Terbinafine Use Research Articles

Terbinafine-induced Myositis: A Case Report

We report a case of terbinafine-induced myositis in a 37-year-old Asian male patient treated for Tinea cruris. The patient complained of severe generalized body aches, weakness, fever, fatigue, and passing of concentrated urine after consuming one dose of terbinafine 250 mg tablet, which worsened after the second dose. At the presentation, the patient was afebrile, fatigued, and had difficulty moving. All the laboratory parameters were normal, except N-acetyl-cysteine-(NAC)-activated creatine kinase, which was elevated to 276 U/L. There was a slight elevation in alanine transaminase (ALT) levels (44 U/L) and albumin-to-globulin ratio (1.8). The oral terbinafine was stopped. Patient was prescribed with tablet acetaminophen 650 mg thrice daily for two days and as needed thereafter, to manage myalgia. The patient reported being symptomatically better after six days of terbinafine withdrawal. The Naranjo’s causality assessment scale score was eight, indicating a probable relation between drug exposure (terbinafine use) and adverse drug reaction (myositis). The severity of terbinafine-induced myositis in this patient was moderate (level 3) as categorized by the Modified Hartwig and Siegel scale.

Terbinafine-induced Toxic Epidermal Necrolysis in Pregnancy: A Case Report.

case reports; pregnancy; Stevens-Johnson syndrome; toxic epidermal necrolysis.

Unique Presentation and Unusual Cause of Acute Generalized Exanthematous Pustulosis: Case Report

Acute generalized exanthematous pustulosis (AGEP) is a febrile, pustular eruption that has been reported in all ages. Three weeks following oral terbinafine use, a 64-year-old male patient was admitted to the hospital for diffuse, nearly confluent erythematous plaques and desquamation, fevers, chills, and ulcer formation on his lower mucosal lip and tongue. Ten days prior to presentation, he was evaluated and discharged with a prednisone 60 mg taper for suspected erythema multiforme. Terbinafine was discontinued and the patient was monitored for systemic involvement. Recognition of subtle pustules on a background of EM-like lesions may facilitate the timely diagnosis and appropriate treatment of AGEP.

Cutaneous Sporotrichosis of Face with Verrucous Lesions over Nose, Successfully Treated with a Combination of Itraconazole and Terbinafine: A Case Report.

