Giotrif Adverse Reactions

Summary of the safety profile: The types of adverse reactions (ADRs) were generally associated with the EGFR inhibitory mode of action of afatinib. The summary of all ADRs is shown in Table 8. The most frequent ADRs were diarrhoea and skin related adverse events (see Precautions) as well as stomatitis and paronychia (see also Table 9, 10 and 11). Overall, dose reduction (see Dosage & Administration) led to a lower frequency of common adverse reactions.
In patients treated with once daily GIOTRIF 40 mg, dose reductions due to ADRs occurred in 57% of the patients in LUX-Lung 3 trial and in 25% of the patients in the LUX-Lung 8 trial. Discontinuation due to ADRs diarrhoea and rash/acne was 1.3% and 0% in LUX-Lung 3 and 3.8% and 2.0% in LUX-Lung 8, respectively. ILD-like adverse reactions were reported in 0.7% of afatinib treated patients. Bullous, blistering and exfoliative skin conditions have been reported including rare cases suggestive of Stevens-Johnson syndrome and toxic epidermal necrolysis although in these cases there were potential alternative aetiologies (see Precautions).
In the pivotal LUX-Lung 8 (1200.125) trial a total of 392 patients with Squamous NSCLC were treated with GIOTRIF with a starting dose of 40 mg once daily and a total of 395 patients were treated with 150 mg erlotinib once daily. After the first treatment cycle (28 days) the dose of GIOTRIF was escalated to 50 mg in 39 (10%) patients. The overall incidence of ADRs in patients treated with GIOTRIF or erlotinib was 93% vs. 81% respectively. The incidence of diarrhoea ADRs was higher in the GIOTRIF-treated patients compared to erlotinib (70% vs. 33%), while incidence of rash/acne was similar in both groups (67% vs. 67%). Dose reductions due to adverse events occurred in 27% of GIOTRIF-treated patients. Treatment was discontinued due to ADRs in 11% of patients treated with GIOTRIF, and in 5% of erlotinib treated patients.
Tabulated list of adverse reactions: Table 8 summarises the frequencies of ADRs pooled from all NSCLC trials and from post-marketing experience with daily GIOTRIF doses of 40 mg (N=497) or 50 mg (N=1638) as monotherapy. The following terms are used to rank the ADRs by frequency: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 8.)

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Description of selected adverse reactions: Very common ADRs in GIOTRIF-treated patients occurring in at least 10% of patients in trial LUX-Lung 3 and LUX-Lung 7 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Tables 9 and 10. (See Table 9.)

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The safety of GIOTRIF monotherapy in patients with squamous cell carcinoma of the lung receiving 40 mg starting dose was assessed in trial LUX-Lung 8. The most frequent ADRs were associated with the EGFR inhibitory mode of action of GIOTRIF and were consistent with trials LUX-Lung 3 and LUX-Lung 1 in patients with adenocarcinoma of the lung. The majority of patients with ADRs (65%) had Grade 1 or 2 events. The ADR of CTCAE grade 3/4 diarrhoea occurred in 9.9%/0.5% of patients. The rate of drug-related CTCAE grade 3 rash was 5.9%. ADRs led to discontinuation of treatment for 11% of patients. Discontinuation of treatment due to ADRs diarrhoea and rash/acne regardless of severity grade occurred in 3.8% and 2.0% of patients. (See Table 10.)

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Liver function test abnormalities: Liver function test abnormalities (including elevated ALT and AST) were observed in patients receiving GIOTRIF 40 mg. These elevations were mainly transient and did not lead to discontinuation. Grade 2 (>2.5 to 5.0 times upper limit of normal (ULN)) ALT elevations occurred in <8% of patients treated with this medicinal product. Grade 3 (>5.0 to 20.0 times ULN) elevations occurred in <4% of patients treated with GIOTRIF (see Precautions).
Description of selected adverse reactions: Very common ADRs in GIOTRIF-treated patients occurring in at least 10% of patients in trial LUX-Lung 8 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 11. (See Table 11.)

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Liver function test abnormalities: Liver function test abnormalities (including elevated ALT and AST) were observed in patients receiving GIOTRIF 40 mg. These elevations were mainly transient and did not lead to discontinuation. Grade 2 ALT elevations occurred in 1% and Grade 3 elevations occurred in 0.8% of patients treated with GIOTRIF (see Precautions).