Risk of serious skin disorders among users of oral antifungals. A population-based study.
Jordi Castellsague1, Luís-Alberto García-Rodríguez2, Alberto Duque1, Susana Pérez1
1 Novartis Global Epidemiology, Barcelona, Spain2 Spanish Centre for Pharmacopidemiologic Research (CEIFE), Madrid, Spain‘These authors contributed equally to this work’.Abstract Background
Serious skin disorders have been associated with the use of oral antifungals in a number of
case reports and series of cases. However the incidence of these disorders remains
We estimated the risk of serious skin disorders in a cohort of users of oral antifungals
identified in the general population of the General Practice Research Database in UK. The
cohort included 61,858 patients, 20 to 79 years old, who had received at least one
prescription for either oral fluconazole, griseofulvin, itraconazole, ketoconazole, or
The background rate of serious cutaneous adverse reactions (the one corresponding to non
use of oral antifungals) was 3.9 per 10,000 person-years (95% CI 2.9-5.2). Incidence rates
for current use were 15.4 per 10,000 person-years (1.9-55.7) for itraconazole, 11.1 (3.0-
28.5) for terbinafine, 10.4 (1.3-37.5) for fluconazole, and 4.6 (0.1-25.8) for griseofulvin.
Itraconazole was the antifungal associated with the highest relative risk, 3.9 (0.5-15.0),
when compared to the risk among non users, followed by terbinafine and fluconazole with
relative risks of 2.8 (0.7-7.8) and 2.6 (0.3-10.1), respectively. Conclusion
We conclude that cutaneous disorders associated with the use of oral antifungals in this
study were all of mild severity and that the risk associated with the use of oral antifungals
was slightly higher than the risk in non-users. The safety profile of terbinafine regarding
cutaneous disorders is similar to other antifungals and in the very low range of risks
Background
Serious skin disorders including toxic epidermal necrolysis, Stevens-Johnson syndrome,
erythema multiforme, angioedema and acute generalized exanthematous pustulosis have
been associated with the use of oral antifungals in a number of case reports and
retrospective series of cases. However, studies examining the risk associated with the use of
oral antifungal drugs are not available.
In the present study we estimated the risk of potentially serious skin disorders in a cohort of
users of oral antifungals identified in the general population of UK using the General
Population and methods Source population
The GPRD contains clinical computerized information entered in a standardized manner by
general practitioners (GPs) on their patients. Around 1,500 GPs, covering a population
exceeding 3 million, have agreed to provide systematically their data files anonymously to
the Office of National Statistics (ONS) and to allow the information to be used for research
purposes.(1) Upon receiving the data from the GPs, ONS organizes this information and
performs a series of quality checks. The computerized information includes demographics,
details of each visit, a summary of specialists' clinical notes and hospital letters, results of
laboratory tests and a free text section. A modification of the Oxford Medical Information
System (OXMIS) classification system is used to code specific diagnoses, and a drug
dictionary based on data from the Prescription Pricing Authority is used to code drugs.(2)
Prescriptions issued by the general practitioner are directly generated by the computer
system with dosage instructions included. Also, the indication for treatment is required for
all new courses of therapy. Recorded information can be validated and completed through
review of original paper-based medical records. Validation studies with the GPRD have
documented the recording of medical data in the GP’s computers to be near to
Study cohort
The study cohort comprised all patients aged 20-79 who had received at least one
prescription for either oral fluconazole, griseofulvin, itraconazole, ketoconazole, or
terbinafine between January 1, 1991 and March 31, 1997. We excluded all patients with a
prior history of diseases or conditions predisposing to cutaneous disorders including
neoplasms, AIDS, and systemic and immunosupressive disorders and therapies. Patients
with a previous history of skin disorders were similarly excluded. The final study cohort
was constituted by 61,858 patients. We followed-up each patient in the study cohort from
the date of the first antifungal drug prescription until the earliest occurrence of: a) code for
any of the study endpoints: toxic epidermal necrolysis, Stevens-Johnson syndrome,
erythema multiforme, angioedema, or acute generalized exanthematous pustulosis; b) one
of the exclusion conditions mentioned above; c) age greater than 80; d) death; or e) date of
Case definition and ascertainment
In a first step we identified potential cases through an automated search for the OXMIS
codes listed in table 1. The computerized information of these potential cases was manually
reviewed to discard patients with any of the study exclusion criteria: neoplasms, AIDS, and
systemic and immunosupressive disorders and therapies. The remaining cases were
validated through a structured questionnaire administered to the GPs along with review of
all medical records provided anonymously by the GPs. All the process of case identification
and validation was done blindly to the use of medications.
