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Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents

Abstract

Azole antifungals are first-line options in the prophylaxis and treatment of invasive fungal infections. They are often used for prolonged (weeks to months) periods of time, particularly in patients with hematologic malignancies, or in those who have received a solid organ or hematopoietic stem cell transplant. Long-term use of azoles is associated with hepatotoxicity and hormone-related effects, including gynecomastia, alopecia, decreased libido, oligospermia, azoospermia, impotence, hypokalemia, hyponatremia, and (rarely) adrenal insufficiency. Voriconazole and posaconazole have been associated with peripheral neuropathies, and itraconazole and voriconazole with pancreatitis. In addition, voriconazole has been associated with periostitis, phototoxic reactions, and squamous cell carcinoma. Since many at-risk patients are commonly receiving multiple medications, it can be difficult for care providers to identify antifungal agent causality or contribution to patient symptoms. Knowledge and recognition of adverse events caused by azoles, leading to dose reduction or discontinuation, can generally reverse these adverse events.

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References

  1. 1.

    Enoch DA, Yang H, Aliyu SH, Micallef C. The changing epidemiology of invasive fungal infections. In: Methods in molecular biology. 2017. p. 17–65.

  2. 2.

    Patel TS, Eschenauer GA, Stuckey LJ, Carver PL. Antifungal prophylaxis in lung transplant recipients. Transplantation. 2016;100(9):1815–26.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    McCoy D, Depestel DD, Carver PL. Primary antifungal prophylaxis in adult hematopoietic stem cell transplant recipients: current therapeutic concepts. Pharmacotherapy. 2009;29(11):1306–25.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Eschenauer GA, Lam SW, Carver PL. Antifungal prophylaxis in liver transplant recipients. Liver Transplant. 2009;15(8):842–58.

    Article  Google Scholar 

  5. 5.

    Levine MT, Chandrasekar PH. Adverse effects of voriconazole: over a decade of use. Clin Transplant. 2016;30(11):1377–86.

    Article  PubMed  Google Scholar 

  6. 6.

    Kyriakidis I, Tragiannidis A, Munchen S, Groll AH. Clinical hepatotoxicity associated with antifungal agents. Expert Opin Drug Saf. 2017;16(2):149–65.

    CAS  PubMed  Google Scholar 

  7. 7.

    Girmenia C, Iori AP. An update on the safety and interactions of antifungal drugs in stem cell transplant recipients. Expert Opin Drug Saf. 2017;16(3):329–39.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Ayub A, Kenney CV, McKiernan FE. Multifocal nodular periostitis associated with prolonged voriconazole therapy in a lung transplant recipient. J Clin Rheumatol. 2011;17(2):73–5.

    Article  PubMed  Google Scholar 

  9. 9.

    Becce F, Malghem J, Lecouvet FE, Vande Berg BC, Omoumi P. Clinical images: voriconazole-induced periostitis deformans. Arthritis Rheum. 2012;64(10):3490.

    Article  PubMed  Google Scholar 

  10. 10.

    Baird JH, Birnbaum BK, Porter DL, Frey NV. Voriconazole-induced periostitis after allogeneic stem cell transplantation. Am J Hematol. 2015;90(6):574–5.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Hirota K, Yasoda A, Fujii T, Inagaki N. Voriconazole-induced periostitis in a patient with overlap syndromes. BMJ Case Rep. 2014. https://doi.org/10.1136/bcr-2013-203485.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lustenberger DP, Granata JD, Scharschmidt TJ. Periostitis secondary to prolonged voriconazole therapy in a lung transplant recipient. Orthopedics. 2011;34(11):e793–6.

    PubMed  Google Scholar 

  13. 13.

    Rad B, Saleem M, Grant S, Florkowski C, Coates P, Gordon D, et al. Fluorosis and periostitis deformans as complications of prolonged voriconazole treatment. Ann Clin Biochem. 2015;52(Pt 5):611–4.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Rossier C, Dunet V, Tissot F, Aubry-Rozier B, Marchetti O, Boubaker A. Voriconazole-induced periostitis. Eur J Nucl Med Mol Imaging. 2012;39(2):375–6.

    Article  PubMed  Google Scholar 

  15. 15.

    Skiles JL, Imel EA, Christenson JC, Bell JE, Hulbert ML. Fluorosis because of prolonged voriconazole therapy in a teenager with acute myelogenous leukemia. J Clin Oncol. 2011;29(32):e779–82.

    Article  PubMed  Google Scholar 

  16. 16.

    Tailor TD, Richardson ML. Case 215: voriconazole-induced periostitis. Radiology. 2015;274(3):930–5.

    Article  PubMed  Google Scholar 

  17. 17.

    Tedja R, El-Sherief A, Olbrych T, Gordon S. Multifocal periostitis as a complication of chronic use of voriconazole in a lung transplant recipient. Transplant Infect Dis. 2013;15(4):424–9.

    Article  CAS  Google Scholar 

  18. 18.

    Wise SM, Wilson MA. A case of periostitis secondary to voriconazole therapy in a heart transplant recipient. Clin Nucl Med. 2011;36(3):242–4.

    Article  PubMed  Google Scholar 

  19. 19.

    Paudyal S, Dummer S, Battu P, Taylor S, Sharma S, Carbone L. Fluffy periostitis induced by voriconazole. Arthritis Rheumatol (Hoboken, NJ). 2015;67(12):3297.

    Article  Google Scholar 

  20. 20.

    Glushko T, Colmegna I. Voriconazole-induced periostitis. CMAJ Can Med Assoc J. 2015;187(14):1075.

    Article  Google Scholar 

  21. 21.

    Chen L, Mulligan ME. Medication-induced periostitis in lung transplant patients: periostitis deformans revisited. Skelet Radiol. 2011;40(2):143–8.

    Article  Google Scholar 

  22. 22.

    Gerber B, Guggenberger R, Fasler D, Nair G, Manz MG, Stussi G, et al. Reversible skeletal disease and high fluoride serum levels in hematologic patients receiving voriconazole. Blood. 2012;120(12):2390–4.

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Moon WJ, Scheller EL, Suneja A, Livermore JA, Malani AN, Moudgal V, et al. Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain. Clin Infect Dis. 2014;59(9):1237–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Tarlock K, Johnson D, Cornell C, Parnell S, Meshinchi S, Baker KS, et al. Elevated fluoride levels and periostitis in pediatric hematopoietic stem cell transplant recipients receiving long-term voriconazole. Pediatr Blood Cancer. 2015;62(5):918–20.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Wang TF, Wang T, Altman R, Eshaghian P, Lynch JP 3rd, Ross DJ, et al. Periostitis secondary to prolonged voriconazole therapy in lung transplant recipients. Am J Transplant. 2009;9(12):2845–50.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Thompson GR 3rd, Bays D, Cohen SH, Pappagianis D. Fluoride excess in coccidioidomycosis patients receiving long-term antifungal therapy: an assessment of currently available triazoles. Antimicrob Agents Chemother. 2012;56(1):563–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Wermers RA, Cooper K, Razonable RR, Deziel PJ, Whitford GM, Kremers WK, et al. Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy. Clin Infect Dis. 2011;52(5):604–11.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Adwan MH. Voriconazole-induced periostitis: a new rheumatic disorder. Clin Rheumatol. 2017;36(3):609–15.

    Article  PubMed  Google Scholar 

  29. 29.

    Pineda C, Martinez-Lavin M. Voriconazole-induced periostitis vs. hypertrophic osteoarthropathy. Clin Rheumatol. 2017;36(7):1693–4.

    Article  PubMed  Google Scholar 

  30. 30.

    Pettit NN, Carver PL. Isavuconazole: a new option for the management of invasive fungal infections. Ann Pharmacother. 2015;49(7):825–42.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Roffey SJ, Cole S, Comby P, Gibson D, Jezequel SG, Nedderman AN, et al. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos. 2003;31(6):731–41.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Buzalaf MA, Whitford GM. Fluoride metabolism. Monogr Oral Sci. 2011;22:20–36.

    Article  PubMed  Google Scholar 

  33. 33.

    Allen KC, Sanchez CJ Jr, Niece KL, Wenke JC, Akers KS. Voriconazole enhances osteogenic activity of human osteoblasts in vitro through a fluoride-independent mechanism. Antimicrob Agents Chemother. 2015;59(12):7205–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Schmidt K, McLaren A, Pauken C, McLemore R. Voriconazole is cytotoxic at locally delivered concentrations: a pilot study. Clin Orthop Relat Res. 2013;471(10):3165–70.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Vfend(R)[package insert]. New York; Pfizer, Inc.; 2016.

  36. 36.

    Sporanox (R) [package insert].Titusville: Janssen Pharmaceutical Companies; 2017.

