Iressa

Description

Gefitinib is a kinase inhibitor with the chemical name 4-Quinazolinamine N-(3-chloro-4-fluorophenyl)-7-methoxy-6-3-(4-morpholinyl) propoxy. Its molecular formula is C22H24ClFN4O3, and it has a relative molecular mass of 446.9 daltons. Gefitinib appears as a white-colored powder and is classified as a free base. The molecule exhibits pKa values of 5.4 and 7.2, demonstrating sparing solubility at pH 1, while being practically insoluble above pH 7. The solubility decreases sharply between pH 4 and pH 6. In non-aqueous solvents, gefitinib is freely soluble in glacial acetic acid and dimethyl sulfoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol, and acetonitrile.

IRESSA® (gefitinib) is available in the form of brown film-coated tablets, each containing 250 mg of gefitinib for oral administration. The inactive ingredients in the tablet core include lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, and magnesium stearate. The tablet coating consists of hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide, and yellow ferric oxide.

Uses and Indications

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

Limitations of Use: The safety and efficacy of IRESSA have not been established in patients with tumors harboring EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations.

Dosage and Administration

The recommended dose for the medication is 250 mg, administered orally once daily. It may be taken with or without food, allowing for flexibility in patient adherence. Healthcare professionals should ensure that patients are informed about the dosing schedule and the option to take the medication in conjunction with meals if preferred.

Contraindications

There are no contraindications associated with the use of this product. It is not classified as a controlled substance, and there are no identified risks of abuse, misuse, or dependence.

Warnings and Precautions

Interstitial lung disease (ILD) has been reported in patients receiving IRESSA. Healthcare professionals should monitor patients for any worsening of respiratory symptoms and consider withholding IRESSA in such cases. If ILD is confirmed, discontinuation of IRESSA is necessary.

Hepatotoxicity is another significant concern associated with IRESSA. It is recommended that periodic liver function tests be conducted to monitor liver health. Should there be any elevations in ALT and/or AST levels classified as Grade 2 or higher, IRESSA should be withheld. In cases of severe hepatic impairment, discontinuation of the medication is warranted.

Gastrointestinal perforation is a serious adverse effect that necessitates immediate discontinuation of IRESSA. Additionally, if a patient experiences Grade 3 or higher diarrhea, IRESSA should be withheld until the condition is resolved.

Ocular disorders, including keratitis, require careful attention. If patients exhibit signs or symptoms of severe or worsening ocular conditions, IRESSA should be withheld. Persistent ulcerative keratitis mandates discontinuation of the medication.

Patients may also experience bullous and exfoliative skin disorders. In instances of Grade 3 or higher skin reactions or exfoliative conditions, it is advised to withhold IRESSA.

It is crucial to inform patients about the potential for embryo-fetal toxicity associated with IRESSA. Healthcare providers should counsel patients on the risk of fetal harm and the importance of using effective contraception during treatment.

Side Effects

Adverse reactions associated with IRESSA have been observed in clinical trials and postmarketing experiences, with a range of common and serious reactions reported.

Common adverse reactions include skin reactions and diarrhea, which were noted to occur in patients during treatment.

Serious adverse reactions necessitate careful monitoring and management. Interstitial lung disease (ILD) has been reported in patients taking IRESSA; it is recommended to withhold the medication for any worsening of respiratory symptoms and to discontinue it if ILD is confirmed. Hepatotoxicity is another serious concern; periodic liver function testing is advised, and IRESSA should be withheld for Grade 2 or higher elevations in ALT and/or AST. In cases of severe hepatic impairment, discontinuation of IRESSA is warranted.

Gastrointestinal perforation is a critical adverse reaction that requires immediate discontinuation of IRESSA. Diarrhea, while common, can also be serious; treatment should be withheld for Grade 3 or higher diarrhea. Ocular disorders, including keratitis, have been reported, and IRESSA should be withheld for any signs or symptoms of severe or worsening ocular conditions, with discontinuation recommended for persistent ulcerative keratitis. Additionally, bullous and exfoliative skin disorders may occur, necessitating withholding of IRESSA for Grade 3 or higher skin reactions or exfoliative conditions.

