Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The overall safety profile of Akeega is based on data from a Phase 3, randomised, double-blind, placebo-controlled study, MAGNITUDE cohort 1 (N=212). The most common adverse reactions of all grades occurring in >10% in the niraparib plus AAP arm were anaemia (52.4%), hypertension (34.0%), constipation (34.0%), fatigue (31.1%), nausea (25.0%), thrombocytopenia (24.1%), dyspnoea (18.9%), arthralgia (18.4%), back pain (17.9%), asthenia (17.0%), neutropenia (16.0%), decreased appetite (15.6%), hypokalaemia (15.6%), vomiting (15.1%), dizziness (13.2%), abdominal pain (12.7%), hyperglycaemia (12.7%), blood alkaline phosphatase increased (11.8%), weight decreased (11.8%), insomnia (11.3%), leukopenia (10.8%), lymphopenia (10.8%), blood creatinine increased (10.4%), and urinary tract infection (10.4%). The most frequently observed Grade 3-4 adverse reactions were anaemia (30.7%), hypertension (16.5%), thrombocytopenia (8.5%), neutropenia (6.6%), blood alkaline phosphatase increased (5.7%), and hypokalaemia (5.7%).

Tabulated list of adverse reactions
Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3:     Adverse reactions identified in clinical studies
System Organ Class          Frequency          Adverse reaction
Infections and              very common        urinary tract infection infestations                common             pneumoniae, bronchitis, nasopharyngitis uncommon           urosepsis, conjunctivitis
Blood and lymphatic         very common        anaemia, thrombocytopenia, neutropenia, system disorders                               leukopenia, lymphopenia not known          pancytopenia7
Immune system disorders not known              hypersensitivity (including anaphylaxis)7 Endocrine disorders         not known          adrenal insufficiency9 Metabolism and nutrition very common           decreased appetite, hypokalaemia, disorders                                      hyperglycaemia common             hypertriglyceridaemia
Psychiatric disorders       very common        insomnia common             depression, anxiety uncommon           confusional state not known          cognitive impairment8
Nervous system disorders very common           dizziness common             headache, cognitive disorder uncommon           dysgeusia

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                                 not known          posterior reversible encephalopathy syndrome (PRES)7
Cardiac disorders               common             tachycardia, palpitations, atrial fibrillation, cardiac failure1, myocardial infarction, angina pectoris2 uncommon           QT prolongation
Vascular disorders              very common        hypertension not known          hypertensive crisis7
Respiratory, thoracic and       very common        dyspnoea mediastinal disorders           common             cough, pulmonary embolism, pneumonitis uncommon           epistaxis not known          allergic alveolitis9
Gastrointestinal                very common        constipation, nausea, vomiting, disorders                                          abdominal pain3 common             dyspepsia, diarrhoea, abdominal distention, stomatitis, dry mouth uncommon           mucosal inflammation
Hepatobiliary disorders         common             hepatic failure4
Skin and subcutaneous           common             rash5 tissue disorders                uncommon           photosensitivity
Musculoskeletal and             very common        back pain, arthralgia connective tissue               common             myalgia disorders                       not known          myopathy9, rhabdomyolysis9 Renal and urinary               common             haematuria disorders
General disorders and           very common        fatigue, asthenia administration site             common             oedema peripheral conditions
Investigations                  very common        blood alkaline phosphatase increased, weight decreased, blood creatinine increased common             AST increased, ALT increased uncommon           gamma-glutamyl transferase increased
Injury, poisoning and           common             fractures6 procedural complications
1
Includes cardiac failure congestive, cor pulmonale, left ventricular dysfunction 2
Includes coronary artery disease, acute coronary syndrome
3
Includes abdominal pain upper, abdominal pain lower
4
Includes hepatic cytolysis, hepatotoxicity, hepatic failure
5
Includes rash, erythema, dermatitis, rash maculo-papular, rash pruritic 6
Includes osteoporosis and osteoporosis-related fractures
7
Not observed with Akeega. Reported in post-marketing experience with niraparib monotherapy 8
Not observed with Akeega. Reported with niraparib monotherapy
9
Not observed with Akeega. Reported in post-marketing experience with abiraterone monotherapy

Description of selected adverse reactions
Haematological toxicities
Haematological toxicities (anaemia, thrombocytopenia and neutropenia) including laboratory findings are the most frequent adverse reactions attributable to niraparib (a component of Akeega). These toxicities generally occurred within the first three months of treatment with the incidence decreasing over time.

