Itraconazole
Itraconazole: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. For violations of liver function
- 13. Use in the elderly
- 14. Drug interactions
- 15. Analogs
- 16. Terms and conditions of storage
- 17. Terms of dispensing from pharmacies
- 18. Reviews
- 19. Price in pharmacies
Latin name: Itraconazole
ATX code: J02AC02
Active ingredient: Itraconazole
Producer: Biocom CJSC (Russia), Atoll (Russia), Sandoz (Slovenia)
Description and photo update: 19.10.2018
Prices in pharmacies: from 274 rubles.
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Itraconazole is a broad-spectrum antifungal oral agent.
Release form and composition
Dosage form - capsules: size No. 0, hard gelatinous, depending on the manufacturer - with a white body and a red cap, or with an orange body and cap, or with a transparent natural gelatin color body and an opaque blue cap (1, 3, 4 each, 5, 6 or 7 pcs. In blister packs, in a cardboard bundle 1-5 packs; 5 or 10 pcs. In a blister pack, in a cardboard bundle 1-6 or 10 packs; 15 pcs. In blisters, in cardboard box 1 blister; 5, 10, 15, 20, 30, 50 or 100 pcs. in polymer cans, in a cardboard box 1 can).
Active ingredient: itraconazole, in 1 capsule - 100 mg.
The composition of additional substances differs depending on the manufacturer of the drug.
Capsules with a white body and a red cap:
- auxiliary components: neutral pellets (sugar balls), propylene glycol 20,000, povidone K-30, hypromellose-E5 (HPME-E5), sucrose, eudragit E-100 (copolymer of methyl, dimethylaminoethyl and butyl methacrylate);
- capsule: gelatin, methyl parahydroxybenzoate, propyl parahydroxybenzoate; body dye - titanium dioxide (E 171); cap dyes - titanium dioxide (E 171), Ponso 4R (E 124) and sunset yellow (E 110).
Capsules with orange body and cap:
- auxiliary components: sugar pellets, poloxamer 188 (lutrol) micronized, hypromellose, poloxamer 188 (lutrol);
- capsule: gelatin, purified water, titanium dioxide, sunset yellow dye.
Capsules with a transparent natural gelatin color body and an opaque blue cap:
- auxiliary components: sugar crumbs (sucrose, starch syrup), sucrose, sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, hypromellose, butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer [1: 2: 1] (eudragit E 100);
- capsule: body - gelatin; cap - gelatin, titanium dioxide and indigo carmine dye.
Pharmacological properties
Pharmacodynamics
Itraconazole is a triazole derivative, a synthetic antifungal agent, the mechanism of which is caused by inhibition of the biosynthesis of the main component of the fungal cell membrane - ergosterol, which is involved in maintaining the structural integrity of the membrane. Thus, due to impaired synthesis, membrane permeability and cell lysis change.
The drug is active against infectious diseases caused by the following fungi: dermatophytes (Mikrosrorum spp., Trichophyton spp., Epidermofyton floccosum), yeast-like fungi (Candida spp., Including C. krusei, C. tropicalis, C. albicans and C. parapsilosis, as well as Malassezia spp., Crüptoccus neoformans, Geotrichum spp., Trichosporon spp.), Coccidioides immitis, Sporothrix schenckii, Pseudallescheria boydii, Histoplasma spp. (including H. capsulatum), Blastomyces dermatitidis, Fonescea spp., Penicillium marneffei, Aspergillus spp., Cladosporium spp., Paracoccidioides brasiliensis and many others.
The least sensitive to the action of itraconazole are Candida species such as Candida glabrata, Candida tropicalis and Candida krusei.
Itraconazole is not active against the following fungi: Scopulariopsis spp., Scedosporium spp., Fusarium spp., Zygomycetes (Rhizomucor spp., Rhizopus spp., Absidia spp., Mucor spp.).
Resistance to azoles, including itraconazole, develops slowly and is usually the result of several genetic mutations. The mechanisms of resistance formation include overexpression of the ERG11 gene, which encodes the enzyme 14α-demethylase, which is the main target of the action of azoles, and ERG11 point mutations, leading to the activation of transport systems and / or a decrease in the binding of enzymes to azoles, resulting in increased excretion of the drug.
Itraconazole-resistant strains of Aspergillus fumigates have been reported.
Studies have noted cross-resistance of Candida spp. to drugs from the group of azoles, however, resistance to one of the drugs in this group does not necessarily mean the presence of resistance to other drugs from the same group.