We defined as a case of potentially serious skin disorder any patient in the study cohort
with a first ever diagnosis of toxic epidermal necrolysis, Stevens-Johnson syndrome,
erythema multiforme, angioedema, or acute generalized exanthematous pustulosis,
recorded in the database during the study period. We required confirmation of the diagnosis
based on the questionnaire filled by the GP and the review of medical records when
Exposure definition
Person time at risk was aggregated in three different time windows according to use of the
study antifungal drugs. Current use encompassed all the days of prescribed treatment plus
an additional period of 14 days at the end of treatment. Past use was defined as the period
of 90 days following the time window of current use. Finally, the time period starting after
Analysis
Incidence rates of serious skin disorders were calculated using as denominator both the
number of patients exposed to each individual antifungal drug and the corresponding
person-time at risk. Ninety-five percent confidence intervals were computed on the basis of
a Poisson distribution of case counts within categories of use.(5) The Stata program was
used to obtain estimates of rate ratios.(6)
A total of 61,858 patients received 120,807 prescriptions for oral antifungals. The age and
sex distribution of the study cohort is presented in table 2. Fluconazole, itraconazole, and
ketoconazole were mainly prescribed to young women, whereas griseofulvin and
terbinafine were predominantly prescribed to middle aged men.
We identified 113 potential cases of serious skin disorders. Of these, 26 (23%) were
excluded after review of their computerized information. Medical records were requested to
the GPs for the remaining 87 patients. Review of medical records led to confirm 62 cases
and to exclude 25 additional patients. For three of these excluded patients medical records
were not available. The reasons of exclusion after the review of both computerized
information and medical records are summarized in table 3.
Of the 62 confirmed cases, 47 (76%) occurred during the period of non use of oral
antifungals, 6 (10%) during past use, and 9 (14%) during current use. Specific diagnostics
for the three categories of use are presented in table 4. Angioedema was the more frequent
disorder (65%), followed by erythema multiforme (21%). There were two cases of Stevens-
Johnson syndrome and one case of dermatitis exfoliative. No cases of toxic epidermal
necrolysis and acute generalized exanthematous pustulosis were identified. None of the 62
cases was life-threatening. Most cases (69%) were diagnosed and managed by the GP, 17
cases (27%) by the dermatologist, and two (3%) required hospitalization. These two cases
with hospitalization occurred among non-users of oral antifungals. Rates in non-users
The overall background rate corresponding to non-users of oral antifungals was 3.9 per
10,000 person-years (95% CI 2.9-5.2). Among non-users there were 32 (68%) cases with
angioedema, 13 (28%) with erythema multiforme, 1 (2%) with dermatitis exfoliative, and 1
(2%) Stevens-Johnson syndrome. Most cases (66%) were diagnosed and managed by the
general practitioner, 14 (30%) by the dermatologist and 2 (4%) required hospitalization.
These two last cases were hospitalized because of angioedema. The case with dermatitis
exfoliative was diagnosed by the general practitioner and the one with Stevens-Johnson
Rates in current users
For current users, two cases occurred during treatment with fluconazole (one angioedema
and one erythema multiforme), one with griseofulvin (angioedema), two with itraconazole
(one angioedema and one erythema multiforme) and four with terbinafine (two cases with
angioedema, one with erythema multiforme, and one with Stevens-Johnson syndrome)
(table 5). The case with Stevens-Johnson syndrome was diagnosed and managed by the
general practitioner without requiring hospitalization. Concurrent treatment with drugs
potentially related with serious skin disorders was found in two patients, both with
angioedema. One exposed to griseofulvine was taking cefalexine and diclofenac and the
other with current use of itraconazole was concurrently treated with prednisolone.