In the MAGNITUDE study and other Akeega studies, the following haematological parameters were inclusion criteria: absolute neutrophil count (ANC) ≥ 1 500 cells/μL; platelets ≥ 100 000 cells/μL and haemoglobin ≥ 9 g/dL. Haematological adverse reactions were managed with laboratory monitoring and dose modifications (see sections 4.2 and 4.4).


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Anaemia
Anaemia was the most frequent adverse reaction (52.4%) and most commonly observed Grade 3-4 event (30.7%) in the MAGNITUDE study. Anaemia occurred early during the course of therapy (median time to onset of 64 days). In the MAGNITUDE study, dose interruptions occurred in 24.1% and dose reductions in 13.7% of patients. Twenty-seven percent of patients received at least one anaemia-related red blood cell transfusion. Anaemia caused discontinuation in a relatively small number of patients (2.8%).

Thrombocytopenia
In the MAGNITUDE study, 24.1% of treated patients reported thrombocytopenia while 8.5% of patients experienced Grade 3-4 thrombocytopenia. Median time from first dose to first onset was 71 days. In the MAGNITUDE study, thrombocytopenia was managed with dose modification (interruption 11.3% and reduction in 2.8%) and platelet transfusion (3.8%) where appropriate (see section 4.2). Discontinuation occurred in 0.5% of patients. In the MAGNITUDE study, 1.9% of patients experienced a nonlife-threatening bleeding event.

Neutropenia
In the MAGNITUDE study, 16.0% of patients experienced neutropenia with Grade 3-4 neutropenia reported in 6.6% of patients. Median time from first dose to first report of neutropenia was 65 days.
Neutropenia led to treatment interruption in 6.6% of patients and dose reduction in 1.4%. There were no treatment discontinuations due to neutropenia. In the MAGNITUDE study, 0.9% of patients had a concurrent infection.

Hypertension
Hypertension is an adverse reaction for both components of Akeega and patients with uncontrolled hypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg) were excluded in all combination studies. Hypertension was reported in 34% of patients of whom 16.5% had Grade ≥ 3. The median time to onset of hypertension was 60.5 days. Hypertension was managed with adjunctive medicinal products.

Patients should have blood pressure controlled before initiating Akeega and blood pressure should be monitored on treatment (see section 4.4).

Cardiac events
In the MAGNITUDE study, the incidence of TEAEs of cardiac disorder (all grades) was similar in both arms, except for the arrhythmia category, where AEs were observed in 13.2% of patients in the niraparib plus AAP arm and 7.6% of patients in the placebo plus AAP arm (see section 4.4). Higher frequency of arrhythmias was largely due to low grade events of palpitations, tachycardias and atrial arrhythmias.

The median time to onset of the events of arrhythmias was 81 days in the niraparib plus AAP arm and 262 days in the placebo plus AAP arm. Events of arrhythmia were resolved in 64.3% of patients in the niraparib plus AAP arm and 62.5% of subjects in the placebo plus AAP arm.

The incidence of cardiac failure, cardiac failure acute, cardiac failure chronic, cardiac failure congestive was 2.8% in the niraparib plus AAP arm vs 1.9% in placebo plus AAP arm. The median time to onset of the AESI of cardiac failure was 312 days in the niraparib plus AAP arm and 83 days in the placebo plus AAP arm. Events of cardiac failure were resolved in 16.7% of patients in the niraparib plus AAP arm and 25% of patients in the placebo plus AAP arm.

The grouped term of ischaemic heart disease (included preferred terms of angina pectoris, acute myocardial infarction, acute coronary syndrome, unstable angina, and arteriosclerosis coronary artery) occurred in 5.2% of the niraparib plus AAP arm vs 4.7% in the placebo plus AAP arm. The median time to onset of the AESI of ischaemic heart disease was 684 days in the niraparib plus AAP arm and 296 days in the placebo plus AAP arm. Events of ischaemic heart disease were resolved in 81.8% of patients in the niraparib plus AAP arm and 80% of patients in the placebo plus AAP arm.

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Hepatotoxicity
The overall incidence of hepatotoxicity in the MAGNITUDE study was similar for the niraparib plus AAP (14.2%) and placebo plus AAP (12.8%) arms (see sections 4.2 and 4.4). The majority of these events were low grade aminotransferase elevations. Grade 3 events occurred in 1.4% of patients in the niraparib plus AAP arm and a Grade 4 event occurred in only one patient (0.5%). The incidence of SAEs was also 1.4%. The median time to onset of hepatotoxicity in the MAGNITUDE study was 43 days. Hepatotoxicity was managed with dose interruptions in 1.9% and dose reduction in 0.9% of patients. In the MAGNITUDE study, 0.9% of patients discontinued treatment due to hepatotoxicity.

Paediatric population
No studies have been conducted in paediatric patients with Akeega.

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