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DRUG RECORD

 

GEFITINIB

OVERVIEW
Gefitinib

 

Introduction

Gefitinib is a selective tyrosine kinase receptor inhibitor used in the therapy of non-small cell lung cancer.  Gefitinib therapy is associated with transient elevations in serum aminotransferase levels and rare instances of clinically apparent acute liver injury.

 

Background

Gefitinib (ge fi' ti nib) is a selective inhibitor of the tyrosine kinase receptor of epidermal growth factor (EGFR), which is often mutated and over expressed in cancer cells, particularly non-small cell lung cancer and some forms of breast cancer.  The mutated EGF tyrosine kinase receptor is constitutively expressed which causes unregulated cell growth and proliferation.  By inhibition of this growth factor receptor, gefitinib blocks the intracellular Ras signaling transduction cascade, which results in inhibition of the malignant cell growth.  Highest rates of response to gefitinib are seen in patients with activating mutations of EGFR in the tumor tissue.  Gefitinib received approval for use in the United States in 2009 for the treatment of advanced non-small cell lung cancer after failure of other therapies, but has been available in Japan since 2002.  Gefitinib is available in tablets of 250 mg under the brand name Iressa.  The recommended dose is 250 mg by mouth once daily, with dose modification based upon tolerance.  Side effects are common and include diarrhea, nausea, vomiting, anorexia, mouth ulcers, conjunctivitis, rash, pruritus and fatigue.  Uncommon serious side effects include interstitial lung disease and corneal erosions.

 

Hepatotoxicity

In large early clinical trials, elevations in serum aminotransferase levels occurred in 9% to 13% of patients treated with standard doses of gefitinib, and 2% to 4% of patients had to stop therapy because of elevations above 5 times the upper limit of normal.  Serum enzyme elevations typically arise after 4 to 12 weeks of treatment with a hepatocellular pattern.  Immunoallergic and autoimmune features have not been described, but rash is common in patients receiving gefitinib.  Most cases of liver injury due to gefitinib in the literature have been minimally or not symptomatic, and the injury resolved within 1 to 2 months of stopping the drug.  Restarting therapy was usually followed by rapid recurrence of serum enzyme elevations, and corticosteroid therapy did not appear to prevent this recurrence.  In some instances, lower doses were tolerated with minimal or no ALT elevations.  Periodic monitoring of liver tests during therapy is recommended.

 

Mechanism of Injury

The cause of the liver injury due to gefitinib is unknown. Gefitinib is metabolized in the liver largely via CYP 3A4, and liver injury may be due to accumulation of a toxic or immunogenic intermediate.

 

Outcome and Management

Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose interruption.  If changes persist, are severe, or reoccur on restarting, gefitinib should be discontinued.  There have been no published reports of acute liver failure, chronic hepatitis or vanishing bile duct syndrome due to gefitinib.  Patients with liver abnormalities during gefitinib therapy generally tolerate other tyrosine kinase receptor inhibitors.

 

Drug Class:  Antineoplastic Agents, Protein Kinase Inhibitors

 

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CASE REPORT
Gefitinib

 

Case 1.  Serum aminotransferase elevations during gefitinib therapy.
[Modified from:  Takeda M, Okamoto I, Fukuoka M, Nakagawa K. Successful treatment with erlotinib after gefitinib-related severe hepatotoxicity. J Clin Oncol 2010; 28: e273-4. PubMed Citation]

 

A 66 year old woman with metastatic non-small cell adenocarcinoma of the lung developed serum aminotransferase elevations during therapy with gefitinib (250 mg daily).  She was a nonsmoker and the lung cancer was shown to harbor a deletion in exon 19 of the epidermal growth factor receptor gene, which has been shown to confer sensitivity to inhibition by gefitinib.  Serum aminotransferase levels were normal before and during the first 8 weeks of treatment, but became moderately elevated at week 13 (Table).  Nevertheless, gefitinib was continued and ursodiol and glycyrrhizate [an herbal medication used in Japan as therapy of liver disease] were started.  Serum enzymes gradually improved.  However, 36 weeks after starting gefitinib, ALT levels rose markedly [ALT 1011 and AST 599 U/L] and gefitinib was stopped.  She was taking no other medications.  Abdominal ultrasound was unremarkable.  Serum enzymes decreased with stopping gefitinib and 7 weeks later they were normal.  Erlotinib (150 mg daily) was started and serum aminotransferase levels remained normal during long term therapy (15 weeks at the time of the report).

