Overview
11 DESCRIPTION Gefitinib is a kinase inhibitor. The chemical name of gefitinib is 4-Quinazolinamine N -(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl) propoxy] and the following structural formula: Gefitinib has the molecular formula C 22 H 24 ClFN 4 O 3 , a relative molecular mass of 446.9 daltons and is a white-colored powder. Gefitinib is a free base. The molecule has pK a s of 5.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells and plays a role in the processes of cell growth and proliferation. Some EGFR activating mutations (exon 19 deletion or exon 21 point mutation L858R) within NSCLC cells have been identified as contributing to the promotion of tumor cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis. Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signaling and blocking EGFR-dependent proliferation.
Indications
- 1 INDICATIONS AND USAGE Gefitinib tablets are indicated 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 [ see Clinical Studies (14) ]. Limitation of Use: Safety and efficacy of gefitinib tablets have not been established in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations [ see Clinical Studies (14) ].
Common Doses
- 250 mg
- 500 mg
Dosage
2 DOSAGE AND ADMINISTRATION Recommended dose is 250 mg orally, once daily with or without food. (2.2) 2.1 Patient Selection Select patients for the first-line treatment of metastatic NSCLC with gefitinib tablets based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in their tumor or plasma specimens[ see Indications and Usage (1) , Clinical Studies (14) ]. If these mutations are not detected in a plasma specimen, test tumor tissue if feasible. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.
Contraindications
- 4 CONTRAINDICATIONS None. None. (4)
Side Effects
- 6 ADVERSE REACTIONS The following adverse drug reactions are discussed in more detail in other sections of the labeling: • Interstitial Lung Disease [ see Warnings and Precautions (5.1) ] • Hepatotoxicity [ see Warnings and Precautions (5.2) ] • Gastrointestinal Perforation [ see Warnings and Precautions (5.3) ] • Severe or Persistent Diarrhea [ see Warnings and Precautions (5.4) ] • Ocular Disorders including Keratitis [ see Warnings and Precautions (5.5) ] • Bullous and Exfoliative Skin Disorders [ see Warning and Precautions (5.
Interactions
- 7 DRUG INTERACTIONS •CYP3A4 Inducer: Increase gefitinib tablets to 500 mg daily in patients receiving a strong CYP3A4 inducer. ( 2.4 , 7.1 ) •CYP3A4 Inhibitor: Monitor adverse reactions if concomitant use with gefitinib tablets. ( 7.1 ) •Drugs Affecting Gastric pH: Avoid concomitant use of gefitinib tablets with proton pump inhibitors, if possible. ( 7.1 ) •Hemorrhage in patients taking warfarin: Monitor changes in prothrombin time or INR. ( 7.2 ) 7.