Incidence rates of serious cutaneous disorders for current use of individual antifungal drugs
are presented in table 6. The highest rate was for itraconazole (15.4 per 10,000 person-
years), followed by terbinafine (11.1 per 10,000 person-years), fluconazole (10.4 per
10,000 person-years), and griseofulvin (4.6 per 10,000 person-years). Itraconazole was the
antifungal drug associated with the greatest relative risk (3.9, 95% CI 0.5-15.0) compared
to the background risk of non users, followed by terbinafine (2.8, 95% CI 0.7-7.8) and
Rates in past users
Of the six cases with past use of oral antifungals four had been exposed to terbinafine (two
with angioedema and two with erythema multiforme) and two to fluconazole (one
angioedema and one erythema multiforme) (table 7). The number of days from the end of
treatment with oral antifungals to start of symptoms ranged from 16 to 77 for past users of
terbinafine. The number of days were 43 and 55 for the two past users of fluconazole.
Current use of other drugs potentially related with serious skin disorders was found in two
patients with past exposure to terbinafine and in one patient with past use of fluconazole.
The incidence rate of serious skin disorders for past users of terbinafine was 11.1 per
10,000 person-years (95% CI 3.0-28.3) and that for past users of fluconazole 2.1 (0.3-7.7).
The corresponding relative risk compared to the rate in non-users were 2.8 (1.0-7.8) for
terbinafine and 0.5 (0.1-2.2) for fluconazole (table 7). Discussion
In this study we estimated the risk of serious skin disorders in a cohorts of 61,858 users of
oral antifungals. Of the 62 confirmed cases 9 occurred among current users, 6 among past
users, and 47 among non-users of oral antifungals. The risk associated with individual
current use of antifungals, as compared to non-use, were 1.2 for griseofulvine, 2.6 for
fluconazole, 2.8 for terbinafine, and 3.9 for itraconazole. All these relative risks were based
on a very small number of exposed cases, between one and four, and the confidence
intervals were wide, not statistically significant, and overlapped among them.
The selected skin disorders assessed in this study are those commonly considered as
potentially severe or life-threatening. However, the potential for severity is highly variable
among the different disorders and also within a same condition. Toxic epidermal necrolysis
is perhaps the most severe dermatosis and we did not identify any case neither in exposed
Most of the cases identified in this study were not severe enough to require hospitalization
and none was life-threatening. Only two cases of angioedema, which occurred among non-
users of antifungals, had to be hospitalized. All exposed cases were treated by the general
practitioner or by the dermatologist. This indicates that severe, life-threatening skin
disorders associated with the use of oral antifungals are extremely rare.
A consideration to this study is the potential for misclassification of specific diagnostics.
Although cases identified were validated by asking to the corresponding general
practitioner confirmation of the diagnosis, we did not assess the clinical characteristics of
the specific skin disorder. This could result in misclassification of diagnostics particularly
among those cases not referred to the dermatologist. Also, some forms of cutaneous
reactions are sometimes difficult to differentiate among them specially in those cases with
mild severity. Thus, misclassification could occur between the diagnosis of erythema
multiforme and mild forms of Stevens-Johnson syndrome.
We defined current use of antifungals as all the days of prescribed treatment plus an
additional period of two weeks after the end of treatment. Most cutaneous adverse reactions
to drugs occur during the first three or four weeks of treatment.(7) With the additional
period of two weeks after the end of treatment we ensured the capture of disorders
appearing at the very end of treatment. For past use of oral antifungals we considered a
period of 90 days after the end of the current use time window. The rationale for including
a period of past use in pharmacoepidemiological studies is to examine drug effects with late
onset that is with a long latency period. However, it is considered that adverse cutaneous
reactions to drugs mainly occur during the period of active treatment. Thus, attribution of
cutaneous disorders to the past use of specific drugs is more problematic and difficult to
interpret than attribution to, active treatment.