It is important to note that IRESSA carries a risk of embryo-fetal toxicity, which can cause fetal harm. Patients should be advised of this potential risk and the necessity of using effective contraception during treatment.

Overall, adverse events related to IRESSA were predominantly mild to moderate in severity and aligned with the known safety profile of the medication.

Drug Interactions

Concomitant use of IRESSA with strong CYP3A4 inducers necessitates an increase in the IRESSA dosage to 500 mg daily to maintain therapeutic efficacy.

When IRESSA is used alongside CYP3A4 inhibitors, it is essential to monitor patients for potential adverse reactions due to increased drug exposure.

The use of proton pump inhibitors (PPIs) with IRESSA should be avoided if possible, as these drugs can significantly affect gastric pH and potentially alter the absorption and effectiveness of IRESSA.

For patients on warfarin, careful monitoring of prothrombin time or INR is advised to detect any changes that may indicate an increased risk of hemorrhage.

Packaging & NDC

The table below lists all NDC Code configurations of Iressa (gefitinib), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of IRESSA in pediatric patients have not been established. There are currently no data available to support its use in children or adolescents. Therefore, caution is advised when considering treatment options for this population.

Geriatric Use

In clinical trials involving 823 patients, 45% (374 patients) were aged 65 years and older, with 11% (93 patients) aged 75 years and older. The data indicate that there were no overall differences in safety profiles between elderly patients (65 years and older) and those younger than 65 years.

However, there is insufficient information to evaluate potential differences in efficacy between geriatric patients and their younger counterparts. Therefore, while no specific dosage adjustments are recommended based solely on age, healthcare providers should remain vigilant in monitoring elderly patients for any adverse effects, given the variability in individual responses to treatment in this population.

Pregnancy

Based on its mechanism of action and animal data, IRESSA (gefitinib) can cause fetal harm when administered to a pregnant woman. Animal reproductive studies have demonstrated that oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Pregnant women should be advised of the potential hazard to a fetus or 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. A single-dose study in rats indicated 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 pronounced at a dose of 20 mg/kg (approximately equivalent to 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, healthcare professionals should carefully consider the risks when prescribing IRESSA to women of childbearing potential and pregnant patients.

Lactation

It is not known whether IRESSA is excreted in human milk. However, animal studies have shown that gefitinib and its metabolites are present in rat milk at concentrations higher than those in maternal plasma. Specifically, levels of gefitinib and its metabolites were found to be 11-to-19-fold higher in milk than in blood following oral exposure of lactating rats to a dose of 5 mg/kg. Due to the potential for serious adverse reactions in nursing infants from IRESSA, it is advised that lactating mothers discontinue breast-feeding during treatment with IRESSA.

Renal Impairment

There is no specific information regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment should undergo periodic liver function testing to monitor for hepatotoxicity. In the event of Grade 2 or higher elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), IRESSA should be withheld. If severe hepatic impairment is identified, discontinuation of IRESSA is recommended. Regular monitoring and appropriate management of liver function are essential to ensure patient safety and treatment efficacy.

Overdosage

In cases of suspected overdose with IRESSA, it is essential to take immediate action to ensure patient safety. The recommended initial step is to interrupt the administration of IRESSA. Following this, supportive care should be instituted, and the patient should be closely observed until clinical stabilization is achieved.

Clinical data indicate that in a study involving twenty-three patients treated weekly with doses ranging from 1500 mg to 3500 mg, the exposure to IRESSA did not increase proportionally with the increasing dose. This suggests that the pharmacokinetics of IRESSA may not be significantly altered by higher doses within this range.

Adverse events reported in these cases were predominantly mild to moderate in severity and aligned with the established safety profile of IRESSA. It is important to note that there are no specific measures or treatments recommended for managing IRESSA overdose. Therefore, the focus should remain on supportive care and monitoring the patient’s condition until they are stabilized.

Nonclinical Toxicology

Gefitinib has undergone extensive evaluation for genotoxicity through a series of in vitro assays, including bacterial mutation tests, mouse lymphoma assays, and human lymphocyte tests, as well as an in vivo rat micronucleus test. The results from these studies indicate that gefitinib does not induce genetic damage under the tested conditions.

