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*If further dose reduction below 100 mg/day is required, discontinue Zejula. Table 2: Dose modifications for nonhaematologic adverse reactions Nonhaematologic CTCAE* ≥ Grade 3 treatmentrelated 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 level per Table 1. Second occurrence: • Withhold Zejula for a maximum of 28 days or until resolution of adverse reaction. • Resume Zejula at a reduced dose or discontinue per Table 1. CTCAE ≥ Grade 3 treatmentrelated 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 3: 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 of the complete SmPC). 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 coadministration 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 per Table 1 based on clinical evaluation. •If platelet count is < 75,000/μL at any time, resume at a reduced dose per Table 1. 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 per Table 1. •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 per Table 1. •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 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 (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 of the complete SmPC). Hepatic impairment No dose adjustment is needed in patients with mild hepatic impairment (either aspartate aminotransferase (AST) > upper limit of normal (ULN) and total bilirubin (TB) ≤ ULN or any AST and TB > 1.0 x – 1,5 x ULN). For patients with moderate hepatic impairment (any AST and TB > 1.5 x - 3 x ULN) the recommended starting dose of Zejula is 200 mg once daily. There are no data in patients with severe hepatic impairment (any AST and TB > 3 x ULN); use with caution in these patients (see sections 4.4 and 5.2 of the complete SmPC). 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 Zejula is for oral use. It is advised to take Zejula tablets without food (at least 1 hour before or 2 hours after a meal) or with a light meal (see section 5.2 of the complete SmPC). Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the complete SmPC. Breastfeeding (see section 4.6 of the complete SmPC). Undesirable effects Summary of the safety profile ADRs of all grades occurring in ≥ 10% of the 851 patients receiving Zejula monotherapy in the pooled PRIMA (either 200 mg or 300 mg starting dose) and NOVA trials were nausea, anaemia, thrombocytopenia, fatigue, constipation, vomiting, headache, insomnia, platelet count decreased, neutropenia, abdominal pain, decreased appetite, diarrhoea, dyspnoea, hypertension, asthenia, dizziness, neutrophil count decreased, cough, arthralgia, back pain, white blood cell count decreased, and hot flush. The most common serious adverse reactions > 1% (treatmentemergent frequencies) were thrombocytopenia and anaemia. Tabulated list of adverse reactions The following adverse reactions have been identified based on clinical trials and post-marketing surveillance in patients receiving Zejula monotherapy (see Table 4). Frequencies of occurrence of undesirable effects are based on pooled adverse events data generated from the PRIMA and NOVA studies (fixed starting dose of 300 mg/day) where patient exposure is known and defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 4: Tabulated list of adverse reactions System Organ Class Infections and infestations Frequency of all CTCAE* grades: Very common Urinary tract infection Common Bronchitis, conjunctivitis Frequency of CTCAE* grade 3 or 4: Uncommon Urinary tract infection, bronchitis Blood and lymphatic system disorders Frequency of all CTCAE* grades: Very common Thrombocytopenia, anaemia, neutropenia, leukopenia Uncommon Pancytopenia, febrile neutropenia Frequency of CTCAE* grade 3 or 4: Very common Thrombocytopenia, anaemia, neutropenia Common Leukopenia Uncommon Pancytopenia, febrile neutropenia Immune system disorders Frequency of all CTCAE* grades: Common Hypersensitivity^† Frequency of CTCAE* grade 3 or 4: Uncommon Hypersensitivity Metabolism and nutrition disorders Frequency of all CTCAE* grades: Very common Decreased appetite Common Hypokalemia Frequency of CTCAE* grade 3 or 4: Common Hypokalemia Uncommon Decreased appetite Psychiatric disorders Frequency of all CTCAE* grades: Very common Insomnia Common Anxiety, depression, cognitive impairment^†† Uncommon Confusional state Frequency of CTCAE* grade 3 or 4: Uncommon Insomnia, anxiety, depression, confusional state Nervous system disorders Frequency of all CTCAE* grades: Very common Headache, dizziness Common Dysgeusia Rare Posterior Reversible Encephalopathy Syndrome (PRES)** Frequency of CTCAE* grade 3 or 4: Uncommon Headache Cardiac disorders Frequency of all CTCAE* grades: Very common Palpitations Common Tachycardia Vascular disorders Frequency of all CTCAE* grades: Very common Hypertension Rare Hypertensive crisis Frequency of CTCAE* grade 