Zejula

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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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. 
 



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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.  



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Table 2: Dose modifications for haematologic adverse reactions 
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. 



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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 at least weekly for two months, monitored monthly afterwards for the first year and 
periodically thereafter during treatment with Zejula. Home blood pressure monitoring may be 



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considered for appropriate patients with instruction to contact their health care provider in case of rise 
in blood pressure. 
 
Hypertension should be medically managed with antihypertensive medicinal products as well as 
adjustment of the Zejula dose (see section 4.2), if necessary. In the clinical programme, blood pressure 
measurements were obtained on Day 1 of each 28-day cycle while the patient remained on Zejula. In 
most cases, hypertension was controlled adequately using standard antihypertensive treatment with or 
without Zejula dose adjustment (see section 4.2). Zejula should be discontinued in case of 
hypertensive crisis or if medically significant hypertension cannot be adequately controlled with 
antihypertensive therapy. 
 
Posterior Reversible Encephalopathy Syndrome (PRES) 
 
There have been reports of Posterior Reversible Encephalopathy Syndrome (PRES) in patients 
receiving Zejula (see section 4.8). PRES is a rare, reversible, neurological disorder which can present 
with rapidly evolving symptoms including seizures, headache, altered mental status, visual 
disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES 
requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). 
 
In case of PRES, it is recommended to discontinue Zejula and to treat specific symptoms including 
hypertension. The safety of reinitiating Zejula therapy in patients previously experiencing PRES is not 
known. 
 
Pregnancy/contraception 
 
Zejula should not be used during pregnancy or in women of childbearing potential not willing to use 
reliable contraception during therapy and for 1 month after receiving the last dose of Zejula (see 
section 4.6). A pregnancy test should be performed on all women of childbearing potential prior to 
treatment. 
 
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 



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administered concomitantly with medicinal products known to inhibit (e.g. itraconazole, ritonavir, and 
clarithromycin) or induce CYP enzymes (e.g. rifampin, carbamazepine, and phenytoin). 
 
Niraparib as a substrate of efflux transporters (P-gp, BCRP, BSEP, MRP2, and MATE1/2) 
Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). 
However, due to its high permeability and bioavailability, the risk of clinically relevant interactions 
with medicinal products that inhibit these transporters is unlikely. Therefore, no dose adjustment for 
Zejula is required when administered concomitantly with medicinal products known to inhibit P-gp 
(e.g. amiodarone, verapamil) or BCRP (e.g. osimertinib, velpatasvir, and eltrombopag). 
 
Niraparib is not a substrate of bile salt export pump (BSEP), or multidrug resistance-associated protein 
2 (MRP2). The major primary metabolite M1 is not a substrate of P-gp, BCRP, BSEP, or MRP2. 
Niraparib is not a substrate of multidrug and toxin extrusion (MATE)-1 or 2, while M1 is a substrate 
of both. 
 
Niraparib as a substrate of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1) 
Neither niraparib nor M1 is a substrate of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 
(OATP1B3), or organic cation transporter 1 (OCT1). No dose adjustment for Zejula is required when 
administered concomitantly with medicinal products known to inhibit OATP1B1 or 1B3 (e.g. 
gemfibrozil, ritonavir), or OCT1 (e.g. dolutegravir) uptake transporters. 
 
Niraparib as a substrate of renal uptake transporters (OAT1, OAT3, and OCT2) 
Neither niraparib nor M1 is a substrate of organic anion transporter 1 (OAT1), 3 (OAT3), and organic 
cation transporter 2 (OCT2). No dose adjustment for Zejula is required when administered 
concomitantly with medicinal products known to inhibit OAT1 (e.g. probenecid) or OAT3 (e.g. 
probenecid, diclofenac), or OCT2 (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). 
 
Inhibition of UDP-glucuronosyltransferases (UGTs)  
Niraparib did not exhibit inhibitory effect against the UGT isoforms (UGT1A1, UGT1A4, UGT1A9, 
and UGT2B7) up to 200 µM in vitro. Therefore, the potential for a clinically relevant inhibition of 
UGTs by niraparib is minimal. 
 
