Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Adverse reactions (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
Blood and lymphatic system       Very common                        Very common disorders                        Thrombocytopenia, anaemia,         Thrombocytopenia, anaemia, neutropenia, leukopenia            neutropenia
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
System Organ Class              Frequency of all CTCAE*         Frequency of CTCAE* grades                          grade 3 or 4
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 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. 1

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). 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 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.

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.

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. 2

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/
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