Gefitinib

Approved Indications:

• Non-Small Cell Lung Cancer (NSCLC):
• First-line treatment of patients with metastatic NSCLC whose tumors have specific epidermal growth factor receptor (EGFR) activating mutations (exon 19 deletions or exon 21 L858R substitution mutations).
• Treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.
• Off-label/Clinically Accepted Uses:
• Investigational use in other solid tumors expressing EGFR mutations (e.g., certain head and neck cancers).
• Occasionally used in combination with other agents in clinical trials.

• Adults:
• Standard dose: 250 mg orally once daily until disease progression or unacceptable toxicity.
• Pediatrics:
• Safety and efficacy not established; generally not recommended.
• Elderly:
• No dose adjustment required; monitor tolerability.
• Renal Impairment:
• No dose adjustment necessary.
• Hepatic Impairment:
• Mild to moderate impairment: no adjustment.
• Severe impairment: use with caution; limited data.
• Administration:
• Take orally with or without food.
• Swallow tablets whole; do not crush or chew.
• Take at the same time each day for consistent blood levels.

Gefitinib is a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It competitively binds to the ATP-binding site of the EGFR tyrosine kinase domain, inhibiting autophosphorylation of EGFR and blocking downstream signaling pathways involved in cell proliferation, survival, angiogenesis, and metastasis. This inhibition leads to decreased tumor cell growth and induces apoptosis, particularly effective in tumors harboring activating EGFR mutations.

• Absorption: Oral bioavailability is moderate; peak plasma concentrations occur approximately 3–7 hours post-dose.
• Distribution: Widely distributed with a volume of distribution around 1400 L; approximately 90% bound to plasma proteins.
• Metabolism: Primarily metabolized by hepatic cytochrome P450 enzymes CYP3A4, CYP3A5, and to a lesser extent CYP1A1 and CYP2D6.
• Active Metabolites: Minor metabolites with limited activity.
• Elimination: Mainly excreted via feces (approximately 86%) and urine (about 7%).
• Half-life: Approximately 28 hours, supporting once-daily dosing.

• Pregnancy:
• FDA Category D: Evidence of human fetal risk exists. Use only if potential benefits justify risks.
• Lactation:
• Unknown if excreted in human milk. Due to potential for serious adverse reactions, breastfeeding is generally not recommended during treatment.

• Primary Therapeutic Class: Antineoplastic agent
• Subclass: EGFR tyrosine kinase inhibitor (TKI), targeted therapy

• Known hypersensitivity to Gefitinib or any formulation components.
• Concurrent use with strong CYP3A4 inducers or inhibitors without dose adjustment (due to altered drug levels).
• Severe hepatic impairment without careful monitoring.

• Interstitial Lung Disease (ILD): Rare but potentially fatal; monitor for new or worsening respiratory symptoms.
• Hepatotoxicity: Monitor liver function tests; discontinue if severe hepatotoxicity occurs.
• Gastrointestinal Toxicity: Diarrhea and nausea common; monitor for dehydration and electrolyte imbalance.
• Dermatologic Reactions: Rash and dry skin frequent; severe cases may require treatment interruption.
• Ocular Toxicity: Monitor for eye irritation or inflammation.
• Drug Interactions: Monitor when combined with CYP3A4 modulators.
• Renal Impairment: Caution advised despite no formal dose adjustment.

Common Adverse Effects:

• Dermatologic: Acneiform rash, dry skin, pruritus
• Gastrointestinal: Diarrhea, nausea, vomiting, stomatitis
• Respiratory: Cough, dyspnea
• Fatigue and anorexia

Serious/Rare Side Effects:

• Interstitial lung disease (potentially fatal)
• Hepatotoxicity (elevated liver enzymes, jaundice)
• Severe cutaneous reactions (rare)
• Eye disorders including keratitis

Onset: Most side effects occur within the first few weeks but can occur anytime during treatment.

• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): Increase Gefitinib plasma concentration → risk of toxicity.
• CYP3A4 Inducers (e.g., rifampin, phenytoin): Decrease Gefitinib levels → reduced efficacy.
• Warfarin: Potential interaction affecting INR; monitor coagulation status.
• No significant interaction with food; can be taken with or without meals.
• Avoid concomitant use with St. John’s Wort (CYP3A4 inducer).

• FDA and EMA approvals emphasize testing for EGFR mutations prior to therapy initiation to identify suitable patients.
• Updated guidelines recommend monitoring for ILD and liver toxicity closely during treatment.
• Newer generation EGFR TKIs have emerged, but Gefitinib remains a frontline option where accessible.
• Ongoing research on combination regimens and resistance mechanisms continues.

• Store at controlled room temperature between 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep in tightly closed containers.
• Do not freeze.
• Keep out of reach of children.