Itraconazole
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Pharmacological properties
Itraconazole - a derivative of triazole, has a wide spectrum of action. in vitro studies have shown that itraconazole inhibits ergosterol synthesis in fungal cells. Ergosterol is an important component of the cell membrane of fungi, suppressing its synthesis provides an antifungal effect.
Relative to itraconazole, the limit values are set only for Candida spp. For superficial mycotic infections (CLSI M27-A2 limit values not determined by EUCAST methodology). CLSI limit values are: sensitive ≤0.125, sensitive dose-dependent 0.25–0.5, resistant ≥1 μg / ml. Limit values are not set for mycelial fungi.
In vitro studies have shown that itraconazole inhibits the growth of a wide range of fungi pathogenic for humans in concentrations typically ≤1 μg / ml. They include: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeast (Candida spp., Including C. albicans, C. glabrata and C. krusei, Cryptococcus neoformans, Pityrosporum spp., Trichosporon spp., Geotrichum spp.), Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, Coccidiodes immitis, Pseudallescheria boydii, Penicillium marnene.
Candida krusei, Candida glabrata, and Candida tropicalis are generally the least susceptible Candida species, and some isolates show in vitro resistance to itraconazole.
The main types of fungi that are not suppressed by itraconazole are zygomycetes (Rhizopus spp., Rhizomucor spp., Mucor spp. And Absidia spp.), Fusarium spp., Scedosporium proliferans and Scopulariopsis spp.
Pharmacokinetics Absorption. Itraconazole is rapidly absorbed after oral administration. Cmax in blood plasma after oral administration is achieved within 2-5 hours. The absolute bioavailability of itraconazole is 55%. Maximum oral bioavailability is achieved when consumed immediately after taking high-calorie food.
Distribution. Most of itraconazole binds to plasma proteins (99.8%), with albumin being the main binding component (99.6% for hydroxymethabolite). Intraconazole also has a high affinity for fats. Only 0.2% of itraconazole in the blood remains as an unbound substance. The volume of distribution of itraconazole is quite significant (700 l), from which we can assume its extensive distribution in the tissues: the concentration in the lungs, kidneys, liver, bones, stomach, spleen and muscles is 2-3 times higher than the concentration in blood plasma. The accumulation of itraconazole in keratin tissues, especially in the skin, was 4 times higher than in plasma.
Biotransformation. Itraconazole is significantly broken down in the liver with the formation of a large number of metabolites. One of these metabolites is hydroxyitraconazole, which has an in vitro antifungal effect similar to itraconazole. The concentration of hydroxyitraconazole in blood plasma is approximately 2 times higher than itraconazole.
According to in vitro studies, CYP 3A4 is the main enzyme involved in the metabolism of itraconazole.
Approximately 35% of itraconazole is excreted in the form of inactive metabolites in the urine and about 54% with feces. The excretion of the initial drug substance by the kidneys is less than 0.03% of the dose, while the excretion of the unchanged substance with feces varies from 3 to 18%. Itraconazole clearance decreases at higher doses due to saturated hepatic metabolism.
Linearity / nonlinearity. Due to the nonlinear pharmacokinetics, itraconazole accumulates in plasma after repeated administration. The equilibrium concentration is reached within 15 days, the value of Cmax and AUC 4-7 times higher than after a single application. Medium T½ 40 hours after repeated doses.
Special categories of patients. Liver failure. Pharmacokinetic studies using itraconazole in a single dose of 100 mg were performed in 6 healthy and 12 patients with cirrhosis. There was no clinically significant difference in AUC between the two groups. A clinically significant decrease in mean C was recorded in patients with cirrhosis.max (47%) and a 2 times increase in T½ itraconazole (37 ± 17 hours versus 16 ± 5 hours).
No data are available regarding the long-term use of itraconazole in patients with cirrhosis.
Renal failure.Only a limited amount of data is available on the use of oral itraconazole in patients with impaired renal function. Caution should be exercised when prescribing the drug to this category of patients.
Indications
Mycoses caused by pathogens sensitive to itraconazole: vulvovaginal candidiasis; dermatological / ophthalmic fungal diseases: dermatomycosis, pityriasis versicolor, fungal keratitis; oral candidiasis; onychomycosis caused by dermatophytes and / or yeast; systemic mycoses: systemic aspergillosis or candidiasis, cryptococcosis, including cryptococcal meningitis (in patients with reduced immunity and in all patients with cryptococcosis of the central nervous system, eszol is prescribed only if treatment with other antifungal drugs is ineffective); histoplasmosis, sporotrichosis, paracoccidioidosis, blastomycosis and other systemic mycoses, which are extremely rare.
