This information is intended for use by health professionals

 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 × 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 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

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.

Missing dose

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

Dose adjustments for adverse reactions

Recommendations for the management of adverse reactions are provided in Table 1. 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 reduce the 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 Zejula be discontinued.

Dose reductions may be implemented based on adverse reactions. The recommended dose reductions are first from three hard capsules daily (300 mg) to two hard capsules daily (200 mg). If further dose reduction is needed, a second dose reduction from two hard capsules daily (200 mg) to one capsule daily (100 mg) may be implemented.

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

Table 1: Dose modifications for non-haematologic adverse reactions

Non-haematologic CTCAE* ≥ Grade 3 treatment-related adverse reaction where prophylaxis is not considered feasible or adverse reaction persists despite treatment

First occurrence:

• Withhold Zejula for a maximum of 28 days or until resolution of adverse reaction.

• Resume Zejula at a reduced dose (200 mg/day).

Second occurrence:

• Withhold Zejula for a maximum of 28 days or until resolution of adverse reaction.

• Resume Zejula at a reduced dose (100 mg/day).

CTCAE ≥ Grade 3 treatment-related adverse reaction lasting more than 28 days while patient is administered Zejula 100 mg/day

Discontinue treatment.

*CTCAE=Common Terminology Criteria for Adverse Events

Table 2: Dose modifications for haematologic adverse reactions

Haematologic adverse reactions have been observed during the treatment with Zejula especially during the initial phase of the treatment. It is therefore recommended to monitor complete blood counts (CBCs) weekly during the first month of treatment and modify the dose as needed. After the first month, it is recommended to monitor CBCs monthly and periodically after this time (see section 4.4). Based on individual laboratory values, weekly monitoring for the second month may be warranted.

Haematologic adverse reaction requiring transfusion or haematopoietic growth factor support

• For patients with platelet count ≤ 10,000/μL, platelet transfusion should be considered. If there are other risk factors for bleeding such as co-administration of anticoagulation or antiplatelet medicinal products, consider interrupting these substances and/or transfusion at a higher platelet count.

• Resume Zejula at a reduced dose.

Platelet count < 100,000/μL

First occurrence:

• Withhold Zejula for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥ 100,000/µL.

• Resume Zejula at same or reduced dose based on clinical evaluation.

• If platelet count is < 75,000/μL at any time, resume at a reduced dose.

Second occurrence:

• Withhold Zejula for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥ 100,000/µL.

• Resume Zejula at a reduced dose.

• Discontinue Zejula if the platelet count has not returned to acceptable levels within 28 days of the dose interruption period, or if the patient has already undergone dose reduction to 100 mg QD.

Neutrophil < 1,000/µL or Haemoglobin < 8 g/dL

• Withhold Zejula for a maximum of 28 days and monitor blood counts weekly until neutrophil counts return to ≥ 1,500/µL or haemoglobin returns to ≥ 9 g/dL.

• Resume Zejula at a reduced dose.

• Discontinue Zejula if neutrophils and/or haemoglobin have not returned to acceptable levels within 28 days of the dose interruption period, or if the patient has already undergone dose reduction to 100 mg QD.

Confirmed diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML)

• Permanently discontinue Zejula.

Patients with low body weight

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 to moderate hepatic impairment. There are no data in patients with severe hepatic impairment; use with caution in these patients (see section 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

In the NOVA study, patients eligible for Zejula therapy had the following baseline haematologic parameters: absolute neutrophil count (ANC) ≥ 1,500 cells/µL; platelets ≥ 100,000 cells/µL and haemoglobin ≥ 9 g/dL prior to therapy. Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) have been reported in patients treated with Zejula. 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. If a patient develops severe persistent haematologic toxicity including pancytopenia that does not resolve within 28 days following interruption, Zejula should be discontinued.

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 that does not resolve within 28 days following interruption, Zejula should be discontinued.

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

Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), including cases with fatal outcome, have been reported in a small number of patients who received Zejula 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 Zejula in clinical studies.

The duration of Zejula 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 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. Pre-existing hypertension should be adequately controlled before starting Zejula treatment. Blood pressure should be monitored monthly for the first year and periodically thereafter during treatment with Zejula.

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.

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.

