Gefitinib

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. Gefitinib is sparingly soluble at pH 1 and is practically insoluble above pH 7, with solubility decreasing 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.

Gefitinib is formulated as brown film-coated tablets for oral administration, each containing 250 mg of gefitinib. 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 polyvinyl alcohol-part hydrolysed, polyethylene glycol 3350, talc, titanium dioxide, red ferric oxide, ferrosoferric oxide, and yellow ferric oxide.

Uses and Indications

Gefitinib tablets are 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 gefitinib tablets have not been established in patients whose tumors harbor 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

Patients receiving gefitinib tablets should be closely monitored for several serious adverse effects, necessitating specific actions based on clinical findings.

Interstitial Lung Disease (ILD) ILD has been reported in patients taking gefitinib. In cases of worsening respiratory symptoms, it is imperative to withhold gefitinib tablets. Should ILD be confirmed, discontinuation of gefitinib is required.

Hepatotoxicity Periodic liver function tests must be conducted to monitor liver health. If there are elevations in ALT and/or AST of Grade 2 or higher, gefitinib tablets should be withheld. In instances of severe hepatic impairment, discontinuation of gefitinib is warranted.

Gastrointestinal Perforation In the event of gastrointestinal perforation, gefitinib tablets must be discontinued immediately.

Diarrhea For patients experiencing Grade 3 or higher diarrhea, it is necessary to withhold gefitinib tablets until the condition improves.

Ocular Disorders Patients should be monitored for signs and symptoms of severe or worsening ocular disorders, including keratitis. If such symptoms arise, gefitinib tablets should be withheld. Persistent ulcerative keratitis necessitates discontinuation of the medication.

Bullous and Exfoliative Skin Disorders In cases of Grade 3 or higher skin reactions or exfoliative conditions, gefitinib tablets should be withheld to prevent further complications.

Embryo-fetal Toxicity Gefitinib can cause fetal harm. Healthcare professionals must advise patients of the potential risks to a fetus and recommend the use of effective contraception during treatment.

Laboratory Tests Regular liver function testing is essential to ensure patient safety while on gefitinib therapy.

Side Effects

Adverse reactions associated with gefitinib tablets have been observed in clinical trials and postmarketing experiences. The adverse reactions can be categorized into common and serious reactions.

Common adverse reactions reported include skin reactions and diarrhea. These events were generally mild to moderate in severity and consistent with the known safety profile of gefitinib tablets.

Serious adverse reactions include interstitial lung disease (ILD), which has been documented in patients taking gefitinib tablets. In cases of worsening respiratory symptoms, it is recommended to withhold gefitinib tablets, and discontinuation is advised if ILD is confirmed. Hepatotoxicity is another serious concern; periodic liver function testing should be conducted, with withholding of gefitinib tablets for Grade 2 or higher elevations in ALT and/or AST, and discontinuation for severe hepatic impairment.

Gastrointestinal perforation is a critical adverse reaction that necessitates immediate discontinuation of gefitinib tablets. Diarrhea, while common, can also be serious; withholding of gefitinib tablets is recommended for Grade 3 or higher diarrhea. Ocular disorders, including keratitis, require withholding of gefitinib tablets for any signs or symptoms of severe or worsening conditions, with discontinuation indicated for persistent ulcerative keratitis. Additionally, bullous and exfoliative skin disorders warrant withholding of gefitinib tablets for Grade 3 or higher skin reactions or exfoliative conditions.

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

Drug Interactions

Concomitant use of gefitinib tablets with drugs that induce or inhibit CYP3A4 may necessitate dosage adjustments or increased monitoring for adverse effects.

CYP3A4 Inducers When gefitinib is administered alongside a strong CYP3A4 inducer, it is recommended to increase the gefitinib dosage to 500 mg daily to maintain therapeutic efficacy.

CYP3A4 Inhibitors In the presence of a CYP3A4 inhibitor, healthcare providers should closely monitor patients for any adverse reactions associated with gefitinib, as the inhibitor may increase gefitinib plasma concentrations.

