The safety database includes 941 patients from clinical trials and approximately 23,000 patients in the Expanded Access Program.

Table 3 includes drug-related adverse events with an incidence of ≥ 5% for the 216 patients who received either 250 mg or 500 mg of IRESSA monotherapy for treatment of NSCLC. The most common adverse events reported at the recommended 250 mg daily dose were diarrhea, rash, acne, dry skin, nausea, and vomiting (see PRECAUTIONS - INFORMATION FOR PATIENTS and DOSAGE AND ADMINISTRATION – Dosage Adjustment sections). The 500 mg dose showed a higher rate for most of these adverse events.

Table 4 provides drug-related adverse events with an incidence of ≥ 5% by CTC grade for the patients who received the 250 mg/day dose of IRESSA monotherapy for treatment of NSCLC. Only 2% of patients stopped therapy due to an adverse drug reaction (ADR). The onset of these ADRs occurred within the first month of therapy.

Table 3 - Drug-Related Adverse Events With an Incidence of ≥ 5% in either 250 mg or 500 mg Dose Group

Table 4 - Drug Related Adverse Events ≥ 5% at 250 mg dose by Worst CTC Grade (n=102)

Other adverse events reported at an incidence of <5% in patients who received either 250 mg or 500 mg as monotherapy for treatment of NSCLC (along with their frequency at the 250 mg recommended dose) include the following: peripheral edema (2%), amblyopia (2%), dyspnea (2%), conjunctivitis (1%), vesiculobullous rash (1%), and mouth ulceration (1%).

Interstitial Lung Disease

Cases of interstitial lung disease (ILD) have been observed in patients receiving IRESSA at an overall incidence of about 1%. Approximately 1/3 of the cases have been fatal. The reported incidence of ILD was about 2% in the Japanese post-marketing experience, about 0.3% in approximately 23,000 patients treated with IRESSA in a US expanded access program and about 1% in the studies of first-line use in NSCLC (but with similar rates in both treatment and placebo groups). Reports have described the adverse event as interstitial pneumonia, pneumonitis and alveolitis. Patients often present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization. ILD has occurred in patients who have received prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no previous therapy (12% of reported cases). Patients with concurrent idiopathic pulmonary fibrosis whose condition worsens while receiving IRESSA have been observed to have an increased mortality compared to those without concurrent idiopathic pulmonary fibrosis.

In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), IRESSA therapy should be interrupted and a prompt investigation of these symptoms should occur. If interstitial lung disease is confirmed, IRESSA should be discontinued and the patient treated appropriately (see WARNINGS - Pulmonary Toxicity, PRECAUTIONS - INFORMATION FOR PATIENTS and DOSAGE AND ADMINISTRATION - Dosage Adjustment sections).

In patients receiving IRESSA therapy, there were reports of eye pain and corneal erosion/ulcer, sometimes in association with aberrant eyelash growth (see PRECAUTIONS - INFORMATION FOR PATIENTS section). Hemorrhage, such as epistaxis and hematuria have been reported in patients receiving IRESSA. There were also rare reports of pancreatitis and very rare reports of corneal membrane sloughing, ocular ischemia/hemorrhage, toxic epidermal necrolysis, erythema multiforme, and allergic reactions, including angioedema and urticaria.

International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on IRESSA therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR (see CLINICAL PHARMACOLOGY - Drug-Drug Interactions and PRECAUTIONS - DRUG INTERACTIONS sections).

Data from non-clinical (in vitro and in vivo) studies indicate that gefitinib has the potential to inhibit the cardiac action potential repolarization process (eg, QT interval). The clinical relevance of these findings is unknown.

Substances that are inducers of CYP3A4 activity increase the metabolism of gefitinib and decrease its plasma concentrations. In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin, a dose increase to 500 mg daily should be considered in the absence of severe adverse drug reaction, and clinical response and adverse events should be carefully monitored (see CLINICAL PHARMACOLOGY - Pharmacokinetics-Drug-Drug Interactions and DOSAGE AND ADMINISTRATION - Dosage Adjustment sections).

International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on IRESSA therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR (see CLINICAL PHARMACOLOGY - Pharmacokinetics-Drug-Drug Interactions and ADVERSE REACTIONS sections).

Substances that are potent inhibitors of CYP3A4 activity (eg, ketoconazole and itraconazole) decrease gefitinib metabolism and increase gefitinib plasma concentrations. This increase may be clinically relevant as adverse experiences are related to dose and exposure; therefore, caution should be used when administering CYP3A4 inhibitors with IRESSA (see CLINICAL PHARMACOLOGY - Pharmacokinetics-Drug-Drug Interactions and ADVERSE REACTIONS sections).

Drugs that cause significant sustained elevation in gastric pH (histamine H₂-receptor antagonists such as ranitidine or cimetidine) may reduce plasma concentrations of IRESSA and therefore potentially may reduce efficacy (see CLINICAL PHARMACOLOGY - Drug-Drug Interactions section).

Phase II clinical trial data, where IRESSA and vinorelbine have been used concomitantly, indicate that IRESSA may exacerbate the neutropenic effect of vinorelbine.

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