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Iressa

Generic Name: Gefitinib
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin)propoxy]-4-quinazolamine
Molecular Formula: C22H24ClFN4O3
CAS Number: 184475-35-2

Introduction

Antineoplastic agent; epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.1 2 3 4

Uses for Iressa

Non-small Cell Lung Cancer (NSCLC)

First-line treatment of metastatic NSCLC in patients with tumors positive for EGFR exon 19 deletions (del19) or exon 21 (L858R) substitution mutations as detected by an FDA-approved diagnostic test (e.g., therascreen EGFR RGQ PCR Kit).1 18 19 24 Information on FDA-approved companion diagnostic tests for the detection of EGFR mutations in NSCLC is available at .1

Designated an orphan drug by FDA for treatment of EGFR mutation-positive NSCLC.17

Gefitinib originally received accelerated approval in 2003 for the treatment of locally advanced or metastatic NSCLC following failure of a platinum-based and docetaxel regimen, but was voluntarily withdrawn from the market when subsequent confirmatory clinical trials failed to verify clinical benefit.20 21 24 The current approval is for a different patient population (i.e., previously untreated, EGFR-mutation positive) than the 2003 approval.1 18 19 23 24

Safety and efficacy not established in patients with metastatic NSCLC whose tumors harbor EGFR mutations other than exon 19 deletions or exon 21 substitution mutations.1

Iressa Dosage and Administration

General

  • Confirm presence of EGFR del19 or L858R substitution mutations by an FDA-approved diagnostic test prior to initiating therapy.1

Restricted Distribution

  • Available through a limited network of specialty pharmacies and distributors.15 Consult the Iressa website () for specific ordering and availability information.15

Administration

Oral Administration

Administer orally once daily without regard to meals.1

For patients with difficulty swallowing solids, may disperse tablet in a container with 120–240 mL (4–8 ounces) of water.1 Stir the tablet in water for approximately 15 minutes until it is dispersed.1 Immediately drink liquid (containing dispersed tablet) or administer through a nasogastric tube, then rinse container with 120–240 mL of water and immediately drink liquid or administer through a nasogastric tube.1

If a dose of gefitinib is missed and cannot be taken within 12 hours, do not take the missed dose and take the next dose at the regularly scheduled time.1

Dosage

Adults

NSCLC
Oral

250 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

If used concomitantly with a potent CYP3A4 inducer, increase dosage to 500 mg once daily in the absence of severe adverse drug reactions.1 When the CYP3A4 inducer is discontinued, resume gefitinib at 250 mg once daily after 7 days.1

Therapy Interruption for Toxicity

Temporarily interrupt (for up to 14 days) therapy in patients who develop new or worsening pulmonary symptoms (e.g., dyspnea, cough, fever), grade 2 or greater elevations in ALT and/or AST concentrations, grade 3 or greater diarrhea, severe or worsening ocular disorders (including keratitis), or grade 3 or greater dermatologic reactions.1 May resume gefitinib therapy when toxicity resolves completely or improves to grade 1.1 (See Cautions.)

Permanently discontinue therapy in patients who develop confirmed interstitial lung disease, severe hepatic impairment, GI perforation, or persistent ulcerative keratitis.1 (See Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations.1 Monitor patients with moderate or severe hepatic impairment for adverse effects.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

No specific dosage recommendations.1 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No specific dosage recommendations.1

Poor CYP2D6 Metabolizer Phenotype

Because of increased systemic exposure, monitor closely for adverse effects.1 Routine dosage adjustment not necessary.1 (See Special Populations under Pharmacokinetics.)

Gender

No dosage adjustment required.1

Cautions for Iressa

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Interstitial Lung Disease

Interstitial lung disease or interstitial lung disease-like events (e.g., lung infiltration, pneumonitis, ARDS, pulmonary fibrosis), sometimes fatal, reported.1 18

In patients who develop worsening pulmonary symptoms (e.g., dyspnea, cough, fever), temporarily interrupt therapy for up to 14 days and promptly evaluate patient for interstitial lung disease.1 (See Therapy Interruption for Toxicity under Dosage and Administration.) If diagnosis of interstitial lung disease is confirmed, permanently discontinue gefitinib.1

Hepatic Toxicity

Abnormal liver function tests (e.g., elevations in ALT, AST, and bilirubin concentrations), sometimes fatal, reported.1

Perform liver function tests periodically during therapy.1 Temporarily interrupt therapy for up to 14 days in patients who develop grade 2 or greater elevations in ALT and/or AST concentrations.1 (See Therapy Interruption for Toxicity under Dosage and Administration.) Permanently discontinue gefitinib in patients who develop severe hepatic impairment.1

