What Is Gefitinib (Iressa)? FDA Approval, Licensing and Reimbursement in Turkey
In this article
- FDA Approval: Yes (First approval: May 5, 2003)
- Brand Name: Iressa
- Active Ingredient: Gefitinib
- Administration: Oral tablet (generally 250 mg)
- Class: Tyrosine kinase inhibitor (TKI)
- Category: Antineoplastic / Targeted Therapy
- Manufacturer: AstraZeneca
- Availability in Turkey: Licensed and approved in Turkey.
- Approved Cancers: Epidermal growth factor receptor (EGFR) mutation-positive advanced or metastatic non-small cell lung cancer (NSCLC)
What Is Gefitinib? How Does It Work?
Gefitinib is an oral targeted cancer drug used particularly for NSCLC carrying specific genetic alterations (EGFR mutations). It belongs to the tyrosine kinase inhibitor (TKI) class.
Mechanism of Action
Gefitinib blocks the tyrosine kinase region of EGFR on cancer cell surfaces. EGFR signaling triggers growth and proliferation; mutations can make it continuously active, causing uncontrolled division. By stopping this signaling, gefitinib slows or halts tumor growth and induces apoptosis in some cells.
FDA (US Food and Drug Administration) Approval History
July 13, 2015 Approval: The FDA approved Iressa (gefitinib) for first-line metastatic NSCLC treatment.
May 5, 2003 Approval: AstraZeneca obtained FDA approval for Iressa (gefitinib, ZD1839) for advanced or metastatic NSCLC as third-line (3rd-line) treatment or beyond.
Licensing in Turkey
Licensed by the Ministry of Health's TİTCK. Included in the List of Medicines Subject to Additional Monitoring as of May 18, 2022.
SGK Reimbursement Status
SGK reimburses gefitinib until progression in metastatic/progressive nonsquamous NSCLC positive for EGFR exon 19 deletion or exon 21 L858R mutation.
- Reimbursed until progression for metastatic nonsquamous NSCLC with EGFR exon 19 deletion and/or exon 21 mutation demonstrated by an accredited laboratory.
March 2026 Price: Iressa 250 mg tablets cost 35,750.73 TL.
The Cost of One “Cycle” (1 Month) of Gefitinib
Gefitinib is generally taken 250 mg 1 time daily . Costs are therefore usually assessed over 1 month (30 days) of treatment.
| Daily Dose | 30-Day Requirement | Reference Price | Approximate 1-Month Cost | Note |
|---|---|---|---|---|
| 250 mg/day (standard) | 30 tablets | Iressa 250 mg tablets: 33,699.48 TL | 33,699.48 TL | Assumes one pack provides 1 month of treatment. |
Resistance Mechanisms
Gefitinib acts as an EGFR TKI. During or after treatment, some cancer cells bypass this blockade through various mechanisms:
Secondary EGFR Mutations: T790M is the most common mechanism. This new EGFR mutation changes the gefitinib binding site, preventing tyrosine kinase inhibition. T790M accounts for up to 50% of acquired resistance.
Alternative Pathway Activation: Cancer cells activate other pathways, such as MET amplification, allowing continued growth despite EGFR blockade. Increased MET copy number creates a bypass pathway.
Phenotypic Change: Some cells undergo epithelial-mesenchymal transition (EMT), changing morphology and biology. Reduced EGFR dependence may confer resistance.
Other Genetic Alterations:
- HER2 gene amplification
- PI3KCA mutation
- BRAF mutation
and similar changes may activate alternative pathways and reduce gefitinib effects.
Cellular Drug Transport: Overexpression of transport proteins (e.g., ABC transporters) that lower intracellular drug concentrations may also contribute to resistance.
- Summary: T790M is the most common resistance mechanism; second- and third-generation EGFR-TKIs (e.g., osimertinib) are therefore used in T790M-positive patients. Other mechanisms generally involve bypass activation and phenotypic change.
Pharmacokinetics
Absorption
- Gefitinib is well absorbed orally, with approximately 60% bioavailability.
- Food has little effect, although high-fat meals may slightly increase absorption.
- Peak plasma concentration (Tmax) is generally reached within 3-7 hours.
Distribution
- Plasma protein binding is high (~90%).
- Widely distributed into tissues, particularly tumor and lung tissue.
