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Pronunciation
(ge FI tye nib)
Generic Available (U.S.)
No
Index Terms
Prescribing and Access Restrictions
As of September 15, 2005, distribution of gefitinib (IRESSA®) is limited to patients enrolled in the IRESSA® Access Program. Under this program, access to gefitinib will be limited to the following groups:
Patients who are currently receiving and benefiting from gefitinib
Patients who have previously received and benefited from gefitinib
Previously-enrolled patients or new patients in non-Investigational New Drug (IND) clinical trials involving gefitinib if these protocols were approved by an IRB prior to June 17, 2005
New patients may also receive gefitinib if the manufacturer (AstraZeneca) decides to make it available under IND, and the patients meet the criteria for enrollment under the IND
Additional information on the IRESSA® Access Program, including enrollment forms, may be obtained by calling AstraZeneca at 1-800-601-8933 or via the web at www.Iressa-access.com
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of locally advanced or metastatic nonsmall cell lung cancer (NSCLC) after failure of platinum-based and docetaxel therapies. Treatment is limited to patients who are benefiting or have benefited from treatment with gefitinib.
Note: Due to the lack of improved survival data from clinical trials of gefitinib, and in response to positive survival data with another EGFR inhibitor, according to the U.S. labeling, physicians are advised to use treatment options other than gefitinib in patients with advanced nonsmall cell lung cancer following one or two prior chemotherapy regimens when they are refractory/intolerant to their most recent regimen.
Canada labeling: First-line treatment of locally advanced or metastatic NSCLC with activating mutations of EGFR-TK
Use: Unlabeled
First-line treatment of NSCLC with known EGFR mutation
Pregnancy Risk Factor
D
Pregnancy Considerations
Animal studies have demonstrated fetal harm; there are no well-controlled studies in pregnant women. The risk of fetal harm should be carefully weighed. Women of childbearing potential should be advised to avoid pregnancy.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.
Contraindications
Hypersensitivity to gefitinib or any component of the formulation
Warnings/Precautions
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Diarrhea: Interruption of therapy may be required in patients with poorly tolerated diarrhea.
• Eye irritation: Promptly evaluate eye pain. Therapy may be interrupted based on appropriate medical evaluation; may be reinitiated following resolution of symptoms or eye changes.
• Hepatotoxicity: Asymptomatic increases in transaminases have been reported; monitor liver function periodically and discontinue if elevations/changes are severe.
• Pulmonary toxicity: Rare, sometimes fatal, pulmonary toxicity, including interstitial lung disease (ILD) (eg, alveolitis, interstitial pneumonia, pneumonitis) has occurred. ILD has occurred in patients with prior radiation therapy, prior chemotherapy, and less commonly in treatment naïve patients. Therapy should be interrupted in patients with acute onset or worsening pulmonary symptoms (dyspnea, cough, fever); discontinue if interstitial pneumonitis is confirmed. An increase in mortality was observed in patients with concurrent idiopathic pulmonary fibrosis.
• Skin reactions: Interruption of therapy may be required in patients with adverse skin reactions.
Disease-related concerns:
• Hepatic impairment: Gefitinib exposure may be increased in patients with hepatic impairment.
• NSCLC genomics: EGFR mutations, specifically exon 19 deletions and exon 21 mutation (L858R), are associated with better response to gefitinib in patients with NSCLC (Riely, 2006).
Concurrent drug therapy issues:
• CYP3A4: There is a high potential for CYP3A4 mediated interactions with gefitinib. Concurrent use with CYP3A4 inducers may decrease gefitinib levels; consider increased gefitinib doses (to 500 mg) with close monitoring if concurrent use with inducers cannot be avoided. CYP3A4 inhibitors may increase gefitinib levels, use caution with concurrent administration.
