level 3 (Moderate)

      • Cholera Vaccine
      • Dengue Tetravalent Vaccine, Live
      • SARS-CoV-2 (COVID-19) vaccines
      • SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine
      • SARS-CoV-2 Virus (COVID-19) mRNA Vaccine
      • SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine
      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. [60871] Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine. [60092] [64100] [65107] 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. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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. [65107] [66080] SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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. [65107] [66080]
      Revision Date: 01/11/2024, 04:54:00 PM

      References

      60092 - Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014; 58: e44-100.60871 - Vaxchora (Cholera Vaccine, live, oral) package insert. Redwood City, CA: Emergent Travel Health Inc.; 2022 Dec.64100 - Dengvaxia (dengue tetravalent vaccine, live) package insert. Swiftwater, PA: Sanofi Pasteur Inc.; 2023 August.65107 - Kroger A, Bahta L, Hunter P. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP).Available on the world wide web at https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. Revised April 27, 2022. Accessed on July 14, 2022.66080 - Food and Drug Administration (FDA). Fact Sheet for Healthcare Providers Administering Vaccine: Emergency Use Authorization (EUA) of Pfizer-BioNTech COVID-19 Vaccine to Prevent Coronavirus Disease 2019 (COVID-19) for 12 years and older. Purple cap and purple border. Retrieved November 22, 2022.

      Monitoring Parameters

      • blood pressure
      • CBC with differential
      • heart rate
      • pregnancy testing

      US Drug Names

      • Zejula
      ;