Niraparib - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

What Is Niraparib?

Niraparib is a medication used to treat cancer of the ovaries, fallopian tubes, and peritoneum. It was designated an orphan medicine on August 4th, 2010, as it is used to treat a rare disease.

Is Niraparib FDA-approved?

Niraparib was first approved by the United States Food and Drug Administration on March 27th, 2017, and by the European Medicines Agency on 16th November 2017, for the treatment of recurrent ovarian cancer in women.

How Does Niraparib Work?

Poly (ADP-ribose) polymerase (PARP 1) and (PARP 2) are the enzymes responsible for repairing the damaged deoxyribonucleic acid (DNA) in cells during cell division and new cell formation. Niraparib blocks the action of these enzymes, and the damaged DNA of the cancer cells cannot be repaired, resulting in cell death.

What Are the Indications of Niraparib?

• Niraparib is used in the treatment of advanced ovarian cancer in women, including cancer of the ovaries, fallopian tubes, and peritoneum, who have received prior treatment of three or more chemotherapy regimens.

• It maintains patients whose cancer cells have shrunk or disappeared following platinum-based chemotherapy.

• It is also indicated in treating the recurrence of epithelial ovarian, primary peritoneal, or fallopian tube cancer in women under platinum-based chemotherapy.

Dosage and Administration

• Dosage Form: Niraparib is available as 100 mg capsules.

• First-line maintenance treatment for advanced ovarian cancer:

  • 200 mg once daily (two 100 mg capsules) for patients who:

    • Weigh less than 77 kg, or

    • Have a platelet count below 1,50,000/microliter.

  • 300 mg once daily (three 100 mg capsules) for patients who:

    • Weigh 77 kg or more, or

    • Have a platelet count of 1,50,000/microliter or higher.

  • Treatment must be started within 12 weeks after completing platinum-based chemotherapy.

• Maintenance treatment for recurrent ovarian cancer:

  • 300 mg once daily, taken orally.

  • Treatment should begin within 8 weeks after completing platinum-based chemotherapy.

• After three or more chemotherapy regimens (advanced ovarian cancer):

  • 300 mg once daily, taken orally.

Treatment with Niraparib must be continued until disease progression or until unacceptable toxicity. The recommended dose must be taken at the same time each day, with or without food.

Warning and Precautions

• Serious Blood Cancers: Rare cases of AML and MDS have occurred with Niraparib, especially in patients previously treated with chemotherapy or radiotherapy. Stop Niraparib if diagnosed.

• Pregnancy Risk: Niraparib can harm the fetus. Effective contraception is required during treatment and for 6 months after stopping.

• Blood Disorders: Niraparib may cause low blood counts. Monitor blood counts regularly and discontinue if they do not recover within 28 days.

• High Blood Pressure: Niraparib can cause hypertension. Monitor blood pressure closely, particularly in patients with heart disease.

What Are the Adverse Reactions of Niraparib?

Serious adverse reactions reported during the treatment of Niraparib include;

• Bone marrow suppression.

• Myelodysplastic syndrome or acute myeloid leukemia.

• Cardiovascular effects.

The most common adverse reactions include;

• Nausea and vomiting.

• Fatigue.

• Musculoskeletal pain.

• Abdominal pain.

• Diarrhea.

• Cough.

• Acute kidney injury.

• Headache and dizziness.

• Decreased appetite.

• Urinary tract infection.

• Hypomagnesemia.

• Dyspnea.

For Patients

Storage Instructions

Niraparib is available in 100 mg capsules, and it must be stored at 20 to 25 degrees Celsius and must be kept out of reach of children.

What Is the Most Important Information About Niraparib?

• Niraparib can cause high blood pressure; the doctor will periodically check the blood pressure and heart rate during treatment.

• It can cause serious side effects such as bone marrow problems or a type of cancer of the blood called acute myeloid leukemia; therefore, the doctor may stop the treatment if the patient develops any of these conditions.

