ZEJULA 100 MG HARD CAPSULE - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Zejula 100 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains niraparib tosylate monohydrate equivalent to 100 mg niraparib.

Excipients with known effect

Each hard capsule contains 254.5 mg of lactose monohydrate (see section 4.4).

Each hard capsule shell also contains the colouring agent tartrazine (E 102) [0.0172 mg].

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Hard capsule (capsule).

Hard capsule of approximately 22 mm x 8 mm; white body with “100 mg” printed in black ink and purple cap with “Niraparib” printed in white ink.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Zejula is indicated:

as monotherapy for the maintenance treatment of adult patients with advanced epithelial (FIGO Stages III and IV) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy.

as monotherapy for the maintenance treatment of adult patients with platinum sensitive relapsed high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum based chemotherapy.

4.2 Posology and method of administration

Treatment with Zejula should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Posology

First-line ovarian cancer maintenance treatment

The recommended starting dose of Zejula is 200 mg (two 100-mg capsules), taken once daily. However, for those patients who weigh > 77 kg and have baseline platelet count > 150,000/pL, the recommended starting dose of Zejula is 300 mg (three 100mg capsules), taken once daily (see section 4.4 and 4.8).

Recurrent ovarian cancer maintenance treatment

The dose is three 100 mg hard capsules once daily, equivalent to a total daily dose of 300 mg.

Patients should be encouraged to take their dose at approximately the same time each day. Bedtime administration may be a potential method for managing nausea.

It is recommended that treatment should be continued until disease progression or toxicity.

Missing dose

If patients miss a dose, they should take their next dose at its regularly scheduled time.

Dose adjustments for adverse reactions

The recommended dose modifications for adverse reactions are listed in Tables 1, 2 and 3.

In general, it is recommended to first interrupt the treatment (but no longer than

28 consecutive days) to allow the patient to recover from the adverse reaction and then restart at the same dose. In the case that the adverse reaction recurs, it is recommended to interrupt the treatment and then resume at the lower dose. If adverse reactions persist beyond a 28-day dose interruption, it is recommended that Zejula be discontinued. If adverse reactions are not manageable with this strategy of dose interruption and reduction, it is recommended that

counts return to > 100,000/^L.

Resume Zejula at same or reduced dose per

Patients with low body weight in recurrent ovarian cancer maintenance treatment Approximately 25 % of patients in the NOVA study weighed less than 58 kg, and approximately 25 % of patients weighed more than 77 kg. The incidence of Grade 3 or 4 ADRs was greater among low body weight patients (78 %) than high body weight patients (53 %). Only 13 % of low body weight patients remained at a dose of 300 mg beyond Cycle 3. A starting dose of 200 mg for patients weighing less than 58 kg may be considered.

Elderly

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

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 haemodialysis; use with caution in these patients (see section 5.2).

Hepatic impairment

No dose adjustment is needed in patients with mild hepatic impairment (either aspartate aminotransferase (AST) > upper limit of normal (ULN) and total bilirubin (TB) < ULN or any AST and TB > 1.0 x – 1,5 x ULN). For patients with moderate hepatic impairment (any AST and TB > 1.5 x – 3 x ULN) the recommended starting dose of Zejula is 200 mg once daily. There are no data in patients with severe hepatic impairment (any AST and TB > 3 x ULN); use with caution in these patients (see sections 4.4 and 5.2).

Patients with ECOG performance status 2 to 4

Clinical data are not available in patients with ECOG performance status 2 to 4.

Paediatric population

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

Method of administration

Oral use. The capsules should be swallowed whole with water. The capsules should not be chewed or crushed.

Zejula can be taken without regard to meals.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast feeding (see section 4.6).

4.4 Special warnings and precautions for use

Haematologic adverse reactions

Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) have been reported in patients treated with Zejula (see section 4.8). Patients with lower body weight or lower baseline platelet count may be at increased risk of Grade 3+ thrombocytopenia (see section 4.2).

Testing complete blood counts weekly for the first month, followed by monthly monitoring for the next 10 months of treatment and periodically after this time is recommended to monitor for clinically significant changes in any haematologic parameter during treatment (see section 4.2).

If a patient develops severe persistent haematologic toxicity including pancytopenia that does not resolve within 28 days following interruption, Zejula should be

Due to the risk of thrombocytopenia, anticoagulants and medicinal products known to reduce the thrombocyte count should be used with caution (see section 4.8).

Myelodysplastic syndrome/acute myeloid leukaemia

Cases of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) have been observed in patients treated with Zejula monotherapy or combination therapy in clinical trials and postmarketing.