Regarding terbinafine the risk of skin disorders was about three times higher than the risk
in non-users and similar to the risk of other antifungals. This relative risk lies in the very
low range of risks of severe skin disorders associated to other drugs. In an international
case-control study the drugs associated with the highest risk of hospitalization for Stevens-
Johnson syndrome and toxic epidermal necrolysis were antiepileptics (relative risk=242),
sulfonamides (RR=172), trimethroprim-sulfamethoxazole (RR=160), NSAIDS (RR=72),
chlormezanone (RR=62), corticosteroids (RR=54), allopurinol (RR=52), cephalosporins
(RR=14), quinolones (RR=10), tetracyclines (RR=8.1), and aminopenicillines
(RR=6.7).(8,9) The number of cases of Stevens-Johnson syndrome and epidermal
necrolysis attributable to these drugs ranged from 4.5 per million users of sulfonamides to
0.2 per million users of aminopenicillines. Conclusions
We conclude that cutaneous disorders associated with the use of oral antifungals in this
study were all of mild severity and that the risk associated with the use of oral antifungals
was slightly higher than the risk in non-users. The safety profile of terbinafine regarding
cutaneous disorders is similar to other antifungals and in the very low range of risks
Competing Interests
Jordi Castellsague, AlbertoDuque, and Susana Perez were employees of Novartis
Pharmaceuticals at the moment of conducting this study and writing the corresponding
Luís Alberto García-Rodríguez received a grant from Novartis Pharmaceuticals to conduct
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International Case-control Study on Severe Cutaneous Adverse Reactions: Lancet 1999
Table 1. OXMIS codes used for case identification OXMIS code Diagnosis Table 2. Age and sex distribution of the study cohort of users of oral antifungals* Fluconazole Griseofulvin Itraconazole Ketoconazole Terbinafine
* Some of the cohort members received more than one antifungal drug during the study period. Table 3. Exclusions after review of computer patient profiles and medical records
*One patient had a bronchogenic carcinoma and the otherwas HIV positive
Table 4. Serious skin disorders according to source of diagnosis Source of diagnosis Diagnosis Current use General practitioner Dermatologist Hospitalization Table 5. Characteristics of cases of serious skin disorders with current exposure to oral antifungals Current use Duration of Diagnosis Source of Co-medication treatment diagnosis potentially related with serious skin disorders Fluconazole Fluconazole Griseofulvin Itraconazole Itraconazole Terbinafine Terbinafine Terbinafine Terbinafine Table 6. Crude incidence rates of serious skin disorders among current users of oral antifungals Antifungal Patients Person-years Cumulative incidence Incidence rate Relative risk* per 10,000 patients per 10,000 person-years Fluconazole Griseofulvin Itraconazole Ketoconazole Terbinafine
CI=Confidence interval* Incidence rate ratio using non-use person-time as the reference category. Table 7. Characteristics of cases of serious skin disorders with past exposure to oral antifungals Duration of Days from last dose Dose Diagnosis Source of Current use with treatment intake to initial diagnosis drugs potentially symptoms related with serious skin disorders Fluconazole Fluconazole Terbinafine Terbinafine Terbinafine Terbinafine
Editors-in-Chief Editorial Staff Kevin J Tracey, MD Christopher J Czura The Feinstein Institute for Medical Research The Feinstein Institute for Medical Research Anthony Cerami, PhD Margot Gallowitsch-Puerta The Feinstein Institute for Medical Research Mollie Medcast Episode 10 Transcript: Sepsis, Cardiac Proinflammatory StressHello and welcome back to “Mollie Medca
Dear_______________________________ M.P./ Hon. Member/ Rt. Hon. Member (cc: Minister of Health, Leona Aglukkaq, Deputy Minister, Glenda Yeates) Please stop Health Canada (HC) from removing my access to more Natural Health Products (NHPs) without valid evidence of harm! Yet another valuable NHP called nattokinase is about to be refused. It has been consumed in fermented soybeans for more th