GI Perforation

GI perforation reported.1

Permanently discontinue gefitinib in patients who develop GI perforation.1

Diarrhea

Severe diarrhea reported.1

If severe (grade 3 or greater) or persistent (lasting up to 14 days) diarrhea occurs, temporarily interrupt therapy for up to 14 days.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Ocular Disorders including Keratitis

Ocular disorders (e.g., keratitis, corneal erosion, abnormal eyelash growth, conjunctivitis, blepharitis, dry eye) reported.1

Temporarily interrupt therapy for up to 14 days in patients who develop severe or worsening ocular disorders, including keratitis.1 (See Therapy Interruption for Toxicity under Dosage and Administration.) Permanently discontinue gefitinib in patients who develop persistent ulcerative keratitis.1

Dermatologic Effects

Bullous conditions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme, reported rarely.1

Temporarily interrupt therapy for up to 14 days or discontinue therapy in patients who develop severe bullous, blistering, or exfoliating conditions.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Fetal toxicity (e.g., decreased fetal weight, abortion) and neonatal mortality shortly after parturition observed in animals.1 Crosses the placenta.1 26

Avoid pregnancy during therapy.1 Women of childbearing potential should use effective contraception while receiving the drug and for ≥2 weeks after the drug is discontinued.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Impairment of Fertility

May decrease female fertility based on animal findings.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Gefitinib and its metabolites are distributed into milk in rats; not known whether distributed into human milk.1 Women receiving gefitinib should not breast-feed.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety relative to younger adults in 2 controlled studies.1 Insufficient experience in patients ≥65 years of age to determine differences in efficacy between geriatric patients and younger adults.1

Hepatic Impairment

Increased systemic exposure has been reported in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment due to cirrhosis.1 (See Special Populations under Pharmacokinetics.)

Monitor patients with moderate to severe hepatic impairment for adverse effects.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Not studied in patients with severe renal impairment; however, <4% of the drug and its metabolites are excreted by the kidneys.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Skin reactions/rash (e.g., acne, maculopapular rash, acneiform dermatitis, erythema, generalized rash, papular rash, pruritic rash, macular rash, dry skin, erythema),1 18 diarrhea,1 18 nausea,1 18 vomiting,1 18 decreased appetite,1 18 asthenia,1 18 pyrexia,1 stomatitis,1 eye disorders (e.g., conjunctivitis, blepharitis, dry eye),1 nail disorders (e.g., nail infections, onychoclasis, onycholysis, paronychia),1 increased ALT/AST concentrations,1 18 proteinuria.1

Interactions for Iressa

Metabolized principally by CYP3A4 and, to a lesser extent, by CYP2D6.1 14 Does not inhibit CYP isoenzymes 1A2, 2C9, or 3A4 in vitro, but may inhibit 2C19 and 2D6 at high drug concentrations.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 and CYP2D6 inhibitors: Potential pharmacokinetic interaction (decreased metabolism and increased systemic exposure of gefitinib).1 25 If used concomitantly with a potent CYP3A4 or CYP2D6 inhibitor, monitor for signs of toxicity.1 (See Specific Drugs under Interactions.)

CYP3A4 inducers: Potential pharmacokinetic interaction (increased metabolism and decreased plasma concentrations of gefitinib).1 25 If used concomitantly with a potent CYP3A4 inducer, increase gefitinib dosage to 500 mg daily in the absence of severe adverse effects.1 When the CYP3A4 inducer is discontinued, resume gefitinib at 250 mg once daily after 7 days.1 (See Specific Drugs under Interactions.)

Drugs Affecting Gastric Acidity

Possible pharmacokinetic interaction (decreased plasma gefitinib concentrations and possible reduction in efficacy) with drugs that cause gastric pH elevation.1 10 (See Specific Drugs under Interactions.)

Specific Drugs

Drug

Interaction

Comments

Antacids

Possible decreased gefitinib concentrations1

Sodium bicarbonate and ranitidine (to achieve gastric pH ≥5) decreased gefitinib AUC by 47%1 14

Administer antacid 6 hours before or after gefitinib1

Antidepressants, tricyclics (TCAs)

Increased metabolism and decreased plasma concentrations of gefitinib1

Increase gefitinib dosage to 500 mg daily in the absence of severe adverse effects1

When the TCA is discontinued, resume gefitinib at 250 mg once daily after 7 days1

Antifungals, azoles (e.g., itraconazole, ketoconazole)

Itraconazole (CYP3A4 inhibitor) increased gefitinib AUC and peak concentrations by approximately 80 and 51%, respectively1 14

Monitor for adverse effects1

Histamine H2-receptor antagonists (e.g., cimetidine, famotidine, ranitidine)

