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Pharmacotherapeutic Group: Antimycotic for systemic use, triazole and tetrazole derivatives. ATC Code: J02A C02.
Pharmacology: Pharmacodynamics: Mechanism of action: In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.
Pharmacokinetic (PK)/Pharmacodynamic (PD) relationship: The PK/PD relationship for itraconazole, and for triazoles in general, is poorly understood.
Pharmacodynamic effects: Microbiology: Itraconazole, a triazole derivative, has a broad spectrum of activity.
For itraconazole, interpretive breakpoints have not been established by CLSI for the Candida spp. and the filamentous fungi.
EUCAST breakpoints or itraconazole have been established for Aspergillus flavus, A. fumigatus, A. nidulans and A. terreus, and are as follows: susceptible ≤1 mg/L, resistant >1 mg/L. EUCAST breakpoints for itraconazole have been established for Candida albicans and C. dubliniensis, and are as follows: susceptible ≤0.06 mg/L, resistant >0.06 mg/L. EUCAST breakpoints for itraconazole have been established for Candida parapsilosis and C. tropicalis, and are as follows: susceptible ≤0.125 mg/L, resistant >0.125 mg/L. Interpretive breakpoints have not been established by EUCAST for Candida glabrata, C. krusei, C. guilliermondii, Cryptococcus neoformans, Aspergillus niger, and Non-species related breakpoints for Candida and Aspergillus.
In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually ≤1 μg/mL. These include: Aspergillus spp., Blastomyces dermatitidis, Cladosporium spp., Coccidioides immitis, Cryptococcus neoformans, Geotrichum spp., Histoplasma spp., including H. capsulatum, Paracoccidioides brasiliensis, Penicillium marneffei, Sporothrix schenckii and Trichosporon spp. Itraconazole also displayed activity in vitro against Epidermophyton floccosum, Fonsecaea spp., Malassezia spp., Microsporum spp., Pseudallescheria boydii, Trichophyton spp. and various other yeasts and fungi.
The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
Azole resistance appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross-resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.
Pharmacokinetics: General pharmacokinetic characteristics: Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/mL, 1.1 μg/mL and 2.0 μg/mL after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.
Absorption: Capsule: Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when the capsules are taken immediately after a full meal.
Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases (see Precautions, and Interactions). Absorption of itraconazole under fasted conditions in these subjects is increased when SPORANOX capsules are administered with an acidic beverage (such as a non-diet cola). When SPORANOX capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that observed when SPORANOX capsules were administered alone. (See Interactions.)
Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of drug is given. (See Precautions.)
Oral solution: Itraconazole is rapidly absorbed after administration of the oral solution. Peak plasma concentrations of itraconazole are reached within 2.5 hours following administration of the oral 30 solution under fasting conditions. The observed absolute bioavailability of itraconazole under fed conditions is about 55% and increases by 30% when the oral solution is taken in fasting conditions.
Itraconazole exposure is greater with the oral solution than with the capsule formulation when the same dose of drug is given. (See Precautions.)
Distribution: 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 plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid.
Metabolism: Itraconazole is extensively metabolized 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.
Excretion: Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (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, fecal 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.
Special populations: Hepatic impairment: Itraconazole is predominantly metabolized 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 twofold 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 Dosage & Administration, and Precautions).
Renal impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups.
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 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 also Dosage & Administration and Precautions.)
Pediatrics: Limited pharmacokinetic data are available on the use of itraconazole in the pediatric 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.
Oral solution: Hydroxypropyl-β-Cyclodextrin: The oral bioavailability of hydroxypropyl-β-cyclodextrin given as a solubilizer of itraconazole in oral solution is on average lower than 0.5% and is similar to that of hydroxypropyl-β-cyclodextrin alone. This low oral bioavailability of hydroxypropyl-β-cyclodextrin is not modified by the presence of food and is similar after single and repeated administrations.
Toxicology: Non-Clinical Information: Itraconazole has been tested in a standard battery of non-clinical safety studies.
