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

Overview

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. 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 deoxyribose nucleic 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

• Niraparib is available as 100 mg capsules and is recommended at a dose of 200 mg (two 100 mg capsules) for patients less than 77 kg or with a platelet count less than 1,50,000/microliter and 300 mg (three 100 mg capsules) for patients above 77 kg, or with a platelet count of more than 1,50,000/microliter; to be taken orally once a day. For patients under first-line maintenance treatment for advanced ovarian cancer, Niraparib must be started not later than 12 weeks post their platinum-based chemotherapy.

• For patients with recurrent ovarian cancer, 300 mg of Niraparib is recommended orally once daily; maintenance treatment must be started no later than eight weeks post their platinum-based chemotherapy.

• Niraparib is recommended at a dose of 300 mg to be taken orally once daily after three or more chemotherapy regimens for patients with advanced ovarian cancer.

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

Warning and Precautions

• Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), including fatal cases, was reported in clinical trials in patients receiving Niraparib as a monotherapy or a combination therapy. In patients who received previous platinum-based chemotherapy or radiotherapy, the development of AML or MDS was seen with prior treatment of Niraparib from 0.5 months to 4.9 years. Therefore, if AML or MDS is confirmed, the treatment with Niraparib must be discontinued.

• Niraparib has the potential to harm the fetus if administered to pregnant women; it is due to its mechanism of action that it targets the actively dividing cells. Therefore, females of reproductive potential are advised to use effective contraception during the treatment with Niraparib and for about six months after the last dose.

• Hematologic adverse reactions, including thrombocytopenia, anemia, and neutropenia, were reported in patients under the treatment of Niraparib, leading to the drug's discontinuation. Therefore, Niraparib must be started once the patients completely recover from hematological toxicity due to previous chemotherapy. The blood counts must be monitored monthly for 11 months and periodically afterward. If the hematological toxicities are not resolved within 28 days, Niraparib must be discontinued, and the patient must be referred to a hematologist for further investigations.

• Hypertension and hypertensive crises were reported in some patients under the treatment of Niraparib, which led to the discontinuation of the drug; hence blood pressure and heart rate must be monitored weekly for the first two months, followed by monthly for the first year and periodic following that. Patients with a known case of cardiovascular disorders, cardiac arrhythmias, and coronary insufficiency must be closely monitored, and dose adjustments are made accordingly if necessary.

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

What Is Niraparib?

Niraparib is a prescription medicine used to maintain advanced ovarian cancer, including cancer of the fallopian tubes (tubes that connect the ovaries to the uterus) and the peritoneum (membrane or lining around the abdomen). It is used in newly diagnosed and relapsed cancer cases that had previously shrunk following the chemotherapy.

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 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 unknown 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 Nirapaib Be Taken?

Niraparib must be taken as prescribed by the doctor at the same time daily, with or without food. The capsule must be whole and not chewed, crushed, or split before swallowing. The treatment must not be stopped without consulting the doctor. In case of nausea, Niraparib can be taken at bedtime. 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. 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 the ability of malignant cells 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 include magnesium stearate and lactose monohydrate in the capsule fill.

Clinical Pharmacology

Mechanism of Action

Niraparib is an inhibitor of the enzymes PARP-1 and PARP-2, which are responsible for DNA repair. Invitro studies demonstrate the involvement of Niraparib-induced cytotoxicity in the inhibition of the PARP enzymatic activity and increased PARP-DNA complex formation, which leads 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 over the baseline compared to the placebo arm. Niraparib has the potential for QTc prolongation, which was evaluated in randomized, placebo-controlled trials. Still, significant changes were not detected following the treatment of Niraparib at the dose of 300 mg once daily compared to the 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 two folds for the dose range from 30 to 400 mg, following 21 days of repeated daily doses.

After an oral administration of Niraparib, the peak plasma concentration reached within three hours with an absolute bioavailability of approximately 73 percent; a concomitant administration of a high-fat meal, no significant changes were observed in 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 gets metabolized to form a major inactive metabolite by carboxylesterases and undergoes glucuronidation. The mean half-life following the administration of multiple doses of 300 mg Niraparib is 36 hours, with an apparent total clearance of 16.2 L/h; 47.5 percent was recovered in urine and 38.8 percent 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 indicating a potential for genotoxicity in humans. Niraparib demonstrated a potential to cause cardiovascular and CNS effects, and it also crossed the blood-brain barrier in animals following an 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 matched placebo. It demonstrated a significant improvement in progression-free survival for patients with Niraparib compared to the placebo.

• 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 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 a significant improvement in progression-free survival for patients with Niraparib in both cohorts compared to the placebo.

• 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 three or more prior chemotherapy were selected using a clinical trial assay. The major efficacy outcome showed an objective response rate and partial response rate 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 is available regarding its use in pregnant females. It is known to cause teratogenetic 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 to younger patients regarding the safety and effectiveness of Niraparib; however, increased sensitivity in some older patients cannot be ruled out.

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