Gefitinib Tablets

Indications

• Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor (EGFR)

Dosage

Adults: The usual adult dose is 250 mg once daily.

Mechanism of action

Gefitinib inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase by binding to its ATP-binding site. This inhibition interferes with the activation of downstream signaling cascades that lead to cell proliferation and survival, particularly in cancers where EGFR is overexpressed, such as lung and breast cancers.

Pharmacodynamics

Gefitinib reduces the phosphorylation of various tyrosine kinases linked to transmembrane cell surface receptors, particularly those associated with the EGFR. As EGFR is present on both normal and cancer cells, the inhibition leads to decreased malignant cell proliferation and promotes apoptosis in cells that are dependent on EGFR signaling.

Pharmacokinetics

After oral administration, gefitinib is well absorbed, with peak plasma concentrations reached in approximately 3 to 7 hours. It has a large volume of distribution and is extensively metabolized by the liver, primarily via CYP3A4. The elimination half-life is approximately 48 hours, and it is excreted mainly in feces. Food can affect its absorption, and it is recommended to take gefitinib with a high-fat meal to enhance bioavailability.

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Rash
• Anorexia
• Fatigue
• Dry skin
• Pruritus
• Increased liver enzymes
• Hepatic failure
• Pneumonitis
• Interstitial lung disease
• Keratitis
• Ulcerative keratitis
• Weight increase
• Neutropenia
• Thrombocytopenia
• Wernicke’s encephalopathy

Interactions

• St. John's Wort (decreases exposure)
• Dronedarone (increases exposure)
• Eslicarbazepine (decreases exposure)
• Oxcarbazepine (decreases exposure)
• Antifungals (azoles) (increases exposure)
• Bupropion (increases exposure)
• Cinacalcet (increases exposure)
• Cobicistat (increases exposure)
• Gefitinib with coumarins (increases anticoagulant effect)
• Crizotinib (increases exposure)

Precautions

• Monitor for signs of interstitial lung disease or pneumonia
• Assess liver function prior to initiation and during treatment
• Use caution in patients with a history of keratitis
• Avoid in pregnancy and breastfeeding

Pregnancy

Avoid during pregnancy due to toxicity observed in animal studies.

Breast-feeding

Avoid during treatment and for at least 1 month after the last dose.

Storage

Store at room temperature, protected from light and moisture.

Formulations

• Tablets: 250 mg

Mechanism of action

Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase that binds to the adenosine triphosphate (ATP)-binding site of the enzyme. EGFR is often shown to be overexpressed in certain human carcinoma cells, such as lung and breast cancer cells. Overexpression leads to enhanced activation of the anti-apoptotic Ras signal transduction cascades, subsequently resulting in increased survival of cancer cells and uncontrolled cell proliferation. Gefitinib is the first selective inhibitor of the EGFR tyrosine kinase which is also referred to as Her1 or ErbB-1. By inhibiting EGFR tyrosine kinase, the downstream signaling cascades are also inhibited, resulting in inhibited malignant cell proliferation.

Pharmacodynamics

Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells.