Increase in cetuximab-induced skin rash and hypomagnesemia in patients receiving concomitant treatment with proton pump inhibitors (PPIs): a possible drug interaction?

  • Mahmoud Abu-Amna
  • Gil Bar-SelaEmail author
Original Article



In a previous study, we found that co-administration of proton pump inhibitors (PPIs) with cetuximab was associated with increased skin toxicity. Both these drugs can induce hypomagnesemia. The aim of this study was to retrospectively explore the possible influence of PPI drugs on cetuximab skin toxicity and the potential synergistic effect of hypomagnesemia.

Patients and methods

The files of all eligible patients treated with cetuximab during 2015–2016 with metastatic colorectal carcinoma (mCRC) or head and neck (H&N) carcinoma were reviewed. The concomitant use of PPIs was defined if a drug belonging to that class was included in the patient’s chronic medications list.


One hundred eighteen patients (61 with H&N carcinoma, 57 with mCRC) were included in the study, and 58 of the 118 patients received PPIs concomitantly with cetuximab. Skin toxicity of any grade was reported in 33/58 (56.9%) patients on PPIs compared with 22/60 (36.7%) patients (p = 0.08) with grade 3–4 in 19/58 (32.8%) and 2/60 (3.3%), respectively (p = 0.001). Hypomagnesemia (Mg serum level < 1.2 mg/dL) was reported in 14/58 (25.9%) PPI-treated patients, compared with 5/60 (10.4%) patients not on PPIs (p = 0.08). Grade 3–4 skin toxicity or hypomagnesemia (Mg < 0.9 mg/dL) was reported in 23/58 (39.7%) patients on concomitant treatment with PPIs, compared with 3/60 (5%) patients not on PPIs (p = 0.001).


Both the rate and the severity of cetuximab-induced skin toxicity and hypomagnesemia were increased by chronic concomitant administration of PPIs. A prospective study is needed to confirm the possible interaction between cetuximab and PPIs.


