gefitinib

High Alert

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.

Action ⬆ ⬇

Inhibits activation of kinases found in transmembrane cell surface receptors, including EGFR.

Therapeutic effects:

Prolonged progression-free survival.

Pharmacokinetics ⬆ ⬇

Absorption: 60% absorbed following oral administration.

Distribution: Extensively distributed.

Metabolism/Excretion: Primarily metabolized by the liver by the CYP3A4 isoenzyme, with some metabolism via the CYP2D6 isoenzyme; the CYP2D6 isoenzyme exhibits genetic polymorphism (∼7% of population may be poor metabolizers and may have significantly ↑ gefitinib concentrations and an ↑ risk of adverse effects). Primarily excreted in feces, with <4% excreted in urine.

Half-Life: 48 hr.

Time/Action Profile ⬆ ⬇

(plasma levels)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	3–7 hr	unknown

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Idiopathic pulmonary fibrosis (↑ risk of pulmonary toxicity);
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

Derm: rash, alopecia, ERYTHEMA MULTIFORME, pruritus, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS

EENT: aberrant eyelash growth, blepharitis, conjunctivitis, corneal erosion/ulcer, dry eye, nose bleeding

F and E: dehydration

GI: anorexia, diarrhea, nausea, vomiting, dry mouth, GI PERFORATION, HEPATOTOXICITY, mouth ulceration

GU: ↓fertility (females), ↑serum creatinine, hematuria

Metab: weight loss

Resp: dyspnea, INTERSTITIAL LUNG DISEASE

Misc: fever, HYPERSENSITIVITY REACTIONS (INCLUDING ANGIOEDEMA)

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A4 inducers, including rifampin and phenytoin, ↓ blood levels and effects (↑ dose of gefitinib to 500 mg/day).
Strong CYP3A4 inhibitors, including ketoconazole and itraconazole, ↑ blood levels and effects.
Absorption and effectiveness may be ↓ by drugs that gastric pH including H2 receptor antagonists, proton pump inhibitors, and antacids; take gefitinib 12 hr after last dose or 12 hr before the next dose of proton pump inhibitor; take gefitinib 6 hr after last dose or 6 hr before next dose H₂ receptor antagonist or antacid.
May ↑ risk of bleeding with warfarin.

Route/Dosage ⬆ ⬇

PO (Adults ): 250 mg once daily; Concurrent use of rifampin or phenytoin: 500 mg once daily (resume 250 mg once daily dose 7 days after discontinuing strong CYP3A4 inducer).

Availability ⬆ ⬇

(Generic available)

Tablets: 250 mg

Assessment ⬆ ⬇

Assess for signs of pulmonary toxicity (dyspnea, cough, fever). Withhold gefitinib during diagnosis. If interstitial lung disease is confirmed, discontinue gefitinib and treat appropriately.
Assess patient for eye symptoms such as pain during therapy. May require interruption of therapy and removal of aberrant eyelash. After symptoms and eye changes have resolved, may reinstate therapy.
Monitor for rash. Interrupt or discontinue therapy if severe bullous, blistering or exfoliating conditions develop.

Lab Test Considerations:

Patient selection is 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: http://www.fda.gov/CompanionDiagnostics.Monitor liver function tests periodically. May cause ↑ transaminases, bilirubin, and alkaline phosphatase. Withhold gefitinib in patients with worsening liver function tests; discontinue gefitinib if elevations are severe.
- Monitor for changes in prothrombin time and INR in patients taking warfarin. May cause ↑ levels.

Implementation ⬆ ⬇

FDA-approved test must be used to detect EGFR mutations in NSCLC. Patients must have EGFR exon 19 deletions or exon 21 substitutions to use gefitinib.
PO: Administer one tablet daily without regard to food. Tablets can also be dispersed in 4–8 oz of drinking water (noncarbonated). No other liquids should be used. Drop the tablet in the water, without crushing it, stir until the tablet is dispersed (approximately 15 min); drink the liquid immediately. Rinse glass with half a glass of water and drink. Liquid can also be administered through a nasogastric tube.
- May interrupt therapy briefly (14 days) for patients with poorly tolerated diarrhea with dehydration or skin adverse reactions. Follow by restarting 250 mg dose.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take gefitinib as directed. Take missed doses up to 12 hrs of next dose. Advise patient to read the Instruction Sheet with each Rx refill; new information may be available.
Advise patient to notify health care professional promptly if severe persistent diarrhea, nausea, vomiting, or anorexia occur; if shortness of breath or cough occur or worsen; or if eye irritation or other new symptoms develop.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 2 wk after last dose, to avoid breastfeeding during therapy, and to notify health care professional if pregnancy is suspected. May impair fertility in females.

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Pronunciation ⬇

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