  37. 37.

    Nizoral(R) [package insert].Titusville: Janssen Pharmaceuticals, Inc.; 2013.

  38. 38.

    Noxafil (R) [package insert]. Whitehouse: Merck & Co., Inc.; 2017.

  39. 39.

    Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Bang LE, Bundgaard H, et al. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013;61(1):44–53.

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med. 1995;333(10):664–5.

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Hazin R, Abuzetun JY, Suker M, Porter J. Rhabdomyolysis induced by simvastatin-fluconazole combination. J Natl Med Assoc. 2008;100(4):444–6.

    Article  PubMed  Google Scholar 

  42. 42.

    Horn M. Coadministration of itraconazole with hypolipidemic agents may induce rhabdomyolysis in healthy individuals. Arch Dermatol. 1996;132(10):1254.

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol. 2004;94(9):1140–6.

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Shanmugam VK, Matsumoto C, Pien E, Rosen J, Kumar P, Whelton S, et al. Voriconazole-associated myositis. J Clin Rheumatol. 2009;15(7):350–3.

    Article  PubMed  Google Scholar 

  45. 45.

    Ferrari M, Bodini I, Lo Cascio V. Rhabdomyolysis after the administration of itraconazole to an asthmatic patient with bronchopulmonary aspergillosis. Respiration. 2004;71(3):289–91.

    Article  PubMed  Google Scholar 

  46. 46.

    Garty BZ, Kauli R, Livni E, Laron Z, Nitzan M. Myopathy associated with ketoconazole treatment. Am J Dis Child (1960). 1991;145(9):970–1.

    CAS  Google Scholar 

  47. 47.

    Porter CC, Carver AE, Albano EA. Vincristine induced peripheral neuropathy potentiated by voriconazole in a patient with previously undiagnosed CMT1X. Pediatr Blood Cancer. 2009;52(2):298–300.

    Article  PubMed  Google Scholar 

  48. 48.

    Pana ZD, Roilides E. Risk of azole-enhanced vincristine neurotoxicity in pediatric patients with hematological malignancies: old problem - new dilemma. Pediatr Blood Cancer. 2011;57(1):30–5.

    Article  PubMed  Google Scholar 

  49. 49.

    Eiden C, Palenzuela G, Hillaire-Buys D, Margueritte G, Cociglio M, Hansel-Esteller S, et al. Posaconazole-increased vincristine neurotoxicity in a child: a case report. J Pediatr Hematol Oncol. 2009;31(4):292–5.

    Article  PubMed  Google Scholar 

  50. 50.

    Iwamoto T, Ishibashi M, Fujieda A, Masuya M, Katayama N, Okuda M. Drug interaction between itraconazole and bortezomib: exacerbation of peripheral neuropathy and thrombocytopenia induced by bortezomib. Pharmacotherapy. 2010;30(7):661–5.

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Vincristine[package insert]. Lake Forest: Hospira, Inc; 2017.

  52. 52.

    Ponticelli C, Campise MR. Neurological complications in kidney transplant recipients. J Nephrol. 2005;18(5):521–8.

    PubMed  Google Scholar 

  53. 53.

    Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int. 2000;13(5):313–26.

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol. 1999;246(5):339–46.

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Singh R, Cundy T. Itraconazole-induced painful neuropathy in a man with type 1 diabetes. Diabetes Care. 2005;28(1):225.

    Article  PubMed  Google Scholar 

  56. 56.

    Boussaud V, Daudet N, Billaud EM, Lillo-Le Louet A, Chevalier P, Amrein C, et al. Neuromuscular painful disorders: a rare side effect of voriconazole in lung transplant patients under tacrolimus. J Heart Lung Transplant. 2008;27(2):229–32.

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Tsiodras S, Zafiropoulou R, Kanta E, Demponeras C, Karandreas N, Manesis EK. Painful peripheral neuropathy associated with voriconazole use. Arch Neurol. 2005;62(1):144–6.

    Article  PubMed  Google Scholar 

  58. 58.

    Karadi RL, Gow D, Kellett M, Denning DW, O’Driscoll RB. Itraconazole associated quadriparesis and edema: a case report. J Med Case Rep. 2011;5:140.

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Lestner JM, Denning DW. Tremor: a newly described adverse event with long-term itraconazole therapy. J Neurol Neurosurg Psychiatry. 2010;81(3):327–9.

    Article  PubMed  Google Scholar 

  60. 60.

    Baxter CG, Marshall A, Roberts M, Felton TW, Denning DW. Peripheral neuropathy in patients on long-term triazole antifungal therapy. J Antimicrob Chemother. 2011;66(9):2136–9.

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Vazquez JA, Skiest DJ, Tissot-Dupont H, Lennox JL, Boparai N, Isaacs R. Safety and efficacy of posaconazole in the long-term treatment of azole-refractory oropharyngeal and esophageal candidiasis in patients with HIV infection. HIV Clin Trials. 2007;8(2):86–97.

    Article  CAS  PubMed  Google Scholar 

  62. 62.

    Davis MR, Nguyen MH, Donnelley MA, Thompson III GR. Tolerability of long-term fluconazole therapy. J Antimicrob Chemother. 2018;74(3):768–71.

    Article  Google Scholar 

  63. 63.

    Navarro VJ, Seeff LB. Liver injury induced by herbal complementary and alternative medicine. Clin Liver Dis. 2013;17(4):715–35 (x).

    Article  PubMed  Google Scholar 

  64. 64.

    Aksoy F, Akdogan E, Aydin K, Yilmaz M, Altunayoglu V, Sozen EE, et al. Voriconazole-induced neuropathy. Chemotherapy. 2008;54(3):224–7.

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    Gendrot A, de La Blanchardiere A, de La Gastine B, Fromager G, Massias L, Verdon R. Painful peripheral neuropathy associated with voriconazole during the treatment of chronic cavitary pulmonary aspergillosis. La Revue de medecine interne/fondee par la Societe nationale francaise de medecine interne. 2010;31(2):163–6.

    CAS  Google Scholar 

  66. 66.

    Ruiz-Ramos J, Salavert-Lleti M, Monte-Boquet E, Lorente-Fernandez L, Gil-Gomez I, Poveda-Andres JL. Anidulafungin-induced alopecia. Ann Pharmacother. 2014;48(5):660–2.

    Article  CAS  PubMed  Google Scholar 

  67. 67.

    Kauffman CA, Carver PL. Use of azoles for systemic antifungal therapy. Adv Pharmacol. 1997;39:143–89.

    Article  CAS  PubMed  Google Scholar 

  68. 68.

    Shear NH. Alopecia associated with fluconazole therapy. Ann Intern Med. 1996;125(2):153 (author reply -4).

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    Goldsmith LA. Alopecia associated with fluconazole therapy. Ann Intern Med. 1996;125(2):153 (author reply -4).

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Weinroth SE, Tuazon CU. Alopecia associated with fluconazole treatment. Ann Intern Med. 1993;119(7 Pt 1):637.

    Article  CAS  PubMed  Google Scholar 

  71. 71.

    Pappas PG, Kauffman CA, Perfect J, Johnson PC, McKinsey DS, Bamberger DM, et al. Alopecia associated with fluconazole therapy. Ann Intern Med. 1995;123(5):354–7.

    Article  CAS  PubMed  Google Scholar 

  72. 72.

    Stevens DA, Diaz M, Negroni R, Montero-Gei F, Castro LG, Sampaio SA, et al. Safety evaluation of chronic fluconazole therapy. Fluconazole Pan-American Study Group. Chemotherapy. 1997;43(5):371–7.

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    Sugar AM, Alsip SG, Galgiani JN, Graybill JR, Dismukes WE, Cloud GA, et al. Pharmacology and toxicity of high-dose ketoconazole. Antimicrob Agents Chemother. 1987;31(12):1874–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Nguyen Y, Lee A, Fischer G. Management of chronic vulvovaginal candidiasis: a long term retrospective study. Australas J Dermatol. 2017;58(4):e188–92.

    Article  PubMed  Google Scholar 

  75. 75.

    Raad II, Graybill JR, Bustamante AB, Cornely OA, Gaona-Flores V, Afif C, et al. Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections. Clin Infect Dis. 2006;42(12):1726–34.

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    Hilliard T, Edwards S, Buchdahl R, Francis J, Rosenthal M, Balfour-Lynn I, et al. Voriconazole therapy in children with cystic fibrosis. J Cyst Fibros. 2005;4(4):215–20.

    Article  CAS  PubMed  Google Scholar 

  77. 77.

    Malani AN, Kerr L, Obear J, Singal B, Kauffman CA. Alopecia and nail changes associated with voriconazole therapy. Clin Infect Dis. 2014;59(3):e61–5.

