ZEJULA 100mg film-coated tablets medication leaflet

Zejula 100 mg hard capsules

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

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

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

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

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

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 inresponse (complete or partial) following completion of first-line platinum-based chemotherapy.

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

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

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/μL, therecommended starting dose of Zejula is 300 mg (three 100-mg capsules), taken once daily (seesection 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. Bedtimeadministration 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 casethat the adverse reaction recurs, it is recommended to interrupt the treatment and then resume at thelower 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 interruptionand reduction, it is recommended that Zejula be discontinued.

Table 1: Recommended dose modifications for adverse reactions

Starting dose level 200 mg 300 mg

First dose reduction 100 mg/day 200 mg/day (two 100-mg capsules)

Second dose reduction Discontinue Zejula. 100 mg/daya (one 100-mg capsule)a If further dose reduction below 100 mg/day is required, discontinue Zejula.

Table 2: Dose modifications for non-haematologic adverse reactions

Non-haematologic CTCAE ≥Grade 3 treatment-related First occurrence:

adverse reaction where prophylaxis is not considered * Withhold Zejula for a maximum offeasible or adverse reaction persists despite treatment 28 days or until resolution ofadverse reaction.

* Resume Zejula at a reduced doselevel per Table 1.

Second occurrence:

* Withhold Zejula for a maximum of28 days or until resolution ofadverse reaction.

* Resume Zejula at a reduced doseor discontinue per Table 1.

CTCAE ≥Grade 3 treatment-related adverse reaction Discontinue treatment.

lasting more than 28 days while patient is administered

Zejula 100 mg/day

CTCAE=Common Terminology Criteria for Adverse Events.

Table 3: Dose modifications for haematologic adverse reactions

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

* For patients with platelet count ≤10,000/μL, platelettransfusion should be considered. If there are other risk

Haematologic adverse reactionfactors for bleeding such as co-administration ofrequiring transfusion oranticoagulation or antiplatelet medicinal products,haematopoietic growth factorconsider interrupting these substances and/orsupporttransfusion at a higher platelet count.

* Resume Zejula at a reduced dose per Table 1.

First occurrence:

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

* Resume Zejula at same or reduced dose per Table 1based on clinical evaluation.

* If platelet count is <75,000/μL at any time, resume at areduced dose per Table 1.

P latelet count <100,000/μL Second occurrence:

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

* Resume Zejula at a reduced dose per Table 1.

* Discontinue Zejula if the platelet count has not returnedto acceptable levels within 28 days of the doseinterruption period, or if the patient has alreadyundergone dose reduction to 100 mg daily.

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

Neutrophil <1,000/µL or * Resume Zejula at a reduced dose per Table 1.

Haemoglobin <8 g/dL * Discontinue Zejula if neutrophils and/or haemoglobinhave not returned to acceptable levels within 28 days ofthe dose interruption period, or if the patient has alreadyundergone dose reduction to 100 mg daily.

Confirmed diagnosis ofmyelodysplastic syndrome (MDS)

* Permanently discontinue Zejula.

or acute myeloid leukaemia(AML)

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 adverse reactions was greateramong low body weight patients (78%) than high body weight patients (53%). Only 13% of low bodyweight patients remained at a dose of 300 mg beyond Cycle 3. A starting dose of 200 mg for patientsweighing less than 58 kg may be considered.

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

No dose adjustment is necessary for patients with mild to moderate renal impairment. There are nodata in patients with severe renal impairment or end stage renal disease undergoing haemodialysis; usewith caution in these patients (see section 5.2).

No dose adjustment is needed in patients with mild hepatic impairment (either aspartateaminotransferase (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 patientswith severe hepatic impairment (any AST and TB >3 x ULN); use with caution in these patients (seesections 4.4 and 5.2).

Patients with an Eastern Cooperative Oncology Group (ECOG) performance status 2 to 4

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

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

Zejula is for oral use. The capsules should be swallowed whole with water. The capsules should not bechewed or crushed.

Zejula capsules can be taken without regard to meals (see section 5.2).

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

Breast-feeding (see section 4.6).

Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) have been reported inpatients treated with Zejula (see section 4.8). Patients with lower body weight or lower baselineplatelet 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 thenext 10 months of treatment and periodically after this time is recommended to monitor for clinicallysignificant changes in any haematologic parameter during treatment (see section 4.2).

If a patient develops severe persistent haematologic toxicity including pancytopenia that does notresolve within 28 days following interruption, Zejula should be discontinued.

