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niraparib
Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, and acts to increase the formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death. Increased cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2.
| Bioavailability |
~73% |
| Effects with food |
Administration with a high-fat, high-calorie meal resulted in a 22% decrease in Cmax compared to fasted conditions. However, food did not significantly affect the AUC. |
| Peak plasma levels |
Cmax is reached in approximately 3 hours. |
| Cross blood brain barrier? |
Yes (in pre-clinical models) |
| PPB |
83% |
Niraparib is metabolized by carboxylesterases.
| Inactive metabolites |
Yes |
| Active metabolites |
No |
| Half-life | 48 to 51 hours (approximately 2 days) |
| Feces |
Average 38.8%; 18.7% unchanged drug from pooled samples collected over 6 days |
| Urine |
Average 47.5%; 11% unchanged drug from pooled samples collected over 6 days |
- Epithelial ovarian cancer
- Fallopian tube cancer
- Primary peritoneal cancer
Refer to the product monograph for a full list and details of approved indications
Emetogenic Potential:
The following table lists adverse effects that occurred in ≥ 10% of patients in a phase III placebo-controlled study for the first-line maintenance treatment of advanced ovarian cancer where patients received an individualized starting dose of niraparib. It also includes severe, life-threatening and post-marketing adverse effects from other sources. Adverse effects marked with “^” were observed in maintenance treatment of recurrent ovarian cancer.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Hypertension (17%) (9% severe) | E D L | |||
| Palpitations (10%) ^ | E | ||||
| Dermatological | Photosensitivity (<10%) | E | |||
| Gastrointestinal | Abdominal pain (28%) | E | |||
| Anorexia (19%) | E | ||||
| Constipation (33%) | E | ||||
| Diarrhea (14%) | E | ||||
| Dyspepsia (18%) ^ | E | ||||
| GI obstruction (3%) (severe) | E | ||||
| Mucositis (20%) ^ | E | ||||
| Nausea, vomiting (53%) (generally mild) | I E | ||||
| General | Fatigue (48%) | E | |||
| Hematological | Myelosuppression ± infection (54%) (including anemia) (21% severe) | E | |||
| Hepatobiliary | ↑ LFTs (8%) | E | |||
| Hypersensitivity | Hypersensitivity (<10%) (including anaphylaxis) | I E | |||
| Musculoskeletal | Musculoskeletal pain (37%) | E | |||
| Neoplastic | Leukemia (secondary) (<1%) | E D L | |||
| Nervous System | Cognitive disturbance (<10%) (including hallucinations) | E | |||
| Dizziness (11%) | E | ||||
| Dysgeusia (10%) ^ | E | ||||
| Headache (22%) | E | ||||
| Insomnia (21%) | E | ||||
| Posterior reversible encephalopathy syndrome (PRES) (<1%) | E | ||||
| Renal | Other - acute kidney injury (12%) (<1% severe, including increased creatinine/urea, renal failure) | E | |||
| Reproductive and breast disorders | Hot flashes (>10%) | E D | |||
| Respiratory | Cough, dyspnea (19%) | E | |||
| Pneumonitis (<1%) | E | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for niraparib include myelosuppression ± infection, nausea/vomiting, fatigue, musculoskeletal pain, constipation, abdominal pain, headache, insomnia and mucositis.
Thrombocytopenia was commonly reported, with a median time of 22 days (ranging from 15 to 335 days) from the first niraparib dose to onset, and a median duration 6 days (ranging from 1 to 374 days).
Hypertension and hypertensive crisis have been reported but rarely lead to treatment discontinuation. The median time from the first niraparib dose to onset of grade 3 or 4 hypertension was 43 days (ranging from 1 to 531 days), with a median duration 12 days (ranging from 1 to 61 days).
Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) including fatal cases, have been rarely reported. The duration of niraparib treatment prior to the development of MDS/AML varied from <1 month to approximately 5 years. All patients had received prior chemotherapy with platinum-based regimens and/or other DNA-damaging agents, including radiotherapy.
Refer to protocol by which patient is being treated.
Patients should have recovered from hematologic toxicities (≤ grade 1) from previous chemotherapy prior to initiating niraparib treatment.
Existing hypertension should be adequately controlled before initiating niraparib treatment.
Patients <77 kg or with a platelet count <150 x 109/L:*
Oral: 200 mg Daily
Patients ≥77 kg and with a platelet count ≥150 x 109/L:*
Oral: 300 mg Daily
*based on pCODR, Berek et al.
| Dose Level | Niraparib Dose (mg/day) | |
| 0 | 200 | 300 |
| -1 | 100 | 200 |
| -2 | Discontinue | 100 |
| -3 | Discontinue | |
| Toxicity | Criteria | Action |
| Platelet count <100 x 109/L | First occurrence |
Hold. Monitor blood counts weekly* Resume at same dose or at 1 dose level ↓. If platelet count was <75 x 109/L, resume at 1 dose level ↓. |
| Second occurrence |
Hold. Monitor blood counts weekly.* Resume at 1 dose level ↓.
