Niranib

The recommended dose of Niraparib as monotherapy is 300 mg (three 100 mg capsules) taken orally once daily. Instruct patients to take their dose of Niraparib at approximately the same time each day. Each capsule should be swallowed whole. Niraparib may be taken with or without food. Bedtime administration may be a potential method for managing nausea. Patients should start treatment with Niraparib no later than 8 weeks after their most recent platinum-containing regimen. Niraparib treatment should be continued until disease progression or unacceptable toxicity. In the case of a missed dose of Niraparib, instruct patients to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose of Niraparib, an additional dose should not be taken.

Niraparib is for oral use. The capsules should be swallowed whole with water. The capsules should not be chewed or crushed. Niraparib can be taken without regard to meals.

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.

There is no specific treatment in the event of Niraparib overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.

Niraparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Niraparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death. Increased Niraparib-induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency that had either mutated or wild type BRCA1/2.

Absorption: The absolute bioavailability of niraparib is approximately 73%. Following oral administration of Niraparib, peak plasma concentration, Cmax, is reached within 3 hours. Concomitant administration of a high fat meal (800-1,000 calories with approximately 50% of total caloric content of the meal from fat) did not significantly affect the pharmacokinetics of Niraparib.

Distribution: Niraparib is 83.0% bound to human plasma proteins. The average (±SD) apparent volume of distribution (Vd/F) was 1220 (±1114) L. In a population pharmacokinetic analysis, the Vd/F of Niraparib was 1074 L in cancer patients.

Elimination: Following multiple daily doses of 300 mg Niraparib, the mean half-life (t1/2) is 36 hours. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients.

Metabolism: Niraparib is metabolized primarily by carboxylesterases (CEs) to form a major inactive metabolite, which subsequently undergoes glucuronidation.

Excretion: Following administration of a single oral 300 mg dose of radio-labeled Niraparib, the average percent recovery of the administered dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine and 38.8% (range 28.3% to 47.0%) in feces. In pooled samples collected over 6 days, unchanged Niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively

Myelodysplastic syndrome/acute myeloid leukaemia: Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), including cases with fatal outcome, have been reported in a small number of patients who received Niraparib or placebo. In the pivotal Phase 3 international trial (ENGOT-OV16), the incidence of MDS/AML in patients who received niraparib (1.4%) was similar to that in patients who received placebo (1.1%). Overall, MDS/AML has been reported in 7 out of 751 (0.9%) patients treated with Niraparib in clinical studies. The duration of Niraparib treatment in patients prior to developing MDS/AML varied from 1 month to > 2 years. The cases were typical of secondary, cancer therapy-related MDS/AML. All patients had received multiple platinum-containing chemotherapy regimens and many had also received other DNA damaging agents and radiotherapy. Some of the patients had a history of bone marrow dysplasia. If MDS and/or AML are confirmed while on treatment with Niraparib, treatment should be discontinued and the patient treated appropriately.

Hypertension including hypertensive crisis: Hypertension, including hypertensive crisis, has been reported with the use of Niraparib. Pre-existing hypertension should be adequately controlled before starting Niraparib treatment. Blood pressure should be monitored monthly for the first year and periodically thereafter during treatment with Niraparib. Hypertension should be medically managed with antihypertensive medicinal products as well as adjustment of the Niraparib dose, if necessary. In the clinical programme, blood pressure measurements were obtained on Day 1 of each 28-day cycle while the patient remained on Niraparib. In most cases, hypertension was controlled adequately using standard antihypertensive treatment with or without Niraparib dose adjustment. Niraparib should be discontinued in case of hypertensive crisis or if medically significant hypertension cannot be adequately controlled with antihypertensive therapy.

Pregnancy/contraception: Niraparib should not be used during pregnancy or in women of childbearing potential not willing to use reliable contraception during therapy and for 1 month after receiving the last dose of Niraparib. A pregnancy test should be performed on all women of childbearing potential prior to treatment.

Lactose: Niraparib hard capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

Tartrazine (E102): This medicinal product contains tartrazine (E 102), which may cause allergic reactions.

Cytotoxic Chemotherapy