Dear Editor, A 13-year-old boy presented with nasal erythematous, crusted, confluent papules, and nodules persisting for approximately 35 days [Figure 1]. The patient denied contact with sick cats but mentioned playing in the bushes. The clinical diagnosis was cutaneous sporotrichosis, and he started treatment with itraconazole 100 mg per day, which was administered orally for 10 days and then increased to 200 mg per day. The exudate from the skin lesions was directly examined by a potassium hydroxide test, which was negative for fungal presence. At 25°C, a mycosal media culture of the exudate revealed colonies resembling Sporothrix sp, which appeared membranous, beige, wrinkled, and with a blackened halo [Figure 2]. At 37°C, phenotypic reversal for creamy colonies with beige and colorless verse was observed, thus demonstrating dimorphism. The lactophenol cotton blue stain revealed hyaline septate hyphae [Figure 3]. On day 44 of itraconazole treatment alone, the lesions became severely crusted, demonstrating no improvements. Thus, 250 mg of oral terbinafine was added to the treatment regimen. On day 60 of itraconazole use, a skin biopsy was performed. Grocott silver stain revealed rare samples of fungal structures [Figure 4]. Histopathology showed acanthosis of the epidermis, areas with perivascular mononuclear inflammatory infiltrate and fibrosis [Figure 5]. On day 226 of itraconazole and day 182 of terbinafine use, clinical improvement was noted, indicating the end of oral antifungal drugs [Figure 6]. The patient underwent Laser Erbium YAG, an ablative laser, to achieve favorable aesthetic results for the scar and uniformization of the skin of the nasal region.Figure 1: Infiltrated erythematous nodules of sporotrichosis on the nose with verrucous appearanceFigure 2: Culture at 25°C, showing colonies of membranous, beige, wrinkled with a blackened halo, resembling Sporothrix speciesFigure 3: The hyaline septate hyphae of Sporothrix spp. with one pyriform microconidia in daisy arrangement (lactophenol cotton blue stain, ×40)Figure 4: Grocott silver stain presenting a fungal structures (40x)Figure 5: Acanthosis of the epidermis, areas with perivascular mononuclear inflammatory infiltrate, and intense remodeling of dermal collagen with fibrosis. (H and E, 10x)Figure 6: Clinical improvement after terbinafine and itraconazole use. Only residual erythema, papules and nodulesSporotrichosis is a subcutaneous mycosis caused by a thermodimorphic fungus, Sporothrix spp., most commonly S. brasiliensis, S. schenckii, and S. globosa.[1] The lesions manifest in different clinical forms: mainly lymphocutaneous, fixed, cutaneous, disseminated, and extracutaneous. Recently, the incidence of various diseases caused by Sporothrix has been increasing in Brazil, particularly a high disease rate in urban areas. Felines have been reported as a new source of infection that spreads diseases.[2] Itraconazole is a first-line treatment for Sporothrix, but some strains, mainly S. brasiliensis, are resistant.[3–5] Moreover, itraconazole content sometimes does not match the concentrations indicated by manufacturers.[3] Itraconazole has certain pharmacokinetic concerns because of several drug interactions. For example, a high gastric pH reduces its bioavailability. Terbinafine is an alternative drug that can effectively treat cutaneous sporotrichosis, and it is affordable and has fewer interactions with other drugs.[1,4,5] To improve therapeutic outcome, itraconazole has been combined with a second drug and demonstrated good results, for example, with supersaturated potassium iodide (SSKI) solution.[6] SSKI is an alternative for cutaneous forms, which is primarily used for infants. However, compared with terbinafine, SSKI has side effects and issues, such as a lack of standardized commercial formulation and unknown mechanisms of action.[1,4] Studies describing the use of itraconazole with terbinafine are limited. In vitro, terbinafine and itraconazole have synergistic effects because both disrupt ergosterol synthesis in the cell membrane of fungi at different stages. This mechanism is beneficial due to accelerated response against chromoblastomycosis, onychomycosis, and sporotrichosis, where facial lesions can cause aesthetic stigmas and affect the quality of life of patients. In conclusion, the combination of terbinafine and itraconazole can effectively inhibit disease progression faster and thus prevent excessive fibrosis and scars.[5,7–10] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

