Drug Safety

, Volume 36, Issue 7, pp 491–503 | Cite as

Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives

  • Rashmi R. ShahEmail author
  • Joel Morganroth
  • Devron R. Shah
Review Article


The introduction of small-molecule tyrosine kinase inhibitors (TKIs) in clinical oncology has transformed the treatment of certain forms of cancers. As of 31 March 2013, 18 such agents have been approved by the US Food and Drug Administration (FDA), 15 of these also by the European Medicines Agency (EMA), and a large number of others are in development or under regulatory review. Unexpectedly, however, their use has been found to be associated with serious toxic effects on a number of vital organs including the liver. Drug-induced hepatotoxicity has resulted in withdrawal from the market of many widely used drugs and is a major public health issue that continues to concern all the stakeholders. This review focuses on hepatotoxic potential of TKIs. The majority of TKIs approved to date are reported to induce hepatic injury. Five of these (lapatinib, pazopanib, ponatinib, regorafenib and sunitinib) are sufficiently potent in this respect as to require a boxed label warning. Onset of TKI-induced hepatotoxicity is usually within the first 2 months of initiating treatment, but may be delayed, and is usually reversible. Fatality from TKI-induced hepatotoxicity is uncommon compared to hepatotoxic drugs in other classes but may lead to long-term consequences such as cirrhosis. Patients should be carefully monitored for TKI-induced hepatotoxicity, the management of which requires individually tailored reappraisal of the risk/benefit. The risk is usually manageable by dose adjustment or a switch to a suitable alternative TKI. Confirmation of TKI-induced hepatotoxicity can present challenges in the presence of hepatic metastasis and potential drug interactions. Its diagnosis in a patient with TKI-sensitive cancer requires great care if therapy with the TKI suspected to be causal is to be modified or interrupted as a result. Post-marketing experience with drugs such as imatinib, lapatinib and sorafenib suggests that the hepatotoxic safety of all the TKIs requires diligent surveillance.


Imatinib Sorafenib Sunitinib Gefitinib Erlotinib 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Conflict of Interest

The authors have no conflicts of interest that are directly relevant to the content of this review and have not received any financial support for writing it. RRS was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK. JM is the Chief Cardiac Consultant to eResearchTechnology Inc (eRT), Philadelphia, PA, USA which provides cardiac safety services to drug development companies. Both RRS and JM now provide expert consultancy services on development of new drugs to a number of pharmaceutical companies. DRS is a first-year house officer at a district general hospital and has no consultancy relationships.


  1. 1.
    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172–87.PubMedCrossRefGoogle Scholar
  2. 2.
    Chen MH, Kerkela R, Force T. Mechanisms of cardiomyopathy associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118:84–95.PubMedCrossRefGoogle Scholar
  3. 3.
    Amir E, Seruga B, Martinez-Lopez J, et al. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol. 2011;29:2543–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarization (QT interval). Drug Saf. 2013. doi: 10.1007/s40264-013-0047-5.
  5. 5.
    Shah DR, Shah RR, Morganroth J. Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy. Drug Saf. 2013. doi: 10.1007/s40264-013-0050-x.
  6. 6.
    Seruga B, Sterling L, Wang L, et al. Reporting of serious adverse drug reactions of targeted anticancer agents in pivotal phase III clinical trials. J Clin Oncol. 2011;29:174–85.PubMedCrossRefGoogle Scholar
  7. 7.
    Niraula S, Seruga B, Ocana A, et al. The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs. J Clin Oncol. 2012;30:3012–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. 2005;42:481–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Andrade RJ, Lucena MI, Fernández MC, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish Registry over a 10-year period. Gastroenterology 2005;129:512–21. Erratum in: Gastroenterology. 2005;129:1808.Google Scholar
  10. 10.
    Shah RR. Drug-induced hepatotoxicity: pharmacokinetic perspectives and strategies for risk reduction. Advers Drug React Toxicol Rev. 1999;18:181–233.Google Scholar
  11. 11.
    Srivastava A, Maggs JL, Antoine DJ, et al. Role of reactive metabolites in drug-induced hepatotoxicity. Handb Exp Pharmacol. 2010;196:165–94.PubMedCrossRefGoogle Scholar
  12. 12.
    Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16:3041–53.PubMedCrossRefGoogle Scholar
  13. 13.
    Andrade RJ, Robles M, Ulzurrun E, et al. Drug-induced liver injury: insights from genetic studies. Pharmacogenomics. 2009;10:1467–87.PubMedCrossRefGoogle Scholar
  14. 14.
