Ovaxa Capsule

Ovaxa 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

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.

Inhibition of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Neither Ovaxa nor M1 is an inhibitor of any active ubstance-metabolising CYP enzymes, namely CYP1A1/2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5. Even though inhibition of CYP3A4 in the liver is not expected, the potential to inhibit CYP3A4 at the intestinal level has not been established at relevant Ovaxa concentrations. Therefore, caution is recommended when Ovaxa is combined with active substances the metabolism of which is CYP3A4-dependent and, notably, those having a narrow therapeutic range (e.g. ciclosporin, tacrolimus, alfentanil, ergotamine, pimozide, quetiapine and halofantrine).

Induction of CYPs (CYP1A2 and CYP3A4): Neither Ovaxa nor M1 is a CYP3A4 inducer in vitro. In vitro, Ovaxa weakly induces CYP1A2 at high concentrations and the clinical relevance of this effect would not be completely ruled out. M1 is not a CYP1A2 inducer. Therefore, caution is recommended when Ovaxa is combined with active substances the metabolism of which is CYP1A2-dependent and, notably, those having a narrow therapeutic range (e.g. clozapine, theophylline and ropinirole).

Hypersensitivity to the active substance or to any of the excipients & breast-feeding.

In the pivotal ENGOT-OV16 study, adverse reactions (ADRs) occurring > 10% of patients receiving Ovaxa 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.

Women of childbearing potential/contraception in females Women of childbearing potential should not become pregnant while on treatment and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. Women of childbearing potential must use effective contraception during therapy and for 1 month after receiving the last dose of Niraparib.

Pregnancy: There are no or limited amount of data from the use of Niraparib in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted. However, based on its mechanism of action, niraparib could cause embryonic or foetal harm, including embryo-lethal and teratogenic effects, when administered to a pregnant woman. Niraparib should not be used during pregnancy.

Breast-feeding: It is unknown whether niraparib or its metabolites are excreted in human milk. Breast-feeding is contraindicated during administration of Niraparib and for 1 month after receiving the last dose.

Fertility: There are no clinical data on fertility. A reversible reduction of spermatogenesis was observed in rats and dogs.

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 Ovaxa or placebo. In the pivotal Phase 3 international trial (ENGOT-OV16), the incidence of MDS/AML in patients who received Ovaxa (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 Ovaxa in clinical studies. The duration of Ovaxa 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 Ovaxa, treatment should be discontinued and the patient treated appropriately.

Hypertension including hypertensive crisis: Hypertension, including hypertensive crisis, has been reported with the use of Ovaxa. Pre-existing hypertension should be adequately controlled before starting Ovaxa treatment. Blood pressure should be monitored monthly for the first year and periodically thereafter during treatment with Ovaxa. Hypertension should be medically managed with antihypertensive medicinal products as well as adjustment of the Ovaxa 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 Ovaxa. In most cases, hypertension was controlled adequately using standard antihypertensive treatment with or without Ovaxa dose adjustment. Ovaxa should be discontinued in case of hypertensive crisis or if medically significant hypertension cannot be adequately controlled with antihypertensive therapy.

Pregnancy/contraception: Ovaxa 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 Ovaxa. A pregnancy test should be performed on all women of childbearing potential prior to treatment.

Lactose: Ovaxa 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.

Elderly: No dose adjustment is necessary for elderly patients (> 65 years). There are limited clinical data in patients aged 75 or over.

Paediatric population: The safety and efficacy of Ovaxa in children and adolescents below 18 years of age have not yet been established. No data are available.

Renal impairment: No dose adjustment is necessary for patients with mild to moderate renal impairment. There are no data in patients with severe renal impairment or end-stage renal disease undergoing hemodialysis; use with caution in these patients.

Hepatic impairment: No dose adjustment is needed in patients with mild to moderate hepatic impairment. There are no data in patients with severe hepatic impairment; use with caution in these patients.

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

Cytotoxic Chemotherapy

Store in a cool and dry place. Do not store above 30°C. Do not take Ovaxa if it is suspected of having been exposed to temperatures greater than 40°C or 104°F. Keep Ovaxa out of the reach and sight of children.