    Article  PubMed  Google Scholar 

  78. 78.

    Eil C. Ketoconazole binds to the human androgen receptor. Hormone Metab Res. 1992;24(8):367–70.

    Article  CAS  Google Scholar 

  79. 79.

    Satoh T, Tomikawa Y, Takanashi K, Itoh S, Itoh S, Yoshizawa I. Studies on the interactions between drugs and estrogen. III. Inhibitory effects of 29 drugs reported to induce gynecomastia on the glucuronidation of estradiol. Biol Pharm Bull. 2004;27(11):1844–9.

    Article  CAS  PubMed  Google Scholar 

  80. 80.

    Satoh T, Munakata H, Fujita K, Itoh S, Itoh S, Kamataki T, et al. Studies on the interactions between drug and estrogen. II. On the inhibitory effect of 29 drugs reported to induce gynecomastia on the oxidation of estradiol at C-2 or C-17. Biol Pharm Bull. 2003;26(5):695–700.

    Article  CAS  PubMed  Google Scholar 

  81. 81.

    Satoh T, Itoh S, Seki T, Itoh S, Nomura N, Yoshizawa I. On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production. J Steroid Biochem Mol Biol. 2002;82(2–3):209–16.

    Article  CAS  PubMed  Google Scholar 

  82. 82.

    Pont A, Williams PL, Loose DS, Feldman D, Reitz RE, Bochra C, et al. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med. 1982;97(3):370–2.

    Article  CAS  PubMed  Google Scholar 

  83. 83.

    Pont A, Williams PL, Azhar S, Reitz RE, Bochra C, Smith ER, et al. Ketoconazole blocks testosterone synthesis. Arch Intern Med. 1982;142(12):2137–40.

    Article  CAS  PubMed  Google Scholar 

  84. 84.

    Pont A, Graybill JR, Craven PC, Galgiani JN, Dismukes WE, Reitz RE, et al. High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch Intern Med. 1984;144(11):2150–3.

    Article  CAS  PubMed  Google Scholar 

  85. 85.

    Pont A, Goldman ES, Sugar AM, Siiteri PK, Stevens DA. Ketoconazole-induced increase in estradiol-testosterone ratio. Probable explanation for gynecomastia. Arch Intern Med. 1985;145(8):1429–31.

    Article  CAS  PubMed  Google Scholar 

  86. 86.

    Grosso DS, Boyden TW, Pamenter RW, Johnson DG, Stevens DA, Galgiani JN. Ketoconazole inhibition of testicular secretion of testosterone and displacement of steroid hormones from serum transport proteins. Antimicrob Agents Chemother. 1983;23(2):207–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Saad AH, DePestel DD, Carver PL. Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy. 2006;26(12):1730–44.

    Article  CAS  PubMed  Google Scholar 

  88. 88.

    Khosla S, Wolfson JS, Demerjian Z, Godine JE. Adrenal crisis in the setting of high-dose ketoconazole therapy. Arch Intern Med. 1989;149(4):802–4.

    Article  CAS  PubMed  Google Scholar 

  89. 89.

    Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32(1):81–151.

    Article  PubMed  Google Scholar 

  90. 90.

    Touchette MA, Chandrasekar PH, Milad MA, Edwards DJ. Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man. Br J Clin Pharmacol. 1992;34(1):75–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Satoh T, Fujita KI, Munakata H, Itoh S, Nakamura K, Kamataki T, et al. Studies on the interactions between drugs and estrogen: analytical method for prediction system of gynecomastia induced by drugs on the inhibitory metabolism of estradiol using Escherichia coli coexpressing human CYP3A4 with human NADPH-cytochrome P450 reductase. Anal Biochem. 2000;286(2):179–86.

    Article  CAS  PubMed  Google Scholar 

  92. 92.

    Boscaro M, Sonino N, Rampazzo A, Mantero F. Response of pituitary-adrenal axis to corticotrophin releasing hormone in patients with Cushing’s disease before and after ketoconazole treatment. Clin Endocrinol. 1987;27(4):461–7.

    Article  CAS  Google Scholar 

  93. 93.

    Boscaro M, Sonino N, Rampazzo A, Menegus AM, Mantero F. ACTH response to corticotropin releasing hormone in Cushing’s disease before and after ketoconazole: in vivo and in vitro studies. Hormone Metab Res Suppl Ser. 1987;16:60–2.

    CAS  Google Scholar 

  94. 94.

    Engelhardt D, Weber MM, Miksch T, Abedinpour F, Jaspers C. The influence of ketoconazole on human adrenal steroidogenesis: incubation studies with tissue slices. Clin Endocrinol. 1991;35(2):163–8.

    Article  CAS  Google Scholar 

  95. 95.

    Engelhardt D, Weber MM. Therapy of Cushing’s syndrome with steroid biosynthesis inhibitors. J Steroid Biochem Mol Biol. 1994;49(4–6):261–7.

    Article  CAS  PubMed  Google Scholar 

  96. 96.

    Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med. 1987;317(13):812–8.

    Article  CAS  PubMed  Google Scholar 

  97. 97.

    van der Pas R, Hofland LJ, Hofland J, Taylor AE, Arlt W, Steenbergen J, et al. Fluconazole inhibits human adrenocortical steroidogenesis in vitro. J Endocrinol. 2012;215(3):403–12.

    Article  CAS  PubMed  Google Scholar 

  98. 98.

    Sonino N. The endocrine effects of ketoconazole. J Endocrinol Invest. 1986;9(4):341–7.

    Article  CAS  PubMed  Google Scholar 

  99. 99.

    National Institute of Allergy and Infectious Diseases Mycoses Study Group. Treatment of blastomycosis and histoplasmosis with ketoconazole. Results of a prospective randomized clinical trial. Ann Intern Med. 1985;103(6 (Pt 1)):861–72.

    Google Scholar 

  100. 100.

    Deepinder F, Braunstein GD. Drug-induced gynecomastia: an evidence-based review. Expert Opin Drug Saf. 2012;11(5):779–95.

    Article  CAS  PubMed  Google Scholar 

  101. 101.

    Tucker RM, Haq Y, Denning DW, Stevens DA. Adverse events associated with itraconazole in 189 patients on chronic therapy. J Antimicrob Chemother. 1990;26(4):561–6.

    Article  CAS  PubMed  Google Scholar 

  102. 102.

    Albert SG, DeLeon MJ, Silverberg AB. Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients. Crit Care Med. 2001;29(3):668–70.

    Article  CAS  PubMed  Google Scholar 

  103. 103.

    Gradon JD, Sepkowitz DV. Fluconazole-associated acute adrenal insufficiency. Postgrad Med J. 1991;67(794):1084–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    McCance DR, Ritchie CM, Sheridan B, Atkinson AB. Acute hypoadrenalism and hepatotoxicity after treatment with ketoconazole. Lancet. 1987;1(8532):573.

    Article  CAS  PubMed  Google Scholar 

  105. 105.

    Michaelis G, Zeiler D, Biscoping J, Fussle R, Hempelmann G. Function of the adrenal cortex during therapy with fluconazole in intensive care patients. Mycoses. 1993;36(3–4):117–23.

    CAS  PubMed  Google Scholar 

  106. 106.

    Santhana Krishnan SG, Cobbs RK. Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient. Postgrad Med J. 2006;82(971):e23.

    Article  CAS  PubMed  Google Scholar 

  107. 107.

    Sharkey PK, Rinaldi MG, Dunn JF, Hardin TC, Fetchick RJ, Graybill JR. High-dose itraconazole in the treatment of severe mycoses. Antimicrob Agents Chemother. 1991;35(4):707–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Shibata S, Kami M, Kanda Y, Machida U, Iwata H, Kishi Y, et al. Acute adrenal failure associated with fluconazole after administration of high-dose cyclophosphamide. Am J Hematol. 2001;66(4):303–5.

    Article  CAS  PubMed  Google Scholar 

  109. 109.

    Tiao GM, Martin J, Weber FL, Cohen RM, Hanto DW. Addisonian crisis in a liver transplant patient due to fluconazole withdrawal. Clin Transplant. 1999;13(1 Pt 1):62–4.

    Article  CAS  PubMed  Google Scholar 

  110. 110.

    Miller A, Brooks LK, Poola-Kella S, Malek R. Posaconazole-induced adrenal insufficiency in a case of chronic myelomonocytic leukemia. Case Rep Endocrinol. 2018;2018:2170484.

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Costa S, Barone G, Vento G, Tirone C, Perelli S, Romagnoli C. Adrenocortical insufficiency is not a problem in preterm infants treated with antifungal prophylaxis with fluconazole. Acta paediatrica (Oslo, Norway: 1992). 2014;103(6):e234–e237.

  112. 112.

