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A review of selected systemic antifungal

drugs for use in dogs and cats
Jan 01, 2008
By Butch KuKanich, DVM, PhD, DACVCP

ITRACONAZOLE
Itraconazole is preferred to ketoconazole for most fungal infections in people because of
its increased activity and decreased adverse effects.16 It is available as 100-mg capsules
and as a suspension (10 mg/ml). The capsules contain beads coated with itraconazole,
which facilitates drug absorption from the intestines. The use of compounded itraconazole
from bulk chemical is not recommended because of its low solubility and poor stability. The
commercially available formulations of itraconazole are incorporated into a hydroxypropyl-
beta-cyclodextrin carrier, so the bulk compounded formulations are not equivalent.
Reformulating the capsules into smaller doses has been successful, but the beads must
remain intact. The cost of itraconazole for a 44-lb dog (5 mg/kg orally once a day) is about
$8/day.
Potential indications
Clinical uses for itraconazole include treating all of the fungal infections listed for
ketoconazole, but itraconazole is preferred to ketoconazole because of its increased
activity and decreased adverse effects.1 Aspergillus species is more sensitive to
itraconazole than to ketoconazole, but resistance does occur. 1Itraconazole may be less
active against Leishmania species compared with the other azoles.17
Itraconazole's activity against Sporothrix schenckii is variable but itraconazole is
considered the treatment of choice. In comparison to itraconazole, terbinafine, which is
discussed in more detail later, has greater in vitro potency as well as demonstrated
successful treatment of clinical cases in people.18,19
Pharmacokinetics
Itraconazole is highly protein-bound (> 99%) but is well-distributed throughout the body. It
accumulates in skin, liver, fat, and the adrenal medulla. Itraconazole does not reach
minimum inhibitory concentrations in the cerebrospinal fluid, but it has been effective in
experimental models of CNS disease and in cats with Cryptococcus species CNS
infections.1 In dogs, itraconazole is metabolized in part to hydroxyitraconazole, which has
antifungal activity similar to that of the parent compound.
Itraconazole is variably absorbed after oral administration in dogs and cats. 20,21 In dogs,
itraconazole absorption is above 90% when capsules are administered with food
compared with about 40% absorption in fasted patients. In fasted cats, itraconazole
solution is about 70% absorbed.21
Itraconazole is primarily eliminated by hepatic metabolism and biliary secretion, with less
than 1% of the drug eliminated by renal mechanisms. 20The half-life in dogs and cats is 28
to 30 hours after a single dose. The half-life increases with multiple doses. Itraconazole is
highly lipophilic, so concentrations in tissues persist longer than plasma concentrations. As
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a result of itraconazole accumulation in tissue such as the stratum corneum, pulse dosing
has been effective in treating Malassezia dermatitis in dogs (5 mg/kg orally once a day for
two days, repeated weekly for three weeks) and dermatophyte infections in cats (5 to 10
mg/kg orally once a day for seven days, then alternating one week on, one week off until a
cure is achieved).22However, systemic treatment with itraconazole as a sole treatment
forMalassezia otitis has resulted in poor responses, and adjunctive treatments, such as
topical medications, are suggested.22
Drug interactions and adverse effects
Itraconazole appears to be better tolerated than ketoconazole in dogs and cats.
Itraconazole can result in nausea, vomiting, and anorexia, but these signs may occur less
frequently and appear to be dose-dependent.23Hepatotoxicosis may occur in as many as
10% of dogs receiving long-term treatment with itraconazole. 23 As with ketoconazole, slight
increases in liver enzyme activities can occur with itraconazole administration but are not
indicative of hepatotoxicosis. The increases in liver enzyme activities appear to be
correlated with increasing itraconazole plasma concentrations and dosages. 1,23 In contrast
to ketoconazole, itraconazole has minimal effects on cortisol and testosterone
concentrations.24

Itraconazole inhibits CYP-mediated drug metabolism similar to ketoconazole but to less of

an extent.25 However drug-drug interactions with itraconazole may include those listed for
ketoconazole. Itraconazole, similar to ketoconazole, is also a Pgp efflux pump
inhibitor.11 Itraconazole absorption is decreased when the drug is administered with gastric
acid suppression treatment, so it should not be administered concurrently. Itraconazole
has a negative inotropic effect, which may lead to congestive heart failure in patients with
impaired ventricular function.16 Long-term administration of phenobarbital increases
itraconazole metabolism and may require increased dosages to maintain similar efficacy.