Niraparib

Chemical formula: C₁₉H₂₀N₄O  Molecular mass: 320.396 g/mol  PubChem compound: 24958200

Interactions

Niraparib interacts in the following cases:

OCT1 substrates

In vitro, niraparib weakly inhibits the organic cation transporter 1 (OCT1) with an IC50 = 34.4 μM. Caution is recommended when niraparib is combined with active substances that undergo an uptake transport by OCT1 such as metformin.

MATE1 substrates, MATE2 substrates

Niraparib is an inhibitor of MATE1 and -2 with IC50 of 0.18 µM and ≤0.14 µM, respectively. Increased plasma concentrations of co-administered medicinal products that are substrates of these transporters (e.g. metformin) cannot be excluded.

CYP1A2 substrates

In vitro, niraparib weakly induces CYP1A2 at high concentrations and the clinical relevance of this effect could not be completely ruled out. M1 is not a CYP1A2 inducer. Therefore, caution is recommended when niraparib is combined with active substances the metabolism of which is CYP1A2-dependent and, notably, those having a narrow therapeutic range (e.g. clozapine, theophylline, and ropinirole).

CYP3A4 substrates

Even though inhibition of CYP3A4 in the liver is not expected, the potential to inhibit CYP3A4 at the intestinal level has not been established at relevant niraparib concentrations. Therefore, caution is recommended when niraparib is combined with active substances the metabolism of which is CYP3A4-dependent and, notably, those having a narrow therapeutic range (e.g. ciclosporin, tacrolimus, alfentanil, ergotamine, pimozide, quetiapine, and halofantrine).

P-gp substrates, BCRP substrates

In vitro, niraparib inhibits P-gp very weakly and BCRP with an IC50 = 161 µM and 5.8 µM, respectively. Therefore, a clinically meaningful interaction related to an inhibition of these efflux transporters, although unlikely, cannot be excluded. Caution is then recommended when niraparib is combined with substrates of BCRP (irinotecan, rosuvastatin, simvastatin, atorvastatin, and methotrexate).

Severe renal impairment, end stage renal disease

There are no data in patients with severe renal impairment or end stage renal disease undergoing haemodialysis; use with caution in these patients.

Moderate hepatic impairment

For patients with moderate hepatic impairment (any AST and TB > 1.5 x – 3 x ULN) the recommended starting dose of niraparib is 200 mg once daily.

Severe hepatic impairment

There are no data in patients with severe hepatic impairment (any AST and TB > 3 x ULN); use with caution in these patients.

Patients with severe hepatic impairment could have increased exposure of niraparib based on data from patients with moderate hepatic impairment and should be carefully monitored.

Fertility

There are no clinical data on fertility. A reversible reduction of spermatogenesis was observed in rats and dogs.

Pregnancy

There are no or limited amount of data from the use of niraparib in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted. However, based on its mechanism of action, niraparib could cause embryonic or foetal harm, including embryo-lethal and teratogenic effects, when administered to a pregnant woman. Niraparib should not be used during pregnancy.

Nursing mothers

It is unknown whether niraparib or its metabolites are excreted in human milk. Breast-feeding is contraindicated during administration of niraparib and for 1 month after receiving the last dose.

Carcinogenesis, mutagenesis and fertility

Women of childbearing potential/contraception in females

Women of childbearing potential should not become pregnant while on treatment and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. Women of childbearing potential must use effective contraception during therapy and for 1 month after receiving the last dose of niraparib.

Fertility

There are no clinical data on fertility. A reversible reduction of spermatogenesis was observed in rats and dogs.

Effects on ability to drive and use machines

Niraparib has moderate influence on the ability to drive or use machines. Patients who take niraparib may experience asthenia, fatigue and dizziness. Patients who experience these symptoms should observe caution when driving or using machines.

Adverse reactions


Summary of the safety profile

In the pivotal ENGOT-OV16 study, adverse reactions (ADRs) occurring ≥10% of patients receiving niraparib monotherapy were nausea, thrombocytopenia, fatigue/asthenia, anaemia, constipation, vomiting, abdominal pain, neutropenia, insomnia, headache, decreased appetite, nasopharyngitis, diarrhoea, dyspnea, hypertension, dyspepsia, back pain, dizziness, cough, urinary tract infection, arthralgia, palpitations, and dysgeusia.

The most common serious adverse reactions >1% (treatment-emergent frequencies) were thrombocytopenia and anaemia.

List of adverse reactions

The following adverse reactions have been identified in the ENGOT-OV16 study in patients receiving niraparib monotherapy (see below).

