Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2024;14(2):e2024137 1 Retrospective Cohort Study of Hepatic and Hematologic Toxicity in Terbinafine-Treated Onychomycosis Patients With Reduced Kidney Function at an Academic Institution Kaya L. Curtis1, Jose W. Ricardo2, Yuqing Qiu3, Debra K. Lee4, Jamie Hedrick5, Henry I. Lipner6, Shari R. Lipner2 1 Weill Cornell Medical College, New York, New York, USA 2 Weill Cornell Medicine, Department of Dermatology, New York, New York, USA 3 Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA 4 University of Texas Medical Branch, Galveston, Texas, USA 5 Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA 6 Division of Nephrology, Maimonides Medical Center, Brooklyn, New York, USA Key words: Terbinafine, onychomycosis, renal, hepatic, laboratory monitoring Citation: Curtis KL, Ricardo JW, Qiu Y, et al. Retrospective Cohort Study of Hepatic and Hematologic Toxicity in Terbinafine-Treated Onychomycosis Patients With Reduced Kidney Function at an Academic Institution. Dermatol Pract Concept. 2024;14(2):e2024137. DOI: https://doi.org/10.5826/dpc.1402a137 Accepted: January 31, 2024; Published: April 2024 Copyright: ©2024 Curtis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: Ms. Kaya Curtis, Dr. Jose Ricardo, Ms. Yuqing Qiu, Dr. Debra Lee, Dr. Jamie Hedrick, and Dr. Henry Lipner have no conflicts of interest relevant to the content of the submission. Financial disclosures: Dr. Shari Lipner has served as a consult for Ortho- Dermatologics, BelleTorus Corporation, Eli Lilly, and Moberg Pharmaceuticals. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Shari R. Lipner MD, PhD, 1305 York Avenue, NY, NY 10021. Phone: +1/646-962-3376 Fax: +1/646-962-0033 E-mail: shl9032@med.cornell.edu Introduction Oral terbinafine, a first-line onychomycosis therapy, is primarily excreted renally [1, 2]. Patients with renal impair- ment may have increased hepatic and hematologic toxicity risk. Onychomycosis was ~2x more common in hemodialysis and kidney transplant patients vs. non-renal disease controls in a prospective study (N=510, P=0.03) [3]. Therefore, we aimed to evaluate the association between kidney function and laboratory test abnormality rates in terbinafine-treated onychomycosis patients. Case Presentation Aspartate aminotransferase (AST), alanine aminotrans- ferase (ALT), and complete blood count (CBC) tests of terbinafine-treated adults with onychomycosis (2000-2021) ≤3 months before, during, and ≤3 months after treatment were collected (Supplemental Methods). Of 2,195 records, 734 patients were included, with an average age of 55.2 years (Supplemental Table 1). Two hundred eighty-five patients had abnormal renal function, and proportion of abnormal AST, ALT, and CBC values 2 Research Letter | Dermatol Pract Concept. 2024;14(2):e2024137 were similar during and post-terbinafine treatment vs. pre- treatment (Supplemental Table 2). After matching for age, sex, weight, hepatic/hematologic disease, terbinafine-treated stage 2 chronic renal insufficiency (CRI) vs. stage 1 CRI and stage 3 CRI vs. stage 1 CRI patients had similar labo- ratory abnormality risk during and post-treatment vs. base- line (Table 1). Stage 1 CRI patients had mean 0.02mg/dL serum creatinine change from baseline to during treatment and baseline to post-treatment (both 95% CI: 0.01–0.04, P=0.002, P=0.005, respectively). Mean creatinine was stable from baseline to during and post-treatment for stages 2 and 3 CRI (Supplemental Table 3). Discussion Our study suggests that terbinafine-treated onychomycosis patients with stages 2 or 3 CRI are not at increased risk of developing laboratory abnormalities vs. patients with nor- mal kidney function (stage 1 CRI). Creatinine increased in stage 1 CRI terbinafine-treated patients, which may be due to laboratory variations and was clinically insignificant. We found no difference between baseline and monitoring hepatic and hematologic laboratory values, similar to a ret- rospective cohort study [4] of 4,309 terbinafine courses for dermatophyte infection (majority onychomycosis), where transaminitis, anemia, lymphopenia, and neutropenia rates