Possible decreased gefitinib concentrations1

Ranitidine and sodium bicarbonate (to achieve gastric pH ≥5) decreased gefitinib AUC by 47%1 14

Administer H2-receptor antagonist 6 hours before or after gefitinib1

Metoprolol

Increased systemic exposure of metoprolol by 30%1

Phenytoin

Increased metabolism and decreased plasma concentrations of gefitinib1

Increase gefitinib dosage to 500 mg daily in the absence of severe adverse effects1

When phenytoin is discontinued, resume gefitinib at 250 mg once daily after 7 days1

Proton-pump inhibitors

Possible decreased gefitinib concentrations1 10

Avoid concomitant use, if possible; if concomitant use cannot be avoided, administer proton-pump inhibitor 12 hours before or after gefitinib1

Consider substituting H2-receptor antagonist or antacid (administered 6 hours before or after gefitinib) for proton-pump inhibitor1

Rifampin

Rifampin (potent CYP3A4 inducer) decreased AUC and peak concentrations of gefitinib by 83 and 65%, respectively1 14 25

Increase gefitinib dosage to 500 mg daily in the absence of severe adverse effects1

When rifampin is discontinued, resume gefitinib at 250 mg once daily after 7 days1

Warfarin

INR elevations and/or bleeding reported1

Monitor regularly for changes in PT or INR1

Iressa Pharmacokinetics

Absorption

Bioavailability

Slowly absorbed following oral administration, with peak plasma concentrations attained within 3–7 hours.1 Mean bioavailability is 60%.1

Food

Food does not substantially affect bioavailability.1 14

Special Populations

In healthy poor metabolizers of CYP2D6, mean exposure is twofold higher compared with extensive metabolizers of CYP2D6; however, plasma concentrations of O-desmethyl gefitinib are undetectable.1 (See Poor CYP2D6 Metabolizer Phenotype under Dosage and Administration.)

In patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment due to cirrhosis, mean systemic exposure is increased by 40, 263, or 166%, respectively, compared with healthy individuals with normal hepatic function.1 In patients with liver metastases and moderate hepatic impairment, systemic exposure was similar to that in patients with liver metastases and normal hepatic function.1

Population pharmacokinetic analyses suggest that Clcr (>20 mL/minute) does not have a clinically important effect on steady-state trough concentrations.1 Not studied in patients with severe renal impairment.1

Age, body weight, and ethnicity do not substantially affect pharmacokinetics.1

In population pharmacokinetic analyses of one clinical study, women had 27% higher exposure than men; gender-related differences in exposure not identified in such analyses from other clinical studies.1

Distribution

Extent

Extensively distributed throughout the body.1

Crosses the placenta.1 26 Gefitinib and its metabolites distribute into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

90% in vitro (to albumin and α1-acid glycoprotein).1

Elimination

Metabolism

Extensively metabolized in liver, principally by CYP3A4 and, to a lesser extent, by CYP2D6.1 14 Eight metabolites identified; only O-desmethyl gefitinib has exposure comparable to that of gefitinib, but potency is only 1/14 that of gefitinib.1

Elimination Route

Excreted in feces (86%) and urine (<4%).1

Half-life

48 hours.1

Stability

Storage

Oral

Tablets

20–25°C.1

Actions

  • Antineoplastic agent; EGFR tyrosine kinase inhibitor.1 2 3 4

  • EGFR (HER1, c-ERbB-1) is expressed on the cell surface of both normal and cancer cells and plays a role in cell growth and proliferation.1 Some EGFR-activating mutations (del19 or L858R substitution mutations) within NSCLC cells can promote tumor cell growth, block apoptosis, increase production of angiogenic factors, and facilitate metastasis.1

  • Reversibly inhibits phosphorylation and proliferation of cell lines expressing wild-type EGFR and cell lines expressing del19 or L858R mutations.1 2 3 4

  • Exhibits greater binding affinity for EGFR del19 or L858R substitution mutations than for wild-type EGFR.1

  • Inhibits insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) at clinically relevant concentrations.1

Advice to Patients

  • Importance of reading the manufacturer's patient information.1

  • If a dose of gefitinib is missed, instruct patients to take the missed dose as soon as it is remembered unless it is within 12 hours of the next scheduled dose, in which case they should not take the missed dose.1

  • Risk of interstitial lung disease.1 Importance of immediately informing clinician if new or worsening respiratory symptoms occur (e.g., dyspnea, cough, fever).1

  • Risk of hepatotoxicity and importance of periodic liver function test monitoring.1 Importance of reporting any manifestations of hepatotoxicity (e.g., jaundice, dark or “tea-colored” urine, right upper quadrant pain, light-colored stool, decreased appetite).1