    Magill SS, Puthanakit T, Swoboda SM, Carson KA, Salvatori R, Lipsett PA, et al. Impact of fluconazole prophylaxis on cortisol levels in critically ill surgical patients. Antimicrob Agents Chemother. 2004;48(7):2471–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Blondin MC, Beauregard H, Serri O. Iatrogenic Cushing syndrome in patients receiving inhaled budesonide and itraconazole or ritonavir: two cases and literature review. Endocr Pract. 2013;19(6):e138–e141.

  114. 114.

    Bolland MJ, Bagg W, Thomas MG, Lucas JA, Ticehurst R, Black PN. Cushing’s syndrome due to interaction between inhaled corticosteroids and itraconazole. Ann Pharmacother. 2004;38(1):46–9.

    Article  PubMed  Google Scholar 

  115. 115.

    Daveluy A, Raignoux C, Miremont-Salame G, Girodet PO, Moore N, Haramburu F, et al. Drug interactions between inhaled corticosteroids and enzymatic inhibitors. Eur J Clin Pharmacol. 2009;65(7):743–5.

    Article  CAS  PubMed  Google Scholar 

  116. 116.

    Devenport MH, Crook D, Wynn V, Lees LJ. Metabolic effects of low-dose fluconazole in healthy female users and non-users of oral contraceptives. Br J Clin Pharmacol. 1989;27(6):851–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Duman AK, Fulco PP. Adrenal insufficiency with voriconazole and inhaled/intranasal corticosteroids: case report and systematic review. J Pharm Pract. 2016;30(4):459–63.

    Article  PubMed  Google Scholar 

  118. 118.

    Gilchrist FJ, Cox KJ, Rowe R, Horsley A, Webb AK, Jones AM, et al. Itraconazole and inhaled fluticasone causing hypothalamic-pituitary-adrenal axis suppression in adults with cystic fibrosis. J Cyst Fibros. 2013;12(4):399–402.

    Article  CAS  PubMed  Google Scholar 

  119. 119.

    Glynn AM, Slaughter RL, Brass C, D’Ambrosio R, Jusko WJ. Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion. Clin Pharmacol Ther. 1986;39(6):654–9.

    Article  CAS  PubMed  Google Scholar 

  120. 120.

    Haughey DB, Jusko WJ. Effect of ketoconazole on methylprednisolone pharmacokinetics and receptor/gene-mediated pharmacodynamics. J Pharmacol Exp Ther. 1991;259(2):826–32.

    CAS  PubMed  Google Scholar 

  121. 121.

    Hoover WC, Britton LJ, Gardner J, Jackson T, Gutierrez H. Rapid onset of iatrogenic adrenal insufficiency in a patient with cystic fibrosis-related liver disease treated with inhaled corticosteroids and a moderate CYP3A4 inhibitor. Ann Pharmacother. 2011;45(7–8):e38.

    PubMed  Google Scholar 

  122. 122.

    Jeng S, Chanchairujira T, Jusko W, Steiner R. Prednisone metabolism in recipients of kidney or liver transplants and in lung recipients receiving ketoconazole. Transplantation. 2003;75(6):792–5.

    Article  CAS  PubMed  Google Scholar 

  123. 123.

    Kandrotas RJ, Slaughter RL, Brass C, Jusko WJ. Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol. Clin Pharmacol Ther. 1987;42(4):465–70.

    Article  CAS  PubMed  Google Scholar 

  124. 124.

    Ludwig EA, Slaughter RL, Savliwala M, Brass C, Jusko WJ. Steroid-specific effects of ketoconazole on corticosteroid disposition: unaltered prednisolone elimination. DICP. 1989;23(11):858–61.

    Article  CAS  PubMed  Google Scholar 

  125. 125.

    Skov M, Main KM, Sillesen IB, Muller J, Koch C, Lanng S. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide. Eur Respir J. 2002;20(1):127–33.

    Article  CAS  PubMed  Google Scholar 

  126. 126.

    St Clair K, Maguire JD. Role of fluconazole in a case of rapid onset ritonavir and inhaled fluticasone-associated secondary adrenal insufficiency. Int J STD AIDS. 2012;23(5):371–2.

    Article  CAS  PubMed  Google Scholar 

  127. 127.

    Ulrich B, Frey FJ, Speck RF, Frey BM. Pharmacokinetics/pharmacodynamics of ketoconazole-prednisolone interaction. J Pharmacol Exp Ther. 1992;260(2):487–90.

    CAS  PubMed  Google Scholar 

  128. 128.

    Yamashita SK, Ludwig EA, Middleton E Jr, Jusko WJ. Lack of pharmacokinetic and pharmacodynamic interactions between ketoconazole and prednisolone. Clin Pharmacol Ther. 1991;49(5):558–70.

    Article  CAS  PubMed  Google Scholar 

  129. 129.

    Zurcher RM, Frey BM, Frey FJ. Impact of ketoconazole on the metabolism of prednisolone. Clin Pharmacol Ther. 1989;45(4):366–72.

    Article  CAS  PubMed  Google Scholar 

  130. 130.

    Coss CC, Jones A, Dalton JT. Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin. Investig New Drugs. 2016;34(4):458–67.

    Article  CAS  Google Scholar 

  131. 131.

    Gordijn MS, Gemke RJ, van Dalen EC, Rotteveel J, Kaspers GJ. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. Cochrane Database Syst Rev. 2012(5):CD008727.

  132. 132.

    Vantyghem MC, Balavoine AS, Wemeau JL, Douillard C. Hyponatremia and antidiuresis syndrome. Ann Endocrinol. 2011;72(6):500–12.

    Article  CAS  Google Scholar 

  133. 133.

    Kim KH, Lee S, Lee S, Yun NR, Kim NJ, Yu KS, et al. Voriconazole-associated severe hyponatremia. Med Mycol. 2012;50(1):103–5.

    Article  CAS  PubMed  Google Scholar 

  134. 134.

    Teranishi J, Nagatoya K, Kakita T, Yamauchi Y, Matsuda H, Mori T, et al. Voriconazole-associated salt-losing nephropathy. Clin Exp Nephrol. 2010;14(4):377–80.

    Article  CAS  PubMed  Google Scholar 

  135. 135.

    Xu RA, Lin GY, Hu LF, Shi DW, Ye XL, Liu YJ, et al. Successful management of voriconazole-associated hyponatremia with therapeutic drug monitoring. Antimicrob Agents Chemother. 2013;57(5):2422–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Cadranel J, Philippe B, Hennequin C, Bergeron A, Bergot E, Bourdin A, et al. Voriconazole for chronic pulmonary aspergillosis: a prospective multicenter trial. Eur J Clin Microbiol Infect Dis. 2012;31(11):3231–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Isobe K, Muraoka S, Sugino K, Yamazaki Y, Kikuchi N, Hamanaka N, et al. Case of pulmonary aspergillosis associated with inappropriate antidiuretic hormone syndrome caused by voriconazole therapy. Nihon Kokyuki Gakkai zasshi. 2007;45(6):489–93.

  138. 138.

    Pillans PI, Cowan P, Whitelaw D. Hyponatraemia and confusion in a patient taking ketoconazole. Lancet. 1985;1(8432):821–2.

    Article  CAS  PubMed  Google Scholar 

  139. 139.

    Barton K, Davis TK, Marshall B, Elward A, White NH. Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11beta-hydroxylase enzyme. Clin Kidney J. 2018;11(5):691–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Beck KR, Bachler M, Vuorinen A, Wagner S, Akram M, Griesser U, et al. Inhibition of 11beta-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole. Biochem Pharmacol. 2017;15(130):93–103.

    Article  CAS  Google Scholar 

  141. 141.

    Borelli D. A clinical trial of itraconazole in the treatment of deep mycoses and leishmaniasis. Rev Infect Dis. 1987;9(Suppl 1):S57–S63.

  142. 142.

    Boughton C, Taylor D, Ghataore L, Taylor N, Whitelaw BC. Mineralocorticoid hypertension and hypokalaemia induced by posaconazole. Endocrinol Diabetes Metab Case Rep. 2018. https://doi.org/10.1530/EDM-17-0157.

    Article  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Chakravarty C, Singh PM, Trikha A, Arora MK. Fluconazole-induced recurrent ventricular fibrillation leading to multiple cardiac arrests. Anaesth Intensive Care. 2009;37(3):477–80.

    Article  CAS  PubMed  Google Scholar 

  144. 144.

    Costa I, Castanet J, Lacour JP, Spreux A, Ortonne JP. Vertigo and hypokalemia. Two rare side effects of itraconazole. Therapie. 1994;49(2):149.

  145. 145.