    Bessone F. Non-steroidal anti-inflammatory drugs: what is the actual risk of liver damage? World J Gastroenterol. 2010;16:5651–61.PubMedCrossRefGoogle Scholar
  15. 15.
    Russmann S, Jetter A, Kullak-Ublick GA. Pharmacogenetics of drug-induced liver injury. Hepatology. 2010;52:748–61.PubMedCrossRefGoogle Scholar
  16. 16.
    Tujios S, Fontana RJ. Mechanisms of drug-induced liver injury: from bedside to bench. Nat Rev Gastroenterol Hepatol. 2011;8:202–11.PubMedCrossRefGoogle Scholar
  17. 17.
    Ju C, Reilly T. Role of immune reactions in drug-induced liver injury (DILI). Drug Metab Rev. 2012;44:107–15.PubMedCrossRefGoogle Scholar
  18. 18.
    Pessayre D, Fromenty B, Berson A, et al. Central role of mitochondria in drug-induced liver injury. Drug Metab Rev. 2012;44:34–87.PubMedCrossRefGoogle Scholar
  19. 19.
    Spriet-Pourra C, Auriche M. Drug withdrawal from sale. Scrip reports. Richmond: PJB; 1994.Google Scholar
  20. 20.
    Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics. 2006;7:889–908.PubMedCrossRefGoogle Scholar
  21. 21.
    Chalasani N, Björnsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology. 2010;138:2246–59.PubMedCrossRefGoogle Scholar
  22. 22.
    Daly AK, Donaldson PT, Bhatnagar P, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009;41:816–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Zimmerman HJ, Lewis JH, Ishak KG, et al. Ticrynafen-associated hepatic injury: analysis of 340 cases. Hepatology. 1984;4:315–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Graham DJ, Drinkard CR, Shatin D, et al. Liver enzyme monitoring in patients treated with troglitazone. JAMA. 2001;286:831–3.PubMedCrossRefGoogle Scholar
  25. 25.
    Graham DJ, Green L, Senior JR, et al. Troglitazone-induced liver failure: a case study. Am J Med. 2003;114:299–306.PubMedCrossRefGoogle Scholar
  26. 26.
    Committee for Medicinal Products for Human Use. Non-clinical guideline on drug-induced hepatotoxicity EMEA/CHMP/SWP/150115/2006. European Medicines Agency, London. 24 Jan 2008. Accessed 17 Nov 2012.
  27. 27.
    Committee for Medicinal Products for Human Use. Reflection paper on non-clinical evaluation of drug-induced liver injury (DILI) EMEA/CHMP/SWP/150115/2006. European Medicines Agency, London. 24 Jun 2010. Accessed 17 Nov 2012.
  28. 28.
    Food and Drug Administration. Guidance for industry: drug-induced liver injury: premarketing clinical evaluation. Food and Drug Administration, Rockville, Maryland, USA. Jul 2009. Accessed 17 Nov 2012.
  29. 29.
    Health Canada. Pre-market evaluation of hepatotoxicity in health products. File number: 12-104742-88. Health Canada, Ottawa, Canada. 18 Apr 2012. Accessed 17 Nov 2012.
  30. 30.
    Reuben A. Hy’s law. Hepatology. 2004;39:574–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Lewis JH. The adaptive response (drug tolerance) helps to prevent drug-induced liver injury. Gastroenterol Hepat (NY). 2012;8:333–6.Google Scholar
  32. 32.
    Eder JP, Shapiro GI, Appleman LJ, et al. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. Clin Cancer Res. 2010;16:3507–16.PubMedCrossRefGoogle Scholar
  33. 33.
    Feng B, Xu JJ, Bi YA, et al. Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714. Toxicol Sci. 2009;108:492–500.PubMedCrossRefGoogle Scholar
  34. 34.
    Munster PN, Britten CD, Mita M, et al. First study of the safety, tolerability, and pharmacokinetics of CP-724,714 in patients with advanced malignant solid HER2-expressing tumors. Clin Cancer Res. 2007;13:1238–45.PubMedCrossRefGoogle Scholar
  35. 35.
    Teo YL, Ho HK, Chan A. Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis. Cancer Treat Rev. 2013;39:199–206.PubMedCrossRefGoogle Scholar
  36. 36.
    GlaxoSmithKline. Liver function test (LFT) elevations in cancer patients and users of tyrosine kinase inhibitor (TKI) drugs using the LabRx Database Study No: 113153. Accessed 12 Jan 2013.
  37. 37.