Pharmacokinetics
With repeated administration, itraconazole accumulates in the blood plasma. The maximum concentration (Cmax) and the area under the concentration-time curve (AUC) with prolonged administration is 4-7 times higher than with a single dose. The equilibrium concentration of the drug is usually reached within 15 days. In the case of taking itraconazole once a day, the maximum equilibrium plasma concentration is about 2 μg / ml.
After discontinuation of the drug, the concentration of the substance in the blood plasma decreases to an almost undetectable value within 7-14 days, depending on the dose that was used and the duration of therapy.
The final half-life: with a single dose - 16-28 hours, with multiple doses - 34-42 hours.
After oral administration, itraconazole is rapidly absorbed. Cmax in plasma is reached after 2–5 hours. The absolute bioavailability is approximately 55%. The maximum bioavailability is observed when the drug is taken immediately after a meal.
The connection with plasma proteins (mainly albumin) is 99.8%. The affinity of the substance for lipids was also noted. The volume of distribution is more than 700 liters. Concentrations in the stomach, kidneys, spleen, muscles, bones and lungs are 2-3 times higher than in plasma. Moreover, the concentration of itraconazole in tissues containing keratin (especially in the skin) is approximately 4 times higher than the concentration in plasma.
Despite the fact that in cerebrospinal fluid the level of itraconazole is significantly lower than in plasma, the drug has been shown to be effective against infectious agents present in cerebrospinal fluid.
Itraconazole is metabolized mainly with the participation of the CYP3A4 isoenzyme in the liver with the formation of a large number of metabolites, the main of which is hydroxyitraconazole - in vitro it has an antifungal activity comparable to itraconazole, its plasma concentration is approximately twice the level of itraconazole.
About 35% of the substance is excreted by the kidneys as inactive metabolites, about 54% - by the intestines.
The redistribution of the drug from tissues containing keratin is insignificant, therefore, its excretion from these tissues is associated with the regeneration of the epidermis. In the skin, in contrast to blood plasma, the concentration of itraconazole is maintained for 2-4 weeks after the end of the 4-week course of treatment, and in the keratin of the nail - for 6 months after the end of the 3-month course of therapy.
Since itraconazole is metabolized mainly in the liver, after a single dose of 100 mg, the average maximum concentration in patients with liver cirrhosis is significantly lower than in healthy volunteers. There is no information on the long-term use of the drug for antifungal therapy in patients with concomitant liver cirrhosis.
Information on the use of itraconazole in oral dosage form for the treatment of patients with concomitant renal impairment is limited. Dialysis does not affect the clearance and elimination half-life of itraconazole or hydroxyitraconazole.
Indications for use
Itraconazole is a drug for the treatment of infections caused by sensitive pathogens:
- onychomycosis caused by dermatophytes and / or yeast-like fungi;
- lesions of the skin and mucous membranes: candidiasis of the oral mucosa; vulvovaginal candidiasis; dermatomycosis; fungal keratitis; versicolor versicolor;
- systemic mycoses: sporotrichosis; histoplasmosis; systemic aspergillosis and candidiasis; paracoccidioidomycosis; blastomycosis; cryptococcosis (including cryptococcal meningitis); other rare systemic or tropical mycoses.
Contraindications
- intolerance to fructose, sucrase / isomaltose deficiency, glucose and galactose malabsorption;
- chronic heart failure, including history (with the exception of extremely dangerous or life-threatening infections);
- pregnancy and the period of breastfeeding;
- children under 3 years old;
- simultaneous use of midazolam (oral), triazolam, nisoldipine, eletriptan, substrates of the isoenzyme CYP3A4, ergot alkaloids (ergotamine, dihydroergotamine, ergometrine, methylergometrine);
- hypersensitivity to any component of the drug.
Relative contraindications (conditions / situations requiring caution):
- severe violations of liver and kidney function;
- hypersensitivity to other drugs from the azole group;
- children and old age;
- simultaneous use of drugs that can change the concentration of itraconazole in the blood plasma, and drugs, the concentration of which in the plasma can change under the action of itraconazole.
Instructions for the use of Itraconazole: method and dosage
The capsules should be taken orally, swallowed whole, immediately after a meal.
Treatment of onychomycosis caused by dermatophytes and / or mold and yeast-like fungi can be carried out according to one of two schemes:
- Continuous therapy for lesions of the nail plates of the feet, including with lesions of the nails on the hands: 200 mg per day for 3 months.