Induction of CYPs (CYP1A2 and CYP3A4) 
Neither niraparib nor M1 is a CYP3A4 inducer in vitro. In vitro, niraparib weakly induces CYP1A2 at 
high concentrations and the clinical relevance of this effect 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, MRP2, and MATE1/2) 
Niraparib is not an inhibitor of BSEP or MRP2. In vitro, niraparib inhibits P-gp very weakly and 
BCRP with an IC50 = 161 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). 



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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, MRP2 or 
MATE1/2. 
 
Inhibition of hepatic uptake transporters (OATP1B1, OATP1B3, and OCT1) 
Neither niraparib nor M1 is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1) or 
1B3 (OATP1B3). 
 
In vitro, niraparib weakly inhibits the organic cation transporter 1 (OCT1) with an IC50 = 34.4 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 



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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); and 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, febrile 
neutropenia 

Very common 
Thrombocytopenia, anaemia, 
neutropenia 
Common 
Leukopenia 
Uncommon 
Pancytopenia, febrile 
neutropenia 

Immune system disorders Common 
Hypersensitivity† 

Uncommon 
Hypersensitivity 

Metabolism and nutrition 
disorders 

Very common 
Decreased appetite 
Common 
Hypokalemia 

Common 
Hypokalemia 
Uncommon 
Decreased appetite 

Psychiatric disorders Very common 
Insomnia 
Common 
Anxiety, depression 
Uncommon 
Confusional state 

Uncommon 
Insomnia, anxiety, depression, 
confusional state 

Nervous system disorders Very common 
Headache, dizziness, dysgeusia 
Rare 
Posterior Reversible 
Encephalopathy Syndrome 
(PRES)** 

Uncommon 
Headache 

Cardiac disorders Very common 
Palpitations 

 



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System Organ Class Frequency of all CTCAE 
grades 

Frequency of CTCAE 
grade 3 or 4 

Common 
Tachycardia 

Vascular disorders Very common 
Hypertension 
Rare 
Hypertensive crisis 

Common 
Hypertension 

Respiratory, thoracic and 
mediastinal disorders 

Very common 
Dyspnea, cough, 
nasopharyngitis 
Common 
Epistaxis  
Uncommon 
Pneumonitis 

Common 
Dyspnea  
Uncommon 
Pneumonitis 

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. 
** Based on niraparib clinical trial data. This is not limited to pivotal ENGOT-OV16 monotherapy 
study. 
† Includes hypersensitivity, drug hypersensitivity, anaphylactoid reaction, drug eruption, angioedema, 
and urticaria. 
 
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 



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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 the national reporting system 
listed in Appendix V. 
 
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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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 



13 

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 
(12.9, NR) 

5.5 
(3.8, 7.2) 

9.3 
(7.2, 11.2) 

3.9 
(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 



14 

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* 

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

Es
tim

at
ed

 S
ur

vi
va

l F
un

ct
io

n

0

25

50

75

100

Time since Randomization (Months)

0 2 4 6 8 10 12 14 16 18 20 22 24

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

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

Es
tim

at
ed

 S
ur

vi
va

l F
un

ct
io

n

0

25

50

75

100

Time since Randomization (Months)

0 2 4 6 8 10 12 14 16 18 20 22 24

Treatment

       A: Niraparib B: Placebo

138 125 107 98 89 79 63 44 28 26 16 3 1

65 52 34 21 12 8 6 2 2 2 1 1 0

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

Es
tim

at
ed

 S
ur

vi
va

l F
un

ct
io

n

0

25

50

75

100

Time since Randomization (Months)

0 2 4 6 8 10 12 14 16 18 20 22 24

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

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

Es
tim

at
ed

 S
ur

vi
va

l F
un

ct
io

n

0

25

50

75

100

Time since Randomization (Months)

0 2 4 6 8 10 12 14 16 18 20 22 24

Treatment

       A: Niraparib B: Placebo

234 188 145 113 88 75 57 41 23 21 16 7 3

116 88 52 33 23 19 10 8 4 4 3 1 1



15 

 gBRCAmut non-gBRCAmut 
 Zejula Placebo Zejula Placebo 
Endpoint N = 138 N = 65 N = 234 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 
 



16 

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 
 
Safety 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 
 
Decreased spermatogenesis was observed in rats and dogs at exposure levels below those seen 



17 

clinically and was 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 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30 °C. 
 