    Duarte RF, Lopez-Jimenez J, Cornely OA, Laverdiere M, Helfgott D, Haider S, et al. Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia. Antimicrob Agents Chemother. 2014;58(10):5758–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Ganer A, Arathoon E, Stevens DA. Initial experience in therapy for progressive mycoses with itraconazole, the first clinically studied triazole. Rev Infect Dis. 1987;9(Suppl 1):S77–S86.

  147. 147.

    George JC, Vedamurthy D, Bermudez M, Kennedy JW. Quiz page October 2016: severe hypokalemia, metabolic alkalosis, and malignancy. Am J Kidney Dis. 2016;68(4):A17–9.

    Article  PubMed  Google Scholar 

  148. 148.

    Gonzalez Rozas M, Alvarez Tundidor S, Pineda Alonso M. Severe acute hypokalaemia secondary to voriconazole. Uncommon pharmacological causes of hypokalaemia. Nefrologia. 2011;31(1):112–3.

  149. 149.

    Graybill JR, Stevens DA, Galgiani JN, Dismukes WE, Cloud GA. Itraconazole treatment of coccidioidomycosis. NAIAD Mycoses Study Group. Am J Med. 1990;89(3):282–90.

  150. 150.

    Gueta I, Loebstein R, Markovits N, Kamari Y, Halkin H, Livni G, et al. Voriconazole-induced QT prolongation among hemato-oncologic patients: clinical characteristics and risk factors. Eur J Clin Pharmacol. 2017;73(9):1181–5.

    Article  CAS  PubMed  Google Scholar 

  151. 151.

    Hoffmann WJ, McHardy I, Thompson GR 3rd. Itraconazole induced hypertension and hypokalemia: mechanistic evaluation. Mycoses. 2018;61(5):337–9.

    Article  CAS  PubMed  Google Scholar 

  152. 152.

    Izzedine H, Besse B, Lazareth A, Bourry EF, Soria JC. Hypokalemia, metabolic alkalosis, and hypertension in a lung cancer patient. Kidney Int. 2009;76(1):115–20.

    Article  PubMed  Google Scholar 

  153. 153.

    Kidd D, Ranaghan EA, Morris TC. Hypokalaemia in patients with acute myeloid leukaemia after treatment with fluconazole. Lancet. 1989;1(8645):1017.

    Article  CAS  PubMed  Google Scholar 

  154. 154.

    Kuriakose K, Nesbitt WJ, Greene M, Harris B. Posaconazole-induced pseudohyperaldosteronism. Antimicrob Agents Chemother. 2018;62(5):e02130–17.

    Article  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Mahmood M, Abu Saleh O, Sohail MR. Hypokalemia and hypertension associated with supratherapeutic posaconazole levels. Antimicrob Agents Chemother. 2017;61(4):e00019–17.

    Article  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Martino J, Fisher BT, Bosse KR, Bagatell R. Suspected posaconazole toxicity in a pediatric oncology patient. Pediatr Blood Cancer. 2015;62(9):1682.

    Article  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Nelson MR, Smith D, Erskine D, Gazzard BG. Ventricular fibrillation secondary to itraconazole induced hypokalaemia. J Infect. 1993;26(3):348.

    Article  CAS  PubMed  Google Scholar 

  158. 158.

    Rickman T, Garmany R, Doherty T, Benson D, Okusa MD. Hypokalemia, metabolic alkalosis, and hypertension: Cushing’s syndrome in a patient with metastatic prostate adenocarcinoma. Am J Kidney Dis. 2001;37(4):838–46.

    Article  CAS  PubMed  Google Scholar 

  159. 159.

    Ruiz-Contreras J, Rodriguez R, Gomez de Quero P, Gonzalez Tome MI, Sanchez Diaz JI. Severe hypokalemia and rhabdomyolysis associated with itraconazole therapy. Pediatr Infect Dis J. 2003;22(11):1024–5.

  160. 160.

    Sasaki E, Maesaki S, Kawamura S, Kakeya H, Ohno H, Hirakata Y, et al. Itraconazole-induced hypokalemia in a patient with pulmonary aspergilloma. Nihon Kokyuki Gakkai zasshi. 1999;37(1):36–40.

  161. 161.

    Seow CJ, Young WF Jr. An overlooked cause of hypokalemia. Am J Med. 2017;130(10):e433–5.

    Article  PubMed  Google Scholar 

  162. 162.

    Thompson GR 3rd, Chang D, Wittenberg RR, McHardy I, Semrad A. In vivo 11beta-hydroxysteroid dehydrogenase inhibition in posaconazole-induced hypertension and hypokalemia. Antimicrob Agents Chemother. 2017;61(8):e00760–17.

    Article  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Wassermann T, Reimer EK, McKinnon M, Stock W. Refractory hypokalemia from syndrome of apparent mineralocorticoid excess on low-dose posaconazole. Antimicrob Agents Chemother. 2018;62(7):e02605–17.

    Article  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Yamamoto T, Suzuki K, Yamakoshi M, Yamamoto T, Ariga K. A case of itraconazole-induced hypokalemia with pulmonary aspergilloma. Kansenshogaku zasshi. 1995;69(12):1413–7.

    Article  CAS  PubMed  Google Scholar 

  165. 165.

    Gallardo-Quesada S, Luelmo-Aguilar J, Guanyabens-Calvet C. Hepatotoxicity associated with itraconazole. Int J Dermatol. 1995;34(8):589.

    Article  CAS  PubMed  Google Scholar 

  166. 166.

    Moseley RH. Chapter 26—hepatotoxicity of antimicrobials and antifungal agents. In: DeLeve NKD, editor. Drug-induced liver disease. 3rd ed. Boston: Academic; 2013. p. 463–81.

    Chapter  Google Scholar 

  167. 167.

    Chen M, Bisgin H, Tong L, Hong H, Fang H, Borlak J, et al. Toward predictive models for drug-induced liver injury in humans: are we there yet? Biomark Med. 2014;8(2):201–13.

    Article  CAS  PubMed  Google Scholar 

  168. 168.

    Raschi E, Poluzzi E, Koci A, Caraceni P, Ponti FD. Assessing liver injury associated with antimycotics: concise literature review and clues from data mining of the FAERS database. World J Hepatol. 2014;6(8):601–12.

    Article  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Tverdek FP, Kofteridis D, Kontoyiannis DP. Antifungal agents and liver toxicity: a complex interaction. Expert Rev Anti Infect Ther. 2016;14(8):765–76.

    Article  CAS  PubMed  Google Scholar 

  170. 170.

    Bronstein JA, Gros P, Hernandez E, Larroque P, Molinie C. Fatal acute hepatic necrosis due to dose-dependent fluconazole hepatotoxicity. Clin Infect Dis. 1997;25(5):1266–7.

    Article  CAS  PubMed  Google Scholar 

  171. 171.

    Tuccori M, Bresci F, Guidi B, Blandizzi C, Del Tacca M, Di Paolo M. Fatal hepatitis after long-term pulse itraconazole treatment for onychomycosis. Ann Pharmacother. 2008;42(7):1112–7.

    Article  CAS  PubMed  Google Scholar 

  172. 172.

    Schneeweiss S, Carver PL, Datta K, Galar A, Johnson MD, Johnson MG, et al. Short-term risk of liver and renal injury in hospitalized patients using micafungin: a multicentre cohort study. J Antimicrob Chemother. 2016;71(10):2938–44.

    Article  CAS  PubMed  Google Scholar 

  173. 173.

    Song JC, Deresinski S. Hepatotoxicity of antifungal agents. Curr Opin Investig Drugs (London, England: 2000). 2005;6(2):170–7.

  174. 174.

    Spellberg B, Rieg G, Bayer A, Edwards JE Jr. Lack of cross-hepatotoxicity between fluconazole and voriconazole. Clin Infect Dis. 2003;36(8):1091–3.

    Article  PubMed  Google Scholar 

  175. 175.

    Foo H, Gottlieb T. Lack of cross-hepatotoxicity between voriconazole and posaconazole. Clin Infect Dis. 2007;45(6):803–5.

    Article  PubMed  Google Scholar 

  176. 176.

    Heinz WJ, Egerer G, Lellek H, Boehme A, Greiner J. Posaconazole after previous antifungal therapy with voriconazole for therapy of invasive aspergillus disease, a retrospective analysis. Mycoses. 2013;56(3):304–10.

    Article  CAS  PubMed  Google Scholar 

  177. 177.

    Pinto A, Chan RC. Lack of allergic cross-reactivity between fluconazole and voriconazole. Antimicrob Agents Chemother. 2009;53(4):1715–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    DiPippo AJ, Rausch CR, Kontoyiannis DP. Tolerability of isavuconazole after posaconazole toxicity in leukaemia patients. Mycoses. 2019;62(1):81–6.