- A high volume of distribution (Vd) indicates good tissue penetration.
Metabolism
- Gefitinib is mainly metabolized in the liver.
- CYP3A4 is the main enzyme, with some contribution from CYP2D6 and other CYP enzymes.
- One metabolite (M523595) is considered active, although the parent drug provides most activity.
Elimination
- Gefitinib is mainly eliminated hepatically.
- 86% is excreted in feces and the remainder (approximately 7%) in urine.
- Terminal elimination half-life (t½) is approximately 41 hours, supporting dosing 1 time daily.
Dosing Interval
- The recommended single daily dose for all EGFR-mutant NSCLC patients is 250 mg. Higher doses (e.g., 500 mg/day) have been tested, but efficacy was the same as 250 mg with more adverse effects at 500 mg. Thus, 250 mg/day is the standard effective, tolerable single-dose regimen.
- There is no specific escalation or reduction schedule; discontinue entirely if not tolerated.
- Tablets may be taken with or without food, which does not significantly affect absorption. No special fasting/fed rule is therefore needed.
- Swallow tablets whole. Do not chew, crush or split.
- Take with water. If swallowing is difficult, stir the tablet in a glass of drinking water until fully dispersed and drink immediately; add more water and drink any residue.
- Take 1 time daily at the same time to maintain stable plasma levels.
Drug Interactions
CYP3A4 Inhibitors
- Gefitinib is metabolized by hepatic CYP3A4.
- Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) increase gefitinib levels and adverse effect risk.
- Use caution and monitor adverse effects if these medicines are used.
CYP3A4 Inducers
- Strong CYP3A4 inducers (e.g., rifampicin, phenytoin, carbamazepine, St. John's Wort) reduce gefitinib levels and may lower efficacy.
- Avoid if possible or select alternatives.
Antacids and Proton Pump Inhibitors
- Gastric acid is important for gefitinib absorption.
- Proton pump inhibitors (omeprazole, esomeprazole), H2 receptor antagonists (ranitidine) or continuous antacid use may reduce gefitinib bioavailability by increasing gastric pH.
- If necessary, administer these drugs several hours apart from gefitinib.
Warfarin
- Combined use may increase INR and bleeding risk.
- Monitor coagulation tests (INR) more frequently if used together.
CYP2D6 Substrates
- Gefitinib may partly inhibit CYP2D6, raising plasma levels of CYP2D6 substrates such as metoprolol.
- Use caution despite limited clinical significance.
Precautions
Do Not Use Without an EGFR Mutation: Efficacy is limited to EGFR mutation-positive patients (exon 19 deletion or exon 21 L858R). Do not start without mutation testing.
Interstitial Lung Disease Risk: Rare but serious interstitial lung disease (ILD) may develop. For sudden dyspnea, cough or fever, stop the drug immediately and initiate treatment.
Liver Impairment: Gefitinib is metabolized in the liver. Monitor ALT and AST regularly. Use cautiously in moderate-severe liver impairment.
Eye Adverse Effects: Rare serious findings include corneal ulcers and keratitis. Severe irritation requires ophthalmology assessment.
Diarrhea and Dehydration: Diarrhea is among the most common adverse effects and may progress to kidney failure through substantial fluid loss. Uncontrolled diarrhea may require discontinuation.
Bleeding Risk: Warfarin or similar anticoagulants may increase INR when combined. Regular INR checks are necessary.
Gastric Acid Modifiers: Proton pump inhibitors, H2 blockers and continuous antacids reduce absorption. Pay attention to timing if concurrent use is necessary.
Pregnancy and Breastfeeding: Do not use in pregnancy because of fetotoxicity risk. Breastfeeding should stop in nursing mothers.
Adverse Effects
- Diarrhea (47%)
- Rash (43%)
- Acneiform dermatitis (31%)
- Dry skin (20%)
- Nausea (14%)
- Vomiting (13%)
- Anorexia (12%)
- Fatigue (9%)
- Itching (8%)
- Eye irritation (7%)
- Elevated liver enzymes (ALT, AST) (6-9%)
- Interstitial lung disease (ILD) (1-2%) — serious but rare
- Stomatitis (5%)
- Paronychia (nail-fold infection) (5%)
- Dehydration (secondary to diarrhea) (exact frequency varies)
- Keratitis (less than 1%)
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