The duration of Zejula treatment in patients prior to developing MDS/AML varied from 0.5 months to > 4.9 years. The cases were typical of secondary, cancer therapy-related MDS/AML. All patients had received 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 Zejula, treatment should be discontinued and the patient treated appropriately.

Hypertension, including hypertensive crisis

Hypertension, including hypertensive crisis, has been reported with the use of Zejula (see section 4.8). Pre-existing hypertension should be adequately controlled before starting Zejula treatment. Blood pressure should be monitored at least weekly for two months, monitored monthly afterwards for the first year and periodically thereafter during treatment with Zejula. Home blood pressure monitoring may be considered for appropriate patients with instruction to contact their health care provider in case of rise in blood pressure.

Hypertension should be medically managed with antihypertensive medicinal products as well as adjustment of the Zejula dose (see section 4.2), if necessary. In the clinical programme, blood pressure measurements were obtained on Day 1 of each 28-day cycle while the patient remained on Zejula. In most cases, hypertension was controlled adequately using standard antihypertensive treatment with or without Zejula dose adjustment (see section 4.2). Zejula should be discontinued in case of hypertensive crisis or if medically significant hypertension cannot be adequately controlled with antihypertensive therapy.

Posterior Reversible Encephalopathy Syndrome (PRES)

There have been reports of Posterior Reversible Encephalopathy Syndrome (PRES) in patients receiving Zejula (see section 4.8). PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI).

In case of PRES, it is recommended to discontinue Zejula and to treat specific symptoms including hypertension. The safety of reinitiating Zejula therapy in patients

previously experiencing PRES is not known.

Pregnancy/con­traception

Zejula 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 Zejula (see section 4.6). A pregnancy test should be performed on all women of childbearing potential prior to treatment.

Hepatic impairment

Patients with severe hepatic impairment could have increased exposure of niraparib based on data from patients with moderate hepatic impairment and should be carefully monitored (see sections 4.2 and 5.2).

Lactose

Zejula 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 (E 102)

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

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

The combination of niraparib with vaccines or immunosuppressant agents has not been studied.

The data on niraparib in combination with cytotoxic medicinal products are limited. Therefore, caution should be taken if niraparib is used in combination with vaccines, immunosuppressant agents or with other cytotoxic medicinal products.

Pharmacokinetic interactions

Effect of other medicinal products on niraparib

Niraparib as a substrate of CYPs (CYP1A2 and CYP3A4)

Niraparib is a substrate of carboxylesterases (CEs) and UDP-glucuronosyltran­sferases (UGTs) in vivo. Oxidative metabolism of niraparib is minimal in vivo. No dose adjustment for Zejula is required when administered concomitantly with medicinal products known to inhibit (e.g. itraconazole, ritonavir, and clarithromycin) or induce CYP enzymes (e.g. rifampin, carbamazepine, and phenytoin).

Niraparib as a substrate of efflux transporters (P-gp, BCRP, BSEP, MRP2, and MATE1/2)

Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, due to its high permeability and bioavailability, the risk of clinically relevant interactions with medicinal products that inhibit these transporters is unlikely. Therefore, no dose adjustment for Zejula is required when administered concomitantly with medicinal products known to inhibit P-gp (e.g. amiodarone, verapamil) or BCRP (e.g. osimertinib, velpatasvir, and eltrombopag).

Niraparib is not a substrate of bile salt export pump (BSEP), or multidrug resistance-associated protein 2 (MRP2). The major primary metabolite M1 is not a substrate of P-gp, BCRP, BSEP, or MRP2. Niraparib is not a substrate of multidrug and toxin extrusion (MATE)-1 or 2, while M1 is a substrate of both.

Niraparib as a substrate of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1)

Neither niraparib nor M1 is a substrate of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1). No dose adjustment for Zejula is required when administered concomitantly with medicinal products known to inhibit OATP1B1 or 1B3 (e.g. gemfibrozil, ritonavir), or OCT1 (e.g. dolutegravir) uptake transporters.

Niraparib as a substrate of renal uptake transporters (OAT1, OAT3, and OCT2)

Neither niraparib nor M1 is a substrate of organic anion transporter 1 (OAT1), 3 (OAT3), and organic cation transporter 2 (OCT2). No dose adjustment for Zejula is required when administered concomitantly with medicinal products known to inhibit OAT1 (e.g. probenecid) or OAT3 (e.g. probenecid, diclofenac), or OCT2 uptake transporters (e.g. cimetidine, quinidine).