  • Risk of GI perforation.1 Importance of advising patients to seek immediate medical attention if they experience symptoms of GI perforation (e.g., severe abdominal pain).1

  • Risk of severe or persistent diarrhea.1 Importance of informing clinician if severe or persistent diarrhea occurs.1

  • Risk of ocular disorders, including keratitis.1 Importance of promptly informing clinician if ocular problems (e.g., lacrimation, sensitivity to light, eye pain, redness, blurred vision, other vision changes) occur.1

  • Risk of bullous and exfoliative skin disorders.1 Importance of advising patients to seek immediate medical attention if they develop severe dermatologic reactions (e.g., peeling, blistering).1

  • Risk of fetal harm and loss of pregnancy.1 Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving gefitinib and for ≥2 weeks after discontinuance of therapy.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Importance of women informing clinicians if they plan to breast-feed.1 Importance of advising women to avoid breast-feeding while receiving gefitinib.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors, warfarin) and herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of gefitinib is restricted.15 (See Restricted Distribution under Dosage and Administration.)

Gefitinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

250 mg

Iressa

AstraZeneca

AHFS DI Essentials. © Copyright 2018, Selected Revisions February 26, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AstraZeneca Pharmaceuticals LP. Iressa (gefitinib) tablets prescribing information. Wilmington, DE; 2015 Jul.

2. Culy CR, Faulds D. Gefitinib. Drugs. 2002; 62:2237-48. [PubMed 12381224]

3. Anon. Gefitinib (Iressa) for advanced non-small cell lung cancer. Med Lett Drugs Ther. 2002; 44:77-8. [PubMed 12205428]

4. Baselga J, Averbuch SD. ZD1839 (Iressa) as an anticancer agent. Drugs. 2000; 60 (suppl 1):33-40. [PubMed 11129170]

5. Kris MG, Natale RB, Herbst RS et al. A phase II trial of ZD1839 (Iressa) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). 38th Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, FL, May 2002. Abstract No. 1166.

6. Food and Drug Administration. Briefing document NDA 21-399. From FDA website. Accessed 2003 May 22.

7. Inoue A, Saijo Y, Maemondo M et al. Severe acute interstitial pneumonia and gefitinib. Lancet. 2003; 361:137-9. [PubMed 12531582]

8. Kinoshita A, Fukuda M, Nagashima S, et al. Pulmonary damage during gefitinib monotherapy in patients with non-small cell lung cancer. 39th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL, May 2003. Abstract No. 2809.

9. AstraZeneca Pharmaceuticals, Wilmington, DE: Personal communication.

10. Zucchero FJ, Hogan MJ, Sommer CD, eds. Evaluations of Drug Interactions. St. Louis, MO: FirstDatabank; 2003:18/902.00.

11. FDA public health advisory: new labeling and distribution program for gefitinib (Iressa). Rockville, MD; 2005 Jun 17. From FDA website.

12. Questions and answers on Iressa (gefitinib). Rockville, MD: Food and Drug Administration; 2005 Jun 17. From FDA website.

13. AstraZeneca Pharmaceuticals. Information for healthcare professionals from website for Iressa.

14. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206995Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

15. AstraZeneca Pharmaceuticals. Ordering and patient access. From AstraZeneca for US Healthcare Professionals website. Accessed 2016 Aug 19.

16. AstraZeneca Pharmaceuticals. Iressa (gefitinib) tablets prescribing information. Wilmington, DE; 2005 Jun.

17. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2016 Aug 30.

18. Douillard JY, Ostoros G, Cobo M et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014; 110:55-62. [PubMed 24263064]

19. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361:947-57. [PubMed 19692680]

20. Food and Drug Administration. FDA briefing document from the oncology drugs advisory committee, March 4, 2005. From FDA website.

21. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206995Orig1s000: Summary review. From FDA website.

22. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for industry. Expedited programs for serious conditions- drugs and biologics. 2014 May. From FDA website.

23. Food and Drug Administration. Center for Drug Evaluation and Research. Approval package for application number 206995Orig1s000. From FDA website.

24. Food and Drug Administration. FDA News Release: FDA approves targeted therapy for first-line treatment of patients with a type of metastatic lung cancer. Companion test also approved to identify appropriate patients; 2015 Jul 13. From FDA web site.

25. Swaisland HC, Ranson M, Smith RP et al. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet. 2005; 44:1067-81. [PubMed 16176119]

26. Gil S, Goetgheluck J, Paci A et al. Efficacy and safety of gefitinib during pregnancy: case report and literature review. Lung Cancer. 2014; 85:481-4. [PubMed 24997732]

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