A pharmacovigilance study of terbinafine indication and liver enzyme elevation

To the Editor: Terbinafine is a commonly administered oral and topical antifungal medication. Terbinafine oral treatment regimens are based on the site of infection; nail infections often require a 6 to 12-week treatment schedule, but non-nail (ie, skin or hair) infections can usually be treated for 2 to 6 weeks. While it is commonly regarded that terbinafine-induced liver injury occurs within 30 days,1Maxfield L, Preuss CV, Bermudez R. Terbinafine. [Updated 2021 Aug 31]. In: StatPearls [Internet]. StatPearls Publishing; 2022 January. Accessed July 14, 2022. https://www.ncbi.nlm.nih.gov/books/NBK545218/Google Scholar we hypothesize that indications necessitating longer treatment durations are more likely associated with liver injury/liver enzyme elevation (LEE) events. To analyze this question, we computed a reporting odds ratios (ROR) using drug-event reports extracted from both the FDA Adverse Drug Event Reporting System (FAERS) and Canada Vigilance Adverse Reaction Online (CVARO) databases. It is important to highlight that one of the limitations of these commonly used databases is that the data entered by physicians or pharmaceutical companies is not corroborated or confirmed independently. Raw database files were downloaded from: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html (USA) and https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/adverse-reaction-database/canada-vigilance-online-database-data-extract.html. The FAERS database included reports logged between January 1, 2014, and December 31, 2020. The CVARO database included all publicly available reports from 1965 to September 2021 inclusively. To capture all terbinafine-associated drug reports, we searched both databases using “%terbinafine%” and “%lamisil%” (% represents a wildcard modifier) terms. Additionally, we made sure to exclude topical terbinafine preparations from the search results. Adverse events are encoded in both databases using MedDRA’s list of accepted terminologies. There was a total of 21,034 and 3913 oral terbinafine-associated adverse drug reaction reports in both the FAERS and CVARO databases, respectively. Notably, 247 (FAERS) and 125 (CVARO) of these reports were related to LEE events. Unfortunately, the degree of LEE (eg, 2-fold vs. 100-fold) or its clinical significance is not detailed in the databases. Furthermore, details on other possible interacting medications that patients might be taking are not available from these sources. Following data extraction, the ROR, a classically accepted method of signal generation for common adverse drug reactions in pharmacovigilance studies, was computed.2Rothman K.J. Lanes S. Sacks S.T. The reporting odds ratio and its advantages over the proportional reporting ratio.Pharmacoepidemiol Drug Saf. 2004; 13: 519-523https://doi.org/10.1002/pds.1001Google Scholar, 3Sakaeda T. Tamon A. Kadoyama K. Okuno Y. Data mining of the public version of the FDA adverse event reporting system.Int J Med Sci. 2013; 10: 796-803https://doi.org/10.7150/ijms.6048Google Scholar Table I demonstrates the RORs for terbinafine and LEE events and is further stratified by indication. Isoniazid, a well-known hepatotoxic agent, was used as a comparator to better contextualize the magnitude of terbinafine-LEE associated RORs.Table IROR for terbinafine-LEE reports according to indicationVariables assessedFAERS ROR (CI)CVARO ROR (CI)Terbinafine-LEE ReportsNon-Onychomycosis1.71 (1.07-2.72)1.51 (0.37-6.09)Terbinafine-LEE ReportsNail Infections4.58 (3.84-5.46)4.51 (2.64-7.68)Isoniazid-LEE Reports5.35 (5.06-5.67)5.51 (5.00-6.07)RORs are listed for terbinafine and onychomycosis and non-onychomycosis indications. In brackets are each ROR’s confidence intervals. FDA adverse event reporting system and Canada Vigilance Adverse Reaction Online RORs are listed in their respective columns.CVARO, Canada Vigilance Adverse Reaction Online; FAERS, FDA Adverse Drug Event Reporting System; LEE, liver enzyme elevation; ROR, reporting odds ratio. Open table in a new tab RORs are listed for terbinafine and onychomycosis and non-onychomycosis indications. In brackets are each ROR’s confidence intervals. FDA adverse event reporting system and Canada Vigilance Adverse Reaction Online RORs are listed in their respective columns. CVARO, Canada Vigilance Adverse Reaction Online; FAERS, FDA Adverse Drug Event Reporting System; LEE, liver enzyme elevation; ROR, reporting odds ratio. Terbinafine-LEE RORs were more than 2-fold higher for onychomycosis versus non-onychomycosis (ie, skin and nail) infections in both FAERS and CVARO databases (Table I, Supplementary Table I, available via Mendeley at https://doi.org/10.17632/n8pkb4tzyz.1). Additionally, onychomycosis-indicated LEE RORs more closely approximated isoniazid-LEE RORs compared with non-onychomycosis-LEE RORs in both databases, possibly suggesting a greater likelihood of LEE and liver injury with longer terbinafine use. Our analysis suggests a possible relationship between liver injury and longer usage of terbinafine, which is comparable to that of isoniazid, where older patients undergo monthly blood tests to evaluate for this idiosyncratic event.4Gray E.L. Goldberg H.F. Baseline abnormal liver function tests are more important than age in the development of isoniazid-induced hepatoxicity for patients receiving preventive therapy for latent tuberculosis infection.Intern Med J. 2016; 46: 281-287https://doi.org/10.1111/imj.12979Google Scholar As a result, we emphasize the importance of further investigating this potentially duration-sensitive adverse drug reaction, assessing its clinical significance and impact on patients to better direct clinicians in the safe prescribing of terbinafine in populations at higher risk of liver-related injuries and complications. None disclosed.

