Usage
Gefitinib is prescribed for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test. It is a targeted therapy and belongs to the pharmacological class of tyrosine kinase inhibitors (TKIs). Gefitinib works by inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR), thus blocking downstream signaling pathways involved in cell growth and proliferation in cancer cells with specific EGFR mutations.
Alternate Names
The international nonproprietary name (INN) is gefitinib. A popular brand name under which the drug is marketed is Iressa.
How It Works
Pharmacodynamics: Gefitinib selectively inhibits the tyrosine kinase activity of EGFR in cancer cells harboring specific activating mutations (exon 19 deletions or exon 21 L858R substitutions), leading to inhibition of cell growth and proliferation.
Pharmacokinetics:
- Absorption: Gefitinib is administered orally and is absorbed in the gastrointestinal tract. Food does not significantly affect absorption.
- Metabolism: Primarily metabolized in the liver, mainly via CYP3A4 enzyme.
- Elimination: Excreted primarily via feces, with a small amount in urine.
Mode of Action: Gefitinib competitively binds to the ATP-binding site of the tyrosine kinase domain of EGFR, inhibiting its autophosphorylation and activation. This blocks downstream signaling pathways, including the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways, which are crucial for cell proliferation, survival, and angiogenesis.
Receptor Binding/Enzyme Inhibition: Gefitinib is a reversible inhibitor of EGFR tyrosine kinase.
Elimination Pathways: Primarily hepatic metabolism via CYP3A4, followed by biliary and fecal excretion. A small fraction is excreted unchanged in urine.
Dosage
Standard Dosage
Adults: 250 mg orally once daily, taken with or without food. Continue treatment until disease progression or unacceptable toxicity.
Children: The safety and efficacy of gefitinib in children and adolescents under 18 years of age have not been established.
Special Cases:
- Elderly Patients: No dose adjustment is required.
- Patients with Renal Impairment: No dose adjustment is required for mild to moderate renal impairment. Caution advised in severe renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustment is required for mild to moderate hepatic impairment secondary to liver metastases. Close monitoring recommended in patients with moderate to severe hepatic impairment due to cirrhosis or hepatitis.
- Patients with Comorbid Conditions: Monitor closely for adverse events in patients with pre-existing lung, liver, or gastrointestinal conditions.
Clinical Use Cases
Gefitinib’s clinical use is limited to the treatment of metastatic NSCLC harboring sensitive EGFR mutations as detected by an FDA-approved test. It is not indicated for use in the settings of intubation, surgical procedures, mechanical ventilation, intensive care unit (ICU) use, or emergency situations.
Dosage Adjustments
Dosage interruptions or dose reductions may be necessary for managing toxicities, particularly diarrhea, skin reactions, hepatotoxicity, and interstitial lung disease.
Side Effects
Common Side Effects
Diarrhea, rash, acne, dry skin, nausea, vomiting, decreased appetite, nail problems, hair loss, stomatitis, asthenia.
Rare but Serious Side Effects
Interstitial lung disease (ILD), hepatotoxicity, gastrointestinal perforation, severe diarrhea, ocular disorders (keratitis, corneal erosion), severe skin reactions.
Long-Term Effects
Chronic complications from prolonged use may include skin changes, nail disorders, and dry eye.
Adverse Drug Reactions (ADR)
Clinically significant ADRs requiring immediate intervention: ILD, hepatotoxicity, GI perforation, severe diarrhea, ocular toxicity.
Contraindications
No absolute contraindications. Relative contraindications include severe hypersensitivity to gefitinib.
Drug Interactions
Gefitinib is primarily metabolized by CYP3A4.
- CYP450 Interactions: Strong CYP3A4 inducers (e.g., rifampin, phenytoin, St. John’s Wort) can decrease gefitinib levels. Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) can increase gefitinib levels.
- Other Interactions: Drugs that affect gastric pH (e.g., antacids, H2 blockers, proton pump inhibitors) can alter gefitinib absorption. Monitor INR closely in patients concurrently taking warfarin.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D (evidence of human fetal risk). Avoid pregnancy during gefitinib treatment. Effective contraception is mandatory during and for at least 6 months after treatment discontinuation.
- Breastfeeding: Gefitinib and its metabolites are excreted in breast milk. Discontinue breastfeeding during treatment.
Drug Profile Summary
- Mechanism of Action: Tyrosine kinase inhibitor targeting EGFR.
- Side Effects: Diarrhea, rash, acne, dry skin, nausea, vomiting, decreased appetite, ILD, hepatotoxicity, GI perforation.
- Contraindications: Hypersensitivity to gefitinib.
- Drug Interactions: CYP3A4 inducers and inhibitors, drugs affecting gastric pH, warfarin.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 250 mg orally once daily.
- Monitoring Parameters: Liver function tests, pulmonary function, signs of GI perforation or ocular toxicity.
Popular Combinations
Gefitinib is generally used as a monotherapy. Combination strategies are under investigation but not currently standard of care.
Precautions
- General Precautions: Assess EGFR mutation status prior to initiating therapy. Monitor for pulmonary, hepatic, gastrointestinal, and ocular toxicities.
- Specific Populations: Avoid use during pregnancy and breastfeeding. Use with caution in patients with pre-existing lung or liver disease. No specific age-related precautions.
- Lifestyle Considerations: No specific restrictions on alcohol or smoking, but patients should follow general health guidelines.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Gefitinib?
A: The standard recommended dosage for Gefitinib is 250 mg orally once daily in adults. It is not recommended for use in children.
Q2: What is the mechanism of action of Gefitinib?
A: Gefitinib is a tyrosine kinase inhibitor that selectively targets EGFR, blocking downstream signaling pathways that promote cancer cell growth and proliferation.
Q3: What are the most common side effects of Gefitinib?
A: Common side effects include diarrhea, skin rash, acne, dry skin, nausea, vomiting, decreased appetite, and nail problems.
A: Serious side effects that require immediate attention include interstitial lung disease, hepatotoxicity, gastrointestinal perforation, and severe ocular toxicity.
Q5: Can Gefitinib be used during pregnancy or breastfeeding?
A: No, Gefitinib is contraindicated during pregnancy and breastfeeding due to the potential for fetal harm and neonatal exposure.
Q6: What are the major drug interactions with Gefitinib?
A: Gefitinib interacts with CYP3A4 inducers and inhibitors, drugs that affect gastric pH, and warfarin.
Q7: Are there any dosage adjustments needed for patients with renal or hepatic impairment?
A: No dosage adjustment is needed for mild to moderate renal or hepatic impairment. Caution is advised for severe impairments.
Q8: How should Gefitinib be administered?
A: Gefitinib is administered orally as a 250 mg tablet once daily, with or without food.
Q9: What should I monitor in patients taking Gefitinib?
A: Monitor for pulmonary toxicity (dyspnea, cough, fever), hepatotoxicity (liver function tests), gastrointestinal symptoms (diarrhea, abdominal pain), and ocular toxicity (eye pain, redness, vision changes).
