Instructions for Itraconazole
Composition Itraconazole:
One capsule contains: active substance
Indications Itraconazole:
- Dermatomycosis
- fungal keratitis
- onychomycosis caused by dermatophytes and / or yeast and molds
- systemic mycoses
- systemic aspergillosis and candidiasis
- cryptococcosis (including cryptococcal meningitis): in patients with immunodeficiency and in all patients with cryptococcosis of the central nervous system
- should be prescribed only in cases where first-line drugs are not applicable in this case or are ineffective
- histoplasmosis
- sporotrichosis
- paracoccidioidomycosis
- blastomycosis
- other rare systemic or tropical mycoses
- candidiasis with damage to the skin or mucous membranes
- including vulvovaginal candidiasis
- pityriasis versicolor
Pharmacodynamics Itraconazole:
Itraconazole Oral, a triazole derivative, is active against infections caused by dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeast-like fungi and yeast (Candida spp., Including C.albicans, C.glabrata and C.krusei, Cryptococcus nephosis spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, Pseudallescheria boydii, Penicillium marneffei, as well as other yeast and mold. Itraconazole Oral disrupts the synthesis of ergosterol, which is an important component of the cell membrane of fungi, which determines the antifungal effect of the drug Itraconazole Oral.
Pharmacokinetics Itraconazole:
Taking antifungal agent in capsules immediately after a meal increases bioavailability. The maximum plasma concentration is achieved within 3-4 hours after ingestion. Excretion from plasma is biphasic with a final T1 / 2 of 24-36 hours. With prolonged use, an equilibrium concentration is achieved within 1-2 weeks. The equilibrium plasma concentration of itraconazole 3-4 hours after taking the drug is 0.4 μg / ml (100 mg when taken once a day), 1.1 μg / ml (200 mg when taken once a day) and 2, 0 μg / ml (200 mg when taken twice a day). Itraconazole is 99.8% bound to plasma proteins. The concentration of Itraconazole Oral in the blood is 60% of the concentration in plasma.
The accumulation of the drug in keratin tissues, especially in the skin, is about 4 times higher than the accumulation in plasma, and its excretion rate depends on the regeneration of the epidermis. Unlike plasma concentrations that are not detectable as early as 7 days after discontinuation of therapy, therapeutic concentrations in the skin persist for 2-4 weeks after discontinuation of the 4-week course of treatment. Itraconazole is found in nail keratin already one week after the start of treatment and persists for at least 6 months after completion of a 3-month course of therapy. Itraconazole is also determined in sebum and to a lesser extent in posture. antifungal agent is well distributed in tissues that are susceptible to fungal infections.
Concentrations in the lungs, kidneys, liver, bones, stomach, spleen and muscles were two to three times higher than the corresponding plasma concentrations. The therapeutic concentrations Itraconazole Oral in the vaginal tissues are maintained for another 2 days after the end of the 3-day course of treatment at a dose of 200 mg per day, and 3 days after the end of the one-day course of treatment at a dose of 200 mg twice a day. Itraconazole Oral is metabolized by the liver to form a large number of metabolites. One of these metabolites is hydroxy antifungal agent, which has an in vitro antifungal effect comparable to that of itraconazole. The antifungal concentrations of the drug, determined by the microbiological method, were approximately 3 times higher than the concentrations measured by HPLC.
Excretion with feces is from 3 to 18% of the dose. Excretion by the kidneys is less than 0.03% of the dose. Approximately 35% of the dose is excreted as metabolites in the urine for 1 week. Since the total T1 / 2 of antifungal agent and its plasma concentration in patients with renal failure are slightly increased, a dose adjustment may be required. Since the total T1 / 2 of Itraconazole Oral and its plasma concentration in patients with cirrhosis are slightly increased, a dose adjustment may be required.
Itraconazole Side Effects:
From the digestive system: dyspepsia (nausea, vomiting, diarrhea, constipation, decreased appetite), abdominal pain, impaired taste, hyperbilirubinemia, increased activity of liver enzymes, hepatitis, acute liver failure, hepatotoxicity.
From the nervous system: headache, dizziness, peripheral neuropathy, paresthesia, hypesthesia. Allergic reactions: anaphylactic and anaphylactoid reactions, serum sickness, skin rash, pruritus, urticaria, angioedema, exudative erythema multiforme (Stevens-Johnson syndrome), polymorphic erythema. From the hemopoietic organs: infrequently - leukopenia, neutropenia, thrombocytopenia. From the side of metabolism: hypertriglyceridemia, hypokalemia.
From the sensory organs: visual impairment, including vagueness and diplopia; tinnitus, transient or permanent deafness. From the cardiovascular system: acute heart failure. From the respiratory system: pulmonary edema.