Analysis of utilization, cost and, prescription trends of onychomycosis medications among Medicare patients

To the Editor: Oral terbinafine and itraconazole as well as topical ciclopirox, efinaconazole, and tavaborole solutions have been approved by the US Food and Drug Administration for onychomycosis treatment.1Lipner S.R. Pharmacotherapy for onychomycosis: new and emerging treatments.Expert Opin Pharmacother. 2019; 20: 725-735Crossref PubMed Scopus (21) Google Scholar,2Lipner S.R. Scher R.K. Onychomycosis: treatment and prevention of recurrence.J Am Acad Dermatol. 2019; 80: 853-867Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Our objectives were to analyze onychomycosis antifungal prescription cost and trends in utilization by dermatologists. Medicare provider utilization and payment data, part D, 2013-2018,3Medicare provider utilization and payment data: part D [database].https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Medicare-Provider-Charge-Data/Part-D-PrescriberDate accessed: December 15, 2020Google Scholar were searched for oral terbinafine and itraconazole as well as topical ciclopirox, efinaconazole, and tavaborole prescribed by US dermatologists. Other provider types were excluded. Microsoft Excel was used to perform data analysis. Supply day was calculated by dividing the dispensed amount by the maximum medication used in 1 day. Total cost was calculated as cost per supply day multiplied by the number of supply days. Among oral antifungals, terbinafine claims experienced an annual average growth rate of 6.7%, with total spending increased by 15.1%, during 2013-2018 (Table I). This increase in claim outpaced the corresponding increase in total spending because of decreased cost per supply day ($0.36 to $0.24) (Table II). Comparatively, on average, itraconazole use was 150-fold lower than terbinafine use, with claims peaking in 2014, then decreasing by 0.9% annually, with total spending decreased by 35.6% overall (Table I). Itraconazole cost per supply day decreased by 7.4% during the study period (Table I).Table ITotal number of claims, drug supply days, and cost of oral terbinafine, oral itraconazole, topical ciclopirox, topical efinaconazole, and topical tavaboroleTotal number of claimsYearTerbinafineItraconazoleCiclopiroxEfinaconazoleTavaborole201328,86324978,77300201430,34029685,885940201531,89224288,1692343312201635,30213695,6181688401201737,554225108,8841518253201839,990209119,3821839199Total drug supply daysYearTerbinafineItraconazoleCiclopiroxEfinaconazoleTavaborole2013905,84555071,929,303002014964,00062442,149,1572641020151,023,05247492,246,03370,63010,00820161,156,63525852,490,64055,09512,47620171,233,47245612,888,04749,433738220181,338,74938323,220,61156,5806155Total Cost, $YearTerbinafineItraconazoleCiclopiroxEfinaconazoleTavaborole2013307,332.646,793.24,798,218.70.00.02014283,302.657,236.05,024,159.753,858.40.02015258,128.548,492.34,518,402.01,507,515.8339,722.62016311,248.124,785.74,752,927.41,361,291.7475,897.22017315,195.635,921.45,379,693.41,333,304.5311,679.72018353,805.630,145.55,625,524.21,665,178.7297,213.5 Open table in a new tab Table IICost per supply day of oral terbinafine, oral itraconazole, topical ciclopirox, topical efinaconazole, and topical tavaboroleYearCost per supply day terbinafine, $20130.3420140.2920150.2520160.2720170.2620180.26YearCost per supply day itraconazole, $20138.5020149.17201510.2120169.5920177.8820187.87YearCost per supply day ciclopirox, $20132.5020142.3020152.0020161.9020171.9020181.70YearCost per supply day efinaconazole, $2013None201420.40201521.30201624.70201727.00201829.40YearCost