- Pulse therapy: 200 mg 2 times a day for 1 week, followed by a 3-week break. In case of damage to the nail plates on the hands, 2 such courses are carried out, with damage to the nails on the feet (with or without damage to the nails on the hands) - 3 courses.
The result of treatment can be assessed 6–9 months after the end of the therapeutic course, which is associated with a slower elimination of itraconazole from the nail plate compared to plasma.
Dosing instructions for skin and mucous membrane lesions:
- candidiasis of the oral mucosa: 100 mg 1 time per day for 15 days;
- vulvovaginal candidiasis: 200 mg 2 or 1 times a day for 1 or 3 days, respectively;
- dermatomycosis of smooth skin: 100 or 200 mg 1 time per day for a course of 15 or 7 days, respectively;
- fungal keratitis: 200 mg 1 time per day for 21 days, depending on the development of positive dynamics of treatment, the duration of therapy can be adjusted;
- tinea versicolor: 200 mg 1 time per day for 7 days;
- lesions of highly keratinized areas of the skin (hands and feet): 200 mg 2 times a day or 100 mg 1 time a day for 7 or 30 days.
In case of impaired immunity (in the presence of transplanted organs, neutropenia or AIDS), the bioavailability of itraconazole may decrease, which requires a twofold increase in the dose.
The result of treatment can be assessed 2–4 weeks after the end of the therapeutic course, which is associated with a slower elimination of itraconazole from the skin compared to plasma.
Dosage of the drug for systemic mycoses and the average duration of treatment (it can be adjusted depending on the effectiveness of therapy):
- aspergillosis: 200 mg once a day for 2–5 months. If the infection is invasive or disseminated, the dose is increased to 200 mg 2 times a day;
- candidiasis: 100 or 200 mg once a day for a course from 3 weeks to 7 months. If the disease is invasive or disseminated, the dose is increased to 200 mg 2 times a day;
- blastomycosis: the dose is determined individually and can range from 100 mg 1 time per day to 200 mg 2 times a day, the duration of treatment is 6 months;
- chromomycosis: 100 or 200 mg once a day for 6 months;
- histoplasmosis: 200 mg 1 or 2 times a day for 8 months;
- paracoccidioidomycosis: 100 mg 1 time per day for 6 months *;
- sporotrichosis: 100 mg once a day for 3 months;
- cryptococcal meningitis **: 200 mg 2 times a day, duration of treatment - 2-12 months;
- cryptococcosis **: 200 mg once a day, the course of therapy is from 2 to 12 months.
* There are no data on the effectiveness of this dose for the treatment of paracoccidioidomycosis in AIDS patients.
** For cryptococcosis of the central nervous system in all patients, cryptococcosis and cryptococcal meningitis in immunocompromised patients, Itraconazole is used only if the first-line drugs are ineffective or cannot be prescribed for certain reasons.
Side effects
Distribution of side effects by frequency of occurrence: very often - ≥ 1/10, often - from ≥ 1/100 to <1/10, infrequently - from ≥ 1/1000 to <1/100, rarely - from ≥ 1/10000 to < 1/1000, very rarely - <1/10000 (including isolated cases), the frequency is unknown - the available data do not allow us to calculate the incidence of adverse reactions.
Side effects that may occur during the treatment with Itraconazole:
- infectious and parasitic diseases: infrequently - sinusitis, rhinitis, upper respiratory tract infections;
- from the side of metabolism: very rarely - a decrease in the concentration of potassium ions in the blood, an increase in the content of triglycerides;
- on the part of the organ of vision: rarely - blurry vision; very rarely - diplopia;
- from the immune system: very rarely - anaphylactic and anaphylactoid reactions, angioedema, serum sickness;
- from the organ of hearing and labyrinthine disorders: rarely - ringing in the ears; very rarely - hearing loss (both temporary and permanent);
- on the part of the blood and lymphatic system: rarely - a decrease in the level of leukocytes in the total cellular composition of the blood; very rarely - a decrease in the number of platelets and the number of neutrophils;
- from the respiratory system: very rarely - shortness of breath, pulmonary edema;
- from the musculoskeletal system: very rarely - myalgia, arthralgia;
- on the part of the cardiovascular system: very rarely - arterial hypertension / hypotension, chronic heart failure;
- from the nervous system: infrequently - headache, paresthesia, dizziness; rarely - hypesthesia; very rarely - peripheral neuropathy;
- from the kidneys and urinary tract: rarely - pollakiuria; very rarely - urinary incontinence;
- from the hepatobiliary system: infrequently - increased activity of hepatic transaminases, hyperbilirubinemia; very rarely - hepatitis, severe toxic liver damage (including isolated cases of acute liver failure with a fatal outcome);
- on the part of the reproductive system: infrequently - menstrual irregularities; rarely - erectile dysfunction;
- from the digestive system: often - nausea, abdominal pain; infrequently - flatulence, constipation, diarrhea, dysgeusia, dyspepsia, vomiting; very rarely - pancreatitis;
- on the part of the skin and subcutaneous tissues: often - rash; infrequently - alopecia, pruritus, urticaria, hypersensitivity; very rarely - polymorphic erythema, photosensitivity, exfoliative dermatitis, leukocytoclastic vasculitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome;
- others: infrequently - edematous syndrome; very rarely - hyperthermia;
- laboratory parameters: very rarely - an increase in the activity of blood creatine phosphokinase.