3 or 4: Common Hypertension Respiratory, thoracic and mediastinal disorders Frequency of all CTCAE* grades: Very common Dyspnoea, cough, nasopharyngitis Common Epistaxis Uncommon Pneumonitis Frequency of CTCAE* grade 3 or 4: Uncommon Dyspnoea, epistaxis, pneumonitis Gastrointestinal disorders Frequency of all CTCAE* grades: Very common Nausea, constipation, vomiting, abdominal pain, diarrhoea, dyspepsia Common Dry mouth, abdominal distension, mucosal inflammation, stomatitis Frequency of CTCAE* grade 3 or 4: Common Nausea, vomiting, abdominal pain Uncommon Diarrhoea, constipation, mucosal inflammation, stomatitis, dry mouth Skin and subcutaneous tissue disorders Frequency of all CTCAE* grades: Common Photosensitivity, rash Frequency of CTCAE* grade 3 or 4: Uncommon Photosensitivity, rash Musculoskeletal and connective tissue disorders Frequency of all CTCAE* grades: Very common Back pain, arthralgia Common Myalgia Frequency of CTCAE* grade 3 or 4: Uncommon Back pain, arthralgia, myalgia General disorders and administration site conditions Frequency of all CTCAE* grades: Very common Fatigue, asthenia Common Oedema peripheral Frequency of CTCAE* grade 3 or 4: Common Fatigue, asthenia Investigations Frequency of all CTCAE* grades: Common Gammaglutamyl transferase increased, AST increased, blood creatinine increased, ALT increased, blood alkaline phosphatase increased, weight decreased Frequency of CTCAE* grade 3 or 4: Common Gammaglutamyl transferase increased, ALT increased Uncommon AST increased, blood alkaline phosphatase increased^*CTCAE=Common Terminology Criteria for Adverse Events version 4.02 ^** Based on niraparib clinical trial data. This is not limited to pivotal ENGOT-OV16 monotherapy study. † Includes hypersensitivity, drug hypersensitivity, anaphylactoid reaction, drug eruption, angioedema, and urticaria. ^†† Includes memory impairment, concentration impairment. The adverse reactions noted in the group of patients who were administered a 200 mg starting dose of Zejula based on baseline weight or platelet count were of similar or lesser frequency compared to the group administered a fixed starting dose of 300 mg (Table 4). See below for specific information regarding frequency of thrombocytopenia, anaemia and neutropenia. Description of selected adverse reactions Haematologic adverse reactions (thrombocytopenia, anaemia, neutropenia) including clinical diagnoses and/or laboratory findings generally occurred early during niraparib treatment with the incidence decreasing over time. In the NOVA and PRIMA studies, patients eligible for Zejula therapy had the following baseline haematologic parameters: absolute neutrophil count (ANC) ≥ 1,500 cells/µL; platelets ≥ 100,000 cells/µL and haemoglobin ≥ 9 g/dL (NOVA) or ≥ 10 g/dL (PRIMA) prior to therapy. In the clinical programme, haematologic adverse reactions were managed with laboratory monitoring and dose modifications (see section 4.2 of the complete SmPC). In PRIMA, patients who were administered a starting dose of Zejula based on baseline weight or platelet count, Grade ≥3 thrombocytopenia, anaemia and neutropenia were reduced from 48% to 21%, 36% to 23% and 24% to 15%, respectively, compared to the group administered a fixed starting dose of 300 mg. Discontinuation due to thrombocytopenia, anaemia, and neutropenia occurred, respectively, in 3%, 3%, and 2% of patients. Thrombocytopenia In PRIMA, 39% of Zejula-treated patients experienced Grade 3/4 thrombocytopenia compared to 0.4% of placebo-treated patients with a median time from first dose to first onset of 22 days (range: 15 to 335 days) and with a median duration of 6 days (range: 1 to 374 days). Discontinuation due to thrombocytopenia occurred in 4% of patients receiving niraparib. In NOVA, approximately 60% of patients receiving Zejula experienced thrombocytopenia of any grade, and 34% of patients experienced Grade 3/4 thrombocytopenia. In patients with baseline platelet count less than 180 × 10⁹/L, thrombocytopenia of any grade and Grade 3/4 occurred in 76% and 45% of the patients, respectively. The median time to onset of thrombocytopenia regardless of grade and Grade 3/4 thrombocytopenia was 22 and 23 days, respectively. The rate of new incidences of thrombocytopenia after intensive dose modifications were performed during the first two months of treatment from Cycle 4 was 1.2%. The median duration of thrombocytopenia events of any grade was 23 days, and the median duration of Grade 3/4 thrombocytopenia was 10 days. Patients treated with Zejula who develop thrombocytopenia might have an increased risk of haemorrhage. In the clinical programme, thrombocytopenia was managed with laboratory monitoring, dose modification and platelet transfusion where appropriate (see section 4.2 of the complete SmPC). Discontinuation due to thrombocytopenia events (thrombocytopenia