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

Myelodysplastic syndrome/acute myeloid leukaemia

Cases of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), including cases with fataloutcome, have been observed in patients treated with Zejula monotherapy or combination therapy inclinical trials and postmarketing (see section 4.8).

In clinical trials, the duration of Zejula treatment in patients prior to developing MDS/AML variedfrom 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 alsoreceived other DNA damaging agents and radiotherapy. Some patients had a history of bone marrowsuppression. In the NOVA trial, the incidence of MDS/AML was higher in the gBRCAmut cohort(7.4%) than in the non-gBRCAmut cohort (1.7%).

For suspected MDS/AML or prolonged haematological toxicities, the patient should be referred to ahaematologist for further evaluation. If MDS/AML is confirmed, Zejula treatment should bediscontinued 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. Bloodpressure should be monitored at least weekly for two months, monitored monthly afterwards for thefirst year and periodically thereafter during treatment with Zejula. Home blood pressure monitoringmay be considered for appropriate patients with instruction to contact their health care provider in caseof rise in blood pressure.

Hypertension should be medically managed with antihypertensive medicinal products as well asadjustment of the Zejula dose (see section 4.2), if necessary. In the clinical programme, blood pressuremeasurements were obtained on Day 1 of each 28-day cycle while the patient remained on Zejula. Inmost cases, hypertension was controlled adequately using standard antihypertensive treatment with orwithout Zejula dose adjustment (see section 4.2). Zejula should be discontinued in case ofhypertensive crisis or if medically significant hypertension cannot be adequately controlled withantihypertensive therapy.

Posterior reversible encephalopathy syndrome (PRES)

There have been reports of PRES in patients receiving Zejula (see section 4.8). PRES is a rare,reversible, neurological disorder which can present with rapidly evolving symptoms includingseizures, headache, altered mental status, visual disturbance, or cortical blindness, with or withoutassociated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferablymagnetic resonance imaging (MRI).

In case of PRES, it is recommended to discontinue Zejula and to treat specific symptoms includinghypertension. The safety of reinitiating Zejula therapy in patients previously experiencing PRES is notknown.

Pregnancy/contraception

Zejula should not be used during pregnancy or in women of childbearing potential not willing to usehighly effective contraception during therapy and for 6 months after receiving the last dose of Zejula(see section 4.6). A pregnancy test should be performed on all women of childbearing potential priorto treatment.

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

Zejula hard capsules contain lactose monohydrate. Patients with rare hereditary problems of galactoseintolerance, total 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.

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, cautionshould be taken if niraparib is used in combination with vaccines, immunosuppressant agents or withother cytotoxic medicinal products.

No clinical drug interaction studies have been performed with niraparib.

Effect of niraparib on other medicinal products

Induction of CYP1A2

In vitro, niraparib induces CYP1A2. Therefore, caution is recommended when niraparib is combinedwith active substances the metabolism of which is CYP1A2-dependent and, notably, those having anarrow therapeutic range (e.g. clozapine, theophylline, and ropinirole).

Inhibition of efflux transporters [P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP)and MATE1/2K)]

In vitro, niraparib is an inhibitor of P-gp. As no clinical data are available, it cannot be excluded thatniraparib may increase the systemic exposure of other medicines transported by P-gp that are sensitiveto intestinal P-gp inhibition (e.g., dabigatran etexilate).

In vitro, niraparib is an inhibitor of BCRP. A clinically relevant interaction with BCRP substratescannot be excluded. Caution is therefore recommended when niraparib is combined with substrates of

BCRP (e.g., irinotecan, rosuvastatin, simvastatin, atorvastatin, and methotrexate) due to risk ofincreased systemic exposure.

Niraparib is an inhibitor of MATE1 and -2K in vitro. Plasma concentrations of metformin mayincrease when concomitantly administered with niraparib. Close monitoring of glycaemia isrecommended when starting or stopping niraparib in patients receiving metformin. A dose adjustmentof metformin may be necessary.

Women of childbearing potential should not become pregnant while on treatment and should not bepregnant at the beginning of treatment. A pregnancy test should be performed on all women ofchildbearing potential prior to treatment.

Women of childbearing potential must use highly effective contraception during therapy and for6 months after receiving the last dose of Zejula.

