Itraconazole - instructions for use, dose, side effects, contraindications

Antifungal agent, a derivative of triazole. The mechanism of action is associated with a violation of the synthesis of ergosterol of the fungal cell wall.

"Target" for the action of the drug is the enzyme 14α-demethylase. 14-α-demethylase is part of a group of enzymes known collectively as "cytochrome P450". All enzymes of the cytochrome P450 group contain a hematinic iron-containing pigment. Itraconazole binds to the iron atom of the hematin group and inactivates 14α-demethylase, which leads to a disruption in the synthesis of ergosterol and the accumulation of lanosterol and other sterols.Their incorporation into the membrane instead of ergosterol significantly disrupts the structure and function of the fungal cell membrane. The decrease in the synthesis of ergosterol, as well as the accumulation of 14α-methylsterols, destroys the densely packed acyl chains of the phospholipids of the fungal membranes. Destabilization of the fungal membrane leads to dysfunction of membrane enzymes, including those involved in the electron transport chain, and ultimately to cell death.

Has a broader spectrum of antifungal activity than ketoconazole. Active with respect to Aspergillus spp., Blastomyces dermatitidis, Candida, Coccidioides immitis, Cryptococcus neoformans, Epidermophyton, Microsporum, Trichophyton, Histoplasma capsulatum, Malassezia furfur, Paracoccidioides brasiliensis, Sporothrix schenckii.

Pharmacokinetics:

The bioavailability of itraconazole varies in the range of 40-100%, depending on the dosage form and reception conditions. Bioavailability is higher when taking the solution on an empty stomach. The bioavailability of itraconazole in capsules is maximum when taking capsules immediately after a dense meal.

Binding to plasma proteins - 99.8% (itraconazole), 99.5% (hydroxyitraconazole).

Penetrates into tissues and organs (including the vagina), is contained in the secret of the sebaceous and sweat glands. Accumulated in the lungs, kidneys, liver, bones, stomach, spleen, skeletal muscles (the concentration of itraconazole in these tissues exceeds the plasma in 2-3 times).

Badly passes through the blood-brain barrier.Biotransformiruetsya in the liver (mainly with the participation of CYP3A4) with the formation of a large number of metabolites, including the active (hydroxyitraconazole).

It is excreted by the kidneys (less than 0.03% unchanged, about 40% - in the form of inactive metabolites) and with feces (3-18% unchanged). In patients with renal insufficiency, bioavailability is somewhat reduced compared to patients with normal renal function. In patients with cirrhosis, the half-life is increased.

Therapeutic concentrations in the skin persist for 2-4 weeks after the end of the 4-week course of treatment. Itraconazole is determined in the nail keratin a week after the start of treatment and persists for 6 months after the end of the 3-month course of therapy.

Indications:Vulvovaginal candidiasis, skin mycoses, oral cavity, eyes, onychomycosis caused by dermatophytes and / or yeast, systemic mycoses (including systemic aspergillosis (with resistance or poor tolerance of amphotericin B), candidiasis, cryptococcosis, histoplasmosis, sporotrichosis, paracoccidioidosis, blastomycosis and other, rarely occurring systemic and tropical mycoses).

ICD-10

I.A15-A19 Tuberculosis

I.B35-B49.B35 Dermatophytosis

I.B35-B49.B35.4 Mycosis of the trunk

I.B35-B49.B35.3 Mycosis of the feet

I.B35-B49.B35.2 Mycosis brushes

I.B35-B49.B35.1 Mycosis of nails

I.B35-B49.B35.0 Mycosis of the beard and head

I.B35-B49.B35.6 Epidermophytosis inguinal

I.B35-B49.B36.0 Multicolored lichen

I.B35-B49.B37.0 Candidiasis stomatitis

I.B35-B49.B37.8 Candidiasis of other localizations

I.B35-B49.B37.7 Candida septicemia

I.B35-B49.B37.6 Candidiasis endocarditis (I39.8 *)

