Tagrisso Adverse Reactions

Summary of the safety profile: Studies in EGFR mutation-positive NSCLC patients: The safety of TAGRISSO as a monotherapy is based on pooled data from 1813 patients with EGFR mutation-positive non-small cell lung cancer. These patients received TAGRISSO at a dose of 80 mg daily in four randomised Phase 3 studies (ADAURA, adjuvant; FLAURA and FLAURA2 (monotherapy arm), first-line and AURA3, second line only), two Phase 2 single-arm studies (AURAex and AURA2, second line or later) and one Phase 1 study (AURA1, first-line or later) (see Pharmacology: Pharmacodynamics under Actions). Most adverse reactions were Grade 1 or 2 in severity. The most commonly reported adverse drug reactions (ADRs) were diarrhoea (47%) and rash (46%), paronychia (34%), dry skin (32%), and stomatitis (24%). Grade 3 and Grade 4 adverse reactions across both studies were 11% and 0.2%, respectively. In patients treated with TAGRISSO 80 mg once daily, dose reductions due to adverse reactions occurred in 3.9% of the patients. Discontinuation due to adverse reactions was 5.2%.
The safety of TAGRISSO given in combination with pemetrexed and platinum-based chemotherapy is based on data in 276 patients with EGFR mutation-positive NSCLC and was consistent with TAGRISSO monotherapy and known safety profiles of pemetrexed and platinum-based chemotherapy. The most commonly reported ADRs when TAGRISSO was given in combination with pemetrexed and platinum based chemotherapy were rash (49%), diarrhoea (43%), decreased appetite (31%), stomatitis (31%), paronychia (27%) and dry skin (24%). When TAGRISSO is administered as combination therapy, refer to the Summary of Product Characteristics for the respective combination therapy components prior to initiation of treatment.
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 ms) 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 9 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the 1813 EGFR mutation-positive NSCLC patients who received TAGRISSO monotherapy at a dose of 80 mg daily in the ADAURA, FLAURA, FLAURA2, AURA3, AURAex, AURA2 and AURA1 studies and in 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study.
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). (See Table 9.)

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Description of selected adverse reactions: Interstitial lung disease (ILD): In the FLAURA, FLAURA2 (monotherapy arm) and AURA studies, the incidence of ILD was 11.2% in patients of Japanese ethnicity, 2.3% in patients of non-Japanese Asian ethnicity and 2.7% in non-Asian patients. The median time from first dose to onset of ILD or ILD-like adverse reactions was 85 days (see Precautions).
QTc interval prolongation: Of the 1813 patients in ADAURA, FLAURA, FLAURA2 and AURA studies treated with TAGRISSO monotherapy (80 mg), 1.1% of patients (n=20) were found to have a QTc greater than 500 msec, and 4.3% of patients (n=78) 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, FLAURA2, or AURA studies (see Precautions and Pharmacology: Pharmacodynamics under Actions). In patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, the proportion of patients who experienced a QTc interval prolongation of greater than 500 msec with a greater than 60 msec increase from baseline was low and was similar with monotherapy (1.8% versus 1.5%).
Gastrointestinal effects: In the ADAURA, FLAURA, FLAURA2 and AURA studies (TAGRISSO monotherapy; N=1813), diarrhoea was reported in 47% of patients of which 37% were Grade 1 events, 8.6% Grade 2 and 1.4% were Grade 3; no Grade 4 or 5 events were reported. Dose reduction was required in 0.5% of patients and dose interruption in 1.9%. Four event (0.2%) led to discontinuation. In ADAURA, FLAURA, FLAURA2 (monotherapy arm) and AURA3 the median time to onset was 22 days, 19 days, 22 days and 22 days, respectively, and the median duration of the Grade 2 events was 11 days, 19 days, 17 days and 6 days, respectively. In patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, diarrhoea was reported in 43% of patients versus 41% of patients in monotherapy, most of these diarrhoea events were Grade 1 and Grade 2 events.
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 TAGRISSO treatment. TAGRISSO should be discontinued in patients with confirmed aplastic anaemia (see Dosage & Administration and Precautions).
Elderly: In ADAURA, FLAURA, FLAURA2 and AURA3 (TAGRISSO monotherapy; N=1813), 42% of patients were 65 years of age and older, and 11% were 75 years of age and older. Compared with younger patients (<65), more patients ≥65 years old had reported adverse reactions that led to study dose modifications (interruptions or reductions) (17% versus 10%). 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 (14% versus 10%). No overall differences in efficacy were observed between older and younger patients. A consistent pattern in safety and efficacy results was observed in the analysis of AURA Phase 2 studies. Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, 104 patients were ≥65 years and 23 patients were ≥75 years of age. Older patients (≥65 years) reported similar Grade 3 or higher adverse reactions compared to <65 years old patients (36% versus 36%) respectively. Dose modification for adverse reactions were reported in a higher proportion of patients ≥65 years as compared to <65 years (34% vs 20%).
Low body weight: Patients receiving TAGRISSO monotherapy (80 mg) with low body weight (<50 kg) reported higher frequencies of Grade ≥3 adverse reactions (20% versus 10%) and QTc prolongation (13% versus 6%) than patients with higher body weight (≥50 kg). Patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy with low body weight (<50 kg) reported similar frequencies of Grade ≥3 adverse reactions (32% versus 37%) when compared to patients with higher body weight (≥50 kg). In contrast, dry skin (34% versus 22%) and stomatitis (40% versus 30%) were reported at higher frequencies in patients with low body weight (<50 kg) versus higher body weight (≥50 kg).