Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most common adverse reactions are nausea (64.8%), vomiting (59.7%), diarrhoea (50.4%), neutropenia (44.5%), fatigue/asthenia (44.1%)5, constipation (38.6%), thrombocytopenia (33.5%), abdominal pain (21.6%)4, respiratory tract infection (17%)2, arthralgia (13.6%), decreased appetite (12.7%), febrile neutropenia (11.9%), back pain (11.9%), leucopenia (10.6%), pain in extremity (10.6%) and pneumonia (10.2%)1.


Onureg_API_June2022_clean
Serious adverse reactions occurred in 16.1% of patients receiving Onureg. The most common serious adverse reactions are febrile neutropenia (6.8%) and pneumonia (5.1%)1.

Permanent discontinuation of Onureg due to an adverse reaction occurred in 6.8% of patients. The most common adverse reactions requiring permanent discontinuation are nausea (2.1%), diarrhoea (1.7%), and vomiting (1.3%).

Dose interruptions due to an adverse reaction occurred in 36.4% of patients who received Onureg.
Adverse reactions requiring dose interruption include neutropenia (19.9%), thrombocytopenia (8.5%), nausea (5.5%), diarrhoea (4.2%), vomiting (3.8%), pneumonia (3.4%)1, leucopenia (2.5%), febrile neutropenia (2.1%), and abdominal pain (2.1%)4.

Dose reductions due to an adverse reaction period occurred in 14% of patients who received Onureg.
Adverse reactions requiring dose reduction included neutropenia (5.5%), diarrhoea (3.4%), thrombocytopenia (1.7%), and nausea (1.7%).

Tabulated list of adverse reactions

Table 2 presents the frequency category of ADRs reported in the pivotal Phase 3 study with Onureg. A total of 236 patients received Onureg. The median treatment duration was 11.6 months (range: 0.5 to 74.3 months) for Onureg arm.

Frequencies 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); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions are presented in the table below according to the highest frequency observed.



Onureg_API_June2022_clean
Table 2: Adverse drug reactions (ADRs) in AML patients receiving Onureg maintenance therapy
System organ class                  All gradesa frequency
Infections and infestations         Very common
Pneumonia1, 6, respiratory tract infection2

Common
Influenza, urinary tract infection3, bronchitis, rhinitis
Blood and lymphatic system            Very common disorders                             Neutropenia, thrombocytopenia6, febrile neutropenia6, leucopenia
Metabolism and nutrition disorders Very common
Decreased appetite
Psychiatric disorders                 Common
Anxiety
Gastrointestinal disorders            Very common
Nausea, vomiting, diarrhoea, constipation, abdominal pain4
Musculoskeletal and connective tissue Very common disorders                             Arthralgia, back pain, pain in extremity General disorders and administration Very common site conditions                       Fatigue / asthenia5
Investigations                        Common
Weight decreased a AllAEs with at least 5.0% of patients in the Onureg arm and at least 2.0% higher frequency than the placebo arm.
1 Grouped terms include pneumonia, bronchopulmonary aspergillosis, lung infection, Pneumocystis jirovecii pneumonia, atypical pneumonia, pneumonia bacterial, and pneumonia fungal.
2 Grouped terms include upper respiratory tract infection, respiratory tract infection, and respiratory tract infection viral.
3 Grouped terms include urinary tract infection, urinary tract infection bacterial, Escherichia urinary tract infection, and  cystitis.
4 Grouped terms include abdominal pain, abdominal pain upper, abdominal discomfort, and gastrointestinal pain.
5 Grouped terms include fatigue and asthenia.
6 Adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is  included with death cases).

Description of selected adverse reactions
Haematological toxicity
New or worsening Grade 3 or higher neutropenia (41.1%), thrombocytopenia (22.5%), or febrile neutropenia (11.4%) were commonly reported adverse reactions in patients treated with Onureg. The first occurrence of Grade 3 or 4 neutropenia, thrombocytopenia, or febrile neutropenia occurred within the first 2 cycles in 19.9%, 10.6%, and 1.7%, respectively in patients treated with Onureg. See section 4.2 for monitoring and management guidance.

Gastrointestinal toxicity
Gastrointestinal toxicities were the most frequent adverse reactions in patients treated with Onureg.
Nausea (64.8%), vomiting (59.7%), and diarrhoea (50.4%) were reported in patients treated with Onureg. Grade 3 or higher diarrhoea occurred in 5.1% of patients and Grade 3 or higher vomiting and nausea occurred in 3.0% and 2.5%, respectively in patients treated with Onureg. The first occurrence of Grade 3 or 4 nausea, vomiting, or diarrhoea occurred within the first 2 cycles in 1.7%, 3.0%, and 1.3%, respectively, in patients treated with Onureg. See section 4.2 for monitoring and management guidance.

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

Onureg_API_June2022_clean