Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Summary of the safety profile

The most common adverse reactions were diarrhoea (34%), nausea (25%), and fatigue (21%). The most common severe (grade ≥ 3) adverse reactions were increased ALT (5%), increased AST (4%), and diarrhoea (4%). The most common adverse reactions leading to permanent discontinuation of treatment were increased ALT (1%) and increased AST (1%) and DILI (1%). The most common adverse reactions leading to dose modification were increased ALT (6%), diarrhoea (6%), increased AST (6%), nausea (3%), increased blood alkaline phosphatase (3%) and vomiting (2%).

Tabulated list of adverse reactions

Adverse reactions reported in LUMYKRAS clinical studies are displayed in table 3 below. 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 (cannot be estimated from available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

The safety of LUMYKRAS was evaluated in 359 patients with KRAS G12C mutated solid tumours who received 960 mg orally once daily as monotherapy. The median duration of exposure to LUMYKRAS was 4.1 months (range: 0.02 to 21).

Table 3. Adverse reactions

MedDRA system                 Very common              Common                  Uncommon organ class                   (≥ 1/10)                 (≥ 1/100 to < 1/10)     (≥ 1/1,000 to < 1/100) Blood and lymphatic           Anaemia system disorders
Nervous system                Headache disorders
Respiratory, thoracic         Cough                                            ILD/pneumonitis and mediastinal               Dyspnoea disorders


MedDRA system               Very common              Common                     Uncommon organ class                 (≥ 1/10)                 (≥ 1/100 to < 1/10)        (≥ 1/1,000 to < 1/100) Gastrointestinal            Diarrhoea disorders                   Nausea
Vomiting
Constipation
Abdominal paina
Hepatobiliary disorders                              Drug-induced liver injury

Musculoskeletal and         Arthralgia connective tissue           Back pain disorders
General disorders and       Fatigue administration site         Pyrexia conditions
Investigations              Aspartate                Blood alkaline aminotransferase         phosphatase increased increased                Blood bilirubin
Alanine                  increased aminotransferase         Gamma- increased                glutamyltransferase increased a
Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower 
Description of selected adverse reactions

Elevated liver enzymes
In clinical studies, transient elevations of serum transaminases were observed (see section 4.4).
Elevations of ALT occurred in 14% of subjects and elevations of AST in 16% of subjects, with a median time to onset of 8 weeks (range: 1 to 42) and 8 weeks (range: 0 to 42), respectively. Elevations of ALT resulted in dose interruption and/or reduction in 6.1% of subjects, and elevations of AST resulted in dose interruption and/or reduction in 6.1% of subjects.

ILD/pneumonitis
In clinical studies, among 359 patients who received LUMYKRAS, ILD/pneumonitis occurred in 0.8% of patients, all cases were grade 3 or 4 at onset. The median time to first onset for ILD/pneumonitis was 2 weeks (range: 2 to 18 weeks). LUMYKRAS was discontinued due to ILD/pneumonitis in 0.6% of patients (see sections 4.2 and 4.4).

Elderly
In clinical studies, no overall differences in safety or efficacy were observed between elderly patients (≥ 65 years old) and younger patients (see sections 4.2 and 5.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continous 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/