Systemic antimycotics - side effects 
Review 
SIDE EFFECTS 
OF SYSTEMIC ANTIMYCOTIC TREATMENT 
M. Rogl Butina 
SUMMARY 
Fungal infections are common in humans and their prevalence is stili growing. Most mycotic infections of 
skin, mucosae and their appendages are very appropriate far topical treatment, but far certain clinical 
manifestations ( onychomycosis, tinea capi tis, chronically recidivating vaginal infections and extensive or very 
resistant glabrous skin infections, especially in immunocompromized patients) systemic antimycotic therapy 
seems to be the reasonable choice. The mechanisms of action of oral antifungals that are currently most often 
prescribed in Slovenia and their most common side effects are discussed: adverse events, asymptomatic 
elevations of !iver function tests, symptomatic !iver injury, side effects connected with cytochrome P450 and 
drug interactions. Finally we describe the recommendations about oral antimycotics during pregnancy and 
lactation and their possible interference with the activity of oral contraceptives. 
KEY WORDS 
systemic antimycotics, griseofulvin, itraconazole, jluconazole, terbinafine, adverse events, asymptomatic and 
symptomatic hepatic inju,y, cytochrome P450 enzymes, drug interactions. 
INTRODUCTION 
On the phylogenetical tree there exists a strong 
branch of fungi, consisting of more than 100 000 
species of dermatophytes, yeasts and moulds (1). 
Fungi are eukaryotes - they have a trne nucleus 
with a nuclear membrane, cytoplasmatic membrane, 
and a special celi wall containing chitin. 
Fungal infections are common in humans and 
their prevalence is even growing. Aging of the 
population and expansion of the immunocompromised 
acta dennatovenerologica A.P.A. Vol 7, 98, No 3-4 
population - either because of the underlying illness 
or caused iatrogenetically - are factors that contribute 
most to it. Certainly fungal infections of skin, mucosae 
and their appendages are appropriate far topical 
treatment, but in some situations systemic antimycotic 
therapy has advantages. Fungal infections of deep 
skin layers are often difficult to reache by· local 
antimycotics in efficient concentrations. Topical agents 
can not - with few exceptions - penetrate hair or 
139 
Systemic antimycotics - side effects 
Table l. Laboratory monitoring: Suggested guidelines (6). 
Terbinafine Baseline, repeat monthly Baseline, repeat monthly 
Continuous therapy >4 weeks 
Itraconazole 
Continuous therapy >4 weeks 
Itraconazole 
Pulse therapy 
Fluconazole 
Pulse therapy 
nails, often there are also problems with the vagina! 
wall. Not so rarely there is a problem of patient 
compliance: with awkwardly located lesions or 
prolonged topical treatment compliance is usually 
quite low, some patients even find topical treatment 
cosmetically unacceptable. It seems that oral therapy 
is a reasonable choice in the treatment of onycho-
mycosis, tinea capitis, chronic recidivant vagina! 
infections, and prolonged, extensive, or very resistant 
fungal skin infections. 
What do we expect from antiinfective agents? 
Ideally they should eradicate the infective organism 
without affecting the normal functioning of the host. 
But ideals are hard to reach and we speak of a 
good or successful drug when the balance is strongly 
against the infective organism and in favor of the 
host. This is usually achieved by exploiting differences 
in their structure and function. As already mentioned, 
fungi and humans are eukaryotes, which means they are 
quite similar at the cellular biochemical leve!. Although 
the precise structures of enzymes are species-, organ-
and even membrane-specific, agents which react 
with some fungal enzyme, may at least minimally 
influence the related human enzymes, too. 
MECHANISMS 
In this article we will discuss the side effects of 
systemic antimycotics which are currently most often 
used in Slovenia in the treatment of fungal skin 
infections. These are griseofulvin as the representative 
of the older generation, the new azoles - itraconazole 
and fluconazole and oral allylamin compound -
terbinafine. They have different sites of action (2): 
griseofulvin acts in the nucleus, it interferes with 
140 
Baseline, repeat monthly 
One pulse not indicated; 
Two or three pulses - no specific 
recommendations 
No specific recommendations 
microtubule structure and function, and thus inhibits 
mitosis. The other three are active at the leve! of 
the celi membrane, they inhibit ergosterol biosynthesis 
at two different points: azoles disrupt celi membrane 
biosynthesis by inhibition of cytochrome P 450 
activation of lanosterol demethylase; terbinafine inhibits 
the enzyme squalene epoxidase leading not only to 
ergosterol depletion but also to squalene accumulation 
which is supposed to act toxically on the celi. 
