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Spontaneous reporting of serious cutaneous reactions with protein kinase inhibitors

  • Pharmacoepidemiology and Prescription
  • Published:
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Abstract

Purpose

Our aim was to describe all serious cutaneous adverse drug reactions (ADRs) spontaneously reported in France for all oral protein kinase inhibitors, their characteristics and whether they were labeled (reported in the Summary of Product Characteristics) or not.

Methods

We performed a retrospective observational study in the French PharmacoVigilance Database, selecting for analysis serious cutaneous reactions of patients due to treatment with oral protein kinase inhibitors (erlotinib, gefitinib, imatinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, everolimus) between 1 January 2008 and 31 December 31 2010.

Results

Ninety-four patients suffered from 115 serious cutaneous reactions due to oral protein kinase inhibitors. Serious cutaneous reactions more frequently reported were maculo-papular rash (mostly with imatinib), followed by hand–foot syndrome (specifically with sorafenib) and papulopustular rash (particularly with erlotinib). Patients were mostly males (63 %) with a mean age of 62.6 ± 15.4 years. Drug withdrawal was observed in 73.1 % of cases because of these cutaneous reactions. Delay of occurrence of the ADR varied from 11.5 to 58.5 days. Unlabeled serious reactions were found (17.4 %), including skin ulceration, vasculitis or purpura with sorafenib or sunitinib and drug rash with eosinophilia and systemic symptoms with imatinib.

Conclusion

Some of the serious ADRs spontaneously reported with oral protein kinase inhibitors are labeled and commonly reported in the literature, but others occur only rarely and unlabeled. In our study, most serious ADRs occurred in males within the 2 first months of treatment and were responsible for the withdrawal of therapy with protein kinase inhibitors.

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References

  1. Castot A, Haramburu F, Kreft-Jaïs C (2008) Hospitalisations dues aux effets indésirables des médicaments: résultats d’une étude nationale. Point sur la nouvelle campagne d’information sur les traitements anticoagulants antivitamine K. Available at: http://www.sante.gouv.fr/IMG/pdf/EMIR.pdf. Accessed 4 Jan 2013

  2. Edwards IR, Aronson JK (2000) Adverse drug reactions: definitions, diagnosis, and management. Lancet 356:1255–1259

    Article  PubMed  CAS  Google Scholar 

  3. Lynch TJ Jr, Kim ES, Eaby B et al (2007) Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 12:610–621

    Article  PubMed  CAS  Google Scholar 

  4. Amitay-Laish I, Stemmer SM, Lacouture ME (2011) Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib, and dasatinib. Dermatol Ther 24:386–395

    Article  PubMed  Google Scholar 

  5. Lee WJ, Lee JL, Chang SE et al (2009) Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol 161:1045–1051

    Article  PubMed  CAS  Google Scholar 

  6. Bible KC, Suman VJ, Molina JR et al (2010) Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol 11:962–972

    Article  PubMed  CAS  Google Scholar 

  7. Motzer RJ, Escudier B, Oudard S et al (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116:4256–4265

    Article  PubMed  CAS  Google Scholar 

  8. Montastruc J-L, Sommet A, Lacroix I et al (2006) Pharmacovigilance for evaluating adverse drug reactions: value, organization, and methods. Joint Bone Spine 73:629–632

    Article  PubMed  Google Scholar 

  9. Spreux A, Baldin B, Chichmanian RM (1999) Pharmacovigilance in practice. Transfus Clin Biol 6:254–259

    Article  PubMed  CAS  Google Scholar 

  10. Goldfarb N (2012) Adverse event terminology. J Clin Res Best Pract 8:1–17

    Google Scholar 

  11. Brown EG, Wood L, Wood S (1999) The medical dictionary for regulatory activities (MedDRA). Drug Saf 20:109–117

    Article  PubMed  CAS  Google Scholar 

  12. Bégaud B, Evreux JC, Jouglard J et al (1985) Imputation of the unexpected or toxic effects of drugs. Actualization of the method used in France. Therapie 40:111–118

    PubMed  Google Scholar 

  13. Heidary N, Naik H, Burgin S (2008) Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol 58:545–570

    Article  PubMed  Google Scholar 

  14. Robert C, Soria J-C, Spatz A et al (2005) Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 6:491–500

    Article  PubMed  CAS  Google Scholar 

  15. Pierfitte C, Bégaud B, Lagnaoui R et al (1999) Is reporting rate a good predictor of risks associated with drugs? Br J Clin Pharmacol 47:329–331

    Article  PubMed  CAS  Google Scholar 

  16. Van der Heijden PGM, Van Puijenbroek EP, Van Buuren S et al (2007) On the assessment of adverse drug reactions from spontaneous reporting systems: the influence of under-reporting on odds ratios. Stat Med 21:2027–2044

    Article  Google Scholar 

  17. Bégaud B, Martin K, Haramburu F et al (2002) Rates of spontaneous reporting of adverse drug reactions in France. JAMA 288:1588

    Article  PubMed  Google Scholar 

  18. Théophile H, Arimone Y, Miremont-Salamé G et al (2010) Comparison of three methods (consensual expert judgement, algorithmic and probabilistic approaches) of causality assessment of adverse drug reactions: an assessment using reports made to a French pharmacovigilance centre. Drug Saf 33:1045–1054