Frequencies of occurrence of undesirable effects are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse drug reactions: frequencies based on all-causality adverse events*:

Frequency of all CTCAE grades:

Infections and infestations

Very common: Urinary tract infection

Common: Bronchitis, conjunctivitis

Blood and lymphatic system disorders

Very common: Thrombocytopenia, anaemia, neutropenia

Common: Leukopenia

Uncommon: Pancytopenia, febrile neutropenia

Metabolism and nutrition disorders

Very common: Decreased appetite

Common: Hypokalemia

Psychiatric disorders

Very common: Insomnia

Common: Anxiety, depression

Nervous system disorders

Very common: Headache, dizziness, dysgeusia

Cardiac disorders

Very common: Palpitations

Common: Tachycardia

Vascular disorders

Very common: Hypertension

Respiratory, thoracic and mediastinal disorders

Very common: Dyspnea, cough, nasopharyngitis

Common: Epistaxis

Gastrointestinal disorders

Very common: Nausea, constipation, vomiting, abdominal pain, diarrhoea, dyspepsia

Common: Dry mouth, abdominal distension, mucosal inflammation (including mucositis), stomatitis

Skin and subcutaneous tissue disorders

Common: Photosensitivity, rash

Musculoskeletal and connective tissue disorders

Very common: Back pain, arthralgia

Common: Myalgia

General disorders and administration site conditions

Very common: Fatigue, asthenia

Common: Oedema peripheral

Investigations

Common: Gamma-glutamyl transferase increased, AST increased, blood creatinine increased, ALT increased, blood alkaline phosphatase increased, weight decreased

Frequency of CTCAE grade 3 or 4:

Infections and infestations

Uncommon: Urinary tract infection, bronchitis

Blood and lymphatic system disorders

Very common: Thrombocytopenia, anaemia, neutropenia

Common: Leukopenia

Uncommon: Pancytopenia, febrile neutropenia

Metabolism and nutrition disorders

Common: Hypokalemia

Uncommon: Decreased appetite

Psychiatric disorders

Uncommon: Insomnia, anxiety, depression

Nervous system disorders

Uncommon: Headache

Vascular disorders

Common: Hypertension

Respiratory, thoracic and mediastinal disorders

Common: Dyspnea

Gastrointestinal disorders

Common: Nausea, vomiting, abdominal pain

Uncommon: Diarrhoea, constipation, mucosal inflammation (including mucositis), stomatitis, dry mouth

Skin and subcutaneous tissue disorders

Uncommon: Photosensitivity, rash

Musculoskeletal and connective tissue disorders

Uncommon: Back pain, arthralgia, myalgia

General disorders and administration site conditions

Common: Fatigue, asthenia

Investigations

Common: Gamma-glutamyl transferase increased

Uncommon: AST increased, ALT increased, blood alkaline phosphatase increased

* Frequencies are based on percent of patients using all-causality adverse events.

Description of selected adverse reactions

Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) including clinical diagnoses and/or laboratory findings generally occurred early during niraparib treatment with the incidence decreasing over time.

Thrombocytopenia

Approximately 60% of patients receiving niraparib experienced thrombocytopenia of any grade, and 34% of patients experienced Grade ¾ thrombocytopenia. In patients with baseline platelet count less than 180 × 109/L, thrombocytopenia of any grade and Grade ¾ occurred in 76% and 45% of the patients, respectively. The median time to onset of thrombocytopenia regardless of grade and Grade ¾ thrombocytopenia was 22 and 23 days, respectively. The rate of new incidences of thrombocytopenia after intensive dose modifications were performed during the first two months of treatment from Cycle 4 was 1.2%. The median duration of thrombocytopenia events of any grade was 23 days, and the median duration of Grade ¾ thrombocytopenia was 10 days. Patients treated with niraparib who develop thrombocytopenia might have an increased risk of haemorrhage. In the clinical programme, thrombocytopenia was managed with laboratory monitoring, dose modification and platelet transfusion where appropriate. Discontinuation due to thrombocytopenia events (thrombocytopenia and platelet count decreased) occurred in approximately 3% of the patients.

Anaemia

Approximately 50% of patients experienced anaemia of any grade, and 25% experienced Grade ¾ anaemia. The median time to onset of anaemia of any grade was 42 days, and 85 days for Grade ¾ events. The median duration of anaemia of any grade was 63 days, and 8 days for Grade ¾ events. Anaemia of any grade might persist during niraparib treatment. In the clinical programme, anaemia was managed with laboratory monitoring, dose modification, and where appropriate with red blood cell transfusions. Discontinuation due to anaemia occurred in 1% of patients.

Neutropenia

Approximately 30% of patients receiving niraparib experienced neutropenia of any grade, and 20% of patients experienced Grade ¾ neutropenia. The median time to onset of neutropenia of any grade was 27 days, and 29 days for Grade ¾ events. The median duration of neutropenia of any grade was 26 days, and 13 days for Grade ¾ events. In the clinical programme, neutropenia was managed with laboratory monitoring and dose modifications. In addition, Granulocyte-Colony Stimulating Factor (G-CSF) was administered to approximately 6% of patients treated with niraparib as concomitant therapy for neutropenia. Discontinuation due to neutropenia events occurred in 2% of patients.

Hypertension

Hypertension, including hypertensive crisis, has been reported with niraparib therapy. Hypertension of any grade occurred in 19.3% of patients treated with niraparib. Grade ¾ hypertension occurred in 8.2% of patients. In the clinical programme, hypertension was readily managed with anti-hypertensive medicinal products. Discontinuation due to hypertension occurred in <1% of patients.

Paediatric population

No studies have been conducted in paediatric patients.

Cross-check medications

Review your medication to ensure that there are no potentially harmful drug interactions or contraindications.

Ask the Reasoner

Related medicines

© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.