Effect of niraparib on other medicinal products

Inhibition of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4)

Neither niraparib nor M1 is an inhibitor of any active substance-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 niraparib concentrations. Therefore, caution is recommended when niraparib 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).

Inhibition of UDP-glucuronosyltran­sferases (UGTs)

Niraparib did not exhibit inhibitory effect against the UGT isoforms (UGT1A1, UGT1A4, UGT1A9, and UGT2B7) up to 200 ^M in vitro. Therefore, the potential for a clinically relevant inhibition of UGTs by niraparib is minimal.

Induction of CYPs (CYP1A2 and CYP3A4)

Neither niraparib nor M1 is a CYP3A4 inducer in vitro. In vitro, niraparib weakly induces CYP1A2 at high concentrations and the clinical relevance of this effect could not be completely ruled out. M1 is not a CYP1A2 inducer. Therefore, caution is recommended when niraparib 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).

Inhibition of efflux transporters (P-gp, BCRP, BSEP, MRP2, and MATE1/2)

Niraparib is not an inhibitor of BSEP or MRP2. In vitro, niraparib inhibits P-gp very weakly and BCRP with an IC50 = 161 ^M and 5.8 ^M, respectively. Therefore, a clinically meaningful interaction related to an inhibition of these efflux transporters, although unlikely, cannot be excluded. Caution is then recommended when niraparib is combined with substrates of BCRP (irinotecan, rosuvastatin, simvastatin, atorvastatin, and methotrexate).

Niraparib is an inhibitor of MATE1 and –2 with IC50 of 0.18 ^M and < 0.14 ^M, respectively. Increased plasma concentrations of co-administered medicinal products that are substrates of these transporters (e.g. metformin) cannot be excluded.

The major primary metabolite M1 does not appear to be an inhibitor of P-gp, BCRP, BSEP, MRP2 or MATE1/2.

Inhibition of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1)

Neither niraparib nor M1 is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1) or 1B3 (OATP1B3).

In vitro, niraparib weakly inhibits the organic cation transporter 1 (OCT1) with an IC50 = 34.4 |aM. Caution is recommended when niraparib is combined with active substances that undergo an uptake transport by OCT1 such as metformin.

Inhibition of renal uptake transporters (OAT1, OAT3, and OCT2)

Neither niraparib nor M1 inhibits organic anion transporter 1 (OAT1), 3 (OAT3), and organic cation transporter 2 (OCT2).

All clinical studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

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 Zejula.

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. Zejula 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 Zejula and for 1 month after receiving the last dose (see section 4.3).

Fertility

There are no clinical data on fertility. A reversible reduction of spermatogenesis was observed in rats and dogs (see section 5.3).

4.7 Effects on ability to drive and use machines

Zejula has moderate influence on the ability to drive or use machines. Patients who take Zejula may experience asthenia, fatigue, dizziness or difficulties concentrating. Patients who experience these symptoms should observe caution when driving or using machines.

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions (ADRs) of all grades occurring in > 10 % of the 851 patients receiving Zejula monotherapy in the pooled PRIMA (either 200 mg or 300 mg starting dose) and NOVA trials were nausea, anaemia, thrombocytopenia, fatigue, constipation, vomiting, headache, insomnia, platelet count decreased, neutropenia, abdominal pain, decreased appetite, diarrhoea, dyspnoea, hypertension, asthenia, dizziness, neutrophil count decreased, cough, arthralgia, back pain, white blood cell count decreased, and hot flush.

The most common serious adverse reactions > 1 % (treatment-emergent frequencies) were thrombocytopenia and anaemia.

Tabulated list of adverse reactions

The following adverse reactions have been identified based on clinical trials and post-marketing surveillance in patients receiving Zejula monotherapy (see Table 4). Frequencies of occurrence of undesirable effects are based on pooled adverse events data generated from the PRIMA and NOVA studies (fixed starting dose of 300 mg/day) where patient exposure is known and defined as: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); and very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4: Tabulated list of adverse reactions

Virm A Ti 77 Ť7 i 77 «7      7 Ä I ' Ti ’              7 777

CTCAE=Common Terminology Criteria for Adverse Events version 4.02 **

Based on niraparib clinical trial data. This is not limited to pivotal ENGOT-OV16 monotherapy study.

f Includes hypersensitivity, drug hypersensitivity, anaphylactoid reaction, drug eruption, angioedema, and urticaria.

ff Includes memory impairment, concentration impairment.

The adverse reactions noted in the group of patients who were administered a 200 mg starting dose of Zejula based on baseline weight or platelet count were of similar or lesser frequency compared to the group administered a fixed starting dose of 300 mg (Table 4).