    Article  CAS  PubMed  Google Scholar 

  179. 179.

    Martinez-Casanova J, Carballo N, Luque S, Sorli L, Grau S. Posaconazole achieves prompt recovery of voriconazole-induced liver injury in a case of invasive aspergillosis. Infect Drug Resist. 2018;11:317–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Perissinotti AJ, Marini BL. Managing liver dysfunction in haematology patients: switch antifungals, or use the tincture of time? Mycoses. 2018;62(3):214–6.

    Article  CAS  PubMed  Google Scholar 

  181. 181.

    Yan JY, Nie XL, Tao QM, Zhan SY, Zhang YD. Ketoconazole associated hepatotoxicity: a systematic review and meta- analysis. Biomed Environ Sci. 2013;26(7):605–10.

    PubMed  Google Scholar 

  182. 182.

    Wells C, Lever AM. Dose-dependent fluconazole hepatotoxicity proven on biopsy and rechallenge. J Infect. 1992;24(1):111–2.

    Article  CAS  PubMed  Google Scholar 

  183. 183.

    Gearhart MO. Worsening of liver function with fluconazole and review of azole antifungal hepatotoxicity. Ann Pharmacother. 1994;28(10):1177–81.

    Article  CAS  PubMed  Google Scholar 

  184. 184.

    Fischer MA, Winkelmayer WC, Rubin RH, Avorn J. The hepatotoxicity of antifungal medications in bone marrow transplant recipients. Clin Infect Dis. 2005;41(3):301–7.

    Article  CAS  PubMed  Google Scholar 

  185. 185.

    Jung DS, Tverdek FP, Kontoyiannis DP. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity. Antimicrob Agents Chemother. 2014;58(11):6993–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Lutsar I, Hodges MR, Tomaszewski K, Troke PF, Wood ND. Safety of voriconazole and dose individualization. Clin Infect Dis. 2003;36(8):1087–8.

    Article  PubMed  Google Scholar 

  187. 187.

    Tan K, Brayshaw N, Tomaszewski K, Troke P, Wood N. Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities. J Clin Pharmacol. 2006;46(2):235–43.

    Article  CAS  PubMed  Google Scholar 

  188. 188.

    Gorski E, Esterly JS, Postelnick M, Trifilio S, Fotis M, Scheetz MH. Evaluation of hepatotoxicity with off-label oral-treatment doses of voriconazole for invasive fungal infections. Antimicrob Agents Chemother. 2011;55(1):184–9.

    Article  CAS  PubMed  Google Scholar 

  189. 189.

    Mitsani D, Nguyen MH, Shields RK, Toyoda Y, Kwak EJ, Silveira FP, et al. Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity. Antimicrob Agents Chemother. 2012;56(5):2371–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Luong ML, Hosseini-Moghaddam SM, Singer LG, Chaparro C, Azad S, Lazar N, et al. Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients. Am J Transplant. 2012;12(7):1929–35.

    Article  CAS  PubMed  Google Scholar 

  191. 191.

    Suzuki Y, Tokimatsu I, Sato Y, Kawasaki K, Goto T, Hashinaga K, et al. Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity. Clin Chim Acta. 2013;424:119–22.

    Article  CAS  PubMed  Google Scholar 

  192. 192.

    Matsumoto K, Ikawa K, Abematsu K, Fukunaga N, Nishida K, Fukamizu T, et al. Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes. Int J Antimicrob Agents. 2009;34(1):91–4.

    Article  CAS  PubMed  Google Scholar 

  193. 193.

    Lavrijsen AP, Balmus KJ, Nugteren-Huying WM, Roldaan AC, van’t Wout JW, Stricker BH. Hepatic injury associated with itraconazole. Lancet. 1992;340(8813):251–2.

    Article  CAS  PubMed  Google Scholar 

  194. 194.

    Talwalkar JA, Soetikno RE, Carr-Locke DL, Berg CL. Severe cholestasis related to intraconazole for the treatment of onychomycosis. Am J Gastroenterol. 1999;94(12):3632–3.

    Article  CAS  PubMed  Google Scholar 

  195. 195.

    Porte L, Khatibi S, Hajj LE, Cassaing S, Berry A, Massip P, et al. Scedosporium apiospermum mycetoma with bone involvement successfully treated with voriconazole. Trans R Soc Trop Med Hyg. 2006;100(9):891–4.

    Article  CAS  PubMed  Google Scholar 

  196. 196.

    Mahdi ZM, Synal-Hermanns U, Yoker A, Locher KP, Stieger B. Role of multidrug resistance protein 3 (MDR3) in antifungal-induced cholestasis. Mol Pharmacol. 2016;90(1):23–34.

    Article  CAS  PubMed  Google Scholar 

  197. 197.

    Yoshikado T, Takada T, Yamamoto T, Yamaji H, Ito K, Santa T, et al. Itraconazole-induced cholestasis: involvement of the inhibition of bile canalicular phospholipid translocator MDR3/ABCB4. Mol Pharmacol. 2011;79(2):241–50.

    Article  CAS  PubMed  Google Scholar 

  198. 198.

    Aghai ZH, Mudduluru M, Nakhla TA, Amendolia B, Longo D, Kemble N, et al. Fluconazole prophylaxis in extremely low birth weight infants: association with cholestasis. J Perinatol. 2006;26(9):550–5.

    Article  CAS  PubMed  Google Scholar 

  199. 199.

    Bhat V, Fojas M, Saslow JG, Shah S, Sannoh S, Amendolia B, et al. Twice-weekly fluconazole prophylaxis in premature infants: association with cholestasis. Pediatr Int. 2011;53(4):475–9.

    Article  CAS  PubMed  Google Scholar 

  200. 200.

    Passier JL, van Puijenbroek EP, Jonkers GJ, van Grootheest AC. Pancreatitis associated with the use of itraconazole. Neth J Med. 2010;68(6):285–9.

    CAS  PubMed  Google Scholar 

  201. 201.

    Philip A, Sivaprakasam P, Sagar TG, Ganesan P. Voriconazole-induced pancreatitis in a patient of acute myeloid leukemia and invasive aspergillosis. J Pediatr Hematol Oncol. 2012;34(5):406.

    Article  PubMed  Google Scholar 

  202. 202.

    Williams K, Arron ST. Association of CYP2C19 *17/*17 genotype with the risk of voriconazole-associated squamous cell carcinoma. JAMA Dermatol. 2016;152(6):719–20.

    Article  PubMed  Google Scholar 

  203. 203.

    Mansh M, Binstock M, Williams K, Hafeez F, Kim J, Glidden D, et al. Voriconazole exposure and risk of cutaneous squamous cell carcinoma, aspergillus colonization, invasive aspergillosis and death in lung transplant recipients. Am J Transplant. 2016;16(1):262–70.

    Article  CAS  PubMed  Google Scholar 

  204. 204.

    Zhang S, Neujahr DC, Zwald FO. Recurrent and metastatic squamous cell carcinoma in lung transplant recipient on voriconazole: lessons learned. JAAD Case Rep. 2015;1(6):S12–5.

    Article  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Wojenski DJ, Bartoo GT, Merten JA, Dierkhising RA, Barajas MR, El-Azhary RA, et al. Voriconazole exposure and the risk of cutaneous squamous cell carcinoma in allogeneic hematopoietic stem cell transplant patients. Transpl Infect Dis. 2015;17(2):250–8.

    Article  CAS  PubMed  Google Scholar 

  206. 206.

    Willis ZI, Boyd AS, Di Pentima MC. Phototoxicity, pseudoporphyria, and photo-onycholysis due to voriconazole in a pediatric patient with leukemia and invasive aspergillosis. J Pediatr Infect Dis Soc. 2015;4(2):e22–4.

    Article  Google Scholar 

  207. 207.

    Soresi S, Sabashnikov A, Leaver N, Zeriouh M, Simon AR, Popov AF, et al. Voriconazole tolerability in lung transplant recipients: is N-oxide metabolite responsible for phototoxicity? J Heart Lung Transplant. 2015;34(10):1354–5.

    Article  PubMed  Google Scholar 

  208. 208.

    Sheu J, Hawryluk EB, Guo D, London WB, Huang JT. Voriconazole phototoxicity in children: a retrospective review. J Am Acad Dermatol. 2015;72(2):314–20.

    Article  CAS  PubMed  Google Scholar 

  209. 209.

    Patel VA, Parikh SA, Nayyar PM, Ratner D. Voriconazole-induced multiple squamous cell carcinomas in a patient with chronic lymphocytic leukemia. Dermatol Surg. 2015;41(6):747–9.

    Article  CAS  PubMed  Google Scholar 

  210. 210.