per supply day tavaborole, $2013None2014None201533.90201638.10201742.20201848.30 Open table in a new tab Among topical antifungals, ciclopirox claims experienced an annual average growth rate of 8.7%, with total spending increased by 66.9% overall (Table I). This increase in claim outpaced the increase in spending because of decreased cost per supply day ($2.50 to $1.70) (Table II). Efinaconazole claims peaked in 2015 and then decreased by 5.6% annually (Table I). However, both the total cost and cost per supply day increased yearly by 3091% and 144%, respectively, during 2014-2018 (Table II). Tavaborole claims decreased by 0.9% annually during 2015-2018, and the total cost decreased by 12.5% (Table I). Tavaborole cost per supply day increased by 42.4% annually during 2014-2018 (Table II). During 2013-2018, dermatologists had increased overall prescriptions of terbinafine and ciclopirox in the Medicare population, outpacing Medicare enrollment growth (14.3% increase during 2013-2018).4Centers for Medicare and Medicaid ServicesTwelve-year ever-enrolled trends report (2006-2018 data).https://www.cms.gov/Medicare-Medicaid-Coordination/Medicare-and- Medicaid-Coordination/Medicare-Medicaid-Coordination-Office/DataStatisticalResources/Downloads/MedicareMedicaidDualEnrollmentEverEnrolledTren dsDataBrief2006-2018.pdfDate: 2020Date accessed: December 15, 2020Google Scholar The reasons are likely multifactorial, including easy accessibility, availability of generics, low costs, and excellent safety profiles and efficacies.5Lin K. Lipner S.R. Modeling of usage and estimation of cost for efinaconazole 10% topical solution in the treatment of onychomycosis.J Am Acad Dermatol. 2020; 83: 227-228Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Itraconazole claims did not increase, likely because of higher cost, frequent drug-drug interactions, and unfavorable safety profile compared with that of terbinafine. Although efinaconazole and tavaborole have no reported systemic adverse events, their claims remained relatively flat, likely because of higher cost and lower accessibility and efficacy compared with those of alternatives. Future prescribing patterns will likely change because of patent expirations, availability of lower-priced generics, new antifungal approvals, and the development of devices for onychomycosis treatment. Our study included only Medicare patients, with the exclusion of Medicare Advantage, Medicaid, private insurance plans, and self-pay patients. The database includes only dermatologists who prescribe a medication ≥10 times, limiting our analysis. Because onychomycosis is the most common nail disease seen in clinical practice and Medicare enrollment continues to increase,4Centers for Medicare and Medicaid ServicesTwelve-year ever-enrolled trends report (2006-2018 data).https://www.cms.gov/Medicare-Medicaid-Coordination/Medicare-and- Medicaid-Coordination/Medicare-Medicaid-Coordination-Office/DataStatisticalResources/Downloads/MedicareMedicaidDualEnrollmentEverEnrolledTren dsDataBrief2006-2018.pdfDate: 2020Date accessed: December 15, 2020Google Scholar treatment choices will have a greater impact on health care costs. Dermatologists should consider clinical presentations, comorbidities, efficacy, safety profile, and cost while prescribing therapy for onychomycosis. Further research should focus on utilization, cost, and prescriptions trends in addition to onychomycosis patients with other insurances. Dr Lipner has served as a consultant for Verrica, Hoth Therapeutics, and Ortho-dermatologics. Dr Wang has no conflicts of interest to declare.

