Adverse reactions : תופעות לוואי

4.8 Undesirable effects


Summary of the safety profile
Studies in EGFR mutation-positive NSCLC patients
The data described below reflect exposure to TAGRISSO in 1479 patients with EGFR mutation-positive  non-small cell lung cancer. These patients received TAGRISSO at a dose of 80 mg daily in three randomised Phase 3 studies (ADAURA, adjuvant; FLAURA, first line and AURA3, second line only), two  single-arm studies (AURAex and AURA2, second line or later) and one Phase 1 study (AURA1, first-line  or later) (see section 5.1). Most adverse reactions were Grade 1 or 2 in severity. The most commonly  reported adverse drug reactions (ADRs) were diarrhoea (47%), rash (45%), paronychia (33%), dry skin 
(32%), and stomatitis (24%). Grade 3 and Grade 4 adverse reactions across the studies were 10% and 
0.1%, respectively. In patients treated with TAGRISSO 80 mg once daily, dose reductions due to  adverse reactions occurred in 3.4% of the patients. Discontinuation due to adverse reactions was 4.8%.

Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid  treatment, or any evidence of clinically active ILD were excluded from clinical studies. Patients with  clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram 
(ECG) (e.g. QTc interval greater than 470 msec) were excluded from these studies. Patients were  evaluated for LVEF at screening and every 12 weeks thereafter.

Tabulated list of adverse reactions


Adverse reactions have been assigned to the frequency categories in Table 2 where possible based on  the incidence of comparable adverse event reports in a pooled dataset from the 1479 EGFR mutation  positive NSCLC patients who received TAGRISSO at a dose of 80 mg daily in the ADAURA, FLAURA, 
AURA3, AURAex, AURA 2 and AURA1 studies.

Adverse reactions are listed according to system organ class (SOC) in MedDRA. Within each system  organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first.

Within each frequency grouping, adverse drug reactions are presented in order of decreasing  seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the 
CIOMS III convention and is 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 available data).

Table 2. Adverse reactions reported in ADAURA, FLAURA and AURA studiesª 

CIOMS descriptor/         Frequency of
MedDRA SOC                       MedDRA term              overall frequency (all     CTCAE grade 3 CTCAE grades)     b         or higher b
Blood and lymphatic
Aplastic anaemia               Rare (0.07%)               0.07% system disorders

Metabolism and
Decreased appetite         Very common (19%)         1.1% nutrition disorders

Eye disorders                   Keratitis c           Uncommon (0.7%)           0.1% 

Cardiac disorders               Cardiac failure         Uncommon (0.3%)           0.1% 
Respiratory, thoracic               Epistaxis              Common (5%)              0 and mediastinal disorders             Interstitial lung diseased    Common (3.8%)e           1.1% 
Gastrointestinal                Diarrhoea             Very common (47%)         1.4% disorders                    Stomatitis f          Very common (24%)         0.5% Rashg               Very common (45%)         0.7%
Paronychia h           Very common (33%)         0.4%
Dry skini            Very common (32%)         0.1%
Pruritusj            Very common (17%)         0.1%
Alopecia              Common (4.6%)             0
Urticaria             Common (1.9%)            0.1%

Skin and                   Palmar-plantar subcutaneous tissue           erythrodysaesthesia         Common (1.7%)             0 disorders                    syndrome
Skin hyperpigmentationk      Uncommon (0.8%)            0
Erythema multiforme l       Uncommon (0.3%)            0
Cutaneous Vasculitis m      Uncommon (0.3%)            0
Toxic epidermal necrolysisn                 Not known
Stevens-Johnson
Rare (0.02%)
Syndrome o

Investigations
QTc interval prolongation p   Uncommon (0.8%)

Blood creatine phosphokinase
Common (1.6%)            0.3% increased


Left ventricular ejection
Common (3.2%) fraction decreased q,r
(findings based on test results presented      Leucocytes decreased q       Very common (65%)         1.2% as CTCAE grade
shifts)