See below for specific information regarding frequency of thrombocytopenia, anaemia and neutropenia.

Description of selected adverse reactions

Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) including clinical diagnoses and/or laboratory findings generally occurred early during niraparib treatment with the incidence decreasing over time.

In the NOVA and PRIMA studies, patients eligible for Zejula therapy had the following baseline haematologic parameters: absolute neutrophil count (ANC) > 1,500 cells/^L; platelets > 100,000 cells/^L and haemoglobin > 9 g/dL (NOVA) or > 10 g/dL (PRIMA) prior to therapy. In the clinical programme, haematologic adverse reactions were managed with laboratory monitoring and dose modifications (see section 4.2).

In PRIMA, patients who were administered a starting dose of Zejula based on baseline weight or platelet count, Grade >3 thrombocytopenia, anaemia and neutropenia were reduced from 48% to 21%, 36% to 23% and 24% to 15%, respectively, compared to the group administered a fixed starting dose of 300 mg. Discontinuation due to thrombocytopenia, anaemia, and neutropenia occurred, respectively, in 3%, 3%, and 2% of patients.

Thrombocytopenia

In PRIMA, 39% of Zejula-treated patients experienced Grade 3–4 thrombocytopenia compared to 0.4% of placebo-treated patients with a median time from first dose to first onset of 22 days (range: 15 to 335 days) and with a median duration of 6 days (range: 1 to 374 days). Discontinuation due to thrombocytopenia occurred in 4% of patients receiving niraparib.

In NOVA, approximately 60 % of patients receiving Zejula experienced thrombocytopenia of any grade, and 34 % of patients experienced Grade 3/4 thrombocytopenia. In patients with baseline platelet count less than 180 × 109/L, thrombocytopenia of any grade and Grade 3/4 occurred in 76 % and 45 % of the patients, respectively. The median time to onset of thrombocytopenia regardless of grade and Grade 3/4 thrombocytopenia was 22 and 23 days, respectively. The rate of new incidences of thrombocytopenia after intensive dose modifications were performed during the first two months of treatment from Cycle 4 was 1.2 %. The median duration of thrombocytopenia events of any grade was 23 days, and the median duration of Grade 3/4 thrombocytopenia was 10 days. Patients treated with Zejula who develop thrombocytopenia might have an increased risk of haemorrhage. In the clinical programme, thrombocytopenia was managed with laboratory monitoring, dose modification and platelet transfusion where appropriate (see section 4.2). Discontinuation due to thrombocytopenia events (thrombocytopenia and platelet count decreased) occurred in approximately 3 % of the patients.

In the NOVA study, 48 of 367 (13 %) of patients experienced bleeding with concurrent thrombocytopenia; all bleeding events concurrent with thrombocytopenia were Grade 1 or 2 in severity except for one event of Grade 3 petechiae and haematoma observed concurrently with a serious adverse event of pancytopenia. Thrombocytopenia occurred more commonly in patients whose baseline platelet count was less than 180 × 109/L. Approximately 76 % of patients with lower baseline platelets (< 180 × 109/L) who received Zejula experienced thrombocytopenia of any grade, and 45 % of the patients experienced Grade 3/4 thrombocytopenia. Pancytopenia has been observed in < 1 % of patients receiving niraparib.

Anaemia

In PRIMA, 31% of Zejula-treated patients experienced Grade 3–4 anaemia compared to 2% of placebo-treated patients with a median time from first dose to first onset of 80 days (range: 15 to 533 days) and with a median duration of 7 days (range: 1 to 119 days). Discontinuation due to anaemia occurred in 2% of patients receiving niraparib.

In NOVA, approximately 50 % of patients experienced anaemia of any grade, and 25 % experienced Grade 3/4 anaemia. The median time to onset of anaemia of any grade was 42 days, and 85 days for Grade 3/4 events. The median duration of anaemia of any grade was 63 days, and 8 days for Grade 3/4 events. Anaemia of any grade might persist during Zejula treatment. In the clinical programme, anaemia was managed with laboratory monitoring, dose modification (see section 4.2), and where appropriate with red blood cell transfusions. Discontinuation due to anaemia occurred in 1 % of patients.

Neutropenia

In PRIMA, 21% of Zejula-treated patients experienced Grade 3–4 neutropenia compared to 1% of placebo-treated patients with a median time from first dose to first onset of 29 days (range: 15 to 421 days) and with a median duration of 8 days (range: 1 to 42 days). Discontinuation due to neutropenia occurred in 2% of patients receiving niraparib.