6.5 Nature and contents of container 
 
Aclar/PVC/aluminium foil perforated unit dose blisters in cartons of 84 × 1, 56 × 1 and 28 × 1 hard 
capsules. 



18 

 
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 
 
GlaxoSmithKline (Ireland) Limited 
12 Riverwalk 
Citywest Business Campus 
Dublin 24 
Ireland  
 
 
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 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

  

http://www.ema.europa.eu/


19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 



20 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Manufacturing Packaging Farmaca (MPF) B.V. 
Appelhof 13 
8465 RX Oudehaske 
Netherlands 
 
TESARO Bio Netherlands B.V. 
Joop Geesinkweg 901 
1114 AB Amsterdam-Duivendrecht 
Netherlands 
 
GlaxoSmithKline Trading Services Ltd. 
12 Riverwalk 
Citywest Business Campus 
Dublin 24 
Ireland 
 
Glaxo Operations UK Limited 
(trading as Glaxo Wellcome Operations) 
Harmire Road 
Barnard Castle 
Durham 
DL12 8DT 
United Kingdom 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.  
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 
months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 



21 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zejula 100 mg hard capsules 
niraparib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains niraparib tosylate monohydrate equivalent to 100 mg of niraparib. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose and tartrazine (E 102). See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Hard capsule 
84 × 1 hard capsules 
56 × 1 hard capsules 
28 × 1 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 °C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 



25 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited 
12 Riverwalk 
Citywest Business Campus 
Dublin 24 
Ireland  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1235/001 
EU/1/17/1235/002 
EU/1/17/1235/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ZEJULA 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



26 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zejula 100 mg capsules 
niraparib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



28 

Package leaflet: Information for the patient 
 

Zejula 100 mg hard capsules 
niraparib 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Zejula is and what it is used for 
2. What you need to know before you take Zejula  
3. How to take Zejula 
4. Possible side effects 
5. How to store Zejula 
6. Contents of the pack and other information 
 
 
1. What Zejula is and what it is used for 
 
What Zejula is and how it works 
Zejula contains the active substance niraparib. Niraparib is a type of anti-cancer medicine called a 
PARP inhibitor. PARP inhibitors block an enzyme called poly [adenosine diphosphate-ribose] 
polymerase (PARP). PARP helps cells repair damaged DNA so blocking it means that the DNA of 
cancer cells cannot be repaired. This results in tumour cell death, helping to control the cancer. 
 
What Zejula is used for 
Zejula is used in adult women for the treatment of cancer of the ovary, the fallopian tubes (part of the 
female reproductive system that connects the ovaries to the uterus), or the peritoneum (the membrane 
lining the abdomen). It is used after the cancer has responded to previous treatment with standard 
platinum-based chemotherapy. 
 
 
2. What you need to know before you take Zejula 
 
Do not take Zejula 
• if you are allergic to niraparib or any of the other ingredients of this medicine (listed in 

section 6). 
• if you are breast-feeding. 
 
Warnings and precautions 
Talk to your doctor, pharmacist or nurse before or while taking this medicine if any of the following 
could apply to you: 
 
Low blood-cell counts 
Zejula lowers your blood-cell counts, such as your red blood-cell count (anaemia), white blood-cell 
count (neutropenia), or blood-platelet count (thrombocytopenia). Signs and symptoms you need to 



29 

look out for include fever or infection, and abnormal bruising or bleeding (see section 4 for more 
information). Your doctor will test your blood regularly throughout your treatment. 
 
