Gefitinib

Uses and Indications

Gefitinib tablets are indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test.

Limitations of Use

The safety and efficacy of gefitinib tablets have not been established in patients whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.

No teratogenic or nonteratogenic effects are mentioned in the provided information.

Dosage and Administration

The recommended dosage of Gefitinib (Iressa) is 250 mg administered orally once daily. This dosage can be taken with or without food. Gefitinib is available in both coated and film-coated tablet forms. It is important for healthcare professionals to ensure that patients adhere to the prescribed dosage regimen for optimal therapeutic outcomes.

Contraindications

There are no contraindications for the use of Gefitinib or Iressa.

Warnings and Precautions

Interstitial lung disease (ILD) has been reported in patients taking gefitinib tablets. It is crucial to withhold gefitinib for any worsening of respiratory symptoms and to discontinue the medication if ILD is confirmed.

Hepatotoxicity

Periodic liver function testing is recommended. Gefitinib should be withheld for Grade 2 or higher elevations in ALT and/or AST levels, and discontinued in cases of severe hepatic impairment.

Gastrointestinal Perforation

Discontinue gefitinib tablets immediately if gastrointestinal perforation occurs.

Diarrhea

Withhold gefitinib tablets for Grade 3 or higher diarrhea.

Ocular Disorders

Signs and symptoms of severe or worsening ocular disorders, including keratitis, necessitate withholding gefitinib. Discontinue the medication for persistent ulcerative keratitis.

Skin Reactions

Withhold gefitinib tablets for Grade 3 or higher skin reactions or any exfoliative conditions.

Embryo-fetal Toxicity

Gefitinib can cause fetal harm. Patients should be advised of the potential risk to a fetus and the necessity of using effective contraception during treatment.

Laboratory Tests

Periodic liver function testing is essential to monitor liver health during treatment with gefitinib.

Discontinuation Instructions

Patients should discontinue gefitinib tablets for gastrointestinal perforation and persistent ulcerative keratitis.

Side Effects

• Serious Adverse Reactions:

  • Interstitial Lung Disease (ILD): ILD has been reported in patients taking gefitinib. It is recommended to withhold gefitinib for any worsening of respiratory symptoms and to discontinue the medication if ILD is confirmed.

  • Hepatotoxicity: Periodic liver function testing is advised. Gefitinib should be withheld for Grade 2 or higher elevations in ALT and/or AST, and discontinued in cases of severe hepatic impairment.

  • Gastrointestinal Perforation: Discontinuation of gefitinib is necessary in the event of gastrointestinal perforation.

  • Diarrhea: Withholding gefitinib is recommended for Grade 3 or higher diarrhea.

  • Ocular Disorders including Keratitis: Patients should have gefitinib withheld for signs and symptoms of severe or worsening ocular disorders, including keratitis, and the medication should be discontinued for persistent ulcerative keratitis.

  • Bullous and Exfoliative Skin Disorders: Gefitinib should be withheld for Grade 3 or higher skin reactions or exfoliative conditions.

  • Embryo-fetal Toxicity: Gefitinib can cause fetal harm. Patients should be advised of the potential risk to a fetus and the necessity of using effective contraception.

• Commonly Reported Adverse Drug Reactions (ADRs):

  • Skin reactions

  • Diarrhea (reported in more than 20% of patients and greater than placebo)

• Additional Notes:

  • Adverse events associated with gefitinib were predominantly mild to moderate in severity and consistent with the known safety profile of the medication.

Drug Interactions

Gefitinib, also known as Iressa, is subject to several important drug interactions that can affect its efficacy and safety profile.

Pharmacokinetic Interactions

• CYP3A4 Inducers: In patients receiving a strong CYP3A4 inducer, the dosage of gefitinib should be increased to 500 mg daily to maintain therapeutic levels.

• CYP3A4 Inhibitors: When gefitinib is used concomitantly with a CYP3A4 inhibitor, it is essential to monitor for adverse reactions due to potential increased plasma concentrations of gefitinib.

Pharmacodynamic Interactions

• Drugs Affecting Gastric pH: The concomitant use of gefitinib with proton pump inhibitors should be avoided if possible, as these medications can alter gastric pH and potentially affect the absorption and efficacy of gefitinib.

• Warfarin: Patients taking warfarin while on gefitinib should be closely monitored for changes in prothrombin time or INR, as there is a risk of hemorrhage associated with this combination.

These interactions highlight the need for careful management and monitoring when prescribing gefitinib, particularly in patients who are on multiple medications.

Pediatric Use

The safety and effectiveness of gefitinib tablets (also known as Iressa) in pediatric patients have not been established. There are no available data to support the use of gefitinib in children or adolescents.

Geriatric Use

In clinical trials involving 823 patients, 45% were aged 65 years and older, with 11% aged 75 years and older. No overall differences in safety were observed between elderly patients (65 years and older) and those younger than 65 years. However, there is insufficient information to assess differences in efficacy between older and younger patients. Therefore, while no specific dosage adjustments are recommended based solely on age, careful monitoring of geriatric patients is advised due to the lack of comprehensive efficacy data in this population.