 

Key Points

Medication:Gefitinib (250 mg daily)
Pattern: Hepatocellular (R=unable to calculate)
Severity: 1+ (serum enzyme elevations only)
Latency: 12 weeks to initial elevations, 36 weeks to marked elevations
Recovery: 7 weeks
Other medications:Initially none; later ursodiol and glycyrrhizate

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) AST (U/L) Other
0 Pre 20 20 Gefitinib started
8 weeks 30 30
13 weeks 181 84
14 weeks 200 86
16 weeks 120 80
22 weeks 80 60
26 weeks 40 40
29 weeks 35 40
33 weeks 100 70
36 weeks 0 750 410 Gefitinib stopped
38 weeks 2 weeks 1011 599
40 weeks 4 weeks 410 100
42 weeks 6 weeks 70 70
44 weeks 2 months 40 40 Erlotinib started
12 months 3 months 35 30
14 months 5 months 20 20
Normal Values <35 <40

* Selected values estimated from Figure 1.

Comment

Elevations in serum aminotransferase levels occur in at least 10% of patients treated with gefitinib, but they are usually mild and self-limited and rise to above 5 times the upper limit (approximately 200 U/L) in only 2% to 4% of patients, and even then may not require drug discontinuation.  In this patient, the serum aminotransferase levels rose to more than 20 times the upper limit of normal which led to immediate discontinuation of therapy.  Glycyrrhizate is an extract of licorice which is used in Japan as a hepatoprotective agent and usually given intravenously one to three times weekly, but its dose and regimen were not provided in this report.  The authors also do not mention whether the patient was symptomatic or jaundiced and results of serum alkaline phosphatase, bilirubin and prothrombin time were not given, nor was information provided about previous liver disease, alcohol use, or results of virologic and immunologic tests to rule out other causes of liver injury.  Nevertheless, the timing of presentation and prompt improvement on stopping gefitinib are convincing as was the lack of recurrence with erlotinib treatment.  Monitoring of serum enzymes during gefitinib and erlotinib therapy is warranted and the agents should be discontinued if symptoms or jaundice arise or aminotransferase levels remain above 5 times the upper limit of normal in the absence of other possible etiologies.

 

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PRODUCT INFORMATION
Gefitinib


REPRESENTATIVE TRADE NAMES
Gefitinib – Iressa®


DRUG CLASS
Antineoplastic Agents


COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Gefitinib 184475-35-2 C22-H24-Cl-F-N4-O3 Gefitinib Chemical Structure

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REFERENCES
Gefitinib

 

References updated: 17 March 2014

  1. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase receptor inhibitors).

  2. DeLeve LD. Kinase inhibitors. Gefitinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 556.  (Review of hepatotoxicity of cancer chemotherapeutic agents; gefitinib has been linked to reversible serum aminotransferase elevations, but not clearly to symptomatic, clinically apparent liver injury).

  3. Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, Longo DL, Mitsiades C, Richardson P.  Targeted therapies: tyrosin kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.  (Textbook of pharmacology and therapeutics).

  4. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, 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: 2237-46. PubMed Citation  (Among 210 patients with advanced lung cancer treated with two doses of gefitinib, serum ALT elevations occurred in 14%, were above 5 times ULN in 4.7%, and 4 patients [2%] withdrew from therapy for serum enzyme elevations).

  5. Kris M, Natale RB, Herbst R, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. JAMA 2003; 290: 2149-58. PubMed Citation  (Among 216 patients with advanced lung cancer treated with two doses of gefitinib for an average of 2 months, elevations in ALT >5 times ULN occurred in 3 [1.5%], but none developed symptomatic hepatitis with jaundice).