    Giambrone D, Correa-Selm LM, Firoz BF. An inflammatory skin reaction after cetuximab treatment for aggressive cutaneous squamous cell carcinoma in a heart transplant patient previously taking voriconazole. JAMA Dermatol. 2016;152(12):1385–7.

    Article  PubMed  Google Scholar 

  211. 211.

    Chong PP, Kennedy CC, Hathcock MA, Kremers WK, Razonable RR. Epidemiology of invasive fungal infections in lung transplant recipients on long-term azole antifungal prophylaxis. Clin Transplant. 2016;152(12):1385–7.

    Google Scholar 

  212. 212.

    Wong JY, Kuzel P, Mullen J, Lien D, Mahmood M, Conrad C, et al. Cutaneous squamous cell carcinoma in two pediatric lung transplant patients on prolonged voriconazole treatment. Pediatr Transplant. 2014;18(6):E200–7.

    Article  CAS  PubMed  Google Scholar 

  213. 213.

    Williams K, Mansh M, Chin-Hong P, Singer J, Arron ST. Voriconazole-associated cutaneous malignancy: a literature review on photocarcinogenesis in organ transplant recipients. Clin Infect Dis. 2014;58(7):997–1002.

  214. 214.

    Turegano MM, Lee CC, Malech HL, De Ravin SS, Cowen EW, Brownell I. Recurrent erythematous plaques on sun-exposed sites in an African American boy with chronic granulomatous disease. J Am Acad Dermatol. 2014;70(3):576–80.

    Article  PubMed  PubMed Central  Google Scholar 

  215. 215.

    Smart SE, Crosby T, Jeyakumar A. An adolescent with a skin lesion. Squamous cell carcinoma of the skin secondary to voriconazole-induced photosensitivity. JAMA Otolaryngol Head Neck Surg. 2014;140(10):979–80.

  216. 216.

    Rork JF, Margossian SP, Nambudiri VE, Huang JT. Nonmelanoma skin cancer in childhood after hematopoietic stem cell transplant: a report of 4 cases. J Pediatr Hematol Oncol. 2014;36(3):224–7.

    Article  PubMed  Google Scholar 

  217. 217.

    Neoh CF, Snell GI, Levvey B, Kotsimbos T, Morrissey O, Slavin MA, et al. Lung transplant recipients receiving voriconazole and skin squamous cell carcinoma risk in Australia. Med J Aust. 2014;201(9):543–4.

    Article  PubMed  Google Scholar 

  218. 218.

    Massey PR, Wanat KA, Elenitsas R, Rosenbach M. Atypical lentigines in a man with mixed African American and white race/ethnicity receiving long-term voriconazole therapy. JAMA Dermatol. 2014;150(3):334–5.

    Article  PubMed  Google Scholar 

  219. 219.

    Huang G, Liu Q, Ye X, Yang X, Wei Z, Li W, et al. Invasive pulmonary aspergillosis: a rare complication after microwave ablation. Int J Hyperth. 2014;30(6):412–7.

    Article  Google Scholar 

  220. 220.

    Goyal RK, Gehris RP, Howrie D, Cogley KM, Windreich RM, Venkataramanan R. Phototoxic dermatoses in pediatric BMT patients receiving voriconazole. Pediatr Blood Cancer. 2014;61(7):1325–8.

    Article  CAS  PubMed  Google Scholar 

  221. 221.

    Carrascosa R, Solano-Lopez GE, Vargas E, Fraga J. Squamous cell carcinoma in an immunosuppressed patient on voriconazole. Actas Dermo-sifiliograficas. 2014;105(4):424–6.

    Article  CAS  PubMed  Google Scholar 

  222. 222.

    Barbosa NS, Wetter DA. Bullous phototoxicity from voriconazole. J Emerg Med. 2014;46(3):e83–4.

    Article  PubMed  Google Scholar 

  223. 223.

    Alberdi Soto M, Aguado Gil L, Pretel Irazabal M, Irarrazabal Armendariz I, Lera Imbuluzqueta JM, Bernad Alonso I, et al. Accelerated photoaging induced by voriconazole treated with QS Nd: YAG laser. Case report and review of the literature. J Cosmet Laser Ther. 2014;16(6):314–6.

    Article  PubMed  Google Scholar 

  224. 224.

    McLaughlin JM, Equils O, Somerville KT, Aram JA, Schlamm HT, Welch VL, et al. Risk-adjusted relationship between voriconazole utilization and non-melanoma skin cancer among lung and heart/lung transplant patients. Transpl Infect Dis. 2013;15(4):329–43.

    Article  CAS  PubMed  Google Scholar 

  225. 225.

    Haylett AK, Felton S, Denning DW, Rhodes LE. Voriconazole-induced photosensitivity: photobiological assessment of a case series of 12 patients. Br J Dermatol. 2013;168(1):179–85.

    Article  CAS  PubMed  Google Scholar 

  226. 226.

    Epaulard O, Villier C, Ravaud P, Chosidow O, Blanche S, Mamzer-Bruneel MF, et al. A multistep voriconazole-related phototoxic pathway may lead to skin carcinoma: results from a French Nationwide Study. Clin Infect Dis. 2013;57(12):e182–8.

    Article  CAS  PubMed  Google Scholar 

  227. 227.

    Zwald FO, Spratt M, Lemos BD, Veledar E, Lawrence C, Marshall Lyon G, et al. Duration of voriconazole exposure: an independent risk factor for skin cancer after lung transplantation. Dermatol Surg. 2012;38(8):1369–74.

    Article  CAS  PubMed  Google Scholar 

  228. 228.

    Soler-Palacin P, Frick MA, Martin-Nalda A, Lanaspa M, Pou L, Rosello E, et al. Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study. J Antimicrob Chemother. 2012;67(3):700–6.

    Article  CAS  PubMed  Google Scholar 

  229. 229.

    Singer JP, Boker A, Metchnikoff C, Binstock M, Boettger R, Golden JA, et al. High cumulative dose exposure to voriconazole is associated with cutaneous squamous cell carcinoma in lung transplant recipients. J Heart Lung Transplant. 2012;31(7):694–9.

    Article  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Rondeau S, Couderc L, Dominique S, Pramil S, Leguillon C, Masseline B, et al. High frequency of voriconazole-related phototoxicity in cystic fibrosis patients. Eur Respir J. 2012;39(3):782–4.

    Article  CAS  PubMed  Google Scholar 

  231. 231.

    Markantonis SL, Katelari A, Pappa E, Doudounakis S. Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis. J Cyst Fibros. 2012;11(3):246–52.

    Article  CAS  PubMed  Google Scholar 

  232. 232.

    Hansford JR, Cole C, Blyth CC, Gottardo NG. Idiosyncratic nature of voriconazole photosensitivity in children undergoing cancer therapy. J Antimicrob Chemother. 2012;67(7):1807–9.

    Article  CAS  PubMed  Google Scholar 

  233. 233.

    Feist A, Lee R, Osborne S, Lane J, Yung G. Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole. J Heart Lung Transplant. 2012;31(11):1177–81.

    Article  PubMed  Google Scholar 

  234. 234.

    Elbaum DJ, Cowen EW. Voriconazole-associated phototoxic effects and lentigo formation in an African American man. Arch Dermatol. 2012;148(8):965–6.

    Article  PubMed  Google Scholar 

  235. 235.

    Vohringer S, Schrum J, Ott H, Hoger PH. Severe phototoxicity associated with long-term voriconazole treatment. Journal der Deutschen Dermatologischen Gesellschaft. 2011;9(4):274–6.

  236. 236.

    Riahi RR, Cohen PR. Voriconazole-associated phototoxicity. Dermatol Online J. 2011;17(2):15.

    PubMed  Google Scholar 

  237. 237.

    Vadnerkar A, Nguyen MH, Mitsani D, Crespo M, Pilewski J, Toyoda Y, et al. Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients. J Heart Lung Transplant. 2010;29(11):1240–4.

    Article  PubMed  Google Scholar 

  238. 238.

    Miller DD, Cowen EW, Nguyen JC, McCalmont TH, Fox LP. Melanoma associated with long-term voriconazole therapy: a new manifestation of chronic photosensitivity. Arch Dermatol. 2010;146(3):300–4.

    Article  CAS  PubMed  Google Scholar 

  239. 239.

    Ibrahim SF, Singer JP, Arron ST. Catastrophic squamous cell carcinoma in lung transplant patients treated with voriconazole. Dermatol Surg. 2010;36(11):1752–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. 240.

    Frisch S, Askari SK, Beaty SR, Burkemper CN. X-linked chronic granulomatous disease with voriconazole-induced photosensitivity/ photoaging reaction. J Drugs Dermatol. 2010;9(5):562–4.

    PubMed  Google Scholar 

  241. 241.

