Adverse reactions : תופעות לוואי

4.8    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% (treatment-emergent frequencies) were thrombocytopenia and anaemia.

Tabulated list of adverse reactions

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

Frequencies of occurrence of undesirable effects are based on pooled adverse events data generated from the PRIMA and NOVA studies (fixed starting dose of 300 mg/day) where patient exposure is known and defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4: Tabulated list of adverse reactions
System Organ Class               Frequency of all CTCAE*              Frequency of CTCAE* grades                               grade 3 or 4
Infections and infestations      Very common                          Uncommon Urinary tract infection              Urinary tract infection,
Common                               bronchitis
Bronchitis, conjunctivitis
Neoplasms benign, malignant      Common                               Common and unspecified (including       Myelodysplastic syndrome/            Myelodysplastic syndrome/ cysts and polyps)                acute myeloid leukaemia**            acute myeloid leukaemia** Blood and lymphatic system       Very common                          Very common disorders                        Thrombocytopenia, anaemia,           Thrombocytopenia, anaemia, neutropenia, leukopenia              neutropenia

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System Organ Class             Frequency of all CTCAE*           Frequency of CTCAE* grades                            grade 3 or 4
Uncommon                          Common
Pancytopenia, febrile             Leukopenia neutropenia                       Uncommon
Pancytopenia, febrile neutropenia
Immune system disorders        Common                            Uncommon Hypersensitivity†                 Hypersensitivity
Metabolism and nutrition       Very common                       Common disorders                      Decreased appetite                Hypokalemia Common                            Uncommon
Hypokalemia                       Decreased appetite
Psychiatric disorders          Very common                       Uncommon Insomnia                          Insomnia, anxiety, depression,
Common                            confusional state
Anxiety, depression,
cognitive impairment††
Uncommon
Confusional state
Nervous system disorders       Very common                       Uncommon Headache, dizziness               Headache
Common
Dysgeusia
Rare
Posterior Reversible
Encephalopathy Syndrome
(PRES)**
Cardiac disorders              Very common
Palpitations
Common
Tachycardia
Vascular disorders             Very common                       Common Hypertension                      Hypertension
Rare
Hypertensive crisis
Respiratory, thoracic and      Very common                       Uncommon mediastinal disorders          Dyspnoea, cough,                  Dyspnoea, epistaxis, nasopharyngitis                   pneumonitis
Common
Epistaxis
Uncommon
Pneumonitis
Gastrointestinal disorders     Very common                       Common Nausea, constipation, vomiting,   Nausea, vomiting, abdominal abdominal pain, diarrhoea,        pain dyspepsia                         Uncommon
Common                            Diarrhoea, constipation,
Dry mouth, abdominal              mucosal inflammation,
distension, mucosal               stomatitis, dry mouth inflammation, stomatitis
Skin and subcutaneous tissue   Common                            Uncommon disorders                      Photosensitivity, rash            Photosensitivity, rash Musculoskeletal and            Very common                       Uncommon connective tissue disorders    Back pain, arthralgia             Back pain, arthralgia, myalgia 
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System Organ Class              Frequency of all CTCAE*       Frequency of CTCAE* grades                        grade 3 or 4
Common
Myalgia
General disorders and          Very common                   Common administration site conditions Fatigue, asthenia             Fatigue, asthenia Common
Oedema peripheral
Investigations                 Common                        Common
Gamma-glutamyl transferase    Gamma-glutamyl transferase increased, AST increased,     increased, ALT increased blood creatinine increased,   Uncommon
ALT increased, blood alkaline AST increased, blood alkaline phosphatase increased, weight phosphatase increased decreased
*
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).

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

In the NOVA study, 48 of 367 (13%) of patients experienced bleeding with concurrent thrombocytopenia; all bleeding events concurrent with thrombocytopenia were Grade 1 or 2 in severity except for one event of Grade 3 petechiae and haematoma observed concurrently with a serious adverse 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), and where appropriate with red blood cell transfusions. Discontinuation due to anaemia occurred in 1% of patients.

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

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

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.
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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 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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il