I.B35-B49.B37.4 Candidiasis of other urogenital localizations

I.B35-B49.B37.3 Candidiasis of the vulva and vagina (N77.1 *)

I.B35-B49.B37.2 Candidiasis of skin and nails

I.B35-B49.B37.1 Pulmonary Candidiasis

I.B35-B49.B38 Coccidioidomycosis

I.B35-B49.B39 Histoplasmosis

I.B35-B49.B40 Blastomycosis

I.B35-B49.B41 Paracoccidioidomycosis

I.B35-B49.B42 Sporotrichosis

I.B35-B49.B44 Aspergillosis

I.B35-B49.B45 Cryptococcosis

I.B35-B49.B45.1 Cerebral Cryptococcosis

I.B35-B49.B49 Mycosis, unspecified

Contraindications:

Hypersensitivity, pregnancy, breast-feeding, congestive heart failure, ventricular dysfunction.

Co-administration with substrates of CYP3A4 (methadone, disopyramide, dronedaron, halofantrine, irinotecan, midazolam (for oral administration), lourazidone, felodipine, lercanidipine, nisoldipine, ivabradine, ranolazine, eplerenone, lovastatin); colchicine (in patients with renal or hepatic insufficiency). Simultaneous reception with drugs that can extend the QT interval (terfenadine, astemizole, misolastine, cisapride, dofetilide, triazolam, pimozide, quinidine, beprideil, sertindole, levacetylmethadol). Simultaneous reception with ergot alkaloids (dihydroergotamine, ergotamine, ergometrine, methylergomethrin). Simultaneous administration with inhibitors of hydroxy-methylglutaryl-CoA reductase (atorvastatin, simvastatin, lovastatin).

Deficiency of sugar / isomaltase, intolerance to fructose, glucose-galactose malabsorption syndrome.

Carefully:Caution should be taken in patients with increased sensitivity to other azoles, with coronary heart disease, valvular heart disease, obstructive pulmonary disease, renal failure, liver failure, liver cirrhosis, in elderly patients, in children, when combined with other medicinal means.

Pregnancy and lactation:

Use in pregnancy is allowed only with systemic fungal infections in cases where the expected effect exceeds the potential risk to the fetus.

In experimental studies it was established that itraconazole has an embryotoxic effect and causes fetal development abnormalities.

The action category for fetus by FDA is C.

Breastfeeding mothers should stop breastfeeding (itraconazole penetrates into breast milk).

Dosing and Administration:

Inside, after eating (capsule), on an empty stomach (solution for oral administration).

Onychomycosis - 200 mg once a day for 3 months or 200 mg twice a day for 1 week followed by a break of 3 weeks; with onychomycosis of the feet, 3 courses of treatment are recommended, brushes - 2 courses;

Vulvovaginalth Candidiasis - 200 mg twice a day for 1 day or 200 mg once a day for 3 days;

Pityriasis lichen - 200 mg once a day for 7 days;

Dermatomycosis and candidiasis of the oral cavity - 100-200 mg once a day for 7-15 days (if necessary, repeat the course);

Fungal keratitis - 200 mg once a day for 21 days;

Systemic mycoses - 100-200 mg 1-2 times a day for 2-12 months (depending on the pathogen).

Side effects:

From the side of the digestive system: abdominal pain, nausea, vomiting, constipation, increased activity of liver enzymes, cholestatic jaundice; in some cases - hepatitis.

From the side of the central nervous system and the peripheral nervous system: headache, dizziness; in some cases - peripheral neuropathy.

From the cardiovascular system: in some cases - edema, congestive heart failure and pulmonary edema.

Allergic reactions: skin rash, itchy skin, hives, angioedema, Stevens-Johnson syndrome.

Other: with prolonged use - dysmenorrhea, hair loss, hypokalemia.

Overdose:

Cardiopulmonary insufficiency.

Treatment is symptomatic. Gastric lavage, reception of activated charcoal, symptomatic therapy. It is not removed during hemodialysis. There is no specific antidote.