|
|
| Neutrophil <1 x 109/L |
Hold. Monitor blood counts weekly.* Resume at 1 dose level ↓. |
|
| Hemoglobin <80 g/L |
Hold. Monitor blood counts weekly.* Resume at 1 dose level ↓. |
|
| Hematologic adverse reaction requiring transfusion or hematopoietic growth factor support |
Hold. Consider platelet transfusion for platelets ≤10 x 109/L. If other risk factors are present (e.g., coadministration of anticoagulation or antiplatelet drugs), consider interruption of concurrent therapy and/or transfuse at a higher platelet count. Resume at 1 dose level ↓. |
|
| Signs and symptoms of myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) |
Any | If MDS/AML is confirmed, discontinue |
| Hypertension |
Not adequately controlled with antihypertensive Or Hypertensive crisis |
Discontinue |
| Signs and symptoms of Posterior Reversible Encephalopathy Syndrome (PRES) |
Any | Treat specific symptoms and discontinue |
| All other non-hematologic toxicities that persists despite treatment/prophylaxis | ≥ Grade 3 |
Hold.* Resume at same dose or at 1 dose level ↓. |
*Do not restart until platelets ≥100 x 109/L, ANC ≥1.5 x 109/L, Hb ≥90 g/L and other toxicities have resolved. Discontinue if toxicities have not recovered within 28 days of dose interruption. If blood parameters remain abnormal after 28 days, bone marrow analysis and/or blood cytogenetic analysis are recommended.
|
Hepatic Impairment |
Bilirubin |
|
AST |
Niraparib Dose |
|
Mild |
≤1.5xULN |
and |
any |
No dose adjustment required |
|
≤ULN |
and |
>ULN |
||
|
Moderate |
>1.5 to 3 xULN |
and |
any |
↓ 1 dose level |
|
Moderate or Severe |
>3xULN |
and |
any |
Has not been studied |
| Creatinine Clearance (mL/min) | Niraparib Dose |
| ≥ 30 | No dose adjustment required |
| < 30 or ESRD | Has not been studied |
No dose adjustment required. No overall differences in safety and effectiveness of niraparib were observed between patients ≥ 65 years old and younger but greater sensitivity of some older patients cannot be ruled out.
No dose adjustment required. Analyses suggested that race/ethnicity had no clinically significant effect on the pharmacokinetics of niraparib.
The safety and effectiveness of niraparib in pediatric patients have not been established.
- Niraparib should be taken with or without food at approximately the same time each day. (Bedtime administration may help manage nausea).
- The dose should be swallowed whole, not chewed, crushed, or split.
- If a dose of niraparib is missed, patients should take the next dose at the regularly scheduled time. Patients should not take an additional dose if vomiting or missed doses occur.
- Store at a temperature up to 25°C.
- Patients who have a hypersensitivity to the drug or to any of its components or components of the container.
- Niraparib has moderate influence on the ability to drive or use machines. Caution should be exercised when driving or operating a vehicle or potentially dangerous machinery due to fatigue and dizziness.
- Patients should be counselled to avoid sun exposure when possible while on treatment.
- Niraparib capsules contain tartrazine (FD&C Yellow #5), which may cause allergic-type reactions.
- Niraparib capsules and tablets contain lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
Other Drug Properties:
-
Phototoxicity:
Possible
-
Genotoxicity:
Yes
-
Clastogenicity:
Yes
-
Fetotoxicity:
Yes
Niraparib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for 6 months after the last dose.
-
Fertility effects:
Documented in animals
A reversible reduction of spermatogenesis was observed in animal studies -
Teratogenicity:
Probable
-
Excretion into breast milk:
Breastfeeding is contraindicated during treatment and for 1 month after the last dose.
No formal drug interaction studies have been performed with niraparib.
In vitro, niraparib is a:
- weak inducer of CYP1A2
- weak inhibitor of BCRP, P-gp and OCT1
- inhibitor of MATE-1 and -2
- substrate of P-gp and BCRP
In vivo, niraparib is a substrate of carboxylesterases (CEs) and UDP-glucuronosyltransferases (UGTs).
The potential of niraparib on intestinal CYP3A4 inhibition has not been established.
Caution is recommended when niraparib is combined with active substances with CYP3A4/1A2-dependent metabolism, that undergo uptake transport by OCT1 or with known inhibitors or inducers of carboxylesterases and conjugation (UGT) pathways.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and weekly for the first month of treatment then monthly for the next 11 months and as clinically indicated |
Blood pressure and heart rate |
Baseline and at minimum weekly for the first 2 months of treatment, then monthly for the first year and as clinically indicated (More frequent monitoring may be required in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension) |
Clinical toxicity assessment for infection, hypersensitivity, fatigue, musculoskeletal pain, hot flashes, secondary malignancy, GI, cardiovascular, neurologic and respiratory effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline and as clinically indicated |
Renal function tests |
Baseline and as clinically indicated |
Exceptional Access Program (EAP Website)
- niraparib - For the maintenance treatment of newly diagnosed or recurrent high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, according to clinical criteria
Berek JS, Matulonis UA, Peen U, et al. Safety and dose modification for patients receiving niraparib. Ann Oncol 2018 Aug 1;29(8):1784-92.
González-Martín A et al. PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019 Dec 19;381(25):2391-2402.
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016 Dec 1;375(22):2154-64.
pCODR expert review committee: final recommendation. Niraparib (maintenance for first-line advanced ovarian cancer), April 2021.
pCODR expert review committee: final recommendation. Niraparib (maintenance for recurrent ovarian cancer), September 2020.
Prescribing Information: Zejula (niraparib). Tesaro Inc. August 2017.
Product Monograph: Zejula (niraparib). GlaxoSmithKline Inc. June 2, 2022.
October 2023 Modified Administration guidelines and Other warnings/precautions sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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