Retraction of "Rhabdomyolysis and Acute Kidney Injury Associated With Terbinafine Use: A Case Report".

[This retracts the article DOI: 10.1177/2054358120951371.].

Evaluation of Association Between Oral and Topical Terbinafine Use in Pregnancy and Risk of Major Malformations and Spontaneous Abortion

Terbinafine is a commonly used antifungal agent, but safety data of its use in pregnancy are limited. To examine the association between oral and topical terbinafine exposure in pregnancy and the risk of major malformations and spontaneous abortion. A nationwide, registry-based cohort study was conducted in Denmark from January 1, 1997, to December 31, 2016, in a cohort of 1 650 649 pregnancies. Data analysis was performed from July 11 to October 20, 2019. Pregnancies were matched on propensity scores comparing oral terbinafine exposed vs unexposed (1:10 ratio), topical terbinafine exposed vs unexposed (1:10), and oral vs topical terbinafine exposed (1:1). Filled prescriptions for oral or topical terbinafine. Logistic regression was used to compute prevalence odds ratios for the primary outcome of major malformations and Cox proportional hazards regression was used to compute hazard ratios for the secondary outcome of spontaneous abortion. Based on a cohort of 1 650 649 pregnancies, oral terbinafine-exposed (n = 891 pregnancies; mean [SD] age, 30.4 [6] years) and topical terbinafine-exposed (n = 3174; mean [SD] age, 29.5 [5.4] years) pregnancies were identified; up to a total of 40 650 unexposed pregnancies were included for the matched outcome analyses. In propensity-matched comparisons of the risk of major malformations, the prevalence odds ratios were 1.01 (95% CI, 0.63-1.62) for oral terbinafine-exposed vs unexposed pregnancies (absolute risk difference [ARD], 0.04%; 95% CI, -1.69% to 1.76%), 1.08 (95% CI, 0.81-1.44) for topical terbinafine-exposed vs unexposed pregnancies (ARD, 0.26%; 95% CI, -0.73% to 1.26%), and 1.18 (95% CI, 0.61-2.29) for oral vs topical terbinafine-exposed pregnancies (ARD, 0.59%; 95% CI, -1.71% to 2.88%). For the risk of spontaneous abortion, the hazard ratios were 1.06 (95% CI, 0.86-1.32) for oral terbinafine-exposed vs unexposed pregnancies (ARD, 0.13%; 95% CI, -1.97% to 2.24%), 1.04 (95% CI, 0.88-1.21) for topical terbinafine-exposed vs unexposed pregnancies (ARD, 0.17%; 95% CI, -0.64% to 0.98%), and 1.19 (95% CI, 0.84-1.70) for oral vs topical terbinafine-exposed (ARD, 1.13%; 95% CI, -2.23% to 4.50%) pregnancies. Among pregnancies exposed to oral or topical terbinafine, no increased risk of major malformations or spontaneous abortion was identified.

An Implementation and Visualization of the Tree-Based Scan Statistic for Safety Event Monitoring in Longitudinal Electronic Health Data.

Longitudinal electronic healthcare data hold great potential for drug safety surveillance. The tree-based scan statistic (TBSS), as implemented by the TreeScan® software, allows for hypothesis-free signal detection in longitudinal data by grouping safety events according to branching, hierarchical data coding systems, and then identifying signals of disproportionate recording (SDRs) among the singular events or event groups. The objective of this analysis was to identify and visualize SDRs with the TBSS in historical data from patients using two antifungal drugs, itraconazole or terbinafine. By examining patients who used either itraconazole or terbinafine, we provide a conceptual replication of a previous TBSS analyses by varying methodological choices and using a data source that had not been previously used with the TBSS, i.e., the Optum Clinformatics™ claims database. With this analysis, we aimed to test a parsimonious design that could be the basis of a broadly applicable method for multiple drug and safety event pairs. The TBSS analysis was used to examine incident events and any itraconazole or terbinafine use among US-based patients from 2002 through 2007. Event frequencies before and after the first day of drug exposure were compared over 14- and 56-day periods of observation in a Bernoulli model with a self-controlled design. Safety events were classified into a hierarchical tree structure using the Clinical Classifications Software (CCS) which mapped International Classification of Diseases, 9th Revision (ICD-9) codes to 879 diagnostic groups. Using the TBSS, the log likelihood ratio of observed versus expected events in all groups along the CCS hierarchy were compared, and groups of events that occurred at disproportionally high frequencies were identified as potential SDRs; p-values for the potential SDRs were estimated with Monte-Carlo permutation based methods. Output from TreeScan® was visualized and plotted as a network which followed the CCS tree structure. Terbinafine use (n = 223,968) was associated with SDRs for diseases of the circulatory system (14- and 56-day p = 0.001) and heart (14-day p = 0.026 and 56-day p = 0.001) as well as coronary atherosclerosis and other heart disease (14-day p = 0.003 and 56-day p = 0.004). For itraconazole use (n = 36,025), the TBSS identified SDRs for coronary atherosclerosis and other heart disease (p = 0.002) and complications of an implanted or grafted device (14-day p = 0.001 and 56-day p < 0.05). Use of both drugs was associated with SDRs for diseases of the digestive system at 14days (p < 0.05) and this SDR had been observed among terbinafine users in a previous TBSS analysis with a different data source. The TreeScan® visualization facilitated the identification of the atherosclerosis and other heart disease SDRs as well as highlighting the consistency of the SDR for diseases of the digestive system across drugs and data sources. With the TBSS, we identified potential SDRs related to the circulatory system that may reflect the cardiac risk that was described in the itraconazole product label. SDRs for diseases of the digestive system among terbinafine users were also reported in a previous signal detection analysis, although other SDRs from the previous publications were not replicated. The TBSS visualizations aided in the understanding and interpretation of the TBSS output, including the comparisons to the previous publications. In this conceptual replication, differences in the results observed in our analysis and the previous analyses could be attributable to variation in modeling and design choices as well as factors that were intrinsic to the underlying data sources. The broad consistency, but far from perfect concordance, of our results with the known safety profile of these antifungals including the risks from the itraconazole product label supports the rationale for continued investigations of signal detection methods across differing data sources and populations.