Lymphocytes decreased q                  Very common (62%)                          6% Platelet count decreased q               Very common (53%)                        1.2% Neutrophils decreased q                 Very common (33%)                        3.2% Blood creatinine
Common (9%)                            0
Increased q
Musculoskeletal and connective tissue                              Myositis                            Rare (0.07%) disorders a Data   is pooled from ADAURA, FLAURA and AURA (AURA3, AURAex, AURA 2 and AURA1) studies; only events for patients receiving at least one dose of TAGRISSO as their randomised treatment are summarized.
b National    Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
c Includes    : corneal epithelium defect, corneal erosion, keratitis, punctate keratitis d Includes:   interstitial lung disease (1.8%), pneumonitis (1.9%), organising pneumonia (0.07%)..
e5   CTCAE grade 5 events (fatal) were reported.
f Includes:   mouth ulceration, stomatitis.
g Includes:   acne, dermatitis, dermatitis acneiform, drug eruption,
erythema, folliculitis, pustule, rash, rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, skin erosion.
h Includes:   nail bed disorder, nail bed infection, nail bed inflammation, nail discolouration, nail disorder, nail dystrophy, nail infection, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.
i Includes:   dry skin, eczema, skin fissures, xeroderma, xerosis.
j Includes:   eyelid pruritus, pruritus, pruritus generalised.
k Cases    of erythema dyschromicum perstans have been reported in the post-marketing setting.
l Five   of the 1479 patients in the ADAURA, AURA and FLAURA studies reported erythema multiforme. Post-marketing reports of erythema multiforme have also been received, including 7 reports from a post-marketing surveillance study (N=3578).
m   Estimated frequency. The upper limit of the 95% CI for the point estimate is 3/1142 (0.3%).
n   Reported during post-marketing use.
o
One event was reported in a post-marketing study, and the frequency has been derived from the ADAURA, FLAURA and AURA studies and the post-marketing study (N=5057).
p   Represents the incidence of patients who had a QTcF prolongation >500msec.
q   Represents the incidence of laboratory findings, not of reported adverse events.
r   Represents decreases greater than or equal to 10 percentage points and a drop to less than 50%.


Description of selected adverse reactions

Interstitial lung disease (ILD)
In the ADAURA, FLAURA and AURA studies, the incidence of ILD was 11% in patients of Japanese  ethnicity, 1.6% in patients of non-Japanese Asian ethnicity and 2.5% in non-Asian patients. The median  time to onset of ILD or ILD-like adverse reactions was 84 days (see section 4.4).
QTc interval prolongation
Of the 1479 patients in ADAURA, FLAURA and AURA studies treated with TAGRISSO 80 mg, 0.8% of  patients (n=12) were found to have a QTc greater than 500 msec, and 3.1% of patients (n=46) had an  increase from baseline QTc greater than 60 msec. A pharmacokinetic/pharmacodynamic analysis with 
TAGRISSO predicted a concentration dependent increase in QTc interval prolongation. No QTc-related  arrhythmias were reported in the ADAURA, FLAURA or AURA studies (see sections 4.4 and 5.1).

Gastrointestinal effects
In the ADAURA, FLAURA and AURA studies, diarrhoea was reported in 47% of patients of which 38%  were Grade 1 events, 7.9% Grade 2 and 1.4% were Grade 3; no Grade 4 or 5 events were reported.

Dose reduction was required in 0.3% of patients and dose interruption in 2%. Four events (0.3%) led to  discontinuation. In ADAURA, FLAURA and AURA3 the median time to onset was 22 days, 19 days and 
22 days, respectively, and the median duration of the Grade 2 events was 11 days, 19 days and 6 days,
 respectively.
Haematological events

Early reductions in the median laboratory counts of leukocytes, lymphocytes, neutrophils and platelets  have been observed in patients treated with TAGRISSO, which stabilised over time and then remained  above the lower limit of normal. Adverse events of leukopenia, lymphopenia, neutropenia and  thrombocytopenia have been reported, most of which were mild or moderate in severity and did not lead  to dose interruptions. Rare cases of aplastic anaemia, including fatal events, have been reported in  association with osimertinib treatment. Osimertinib should be discontinued in patients with confirmed  aplastic anaemia (see section 4.2 and 4.4).


Elderly
In ADAURA, FLAURA and AURA3 (N=1479), 43% of patients were 65 years of age and older, and 12% were 75 years of age and older. Compared with younger subjects (<65), more subjects ≥65 years old had reported adverse reactions that led to study dose modifications (interruptions or reductions) (16% versus 9%). The types of adverse events reported were similar regardless of age. Older patients reported more Grade 3 or higher adverse reactions compared to younger patients (13% versus 8%). No overall differences in efficacy were observed between these subjects and younger subjects. A consistent pattern in safety and efficacy results was observed in the analysis of AURA Phase 2 studies.

Low body weight
Patients receiving TAGRISSO 80 mg with low body weight (<50 kg) reported higher frequencies of Grade ≥3 adverse events (46% versus 31%) and QTc prolongation (12% versus 5%) than patients with higher body weight (≥50 kg).


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 an online form: https://sideeffects.health.gov.il