Myelodysplastic syndrome/acute myeloid leukaemia 
Rarely, low blood-cell counts may be a sign of more serious problems with the bone marrow such as 
‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukaemia’ (AML). Your doctor may want to 
test your bone marrow to check for these problems. 
 
High blood pressure 
Zejula can cause high blood pressure, which in some cases, could be severe. Your doctor will measure 
your blood pressure regularly throughout your treatment. He or she may also give you medicine to 
treat high blood pressure and adjust your Zejula dose, if necessary. Your doctor may advise home 
blood pressure monitoring and instruction on when to contact him or her in case of a rise in blood 
pressure. 
 
Posterior Reversible Encephalopathy Syndrome (PRES) 
A rare neurological side effect named Posterior Reversible Encephalopathy Syndrome (PRES) has 
been associated with Zejula treatment. If you have headache, vision changes, confusion or seizure with 
or without high blood pressure, please contact your doctor. 
 
Children and adolescents 
Children under 18 years of age should not be given Zejula. This medicine has not been studied in this 
age group. 
 
Other medicines and Zejula 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Pregnancy 
Zejula should not be taken during pregnancy as it could harm your baby. If you are pregnant, think 
you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this 
medicine. 
 
If you are a woman who could become pregnant you must use reliable contraception while you are 
taking Zejula, and you must continue to use reliable contraception for 1 month after taking your last 
dose. Your doctor will ask you to confirm that you are not pregnant with a pregnancy test before 
starting your treatment. Contact your doctor straightaway if you become pregnant while you are taking 
Zejula. 
 
Breast-feeding 
Zejula should not be taken if you are breast-feeding as it is not known if it passes into breast milk. If 
you are breast-feeding, you must stop before you start taking Zejula and you must not begin 
breast-feeding again until 1 month after taking your last dose. Ask your doctor for advice before 
taking this medicine. 
 
Driving and using machines 
When you are taking Zejula it may make you feel weak, tired or dizzy and therefore influence your 
ability to drive and use machines. Observe caution when driving or using machines. 
 
Zejula contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 
Zejula contains tartrazine (E 102) 
It may cause allergic reactions. 
 
 



30 

3. How to take Zejula 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
The recommended starting dose is 3 capsules taken together once a day (total daily dose of 300 mg), 
with or without food. Take Zejula at approximately the same time each day. Taking Zejula at bedtime 
may help you to manage nausea. 
 
Swallow the capsules whole, with some water. Do not chew or crush the capsules. 
 
Your doctor may recommend a lower dose if you experience side effects (such as nausea, tiredness, 
abnormal bleeding/bruising, anaemia). 
 
Your doctor will check you on a regular basis, and you will normally continue to take Zejula as long 
as you experience benefit, and do not suffer unacceptable side effects. 
 
If you take more Zejula than you should 
If you take more than your normal dose, contact your doctor immediately. 
 
If you forget to take Zejula 
Do not take an additional dose if you miss a dose or vomit after taking Zejula. Take your next dose at 
its scheduled time. Do not take a double dose to make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor straight away if you notice any of the following SERIOUS side effects - you may 
need urgent medical treatment: 
 
Very common (may affect more than 1 in 10 people) 
• Bruising or bleeding for longer than usual if you hurt yourself -- these may be signs of a low 

blood platelet count (thrombocytopenia). 
• Being short of breath, feeling very tired, having pale skin, or fast heartbeat -- these may be signs 

of a low red blood cell count (anaemia). 
• Fever or infection – low white blood cell count (neutropenia) can increase your risk for 

infection. Signs may include fever, chills, feeling weak or confused, cough, pain or burning 
feeling when passing urine. Some infections can be serious and may lead to death. 

 
Common (may affect up to 1 in 10 people) 
•  Reduction in the number of white cells in the blood (leukopenia) 
• Allergic reaction (including severe allergic reaction that can be life-threatening). Signs include 

raised and itchy rash (hives) and swelling—sometimes of the face or mouth (angioedema), 
causing difficulty in breathing, and collapse or loss of consciousness. 