There are no or limited amount of data from the use of niraparib in pregnant women. Animalreproductive and developmental toxicity studies have not been conducted. However, based on itsmechanism of action, niraparib could cause embryonic or foetal harm, including embryo-lethal andteratogenic effects, when administered to a pregnant woman.

Zejula should not be used during pregnancy.

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 thelast dose (see section 4.3).

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

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

Adverse reactions of all grades occurring in ≥10% of the 851 patients receiving Zejula monotherapy inthe 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) werethrombocytopenia and anaemia.

The following adverse reactions have been identified based on clinical trials and post-marketingsurveillance in patients receiving Zejula monotherapy (see Table 4).

Frequencies of occurrence of undesirable effects are based on pooled adverse events data generatedfrom the PRIMA and NOVA studies (fixed starting dose of 300 mg/day) where patient exposure isknown 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

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

System organ class Frequency of all CTCAE Frequency of CTCAEgrades grade 3 or 4

Infections and infestations Very common Uncommon

Urinary tract infection Urinary tract infection,

Common bronchitis

Bronchitis, conjunctivitis

Neoplasms benign, malignant Common Commonand unspecified (including Myelodysplastic syndrome/ Myelodysplastic syndrome/cysts and polyps) acute myeloid leukaemiaa acute myeloid leukaemiaa

Blood and lymphatic system Very common Very commondisorders Thrombocytopenia, anaemia, Thrombocytopenia, anaemia,neutropenia, leukopenia neutropenia

Uncommon Common

Pancytopenia, febrile Leukopenianeutropenia Uncommon

Pancytopenia, febrileneutropenia

Immune system disorders Common Uncommon

Hypersensitivityb Hypersensitivity

Metabolism and nutrition Very common Commondisorders Decreased appetite Hypokalemia

Common Uncommon

Hypokalemia Decreased appetite

Psychiatric disorders Very common Uncommon

Insomnia Insomnia, anxiety, depression,

Common confusional state

Anxiety, depression,cognitive impairmentc

Uncommon

Confusional state

Nervous system disorders Very common Uncommon

Headache, dizziness Headache

Common

Dysgeusia

Rare

Posterior Reversible

Encephalopathy Syndrome(PRES)a

Cardiac disorders Very common

Palpitations

Common

Vascular disorders Very common Common

Hypertension Hypertension

Rare

Hypertensive crisis

Respiratory, thoracic and Very common Uncommonmediastinal disorders Dyspnoea, cough, Dyspnoea, epistaxis,nasopharyngitis pneumonitis

Common

Epistaxis

Uncommon

Pneumonitis

System organ class Frequency of all CTCAE Frequency of CTCAEgrades grade 3 or 4

Gastrointestinal disorders Very common Common

Nausea, constipation, vomiting, Nausea, vomiting, abdominalabdominal pain, diarrhoea, paindyspepsia Uncommon

Common Diarrhoea, constipation,

Dry mouth, abdominal mucosal inflammation,distension, mucosal stomatitis, dry mouthinflammation, stomatitis

Skin and subcutaneous tissue Common Uncommondisorders Photosensitivity, rash Photosensitivity, rash

Musculoskeletal and Very common Uncommonconnective tissue disorders Back pain, arthralgia Back pain, arthralgia, myalgia

Common

Myalgia

General disorders and Very common Commonadministration site conditions Fatigue, asthenia Fatigue, asthenia

Common

Oedema peripheral

Investigations Common Common

Gamma-glutamyl transferase Gamma-glutamyl transferaseincreased, AST increased, increased, ALT increasedblood creatinine increased, Uncommon

ALT increased, blood alkaline AST increased, blood alkalinephosphatase increased, weight phosphatase increaseddecreased

CTCAE=Common Terminology Criteria for Adverse Events version 4.02.a Based on niraparib clinical trial data. This is not limited to pivotal ENGOT-OV16 monotherapystudy.b Includes hypersensitivity, drug hypersensitivity, anaphylactoid reaction, drug eruption, angioedema,and urticaria.c 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 thegroup administered a fixed starting dose of 300 mg (Table 4).

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

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

In NOVA and PRIMA, patients eligible for Zejula therapy had the following baseline haematologicparameters: absolute neutrophil count (ANC) ≥1,500 cells/µL; platelets ≥100,000 cells/µL andhaemoglobin ≥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 (seesection 4.2).

In PRIMA, patients who were administered a starting dose of Zejula based on baseline weight orplatelet 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 doseof 300 mg. Discontinuation due to thrombocytopenia, anaemia, and neutropenia occurred in 3%, 3%,and 2% of patients, respectively.