Overdose
The symptoms observed with overdose were comparable to the dose-dependent side effects that occur with the usual doses of Itraconazole. The drug does not have a specific antidote. Hemodialysis is ineffective. In case of an overdose, gastric lavage is performed with sodium bicarbonate solution, activated carbon is given, and supportive therapy is performed.
special instructions
Reduced gastric acidity interferes with the absorption of itraconazole from capsules. Antacids, if necessary, can be taken no earlier than 2 hours after itraconazole. Patients who receive proton pump inhibitors or H 2 -histamine receptor blockers and patients with achlorhydria should take the drug with drinks containing cola. It is necessary to control the antifungal effect of the drug and, if necessary, increase its dose.
The drug is not recommended for the initial therapy of systemic mycoses, which pose a threat to the life of patients.
Itraconazole has a negative inotropic effect. Cases of development during therapy of chronic heart failure are known. With a daily dose of 400 mg, a more frequent occurrence of heart failure was noted, however, with the use of lower doses, this pattern was not identified, therefore the risk is presumably dose-dependent. For this reason, the drug is contraindicated in chronic heart failure and in the presence of this symptom complex in history, except in cases where antifungal therapy is vital and its expected benefits outweigh the potential risks. When assessing the benefit / risk ratio, the physician should take into account the following: the indication for the prescription of the drug, the dosage regimen and individual risk factors such as the presence of renal failure, obstructive pulmonary disease,valve damage, coronary heart disease, or other diseases that are characterized by edema. Patients should be told about the first symptoms and signs that suggest a malfunction of the heart, when they appear, they should immediately stop taking Itraconazole and consult a doctor.
The drug should be discontinued in the event of peripheral neuropathy, if there is a suspicion that it is associated with taking itraconazole.
Influence on the ability to drive vehicles and complex mechanisms
Studies on the effect of the drug on the psychophysical and cognitive functions of a person have not been conducted. There are known cases of the development of such side effects as dizziness, hearing loss, blurred vision during therapy. If they appear, you should refrain from driving vehicles and performing work with potentially dangerous consequences.
Application during pregnancy and lactation
Itraconazole should not be taken during pregnancy. Moreover, women of childbearing age should use reliable contraceptive methods for the entire period of treatment and after it until the onset of the first menstruation.
According to the instructions, Itraconazole passes into breast milk, therefore, if therapy is justified, breastfeeding women should stop breastfeeding.
Pediatric use
Due to the lack of clinical experience, the drug is contraindicated in children under the age of 3 years; at an older age, it should be used with caution if the expected benefit outweighs the possible risk.
With impaired renal function
Itraconazole should be used with caution in the treatment of patients with renal insufficiency, since data on the treatment of this category of patients with the drug are limited.
The half-life of the drug in case of impaired renal function is slightly increased, in connection with which its concentration in plasma should be monitored, since itraconazole dose adjustment may be required.
For violations of liver function
Itraconazole should be used with caution when treating patients with hepatic impairment.
The half-life of the drug in case of impaired liver function is slightly increased, in connection with which its concentration in plasma should be monitored, because itraconazole dose adjustment may be required.
There are isolated cases of development of severe toxic liver damage during therapy, including acute liver failure, which ends in death. Such complications were usually observed in patients with pre-existing liver diseases, in those with other severe diseases who received itraconazole for systemic indications, as well as in patients who simultaneously received other drugs with hepatotoxic effects. Given this, during treatment with Itraconazole, regular careful monitoring of liver function is indicated. Patients should be warned about the need for immediate medical attention in case of symptoms that may indicate hepatitis, such as nausea, abdominal pain, dark urine, vomiting, anorexia, weakness. These signs are a direct indication for immediate discontinuation of the drug and a study of liver function.