 
Rare (may affect up to 1 in 1000 people) 
• A sudden increase in blood pressure, which may be a medical emergency that could lead to 

organ damage or can be life-threatening. 
• A brain condition with symptoms including seizures (fits), headache, confusion, and changes in 

vision (Posterior Reversible Encephalopathy Syndrome or PRES), which is a medical 
emergency that could lead to organ damage or can be life-threatening. 

 
Talk to your doctor if you get any other side effects. These can include: 



31 

 
Very common (may affect more than 1 in 10 people) 
• Feeling sick 
• Feeling tired 
• Feeling of weakness 
• Constipation 
• Vomiting 
• Stomach pain 
• Inability to sleep 
• Headache 
• Decreased appetite 
• Runny or stuffy nose 
• Diarrhoea 
• Shortness of breath 
• High blood pressure 
• Indigestion 
• Dizziness 
• Cough 
• Urinary tract infection 
• Palpitations (feeling like your heart is skipping beats or beating harder than usual) 
• Abnormal taste in mouth 
 
Common (may affect up to 1 in 10 people) 
• Sunburn-like reactions following exposure to light 
• Swelling in the feet, ankles, legs, and/or hands 
• Low potassium levels in the blood 
• Inflammation or swelling of the air passages between the mouth and nose and the lungs, 

bronchitis 
• Abdominal bloating 
• Feeling of worry, nervousness, or unease 
• Feelings of sadness, depressed 
• Nose bleed 
• Decrease in weight 
• Muscle pain 
• Back pain 
• Joint pain 
• Pink eye 
• Fast heart beat may cause dizziness, chest pain or breathlessness 
• Dry mouth 
• Inflammation of the mouth and/or digestive tract 
• Rash 
• Elevated blood tests 
• Abnormal blood tests 
 
Uncommon (may affect up to 1 in 100 people) 
• Reduction in the number of red blood cells, white blood cells and platelets 
• Confusional state 
• Inflammation of the lungs which can cause shortness of breath and difficulty breathing (non-

infectious pneumonitis) 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


32 

 
 
5. How to store Zejula 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 
expiry date refers to the last day of that month. 
 
Do not store above 30 °C. 
 
Do not use this medicine if you notice any damage or signs of tampering to the pack. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Zejula contains 
 
• The active substance is niraparib. Each hard capsule contains niraparib tosylate monohydrate 

equivalent to 100 mg niraparib. 
 
• The other ingredients (excipients) are:  

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), and povidone (E 1201). 

 
This medicine contains lactose and tartrazine - see section 2 for more information. 
 
What Zejula looks like and contents of the pack 
 
Zejula hard capsules have a white opaque body and a purple opaque cap. The white opaque capsule 
body is printed with ‘100 mg’ in black ink, and the purple capsule cap is printed with ‘Niraparib’ in 
white ink. The capsules contain a white to off-white powder. 
 
The hard capsules are packed in blister packs of  
• 84 × 1 hard capsules 
• 56 × 1 hard capsules 
• 28 × 1 hard capsules 
 
Marketing Authorisation Holder 
GlaxoSmithKline (Ireland) Limited 
12 Riverwalk 
Citywest Business Campus 
Dublin 24 
Ireland  
 
Manufacturer 
Manufacturing Packaging Farmaca (MPF) B.V. 
Appelhof 13 
8465 RX Oudehaske 
Netherlands 
 



33 

TESARO Bio Netherlands B.V. 
Joop Geesinkweg 901 
1114 AB Amsterdam-Duivendrecht 
Netherlands 
 
GlaxoSmithKline Trading Services Ltd. 
12 Riverwalk 
Citywest Business Campus 
Dublin 24 
Ireland 
 
Glaxo Operations UK Limited 
(trading as Glaxo Wellcome Operations) 
Harmire Road 
Barnard Castle 
Durham 
DL12 8DT 
United Kingdom 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Tél/Tel: + 32 (0) 10 85 52 00 
 