SIDE EFFECTS 
Systemic antimycotic drugs can, as any other drug, 
exert side effects either in a direct or indirect way. 
The drug itself may directly affect a physiological 
function or act indirectly - through its metabolites, 
haptens, or drug interactions. They can cause celi 
injury, suppress or induce different metabolic processes 
and/or immunological reactions (3). With oral anti-
mycotics we most often observe the following: 
a) different adverse effects 
b) asymptomatic elevations of !iver function tests 
and symptomatic hepatic injury 
c) effects connected with mammalian cytochrome P 
450 enzymes 
d) drug interactions 
Adverse events (AE) 
AEs may occur with any antimycotic, the exact 
numbers differ in different studies and publications 
(griseofulvin from 13.0 - 20.3% (4) , itraconazole 7.0 
- 12.5%, fluconazole 12.6%, terbinafine 10.0 - 12.0% 
(5)). Oral antimycotics seem to induce similar types 
acta dermatovenerologica A.P.A. Vol 7, 98, No 3-4 
Systemic antimycotics - side effects 
of mainly minor adverse events. 
Gastrointestinal AEs mostly include nausea, abdo-
minal pain, dyspepsia, rarely vomiting or diarrhoea. 
In connection with the nervous system, headaches, 
dizziness, and paraesthesias are mainly quoted. Skin 
symptoms vary from pruritus to maculopapular 
exanthemas or urticaria. 
Asymptomatic elevations of liver 
function tests 
Asymptomatic (pathologic) elevations of liver function 
tests (LFTs) do occur (from 0.1 % with pulse 
itraconazole therapy, 3.0% with terbinafine, 3.3% 
with fluconazole and 4.0% with continuous itraconazole 
therapy and griseofulvin) but are usually reversible 
(6,7). However, when impairment is noted, LFTs 
should be repeated after a week, because the elevation 
may mirror an early onset of hepatotoxicity. 
Symptomatic hepatic injury 
Symptomatic hepatic injury may present as hepato-
cellular, cholestatic or mixed injury. The risk that it 
will develop is actually very low, but it is still a 
source of fear among physicians. It is important to 
know that it has been reported with every available 
antirnycotic, but etiopathogenetically it is generally 
idiosyncratic and also not predictable. According to 
the WHO statistics most of the reported reactions 
developed between the second and the sixth week 
of treatment. 
Only isolated cases connected to griseofulvin were 
reported and probably all were idiosyncratic. Associ-
ation between ketoconazole and hepatobiliary dys-
function was only 1:15000 but it further accentuated 
concern. No hepatotoxicity was associated with one-
week fluconazole pulse therapy. Severe hepatic 
reactions described in association with continuous 
therapy usually occurred in patients already affected 
by an underlying illness. Five cases of reversible 
idiosyncratic hepatitis were connected with itraconazole, 
in all instances with continuous therapy. For 
terbinafine, seven cases of idiosyncratic hepatobiliary 
disorders were reported, six were reversible and in 
one patient !iver function tests remained persistently 
elevated. 
Being aware of these facts a physician must diffe-
rentiate when monitoring LFTs is necessary on 
scientific grounds and when it is performed mostly 
for medicolegal purposes. It is important however, 
to exclude pre-existing hepatic injury. For this reason 
acta dennatovenerologica A.P.A. Vol 7, 98, No 3-4 
an exact history and baseline LFTs are advisable, 
especially when starting a prolonged treatment with 
oral antimycotics (Tablel) (6). Probably of the same 
importance is patient's education concerning self-
observation. When a patient notices clinical signs of 
hepatobiliary dysfunction (malaise, nausea, vomiting, 
weakness, fatigue, anorexia, jaundice, dark urine, 
acholic stools, pruritus) he must visit his doctor 
immediately, the drug should be withdrawn and 
LFTs evaluated. 