    Article  PubMed  Google Scholar 

  19. Valeyrie L, Bastuji-Garin S, Revuz J et al (2003) Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients. J Am Acad Dermatol 48:201–206

    Article  PubMed  Google Scholar 

  20. Choi MK, Woo HY, Heo J et al (2011) Toxic epidermal necrolysis associated with sorafenib and tosufloxacin in a patient with hepatocellular carcinoma. Ann Dermatol 23[Suppl 3]:S404–S407

    Article  PubMed  Google Scholar 

  21. Dean SM, Zirwas M (2010) A second case of sunitinib-associated pyoderma gangrenosum. J Clin Aesthet Dermatol 3:34–35

    PubMed  Google Scholar 

  22. Ten Freyhaus K, Homey B, Bieber T et al (2008) Pyoderma gangrenosum: another cutaneous side-effect of sunitinib? Br J Dermatol 159:242–243

    Article  PubMed  Google Scholar 

  23. Karadimou A, Migou M, Economidi A et al (2011) Leukocytoclastic vasculitis after long-term treatment with sunitinib: a case report. Case Rep Oncol 4:385–391

    Article  PubMed  Google Scholar 

  24. Chung NM, Gutierrez M, Turner ML (2006) Leukocytoclastic vasculitis masquerading as hand-foot syndrome in a patient treated with sorafenib. Arch Dermatol 142:1510–1511

    PubMed  Google Scholar 

  25. Najarian DJ, Packianathan V, Zeitouni NC (2010) Annular leukocytoclastic vasculitis associated with sorafenib administration. J Drugs Dermatol 9:697–698

    PubMed  Google Scholar 

  26. Trinkaus M, Trudeau M, Callum J (2008) Drug-induced immune thrombocytopenic purpura secondary to sunitinib. Curr Oncol 15:152–154

    PubMed  CAS  Google Scholar 

  27. Goldman J, Duval-Modeste A-B, Lambert A et al (2008) Imatinib-induced DRESS. Ann Dermatol Venereol 135:393–396

    Article  PubMed  CAS  Google Scholar 

  28. Le Nouail P, Viseux V, Chaby G et al (2006) Drug reaction with eosinophilia and systemic symptoms (DRESS) following imatinib therapy. Ann Dermatol Venereol 133:686–688

    Article  PubMed  Google Scholar 

  29. Benomar S, Boutayeb S, Afifi Y et al (2009) Hand-foot syndrome and seborrheic dermatitis-like eruption induced by erlotinib. Dermatol Online J 15:2

    PubMed  Google Scholar 

  30. Takahashi Y, Ebi N, Yamaguchi O et al (2011) A case of cutaneous vasculitis caused by erlotinib treatment and a review of literature. Nihon Kokyuki Gakkai Zasshi 49:663–666

    PubMed  Google Scholar 

  31. Pitarch G, Garde J, Torrijos A et al (2008) Adverse cutaneous reactions to erlotinib. Actas Dermosifiliogr 99:54–60

    Article  PubMed  CAS  Google Scholar 

  32. National Institute of Health and National Cancer Institute (2010) Common terminology criteria for adverse events (CTCAE) v4.03. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 4 Jan 2013

  33. Nikolaou V, Stratigos A, Antoniou C et al (2010) Pimecrolimus cream 1 % for the treatment of papulopustular eruption related to epidermal growth factor receptor inhibitors: a case series and a literature review of therapeutic approaches. Dermatology (Basel) 220:243–248

    Article  CAS  Google Scholar 

  34. Anderson R, Jatoi A, Robert C et al (2009) Search for evidence-based approaches for the prevention and palliation of hand-foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs). Oncologist 14:291–302

    Article  PubMed  CAS  Google Scholar 

  35. European Medicines Agency (2012) Tarceva: summary of product characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000618/WC500033994.pdf. Accessed 4 Jan 2013

  36. European Medicines Agency (2013) Sutent: summary of product characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000687/WC500057737.pdf. Accessed 28 Jan 2013

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Authors and Affiliations

  1. Laboratoire de Pharmacologie Médicale et Clinique, Equipe de PharmacoEpidémiologie INSERM U 1027, Faculté de Médecine de l’Université de Toulouse, 37 allées Jules-Guesde, 31000, Toulouse, France

    Emmanuelle Faye, Emmanuelle Bondon-Guitton, Pascale Olivier-Abbal & Jean-Louis Montastruc

  2. Service de Pharmacologie Clinique, Centre Midi-Pyrénées de PharmacoVigilance, de PharmacoEpidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire, Toulouse, France

    Emmanuelle Faye, Emmanuelle Bondon-Guitton, Pascale Olivier-Abbal & Jean-Louis Montastruc

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  1. Emmanuelle Faye
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  2. Emmanuelle Bondon-Guitton
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  3. Pascale Olivier-Abbal
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  4. Jean-Louis Montastruc
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The French Network of Regional Pharmacovigilance Centers

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Correspondence to Emmanuelle Bondon-Guitton.

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Faye, E., Bondon-Guitton, E., Olivier-Abbal, P. et al. Spontaneous reporting of serious cutaneous reactions with protein kinase inhibitors. Eur J Clin Pharmacol 69, 1819–1826 (2013). https://doi.org/10.1007/s00228-013-1532-6

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  • DOI: https://doi.org/10.1007/s00228-013-1532-6

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