    Spataro V. Nilotinib in a patient with postnecrotic liver cirrhosis related to imatinib. J Clin Oncol. 2011;29:e50–2.PubMedCrossRefGoogle Scholar
  38. 38.
    Ridruejo E, Cacchione R, Villamil AG, et al. Imatinib-induced fatal acute liver failure. World J Gastroenterol. 2007;13:6608–11.PubMedGoogle Scholar
  39. 39.
    Kong JH, Yoo SH, Lee KE, et al. Early imatinib-mesylate-induced hepatotoxicity in chronic myelogenous leukaemia. Acta Haematol. 2007;118:205–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Pariente A, Etcharry F, Cales V, et al. Imatinib mesylate-induced acute hepatitis in a patient treated for gastrointestinal stromal tumour. Eur J Gastroenterol Hepatol. 2006;18:785–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Fuster F, Medina L, Vallansot R, et al. Imatinib-induced toxic hepatitis: description of two cases and review of the literature. Artic Span Gastroenterol Hepatol. 2007;30:525–30.CrossRefGoogle Scholar
  42. 42.
    Tonyali O, Coskun U, Yildiz R, et al. Imatinib mesylate-induced acute liver failure in a patient with gastrointestinal stromal tumors. Med Oncol. 2010;27:768–73.PubMedCrossRefGoogle Scholar
  43. 43.
    Weise AM, Liu CY, Shields AF. Fatal liver failure in a patient on acetaminophen treated with sunitinib malate and levothyroxine. Ann Pharmacother. 2009;43:761–6.PubMedCrossRefGoogle Scholar
  44. 44.
    European Medicines Agency. European public assessment reports assessment history and product information. Accessed 12 Jan 2013.
  45. 45.
    Food and Drug Administration. Product reviews and labels. Accessed 12 Jan 2013.
  46. 46.
    Takeda M, Okamoto I, Fukuoka M, et al. Successful treatment with erlotinib after gefitinib-related severe hepatotoxicity. J Clin Oncol. 2010;28:e273–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Seki N, Uematsu K, Shibakuki R, et al. Promising new treatment schedule for gefitinib responders after severe hepatotoxicity with daily administration. J Clin Oncol. 2006;24:3213–4.PubMedCrossRefGoogle Scholar
  48. 48.
    Kijima T, Shimizu T, Nonen S, 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.PubMedCrossRefGoogle Scholar
  49. 49.
    Lim SY, Ando S, Nishiyama K, et al. Multiple myeloma emerging after prolonged gefitinib treatment for non-small cell lung carcinoma. Case Rep Oncol. 2011;4:198–203.PubMedCrossRefGoogle Scholar
  50. 50.
    Spraggs CF, Budde LR, Briley LP, et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 2011;29:667–73.PubMedCrossRefGoogle Scholar
  51. 51.
    Suzumura T, Kimura T, Kudoh S, et al. Comparison of adverse events of erlotinib with those of gefitinib in patients with non-small cell lung cancer: a case-control study in a Japanese population. Osaka City Med J. 2012;58:25–34.PubMedGoogle Scholar
  52. 52.
    Suzumura T, Kimura T, Kudoh S, et al. Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer. BMC Cancer. 2012;12:568.PubMedCrossRefGoogle Scholar
  53. 53.
    Li J, Karlsson MO, Brahmer J, et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J Natl Cancer Inst. 2006;98:1714–23.PubMedCrossRefGoogle Scholar
  54. 54.
    Donahower B, McCullough SS, Kurten R, et al. Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity. Am J Physiol Gastrointest Liver Physiol. 2006;291:G102–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Wang T, Shankar K, Ronis MJ, et al. Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes. Crit Rev Toxicol. 2007;37:413–59.PubMedCrossRefGoogle Scholar
  56. 56.
    Nakagawa H, Maeda S, Hikiba Y, et al. Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. Gastroenterology. 2008;135:1311–21.PubMedCrossRefGoogle Scholar
  57. 57.
    Revuelta-Cervantes J, Mayoral R, Miranda S, et al. Protein tyrosine phosphatase 1B (PTP1B) deficiency accelerates hepatic regeneration in mice. Am J Pathol. 2011;178:1591–604.PubMedCrossRefGoogle Scholar
  58. 58.
    Han D, Shinohara M, Ybanez MD, et al. Signal transduction pathways involved in drug-induced liver injury. Handb Exp Pharmacol. 2010;196:267–310.PubMedCrossRefGoogle Scholar
  59. 59.
    Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Llanos L, Bellot P, Zapater P, et al. Acute hepatitis in a patient with cirrhosis and hepatocellular carcinoma treated with sorafenib. Am J Gastroenterol. 2009;104:257–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Fairfax B, Pratap S, Roberts I, et al. Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma. BMC Cancer. 2012;12:590.PubMedCrossRefGoogle Scholar
  62. 62.
    Herden U, Fischer L, Schafer H, et al. Sorafenib-induced severe acute hepatitis in a stable liver transplant recipient. Transplantation. 2010;90:98–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Schramm C, Schuch G, Lohse AW. Sorafenib-induced liver failure. Am J Gastroenterol. 2008;103:2162–3.PubMedCrossRefGoogle Scholar
  64. 64.
    Marks AB, Gerard R, Fournier P, et al. Sorafenib-induced hepatic encephalopathy. Ann Pharmacother. 2009;43:2121.PubMedCrossRefGoogle Scholar
  65. 65.
    Van Hootegem A, Verslype A, Van Steenbergen W. Sorafenib-induced liver failure: a case report and review of the literature. Case Rep Hepatol. 2011; Article ID 941395, 4 pp.Google Scholar
  66. 66.
    European Medicines Agency. Nexavar: procedural steps taken and scientific information after the authorisation. Accessed 12 Jan 2013.
  67. 67.
    Xu C-F, Reck BH, Xue Z, et al. Pazopanib-induced hyperbilirubinemia is associated with Gilbert’s syndrome UGT1A1 polymorphism. Br J Cancer. 2010;102:1371–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Kleiner DE. The pathology of drug-induced liver injury. Semin Liver Dis. 2009;29:364–72.PubMedCrossRefGoogle Scholar
  69. 69.
    Mandery K, Glaeser H, Fromm MF. Interaction of innovative small molecule drugs used for cancer therapy with drug transporters. Br J Pharmacol. 2012;165:345–62.PubMedCrossRefGoogle Scholar
  70. 70.
    Haouala A, Widmer N, Duchosal MA, et al. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117:e75–87.PubMedCrossRefGoogle Scholar
  71. 71.
    Court MH, Duan SX, von Moltke LL, et al. Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther. 2001;299:998–1006.PubMedGoogle Scholar
  72. 72.
    Mutlib AE, Goosen TC, Bauman JN, et al. Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity. Chem Res Toxicol. 2006;19:701–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol. 1980;10(Suppl 2):291S–8S.PubMedCrossRefGoogle Scholar
  74. 74.
    Gonzalez FJ. The 2006 Bernard B. Brodie Award Lecture. CYP2E1. Drug Metab Dispos. 2007;35:1–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Kostrubsky SE, Sinclair JF, Strom SC, et al. Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicol Sci. 2005;87:146–55.PubMedCrossRefGoogle Scholar
  76. 76.
    Liu Y, Ramirez J, House L, et al. Comparison of the drug-drug interactions potential of erlotinib and gefitinib via inhibition of UDP-glucuronosyltransferases. Drug Metab Dispos. 2010;38:32–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Liu Y, Ramírez J, Ratain MJ. Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors. Br J Clin Pharmacol. 2011;71:917–20.PubMedCrossRefGoogle Scholar
  78. 78.
    Laine JE, Auriola S, Pasanen M, et al. Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica. 2009;39:11–21.PubMedCrossRefGoogle Scholar
  79. 79.
    Committee for Medicinal Products for Human Use. Summary of product characteristics “Glivec” 21/02/2012. Glivec-EMEA/H/C/000406-II/0070. European Medicines Agency, London. Accessed 17 Nov 2012.
  80. 80.
    Food and Drug Administration. Label for Gleevec. Food and Drug Administration, Rockville, Maryland, USA. 31 Jan 2012. Accessed 17 Nov 2012.
  81. 81.
    Nassar I, Pasupati T, Judson JP, et al. Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model. Malays J Pathol. 2010;32:1–11.PubMedGoogle Scholar
  82. 82.
    Kim DW, Tan EY, Jin Y, et al. Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia. Br J Clin Pharmacol. 2011;71:199–206.PubMedCrossRefGoogle Scholar
  83. 83.
    Goodman VL, Rock EP, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367–73.PubMedCrossRefGoogle Scholar
  84. 84.
    Lim AYL, Segarra I, Chakravarthi S, et al. Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice. BMC Pharmacol. 2010;10:14.PubMedCrossRefGoogle Scholar
  85. 85.
    Ohashi Y, Suzuki K, Sakurai M, et al. Safety analysis of eight patients treated with erlotinib after severe gefitinib-induced liver injury. Gan To Kagaku Ryoho. 2010;37:1307–11. (Article in Japanese).PubMedGoogle Scholar
  86. 86.