  6. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004; 350: 2129-39. PubMed Citation  (A mutation in EGF tyrosine kinase receptor was identified in 8 of 9 tumors from patients with a clinical response to gefitinib, but in 0 of 7 nonresponders; in vitro, the mutated receptor was more sensitive than the wild type to inhibition by gefitinib).

  7. Birnbaum A, Ready N. Gefitinib therapy for non-small cell lung cancer. Curr Treat Options Oncol 2005; 6: 75-81. PubMed Citation  (Review of efficacy and safety of gefitinib therapy for non-small cell lung cancer; hepatotoxicity is not discussed).

  8. Kindler HL, Friberg G, Skoog L, Wade-Oliver K, Vokes EE. Phase I/II trial of gefitinib and oxaliplatin in patients with advanced colorectal cancer. Am J Clin Oncol 2005; 28: 340-4. PubMed Citation  (14 patients with advanced lung cancer were treated with gefitinib and oxaliplatin; mild serum ALT elevations occurred in 9 patients [64%]).

  9. Ho C, Davis J, Anderson F, Bebb G, Murray N. Side effects related to cancer treatment: CASE 1. Hepatitis following treatment with gefitinib. J Clin Oncol 2005; 23: 8531-3. PubMed Citation  (57 year old woman with advanced lung cancer developed abnormal liver tests 8 weeks after starting gefitinib [AST ~800 U/L], which resolved in 2 months but recurred within a week of restarting [AST~520 U/L], resolving again and recurring even with concurrent prednisone).

  10. Seki N, Uematsu K, Shibakuki R, Eguchi K. Promising new treatment schedule for gefitinib responders after severe hepatotoxicity with daily administration. J Clin Oncol 2006; 24: 3213-4; author reply 3214-5. PubMed Citation  (Letter in response to Ho [2005] describing 61 year old Japanese woman who had a clinical response to gefitinib therapy, but developed serum ALT elevations after 8 weeks of therapy, recurring on rechallenge, but later tolerated gefitinib with minimal ALT elevations when given every 5 days instead of daily).

  11. Fujiwara Y, Kiura K, Toyooka S, Takigawa N, Tokumo M, Hotta K, Aoe M, et al. Relationship between epidermal growth factor receptor gene mutations and the severity of adverse events by gefitinib in patients with advanced non-small cell lung cancer. Lung Cancer 2006; 52: 99-103. PubMed Citation  (Among 26 patients with non-small cell lung cancer treated with gefitinib, 11 had EGFR mutations in tumor tissue which correlated with tumor response [78% vs 21% in those without], but not with side effects [any ALT elevation in 36% vs 7%, ALT >5 times ULN in 0% vs 7%]).

  12. Reck M, Buchholz E, Romer KS, Krutzfeldt K, Gatzemeier U, Manegold C. Gefitinib monotherapy in chemotherapy-naive patients with inoperable stage III/IV non-small-cell lung cancer. Clin Lung Cancer 2006; 7: 406-11. PubMed Citation  (Among 58 patients with advanced non-small cell lung cancer treated with gefitinib, common toxicities were rash, diarrhea, nausea and fatigue; ALT changes not mentioned).

  13. Carlini P, Papaldo P, Fabi A, Felici A, Ruggeri EM, Milella M, Ciccarese M, et al. Liver toxicity after treatment with gefitinib and anastrozole: drug-drug interactions through cytochrome p450? J Clin Oncol 2006; 24: e60-1. PubMed Citation  (Letter in response to Ho [2005] describing a 63 year old woman with lung cancer who developed rising ALT elevations after 16 weeks of gefitinib therapy [ALT 77 to 213 U/L], which decreased on stopping and rapidly recurred on restarting).

  14. Jiang H. Overview of gefitinib in non-small cell lung cancer: an Asian perspective. Jpn J Clin Oncol 2009; 39: 137-50. PubMed Citation  (Systematic review of the literature on gefitinib therapy of non-small cell lung cancer, focusing upon differences in response rates between Asian and Western patients that is probably due to different rates of activating mutations; rates of adverse events are similar in Asian and non-Asian patients).

