WARNINGS
Pulmonary Toxicity
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.
Based on data from worldwide clinical studies, expanded access/compassionate use and post-marketing use the estimated reporting rate of ILD-type events overall is approximately 0.3% outside of Japan and approximately 3% in Japan. From a phase III double blind clinical trial (1692 patients) comparing IRESSA plus best supportive care (BSC) to placebo plus BSC in patients with advanced NSCLC who had received 1 or 2 prior chemotherapy regimens and were refractory or intolerant to their most recent regimen, 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 Asian ethnicity and the ILD incidence among patients of Asian ethnicity receiving IRESSA 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 IRESSA was 5.8%.
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 ILD is confirmed, IRESSA should be discontinued and the patient treated appropriately (see PRECAUTIONS-Information for Patients, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).
Pregnancy Category D
IRESSA may cause fetal harm when administered to a pregnant woman. A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m2, about 1/5 the recommended human dose on a mg/m2 basis). When pregnant rats were treated with 5 mg/kg from the beginning of organogenesis to the end of weaning gave birth, there was a reduction in the number of offspring born alive. This effect was more severe at 20 mg/kg and was accompanied by high neonatal mortality soon after parturition. In this study a dose of 1 mg/kg caused no adverse effects.
In rabbits, a dose of 20 mg/kg/day (240 mg/m2, about twice the recommended dose in humans on a mg/m2 basis) caused reduced fetal weight.
There are no adequate and well-controlled studies in pregnant women using IRESSA. If IRESSA is used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.
PRECAUTIONS
Hepatotoxicity
Asymptomatic increases in liver transaminases have been observed in IRESSA treated patients; therefore, periodic liver function (transaminases, bilirubin, and alkaline phosphatase) testing should be considered. Discontinuation of IRESSA should be considered if changes are severe.
Patients with Hepatic Impairment
In vitro and in vivo evidence suggest that gefitinib is cleared primarily by the liver. Therefore, gefitinib exposure may be increased in patients with hepatic dysfunction. In patients with liver metastases and moderately to severely elevated biochemical liver abnormalities, however, gefitinib pharmacokinetics were similar to the pharmacokinetics of individuals without liver abnormalities (see CLINICAL PHARMACOLOGY-Pharmacokinetics- Special Populations section). The influence of non-cancer related hepatic impairment on the pharmacokinetics of gefitinib has not been evaluated.
Information for Patients
Patients should be advised to seek medical advice promptly if they develop 1) severe or persistent diarrhea, nausea, anorexia, or vomiting, as these have sometimes been associated with dehydration; 2) an onset or worsening of pulmonary symptoms, ie, shortness of breath or cough; 3) an eye irritation; or, 4) any other new symptom (see WARNINGS-Pulmonary Toxicity, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION-Dosage Adjustment sections).
Women of childbearing potential must be advised to avoid becoming pregnant (see WARNINGS-Pregnancy Category D).
Drug Interactions
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Gefitinib has been tested for genotoxicity in a series of in vitro (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test. Under the conditions of these assays, gefitinib did not cause genetic damage.
A 2-year carcinogenicity study in rats resulted in a small but statistically significant increased incidence of hepatocellular adenomas in both male and female rats and mesenteric lymph node hemangiosarcomas in female rats at the highest dose (10 mg/kg/day) only. The hepatocellular adenomas were also seen in a 2- year carcinogenicity study in mice, which demonstrated a small increased incidence of this finding in male mice dosed at 50 mg/kg/day, and in both male and female mice at the highest dose of 90 mg/kg/day (reduced from 125 mg/kg/day from week 22). The effects reached statistical significance for the female mice, but not for the males. The clinical relevance of these findings is unknown.
Pregnancy
Pregnancy Category D (see WARNINGS and PRECAUTIONS-Information for Patients sections).
Nursing Mothers
It is not known whether IRESSA is excreted in human milk. Following oral administration of carbon-14 labeled gefitinib to rats 14 days postpartum, concentrations of radioactivity in milk were higher than in blood. Levels of gefitinib and its metabolites were 11-to-19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while receiving IRESSA therapy.
Pediatric Use
IRESSA is not indicated for use in pediatric patients as safety and effectiveness have not been established (see CLINICAL PHARMACOLOGY-Special Populations-Pediatric).
In clinical trials of IRESSA alone or with radiation in pediatric patients with primary Central Nervous System (CNS) tumors, cases of CNS hemorrhage and death have been reported. There are insufficient data in pediatric patients to establish a causal relationship. There is no evidence to suggest increased risk of cerebral hemorrhage in adult patients with NSCLC receiving IRESSA.
Geriatric Use
Of the total number of patients participating in trials of second- and third-line IRESSA treatment of NSCLC, 65% were aged 64 years or less, 30.5 % were aged 65 to 74 years, and 5% of patients were aged 75 years or older. No differences in safety or efficacy were observed between younger and older patients.
Patients with Severe Renal Impairment
The effect of severe renal impairment on the pharmacokinetics of gefitinib is not known. Patients with severe renal impairment should be treated with caution when given IRESSA.
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