Gefitinib

Gefitinib is an antineoplastic agent belonging to the pharmacological class of Epidermal Growth Factor Receptor (EGFR) inhibitors.

The FDA approves Gefitinib to treat non-small cell lung cancer (NSCLC) with specific mutations in the epidermal growth factor receptor (EGFR) gene.

Gefitinib slowly absorbs in the gastrointestinal tract, extensively distributes throughout the body, primarily metabolizes in the liver via specific cytochrome P450 enzymes, and is predominantly excreted through faeces, contributing to its significant half-life.

The most common side effects of Gefitinib include nausea, rash, vomiting and weight loss.

Gefitinib is available as an oral tablet.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Gefitinib is an antineoplastic agent belonging to the pharmacological class of Epidermal Growth Factor Receptor (EGFR) inhibitors.

Gefitinib is an adenosine triphosphate (ATP)--binding site inhibitor of EGFR tyrosine kinase. It has frequently been demonstrated that some human carcinoma cells, including lung and breast cancer cells, overexpress EGFR. Increased activation of the anti-apoptotic Ras signal transduction cascades due to overexpression causes cancer cells to survive longer and proliferate uncontrollably. Gefitinib is the first selective inhibitor of EGFR tyrosine kinase, also known as Her1 or ErbB-1. The inhibition of EGFR tyrosine kinase leads to the inhibition of downstream signalling cascades, preventing the proliferation of malignant cells.

Gefitinib reaches peak plasma concentration in 3 to 7 hours.

The steady state is typically attained around ten days of continuous administration.

Gefitinib is available as an oral tablet.

Tablet: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, usually after meals.

Indicated for the management of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors exhibit substitution mutations in exon 21 (L858R) or deletions in exon 19 of the epidermal growth factor receptor (EGFR) following the failure of docetaxel- or platinum-based chemotherapy.

Orally: Patients take Gefitinib orally, using tablets swallowed with water once daily. The tablets should be ingested whole, with or without food, following the prescribed dosage and timing to ensure effectiveness in treating conditions like non-small cell lung cancer. Patients should refrain from crushing, chewing, or breaking the tablets unless instructed by their healthcare provider. Adherence to these instructions is crucial for the medication to work optimally in managing the specified conditions, emphasizing the importance of following the healthcare professional's guidance for proper administration.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablet: 250mg

Gefitinib is available as an oral tablet.

Non-small Cell Lung Cancer

In individuals with EGFR tyrosine kinase (TK) activating mutations, 250 mg once daily should be used as monotherapy until the disease progresses or the toxicity becomes unacceptable.

While on Gefitinib, avoid grapefruit or its juice to prevent potential drug metabolism issues. Be wary of medications, supplements, or herbal products that may interact with Gefitinib. No specific dietary restrictions exist, so maintain regular meals, emphasizing adequate hydration.

The dietary restriction should be individualized as per patient requirements.

Consume an antioxidant-rich diet, and avoid smoking/alcohol.

The adverse reactions related to Gefitinib can be categorized as:

Common Adverse Effects: Diarrhea, decreased appetite, vomiting, and increased ALT levels are reported side effects across different grades

Less Common Adverse Effects: Increased AST and ALT levels, stomatitis, conjunctivitis, blepharitis, dry eye, nail disorders, diarrhoea of varying severity, increased bilirubin, decreased appetite, skin reactions, interstitial lung disease or severe vomiting.

Rare Adverse Effects: Interstitial lung disease, increased bilirubin levels, stomatitis, corneal erosion, aberrant eyelash growth, nail disorders of higher severity, gastrointestinal perforation, ocular keratitis, erythema multiforme, dermatitis bullous, and fatal hepatoxicity.

Urinary and renal disorders: hemorrhagic cystitis, cystitis

Cutaneous vasculitis is a disorder of the skin and subcutaneous tissue.

The clinically relevant drug interactions of Gefitinib are briefly summarized here.