Drugs Affecting Gastric pH The concomitant use of gefitinib tablets 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.

Anticoagulants For patients taking warfarin, it is essential to monitor prothrombin time or INR closely, as gefitinib may increase the risk of hemorrhage, necessitating adjustments in anticoagulant therapy.

Packaging & NDC

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

Pediatric Use

The safety and effectiveness of gefitinib tablets in pediatric patients have not been established. Therefore, caution should be exercised when considering the use of this medication in children and adolescents. Further studies are needed to determine appropriate dosing and potential outcomes in this population.

Geriatric Use

In clinical trials involving 823 patients, 374 patients (45%) were aged 65 years and older, with 93 patients (11%) 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 older and younger patients. Therefore, healthcare providers should exercise caution when prescribing to geriatric patients, considering individual patient factors and closely monitoring for any adverse effects. Additionally, while no specific dosage adjustments are recommended based on age alone, careful assessment of the patient's overall health status and concurrent medications is advised to ensure optimal therapeutic outcomes.

Pregnancy

Gefitinib tablets can cause fetal harm when administered to pregnant patients, as indicated by its mechanism of action and animal data. In reproductive studies conducted in animals, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Therefore, healthcare professionals should advise pregnant women of the potential hazards to a fetus and the risk of pregnancy loss.

The background risk of major birth defects and miscarriage in 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.

Pharmacokinetic studies in rats have demonstrated that gefitinib crosses the placenta following 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 this dose from the beginning of organogenesis to the end of weaning, there was a notable reduction in the number of offspring born alive. This effect was exacerbated 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, administration 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 providers should carefully consider the risks when prescribing gefitinib to women of childbearing potential and discuss effective contraceptive measures to prevent pregnancy during treatment.

Lactation

It is not known whether gefitinib tablets are excreted in human milk. However, animal studies have demonstrated that gefitinib and its metabolites are present in rat milk at concentrations higher than those found in maternal plasma. Specifically, levels of gefitinib and its metabolites were observed 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 gefitinib tablets, it is advised that lactating mothers discontinue breast-feeding during treatment with gefitinib tablets.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

Hepatic Impairment

Patients with hepatic impairment should undergo periodic liver function testing to monitor for potential hepatotoxicity. In cases where alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels are elevated to Grade 2 or higher, gefitinib tablets should be withheld. Additionally, the use of gefitinib is contraindicated in patients with severe hepatic impairment, necessitating discontinuation of the medication in such instances. Regular monitoring and appropriate management of liver function are essential to ensure patient safety and treatment efficacy.

Overdosage

In clinical observations involving twenty-three patients treated weekly with doses ranging from 1500 mg to 3500 mg of gefitinib tablets, it was noted that exposure to the drug did not increase proportionally with escalating doses. This suggests a plateau in the pharmacokinetics of gefitinib at higher dosages.

The adverse events reported in these cases were predominantly mild to moderate in severity, aligning with the established safety profile of gefitinib tablets. Healthcare professionals should remain vigilant for these expected adverse effects, which may include gastrointestinal disturbances, skin reactions, and respiratory symptoms.

In the event of a suspected overdose, it is recommended to immediately interrupt the administration of gefitinib tablets. Supportive care should be instituted, and patients should be closely monitored until clinical stabilization is achieved. It is important to note that there are no specific measures or treatments indicated for managing gefitinib overdose. Therefore, the focus should remain on supportive care and symptomatic management.

Nonclinical Toxicology

Gefitinib has undergone extensive evaluation for genotoxicity 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. 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

Serious side effects associated with gefitinib tablets have been reported in postmarketing experience, including but not limited to:

Lung or breathing problems have been noted, with cases of lung inflammation that may lead to fatal outcomes. Symptoms resembling those of lung cancer, such as trouble breathing, shortness of breath, cough, or fever, have been documented. Patients are advised to inform their healthcare provider immediately if they experience any new or worsening lung issues.