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, with the dose being 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 involved the administration of gefitinib at a dose of 60 mg/m²/day, approximately 0.4 times the recommended daily clinical dose on a mg/m² basis. This study found hepatocellular adenomas and hemangiomas/hemagiosarcomas of the mesenteric lymph nodes in female rats. The clinical significance of these findings remains uncertain.

In a dedicated fertility study in rats, doses of gefitinib at or above 120 mg/m², which is approximately equivalent to the recommended human dose on a mg/m² basis, were associated with an increased incidence of irregular estrous cycles, a reduction in corpora lutea, and decreases in both uterine implants and live embryos per litter.

Postmarketing Experience

Postmarketing experience with IRESSA has identified several adverse events reported voluntarily or through surveillance programs.

Inflammation of the lung has been observed, which may lead to serious outcomes, including death. Symptoms associated with this condition can mimic those of lung cancer, and patients are advised to inform their healthcare provider immediately if they experience any new or worsening respiratory issues, such as trouble breathing, shortness of breath, cough, or fever.

Additionally, inflammation of the liver has been reported, with potential fatal consequences. Patients should seek prompt medical attention if they notice symptoms indicative of liver problems, which may include jaundice (yellowing of the skin or eyes), dark or tea-colored urine, light-colored stools, decreased appetite, or pain in the right upper abdomen.

Diarrhea is a common adverse event associated with IRESSA and can occasionally be severe. Patients are encouraged to contact their healthcare provider if they experience severe diarrhea or persistent diarrhea that does not resolve.

Ocular symptoms have also been reported, including watery eyes, sensitivity to light, blurred vision, eye pain, redness, or any changes in vision. Patients should notify their healthcare provider if they experience these symptoms.

Severe skin reactions, such as peeling or blistering, have been documented, and patients are advised to seek immediate medical assistance if such reactions occur.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) to ensure they are well-informed about the medication.

Patients should be made aware of the risk of interstitial lung disease. They must be instructed to immediately contact their healthcare provider if they experience new onset or worsening pulmonary symptoms, such as dyspnea, cough, or fever.

It is essential to inform patients about hepatotoxicity and the need for regular lab tests to monitor liver function. Patients should be advised to report any new symptoms that may indicate hepatic toxicity to their healthcare provider.

Healthcare providers should also discuss the risk of gastrointestinal perforation associated with IRESSA. Patients must be instructed to seek immediate medical attention if they experience severe abdominal pain.

In the case of severe or persistent diarrhea, patients should be advised to contact their healthcare provider for further evaluation and management.

Patients should be informed about the potential for ocular disorders, including keratitis. They should be encouraged to promptly contact their healthcare provider if they develop any eye symptoms, such as lacrimation, light sensitivity, blurred vision, eye pain, red eye, or changes in vision.

Healthcare providers should make patients aware of the increased risk of bullous and exfoliative skin disorders with IRESSA. Patients must be instructed to seek immediate medical attention for any severe skin reactions.

For pregnant women, it is crucial to discuss the potential risks to a fetus or the possibility of pregnancy loss. Females of reproductive potential should be advised to use effective contraception during treatment with IRESSA and for at least two weeks following the completion of therapy.

Lastly, women should be advised to discontinue breastfeeding during treatment with IRESSA to ensure the safety of their infant.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available for identification. It should be stored at a controlled room temperature ranging from 20°C to 25°C (68°F to 77°F). Care should be taken to ensure that the product is kept within this temperature range to maintain its integrity and efficacy.

Additional Clinical Information

Clinicians are advised to obtain periodic liver function testing for patients undergoing treatment with IRESSA. It is important to counsel pregnant women about the potential risks to a fetus associated with the medication. Additionally, females of reproductive potential should be instructed to use effective contraception during treatment and for at least two weeks after completing therapy.

Postmarketing experience has revealed reports of bullous conditions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme, in patients treated with IRESSA. Specifically, erythema multiforme and dermatitis bullous have been documented in two patients (0.08%) across various non-small cell lung cancer trials (Study 2, Study 3, and Study 4).

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Iressa as submitted by AstraZeneca Pharmaceuticals LP. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)