Adverse Reactions
>10%:
Dermatologic: Rash (43% to 54%), acne (25% to 33%), dry skin (13% to 26%), paronychia (14%)
Gastrointestinal: Diarrhea (48% to 67%; grade 3: 1%), nausea (13% to 18%), vomiting (9% to 12%)
1% to 10%:
Cardiovascular: Peripheral edema (2%)
Dermatologic: Pruritus (8% to 9%)
Gastrointestinal: Anorexia (7% to 10%), weight loss (3% to 5%), mouth ulceration (1%)
Neuromuscular & skeletal: Weakness (4% to 6%)
Ocular: Amblyopia (2%), conjunctivitis (1%)
Respiratory: Dyspnea (2%), interstitial lung disease (1% to 2%; includes alveolitis, interstitial pneumonia, pneumonitis)
<1%, postmarketing, and/or case reports: Aberrant eyelash growth, angioedema, CNS hemorrhage (pediatrics), corneal erosion/ulcer, corneal membrane sloughing, epistaxis, erythema multiforme, eye pain, fever, hematuria, hemorrhage, ocular hemorrhage, ocular ischemia, pancreatitis, toxic epidermal necrolysis, urticaria, vesiculobullous rash
Metabolism/Transport Effects
Substrate of CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits BCRP, CYP2C19 (weak), CYP2D6 (weak)
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Gefitinib. Risk C: Monitor therapy
ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult product labeling for specific recommendations. Risk C: Monitor therapy
Cardiac Glycosides: Antineoplastic Agents may decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Digitoxin. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse drug reactions, consider increasing gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers. Carefully monitor clinical response and development of adverse reactions. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
H2-Antagonists: May decrease the serum concentration of Gefitinib. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Proton Pump Inhibitors: May decrease the serum concentration of Gefitinib. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Gefitinib. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Risk D: Consider therapy modification
Vinorelbine: Gefitinib may enhance the neutropenic effect of Vinorelbine. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Gefitinib may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Grapefruit juice may increase serum gefitinib concentrations.
Herb/Nutraceutical: St John's wort may decrease serum gefitinib concentrations.
Storage
Store tablets at controlled room temperature of 20°C to 25°C (68°F to 77°F). Protect from light and moisture.
Mechanism of Action
Gefitinib is a tyrosine kinase inhibitor (TKI) which inhibits numerous tyrosine kinases associated with transmembrane cell surface receptors found on both normal and cancer cells, including the tyrosine kinase associated with the epidermal growth factor receptor, EGFR. Tyrosine kinase activity appears to be vitally important to cell proliferation and survival.
Pharmacodynamics/Kinetics
Absorption: Oral: Slow
Distribution: 1400 L
Protein binding: 90%, albumin and alpha1-acid glycoprotein
Metabolism: Hepatic, primarily via CYP3A4; forms metabolites
Bioavailability: 60%
Half-life elimination: Oral: 41 hours
Time to peak, plasma: Oral: 3-7 hours
Excretion: Feces (86%); urine (<4%)
Dosage
Oral: Adults:
Nonsmall cell lung cancer (NSCLC): 250 mg once daily
NSCLC, first-line therapy in patients with EGFR mutations (unlabeled use): 250 mg once daily (Maemondo, 2010; Mok, 2009; Sequist, 2008)
Dosage adjustment for concomitant CYP3A4 inducers (eg, phenytoin, rifampin): Consider increasing gefitinib dose to 500 mg once daily with close monitoring
Dosage adjustment for toxicity:
Worsening pulmonary symptoms (cough dyspnea, fever): Interrupt treatment and evaluate promptly; discontinue if interstitial lung disease is confirmed
Diarrhea (poorly tolerated or associated with dehydration) or skin toxicity: Interrupt treatment for up to 14 days; may reinitiate at 250 mg once daily
Ocular symptoms (eye pain): Evaluate and interrupt treatment based on symptoms; once symptoms or eye changes have resolved, may consider reinitiating at 250 mg once daily
Dosage adjustment in renal impairment: No adjustment necessary
Dosage adjustment in hepatic impairment:
Moderate-to-severe impairment due to metastases: No adjustment necessary
Hepatotoxicity during treatment (elevations in transaminases): Discontinue if severe
Administration: Oral
May administer with or without food.
For patients unable to swallow tablets or for administration via NG tube: Tablets may be dispersed in noncarbonated drinking water. Drop whole tablet (do not crush) into 1/2 glass of water; stir until tablet is dispersed (~10 minutes). Drink immediately. Rinse glass with 1/2 glass of water and drink.