    Frick MA, Soler-Palacin P, Martin Nalda A, Guarner ME, Nadal CF. Photosensitivity in immunocompromised patients receiving long-term therapy with oral voriconazole. Pediatr Infect Dis J. 2010;29(5):480–1.

    Article  PubMed  Google Scholar 

  242. 242.

    Epaulard O, Saint-Raymond C, Villier C, Charles J, Roch N, Beani JC, et al. Multiple aggressive squamous cell carcinomas associated with prolonged voriconazole therapy in four immunocompromised patients. Clin Microbiol Infect. 2010;16(9):1362–4.

    Article  CAS  PubMed  Google Scholar 

  243. 243.

    Cowen EW, Nguyen JC, Miller DD, McShane D, Arron ST, Prose NS, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol. 2010;62(1):31–7.

    Article  CAS  PubMed  Google Scholar 

  244. 244.

    Cheng MP, Paquette K, Lands LC, Ovetchkine P, Theoret Y, Quach C. Voriconazole inhibition of vitamin A metabolism: are adverse events increased in cystic fibrosis patients? Pediatr Pulmonol. 2010;45(7):661–6.

    Article  PubMed  Google Scholar 

  245. 245.

    Patel AR, Turner ML, Baird K, Gea-Banacloche J, Mitchell S, Pavletic SZ, et al. Voriconazole-induced phototoxicity masquerading as chronic graft-versus-host disease of the skin in allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2009;15(3):370–6.

    Article  PubMed  PubMed Central  Google Scholar 

  246. 246.

    McCarthy KL, Playford EG, Looke DF, Whitby M. Severe photosensitivity causing multifocal squamous cell carcinomas secondary to prolonged voriconazole therapy. Clin Infect Dis. 2007;44(5):e55–6.

    Article  CAS  PubMed  Google Scholar 

  247. 247.

    Kwong WT, Hsu S. Pseudoporphyria associated with voriconazole. J Drugs Dermatol. 2007;6(10):1042–4.

    PubMed  Google Scholar 

  248. 248.

    Auffret N, Janssen F, Chevalier P, Guillemain R, Amrein C, Le Beller C. Voriconazole photosensitivity: 7 cases. Ann Dermatol Venereol. 2006;133(4):330–2.

    Article  CAS  PubMed  Google Scholar 

  249. 249.

    Racette AJ, Roenigk HH Jr, Hansen R, Mendelson D, Park A. Photoaging and phototoxicity from long-term voriconazole treatment in a 15-year-old girl. J Am Acad Dermatol. 2005;52(5 Suppl 1):S81–5.

    Article  PubMed  Google Scholar 

  250. 250.

    Vandecasteele SJ, Van Wijngaerden E, Peetermans WE. Two cases of severe phototoxic reactions related to long-term outpatient treatment with voriconazole. Eur J Clin Microbiol Infect Dis. 2004;23(8):656–7.

    Article  CAS  PubMed  Google Scholar 

  251. 251.

    Denning DW, Griffiths CE. Muco-cutaneous retinoid-effects and facial erythema related to the novel triazole antifungal agent voriconazole. Clin Exp Dermatol. 2001;26(8):648–53.

    Article  CAS  PubMed  Google Scholar 

  252. 252.

    Malani AN, Aronoff DM. Voriconazole-induced photosensitivity. Clin Med Res. 2008;6(2):83–5.

    Article  PubMed  PubMed Central  Google Scholar 

  253. 253.

    Vanacker A, Fabre G, Van Dorpe J, Peetermans WE, Maes B. Aggressive cutaneous squamous cell carcinoma associated with prolonged voriconazole therapy in a renal transplant patient. Am J Transplant. 2008;8(4):877–80.

    Article  CAS  PubMed  Google Scholar 

  254. 254.

    Morice C, Acher A, Soufir N, Michel M, Comoz F, Leroy D, et al. Multifocal aggressive squamous cell carcinomas induced by prolonged voriconazole therapy: a case report. Case Rep Med. 2010;2010:351084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. 255.

    Verdu-Amoros J, Wilbrand JF, Mayser P, Gattenloehner S, Woessmann W. Pigmented squamous cell carcinoma in an adolescent following long-term treatment with voriconazole. Pediatr Blood Cancer. 2017. https://doi.org/10.1002/pbc.26280.

    Article  PubMed  Google Scholar 

  256. 256.

    Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(18):1941–67.

    Article  CAS  PubMed  Google Scholar 

  257. 257.

    Epaulard O, Leccia MT, Blanche S, Chosidow O, Mamzer-Bruneel MF, Ravaud P, et al. Phototoxicity and photocarcinogenesis associated with voriconazole. Medecine et maladies infectieuses. 2011;41(12):639–45.

    Article  CAS  PubMed  Google Scholar 

  258. 258.

    Rashtak S, Dierkhising RA, Kremers WK, Peters SG, Cassivi SD, Otley CC. Incidence and risk factors for skin cancer following lung transplantation. J Am Acad Dermatol. 2015;72(1):92–8.

    Article  PubMed  Google Scholar 

  259. 259.

    Tolland JP, McKeown PP, Corbett JR. Voriconazole-induced pseudoporphyria. Photodermatol Photoimmunol Photomed. 2007;23(1):29–31.

    Article  CAS  PubMed  Google Scholar 

  260. 260.

    Sharp MT, Horn TD. Pseudoporphyria induced by voriconazole. J Am Acad Dermatol. 2005;53(2):341–5.

    Article  PubMed  Google Scholar 

  261. 261.

    Dolan CK, Hall MA, Blazes DL, Norwood CW. Pseudoporphyria as a result of voriconazole use: a case report. Int J Dermatol. 2004;43(10):768–71.

    Article  PubMed  Google Scholar 

  262. 262.

    Mittal A, Colegio OR. Skin cancers in organ transplant recipients. Am J Transplant. 2017;17(10):2509–30.

    Article  CAS  PubMed  Google Scholar 

  263. 263.

    Chien RN, Yang LJ, Lin PY, Liaw YF. Hepatic injury during ketoconazole therapy in patients with onychomycosis: a controlled cohort study. Hepatology (Baltimore, MD). 1997;25(1):103–7.

    Article  CAS  Google Scholar 

  264. 264.

    Kolaitis NA, Duffy E, Zhang A, Lo M, Barba DT, Chen M, et al. Voriconazole increases the risk for cutaneous squamous cell carcinoma after lung transplantation. Transpl Int. 2017;30(1):41–8.

    Article  CAS  PubMed  Google Scholar 

  265. 265.

    Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806–15.

    Article  CAS  PubMed  Google Scholar 

  266. 266.

    Gill J, Sprenger HR, Ralph ED, Sharpe MD. Hepatotoxicity possibly caused by amphotericin B. Ann Pharmacother. 1999;33(6):683–5.

    Article  CAS  PubMed  Google Scholar 

  267. 267.

    Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65(2):253–61 (quiz 62).

  268. 268.

    Goyal RK. Voriconazole-associated phototoxic dermatoses and skin cancer. Expert Rev Anti Infect Ther. 2015;13(12):1537–46.

    Article  CAS  PubMed  Google Scholar 

  269. 269.

    Ona K, Oh DH. Voriconazole N-oxide and its ultraviolet B photoproduct sensitize keratinocytes to ultraviolet A. Br J Dermatol. 2015;173(3):751–9.

    Article  CAS  PubMed  Google Scholar 

  270. 270.

    Lo Re V 3rd, Carbonari DM, Lewis JD, Forde KA, Goldberg DS, Reddy KR, et al. Oral azole antifungal medications and risk of acute liver injury, overall and by chronic liver disease status. Am J Med. 2016;129(3):283–91 e5.

  271. 271.

    Wang JL, Chang CH, Young-Xu Y, Chan KA. Systematic review and meta-analysis of the tolerability and hepatotoxicity of antifungals in empirical and definitive therapy for invasive fungal infection. Antimicrob Agents Chemother. 2010;54(6):2409–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. 272.

    Kao WY, Su CW, Huang YS, Chou YC, Chen YC, Chung WH, et al. Risk of oral antifungal agent-induced liver injury in Taiwanese. Br J Clin Pharmacol. 2014;77(1):180–9.

    Article  CAS  PubMed  Google Scholar 

  273. 273.

    Greenblatt HK, Greenblatt DJ. Liver injury associated with ketoconazole: review of the published evidence. J Clin Pharmacol. 2014;54(12):1321–9.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Peggy L. Carver.

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Peggy L. Carver, PharmD, FIDP has served as a consultant for Astellas. Lydia L. Benitez, PharmD, BCOP has no conflicts to disclose.

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Benitez, L.L., Carver, P.L. Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents. Drugs 79, 833–853 (2019). https://doi.org/10.1007/s40265-019-01127-8

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