• Blood tests are recommended before initiation and periodically during the treatment with Niraparib to check the blood cell counts.

• Niraparib must not be used for conditions other than those prescribed. It must not be taken by others, even if they have the same symptoms, as it may harm them.

What Must the Patient Inform the Doctor Before Taking Niraparib?

• The doctor must be informed if the patient has high blood pressure, heart problems, or other medical conditions.

• Females must inform if they are pregnant or planning pregnancy before taking Niraparib, as it can harm the fetus or cause miscarriage. A pregnancy test may be performed before the start of the treatment, and effective birth control measures must be used during the treatment and for six months after the last dose of Niraparib.

• Females must inform the doctor if they are breastfeeding or planning to breastfeed, as it is not known if Niraparib can pass into the breast milk. Breastfeeding must not be done during the treatment and for one month after the last dose of Niraparib.

• The doctor must be informed if the patient is taking any medicines, over-the-counter (OTC) medications, vitamins, or herbal supplements before starting treatment with Niraparib.

How Should Niraparib Be Taken?

1. Niraparib must be taken as prescribed by the doctor at the same time daily, with or without food.

2. The capsule must be whole and not chewed, crushed, or split before swallowing.

3. The treatment must not be stopped without consulting the doctor.

4. In case of nausea, Niraparib can be taken at bedtime.

5. If a dose is missed or vomited, the next dose must be taken at the regularly scheduled time, and an extra dose must not be taken.

6. In case of an overdose of Niraparib, the doctor must be contacted immediately.

What Are the Side Effects of Niraparib?

Common side effects of Niraparib include;

• Nausea and vomiting.

• Tiredness.

• Pain in the stomach area.

• Shortness of breath.

• Pain in the joints, muscles, and back.

• Diarrhea.

• Sore throat and mouth ulcers.

• Trouble sleeping.

• Headache and dizziness.

• Loss of appetite.

• Indigestion.

• Constipation.

• Cough.

• Rash.

• Urinary tract infections.

For Doctors

Description

Niraparib is a poly(ADP-ribose) polymerase inhibitor (PARP) that blocks malignant cells' ability to repair DNA damage. It contains 159.4 mg of Niraparib tosylate, equivalent to 100 mg of Niraparib free base as an active ingredient. The inactive ingredients in the capsule fill include magnesium stearate and lactose monohydrate.

Clinical Pharmacology

Mechanism of Action

Niraparib is an inhibitor of the enzymes PARP-1 and PARP-2, which are responsible for DNA repair. In vitro studies demonstrate that Niraparib-induced cytotoxicity involves inhibition of PARP enzymatic activity and increased PARP-DNA complex formation, leading to DNA damage, apoptosis, and cell death.

Pharmacodynamics

Niraparib affects patients' pulse rate and blood pressure at the recommended dose due to the inhibition of dopamine, norepinephrine, and serotonin transporters. In most studies, the mean pulse rate and blood pressure increased in the Niraparib arm relative to baseline, whereas they decreased in the placebo arm. Niraparib has the potential to prolong the QTc interval, as evaluated in randomized, placebo-controlled trials. Still, no significant changes were detected following treatment with Niraparib at a dose of 300 mg once daily compared with placebo.

Pharmacokinetics

After a single dose of administration of 300 mg Niraparib, the mean peak plasma concentration was 804 ng/mL, and the exposure increased with daily doses ranging from 30 mg to 400 mg in a dose-proportional manner. The accumulation ratio was approximately 2-fold over the dose range of 30 to 400 mg after 21 days of daily doses.

After oral administration of Niraparib, the peak plasma concentration was reached within 3 hours, with an absolute bioavailability of approximately 73 percent. Concomitant administration of a high-fat meal did not significantly alter the pharmacokinetics of Niraparib.