Monitoring Parameters
Periodic liver function tests (ALT, AST, bilirubin and alkaline phosphatase), INR or prothrombin time (with concurrently warfarin treatment), pulmonary symptoms
Dietary Considerations
Food does not affect gefitinib absorption.
Patient Education
Take with or without food. Do not take with grapefruit juice. You will need periodic laboratory tests while taking this medication. Maintain adequate hydration, unless instructed to restrict fluid intake. You may experience loss of appetite, nausea, vomiting, or diarrhea. Report immediately persistent diarrhea; skin rash; unusual or persistent respiratory difficulty or wheezing; chest pain or cough; any change in vision, eye pain, or signs of eye infection; unusual weakness; or joint pain.
Additional Information
Oncology Comment: Recent studies have demonstrated a subset of patients who are more likely to respond to treatment with gefitinib. This subset includes: patients of Asian origin, never-smokers, women, patients with bronchoalveolar adenocarcinoma, and patients with EGFR-mutated tumors. Deletion in exon 19 and mutation in exon 21 are the two most commonly found EGFR mutations; both mutations correlate with clinical response, resulting in increased response rates in patients with the mutation (Riely, 2006). Studies have compared gefitinib in treatment naïve patients to combination chemotherapy in the subsets of patients described above, resulting in a longer progression free survival in the gefitinib arm (Mok, 2009). Based on these data, the 2009 ASCO guidelines recommend the first-line use of gefitinib in stage IV with the known EGFR mutation (Azzoli, 2009). The NCCN guidelines recommend erlotinib as first-line therapy for EGFR mutation positive patients with stage IV NSCLC, and also states that gefitinib could be used in place of erlotinib in areas of the world where available. In patients with a kras mutation, however, EGFR-TKI therapy is not recommended.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Mouth ulceration.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
GI side effects are common; use caution with SSRIs. Carbamazepine may decrease gefitinib concentrations, while nefazodone and fluvoxamine may increase its concentrations.
Nursing: Physical Assessment/Monitoring
Assess results of liver function tests on a regular basis.
Oncology: Emetic Potential
Very low (<10%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:
Iressa®: 250 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Iressa)
250 mg (30): $1805.91
Extemporaneously Prepared
Hazardous agent: Use appropriate precautions for handling and disposal.
An oral suspension may be prepared by placing one tablet (whole, do not crush) in half a glass of noncarbonated drinking water. Stir until tablet is disintegrated (~10 minutes), then administer immediately. To ensure the full dose is administered, rinse with half a glass of water and administer residue.
Iressa® prescribing information, AstraZeneca Pharmaceuticals, Wilmington, DE, 2005.
References
Azzoli CG, Baker S Jr, Temin S, et al, “American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer,” J Clin Oncol, 2009, 27(36):6251-66.
Fukuoka M, Yano S, Giaccone G, et al, “Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer,” J Clin Oncol, 2003, 21(12):2237-46.
Inoue A, Kobayashi K, Usui K, et al, “First-Line Gefitinib for Patients With Advanced Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations Without Indication for Chemotherapy,” J Clin Oncol, 2009, 27(9):1394-400.
Maemondo M, Inoue A, Kobayashi K, et al, “Gefitinib or Chemotherapy for Non-Small-Cell Lung Cancer With Mutated EGFR,” N Engl J Med, 2010, 362(25):2380-8.
Mok TS, Wu YL, Thongprasert S, et al, “Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma,” N Engl J Med, 2009, 361(10):947-57.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer,” Version 3.2011. Available at http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf
Riely GJ, Pao W, Pham D, et al, “Clinical Course of Patients With Non-Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated With Gefitinib or Erlotinib,” Clin Cancer Res, 2006, 12(3 Pt 1):839-44.
Sequist LV, Martins RG, Spigel D, et al, “First-Line Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer Harboring Somatic EGFR Mutations,” J Clin Oncol, 2008, 26(15):2442-9.
International Brand Names
Lexi-Comp.com
Last full review/revision February 2012
Content last modified February 2012
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