Side effects related to human 
cytochrome P 450 
Cytochrome P 450 (CYP) enzymes are a very 
irnportant group of enzymes in eukaryotes. In humans 
two of their most important functions are metabolism 
of different endogenous and exogenous agents and 
synthesis of steroid hormones. Any drug with an 
affinity for human CYP enzymes may be associated 
with a certain toxicity. For example when ketoconazole 
has been used, hypoadrenalism, decreased libido, 
impotence and gynecomastia have been observed. 
Triazoles bind weakly and more selectively to the 
mammalian CYP enzymes and no side effects related 
to steroid hormones have been reported, but they 
may influence the metabolism of other drugs. 
Drug interactions 
Drug foteractions are a very important part of 
systemic antimycotics' side effects. The manner in 
which a drug or its metabolites can internet with 
other drugs are of course manifold, concerning oral 
antimycotics there exist two main mechanisms: 
competition for plasma proteins and inhibition or 
induction of CYP enzymes. There is also a third 
mechanism worth mentioning - guilt by association, 
where side effects expressed with older agents are 
automatically (or speculatively) connected to newer 
drugs, even when there are only little or no scientific 
data for such interference (8). 
Protein binding: most antifungals with the exception 
of fluconazole ( only 12% bound) (9) bind strongly 
to plasma proteins (griseofulvin 84%, itraconazole 
99.8%, terbinafine 99% ), and therefore compete 
with other drugs, which may bind to the same 
protein receptors. This can lead to elevated plasma 
concentrations of either substance and possib_ly to 
stronger effects than expected. Because of rapid 
compensatory homeostatic mechanisms this is usually 
only a transient event, but one has to be careful 
141 
Systemic antimycotics - side effects 
Table 2. Systemic antifungal (antimycotic) drugs and drug interactions (11). 
Barbiturates 
Alcohol 
Rifampicin 
Warfarin 
Oral hypoglycaemics 
Phenytoin 
Cyclosporin 
?H1-antagonists 
(terfenadine and 
astemizole) 
Warfarin ?Oral contraceptives 
Oral contraceptives 
Cyclosporine 
Rifampicin 
Isoniazid 
Phenytoin 
H
2
-antagonists 
( antacids and 
anticholinergics) 
Phenytoin 
Warfarin 
Cyclosporin 
H,-antagonists 
(terfenadine 
and astemizole) 
Oral hypoglycaemics 
Digoxin 
?Insulin 
?Corticosteroids 
?Chlordiazepoxide 
Antipyrine 
Oral contraceptives 
Rifampicin 
lsoniazid 
Phenytoin 
H
2
-antagonists 
( antacids and 
anticholinergics) 
Phenobarbitona 
Carbamazepine 
Rifampicin 
Phenobarbital 
Phenytoin None 
Warfarin 
Cyclosporin 
H
1 
-antagonists 
(terfenadine 
and astemizole) 
?Oral hypoglycaemics 
Digoxin 
?Insulin 
?Corticosteroids 
?Chlordiazepoxide 
Triazolam 
Felodipin 
Midazolam 
Cisapride 
Antipyrine 
?Oral contraceptives 
None 
when administering drugs with narrow therapeutic 
index, small volume distributions, or rapid onset of 
action. 
Influence on human cytochrome P 450 enzymes: 
CYP enzymes are a big family of heme-containing 
enzymes which catalyse reactions in the first phase 
of biotransformation of endogenous and exogenous 
agents, including various drugs. There are over 
hundred different, genetically determined enzymes 
located on the membrane of the reticular endoplasmatic 
system, which are classified into families (Arabic 
numbers) and subfamilies ( capi tal letters ), the most 
important being CYP lA, CYP 2C, CYP 2D and 
CYP 3A. Metabolism of many drugs starts with CYP 
enzymes, there may be activated only one or a few 
subfamilies. On the other hand there are many drugs 
that influence the cytochrome P 450 activity. Metabolism 
of antimycotics is usually not problematic and only 
142 acta de1matovenero/ogica A.P.A. Vol 7, 98, No 3-4 
Systemic antimycotics - side effects 
stronger CYP inducers can increase or decrease their 
plasma levels (for example the influence of cimetidin, 
rifampin and phenobarbital on terbinafine biotrans-
formation or influence of rifampin, phenitoin and 
phenobarbital on itraconazole metabolism). Table 2. 