Pregnancy

Based on its mechanism of action and animal data, gefitinib can cause fetal harm when administered to pregnant patients. Animal reproductive studies have demonstrated that oral administration of gefitinib from organogenesis through weaning results in fetotoxicity and neonatal death at doses below the recommended human dose.

Pregnant patients should be advised of the potential hazard to the fetus and the risk of pregnancy loss. 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 for major birth defects is estimated to be 2-4%, and the risk of miscarriage is approximately 15-20% of clinically recognized pregnancies.

In a single-dose study in rats, gefitinib was shown to cross 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 pronounced at a dose of 20 mg/kg (approximately the human clinical dose on a mg/m² basis), which was associated with high neonatal mortality shortly after parturition. Additionally, in rabbits, a dose of 20 mg/kg/day (240 mg/m², about twice the recommended dose in humans on a mg/m² basis) resulted in reduced fetal weight.

Given these findings, it is crucial for healthcare providers to consider the potential risks when prescribing gefitinib to pregnant patients and to discuss these risks thoroughly with them.

Lactation

It is not known whether gefitinib (IRESSA) is excreted in human milk. However, animal studies have demonstrated that gefitinib and its metabolites are present in rat milk at concentrations significantly higher than those found in maternal plasma, with levels being 11-to-19-fold greater in milk than in blood following oral exposure to a dose of 5 mg/kg in lactating rats.

Due to the potential for serious adverse reactions in nursing infants, it is advised that lactating mothers discontinue breastfeeding during treatment with gefitinib. The risks associated with gefitinib exposure in breastfed infants necessitate caution, and healthcare providers should counsel women on the importance of avoiding breastfeeding while on this medication.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available labeling for Gefitinib (Iressa). The provided information does not include any details regarding dosage adjustments, special monitoring, or safety considerations for individuals with reduced kidney function. Consequently, healthcare professionals should exercise caution and consider the lack of guidance when prescribing this medication to patients with renal impairment. Regular monitoring of renal function may be prudent in these cases, although specific recommendations are not outlined in the current labeling.

Hepatic Impairment

Patients with hepatic impairment should undergo periodic liver function testing due to the potential for hepatotoxicity associated with gefitinib (Iressa). In cases where alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are elevated to Grade 2 or higher, gefitinib tablets should be withheld. If severe hepatic impairment is identified, discontinuation of gefitinib is recommended. Monitoring of liver function is essential to ensure patient safety and to guide treatment decisions.

Overdosage

In cases of suspected overdose with gefitinib (also known as Iressa), it is recommended to interrupt the administration of the tablets immediately. Supportive care should be instituted, and patients should be observed until clinical stabilization is achieved.

Clinical experience indicates that doses ranging from 1,500 mg to 3,500 mg have been administered weekly to patients, with no increase in gefitinib exposure observed with escalating doses. Adverse events associated with overdose are generally mild to moderate in severity and align with the known safety profile of gefitinib.

It is important to note that there are no specific measures or treatments indicated following an overdose of gefitinib tablets. Continuous monitoring and supportive care remain the primary interventions in managing such cases.

Nonclinical Toxicology

Gefitinib has undergone extensive nonclinical testing to evaluate its safety profile, including assessments of genotoxicity, carcinogenicity, and fertility impairment.

Genotoxicity

Gefitinib has been evaluated for genotoxic potential through a series of in vitro assays, including bacterial mutation, mouse lymphoma, and human lymphocyte tests, as well as an in vivo rat micronucleus test. Under the conditions of these studies, gefitinib did not induce genetic damage.

Carcinogenesis

In a two-year carcinogenicity study conducted in mice, gefitinib was administered at a dose of 270 mg/m²/day, which is approximately twice the recommended daily dose of 250 mg on a mg/m² basis (the dose was reduced from 375 mg/m²/day after week 22). This study revealed the development of hepatocellular adenomas in female mice. Similarly, a two-year carcinogenicity study in rats at a dose of 60 mg/m²/day (approximately 0.4 times the recommended daily clinical dose on a mg/m² basis) resulted in the occurrence of hepatocellular adenomas and hemangiomas/hemangiosarcomas of the mesenteric lymph nodes in female rats. The clinical relevance of these findings remains uncertain.

Impairment of Fertility

A dedicated fertility study in rats administered gefitinib at doses greater than or equal to 120 mg/m² (approximately equal to the recommended human dose on a mg/m² basis) indicated an increased incidence of irregular estrous cycles, a reduction in corpora lutea, and decreases in both uterine implants and live embryos per litter.

Storage and Handling

Gefitinib is supplied as coated tablets in the following configurations:

• 250 mg tablets are available in bottles containing 30 tablets and 500 tablets.

• Additionally, gefitinib is provided in blisters consisting of 3 cards × 10 tablets, with each carton containing 30 tablets (1 overwrap contains 3 unit dose blister cards, each blister card containing 10 tablets).

Gefitinib tablets should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F). It is recommended to dispense the tablets in a tight, light-resistant container equipped with a child-resistant closure to ensure proper handling and storage.