Niraparib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as tosylate:

Zejula: 100 mg [contains brilliant blue fcf (fd&c blue #1), tartrazine (fd&c yellow #5)]

Pharmacology

Mechanism of Action

Niraparib is a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor, which is highly selective for PARP-1 and PARP-2. PARP-1 and PARP-2 are involved in detecting DNA damage and promote repair (Mirza 2016). Inhibiting PARP enzymatic activity results in DNA damage, apoptosis and cell death. Niraparib induces cytotoxicity in tumor cell lines with and without BRCA1/2 deficiencies.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d/F: 1,074 L

Metabolism

Metabolized by carboxylesterases to an inactive metabolite, which subsequently undergoes glucuronidation.

Excretion

Urine (~48% [at 21 days]; 11% [pooled samples collected over 6 days] as unchanged drug); Feces (~39% [at 21 days]; 19% [pooled samples collected over 6 days] as unchanged drug)

Time to Peak

Within 3 hours

Half-Life Elimination

36 hours

Protein Binding

83%

Use: Labeled Indications

Ovarian, fallopian tube, or primary peritoneal cancer:

Maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in a complete or partial response to platinum-based chemotherapy.

Treatment of advanced ovarian, fallopian tube, or primary peritoneal cancer in patients who have been treated with ≥3 prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency positive status, defined by a deleterious or suspected deleterious BRCA mutation or genomic instability and who have progressed >6 months after response to the last platinum-based chemotherapy. Select patients for therapy based on an approved companion diagnostic for niraparib.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Note: Niraparib is associated with a moderate emetic potential; antiemetics may be necessary to prevent nausea and vomiting.

Ovarian, fallopian tube, or primary peritoneal cancer, advanced (after ≥3 chemotherapy regimens): Oral: 300 mg once daily, continue until disease progression or unacceptable toxicity (Moore 2019). Note: Select patients for niraparib therapy based on homologous recombination deficiency positive status, as defined by either deleterious or suspected deleterious BRCA mutation and/or genomic instability score.

Ovarian, fallopian tube, or primary peritoneal cancer, recurrent (maintenance treatment): Oral: 300 mg once daily, continue until disease progression or unacceptable toxicity (Mirza 2016). Begin treatment no later than 8 weeks following the most recent platinum-containing regimen.

Reduced initial dosing strategy (off-label): Oral: Patients weighing <77 kg and/or with baseline platelets <150,000/mm³: Initial: 200 mg once daily (Berek 2018; Moore 2018). After 2 to 3 months, in the absence of hematologic toxicity, may consider escalation to usual dose of 300 mg once daily (Moore 2018).

Missed/vomited doses: If a dose is missed or vomited, an additional dose should not be taken that day. Resume dosing with the next scheduled daily dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Adverse reactions may be managed with treatment interruption, dose reduction, or discontinuation.

Recommended niraparib dosage adjustment levels:

Starting dose: 300 mg/day

First dose reduction: Reduce to 200 mg/day.

Second dose reduction: Reduce to 100 mg/day.

If further dose reduction below 100 mg/day is needed, discontinue niraparib.

Hematologic toxicity:

Platelets <100,000/mm³:

First occurrence: Withhold treatment for a maximum of 28 days and monitor blood counts weekly. When platelets are ≥100,000/mm³, resume niraparib at the same or at a reduced dose. If platelet count was <75,000/mm³, resume at a reduced dose.

Second occurrence: Withhold treatment for a maximum of 28 days and monitor blood counts weekly. When platelets are ≥100,000/mm³, resume niraparib at a reduced dose. Discontinue if platelet count has not returned to acceptable levels within 28 days of interrupting dose, or if dose has already been reduced to 100 mg/day.

Neutrophils <1,000/mm³ or hemoglobin <8 g/dL: Withhold treatment for a maximum of 28 days and monitor blood counts weekly. When neutrophils are ≥1,500/mm³ or hemoglobin is ≥9 g/dL, resume niraparib at a reduced dose. Discontinue if neutrophils and/or hemoglobin have not returned to acceptable levels within 28 days of interrupting dose, or if dose has already been reduced to 100 mg/day.

Hematologic toxicity requiring transfusion: Withhold niraparib. Consider platelet transfusion for platelets ≤10,000/mm³. If other risk factors (eg, concurrent anticoagulation or antiplatelet therapy), consider interrupting the anticoagulant/antiplatelet and/or transfusing to a higher platelet count. Resume niraparib at a reduced dose.

Secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Discontinue niraparib with confirmed diagnosis of MDS or AML.

Nonhematologic toxicity:

Grade 3 or higher adverse reaction (where prophylactic management is not feasible or persistent despite management): Withhold niraparib for up to 28 days or until resolution; may resume with the dose reduced (up to two dose reductions are permitted).

Grade 3 or higher adverse reaction lasting more than 28 days at a dose of 100 mg/day: Discontinue treatment.

Administration

Oral: Administer at approximately the same time each day, either with or without food. Swallow capsules whole. Niraparib is associated with a moderate emetic potential; antiemetics may be necessary to prevent nausea and vomiting. Consider administering at bedtime to diminish the potential for nausea and vomiting.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F).