Prototheca wickerhamii in a dog with cutaneous, ocular and systemic manifestations and treatment with terbinafine

A two-year-old intact female collie presented with a tentative diagnosis of systemic blastomycosis based on compatible clinical signs and history and a positive urine Blastomyces antigen enzyme immunoassay. The dog...

Aplastic anemia associated with oral terbinafine: a case report and review of the literature.

Onychomycosis (OM) is a common fungal infection of the toenails and/or fingernails that is highly prevalent in the general population and also responsible for significant morbidity. OM is caused by dermatophytes, nondermatophytic molds, or yeast. Today systemic antifungal agents are considered as the gold standard for all types of OM. Here we report a case of aplastic anemia associated with oral terbinafine use and a review of the literature on hematological toxicities associated with terbinafine.

Hearing Impairment Associated with Oral Terbinafine Use

The Netherlands Pharmacovigilance Centre Lareb received reports of six cases of hearing impairment in association with oral terbinafine use. This study describes these cases and provides support for this association from the Lareb database for spontaneous adverse drug reaction (ADR) reporting and from Vigibase™, the ADR database of the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre. The objective of the current study was to identify whether the observed association between oral terbinafine use and hearing impairment, based on cases received by Lareb, constitutes a safety signal. Cases of hearing impairment in oral terbinafine users are described. In a case/non-case analysis, the strength of the association in Vigibase™ and the Lareb database was determined (date of analysis August 2011) by calculating the reporting odds ratios (RORs), adjusted for possible confounding by age, sex and ototoxic concomitant medication. For the purpose of this study, RORs were calculated for deafness, hypoacusis and the combination of both, defined as hearing impairment. In the Lareb database, six reports concerning individuals aged 31-82 years, who developed hearing impairment after starting oral terbinafine, were present. The use of oral terbinafine was disproportionally associated with hypoacusis in both the Lareb database (adjusted ROR 3.9; 95% CI 1.7, 9.0) and in Vigibase™ (adjusted ROR 1.7; 95% CI 1.0, 2.8). Deafness was not disproportionally present in either of the databases. Based on the described cases and the statistical analyses from both databases, a causal relationship between the use of oral terbinafine and hearing impairment is possible. The mechanism by which terbinafine could cause hearing impairment has not been elucidated yet. The pharmacological action of terbinafine is based on the inhibition of squalene epoxidase, an enzyme present in both fungal and human cells. This inhibition might result in a decrease in cholesterol levels in human cells, among which are the outer hair cells of the cochlea. It may be possible that the reduction in cochlear cholesterol levels leads to impaired cochlear function and possibly hearing impairment. In this study we describe hearing impairment as a possible ADR of oral terbinafine, based on six case reports and statistical support from Vigibase™ and the Lareb database. To our knowledge this association has not been described before.

Hearing Impairment Associated with Oral Terbinafine Use

Background: The Netherlands Pharmacovigilance Centre Lareb received reports of six cases of hearing impairment in association with oral terbinafine use. This study describes these cases and provides support for this association from the Lareb database for spontaneous adverse drug reaction (ADR) reporting and from Vigibase™, the ADR database of the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre.