In NOVA, approximately 30 % of patients receiving Zejula experienced neutropenia of any grade, and 20 % of patients experienced Grade 3/4 neutropenia. The median time to onset of neutropenia of any grade was 27 days, and 29 days for Grade 3/4 events. The median duration of neutropenia of any grade was 26 days, and 13 days for Grade 3/4 events. In addition, Granulocyte-Colony Stimulating Factor (G-CSF) was administered to approximately 6 % of patients treated with niraparib as concomitant therapy for neutropenia. Discontinuation due to neutropenia events occurred in 2 % of patients.

Hypertension

In PRIMA, Grade 3–4 hypertension occurred in 6% of Zejula-treated patients compared to 1% of placebo-treated patients with a median time from first dose to first onset of 50 days (range: 1 to 589 days) and with a median duration of 12 days (range: 1 to 61 days). Discontinuation due to hypertension occurred in 0% of patients.

In NOVA, hypertension of any grade occurred in 19.3 % of patients treated with Zejula. Grade 3/4 hypertension occurred in 8.2 % of patients. Hypertension was readily managed with anti-hypertensive medicinal products. Discontinuation due to hypertension occurred in < 1 % of patients.

Paediatric population

No studies have been conducted in paediatric patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: http://www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents, ATC code: L01XK02.

Mechanism of action and pharmacodynamic effects

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 tumour cell lines with or without deficiencies in the BReast CAncer (BRCA) 1 and 2 tumour suppressor genes. In orthotopic high-grade serous ovarian cancer patient-derived xenograft tumours (PDX) grown in mice, niraparib has been shown to reduce tumour growth in BRCA 1 and 2 mutant, BRCA wild-type but homologous recombination (HR) deficient, and in tumours that are BRCA wild-type and without detectable HR deficiency.

Clinical efficacy and safety

First-line ovarian cancer maintenance treatment

PRIMA was a Phase 3 double-blind, placebo-controlled trial in which patients (n=733) in complete or partial response to first-line platinum-based chemotherapy were randomised 2:1 to Zejula or matched placebo. PRIMA was initiated with a starting dose of 300 mg QD in 475 patients (whereof 317 was randomised to the niraparib arm vs. 158 in the placebo arm) in continuous 28-day cycles. The starting dose in PRIMA was changed with Amendment 2 of the Protocol. From that point forward, patients with a baseline body weight >77 kg and baseline platelet count >150,000/pL were administered Zejula 300 mg (3*100 mg capsules) (n=34) or placebo (3 capsules) daily (n=21) while patients with a baseline body weight <77 kg or baseline platelet count <150,000/pL were administered Zejula 200 mg (2*100 mg capsules) (n=122) or placebo (2 capsules) daily (n=61).

Patients were randomised post completion of first-line platinum-based chemotherapy plus/minus surgery. Subjects were randomized within 12 weeks of the first day of the last cycle of chemotherapy.

Subjects had >6 and <9 cycles of platinum-based therapy. Following interval debulking surgery subjects had >2 post-operative cycles of platinum-based therapy. Patients who had received bevacizumab with chemotherapy but could not receive bevacizumab as maintenance therapy were not excluded from the study. Patients could not have received prior PARP inhibitor therapy, including Zejula. Patients who had neoadjuvant chemotherapy followed by interval debulking surgery could have visible residual or no residual disease. Patients with Stage III disease who had complete cytoreduction (i.e., no visible residual disease) after primary debulking surgery were excluded. Randomisation was stratified by best response during the front-line platinum regimen (complete response vs partial response), neoadjuvant chemotherapy (NACT) (Yes vs No); and homologous recombination deficiency (HRD) status [positive (HR deficient) vs negative (HR proficient) or not determined]. Testing for HRD was performed using the HRD test on tumour tissue obtained at the time of initial diagnosis. The CA-125 levels should be in the normal range (or a CA-

125 decrease by > 90 %) during the patient’s front-line therapy, and be stable for at least 7 days.

Patients began treatment on Cycle 1/Day 1 (C1/D1) with Zejula 200 or 300 mg or matched placebo administered QD in continuous 28-day cycles. Clinic visits occurred each cycle (4 weeks ± 3 days).