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, 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). The major primary metabolite M1 is not a substrate of P-gp, BCRP, or BSEP. Niraparib is not a substrate of 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 (e.g. cimetidine, quinidine) uptake transporters.

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).

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 would 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, and MATE1/2)

Niraparib is not an inhibitor of BSEP. In vitro, niraparib inhibits P-gp very weakly and BCRP with an IC50 = 161 µM and 5.8 µM, 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 µM and ≤ 0.14 µM, 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, 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 µM. 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 and dizziness. Patients who experience these symptoms should observe caution when driving or using machines.

4.8 Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

The following adverse reactions have been identified in the ENGOT-OV16 study in patients receiving Zejula monotherapy (see Table 3).

Frequencies of occurrence of undesirable effects are 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); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3: Adverse drug reactions: frequencies based on all-causality adverse events*

System Organ Class

Frequency of all CTCAE grades

Frequency of CTCAE grade 3 or 4

Infections and infestations

Very common

Urinary tract infection

Common

Bronchitis, conjunctivitis

Uncommon

Urinary tract infection, bronchitis

Blood and lymphatic system disorders

Very common

Thrombocytopenia, anaemia, neutropenia

Common

Leukopenia

Uncommon

Pancytopenia

Very common

Thrombocytopenia, anaemia, neutropenia

Common

Leukopenia

Uncommon

Pancytopenia

Metabolism and nutrition disorders

Very common

Decreased appetite

Common

Hypokalemia

Common

Hypokalemia

Uncommon

Decreased appetite

Psychiatric disorders

Very common

Insomnia

Common

Anxiety, depression

Uncommon

Insomnia, anxiety, depression

Nervous system disorders

Very common

Headache, dizziness, dysgeusia

Uncommon

Headache

Cardiac disorders

Very common

Palpitations

Common

Tachycardia

Vascular disorders

Very common

Hypertension

Common

Hypertension

Respiratory, thoracic and mediastinal disorders

Very common

Dyspnea, cough, nasopharyngitis

Common

Epistaxis

Common

Dyspnea

Gastrointestinal disorders

Very common

Nausea, constipation, vomiting, abdominal pain, diarrhoea, dyspepsia

Common

Dry mouth, abdominal distension, mucosal inflammation (including mucositis), stomatitis

Common

Nausea, vomiting, abdominal pain

Uncommon

Diarrhoea, constipation, mucosal inflammation (including mucositis), stomatitis, dry mouth

Skin and subcutaneous tissue disorders

Common

Photosensitivity, rash

Uncommon

Photosensitivity, rash

Musculoskeletal and connective tissue disorders

Very common

Back pain, arthralgia

Common

Myalgia

Uncommon

Back pain, arthralgia, myalgia

General disorders and administration site conditions

Very common

Fatigue, asthenia

Common

Oedema peripheral

Common

Fatigue, asthenia

Investigations

Common

Gamma-glutamyl transferase increased, AST increased, blood creatinine increased, ALT increased, blood alkaline phosphatase increased, weight decreased

Uncommon

AST increased, ALT increased, blood alkaline phosphatase increased

Common

Gamma-glutamyl transferase increased

* Frequencies are based on percent of patients using all-causality adverse events.

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.

Thrombocytopenia

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.

Anaemia

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

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 the clinical programme, neutropenia was managed with laboratory monitoring and dose modifications (see section 4.2). 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

Hypertension, including hypertensive crisis, has been reported with Zejula therapy. Hypertension of any grade occurred in 19.3 % of patients treated with Zejula. Grade 3/4 hypertension occurred in 8.2 % of patients. In the clinical programme, 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

Ireland

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IRL - Dublin 2

Tel: +353 1 6764971 Fax: +353 1 6762517

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United Kingdom

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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. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents, ATC code: L01XX54.

