Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Janssen-Cilag Ltd., 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK
Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivatives
ATC code: J02AC02
Itraconazole inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and disruption of membrane synthesis by fungi.
The PK/PD relationship for itraconazole, and for triazoles in general, is poorly understood and is complicated by limited understanding of antifungal pharmacokinetics.
Resistance of fungi to azoles appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are:
Breakpoints for itraconazole have not yet been established for fungi using EUCAST methods.
Using CLSI methods, breakpoints for itraconazole have only been established for Candida species from superficial mycotic infections. The CLSI breakpoints are: susceptible ≤0.125 mg/L and resistant ≥1 mg/L.
The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
The in vitro susceptibility of fungi to itraconazole depends on the inoculum size, incubation temperature, growth phase of the fungi, and the culture medium used. For these reasons, the minimum inhibitory concentration of itraconazole may vary widely. Susceptibility in the table below is based on MIC90 <1 mg itraconazole/L. There is no correlation between in vitro susceptibility and clinical efficacy.
Commonly susceptible species:
Aspergillus spp.2
Blastomyces dermatitidis1
Candida albicans
Candida parapsilosis
Cladosporium spp.
Coccidioides immitis1
Cryptococcus neoformans
Epidermophyton floccosum
Fonsecaea spp.1
Geotrichum spp.
Histoplasma spp.
Malassezia (formerly Pityrosporum) spp.
Microsporum spp.
Paracoccidioides brasiliensis1
Penicillium marneffei1
Pseudallescheria boydii
Sporothrix schenckii
Trichophyton spp.
Trichosporon spp.
Species for which acquired resistance may be a problem:
Candida glabrata3
Candida krusei
Candida tropicalis3
Inherently resistant organisms:
Absidia spp.
Fusarium spp.
Mucor spp.
Rhizomucor spp.
Rhizopus spp.
Scedosporium proliferans
Scopulariopsis spp.
1 These organisms may be encountered in patients who have returned from travel outside Europe.
2 Itraconazole-resistant strains of Aspergillus fumigatus have been reported.
3 Natural intermediate susceptibility.
Peak plasma concentrations of itraconazole are reached at the end of the intravenous infusion, declining thereafter. Peak plasma concentrations of hydroxy-itraconazole (see Metabolism below) are reached within 3 hours of beginning of a one-hour infusion, declining thereafter.
As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing.
In 4 multiple-dose pharmacokinetic studies in patients, itraconazole IV was administered as a 1-hour infusion of 200 mg itraconazole twice daily on days 1 and 2 of treatment, followed by a 1-hour infusion of 200 mg once daily from day 3 to day 7. Steady-state plasma concentrations of itraconazole and hydroxy-itraconazole were generally reached within 48 and 96 hours, respectively. Itraconazole plasma concentrations >250 ng/ml were achieved in most patients.
Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism. The terminal half life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours after repeated dosing.
Each 200 mg intravenous dose of itraconazole contains 8 g hydroxypropyl-β-cyclodextrin to increase the solubility of itraconazole. The pharmacokinetic profile of this component is described below. (See Itraconazole; see Pharmacokinetic properties – Hydroxypropyl-β-Cyclodextrin.)
Most of the itraconazole in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (>700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in the plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid.
Itraconazole is extensively metabolised by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole.
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in faeces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, faecal excretion of unchanged drug ranges from 3% to 18% of the dose.
As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for at least six months after the end of a 3-month treatment period.
Studies have not been conducted with intravenous itraconazole in patients with hepatic impairment. Itraconazole is predominantly metabolised in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as a capsule. A statistically significant reduction in mean Cmax (47%) and a two-fold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole (see sections 4.2 and 4.4).
A small fraction (<1%) of an intravenous dose of itraconazole is excreted unchanged in urine.
After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50-79 ml/min), moderate (defined in this study as CrCl 20-49 ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were similar to that in healthy subjects (range of means 42-49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function.
Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole (see sections 4.2, 4.3 and 4.4).
h34 Paediatric Population
Limited pharmacokinetic data are available on the use of itraconazole in the paediatric population. Clinical pharmacokinetic studies in children and adolescents aged between 5 months and 17 years were performed with itraconazole capsules, oral solution or intravenous formulation. Individual doses with the capsule and oral solution formulation ranged from 1.5 to 12.5 mg/kg/day, given as once-daily or twice-daily administration. The intravenous formulation was given either as a 2.5 mg/kg single infusion, or a 2.5 mg/kg infusion given once daily or twice daily. For the same daily dose, twice daily dosing compared to single daily dosing yielded peak and trough concentrations comparable to adult single daily dosing. No significant age dependence was observed for itraconazole AUC and total body clearance, while weak associations between age and itraconazole distribution volume, Cmax and terminal elimination rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related to weight.
In patients with normal renal function, the pharmacokinetic profile of hydroxypropyl-β–cyclodextrin, an ingredient of Sporanox intravenous formulation, has a short half-life of 1 to 2 hours, and demonstrates no accumulation following successive daily doses. In healthy subjects and in patients with mild to severe renal insufficiency, the majority (>85%) of an 8 g dose of hydroxypropyl-β-cyclodextrin is eliminated in the urine. Following a single intravenous dose of itraconazole 200 mg, clearance of hydroxypropyl-β-cyclodextrin was reduced in subjects with renal impairment, resulting in higher exposure to hydroxypropyl-β-cyclodextrin. In subjects with mild, moderate, and severe renal impairment, half-life values were increased over normal values by approximately two-, four-, and six-fold, respectively. In these patients, successive infusions may result in accumulation of hydroxypropyl-β-cyclodextrin until steady state is reached. Hydroxypropyl-β-cyclodextrin is removed by haemodialysis.
Nonclinical data on itraconazole revealed no indications for gene toxicity, primary carcinogenicity or impairment of fertility. At high doses, effects were observed in the adrenal cortex, liver and the mononuclear phagocyte system but appear to have a low relevance for the proposed clinical use. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high doses. A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration, and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction and development. In a rat carcinogenicity study hydroxypropyl-β-cyclodextrin produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of the large intestine adenocarcinomas is low and the mechanism of exocrine pancreatic adenocarcinomas induction not considered relevant to humans.
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