and platelet count decreased) occurred in approximately 3% of the patients. In the NOVA study, 48 of 367 (13%) of patients experienced bleeding with concurrent thrombocytopenia; all bleeding events concurrent with thrombocytopenia were Grade 1 or 2 in severity except for one event of Grade 3 petechiae and haematoma observed concurrently with a serious adverse reaction of pancytopenia. Thrombocytopenia occurred more commonly in patients whose baseline platelet count was less than 180 × 10⁹/L. Approximately 76% of patients with lower baseline platelets (< 180 × 10⁹/L) who received Zejula experienced thrombocytopenia of any grade, and 45% of the patients experienced Grade 3/4 thrombocytopenia. Pancytopenia has been observed in < 1% of patients receiving niraparib. Anaemia In PRIMA, 31% of Zejula-treated patients experienced Grade 3/4 anaemia compared to 2% of placebo-treated patients with a median time from first dose to first onset of 80 days (range: 15 to 533 days) and with a median duration of 7 days (range: 1 to 119 days). Discontinuation due to anaemia occurred in 2% of patients receiving niraparib. In NOVA, approximately 50% of patients experienced anaemia of any grade, and 25% experienced Grade 3/4 anaemia. The median time to onset of anaemia of any grade was 42 days, and 85 days for Grade 3/4 events. The median duration of anaemia of any grade was 63 days, and 8 days for Grade 3/4 events. Anaemia of any grade might persist during Zejula treatment. In the clinical programme, anaemia was managed with laboratory monitoring, dose modification (see section 4.2 of the complete SmPC), and where appropriate with red blood cell transfusions. Discontinuation due to anaemia occurred in 1% of patients. Neutropenia In PRIMA, 21% of Zejula-treated patients experienced Grade 3/4 neutropenia compared to 1% of placebo-treated patients with a median time from first dose to first onset of 29 days (range: 15 to 421 days) and with a median duration of 8 days (range: 1 to 42 days). Discontinuation due to neutropenia occurred in 2% of patients receiving niraparib. In NOVA, approximately 30% of patients receiving Zejula experienced neutropenia of any grade, and 20% of patients experienced Grade 3/4 neutropenia. The median time to onset of neutropenia of any grade was 27 days, and 29 days for Grade 3/4 events. The median duration of neutropenia of any grade was 26 days, and 13 days for Grade 3/4 events. In addition, GranulocyteColony Stimulating Factor (GCSF) 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. Myelodysplastic syndrome/Acute myeloid leukaemia In clinical studies, MDS/AML occurred in 1% patients treated with Zejula, with 41% of cases having a fatal outcome. The incidence was higher in patients with relapsed ovarian cancer who had received 2 or more lines of prior platinum chemotherapy and with gBRCAmut following 75 months survival follow- up. All patients had potential contributing factors for the development of MDS/AML, having received previous chemotherapy with platinum agents. Many had also received other DNA damaging agents and radiotherapy. The majority of reports were in gBRCAmut carriers. Some of the patients had a history of previous cancer or of bone marrow suppression. In the PRIMA study, the incidence of MDS/AML was 0.8% in patients receiving Zejula and 0.4% in patients received placebo. In the NOVA study in patients with relapsed ovarian cancer who had received at least two prior lines of platinum chemotherapy, the overall incidence of MDS/AML was 3.8% in patients receiving Zejula and 1.7% in patients receiving placebo at 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 and 3.1% and 0.9% in patients receiving placebo, respectively. Hypertension In PRIMA, Grade 3/4 hypertension occurred in 6% of Zejula-treated patients compared to 1% of placebo-treated patients with a median time from first dose to first onset of 50 days (range: 1 to 589 days) and with a median duration of 12 days (range: 1 to 61 days). Discontinuation due to hypertension occurred in 0% of patients. In NOVA, hypertension of any grade occurred in 19.3% of patients treated with Zejula. Grade 3/4 hypertension occurred in 8.2% of patients. Hypertension was readily managed with antihypertensive 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: Belgium Federal Agency for Medicines and Health Products Division Vigilance Boîte Postale 97 1000 Brussels Madou Website: www. notifieruneffetindesirable.be e-mail: adr@afmps.be Luxembourg Centre Régional de Pharmacovigilance de Nancy ou Division de la pharmacie et des médicaments de la Direction de la santé Site internet : www.guichet. lu/pharmacovigilance MARKETING AUTHORISATION HOLDER GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland DATE OF APPROVAL OF THE TEXT 31/05/2023 (v5) DELIVERY STATUS Medicinal product subject to medical prescription.