The primary endpoint was progression-free survival (PFS), as determined by blinded independent central review (BICR) per RECIST, version 1.1. Overall survival (OS) was a key secondary objective. PFS testing was performed hierarchically: first in the HR deficient population, then in the overall population. The median age of 62 ranged from 32 to 85 years among patients randomised with Zejula and 33 to 88 years among patients randomised with placebo. 89 percent of all patients were white. 69 percent of patients randomised with Zejula and 71% of patients randomised with placebo had an ECOG of 0 at study baseline. In the overall population, 65% of patients had stage III disease and 35% had stage IV disease. In the overall population, the primary tumour site in most patients (> 80 %) was the ovary; most patients (> 90 %) had tumours with serous histology. 67 percent of the patients received NACT. 69 percent of the patients had a complete response to the first-line platinum-based chemotherapy. A total of 6 niraparib patients had received bevacizumab as prior treatment for their ovarian cancer.

PRIMA demonstrated a statistically significant improvement in PFS for patients randomised to Zejula as compared with placebo in the HR deficient and overall population (Table 5, and Figures 1 and 2).

Secondary efficacy endpoints included PFS after the first subsequent therapy (PFS2) and OS (Table 5).

Table 5: Efficacy results – PRIMA (determined by BICR)

*At the time of primary PFS analysis, an estimated survival at two years after randomization of 84% for patients receiving Zejula, as compared to 77% for patients receiving placebo in the overall population.

Data of PFS2 and OS are currently not mature.

Figure 1: Progression-free survival in patients with HR deficient tumours (ITT population, N=373)

Figure 2: Progression-free survival in the overall population (ITT population, N=733)

Subgroup analyses

Within the HR deficient population, a hazard ratio of 0.40 (95% CI [0.27, 0.62]) was observed in the subgroup of patients with BRCAmut ovarian cancer (N = 223). In the subgroup of HR deficient patients without a BRCA mutation (N = 150), a hazard ratio of 0.50 (95% CI [0.31, 0.83]) was observed. In the HR proficient population (N= 249), a hazard ratio of 0.68 (95% CI [0.49, 0.94]) was observed.

In exploratory subgroup analyses of patients who were administered 200 or 300 mg dose of Zejula based on baseline weight or platelet count, comparable efficacy (investigator-assessed PFS) was observed with a hazard ratio of 0.54 (95% CI [0.33, 0.91]) in the HR deficient population, and with a hazard ratio of 0.68 (95% CI [0.49, 0.94]) in the overall population. In the HR proficient subgroup, the dose of 200 mg appeared to give a lower treatment effect compared to the 300 mg dose.

The safety and efficacy of niraparib as maintenance therapy was studied in a Phase 3 randomised, double-blind, placebo-controlled international trial (NOVA) in patients with relapsed predominantly high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who were platinum sensitive, defined by complete response (CR) or partial response (PR) for more than six months to their penultimate (next to last) platinum-based therapy. To be eligible for niraparib treatment, the patient should be in response (CR or PR) following completion of last platinum-based chemotherapy. The CA-125 levels should be normal (or a > 90 % decrease in CA-125 from baseline) following their last platinum treatment, and be stable for at least 7 days. Patients could not have received prior PARP inhibitor therapy, including Zejula. Eligible patients were assigned to one of two cohorts based on the results of a germline BRCA mutation test. Within each cohort, patients were randomised using a 2:1 allocation of niraparib and placebo. Patients were assigned to the gBRCAmut cohort based on blood samples for gBRCA analysis that were taken prior to randomisation. Testing for tBRCA mutation and HRD was performed using the HRD test on tumour tissue obtained at the time of initial diagnosis or at the time of recurrence.

Randomisation within each cohort was stratified by time to progression after the penultimate platinum therapy before study enrolment (6 to < 12 months and > 12 months); use or not of bevacizumab in conjunction with the penultimate or last platinum regimen; and best response during the most recent platinum regimen (complete response and partial response).

Patients began treatment on Cycle 1/Day 1 (C1/D1) with niraparib 300 mg or matched placebo administered QD in continuous 28-day cycles. Clinic visits occurred each cycle (4 weeks ± 3 days).

In the NOVA study, 48 % of patients had a dose interruption in Cycle 1. Approximately 47 % of patients restarted at a reduced dose in Cycle 2.

The most commonly used dose in niraparib-treated patients in the NOVA study was 200 mg.

Progression-free survival was determined per RECIST (Response Evaluation Criteria in Solid Tumors, version 1.1) or clinical signs and symptoms and increased CA-125. PFS was measured from the time of randomisation (which occurred up to 8 weeks after completion of the chemotherapy regimen) to disease progression or death.

The primary efficacy analysis for PFS was determined by blinded central independent assessment and was prospectively defined and assessed for the gBRCAmut cohort and the non-gBRCAmut cohort separately.

Secondary efficacy endpoints included chemotherapy-free interval (CFI), time to first subsequent therapy (TFST), PFS after the first subsequent therapy (PFS2), time to second subsequent therapy (TSST) and OS (overall survival).