In PRIMA, 39% of Zejula-treated patients experienced Grade 3/4 thrombocytopenia compared to0.4% 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 tothrombocytopenia occurred in 4% of patients receiving niraparib.

In NOVA, approximately 60% of patients experienced thrombocytopenia of any grade, and 34% ofpatients experienced Grade 3/4 thrombocytopenia. In patients with baseline platelet count less than180 × 109/L, thrombocytopenia of any grade and Grade 3/4 occurred in 76% and 45% of patients,respectively. The median time to onset of thrombocytopenia regardless of grade and Grade 3/4thrombocytopenia was 22 and 23 days, respectively. The rate of new incidences of thrombocytopeniaafter 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, andthe median duration of Grade 3/4 thrombocytopenia was 10 days. Patients treated with Zejula whodevelop thrombocytopenia might have an increased risk of haemorrhage. In the clinical programme,thrombocytopenia was managed with laboratory monitoring, dose modification and platelettransfusion where appropriate (see section 4.2). Discontinuation due to thrombocytopenia events(thrombocytopenia and platelet count decreased) occurred in approximately 3% of patients.

In NOVA, 13% (48/367) of patients experienced bleeding with concurrent thrombocytopenia; allbleeding events concurrent with thrombocytopenia were Grade 1 or 2 in severity except for one eventof Grade 3 petechiae and haematoma observed concurrently with a serious adverse reaction ofpancytopenia. Thrombocytopenia occurred more commonly in patients whose baseline platelet countwas 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 patientsexperienced Grade 3/4 thrombocytopenia. Pancytopenia has been observed in <1% of patientsreceiving niraparib.

In PRIMA, 31% of Zejula-treated patients experienced Grade 3/4 anaemia compared to 2% ofplacebo-treated patients with a median time from first dose to first onset of 80 days (range: 15 to533 days) and with a median duration of 7 days (range: 1 to 119 days). Discontinuation due toanaemia 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 3/4events. 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 whereappropriate with red blood cell transfusions. Discontinuation due to anaemia occurred in 1% ofpatients.

In PRIMA, 21% of Zejula-treated patients experienced Grade 3/4 neutropenia compared to 1% ofplacebo-treated patients with a median time from first dose to first onset of 29 days (range: 15 to421 days) and with a median duration of 8 days (range: 1 to 42 days). Discontinuation due toneutropenia occurred in 2% of patients receiving niraparib.

In NOVA, approximately 30% of patients experienced neutropenia of any grade, and 20% of patientsexperienced Grade 3/4 neutropenia. The median time to onset of neutropenia of any grade was27 days, and 29 days for Grade 3/4 events. The median duration of neutropenia of any grade was26 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 concomitanttherapy for neutropenia. Discontinuation due to neutropenia events occurred in 2% of patients.

Myelodysplastic syndrome/Acute myeloid leukaemia

In clinical studies, MDS/AML occurred in 1% patients treated with Zejula, with 41% of cases having afatal outcome. The incidence was higher in patients with relapsed ovarian cancer who had received2 or more lines of prior platinum chemotherapy and with gBRCAmut following 75 months survivalfollow-up. All patients had potential contributing factors for the development of MDS/AML, havingreceived previous chemotherapy with platinum agents. Many had also received other DNA damagingagents and radiotherapy. The majority of reports were in gBRCAmut carriers. Some patients had ahistory of previous cancer or of bone marrow suppression.

In PRIMA, the incidence of MDS/AML was 2.3% in patients receiving Zejula and 1.6% in patientsreceiving placebo with a follow-up of 74 months.

In NOVA, in patients with relapsed ovarian cancer who had received at least two prior lines ofplatinum chemotherapy, the overall incidence of MDS/AML was 3.8% in patients receiving Zejulaand 1.7% in patients receiving placebo with a follow-up of 75 months. In gBRCAmut and non-gBRCAmut cohorts, the incidence of MDS/AML was 7.4% and 1.7% in patients receiving Zejula and3.1% and 0.9% in patients receiving placebo, respectively.

In PRIMA, Grade 3/4 hypertension occurred in 6% of Zejula-treated patients compared to 1% ofplacebo-treated patients with a median time from first dose to first onset of 50 days (range: 1 to589 days) and with a median duration of 12 days (range: 1 to 61 days). No patients discontinued

Zejula due to hypertension.