Liver problems have also been reported, including inflammation that may result in death. Symptoms indicative of liver dysfunction, such as jaundice (yellowing of the skin or eyes), dark or tea-colored urine, light-colored stools, decreased appetite, and abdominal pain on the right side, should prompt immediate consultation with a healthcare provider.

Instances of gastrointestinal perforation have been observed, necessitating emergency medical attention for patients experiencing severe abdominal pain.

Diarrhea is a common adverse event associated with gefitinib tablets, with some cases reported as severe. Patients should seek medical advice if they experience severe or persistent diarrhea.

Ocular issues, including watery eyes, sensitivity to light, blurred vision, eye pain, redness, or changes in vision, have been reported. Patients are encouraged to notify their healthcare provider if they encounter any of these symptoms.

Skin reactions, such as redness, rash, itching, and acne, are frequently observed. Severe skin reactions, including peeling or blistering, require immediate medical attention.

Additionally, gefitinib tablets may impact fertility in females, and patients planning to conceive should discuss this with their healthcare provider.

Patients are encouraged to report any side effects to the FDA at 1-800-FDA-1088.

Patient Counseling

Advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the medication's use and potential risks.

Patients should be informed about the risk of interstitial lung disease and advised 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.

Discuss the risk of gastrointestinal perforation associated with gefitinib tablets. Patients should seek immediate medical attention if they experience severe abdominal pain.

Patients should be counseled on the potential for severe or persistent diarrhea and advised to contact their healthcare provider if this occurs.

Ocular disorders, including keratitis, may arise during treatment. Patients should be instructed 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.

Inform patients about the risk of bullous and exfoliative skin disorders associated with gefitinib tablets. They should seek immediate medical attention for any severe skin reactions.

Pregnant women should be made aware of the potential risks to a fetus or the possibility of pregnancy loss. Advise females of reproductive potential to use effective contraception during treatment with gefitinib tablets and for at least two weeks following the completion of therapy. Patients should be instructed to inform their healthcare provider immediately if they become pregnant during treatment.

Women should be advised to discontinue breastfeeding during treatment with gefitinib tablets, as it is not known if the medication passes into breast milk. Discuss alternative feeding options with their healthcare provider during this time.

Patients should inform their healthcare provider about all medical conditions, including any lung or breathing problems, liver issues, vision or eye problems, and any plans for pregnancy.

Females capable of becoming pregnant should be counseled to use an effective method of birth control during treatment and for at least two weeks after the last dose of gefitinib tablets.

Patients should disclose all medications they are taking, including prescription and over-the-counter medicines, vitamins, or herbal supplements. If they are taking a proton pump inhibitor (PPI), H2 blocker, or antacid, they should discuss the best timing for these medications with their healthcare provider.

Patients on the blood thinner warfarin should be informed that their healthcare provider will need to perform regular blood tests to monitor clotting during treatment with gefitinib tablets.

Instruct patients to take gefitinib tablets exactly as prescribed by their healthcare provider. The healthcare provider may adjust the dose, temporarily stop, or permanently discontinue treatment based on the patient's side effects.

Patients should take gefitinib tablets once daily, with or without food. If a dose is missed, they should take it as soon as they remember, unless it is less than 12 hours until the next scheduled dose, in which case they should skip the missed dose and resume their regular dosing schedule.

In the event of an overdose, patients should be advised to contact their healthcare provider or go to the nearest emergency room immediately.

For patients who have difficulty swallowing gefitinib tablets whole, instruct them to place the tablet in a container with 4 to 8 ounces of water, stir for about 15 minutes, and drink the mixture right away. They should then rinse the container with another 4 to 8 ounces of water and drink that immediately as well.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a controlled room temperature of 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 tests for patients undergoing treatment with gefitinib tablets. It is important to counsel pregnant women about the potential risks to a fetus associated with this 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 gefitinib tablets.

FDA Insert (PDF)

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

View full prescribing information (PDF)