Acute oral toxicity studies with itraconazole in mice, rats, guinea pigs and dogs indicate a wide safety margin (8- to 38-fold of Maximum Recommended Human Dose [MRHD] based on mg/m2). Sub (chronic) oral toxicity studies in rats and dogs revealed several target organs or tissues: adrenal cortex, liver and mononuclear phagocyte system as well as disorders of the lipid metabolism presenting as xanthoma cells in various organs.
At high doses of 40 and 80 mg/kg/day in rats (2-and 4-fold of MRHD based on mg/m2), histological investigations of adrenal cortex showed a reversible swelling with cellular hypertrophy of the zona reticularis and fasciculata, which was sometimes associated with a thinning of the zona glomerulosa. Reversible hepatic changes were found at 40 and 160 mg/kg/day. Slight changes were observed in the sinusoidal cells and vacuolation of the hepatocytes, the latter indicating cellular dysfunction, but without visible hepatitis or hepatocellular necrosis. Histological changes of the mononuclear phagocyte system were mainly characterized by macrophages with increased proteinaceous material in various parenchymal tissues.
A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration. No toxicity was observed up to 20 mg/kg (4-fold of MRHD based on mg/m2).
In three toxicology studies using rats, itraconazole induced bone defects. The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility.
Carcinogenicity and mutagenicity: Itraconazole is not a primary carcinogen in rats or mice up to 20 and 80 mg/kg, respectively. In male rats, however, there was a higher incidence of soft-tissue sarcoma, which is attributed to the increase in non-neoplastic, chronic inflammatory reactions of the connective tissue as a consequence of raised cholesterol levels and cholesterosis in connective tissue.
There are no indications of a mutagenic potential of itraconazole.
Reproductive toxicology: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats and mice at high doses. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and macroglossia. The observed skeletal malformation in rats may due to maternal toxicity. No teratogenic effects were found in rabbits up to 80 mg/kg dose (9-fold of MRHD based on mg/m2).
Fertility: There is no evidence of a primary influence on fertility under treatment with itraconazole.
Oral solution: Hydroxypropyl-β-cyclodextrin (HP-β-CD): Single and repeated dose toxicity studies in mice, rats and dogs indicate a wide safety margin after oral and intravenous administration of HP-β-CD. Most effects were adaptive in nature (histological changes in the urinary tract, softening of feces related to the osmotic water retention in the large intestine, activation of the mononuclear phagocyte system) and showed good reversibility.
Slight liver changes occurred at doses of about 30 times the proposed human dose of HP-β-CD.
Oral treatment of juvenile Beagle dogs with HP-β-CD at 1200 mg/kg for a period of up to 13 weeks with a 4-week recovery period was clinically well tolerated with no effects noted when compared to control animals at laboratory or histopathology examination.
Carcinogenicity and mutagenicity: No primary carcinogenicity activity was evidenced in the mouse carcinogenicity study. In the rat carcinogenicity study, an increased incidence of neoplasms in the large intestine (at 5000 mg/kg/day) and in the exocrine pancreas (from 500 mg/kg/day) were seen. Based on a human equivalent dose calculation normalized for body surface area, the recommended clinical dose of SPORANOX Oral Solution contains approximately 1.7 times the amount of HP-β-CD as was in the 500 mg/kg/day dose administered in rats in this carcinogenicity study.
The slightly higher incidence of adenocarcinomas in the large intestines was linked to the hypertrophic/hyperplastic and inflammatory changes in the colonic mucosa brought about by HP-β-CD-induced increased osmotic forces and is considered to be of low clinical relevance. Development of the pancreatic tumors is related to the mitogenic action of cholecystokinin in rats. This finding was not observed in the mouse carcinogenicity study, nor in a 12 month toxicity study in dogs or in a 2-year toxicity study in female cynomolgus monkeys. There is no evidence that cholecystokinin has a mitogenic action in man. However, the clinical relevance of these findings is not applicable.
HP-β-CD is not mutagenic. The chemical structure of HP-β-CD does not raise suspicion for genotoxic activity. Tests on DNA-damage, gene mutations and chromosome aberrations in vitro and in vivo did not reveal any genotoxic activity.
Reproductive toxicology: HP-β-CD has no direct embryotoxic and no teratogenic effects.
Fertility: HP-β-CD has no antifertile effect.