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

No studies have been conducted in paediatric patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment in the event of overdose with Zejula, and symptoms of overdose are notestablished. In the event of an overdose, physicians should follow general supportive measures andshould treat symptomatically.

Pharmacotherapeutic group: antineoplastic agents, 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 mayinvolve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexesresulting in DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity wasobserved in tumour cell lines with or without deficiencies in the BReast CAncer (BRCA) 1 and 2tumour suppressor genes. In orthotopic high-grade serous ovarian cancer patient-derived xenografttumours (PDX) grown in mice, niraparib has been shown to reduce tumour growth in BRCA 1 and 2mutant, BRCA wild-type but homologous recombination (HR) deficient, and in tumours that are BRCAwild-type and without detectable HR deficiency.

First-line ovarian cancer maintenance treatment

PRIMA was a Phase 3 double-blind, placebo-controlled trial in which patients (n = 733) in completeor partial response to first-line platinum-based chemotherapy were randomised 2:1 to niraparib ormatched placebo. PRIMA was initiated with a starting dose of 300 mg daily in 475 patients (whereof317 was randomised to the niraparib arm vs 158 in the placebo arm) in continuous 28-day cycles. Thestarting 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/µL wereadministered niraparib 300 mg (n = 34) or placebo daily (n = 21) while patients with a baseline bodyweight <77 kg or baseline platelet count <150,000/μL were administered niraparib 200 mg (n = 122)or placebo daily (n = 61).

Patients were randomised post completion of first-line platinum-based chemotherapy plus or minussurgery. Subjects were randomised 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 surgerysubjects had ≥2 post-operative cycles of platinum-based therapy. Patients who had receivedbevacizumab with chemotherapy but could not receive bevacizumab as maintenance therapy were notexcluded from the study. Patients could not have received prior PARP inhibitor (PARPi) therapy,including niraparib. Patients who had neoadjuvant chemotherapy followed by interval debulkingsurgery could have visible residual or no residual disease. Patients with Stage III disease who hadcomplete cytoreduction (i.e., no visible residual disease) after primary debulking surgery wereexcluded. Randomisation was stratified by best response during the front-line platinum regimen(complete response vs partial response), neoadjuvant chemotherapy (NACT) (Yes vs No); andhomologous 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 tissueobtained 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 niraparib 200 or 300 mg or matched placeboadministered daily 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 independentcentral review (BICR) per RECIST, version 1.1. PFS testing was performed hierarchically: first in the

HR-deficient population, then in the overall population. Secondary efficacy endpoints included PFSafter the first subsequent therapy (PFS2) and overall survival (OS) (Table 5). The median age was62 years among patients randomised to niraparib (range 32 to 85 years) or placebo (range 33 to 88years). Eighty-nine percent of all patients were white. Sixty-nine percent of patients randomised toniraparib and 71% of patients randomised to placebo had an ECOG of 0 at study baseline. In theoverall population, 65% of patients had stage III disease and 35% had stage IV disease. In the overallpopulation, the primary tumour site in most patients (≥80%) was the ovary; most patients (>90%) hadtumours with serous histology. Sixty-seven percent of patients received NACT. Sixty-nine percent ofpatients had a complete response to the first-line platinum-based chemotherapy. A total of 6 patients inthe Zejula group had received bevacizumab as prior treatment for their ovarian cancer.

PRIMA demonstrated a statistically significant improvement in PFS for patients randomised toniraparib as compared with placebo in the HR-deficient and overall population (Table 5, and Figures 1and 2). Efficacy results for the final analysis of OS data are presented in Table 5.

Table 5: Efficacy results - PRIMA

HR-deficient population Overall population

Zejula Placebo Zejula Placebo(N = 247) (N = 126) (N = 487) (N = 246)

Primary endpoint(determined by BICR)

PFS median, months 21.9 10.4 13.8 8.2(95% CI) (19.3, NE) (8.1, 12.1) (11.5, 14.9) (7.3, 8.5)

Hazard ratio 0.43 0.62(95% CI) (0.31, 0.59) (0.50, 0.76)p-value <0.0001 <0.0001

Secondary endpointsa, b, c

PFS2 median, months 43.4 39.3 30.1 27.6(95% CI) (37.2, 54.1) (30.3, 55.7) (27.1, 33.1) (24.2, 33.1)

Hazard ratio 0.87 0.96(95% CI) (0.66, 1.17) (0.79, 1.17)