More important is the fact that systemic antimycotics 
substantially interfere with CYP enzymes. The most 
important are azoles, which is understandable 
considering their mechanism of action. But again it 
should be stressed that newer agents act much 
more specifically and influence only specific subfamilies. 
Itraconazole for example is a strong inducer of 
CYP 3A enzyme subfamily ( therefore it diminishes 
biotransformation of cisapride, astemizole, cyclosporin, 
terfenadin) and does not influence CYP 2C or CYP 
lA subfamilies, which are for example connected 
with metabolism of sulfonylureas (10). Fluconazole 
in usual doses inhibits only CYP 2C subfamily but 
in larger doses also CYP 3A subfamily. Griseofulvin 
is an inducer of CYP 3A subfamily and can decrease 
plasma concentration of some drugs; most noteworthy 
are warfarin, cyclosporin and oral contraceptives. 
Terbinafine has practically no influence on the meta-
bolism of other drugs (Table 2) (11). 
Special side effects of quoted oral 
antimycotics 
Griseofulvin is derived from a fungus Penicillium 
griseofulvum and may as such crossreact with penicillin. 
Disulfiram-like reaction with alcohol ingestion, rare 
cases of neutropenia and splinter subungual haemorr-
hages were also reported. It was also connected 
with exacerbation of systemic lupus erythematosus 
and is contraindicated in porphyrias, especially in 
porphyria cutanea tarda, as it may increase the 
concentration of porphyrins in the liver and urine. 
Because of its antimitotic action it is strongly contra-
indicated during pregnancy and lactation. 
Itraconazole: animal studies on rats showed embryo-
toxicity, skeleta! malformations antl materna! toxicity 
so it is contraindicated during pregnancy, and contra-
ceptive precautions are advised during itraconazole 
treatment (12). There is no information about excretion 
in breast milk, but because of its lipid solubility it 
is contraindicated during breast-feeding too. 
Fluconazole: there is not much information about 
fluconazole and most side effects were reported in 
critically ill patients with many medicaments where 
it is hard to relate the side effect to a specific drug. 
Terbinafine: unusual but mostly reversible taste (0.7%) 
and smell (0.02%) disturbances were reported (13). 
Although animal studies showed no risk, it is contra-
indicated during pregnancy because no clinical expe-
rience in pregnant women is available. As it is 
excreted in breast milk it is also contraindicated 
during breast-feeding. 
All aforementioned systemic antimycotics are contra-
indicated during pregnancy; but as these agents in 
general cause some important drug interactions, 
concern arose about possible influence of oral anti-
mycotics on the oral contraceptive agents. The basic 
question is, whether oral contraceptives are efficient 
enough when taken together with a systemic 
antimycotic. At the 19th World Congress of Derma-
tology Del Rosso and al. (14) gave a review on 
available case reports and clinical studies. 
Griseofulvin: fifteen cases of breakthrough bleeding, 
five unexplained amenorrhoeas and two unintended 
pregnancies were reported in United Kingdom and 
the Netherlands. In a special study menstrual irregu-
larities have been reported and reproduced after 
rechallenge. Because of that combination, a combi-
ned treatment with griseofulvin and oral contra-
ceptives is best to avoid. 
Fluconazole is supposed to be probably safe in 
the usual doses, but some anecdotal reports of 
intermenstrual bleedings exist and minor fluctuations 
in ethinyl oestradiol and levonorgestrel (increased 
hormona! levels) were reported. 
ltraconazole is considered to be most probably 
safe; no changes in ethinyl oestradiol and even 
increased bioavailability of norethisterone were noticed 
(15). There is one report of unintended pregnancy. 
Terbinafine is also said to be probably safe, but 
caution is recommended because nine reports on 
breakthrough bleeding and one unintended pregnancy 
are available and no in vivo studies are known. 
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AUTIIOR'S ADDRESS 
144 
Mirjam Rogi Butina MD, Department of Dermatovenereology, University Medica! Centre Ljubljana, 
1525 Ljubljana, Zaloška 2, Slovenia. 
acta dennatovenerologica A.P.A. Vol 7, 98, No 3-4