Drug-Drug Interactions: Reduced effectiveness and plasma concentration when using CYP3A4 inducers, such as barbiturates, phenytoin, carbamazepine, and rifampicin. Elevated plasma levels and potential side effect risk when using potent CYP3A4 inhibitors (e.g., clarithromycin, protease inhibitors, and ketoconazole). Increased risk of bleeding incidents and elevated INR when using warfarin. Decreased plasma concentrations, bioavailability, and effectiveness when using medications that raise stomach pH (such as antacids, PPIs, and H2-receptor antagonists). It may make vinorelbine's neutropenic effects worse. It might expose metoprolol to more. NSAIDs and steroids increase the risk of gastrointestinal perforations.

Drug-Food Interaction: Exposure to grapefruit or grapefruit juice increases the risk of toxicity and plasma concentrations. Reduced plasma levels and effectiveness when using St. John's wort.

The common side effects of Gefitinib include:

Diarrhea

Dry skin

Loss of appetite

Nausea

Loss of weight

Rash

Stomatitis, or oral inflammation

Vomiting

Weakness

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

Gefitinib administration to a pregnant woman may result in fetal harm based on its mechanism of action and animal data.

Advise women who are fertile to use birth control during their gefitinib treatment and for at least two weeks after they finish it.

Inform pregnant women about any risks to the developing fetus or the possibility of the pregnancy ending prematurely.

Oral gefitinib administration from organogenesis through weaning caused fetotoxicity and neonatal death in animal reproductive studies at doses lower than the recommended human dose.

It is unclear whether the drug is distributed in human breast milk, and therefore, it is not recommended for use during breastfeeding. However, healthcare providers should assess the mother's clinical necessity for the medication and weigh the developmental and health advantages of breastfeeding against any potential adverse effects the drug or the underlying maternal condition might have on the breastfed infant.

As per the FDA, the safety and efficacy of Gefitinib have not been specifically studied in pediatric patients.

The safety and efficacy of Gefitinib in the geriatric population have yet to be thoroughly established. Efficacy and safety in this group may vary, requiring cautious dosing and close monitoring for potential side effects. Further studies are needed to ascertain its optimal use and risk-benefit profile in older individuals.

Less than four per cent (<4%) of Gefitinib and its metabolites are excreted through the kidney.

Severe renal impairment: Not studied.

Dosage adjustments for Gefitinib are recommended in patients with hepatic impairment. A reduced starting dose might be considered for mild to moderate hepatic impairment.

Severe impairment: Limited; caution is advised.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Gefitinib.

Overconsumption of Gefitinib could lead to diarrhoea and skin rash.

Support Gefitinib overdosage by providing supportive care to sustain essential functions and closely monitoring for side effects. If the ingestion occurred recently, consider treatments like gastric lavage or activated charcoal. Because of the prolonged half-life of Gefitinib, it is essential to monitor and manage any possible side effects, such as hepatotoxicity, diarrhoea, and skin reactions. Assist the patient with supportive care, ensuring they are adequately hydrated, maintaining their electrolyte balance, and managing their symptoms according to their condition. When there is severe toxicity, treat symptoms quickly and with the proper medical care. There is no antidote for Gefitinib overdose; instead, prioritize supportive care and symptomatic management.

The intracellular phosphorylation of multiple tyrosine kinases linked to transmembrane cell surface receptors, such as those related to the epidermal growth factor receptor (EGFR-TK), is inhibited by Gefitinib. Many cancerous and normal cells have EGFR expressed on their surface.

Absorption: Gefitinib undergoes slow absorption from the gastrointestinal tract, exhibiting an approximate bioavailability of 60%. It takes 3 to 7 hours to reach peak plasma concentration.

Distribution: Once absorbed, Gefitinib is extensively distributed throughout the body. It has a large volume of distribution, estimated to be around 1,400 litres. Approximately 90% of Gefitinib binds to plasma proteins, primarily albumin and α1-acid glycoprotein.

Metabolism: In the liver, Gefitinib undergoes extensive metabolism, primarily facilitated by the CYP3A4 isoenzyme and, to a lesser extent, by the CYP2D6 isoenzyme. This metabolism leads to the formation of its primary metabolite, O-desmethyl gefitinib.

Excretion: Gefitinib is eliminated primarily through faeces, with about 86% excreted as metabolites. A minimal amount (less than 4%) is eliminated through urine. Gefitinib has an elimination half-life of approximately 41 to 48 hours.