OS median, monthsd 71.9 69.8 46.6 48.8(95% CI) (55.5, NE) (51.6, NE) (43.7, 52.8) (43.1, 61.0)

Hazard ratio 0.95 1.01(95% CI) (0.70, 1.29) (0.84, 1.23)

PFS = progression-free survival; CI = confidence interval; NE = not evaluable; PFS2 = PFS after thefirst subsequent therapy; OS = overall survival.a Data based on final analysis.b In the HR-deficient population and overall population, 15.8% and 11.7% of patients in the Zejulaarm received subsequent PARPi therapy, respectively.c In the HR-deficient population and overall population, 48.4% and 37.8% of placebo patientsreceived subsequent PARPi therapy, respectively.d The maturity of OS data for the HR-deficient population and overall population was 49.6% and62.5%, respectively.

Figure 1: Progression-free survival in the HR-deficient population - PRIMA (ITT)

Censored Observations

Zejula Placebo

HR (95% CI) 0.43 (0.310,0.588)

Zejula

Placebo

Time since Randomization (Months)

Estimated Survival Function (%)

Figure 2: Progression-free survival in the overall population - PRIMA (ITT)

Censored Observations

Zejula Placebo

HR (95% CI) 0.62 (0.502,0.755)

Zejula

Placebo

Time since Randomization (Months)

PFS subgroup analyses

Within the HR-deficient population, a PFS hazard ratio of 0.40 (95% CI: 0.27, 0.62) was observed inthe subgroup of patients with BRCA mutation 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) wasobserved.

The median PFS in the HR-proficient population (n = 249) was 8.1 months for patients randomised to

Zejula compared with 5.4 months for placebo with a hazard ratio of 0.68 (95% CI: 0.49, 0.94).

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

OS subgroup analyses

In the subgroup of HR-deficient patients with BRCA mutation ovarian cancer (n = 223), an OS hazardratio of 0.94 (95% CI: 0.63, 1.41) was observed. In the subgroup of HR-deficient patients without a

BRCA mutation (n = 149), a hazard ratio of 0.97 (95% CI: 0.62, 1.53) was observed.

The median OS in the HR-proficient population (n = 249) was 36.6 months for patients randomised to

Zejula compared with 32.2 months for placebo, with a hazard ratio of 0.93 (95% CI: 0.69, 1.26).

Estimated Survival Function (%)

Platinum-sensitive recurrent ovarian cancer maintenance treatment

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 predominantlyhigh grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who were platinumsensitive, defined by complete response (CR) or partial response (PR) for more than six months totheir penultimate (next to last) platinum-based therapy. To be eligible for niraparib treatment, thepatient 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 theirlast platinum treatment and be stable for at least 7 days. Patients could not have received prior PARPitherapy, including Zejula. Eligible patients were assigned to one of two cohorts based on the results ofa germline BRCA (gBRCA) mutation test. Within each cohort, patients were randomised using a 2:1allocation of niraparib and placebo. Patients were assigned to the gBRCAmut cohort based on bloodsamples for gBRCA analysis that were taken prior to randomisation. Testing for tumour BRCA(tBRCA) mutation and HRD was performed using the HRD test on tumour tissue obtained at the timeof initial diagnosis or at the time of recurrence.

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

Patients began treatment on Cycle 1/Day 1 (C1/D1) with niraparib 300 mg or matched placeboadministered daily 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% ofpatients 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 (PFS) 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 fromthe time of randomisation (which occurred up to 8 weeks after completion of the chemotherapyregimen) to disease progression or death.

The primary efficacy analysis for PFS was determined by blinded central independent assessment andwas prospectively defined and assessed for the gBRCAmut cohort and the non-gBRCAmut cohortseparately. Overall survival (OS) analyses were secondary outcome measures.

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

Demographics, baseline disease characteristics, and prior treatment history were generally wellbalanced between the niraparib and placebo arms in the gBRCAmut (n = 203) and the non-gBRCAmutcohorts (n = 350). Median ages ranged from 57 to 63 years across treatments and cohorts. The primarytumour site in most patients (>80%) within each cohort was the ovary; most patients (>84%) hadtumours with serous histology. A high proportion of patients in both treatment arms in both cohortshad received 3 or more prior lines of chemotherapy, including 49% and 34% of niraparib patients inthe 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 thanthe placebo arm (14 and 7 cycles, respectively). More patients in the niraparib group continuedtreatment 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 theniraparib arm than in the placebo arm (8 and 5 cycles, respectively). More patients in the niraparibgroup continued treatment for more than 12 months than patients in the placebo group (34.2% and21.1%, respectively).