Lietuva 
GlaxoSmithKline Lietuva UAB 
Tel: + 370 5 264 90 00 
info.lt@gsk.com 
 

България 
ГлаксоСмитКлайн ЕООД  
Teл.: + 359 2 953 10 34 
 

Luxembourg/Luxemburg 
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Belgique/Belgien 
Tél/Tel: + 32 (0) 10 85 52 00 
 

Česká republika 
GlaxoSmithKline, s.r.o. 
Tel: + 420 222 001 111 
cz.info@gsk.com  

Magyarország 
GlaxoSmithKline Kft. 
Tel.: + 36 1 225 5300 
 

 
Danmark 
GlaxoSmithKline Pharma A/S 
Tlf: + 45 36 35 91 00 
dk-info@gsk.com 
 

 
Malta 
GlaxoSmithKline (Malta) Limited 
Tel: + 356 21 238131 

Deutschland 
GlaxoSmithKline GmbH & Co. KG 
Tel.: + 49 (0)89 36044 8701 
produkt.info@gsk.com 

Nederland 
GlaxoSmithKline BV 
Tel: + 31 (0)33 2081100 

 
Eesti 
GlaxoSmithKline Eesti OÜ 
Tel: + 372 6676 900 
estonia@gsk.com 

 
Norge 
GlaxoSmithKline AS 
Tlf: + 47 22 70 20 00 
 

 
Ελλάδα 
GlaxoSmithKline Μονοπρόσωπη A.E.B.E. 
Τηλ: + 30 210 68 82 100 
 

 
Österreich 
GlaxoSmithKline Pharma GmbH 
Tel: + 43 (0)1 97075 0 
at.info@gsk.com 



34 

 
España 
GlaxoSmithKline, S.A. 
Tel: + 34 900 202 700 
es-ci@gsk.com 
 

 
Polska 
GSK Services Sp. z o.o. 
Tel.: + 48 (0)22 576 9000 

France 
Laboratoire GlaxoSmithKline 
Tél: + 33 (0)1 39 17 84 44 
diam@gsk.com 
 

Portugal 
GlaxoSmithKline – Produtos Farmacêuticos, Lda. 
Tel: + 351 21 412 95 00 
FI.PT@gsk.com  

Hrvatska 
GlaxoSmithKline d.o.o. 
Tel: +385 1 6051 999 
 
Ireland 
GlaxoSmithKline (Ireland) Limited 
Tel: + 353 (0)1 4955000 
 

România 
GlaxoSmithKline (GSK) S.R.L.  
Tel: + 4021 3028 208 
 
Slovenija 
GlaxoSmithKline d.o.o. 
Tel: + 386 (0)1 280 25 00 
medical.x.si@gsk.com  

 
Ísland 
Vistor hf. 
Sími: + 354 535 7000 
 

 
Slovenská republika 
GlaxoSmithKline Slovakia s. r. o. 
Tel: + 421 (0)2 48 26 11 11 
recepcia.sk@gsk.com 
 

Italia 
GlaxoSmithKline S.p.A. 
Tel: + 39 (0)45 9218 111 

Suomi/Finland 
GlaxoSmithKline Oy 
Puh/Tel: + 358 (0)10 30 30 30 
Finland.tuoteinfo@gsk.com 
 

Κύπρος 
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22 397000 
gskcyprus@gsk.com  

Sverige 
GlaxoSmithKline AB 
Tel: + 46 (0)8 638 93 00 
info.produkt@gsk.com  

 
Latvija 
GlaxoSmithKline Latvia SIA 
Tel: + 371 67312687 
lv-epasts@gsk.com 

 
United Kingdom 
GlaxoSmithKline UK Ltd 
Tel: + 44 (0)800 221441 
customercontactuk@gsk.com 
 

 
This leaflet was last revised in MM/YYYY. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

 
 
 
 
 
 

 


	ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET