GEPHAL

Gefitinib (originally coded ZD1839) is a drug used in the treatment of certain types of cancer.

Acting in a similar manner to erlotinib (marketed as Tarceva), gefitinib selectively targets the mutant proteins in malignant cells.

It is marketed by AstraZeneca under the trade name Iressa.

For the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies.

Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK).

EGFR is expressed on the cell surface of many normal cells and cancer cells.

Absorbed slowly after oral administration with a mean bioavailability of 60%.

Peak plasma levels occurs 3-7 hours post-administration.

Food does not affect the bioavailability of gefitinib.

Primarily hepatic via

Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.

Elimination is by metabolism (primarily CYP3A4) and excretion in feces.

Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.

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The acute toxicity of gefitinib up to 500 mg in clinical studies has been low.

In non-clinical studies, a single dose of 12,000 mg/m 2 (about 80 times the recommended clinical dose on a mg/m 2 basis) was lethal to rats.

Half this dose caused no mortality in mice.

Symptoms of overdose include diarrhea and skin rash.

Recommended dose is 250 mg orally, once daily with or without food. 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.

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: . 2.2 Recommended Dose The recommended dose of gefitinib tablets is 250 mg orally once daily with or without food until disease progression or unacceptable toxicity.

Do not take a missed dose within 12 hours of the next dose. 2.3 Administration to Patients Who Have Difficulty Swallowing Solids Immerse gefitinib tablets in to 8 ounces of water by dropping the tablet in water, and stir for approximately 15 minutes.

Immediately drink the liquid or administer through a naso-gastric tube.

Rinse the container with to 8 ounces of water and immediately drink or administer through the naso-gastric tube. 2.4 Dose Modification Dose Modifications for Adverse Drug Reactions Withhold gefitinib tablets (for up to 14 days) for any of the following: •Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) •NCI CTCAE Grade 2 or higher in ALT and/or AST elevations •NCI CTCAE Grade 3 or higher diarrhea •Signs and symptoms of severe or worsening ocular disorders including keratitis •NCI CTCAE Grade 3 or higher skin reactions Resume treatment with gefitinib tablets when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1.

Permanently discontinue gefitinib tablets for: •Confirmed interstitial lung disease (ILD) •Severe hepatic impairment •Gastrointestinal perforation •Persistent ulcerative keratitis Dose Modifications for Drug Interactions Strong CYP3A4 Inducers Increase gefitinib tablets to 500 mg daily in the absence of severe adverse drug reaction, and resume gefitinib tablets at 250 mg seven days after discontinuation of the strong CYP3A4 inducer.

Gefitinib is available as 250 mg tablets.

Gefitinib tablets 250 mg are round, biconvex face, brown film-coated, debossed with “QL” on one side and plain on the other side.

Gefitinib tablets are supplied as

Bottles of 30 Tablets (NDC 67184-0531-1) Bottles of 500 Tablets (NDC 67184-0531-2) Blisters of 3 Cards ×10 (NDC 67184-0531-3), each carton contains “30 tablets: 1 overwrap contains 3 unit dose blister cards.

Each blister card contains 10 tablets.” Store at controlled room temperature 20°C-25°C (68°F-77°F) .

Based on its mechanism of action and animal data, gefitinib tablets can cause fetal harm when administered to a pregnant woman.

In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose.

Advise pregnant women of the potential hazard to a fetus or potential risk for loss of the pregnancy.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and miscarriage is 15-20% of clinically recognized pregnancies.

A single dose study in rats showed that gefitinib crosses the placenta after an oral dose of 5 mg/kg (30 mg/m 2, about 0.2 times the recommended human dose on a mg/m 2 basis).

When pregnant rats were treated with 5 mg/kg from the beginning of organogenesis to the end of weaning there was a reduction in the number of offspring born alive.

This effect was more severe at 20 mg/kg (approximate the human clinical dose on a mg/m 2 basis) and was accompanied by high neonatal mortality soon after parturition.

In rabbits, a dose of 20 mg/kg/day (240 mg/m 2, about twice the recommended dose in humans on a mg/m 2 basis) caused reduced fetal weight.

The safety and effectiveness of gefitinib tablets in pediatric patients have not been established.

Of the 823 patients enrolled in two randomized, active-controlled clinical trials 374 patients (45%) were 65 years and older, and 93 patients (11%) were 75 years and older.

No overall differences in safety were observed between patients 65 years and older and those younger than 65 years.

There is insufficient information to assess for differences in efficacy between older and younger patients.