The study met its primary objective of statistically significantly improved PFS for niraparibmaintenance monotherapy compared with placebo in the gBRCAmut cohort as well as in the overallnon-gBRCAmut cohort. Table 6 and Figures 3 and 4 show the results for the PFS primary endpoint forthe primary efficacy populations (gBRCAmut cohort and the overall non-gBRCAmut cohort).

Table 6: Summary of primary objective outcomes in the NOVA studygBRCAmut cohort Non-gBRCAmut cohort

Zejula Placebo Zejula Placebo(N = 138) (N = 65) (N = 234) (N = 116)

PFS median 21.0 5.5 9.3 3.9(95% CI) (12.9, NE) (3.8, 7.2) (7.2, 11.2) (3.7, 5.5)p-value <0.0001 <0.0001

Hazard ratio 0.27 0.45(Zejula:placebo) (0.173, 0.410) (0.338, 0.607)(95% CI)

PFS = progression-free survival; CI = confidence interval; NE = not evaluable.

Figure 3: Progression-free survival in the gBRCAmut cohort based on IRC assessment -

NOVA (ITT)

A: Zejula B: Placebo

HR (95% CI) 0.27 (0.173,0.410)

Time since Randomization (Months)

Estimated Survival Function

Figure 4: Progression-free survival in the non-gBRCAmut cohort /overall based on IRCassessment - NOVA (ITT)

A: Zejula B: Placebo

HR (95% CI) 0.45 (0.338,0.607)

Time since Randomization (Months)

Secondary efficacy endpoints in NOVA

At the final analysis, the median PFS2 in the gBRCAmut cohort was 29.9 months for patients treatedwith niraparib compared to 22.7 months for patients on placebo (HR = 0.70; 95% CI: 0.50, 0.97). Themedian PFS2 in the non-gBRCAmut cohort was 19.5 months for patients treated with niraparibcompared to 16.1 months for patients on placebo (HR = 0.80; 95% CI: 0.63, 1.02).

At the final analysis of overall survival, the median OS in the gBRCAmut cohort (n = 203) was40.9 months for patients treated with niraparib compared with 38.1 months for patients on placebo(HR = 0.85; 95% CI: 0.61, 1.20). The cohort maturity for the gBRCAmut cohort was 76%. The median

OS in the non-gBRCAmut cohort (n = 350) was 31.0 months for patients treated with niraparibcompared with 34.8 months for patients on placebo (HR = 1.06; 95% CI: 0.81, 1.37). The cohortmaturity for the non-gBRCAmut cohort was 79%.

Patient-reported outcomes

Patient-reported outcome 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).

The European Medicines Agency has waived the obligation to submit the results of studies with Zejulain all subsets of the paediatric population in ovarian carcinoma, excluding rhabdomyosarcoma andgerm cell tumours (see section 4.2 for information on paediatric use).

Following a single-dose administration of 300 mg niraparib, niraparib was measurable in plasmawithin 30 minutes and the mean peak plasma concentration (Cmax) for niraparib was reached within3 to 5 hours (ranged 508-875 ng/mL across studies). Following multiple oral doses of niraparib from30 mg to 400 mg once daily, accumulation of niraparib was approximately 2 to 3 folds.

Estimated Survival Function

The systemic exposures (Cmax and AUC) to niraparib increased in a dose-proportional manner whenthe dose of niraparib increased from 30 mg to 400 mg. The absolute bioavailability of niraparib isapproximately 73%, indicating minimal first pass effect. In a population pharmacokinetic analysis ofniraparib, the inter-individual variability in bioavailability was estimated to a coefficient of variation(CV) of 33.8%.

A concomitant high-fat meal did not significantly affect the pharmacokinetics of niraparib afteradministration of 300 mg of niraparib capsule (Cmax decreased by 22% and AUCinf increased by 10%compared with fasting conditions; see section 4.2).

The tablet and capsule formulations have been demonstrated to be bioequivalent. Followingadministration of either one 300 mg tablet or three 100 mg capsules of niraparib in 108 patients withsolid tumours under fasting conditions, the 90% confidence intervals of the geometric mean ratios fortablet compared to capsules for Cmax, AUClast and AUC∞ fell within the limits of bioequivalence(0.80 and 1.25).