    Ku GY, Chopra A. Lopes Gde L Jr. Successful treatment of two lung cancer patients with erlotinib following gefitinib-induced hepatotoxicity. Lung Cancer. 2010;70:223–5.PubMedCrossRefGoogle Scholar
  87. 87.
    Nagano T, Kotani Y, Kobayashi K, et al. Successful erlotinib treatment for a patient with gefitinib-related hepatotoxicity and lung adenocarcinoma refractory to intermittently administered gefitinib. Case Rep Pulmonol. 2011;2011:812972.PubMedGoogle Scholar
  88. 88.
    Kitade H, Yamada T, Igarashi S, 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. (Article in Japanese).PubMedGoogle Scholar
  89. 89.
    Takeda M, Okamoto I, Tsurutani J, et al. Clinical impact of switching to a second EGFR-TKI after a severe AE related to a first EGFR-TKI in EGFR-mutated NSCLC. Jpn J Clin Oncol. 2012;42:528–33.PubMedCrossRefGoogle Scholar
  90. 90.
    Nakatomi K, Nakamura Y, Tetsuya I, et al. Treatment with gefitinib after erlotinib-induced liver injury: a case report. J Med Case Rep. 2011;5:593.PubMedCrossRefGoogle Scholar
  91. 91.
    Kunimasa K, Yoshioka H, Iwasaku M, et al. Successful treatment of non-small cell lung cancer with gefitinib after severe erlotinib-related hepatotoxicity. Intern Med. 2012;51:431–4.PubMedCrossRefGoogle Scholar
  92. 92.
    Chang SC, Chang CY, Chen CY, et al. Successful erlotinib rechallenge after gefitinib-induced acute interstitial pneumonia. J Thorac Oncol. 2010;5:1105–6.PubMedCrossRefGoogle Scholar
  93. 93.
    Fukui T, Otani S, Hataishi R, et al. Successful rechallenge with erlotinib in a patient with EGFR-mutant lung adenocarcinoma who developed gefitinib-related interstitial lung disease. Cancer Chemother Pharmacol. 2010;65:803–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Koma Y, Matsuoka H, Yoshimatsu H, et al. Successful treatment with erlotinib after gefitinib-induced interstitial lung disease: a case report and literature review. Int J Clin Pharmacol Ther. 2012;50:760–4.PubMedGoogle Scholar
  95. 95.
    Tammaro KA, Baldwin PD, Lundberg AS. Interstitial lung disease following erlotinib (Tarceva) in a patient who previously tolerated gefitinib (Iressa). J Oncol Pharm Pract. 2005;11:127–30.PubMedCrossRefGoogle Scholar
  96. 96.
    Lin NU, Sarantopoulos S, Stone JR, et al. Fatal hepatic necrosis following imatinib mesylate therapy. Blood. 2003;102:3455–6.PubMedCrossRefGoogle Scholar
  97. 97.
    Kikuchi S, Muroi K, Takahashi S, et al. Severe hepatitis and complete molecular response caused by imatinib mesylate: possible association of its serum concentration with clinical outcomes. Leuk Lymphoma. 2004;45:2349–51.PubMedCrossRefGoogle Scholar
  98. 98.
    Cross TJ, Bagot C, Portmann B, et al. Imatinib mesylate as a cause of acute liver failure. Am J Hematol. 2006;81:189–92.PubMedCrossRefGoogle Scholar
  99. 99.
    James C, Trouette H, Marit G, et al. Histological features of acute hepatitis after imatinib mesylate treatment. Leukemia. 2003;17:978–9.PubMedCrossRefGoogle Scholar
  100. 100.
    Ohyashiki K, Kuriyama Y, Nakajima A, et al. Imatinib mesylate-induced hepatotoxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis. Leukemia. 2002;16:2160–1.PubMedCrossRefGoogle Scholar
  101. 101.
    Saif MW. Erlotinib-induced acute hepatitis in a patient with pancreatic cancer. Clin Adv Hematol Oncol. 2008;6:191–9.PubMedGoogle Scholar
  102. 102.
    Ho C, Davis J, Anderson F, et al. Side effects related to cancer treatment: hepatitis following treatment with gefitinib. J Clin Oncol. 2005;23:8531–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Rashmi R. Shah
    • 1
    Email author
  • Joel Morganroth
    • 2
  • Devron R. Shah
    • 1
  1. 1.Rashmi Shah Consultancy LtdBuckinghamshireUK
  2. 2.eResearch TechnologyPhiladelphiaUSA

Personalised recommendations