gefitinib (Rx)

>10%

Skin reactions, all grades (47%)

Diarrhea, all grades (29%)

Decreased appetite, all grades (17%)

Vomiting, all grades (14%)

Increased ALT, all grades (11.4%)

1-10%

Increased AST, all grades (7.9%)

Stomatitis, all grades (7%)

Conjunctivitis, blepharitis, and dry eye (6.7%)

Conjunctivitis/blepharitis/dry eye (6%)

Increased ALT, grades 3-4 (5.1%)

Nail disorders, all grades (5%)

Diarrhea, grades 3-4 (3%)

Increased AST, grades 3-4 (3%)

Increased bilirubin, all grades (2.7%)

Decreased appetite, grades 2-3 (2.3%)

Skin reactions, grades 3-4 (2%)

Interstitial lung disease, all grades (1.3%)

Vomiting, grades 3-4 (1.2%)

<1%

Interstitial lung disease, grades 3-4 (0.7%)

Increased bilirubin, grades 3-4 (0.7%)

Stomatitis, all grades (0.3%)

Corneal erosion and aberrant eyelash growth (0.2%)

Nail disorders, grades 3-4 (0.1%)

Gastrointestinal perforation (0.1%)

Ocular keratitis (0.1%)

Erythema multiforme and dermatitis bullous (0.08%)

Fatal hepatoxicity (0.04%)

Postmarketing Reports

Renal and urinary disorders: Cystitis, hemorrhagic cystitis

Skin and subcutaneous tissue disorders: Cutaneous vasculitis

Contraindications

None

Cautions

Interstitial lung disease (ILD) or ILD-like adverse drug reactions reported (eg, lung infiltration, pneumonitis, acute respiratory distress syndrome, or pulmonary fibrosis); permanently discontinue if confirmed

Increased ALT, AST, and bilirubin reported; obtain periodic liver function testing and withhold drug for worsening liver function or discontinue with severe hepatic impairment

Gastrointestinal perforation reported; permanently discontinue

Severe or persistent diarrhea may occur; withhold drug for up to 14 days

Ocular disorders reported (eg, keratitis, corneal erosion, aberrant eyelash growth, conjunctivitis, blepharitis, dry eye); interrupt or discontinue for severe, or worsening ocular disorders

Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme reported rarely; discontinue drug

Based on its mechanism of action and data from animal reproduction studies, gefitinib can cause fetal harm when administered to a pregnant woman (see Pregnancy)

Pregnancy

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

Advise females of reproductive potential to use effective contraception during treatment with gefitinib and for at least 2 weeks following completion of therapy

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

Animal studies

• 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

Lactation

Unknown if distributed in human breast milk; not recommended

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Animal studies

• Animal studies indicate the gefitinib and its metabolites are present in rat milk at a concentration higher than those in maternal plasma
• Because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Reversibly inhibits the kinase activity of wild-type and certain activating mutations of epidermal growth factor receptor (EGFR), preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signalling and blocking EGFR-dependent proliferation

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

Binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than its affinity for the wild-type EGFR

Absorption

Oral bioavailability, mean: 60%

Peak plasma concentration: 3-7 hr

Steady-state achieved: 10 days

Distribution

Protein bound: 90%

Vd: 1400 L

Metabolism

Extensive hepatic metabolism, predominantly by CYP3A4

Major active metabolite component was O-desmethyl gefitinib produced by CYP2D6 metabolism and accounted for 14% of the dose

Elimination

Half-life: 48 hr

Excretion: 86% feces; <4% urine

Pharmacogenomics

CYP2D6 poor metabolizers

• CYP2D6 metabolizes gefitinib to O-desmethyl gefitinib in vitro
• In healthy CYP2D6 poor metabolizers, O-desmethyl gefitinib concentration was not measurable and the mean exposure to gefitinib was 2-fold higher as compared to the extensive metabolizers
• This increase in exposure may be clinically important because some adverse drug reactions are related to higher exposure of gefitinib
• No dose adjustment is recommended in patients with a known CYP2D6 poor metabolizer genotype, but these patients should be closely monitored for adverse reactions

Instructions

May take with or without food

Missed dose: Do not take a missed dose within 12 hr of the next scheduled dose

Difficulty swallowing

• Immerse tablet in 4-8 ounces of water and stir for approximately 15 minutes
• Immediately drink the liquid or administer through a NG tube
• Rinse the container with an additional 4-8 ounces of water and immediately drink or administer through the NG tube to assure complete dose