Niraparib was moderately protein bound in human plasma (83%), mainly with serum albumin. In apopulation pharmacokinetic analysis of niraparib, the apparent volume of distribution (Vd/F) was1,206 L (based on a 70 kg patient) in cancer patients (CV 18.4%), indicating extensive tissuedistribution of niraparib.

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 majorcirculating metabolites.

Following a single oral 300-mg dose of niraparib, the mean terminal half-life (t½) of niraparib rangedfrom 44 to 54 hours (approximately 2 days) across studies. In a population pharmacokinetic analysis,the apparent total clearance (CL/F) of niraparib was 15.9 L/h in cancer patients (CV 24.0%).

Niraparib is eliminated primarily through the hepatobiliary and renal routes. Following an oraladministration of a single 300-mg dose of [14C]-niraparib, on average 86.2% (range 71% to 91%) ofthe dose was recovered in urine and faeces over 21 days. Radioactive recovery in the urine accountedfor 47.5% (range 33.4% to 60.2%) and in the faeces for 38.8% (range 28.3% to 47%) of the dose. Inpooled samples collected over 6 days, 40% of the dose was recovered in the urine primarily asmetabolites and 31.6% of the dose was recovered in the faeces primarily as unchanged niraparib.

Niraparib is an inducer of CYP1A2 in vitro (see section 4.5).

Niraparib is a substrate of P-gp and BCRP. However, due to niraparib’s high permeability andbioavailability, the risk of clinically relevant interactions with medicinal products that inhibit thesetransporters is unlikely.

Niraparib is an inhibitor of P-gp, BCRP, MATE1/2K and organic cation transporter 1 (OCT1) in vitro(see section 4.5).

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 toindividuals with normal renal function. The difference in exposure is not considered to warrant doseadjustment. No patients with pre-existing severe renal impairment or end-stage renal diseaseundergoing hemodialysis were identified in clinical studies (see section 4.2).

In the population pharmacokinetic analysis of data from clinical studies in patients, pre-existing mildhepatic impairment (n = 155) did not influence the clearance of niraparib. In a clinical study of cancerpatients using NCI-ODWG criteria to classify the degree of hepatic impairment, niraparib AUCinf inpatients with moderate hepatic impairment (n = 8) was 1.56 (90% CI: 1.06, 2.30) times the niraparib

AUCinf in patients with normal hepatic function (n = 9) following administration of a single 300 mgdose. Niraparib dose adjustment is recommended for patients with moderate hepatic impairment (seesection 4.2). Moderate hepatic impairment did not have an effect on niraparib Cmax or on niraparibprotein binding. The pharmacokinetics of niraparib have not been assessed in patients with severehepatic impairment (see sections 4.2 and 4.4).

Weight, age and race

Increasing weight was found to increase niraparib volume of distribution in the populationpharmacokinetic analysis. No impact of weight was identified on niraparib clearance or overallexposure.

Age (range 26 to 91 years) was not a significant factor on niraparib clearance or volume of distributionin the population pharmacokinetic analysis.

There are insufficient data across races to conclude on the impact of race on niraparibpharmacokinetics.

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

Safety pharmacology

In vitro, niraparib inhibited the dopamine transporter DAT at concentration levels below humanexposure levels. In mice, single doses of niraparib increased intracellular levels of dopamine andmetabolites 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 neurologicalparameters have been observed in repeat-dose toxicity studies in rats and dogs at estimated CNSexposure levels similar to or below expected therapeutic exposure levels.

Decreased spermatogenesis was observed in rats and dogs at exposure levels below those seenclinically and was largely reversible within 4 weeks of cessation of dosing.

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

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

Carcinogenicity studies have not been conducted with niraparib.

Magnesium stearate

Lactose monohydrate

Titanium dioxide (E 171)

Gelatin

Brilliant blue FCF (E 133)

Erythrosine (E 127)

Tartrazine (E 102)

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)

Not applicable.

3 years.

Do not store above 30°C.

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

Not all pack sizes may be marketed.

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

GlaxoSmithKline Trading Services Limited12 Riverwalk

Citywest Business Campus

Dublin 24

Ireland

D24 YK11

EU/1/17/1235/001

EU/1/17/1235/002

EU/1/17/1235/003

Date of first authorisation: 16 November 2017

Date of latest renewal: 18 July 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.