  15. Sanford M, Scott LJ. Gefitinib: a review of its use in the treatment of locally advanced/metastatic non-small cell lung cancer. Drugs 2009; 69: 2303-28. PubMed Citation  (Review of the pharmacology, efficacy and safety of gefitinib; overall rate of serum enzyme elevations of >5 times ULN was 9% with gefitinib vs 1% in comparative regimens; severe side effects are more common in elderly).

  16. Ohashi Y, Suzuki K, Sakurai M, Ishikawa H, Onishi T, Nakagaki S, Kato T, et al. [Safety analysis of eight patients treated with erlotinib after severe gefitinib-induced liver injury]. Gan To Kagaku Ryoho 2010; 37: 1307-11. Japanese. PubMed Citation  (Abstract only: among 8 patients who developed marked serum ALT elevations on gefitinib therapy, only one had recurrence [with skin rash] when switched to erlotinib).

  17. Kim ST, Lee J, Kim JH, Won YW, Sun JM, Yun J, Park YH, et al. Comparison of gefitinib versus erlotinib in patients with non-small cell lung cancer who failed previous chemotherapy. Cancer 2010; 116: 3025-33. PubMed Citation  (Retrospective analysis of 467 patients with non-small cell lung cancer treated with either gefitinib or erlotinib found similar rates of clinical response; no discussion of adverse events).

  18. Campbell L, Blackhall F, Thatcher N. Gefitinib for the treatment of non-small-cell lung cancer. Expert Opin Pharmacother 2010; 11: 1343-57. PubMed Citation  (Review of structure, mechanism of action, pharmacology, efficacy and safety of gefitinib; "Asymptomatic elevations in liver transaminases and bilirubin also occurred commonly but usually recovered upon discontinuation of therapy. Rarely did hepatitis occur").

  19. Takeda M, Okamoto I, Fukuoka M, Nakagawa K. Successful treatment with erlotinib after gefitinib-related severe hepatotoxicity. J Clin Oncol 2010; 28: e273-4. PubMed Citation  (66 year old woman with lung cancer developed ALT elevations after 36 weeks of treatment with gefitinib [ALT peak ~1011 U/L], resolving within 8 weeks of stopping and not recurring on starting erlotinib: Case 1).

  20. Ku GY, Chopra A, de Lima Lopes G Jr. Successful treatment of two lung cancer patients with erlotinib following gefitinib-induced hepatotoxicity. Lung Cancer 2010; 70: 223-5. PubMed Citation  (Two men, ages 52 and 88 years, with non-small cell lung cancer developed serum ALT elevations 4 and 6 weeks after starting gefitinib [bilirubin normal, peak ALT 354 and 297 U/L], resolving rapidly on stopping and not recurring when switched to erlotinib).

  21. Yin YM, Geng YT, Shao YF, Hu XL, Li W, Shu YQ, Wang ZX. First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer. J Exp Clin Cancer Res 2010; 29: 126. PubMed Citation  (Among 45 Chinese patients with non-small cell lung cancer treated with gefitinib, liver test abnormalities occurred in 3 [7%], but were mild and self-limited).

  22. Nakatomi K, Nakamura Y, Tetsuya I, Kohno S. Treatment with gefitinib after erlotinib-induced liver injury: a case report. J Med Case Reports 2011; 5: 593. PubMed Citation   (31 year old woman with metastatic lung cancer developed enyzme elevations 4 weeks after starting erlotinib [peak ALT 3130 U/L] that fell to normal within 3 weeks of stopping and did not rise again when she was started on gefitinib).

  23. Kijima T, Shimizu T, Nonen S, Furukawa M, Otani Y, Minami T, Takahashi R, et al. Safe and successful treatment with erlotinib after gefitinib-induced hepatotoxicity: difference in metabolism as a possible mechanism. J Clin Oncol 2011; 29: e588-90. PubMed Citation  (Two women, ages 67 and 83 years, with lung cancer developed elevated aminotransferase levels 4 and 8 weeks after starting gefitinib [peak ALT 731 and ~450 U/L, bilirubin and Alk P not given], which resolved upon stopping, recurred on restarting, but did not recur when erlotinib was used).