It has an average apparent volume of distribution of 1220 L, and 83 percent of Niraparib is bound to human plasma proteins, mainly serum albumin. Niraparib is metabolized by carboxylesterases to form a major inactive metabolite and undergoes glucuronidation. The mean half-life following administration of multiple doses of 300 mg Niraparib is 36 hours, with an apparent total clearance of 16.2 L/h; 47.5% was recovered in urine and 38.8% in feces over 21 days. The dose recovered in pooled samples collected over six days was 40 percent in urine and 31.6 percent in feces in an unchanged form.

Non-Clinical Toxicology

Carcinogenicity studies and fertility studies have not been conducted with Niraparib. It was not mutagenic in the Ames assay; however, Niraprib exhibited genomic instability, suggesting potential genotoxicity in humans. Niraparib demonstrated the potential to cause cardiovascular and CNS effects and to cross the blood-brain barrier in animals following oral administration.

Clinical Studies

• PRIMA trial was a double-blind, placebo-controlled trial in which patients with complete or partial response to platinum-based chemotherapy were randomized in a ratio of 2:1 to Niraparib and a matched placebo. It demonstrated a significant improvement in progression-free survival with Niraparib compared to placebo.

• The NOVA trial was a double-blind and placebo-controlled trial conducted in patients with recurrent ovarian, fallopian, or primary peritoneal cancer. It included patients who had received at least two prior platinum-based chemotherapy regimens and were in partial or complete response to the treatment. A 2:1 ratio of 300 mg Niraparib daily or matched placebo within eight weeks of the last therapy was recommended, and the treatment was continued until disease progression or unacceptable toxicity. Patients were divided into two cohorts, and the trial showed that Niraparib improved progression-free survival in both cohorts compared with placebo.

• The QUADRA trial was conducted in 98 patients with advanced ovarian cancer, and the efficacy of Niraparib was studied. Patients with prior exposure to PARP inhibitors were excluded, and patients with 3 or more prior chemotherapies were selected using a clinical trial assay. The primary efficacy outcome showed objective response and partial response rates of 24 percent in the HRD-positive cohort.

Drug Interactions

• On concomitant administration of Itraconazole, Clarithromycin, Ritonavir, or CYP enzyme inducers such as Rifampicin, Phenytoin, Carbamazepine, etc., no adjustment in the dose of Niraparib is required.

• On concomitant administration of P-gp inhibitors such as Amiodarone and Verapamil, or BRCP drugs such as Osimertinib, Velpatasvir, and Eltrombopag, no adjustment in the dose of Niraparib is required.

• The potential to inhibit CYP3A4 at the intestinal level has not been determined, and hence caution is recommended when Niraparib is combined with drugs such as Ergotamine, Quetiapine, Pimozide, Halofantrine, etc.

• Niraparib weakly induces CYP1A2 at high concentrations; hence, caution is recommended when drugs such as Clozapine, Theophylline, and Ropinirole are combined with Niraparib.

Use of Niraparib in Specific Populations

• Pregnancy: Niraparib has the potential to harm the fetus due to its mechanism of action; however, no data are available regarding its use in pregnant females. It is known to cause teratogenic effects and embryo-fetal death in animals, and therefore, Niraparib is not considered for pregnant females. A pregnancy test before the initiation of treatment, along with effective contraception during and after the treatment for six months following the last administered dose of Niraparib, is recommended.

• Lactation: Females are advised not to breastfeed during the treatment with Niraparib and for one month after the last administered dose due to the potential risk of adverse effects in breastfed infants or milk production.

• Pediatric Use: The safety and effectiveness of Niraparib in pediatric patients have not been established.

• Geriatric Use: No significant differences were observed in elderly patients compared with younger patients in terms of safety and effectiveness with Niraparib; however, increased sensitivity in some older patients cannot be ruled out.

• Renal Impairment: Dose adjustment is not required in individuals with mild to moderate renal impairment; however, the safety of Niraparib in patients with severe renal impairment is unknown.

• Hepatic Impairment: Dose adjustment is not needed in individuals with mild hepatic impairment; however, the safety of Niraparib in patients with moderate to severe renal impairment is unknown.