Oral terbinafine use may be linked to hearing impairment

Oral terbinafine use may be linked to hearing impairment

European Surveillance of Antimicrobial Consumption (ESAC): outpatient systemic antimycotic and antifungal use in Europe

To assess the total outpatient systemic antimycotic and antifungal use in Europe, and to identify the antimycotic and antifungal substances most commonly used. Within ESAC (www.esac.ua.ac.be), using the anatomical therapeutic chemical (ATC) and defined daily dose (DDD) classification, data on outpatient use of all 14 antimycotics (12) and antifungals (2) for systemic use (ATC J02 and D01B, respectively), aggregated at the level of the active substance, were collected for 2007. Use was expressed in DDD (WHO ATC/DDD, version 2008) per 1000 inhabitants per day (DID). Only countries for which data on both J02 and D01B use were available were included in the analysis. In 20 European countries (data for Cyprus and Estonia include hospital use), total outpatient systemic antimycotic and antifungal use varied by a factor of 6.7 between the country with the highest (3.03 DID in Belgium) and the country with the lowest (0.45 in Croatia) use. Terbinafine, ketoconazole, itraconazole and fluconazole represented >94% of the total outpatient antimycotic and antifungal use in all countries. Terbinafine use represented >50% of the total systemic antimycotic and antifungal use in 16 out of 20 countries (not in Croatia, Italy, Luxembourg and Bulgaria). We present for the first time a standardized and validated data set of outpatient systemic antimycotic and antifungal use in Europe. Our study demonstrates a variation of antimycotic and antifungal use in Europe, as striking as that of antibiotic use. The ESAC data facilitate the auditing of antimycotic and antifungal prescribing, and the evaluation of the implementation of guidelines and public health policies to promote their judicious use.

Toenails and agranulocytosis

The objective of this article was the study of 12 cases of granulocytopenia associated with terbinafine use in Australia, the most recent, with agranulocytosis, which is described in detail. The mean age of the participants was 64 years (range 35-79 years). Sex was reported in 11 patients and all but one was a woman. Time to onset of neutropenia/agranulocytosis was 4-5 weeks in most cases. Neutropenia was typically severe with neutrophil counts < or = 0.3 x 10(3)/mm3 in all but 3 of 11 patients where counts were given. Terbinafine was stopped in all patients, five were hospitalized and one died of septic shock. Six patients received antibiotics and three were given granulocyte colony stimulating factor. Terbinafine, indicated for the treatment of onychomycosis and ringworm, may rarely be associated with granulocytopenia, which is typically severe. It takes approximately 1 month or longer for the development of manifestations of neutropenia, which include fatigue, fever, sore throat and mouth ulceration. Withdrawal of terbinafine and appropriate management of febrile neutropenia will probably result in a favourable outcome. Patients should be warned about this potentially life-threatening adverse reaction and the warning symptoms.

Objective Assessment of Terbinafine‐Induced Taste Loss

Terbinafine (Lamisil), a widely prescribed oral antifungal agent, reportedly induces taste loss in 0.6% to 2.8% of those taking the drug. However, many so-called taste problems reflect olfactory problems, and the sole empirical study published on this topic, based on whole-mouth testing of a single subject, found no terbinafine-related deficit. In this study, we quantitatively assessed, using well-validated taste and smell tests, chemosensory function in six patients complaining of taste disturbance after terbinafine treatment and compared their test scores to those of six age-, race-, and sex-matched normal controls. Taste function was measured using a 96-trial regional test that assesses sweet, sour, bitter, and salty taste perception within the anterior (cranial nerve [CN] VII) and posterior (CN IX) lingual taste bud fields. Smell function was bilaterally evaluated using the 40-item University of Pennsylvania Smell Identification Test. Taste function for sweet-, sour-, and bitter-tasting stimuli was significantly depressed in both the anterior and posterior lingual regions. For sodium chloride, the decrements were confined to the posterior region. Olfactory function was within normal limits. These findings 1) support anecdotal case reports of taste loss after terbinafine use, 2) demonstrate that all four major taste qualities are affected, and 3) suggest that olfactory dysfunction is not involved. Because self-report markedly underestimates chemosensory deficits, more extensive quantitative testing of patients receiving terbinafine will likely reveal a much higher prevalence of terbinafine-induced taste loss than currently reported. Since being older than 65 years of age and having a low body mass index are reportedly risk factors for terbinafine-induced taste loss, physicians should be particularly on the alert for elderly persons taking this medication who may become depressed or alter their food intake in response to decreased taste sensation.