With increased activity of hepatic enzymes, the presence of active liver disease or postponed toxic liver damage, itraconazole should not be prescribed concurrently with other drugs, except in special cases when the intended benefits for a particular patient justify the possible risks of liver damage. For these categories of patients, treatment should be carried out only with careful monitoring of the activity of liver enzymes.
Use in the elderly
There are limited data on the use of the drug for the treatment of patients of this age group, therefore, itraconazole is prescribed to the elderly only after assessing the benefits and probable risks. In this case, one should take into account the possible age-related decrease in the function of the kidneys, liver and heart, the presence of any concomitant diseases and the simultaneous use of other drugs.
Drug interactions
Drugs that reduce the acidity of gastric juice reduce the absorption of itraconazole.
Inducers of the CYP3A4 isoenzyme (phenytoin, rifabutin, rifampicin) greatly reduce the bioavailability of itraconazole and, as a result, its effectiveness, therefore the use of such combinations is not recommended.
Potent inhibitors of the CYP3A4 isoenzyme (erythromycin, indinavir, ritonavir, clarithromycin) can increase the bioavailability of itraconazole.
Itraconazole is able to inhibit the metabolism of drugs that are cleaved by the CYP3A4 isoenzyme, which may cause prolongation or enhancement of their effects, including side effects.
Along with itraconazole, the following drugs should not be prescribed:
- oral triazolam and midazolam;
- HMG-CoA reductase inhibitors cleaved by the CYP3A4 enzyme (simvastatin, lovastatin);
- cisapride, astemizole, quinidine, levomethadone, mizolastine, sertindole, dofetilide, terfenadine, pimozide;
- ergot alkaloids (methylergometrine, ergometrine, dihydroergotamine, ergotamine).
If necessary, the simultaneous use of the following drugs requires careful monitoring of their action, blood concentration indicators and the development of side effects:
- glucocorticosteroids: budesonide, methylprednisolone, dexamethasone;
- indirect anticoagulants;
- blockers of slow calcium channels, cleaved by the enzyme CYP3A4: verapamil, dihydropyridine;
- HIV protease inhibitors: indinavir, ritonavir, saquinavir;
- inhibitors of reductase HMG-CoA, cleaved by the enzyme CYP3A4: atorvastatin;
- immunosuppressive drugs: tacrolimus, cyclosporine, sirolimus;
- antineoplastic drugs: pink vinca alkaloids, docetaxel, busulfan, trimetrexate;
- other drugs: intravenous midazolam, brotizolam, buspirone, carbamazepine, halofantrine, rifabutin, digoxin, cilostazol, ebastin, eletriptan, alprazolam, repaglinide, reboxetine, alfentanil, disopyramide.
There was no effect of itraconazole on the metabolism of norethisterone and ethinyl estradiol.
No interaction was found between itraconazole and fluvastatin, zidovudine.
In vitro studies, it was found that there is no interaction with plasma protein binding between itraconazole and drugs such as indomethacin, diazepam, sulfadiazine, propranolol, tolbutamide, cimetidine, imipramine.
Analogs
Itraconazole analogues are: Irunin, Itrazol, Orungal, Isol, Orungamin, Itrungar, Itral, Mikokur, Itracon, Sporaxol, Orunzol, Metrix, Itrasin, Trioxal, Ikonazol, Funit, Sporagal, Eszol, Mikostop.
Terms and conditions of storage
Keep out of the reach of children, dry, protected from light at temperatures up to 25 ° C.
The shelf life is 3 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews about Itraconazole
According to reviews, Itraconazole is an effective antifungal agent. However, quite often patients complain about the side effects of the drug.
Price for Itraconazole in pharmacies
The price for Itraconazole is 335–485 rubles per pack of 14 capsules.
Itraconazole: prices in online pharmacies
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Drug name Price Pharmacy |
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Itraconazole 100 mg capsule 15 pcs. 274 r Buy |
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Itraconazole 100 mg capsule 14 pcs. 343 r Buy |
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Itraconazole 100 mg capsule 14 pcs. 346 r Buy |
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Itraconazole capsules 100mg 15 pcs. 418 RUB Buy |
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Itraconazole capsules 100mg 14 pcs. 445 RUB Buy |
Maria Kulkes Medical journalist About the author
Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