Demographics, baseline disease characteristics, and prior treatment history were generally well balanced between the niraparib and placebo arms in the gBRCAmut (n = 203) and the non-gBRCAmut cohorts (n = 350). Median ages ranged from 57 to 63 years across treatments and cohorts. The primary tumour site in most patients (> 80 %) within each cohort was the ovary; most patients (> 84 %) had tumours with serous histology. A high proportion of patients in both treatment arms in both cohorts had received 3 or more prior lines of chemotherapy, including 49 % and 34 % of niraparib patients in the gBRCAmut and non-gBRCAmut cohorts, respectively. Most patients were age 18 to 64 years (78 %), Caucasian (86 %) and had an ECOG performance status of 0 (68 %).

In the gBRCAmut cohort, the median number of treatment cycles was higher in the niraparib arm than the placebo arm (14 and 7 cycles, respectively). More patients in the niraparib group continued treatment for more than 12 months than patients in the placebo group (54.4 % and 16.9 % respectively).

In the overall non-gBRCAmut cohort, the median number of treatment cycles was higher in the niraparib arm than in the placebo arm (8 and 5 cycles, respectively). More patients in the niraparib group continued treatment for more than 12 months than patients in the placebo group (34.2 % and 21.1 %, respectively).

The study met its primary objective of statistically significantly improved PFS for niraparib maintenance monotherapy compared with placebo in the gBRCAmut cohort (HR 0.27; 95 % CI* 0.173, 0.410; p < 0.0001) as well as in the overall non-gBRCAmut cohort (HR 0.45; 95 % CI* 0.338, 0.607; p < 0.0001). Table 6 and Figures 3 and 4 show the results for the PFS primary endpoint for the primary efficacy populations (gBRCAmut cohort and the overall non-gBRCAmut cohort). A sensitivity analysis of investigator PFS showed the following results for the gBRCAmut cohort: HR 0.27 (95 % CI*, 0.182, 0.401; p < 0.0001); median PFS 14.8 months (95% CI*, 12.0, 16.6) for niraparib and median PFS 5.5 months (95% CI*, 4.9, 7.2) for placebo, and for the non-gBRCAmut cohort: HR 0.53 (95 % CI*, 0.405, 0.683; p < 0.0001); median PFS 8.7 months (95 % CI*, 7.3, 10.0) for niraparib and median PFS 4.3 months (95% CI*, 3.7, 5.5) for placebo.

Table 6: Summary of primary objective outcomes in the NOVA study

* CI denotes confidence interval.

Prior to unblinding of the study, tumours of patients were tested for the presence of HRD using an experimental HRD test, which evaluates three indirect measures of tumour genome instability: loss of heterozygosity, telomeric allelic imbalance (TAI), and large-scale state transitions. In the HR deficient group, the hazard ratio was 0.38 (95 % CI, 0.243, 0.586; p < 0.0001). In the HR proficient group, the hazard ratio was 0.58 (95 % CI, 0.361, 0.922; p = 0.0226). The experimental test was not able to discriminate which patients would or would not benefit from niraparib maintenance therapy.

Figure 3: Kaplan-Meier plot for progression-free survival in the gBRCAmut cohort based on IRC assessment (ITT population, N = 203)

Time since Randomization (Months)

Figure 4: Kaplan-Meier plot for progression-free survival in the non-gBRCAmut cohort overall based on IRC assessment (ITT population, N = 350)

The secondary endpoints CFI, TFST, and PFS2 demonstrated a statistically significant and persistent treatment effect in favour of the niraparib treatment arm in the gBRCAmut cohort and the overall non-gBRCAmut cohort (Table 7).

Table 7: Secondary endpoints*

Chemotherapy-free interval

Time to first subsequent treatment

*CI denotes confidence interval, gBRCAmut germline BRCA mutation, and NR not reached

Patient-reported outcome (PRO) data from validated survey tools (FOSI and EQ-5D) indicate that niraparib-treated patients reported no difference from placebo in measures associated with quality of life (QoL).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Zejula in all subsets of the paediatric population in ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumours).

5.2 Pharmacokinetic properties

Absorption

Following a single-dose administration of 300 mg niraparib under fasting conditions, niraparib was measurable in plasma within 30 minutes and the mean peak plasma concentration (Cmax) for niraparib was reached in about 3 hours [804 ng/mL (% CV:50.2 %)]. Following multiple oral doses of niraparib from 30 mg to 400 mg once daily, accumulation of niraparib was approximately 2 to 3 folds.

