Gefitinib – Uses, Dosage, Side Effects, Interaction

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.

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Gefitinib is the first selective inhibitor of epidermal growth factor receptor’s (EGFR) tyrosine kinase domain. Thus gefitinib is an EGFR inhibitor. The target protein (EGFR) is a member of a family of receptors (ErbB) which includes Her1(EGFR), Her2(Erb-B2), Her3(Erb-B3), and Her4 (Erb-B4). EGFR is overexpressed in the cells of certain types of human carcinomas – for example in lung and breast cancers. This leads to inappropriate activation of the anti-apoptotic Ras signaling cascade, eventually leading to uncontrolled cell proliferation. Research on gefitinib-sensitive non-small cell lung cancers has shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways.^[rx][rx] These mutations tend to confer increased sensitivity to tyrosine kinase inhibitors such as gefitinib and erlotinib. Of the types of non-small cell lung cancer histologies, adenocarcinoma is the type that most often harbors these mutations. These mutations are more commonly seen in Asians, women, and non-smokers (who also tend to more often have adenocarcinoma). Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-the binding site of the enzyme.^[rx] Thus the function of the EGFR tyrosine kinase in activating the anti-apoptotic Ras signal transduction cascade is inhibited, and malignant cells are inhibited.^[rx]

Use in Cancer

Gefitinib is approved to treat:

• Non-small cell lung cancer (NSCLC) that has metastasized (spread to other parts of the body). It is used as first-line treatment in patients whose tumors have certain EGFR gene mutations.

Gefitinib is also being studied in the treatment of other types of cancer.

Contraindications

• a type of inflammation? of the lung called interstitial pneumonitis
• a condition where there is a formation of fibrous tissue in the lung called pulmonary fibrosis?
• liver problems
• severe renal? impairment
• pregnancy
• a patient who is producing milk and breastfeeding

Dosage?

Strengths: 250 mg

Non-Small Cell Lung Cancer

• 250 mg orally once a day until disease progression? or unacceptable toxicity
• Select patients for the first-line treatment of metastatic NSCLC with this drug based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in their tumor or plasma specimens.
  

  NOTE: For patients who have difficulty swallowing tablets immerse the tablet in 4 to 8 ounces of water (noncarbonated) and stir until dispersed (about 15 minutes). Drink the liquid or administer through a nasogastric tube. Rinse the container with 4 to 8 ounces of water and drink or administer through nasogastric tube.

Dose Adjustments

Withhold therapy for up to 14 days for the following adverse drug reactions and resume when fully resolved to Grade 1:

• Acute onset? or worsening of pulmonary symptoms (e.g., dyspnea?, cough?, fever?)
• Grade 2 or higher in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations
• Grade 3 or higher diarrhea?
• Severe or worsening ocular disorders including keratitis
• Grade 3 or higher skin reactions

Permanently discontinue therapy for:

• Confirmed interstitial lung disease? (ILD)
• Severe hepatic impairment
• GI perforation
• Persistent ulcerative? keratitis

Concomitant use with strong CYP450 3A4 inducers:

• Avoid concomitant use if possible.
• If concomitant use is required, increase dose to 500 mg orally once a day (in the absence of severe adverse drug reaction); resume at 250 mg dose 7 days after discontinuation of the strong CYP450 3A4 inducer.

Concomitant use with proton-pump inhibitor/H2 receptor antagonist/antacid:

• Avoid concomitant use if possible.
• If concomitant use is required, take this drug 12 hours after the last dose of the proton-pump inhibitor or 12 hours before the next dose of the proton-pump inhibitor.
• Take this drug 6 hours after the last dose of the H2-receptor antagonist or antacid, or 6 hours before the next dose of the H2-receptor antagonist or antacid.

Administration Advice:

• Therapy should be initiated and supervised by a physician experienced in the use of anticancer therapies.
• This drug should be taken at about the same time each day, with or without food.
• A missed dose should not be taken within 12 hours of the next dose.

Side Effects

The Most Common

• dry skin
• itching?
• rash?
• acne?
• mouth sores
• weakness?
• new or worsening shortness of breath?, cough, or fever
• severe or ongoing diarrhea
• severe abdominal pain?
• loss of appetite?
• eye pain?, redness, or irritation
• vision changes
• watery eyes
• eye sensitivity to light
• hives?
• blisters or peeling skin
• swelling of the eyes, face, lips, tongue, throat, hands, arms, feet, ankles or lower legs
• nausea
• vomiting
• yellowing of the skin or eyes
• dark urine
• pale stools
• pain or discomfort in the right upper stomach area

More common

• Abdominal or stomach pain or tenderness
• clay-colored stools
• dark urine
• decreased appetite
• diarrhea, severe
• fever
• headache
• itching or skin rash
• loss of appetite
• nausea and vomiting
• swelling of the feet or lower legs
• unusual tiredness or weakness
• yellow eyes or skin
• Burning, dry, or itching eyes
• chest pain
• chills
• cough
• difficult breathing
• discharge or excessive tearing
• dry eyes
• a general feeling of discomfort or illness
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• thickening of bronchial secretions
• troubled breathing
• troubled or quick, shallow breathing

Rare

• severe or ongoing diarrhea;
• sudden chest pain or discomfort, new or worsening cough with fever, trouble breathing;
• blurred vision, watery eyes, eye pain or redness, eyes being more sensitive to light;
• liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• signs of stomach bleeding–severe stomach pain, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds; or
• severe skin reaction–fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.
• Blistering, peeling, or loosening of the skin
• bloody, black, or tarry stools
• eye redness, irritation, or pain
• heartburn
• indigestion
• joint or muscle pain
• red skin lesions, often with a purple center
• severe abdominal or stomach pain, cramping, or burning
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• vomiting of material that looks like coffee grounds, severe and continuing

Drug Interactions

Pregnancy and Lactation

AU TGA pregnancy category: C
US FDA pregnancy category: Not assigned.

Pregnancy

Based on its mechanism of action and animal data, IRESSA 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 (see Animal Data). 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

Lactation

No information is available on the clinical use of gefitinib during breastfeeding. Because gefitinib is 90% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 48 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during gefitinib therapy.

References