were low and comparable to baseline. In a population-based study [5] of 12,376 patients, incidence of terbinafine- induced liver injury was 1.6/10,000 persons. Since terbinafine is primarily excreted in the urine (80%), with creatinine clearance decreased by 50% in patients with <50 mL/min [1], reducing daily terbinafine dosage by half has been suggested for patients with reduced renal function [2]. However, the package insert does not mention dose reduction Table 1. Risk of developing laboratory abnormalities in terbinafine-treated patients with Stage 2/ Stage 3 CRI compared to patients with stage 1 CRI* Stage 2 CRI compared to stage 1 CRI Outcome variable  Odds ratio   95% confidence interval   P value   Abnormal AST results post-treatment   1.21 0–785.34 0.131 Abnormal AST results during treatment   0.85 0.36–2.02 0.717 Abnormal ALT results post-treatment   0.29 0.06–1.48 0.137 Abnormal ALT results during treatment    0.98 0–644.37 0.994 Abnormal CBC results post-treatment   1.01 0.4–2.55 0.981 Abnormal CBC results during treatment   1.49 0.67–3.3 0.329 Stage 3 CRI compared to stage 1 CRI Outcome variable  Odds ratio   95% confidence interval   P value   Abnormal AST results post-treatment** -- -- -- Abnormal AST results during treatment   0.9 0.11–7.17 0.924 Abnormal ALT results post-treatment**  -- -- -- Abnormal ALT results during treatment** --  -- -- Abnormal CBC results post-treatment   3.66 0.5–26.79 0.202 Abnormal CBC results during treatment   3.35 0.54–20.82 0.194 *After matching and adjusting for covariates, including age, sex, weight, presence of hepatic/hematologic disease, and baseline AST, ALT, CBC laboratory tests. **Odds ratios could not be calculated due to lack of laboratory values in stage 1 or stage 3 groups. Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; CBC: complete blood count; CRI: chronic renal insufficiency. Research Letter | Dermatol Pract Concept. 2024;14(2):e2024137 3 in renally impaired patients [1], with a paucity of studies to support this recommendation. In a retrospective study of 13 kidney transplant recipients (creatinine <3.39 mg/dL) treated with terbinafine (250 mg daily, 12 weeks) for ony- chomycosis, none had hepatic or hematologic abnormalities, suggesting that terbinafine may be safe even in patients with severely reduced kidney function [4]. Limitations include small sample size, confounding bias, single-center design, and lack of consideration of dosage and adverse event-related treatment interruptions. Few patients had severe renal impairment. Conclusions In sum, onychomycosis patients with mild to moderate reduced kidney function do not seem to have increased risk of developing laboratory abnormalities with terbinaf- ine treatment, and dose reduction may not be necessary. We recommend checking baseline creatinine to evaluate renal function before prescribing terbinafine for onychomycosis treatment, pending larger multicenter trials evaluating ony- chomycosis patients with kidney disease. References 1. Lamisil Oral Tablets, Terbinafine HCl Oral Tablets [package in- sert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017. 2. Elewski B, Tavakkol A. Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality. Ther Clin Risk Manag. 2005 Dec;1(4):299-306. 3. Filho AMS, Ventura CG, Criado PR, Del Negro GB, Freitas RS, Luiz OC, Giudice MC, Neto ED, Benard G. Hemodialysis and Kidney Transplantation as Predisposing Conditions to Onycho- mycosis. Nephron. 2017;137(1):38-46. 4. Stolmeier DA, Stratman HB, McIntee TJ, Stratman EJ. Utility of Laboratory Test Result Monitoring in Patients Taking Oral Terbinafine or Griseofulvin for Dermatophyte Infections. JAMA Dermatol. 2018 Dec 1;154(12):1409-1416. 5. Kao WY, Su CW, Huang YS, Chou YC, Chen YC, Chung WH, Hou MC, Lin HC, Lee FY, Wu JC. Risk of oral antifungal agent-induced liver injury in Taiwanese. Br J Clin Pharmacol. 2014 Jan;77(1):180-9. 6. Moreno-Sabater A, Ouali N, Chasset F, Frances C, Senet P, Faucon C, Hennequin C, Bachmeyer C. Severe onychomycosis management with oral terbinafine in a kidney transplantation setting: Clinical follow-up by image analysis. Mycoses. 2021 Mar;64(3):309-315.