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U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner FDA Approves IRESSA (gefitinib)

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FDA Approves IRESSA® (gefitinib) for Treating Locally Advanced or Metastatic Non-Small Cell Lung Cancer Expressing Epidermal Growth Factor Receptor (EGFR) Exon 19 Deletion or Exon 21 (L858R) Substitution Mutations

On July 13, 2015, the United States Food and Drug Administration (FDA) approved IRESSA (gefitinib) tablets, an epidermal grow factor receptor (EGFR) tyrosine kinase inhibitor, for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. The recommended dose of IRESSA tablets is 250 mg orally once daily (QD) taken with or without food. The following are key clinical pharmacology related highlights from the regulatory review of this application:

General Pharmacokinetics and Pharmacodynamics of Gefitinib

  • Absolute bioavailability (tablets): 59% (Tmax of 3-5 hours) in cancer patients.
  • Plasma protein binding: 91%.
  • Terminal half-life (mean): 41 hours.
  • Metabolism: Extensive. Predominately by CYP3A and CYP2D6.
  • Excretion: Less than 4% of parent and metabolites are excreted via the kidney.
  • Exposure-safety: Dose reduction due to toxicity was relatively low in the Phase 2 studies in NSCLC patients (~10%) when the recommended dose was doubled. An exploratory exposure response analysis showed an increase in the incidence of interstitial lung disease (ILD) with a greater than 2 fold increase in the gefitinib exposure.

Drug Interaction Potential

  • International Normalized Ratio (INR) elevations and/or hemorrhage have been reported in some patients taking warfarin while on IRESSA therapy.
  • A ranitidine induced increase in gastric pH to 5 or greater reduced the gefitinib exposure (AUC) by 47% and Cmax by 71% in a clinical study. Avoid concomitant use of proton pump inhibitors (PPI), if possible.  If treatment with a PPI is required, IRESSA should be taken 12 hours after the last dose or 12 hours before the next dose of the PPI.  IRESSA can be taken 6 hours after or 6 hours before an H2-receptor antagonist or an antacid.
  • Coadministration with a strong CYP3A4 inducer (i.e., rifampicin) decreased gefitinib exposure by 83% in a clinical study. Increase IRESSA dosage to 500 mg daily when it is co-administered with a strong CYP3A4 inducer.
  • Coadministration with a strong CYP3A4 inhibitor (itraconazole) increased gefitinib exposure by 80% in a clinical study. However, no dose adjustment is recommended with co-administration of a strong CYP3A4 inhibitor based on the observed less than 1% dose reduction rate with the 250 mg daily dose regimen and 10% dose reduction rate when the recommended dosage was doubled in clinical studies.
  • Gefitinib is a substrate of P-glycoprotein in vitro. Transporter saturation was observed at higher concentrations.  The clinical implications of these findings are not known.

Use in Specific Populations

  • Exposure to gefitinib was approximately 1.4-, 3.6-, and 2.7-fold higher in subjects with mild, moderate, and severe cirrhotic hepatic impairment, respectively, compared to subjects with normal hepatic function in a clinical study.  Therefore, cirrhotic patients should be monitored frequently for signs of increased toxicities. In a separate study in cancer patients with hepatic impairment secondary to liver metastases, gefitinib exposures were similar in patients with moderate and severe metastatic hepatic impairment compared to patients with normal hepatic function. Therefore, a dose adjustment is not recommended patients with hepatic impairment secondary to liver metastases
  • Healthy CYP2D6 poor metabolizers had 2.1-fold higher gefitinib exposure compared to extensive metabolizers. However, a dose adjustment is not recommended due to the low rate of dose adjustment at this exposure in clinical studies. These patients should be monitored frequently for signs of increased toxicities.
  • No clinical studies were conducted with IRESSA in patients with severe renal impairment.

Safety and Efficacy

The efficacy and safety of IRESSA was demonstrated in a multicenter, single-arm, open-label clinical trial. The primary endpoint of objective response rate was 50% [95% confidence interval (CI): 40, 60]. The median duration of response was 6 months (95% CI: 5.6, 11.1 months). These results were supported by another randomized trial which reported that a retrospective analysis of the subgroup of 186 EGFR mutation-positive patients suggested an improvement in progression free survival with IRESSA (n=88) compared to carboplatin/paclitaxel (n=98).

The most common adverse events (AEs) were rash, diarrhea, dry skin, nausea, vomiting, cough, and asthenia. Interstitial lung disease, a known AE associated with gefitinib use that is more common in Asian patients, was reported in 1 (1%) Caucasian patient and in 16 (2.6%) Asian patients.

Full prescribing information is available at
The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (

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This Burst was prepared by the Clinical Pharmacology Review Team including Robert Schuck, Clinical Pharmacologist, Genomics and Targeted Therapy Group, and Hong Zhao, Team Leader, Division of Clinical Pharmacology V, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology

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