Apo-Gefitinib Adverse Reactions

Adverse Drug Reaction Overview: Adverse drug reactions (ADR) found to be associated with treatment with gefitinib tablets are shown in Table 5. The most common adverse drug reactions reported at the recommended 250 mg daily dose, occurring in more than 20% of patients, are diarrhoea, sometimes associated with dehydration and mainly mild or moderate in nature (CTC grade 1 or 2) and less commonly, severe (CTC grade 3 or 4); and skin reactions (including rash, acne, dry skin and pruritus) (Table 5). Approximately 10% of patients had a severe ADR (Common Toxicity Criteria, (CTC) grade 3 or 4). Approximately 3% of patients stopped therapy due to an ADR. The onsets of these ADRs usually occurred within the first month of therapy and were generally mild and non-cumulative as well as reversible.
ADRs have been assigned to the frequency categories in Table 5 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 gefitinib-treated patients) (see Pharmacology: Clinical Trials under Actions). In assigning these frequencies no account was taken of the frequency of reports within the comparative treatment groups or whether the investigator considered it to be related to study medication. The frequency of ADRs relating to abnormal laboratory values is based on patients with a change in baseline of 2 or more CTC grades in the relevant laboratory parameters. (See Table 5.)

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Clinical Trial Adverse Drug Reactions: IPASS STUDY (D791A00007): In IPASS, the most commonly reported adverse events for patients treated with gefitinib tablets were diarrhoea and skin reactions (including rashes/acnes, dry skin and pruritus). Overall, for gefitinib-treated patients with an EGFR mutation positive status, the profile of the most common adverse events was similar to that reported in the overall population and consistent with the known safety profile of gefitinib.
Gefitinib had a more favourable tolerability profile than carboplatin/paclitaxel doublet chemotherapy, indicated by fewer CTC grade 3, 4 or 5 adverse events (31.6% versus 62.5%), fewer dose modifications due to toxicity (16.1% versus 35.2% [carboplatin] / 37.5% [paclitaxel]) and fewer adverse events leading to discontinuation of randomized treatment (6.9% versus 13.6%). In addition, fewer treatment-related adverse events (88.6% versus 96.6%) were reported with gefitinib compared with carboplatin/paclitaxel.
Table 6 summarizes the most commonly reported adverse events observed with gefitinib and carboplatin/paclitaxel therapies in the IPASS trial irrespective of causality. (See Table 6.)

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Formal statistical analyses were performed for ten pre-specified events possibly associated with gefitinib or carboplatin/paclitaxel treatment. This included relevant adverse events of any CTC grade and laboratory parameter values of CTC grade ≥3 (worsenings from baseline only) occurring during the period on randomized treatment (Table 7). Events of rashes/acnes, diarrhoea and CTC Grade ≥3 liver transaminases were reported at a statistically significantly higher incidence in the gefitinib arm. Events of neurotoxicity, and CTC Grade ≥3 haematological toxicity (CTC Grade ≥3 neutropenia, leukopenia, thrombocytopenia, and anaemia) were reported at a statistically significantly higher incidence in the carboplatin/paclitaxel arm. Although nausea and vomiting were included in the group of five events considered possibly associated with gefitinib treatment, the incidence of both was statistically significantly higher in the carboplatin/paclitaxel arm despite premedication. (See Table 7.)

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Interstitial Lung Disease (ILD): In the phase III open-label IPASS trial (see Pharmacology: Clinical Trials under Actions) comparing gefitinib to carboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected patients with advanced NSCLC in Asia, the incidence of ILD-type events was 2.6% on the gefitinib treatment arm versus 1.4% on the carboplatin/paclitaxel treatment arm.
In the INTEREST trial, the incidence of ILD type events was similar for both treatments (gefitinib 10 patients [1.4%] versus docetaxel 8 patients [1.1%]).
In the ISEL trial, the incidence of ILD-type events in the overall population was similar, and approximately 1% in both treatment arms. The majority of ILD-type events reported were from patients of Oriental ethnicity and the ILD incidence among patients of Oriental ethnicity receiving gefitinib therapy and placebo was similar, approximately 3% and 4%, respectively. One ILD-type event was fatal, and this occurred in a patient receiving placebo.
In a Post-Marketing Surveillance study in Japan (3350 patients) the reported rate of ILD-type events in patients receiving gefitinib was 5.8%.
In a Japanese Pharmacoepidemiological case-control study (see Respiratory under Precautions) in patients with NSCLC, the crude cumulative incidence of ILD (unadjusted for imbalances in patient characteristics) at 12 weeks follow-up was 4.0% in patients receiving gefitinib and 2.1% in those receiving chemotherapy and the adjusted odds ratio (OR) of developing ILD was 3.2 (95% confidence interval (CI) 1.9 to 5.4) for gefitinib versus chemotherapy. An increased risk of ILD on gefitinib relative to chemotherapy was seen predominantly during the first 4 weeks of treatment (adjusted OR 3.8; 95% CI 1.9 to 7.7); thereafter the relative risk was lower (adjusted OR 2.5; 95% CI 1.1 to 5.8).
Post-Market Adverse Drug Reactions: The following safety signals have been raised from post-marketing adverse event reports: ILD, pancreatitis, allergic reactions (including angioedema and urticaria), hepatitis and pyrexia.