July 28, 2015
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Iressa

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Iressa




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Interstitial Lung Disease (ILD)

ILD or ILD-like adverse drug reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis) occurred in 1.3% of the 2462 patients who received IRESSA across clinical trials; of these, 0.7% were Grade 3 or higher and 3 cases were fatal.

Withhold IRESSA and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms such as dyspnea, cough and fever. Permanently discontinue IRESSA if ILD is confirmed [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].

Hepatotoxicity

In patients who received IRESSA across clinical trials, 11.4% of patients had increased alanine aminotransferase (ALT), 7.9% of patients had increased aspartate aminotransferase (AST), and 2.7% of patients had increased bilirubin. Grade 3 or higher liver test abnormalities occurred in 5.1% (ALT), 3.0% (AST), and 0.7% (bilirubin) of patients. The incidence of fatal hepatotoxicity was 0.04%.

Obtain periodic liver function testing. Withhold IRESSA in patients with worsening liver function and discontinue in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, Use In Specific Populations].

Gastrointestinal Perforation

Gastrointestinal perforation occurred in three (0.1%) of the 2462 IRESSA-treated patients across clinical trials [see ADVERSE REACTIONS]. Permanently discontinue IRESSA in patients who develop gastrointestinal perforation [see DOSAGE AND ADMINISTRATION].

Severe Or Persistent Diarrhea

Grade 3 or 4 diarrhea occurred in 3% of 2462 IRESSA-treated patients across clinical trials. Withhold IRESSA for severe or persistent (up to 14 days) diarrhea [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS].

Ocular Disorders Including Keratitis

Ocular disorders [keratitis (0.1%), corneal erosion and aberrant eyelash growth (0.2%), conjunctivitis, blephritis and dry eye (6.7%)] occurred in the 2462 IRESSA-treated patients across clinical trials. The incidence of Grade 3 ocular disorders was 0.1% [see ADVERSE REACTIONS]. Interrupt or discontinue IRESSA for severe, or worsening ocular disorders [see DOSAGE AND ADMINISTRATION].

Bullous And Exfoliative Skin Disorders

Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme have been reported from treatment with IRESSA. Erythema multiforme and dermatitis bullous have been reported in two patients (0.08%) across NSCLC trials (Study 2, Study 3 and Study 4). IRESSA treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.

Embryo-fetal Toxicity

Based on its mechanism of action and data from animal reproduction studies IRESSA can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy [see Use in Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labelling (PATIENT INFORMATION).

Interstitial Lung Disease: Advise patients to immediately contact their healthcare provider for new onset or worsening of pulmonary symptoms such as dyspnea, cough and fever [see WARNINGS AND PRECAUTIONS].

Hepatotoxicity: Inform patients that they will need to undergo lab tests to monitor for liver function. Advise patients to contact their healthcare provider to report any new symptoms indicating hepatic toxicity [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Perforation: Advise patients that IRESSA can increase the risk of gastrointestinal perforation and to seek immediate medical attention for severe abdominal pain [see WARNINGS AND PRECAUTIONS].

Severe or Persistent Diarrhea: Advise patients to contact their healthcare provider for severe or persistent diarrhea [see WARNINGS AND PRECAUTIONS].

Ocular Disorders including Keratitis: Advise patients promptly to contact their healthcare provider if they develop eye symptoms, lacrimation, light sensitivity, blurred vision, eye pain, red eye or changes in vision [see WARNINGS AND PRECAUTIONS]

Bullous and Exfoliative Skin Disorders: Advise patients that IRESSA can increase the risk of bullous and exfoliative skin disorders and to seek immediately medical attention for severe skin reactions [see WARNINGS AND PRECAUTIONS].

Embryo-fetal Toxicity: Advise pregnant women of the potential risk to a fetus or potential risk for loss of the pregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy [see Use in Specific Populations].

Lactation: Advise women to discontinue breast-feeding during treatment with IRESSA [see Use In Specific Populations].

Nonclinical Toxicology

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.

In a two-year carcinogenicity study in mice, administration of gefitinib at a dose of 270 mg/m²/day (approximately twice the recommended daily dose of 250 mg on a mg/m² basis; dose reduced from 375 mg/m²/day from week 22) caused hepatocellular adenomas in females. In a two-year carcinogenicity study in rats, administration of gefitinib at 60 mg/m²/day (approximately 0.4 times the recommended daily clinical dose on a mg/m² basis) caused hepatocellular adenomas and hemangiomas/hemagiosarcomas of the mesenteric lymph nodes in female rats. The clinical relevance of these findings is unknown.

In a dedicated fertility study in rats at doses ≥ 120 mg/m² (approximately equal to the recommended human dose of gefitinib on a mg/m² basis), animals presented with an increased incidence of irregular estrous, decreased corpora lutea, and decreases in uterine implants and live embryos per litter.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action and animal data, IRESSA can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose (see Animal Data). Advise pregnant women of the potential hazard to a fetus or potential risk for loss of the pregnancy.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and miscarriage is 15-20% of clinically recognized pregnancies.

Data

Animal Data

A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m², about 0.2 times 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 there was a reduction in the number of offspring born alive. This effect was more severe at 20 mg/kg (approximate the human clinical dose on a mg/m² basis) and was accompanied by high neonatal mortality soon after parturition. 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.

Lactation

Risk Summary

It is not known whether IRESSA is excreted in human milk. Animal studies indicate the gefitinib and its metabolites are present in rat milk at a concentration higher than those in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from IRESSA, advise women to discontinue breast-feeding during treatment with IRESSA.

Data

Animal Data

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.

Females And Males Of Reproductive Potential

Contraception

Based on its mechanism of action and animal data, IRESSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with IRESSA and for at least two weeks following completion of therapy.

Infertility

IRESSA may result in reduced fertility in females of reproductive potential [see Nonclinical Toxicology].

Pediatric Use

The safety and effectiveness of IRESSA in pediatric patients have not been established.

Geriatric Use

Of the 823 patients enrolled in two randomized, active-controlled clinical trials 374 patients (45%) were 65 years and older, and 93 patients (11%) were 75 years and older. No overall differences in safety were observed between patients 65 years and older and those younger than 65 years. There is insufficient information to assess for differences in efficacy between older and younger patients.

Renal Impairment

Less than four percent ( < 4%) of gefitinib and its metabolites are excreted via the kidney. No clinical studies were conducted with IRESSA in patients with severe renal impairment.

Hepatic Impairment

The systemic exposure of gefitinib was compared in patients with mild, moderate, or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification) and healthy subjects with normal hepatic function (N=10/group). The mean systemic exposure (AUC0-∞) was increased by 40% in patients with mild impairment, 263% in patients with moderate impairment, and 166% in patients with severe hepatic impairment. Monitor adverse reactions when IRESSA is administered to patients with moderate and severe hepatic impairment.

In a study comparing 13 patients with liver metastases and moderate hepatic impairment (addition of CTC grade of baseline AST/SGOT, ALP, and bilirubin equals 3 to 5) to 14 patients with liver metastases and normal hepatic function, the systemic exposure of gefitinib was similar [see WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 7/15/2015
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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