The systemic exposures (Cmax and AUC) to niraparib increased in a dose-proportional manner when the dose of niraparib increased from 30 mg to 400 mg. The absolute bioavailability of niraparib is approximately 73 %, indicating minimal first pass effect. In a population pharmacokinetic analysis of niraparib, the inter-individual variability in bioavailability was estimated to a coefficient of variation (CV) of 31%.

A concomitant high-fat meal did not significantly affect the pharmacokinetics of niraparib after administration of 300 mg of niraparib.

Distribution

Niraparib was moderately protein bound in human plasma (83.0 %), mainly with serum albumin. In a population pharmacokinetic analysis of niraparib, the apparent volume of distribution (Vd/F) was 1,311 L (based on a 70 kg patient) in cancer patients (CV 116%), indicating extensive tissue distribution of niraparib.

Biotransformation

Niraparib is metabolised primarily by carboxylesterases (CEs) to form a major inactive metabolite, M1. In a mass balance study, M1 and M10 (the subsequently formed M1 glucuronides) were the major circulating metabolites.

Elimination

Following a single oral 300-mg dose of niraparib, the mean terminal half-life (t/2) of niraparib ranged from 48 to 51 hours (approximately 2 days). In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.5 L/h in cancer patients (CV 23.4%).

Niraparib is eliminated primarily through the hepatobiliary and renal routes. Following an oral administration of a single 300-mg dose of [14C]-niraparib, on average 86.2 % (range 71 % to 91 %) of the dose was recovered in urine and faeces over 21 days. Radioactive recovery in the urine accounted for 47.5 % (range 33.4 % to 60.2 %) and in the faeces for 38.8 % (range 28.3 % to 47.0 %) of the dose. In pooled samples collected over 6 days, 40.0 % of the dose was recovered in the urine primarily as metabolites and 31.6 % of the dose was recovered in the faeces primarily as unchanged niraparib.

Special populations

Renal impairment

In the population pharmacokinetic analysis, patients with mild (creatinine clearance 60–90 ml/min) and moderate (30–60 mL/min) renal impairment had mildly reduced niraparib clearance compared to individuals with normal renal function (7–17% higher exposure in mild and 17–38% higher exposure in moderate renal impairment). The difference in exposure is not considered to warrant dose adjustment. No patients with pre-existing severe renal impairment or end-stage renal disease undergoing hemodialysis were identified in clinical studies (see section 4.2).

Hepatic impairment

In the population pharmacokinetic analysis of data from clinical studies in patients, pre-existing mild hepatic impairment (n=155) did not influence the clearance of niraparib. In a clinical study of cancer patients using NCI-ODWG criteria to classify the degree of hepatic impairment, niraparib AUCinf in patients with moderate hepatic impairment (n=8) was 1.56 (90% CI: 1.06 to 2.30) times the niraparib AUCinf in patients with normal hepatic function (n=9) following administration of a single 300 mg dose. Niraparib dose adjustment is recommended for patients with moderate hepatic impairment (see section 4.2). Moderate hepatic impairment did not have an effect on niraparib Cmax or on niraparib protein binding. The pharmacokinetics of niraparib have not been assessed in patients with severe hepatic impairment (see sections 4.2 and 4.4).

Weight, age and race

Increasing weight was found to increase niraparib volume of distribution in the population pharmacokinetic analysis. No impact of weight was identified on niraparib clearance or overall exposure. Dose adjustment according to body weight is not warranted from a pharmacokinetic point of view.

Increasing age was found to decrease niraparib clearance in the population pharmacokinetic analysis. The average exposure in a 91-year old patient was predicted to be 23% higher than in a 30-year old patient. The impact of age is not considered to warrant dose adjustment.

There is insufficient data across races to conclude on the impact of race on niraparib pharmacokinetics.

Paediatric population

No studies have been conducted to investigate the pharmacokinetics of niraparib in paediatric patients.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content

Magnesium stearate

Lactose monohydrate

Capsule shell

Titanium dioxide (E 171)

Gelatin

Brilliant blue FCF (E 133)

Erythrosine (E 127)

Tartrazine (E 102)

Printing ink

Shellac (E 904)

Propylene glycol (E 1520)

Potassium hydroxide (E 525)

Black iron oxide (E 172)

Sodium hydroxide (E 524)

Povidone (E 1201)

Titanium dioxide (E 171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30 °C.

6.5 Nature and contents of container

Aclar/PVC/aluminium foil perforated unit dose blisters in cartons of 84 × 1, 56 × 1 and 28 × 1 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.