  24. Lai YC, Lin PC, Lai JI, Hsu SY, Kuo LC, Chang SC, Wang WS. Successful treatment of erlotinib-induced acute hepatitis and acute interstitial pneumonitis with high-dose corticosteroid: a case report and literature review. Int J Clin Pharmacol Ther 2011 Jul; 49: 461-6. PubMed Citation  (74 year old man developed interstitial pneumonitis and mild serum enzyme elevations 1 month after starting erlotinib [ALT 116 U/L], both of which improved within days on high dose corticosteroids).

  25. Chen J, Gu R, Wang Q, Dassarath M, Yin Z, Yang K, Wu G. Gefitinib-induced hepatotoxicity in patients treated for non-small cell lung cancer. Onkologie 2012; 35: 509-13. PubMed Citation  (Among 92 patients with non-small cell lung cancer treated with gefitinib, 6 [7%] had ALT elevations [range 47-91 U/L] arising 1 week to 6 months after starting, but only one required dose adjustment and all resolved).

  26. Maemondo M, Minegishi Y, Inoue A, Kobayashi K, Harada M, Okinaga S, Morikawa N, et al. First-line gefitinib in patients aged 75 or older with advanced non-small cell lung cancer harboring epidermal growth factor receptor mutations: NEJ 003 study. J Thorac Oncol 2012; 7: 1417-22. PubMed Citation  (Among 31 elderly patients with non-small cell lung cancer, 6 [19%] developed ALT or AST levels above 5 times ULN).

  27. Kunimasa K, Yoshioka H, Iwasaku M, Nishiyama A, Korogi Y, Masuda G, Takaiwa T, et al. Successful treatment of non-small cell lung cancer with gefitinib after severe erlotinib-related hepatotoxicity. Intern Med 2012; 51: 431-4. PubMed Citation  (64 year old woman developed liver test elevations 5 weeks after starting erlotinib for non-small cell lung cancer [bilirubin normal, ALT 129 rising to 617 U/L], recurring when erlotinib was restarted [ALT 1008 U/L by day 3], but not when switched to gefitinib).

  28. Takimoto T, Kijima T, Otani Y, Nonen S, Namba Y, Mori M, Yokota S, et al. Polymorphisms of CYP2D6 Gene and Gefitinib-Induced Hepatotoxicity. Clin Lung Cancer 2013 May 9. [Epub ahead of print] PubMed Citation  (Distribution of polymorphisms of CYP2D6 gene were similar in 55 patients who developed ALT elevations during gefitinib therapy as found in the general Japanese population; 17 patients were swithced to erlotinib and did not have recurrence).

  29. Kitade H, Yamada T, Igarashi S, Hokkoku K, Mori M, Shintaku K, Sagawa M, et al. [Efficacy of low-dose erlotinib against gefitinib-induced hepatotoxicity in a patient with lung adenocarcinoma harboring EGFR mutations]. Gan To Kagaku Ryoho 2013; 40: 79-81. Japanese. PubMed Citation  (Abstract only: 80 year old woman developed ALT elevations [3-5 times ULN] during gefitnib therapy, which resolved on stopping and did not recur with erlotinib therapy given for 3 years).

  30. Yoshida T, Yamada K, Azuma K, Kawahara A, Abe H, Hattori S, Yamashita F, et al. Comparison of adverse events and efficacy between gefitinib and erlotinib in patients with non-small-cell lung cancer: a retrospective analysis. Med Oncol 2013; 30: 349. PubMed Citation  (Comparison of side effects in 107 patients with non-small cell lung cancer treated with gefitinib and 35 treated with erlotinib found "liver dysfunction" more frequent with gefitinib than erlotinib [13% vs 6%], whereas overall adverse events leading to drug discontinuation were less common [13% vs 26%]).

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OTHER REFERENCE LINKS
Gefitinib
  1. PubMed logoRecent References on Gefitinib

  2. Clinical Trials logoTrials on Gefitinib

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