Proton pump inhibitors Cetuximab Skin toxicity Hypomagnesemia Colorectal carcinoma Head and neck carcinoma 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C, PETACC-8 Study Investigators (2014) Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol 15:862–873. CrossRefPubMedGoogle Scholar
  2. 2.
    Lacouture ME, Melosky BL (2007) Cutaneous reactions to anticancer agents targeting the epidermal growth factor receptor: a dermatology-oncology perspective. Skin Ther Lett 12:1–5Google Scholar
  3. 3.
    Duffy A, Rahma O, Greten TF (2013) Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: results from a randomized trial of the GERMAN AIO CRC Study Group. Int J Cancer 132:1718. CrossRefPubMedGoogle Scholar
  4. 4.
    Zaniboni A, Formica V (2016) The Best. First. Anti-EGFR before anti-VEGF, in the first-line treatment of RAS wild-type metastatic colorectal cancer: from bench to bedside. Cancer Chemother Pharmacol 78:233–244. CrossRefPubMedGoogle Scholar
  5. 5.
    Bezabeh S, Mackey AC, Kluetz P, Jappar D, Korvick J (2012) Accumulating evidence for a drug-drug interaction between methotrexate and proton pump inhibitors. Oncologist 17:550–554. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Breedveld P, Zelcer N, Pluim D, Sönmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH (2004) Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res 64:5804–5811CrossRefGoogle Scholar
  7. 7.
    Joerger M, Huitema AD, van den Bongard HJ, Baas P, Schornagel JH, Schellens JH, Beijnen JH (2006) Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients. Br J Clin Pharmacol 62:71–80CrossRefGoogle Scholar
  8. 8.
    Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A (2010) Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 38:92–99. CrossRefPubMedGoogle Scholar
  9. 9.
    Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J (2008) Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopidogrel Aspirin) study. J Am Coll Cardiol 51:256–260. CrossRefPubMedGoogle Scholar
  10. 10.
    Bar-Sela G, Avgush S, Kaidar-Person O, Beny A, Semenisty V, Liel Y, Bergman R, Khamaysi Z (2016) Acne during adolescence did not predict skin rash reaction to cetuximab. Anticancer Drugs 27:1033–1037. CrossRefPubMedGoogle Scholar
  11. 11.
    Epstein M, McGrath S, Law F (2006) Proton pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med 355:1834–1836CrossRefGoogle Scholar
  12. 12.
    Broeren MA, Geerdink EA, Vader HL, van den Wall Bake AW (2009) Hypomagnesemia induced by several proton-pump inhibitors. Ann Intern Med 151:755–756. CrossRefPubMedGoogle Scholar
  13. 13.
    MacKay JD, Bladon PT (2010) Hypomagnesemia due to proton pump inhibitor therapy: a clinical case series. QJM 103:387–395. CrossRefPubMedGoogle Scholar
  14. 14.
    Melichar B, Králíčková P, Hyšpler R, Kalábová H, Cerman J Jr, Holečková P, Studentová H, Malířová E (2012) Hypomagnesaemia in patients with metastatic colorectal carcinoma treated with cetuximab. Hepatogastroenterology 59:366–371. CrossRefPubMedGoogle Scholar
  15. 15.
    Fakih MG, Wilding G, Lombardo J (2006) Cetuximab-induced hypomagnesemia in patients with colorectal cancer. Clin Colorectal Cancer 6:152–156CrossRefGoogle Scholar
  16. 16.
    Cao Y, Liao C, Tan A, Liu L, Gao F (2010) Meta-analysis of incidence and risk of hypomagnesemia with cetuximab for advanced cancer. Chemotherapy 56:459–465. CrossRefPubMedGoogle Scholar
  17. 17.
  18. 18.
    Wagner LI, Lacouture ME (2007) Dermatologic toxicities associated with EGFR inhibitors: the clinical psychologist’s perspective. Impact on health-related quality of life and implications for clinical management of psychological sequelae. Oncology (Williston Park) 21(11 Suppl 5):34–36Google Scholar
  19. 19.
    Láng I, Köhne CH, Folprecht G, Rougier P, Curran D, Hitre E, Sartorius U, Griebsch I, Van Cutsem E (2013) Quality of life analysis in patients with KRAS wild-type metastatic colorectal cancer treated first-line with cetuximab plus irinotecan, fluorouracil and leucovorin. Eur J Cancer 49:439–448. CrossRefPubMedGoogle Scholar
  20. 20.
    Jatoi A, Green EM, Rowland KM Jr, Sargent DJ, Alberts SR (2009) Clinical predictors of severe cetuximab-induced rash: observations from 933 patients enrolled in north central cancer treatment group study N0147. Oncology 77:120–123. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Micromedex Healthcare Series [Internet database]. Thomson Healthcare, Greenwood Village. Updated periodically.
  22. 22.
    Qiu Z, Liu H, He L, Ma Y, Song H, Bai W, Yu M (2016) Proton pump inhibitor-induced exfoliative dermatitis: a case report. Exp Ther Med 11:543–546CrossRefGoogle Scholar
  23. 23.
    Sachs G, Shin JM, Howden CW (2006) Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther 23(Suppl 2):2–8CrossRefGoogle Scholar
  24. 24.
    Budha NR, Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ, Holden SN, Benet LZ, Ware JA (2012) Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther 92:203–213. CrossRefPubMedGoogle Scholar
  25. 25.
    Quamme GA (1997) Renal magnesium handling: new insights in understanding old problems. Kidney Int 52:1180–1195CrossRefGoogle Scholar
  26. 26.
    Al-Ghamdi SM, Cameron EC, Sutton RA (1994) Magnesium deficiency: pathophysiologic and clinical overview. Am J Kidney Dis 24:737–752CrossRefGoogle Scholar
  27. 27.
    Schrag D, Chung KY, Flombaum C, Saltz L (2005) Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst 97:1221–1224CrossRefGoogle Scholar
  28. 28.
    Kuipers MT, Thang HD, Arntzenius AB (2009) Hypomagnesaemia due to use of proton pump inhibitors—a review. Neth J Med 67:169–172PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of OncologyRambam Health Care CampusHaifaIsrael
  2. 2.Center for Malignant DiseasesEmek Medical CenterAfulaIsrael
  3. 3.Faculty of MedicineTechnion-Israel Institute of TechnologyHaifaIsrael

Personalised recommendations