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Hypertension (20%)

Central nervous system: Fatigue (≤57%), insomnia (27%), headache (26%), dizziness (18%), anxiety (11%)

Dermatologic: Skin rash (21%)

Gastrointestinal: Nausea (74%), constipation (40%), vomiting (34%), decreased appetite (25%), stomatitis (≤20%), dyspepsia (18%)

Genitourinary: Urinary tract infection (13%)

Hematologic & oncologic: Thrombocytopenia (61%; grades 3/4: 29%), anemia (50%; grades 3/4: 25%), neutropenia (30%; grades 3/4: 20%), leukopenia (17%; grades 3/4: 5%)

Hepatic: Increased serum aspartate aminotransferase (≤36%), increased serum alanine aminotransferase (≤28%)

Neuromuscular & skeletal: Asthenia (≤57%), back pain (18%)

Respiratory: Nasopharyngitis (23%), dyspnea (20%), cough (16%)

1% to 10%:

Cardiovascular: Palpitations (10%), peripheral edema, tachycardia

Central nervous system: Depression

Endocrine & metabolic: Hypokalemia, increased gamma-glutamyl transferase, weight loss

Gastrointestinal: Dysgeusia (10%), xerostomia (10%)

Hepatic: Increased serum alkaline phosphatase

Ophthalmic: Conjunctivitis

Renal: Increased serum creatinine

Respiratory: Bronchitis, epistaxis

<1%: Acute myelocytic leukemia, myelodysplastic syndrome

Postmarketing: Anaphylaxis, confusion, disorientation, hallucination, hypersensitivity reaction, hypertensive crisis, pneumonia, reversible posterior leukoencephalopathy syndrome, skin photosensitivity

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Thrombocytopenia, anemia and neutropenia commonly occur, including grade 3 and 4 events (which rarely required discontinuation). Monitor blood counts weekly for the first month, then monthly for 11 months, then periodically thereafter. Do not initiate niraparib until hematologic toxicity due to previous chemotherapy has resolved to grade 1 or lower. Hematologic toxicity may require treatment interruption, dose reduction, or discontinuation. If hematologic toxicities do not resolve with 28 days following interruption, discontinue niraparib and obtain consult with hematology for further assessment, including marrow and cytogenetic analysis. In patients with low body weight (<77 kg) and/or low baseline platelets (<150,000/mm³), an initial reduced dosing strategy is suggested to reduce hematologic toxicity while maintaining efficacy (Berek 2018; Moore 2018).
• Cardiovascular effects: Hypertension and hypertensive crisis have been reported, including grade 3 and 4 hypertension (hypertension required discontinuation in rare cases). The median time from the first niraparib dose to hypertension onset was 15 to 77 days (range: 1 to 504 days). Monitor blood pressure and heart rate at least weekly for the first 2 months of therapy, then monthly for the first year and periodically thereafter. Patients with cardiac disorders (especially coronary insufficiency, arrhythmias and hypertension) should be monitored closely. If necessary, hypertension should be managed with antihypertensives and niraparib dose adjustment.
• Gastrointestinal toxicity: Niraparib is associated with a moderate emetic potential; antiemetics may be necessary to prevent nausea and vomiting. Consider administering niraparib at bedtime to diminish the potential for nausea and vomiting. Nausea, vomiting, constipation, and mucositis/stomatitis have been reported.
• Secondary malignancy: Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) have been reported (rare), including fatal cases. The duration of niraparib treatment prior to the development of MDS/AML varied from <2 months to >4 years. All patients had received prior chemotherapy, including platinum-based regimens, and/or other DNA-damaging agents, including radiotherapy. Discontinue niraparib if MDS/AML is confirmed.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Homologous recombination deficiency status: Select patients for the treatment of advanced ovarian cancer (after ≥3 prior chemotherapy regimens) based on the presence of homologous recombination deficiency positive status, as defined by either deleterious or suspected deleterious BRCA mutation, or genomic instability and progression >6 months after response to the last platinum-based chemotherapy. Select patients for therapy based on an approved companion diagnostic for niraparib. Information on approved diagnostic tests may be found at http://www.fda.gov/companiondiagnostics.

Monitoring Parameters

Homologous recombination deficiency status in patients with advanced ovarian cancer (after ≥3 prior chemotherapy regimens); CBC with differential (weekly for the first month, then monthly for 11 months, then periodically); pregnancy test (prior to treatment; in females of reproductive potential). Monitor blood pressure and heart rate at least weekly for the first 2 months, then monthly for the first year and periodically thereafter. Monitor adherence.

Pregnancy

Pregnancy Considerations

Animal reproduction studies have not been conducted, however based on the mechanism of action, niraparib may cause fetal harm if used during pregnancy. Pregnancy testing should be conducted prior to treatment and effective contraception should be used during therapy and for at least 6 months after the last dose in females of reproductive potential.

Patient Education

What is this drug used for?

• It is used to treat ovarian, fallopian tube, or peritoneal cancer.

Frequently reported side effects of this drug

• Loss of strength and energy
• Back pain
• Nausea
• Vomiting
• Constipation
• Diarrhea
• Abdominal pain
• Heartburn
• Change in taste
• Trouble sleeping
• Anxiety
• Nose irritation
• Throat irritation
• Mouth irritation
• Mouth sores
• Dry mouth
• Lack of appetite
• Fatigue
• Muscle pain
• Joint pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Kidney problems like not able to pass urine, blood in your urine, change in amount of urine passed, or weight gain
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Weight loss
• Abnormal heartbeat
• Abdominal swelling
• Shortness of breath
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.