Interaction:

Alkaloids of ergot (dihydroergotamine, ergometrine, ergotamine, methylergomethrin) - the risk of ergotism. Joint use is contraindicated!

Alfentanil, eletriptan - decrease in their clearance, increase in effects and toxicity.

Astemizole, cisapride, pimozide, terfenadine - increase in their concentration in the blood, prolongation of the QT interval (sudden death possible). Joint use is contraindicated!

Antacids, H2-receptor blockers, inhibitors of H +, K + -ATPase (omeprazole), anticholinergics, sucralfate, reducing the acidity of the gastrointestinal tract, reduce the absorption of itraconazole; should divide the reception for 2 hours.

Atorvastatin, lovastatin, simvastatin - increase in their concentrations in the plasma, the development of rhabdomyolysis. Joint use is contraindicated!

Calcium channel blockers (felodipine, nifedipine, verapamil) - the onset of edema, an increase in the negative inotropic effect of itraconazole.

Budesonide, dexamethasone, methylprednisolone - slowing down their metabolism, enhancing effects and toxicity.

Buspirone - a significant increase in its concentration in the blood, increased effects and toxicity.

Busulfan, docetaxel, vinca alkaloids - inhibition of their metabolism, enhancement of effects and toxicity.

Warfarin - strengthening of anticoagulant action.

Hypoglycemic agents (sulfonylurea preparations, for example glibenclamide) - increasing their concentration in the blood, the development of hypoglycemia.

Diazepam, alprazolam, midazolam, triazolam - increasing their concentration in the blood, strengthening and lengthening their sedative and hypnotic activity.

Digoxin - increasing its concentration in the blood and toxicity.

Didanosine - decreased gastric acidity, inhibition of itraconazole absorption; should divide the reception for 2 hours.

Dysopyramide - the risk of prolonging the QT interval.

Inhibitors of CYP3A4 - an increase in the plasma concentration of itraconazole.

Indinavir, ritonavir, saquinavir - mutual increase in plasma concentrations.

Inductors CYP3A4 - an increase in the clearance of itraconazole.

Carbamazepine, phenobarbital, phenytoin - a decrease in the concentration of voriconazole in the blood, therapeutic inefficiency or exacerbation of the infection.

Macrolide antibiotics (erythromycin, clarithromycin) - increased concentration and toxicity of voriconazole. Joint use is undesirable.

Nevirapine - decreased bioavailability of voriconazole.

Polyene antifungal agents (including amphotericin B) - a decrease in the activity of polyene antibiotics.

Rifampicin, isoniazid - a decrease in the content of azoles in the blood, inefficiency or exacerbation of the infection.

Phenytoin - increasing its concentration in the blood, increasing efficacy and toxicity.

Quinidine - increasing its concentration in the blood and the risk of cardiovascular complications. Joint use is contraindicated!

Cyclosporine, tacrolimus - To increase their toxicity.

Special instructions:

The most hepatotoxic antifungal agent.

In patients with impaired immunity (AIDS, condition after organ transplantation, neutropenia), an increase in dose may be required (due to a decrease in the bioavailability of itraconazole).

When appointing patients with chronic heart failure, an individual assessment of the benefit-risk ratio is necessary, taking into account factors such as the severity of the indications, the dosing regimen, individual risk factors (heart disease, including coronary heart disease, valve damage), chronic obstructive pulmonary disease, renal insufficiency. If there are signs or symptoms of congestive heart failure, as well as neuropathy, itraconazole treatment should be discontinued.

In the process of treatment with itraconazole, it is necessary to monitor the function of the liver (especially with prolonged admission). With an increased level of transaminases, the drug is prescribed if the expected effect of therapy exceeds the possible risk of liver damage. In patients with cirrhosis of the liver and / or with impaired renal function, it is necessary to monitor the concentration of itraconazole in the plasma and, if necessary, adjust the dose.

Women of childbearing age should use adequate methods of contraception throughout the course of treatment, until the onset of the first menstruation after it is completed.

Instructions

Itraconazole (Itraconazolum)