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

The safety and efficacy of niraparib as maintenance therapy was studied in a Phase 3 randomised, double-blind, placebo-controlled international trial (ENGOT-OV16 / 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 homologous recombination deficiency (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 enrollment (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 4 shows 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 4: Summary of primary objective outcomes in the ENGOT-OV16 study

gBRCAmut cohort

Non-gBRCAmut cohort

niraparib

(N = 138)

placebo

(N = 65)

niraparib

(N = 234)

placebo

(N = 116)

PFS median (95% CI*)

21.0

5.5

9.3

3.9

(12.9, NR)

(3.8, 7.2)

(7.2, 11.2)

(3.7, 5.5)

p-value

< 0.0001

< 0.0001

Hazard ratio (HR)

(Nir:plac) (95 % CI*)

0.27

(0.173, 0.410)

0.45

(0.338, 0.607)

* 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 HRDpos group, the hazard ratio was 0.38 (95 % CI, 0.243, 0.586; p < 0.0001). In the HRDneg 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 1: Kaplan-Meier plot for progression-free survival in the gBRCAmut cohort based on IRC assessment (ITT population, N = 203)

Figure 2: 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 5).

Table 5: Secondary endpoints*

Endpoint

gBRCAmut

non-gBRCAmut

Zejula

N = 138

Placebo

N = 65

Zejula

N = 234

Placebo

N = 116

Chemotherapy-free interval

Median (95 % CI) - mo

22.8

(17.9-NR)

9.4

(7.9-10.6)

12.7

(11.0-14.7)

8.6

(6.9-10.0)

P value

< 0.001

< 0.001

Hazard ratio (95 % CI)

0.26 (0.17-0.41)

0.50 (0.37-0.67)

Time to first subsequent treatment

Median (95 % CI) - mo

21.0

(17.5-NR)

8.4

(6.6-10.6)

11.8

(9.7-13.1)

7.2

(5.7-8.5)

P value

< 0.001

< 0.001

Hazard ratio (95 % CI)

0.31 (0.21-0.48)

0.55 (0.41-0.72)

Progression-free survival 2

Median (95 % CI) - mo

25.8

(20.3-NR)

19.5

(13.3-NR)

18.6

(16.2-21.7)

15.6

(13.2-20.9)

P value

0.006

0.03

Hazard ratio (95 % CI)

0.48 (0.28-0.82)

0.69 (0.49-0.96)

*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.

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 Vd/F was 1,074 L in cancer patients, 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 (t½) 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 16.2 L/h in cancer patients.

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 feces over 21 days. Radioactive recovery in the urine accounted for 47.5 % (range 33.4 % to 60.2 %) and in the feces 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 feces primarily as unchanged niraparib.

Special populations

Renal impairment

In the population pharmacokinetic analysis of data from clinical studies in patients, pre-existing mild (CLCr < 90 - ≥ 60 ml/min) and moderate (CLCr < 60 - ≥ 30 mL/min) renal impairment did not influence the clearance of niraparib. 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 and moderate hepatic impairment did not influence the clearance of niraparib. The pharmacokinetics of niraparib have not been assessed in patients with severe hepatic impairment (see section 4.2).

Age, weight and race

Population pharmacokinetic analyses indicated that age, weight and race had no significant impact on the pharmacokinetics of niraparib.

Paediatric population

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

5.3 Preclinical safety data

Secondary pharmacology

In vitro, niraparib inhibited the dopamine transporter DAT at concentration levels below human exposure levels. In mice, single doses of niraparib increased intracellular levels of dopamine and metabolites in cortex. Reduced locomotor activity was seen in one of two single dose studies in mice. The clinical relevance of these findings is not known. No effect on behavioural and/or neurological parameters have been observed in repeat-dose toxicity studies in rats and dogs at estimated CNS exposure levels similar to or below expected therapeutic exposure levels.

Repeat-dose toxicity

In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months' duration in rats and dogs. The major primary target organ for toxicity in both species was the bone marrow, with associated changes in peripheral haematology parameters. Additionally, decreased spermatogenesis was seen in both species. These findings occurred at exposure levels below those seen clinically, and were largely reversible within 4 weeks of cessation of dosing.

Genotoxicity

Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test but was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans.

Reproductive toxicology

Reproductive and developmental toxicity studies have not been conducted with niraparib.

Carcinogenicity

Carcinogenicity studies have not been conducted with niraparib.

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)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 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 and other handling

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

7. Marketing authorisation holder

TESARO UK LIMITED

55 Baker Street

London

W1U 7EU

United Kingdom

8. Marketing authorisation number(s)

EU/1/17/1235/001

EU/1/17/1235/002

EU/1/17/1235/003

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 16 November 2017

10. Date of revision of the text

12/2017