Application
Apply inside. for optimal absorption of the drug, it is necessary to take eszol immediately after a meal. tablets should be swallowed whole.
Treatment regimens for adults
| Indications for use | Dose | Duration |
| Gynecological diseases | ||
| • vulvovaginal candidiasis | 200 mg 1-2 times a day | 1-3 days |
| Dermatological / ophthalmic diseases | ||
| • pityriasis versicolor | 200 mg once a day | 7 days |
| • dermatomycosis | 200 mg once a day | 7 days |
| If areas with a significant degree of keratinization are affected (for example, epidermophytosis of the hands and feet), treatment with doses of 200 mg 2 times a day for 7 days is necessary | ||
| • oral candidiasis | 100 mg once daily | 15 days |
| The dose should be increased to 200 mg once a day for 15 days for patients with neutropenia or AIDS due to a violation of their absorption | ||
| • fungal keratitis | 200 mg once a day | 21 day |
| • onychomycosis (continuous treatment) | One course: 2 tablets 2 times a day (200 mg 2 times a day) for 1 week | For the treatment of fungal lesions of the nail plates on the hands, 2 courses are recommended. For the treatment of fungal lesions of the nail plates on the toes, 3 courses should be used. The interval between courses should be 3 weeks. Clinical results will appear after completion of treatment as nails grow. |
Treatment of onychomycosis caused by dermatophytes and / or yeast can also be carried out using pulse therapy.
| Localization of onychomycosis | A week | ||||
| 1st | 2nd, 3rd, 4th | 5th | 6th, 7th, 8th | 9th | |
| Damage to the nail plates on the toes with damage to the nails on the hands, and without it | 1st course of pulse therapy | Weeks during which itraconazole is not taken | 2nd course of pulse therapy | Weeks during which itraconazole is not taken | 3rd course of pulse therapy |
| Damage to the nail plates only on the hands | 1st course of pulse therapy | Weeks during which itraconazole is not taken | 2nd course of pulse therapy | ||
Optimal clinical and mycological effects are achieved within 2–4 weeks after the end of treatment of skin infections, vulvovaginal candidiasis and oral candidiasis, and after 6–9 months after completion of treatment of infection of the nail plates. This is due to the fact that the removal of itraconazole from the tissues of the skin, nails and mucous membranes is slower than from blood plasma.
The duration of treatment of systemic fungal lesions should be corrected depending on the mycological and clinical response to therapy:
| Systemic mycoses | |||
| Indications for use | Dosage | The average duration of treatment | Notes |
| Aspergillosis | 200 mg once a day | 2–5 months | Increasing the dose to 200 mg 2 times a day in case of an invasive or disseminated disease |
| Candidiasis | 100-200 mg once a day | from 3 weeks to 7 months | Increasing the dose to 200 mg 2 times a day in case of an invasive or disseminated disease |
| Cryptococcosis (without signs of meningitis) | 200 mg once a day | from 2 months to 1 year | |
| Cryptococcal meningitis | 400 mg once daily | from 2 months to 1 year | Maintenance therapy (see SPECIAL INSTRUCTIONS) |
| Histoplasmosis | From 200 mg 1 time per day to 200 mg 2 times per day | 8 month | |
| Sporotrichosis | 100 mg once daily | 3 month | |
| Paracoccidioidomycosis | 100 mg once daily | 6 months | There is insufficient data on the effectiveness of the indicated dosage regimen in AIDS patients |
| Chromomycosis | 100-200 mg once a day | 6 months | |
| Blastomycosis | From 100 mg 1 time per day to 200 mg 2 times per day | 6 months | |
Children. Eszol should not be prescribed to children, unless the expected benefit significantly exceeds the potential risks (see SPECIAL INSTRUCTIONS).
Elderly patients. Eszol should not be prescribed to elderly patients, unless the expected benefit significantly exceeds the potential risks (see SPECIAL INSTRUCTIONS).
Patients with impaired renal function. The oral bioavailability of the drug may be reduced in patients with renal failure; dose adjustment should be considered (see SPECIAL INSTRUCTIONS).
Patients with impaired liver function. Itraconazole is predominantly metabolized in the liver. Final t½ itraconazole in patients with cirrhosis is somewhat elongated. Oral bioavailability in patients with cirrhosis is slightly reduced. A dose adjustment should be considered (see SPECIAL INSTRUCTIONS).
Contraindications
Eszole is contraindicated in patients with known hypersensitivity to the drug or its components.
The simultaneous use of the following medicines with Eszole tablets is contraindicated (see INTERACTION):
- substrates CYP ZA4, which can extend the Q – T interval, such as astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadil), misolastine, pimozide, quinidine, sertindole and terfenadine. At the same time
210 Items
2020-07-30
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