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Pulmonary Toxicity

Cases of interstitial lung disease (ILD) have been observed in patients receiving IRESSA (getfitinib) 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 (getfitinib) 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 (getfitinib) 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 (getfitinib) therapy should be interrupted and a prompt investigation of these symptoms should occur. If interstitial lung disease is confirmed, IRESSA (getfitinib) 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 (getfitinib) 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 5mg/kg (30 mg/m², about 1/5 the recommended human dose on a mg/m²basis). 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/m²basis) caused reduced fetal weight.

There are no adequate and well-controlled studies in pregnant women using IRESSA (getfitinib) . If IRESSA (getfitinib) 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.

Hepatotoxicity

Asymptomatic increases in liver transaminases have been observed in IRESSA (getfitinib) -treated patients; therefore, periodic liver function (transaminases, bilirubin, and alkaline phosphatase) testing should be considered. Discontinuation of IRESSA (getfitinib) should be considered if changes are severe.

Patients with Hepatic Impairment

In vitroand 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 pharmacoki-netics 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.

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.

Carcinogenicity studies have not been conducted with gefitinib.

Pregnancy

Pregnancy Category D (see WARNINGS and PRECAUTIONS - INFORMATION FOR PATIENTS sections).

Nursing Mothers

It is not known whether IRESSA (getfitinib) 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 (getfitinib) therapy.

Pediatric Use

IRESSA (getfitinib) is not indicated for use in pediatric patients, as safety and effectiveness have not been established. In clinical trials of IRESSA (getfitinib) alone or with radiation in pediatric patients with primary Central Nervous System (CNS) tumors, cases of CNS hemor-rhageand 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 (getfitinib) .

Geriatric Use

Of the total number of patients participating in trials of second- and third-line IRESSA (getfitinib) treatment of NSCLC, 65% were aged 64 years or less, 30.5% were aged 65 to 74years, 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 (getfitinib) .

Last reviewed on RxList: 10/2/2008
This monograph has been modified to include the generic and brand name in many instances.