From the skin: exfoliative dermatitis, leukoclastic vasculitis. From the musculoskeletal system: myalgia, arthralgia.
From the genitourinary system: pollakiuria, urinary incontinence, erectile dysfunction, menstrual irregularities. Other: alopecia, edematous syndrome, photosensitivity.
Special conditions Itraconazole:
- Women of childbearing age taking Itraconazole Oral capsules need to use adequate methods of contraception throughout the course of treatment until the onset of the first menstruation after its completion. - antifungal agent was found to have a negative inotropic effect.
With the simultaneous administration of Itraconazole Oral and blockers of "slow" calcium channels, which may have the same effect, caution must be exercised. Cases of congestive heart failure associated with Itraconazole Oral have been reported. antifungal agent should not be taken in patients with chronic heart failure or with a history of the disease, unless the potential benefit significantly exceeds the potential risk.
In an individual assessment of the benefit-risk ratio, factors such as the severity of the indications, dosing regimen and individual risk factors for congestive heart failure should be taken into account. Risk factors include the presence of heart disease, such as coronary heart disease or valve damage; serious lung diseases such as obstructive pulmonary disease; renal failure or other diseases accompanied by edema.
Such patients should be informed of the signs and symptoms of congestive heart failure. Treatment should be carried out with caution, while it is necessary to monitor the patient for symptoms of congestive heart failure.
When they appear, Itraconazole Oral capsules should be discontinued. - With reduced acidity of gastric juice: in this condition, the absorption of antifungal agent from the capsules is impaired. Patients taking antacids (for example, aluminum hydroxide) are recommended to use them no earlier than 2 hours after taking Itraconazole capsules. Patients with achlorhydria or those using H2 histamine receptor blockers and proton pump inhibitors are advised to take Itraconazole Oral with cola capsules.
- In very rare cases, when Itraconazole Oral was used, severe toxic liver damage developed, including cases of fatal acute liver failure.
In most cases, this was noted in patients who already had liver disease, in patients with other serious diseases who received itraconazole therapy but systemic indications, as well as in patients receiving other drugs with hepatotoxic effects.
Some patients did not reveal obvious risk factors for liver damage. Several such cases occurred in the first month of therapy, and some in the first week of treatment. In this regard, it is recommended to regularly monitor liver function in patients receiving Itraconazole Oral therapy.
Patients should be warned about the need to immediately contact their doctor in case of symptoms suggesting the onset of hepatitis, namely: anorexia, nausea, vomiting, weakness, abdominal pain and dark urine. In the event of such symptoms, it is necessary to immediately stop therapy and conduct a liver function test.
Patients with increased activity of liver enzymes or liver disease in the active phase, or with toxic liver damage while taking other drugs should not be prescribed Itraconazole Oral treatment, unless the expected benefit justifies the risk of liver damage. In these cases, it is necessary to monitor the activity of liver enzymes during treatment.
- Dysfunction of the liver: antifungal agent is metabolized mainly in the liver. Since in patients with impaired liver function the full T1 / 2 of itraconazole is slightly increased, it is recommended to monitor plasma concentrations of Itraconazole Oral and adjust the dose of the drug if necessary. - Impairment of renal function: Since in patients with renal insufficiency the total T1 / 2 of itraconazole is slightly increased, it is recommended to monitor plasma concentrations of antifungal agent and, if necessary, adjust the dose of the drug. - Patients with immunodeficiency: oral bioavailability of Itraconazole Oral may be reduced in some patients with impaired immunity, for example, patients with neutropenia, AIDS patients, or undergoing organ transplant surgery. - Patients with systemic fungal infections that are life-threatening: due to the pharmacokinetic characteristics of Itraconazole Oral in the form of capsules, it is not recommended to begin treatment of systemic mycoses that pose a threat to the life of patients. - AIDS patients:
the attending physician should assess the need for prescribing maintenance therapy for AIDS patients who have previously received treatment for systemic fungal infections, for example, sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (both meningeal and non-meningeal), which have a risk of relapse, - Treatment should be discontinued if peripheral neuropathy occurs, which may be associated with taking Itraconazole Oral capsules. - There is no evidence of cross-sensitivity to itraconazole and other azole antifungal drugs. Effect of the drug on the ability to drive vehicles and other mechanisms: Itraconazole causes side effects from the central nervous system and sensory organs, such as dizziness, blurred vision, including vagueness and diplopia, which can affect the ability to drive vehicles and work with mechanisms.
Contraindications Itraconazole:
Hypersensitivity to antifungal agent and any of the components of the drug
simultaneous administration of the following preparations with Itraconazole Oral capsules: substrates of the CYP3A4 isoenzyme extending the QT interval (astemizole, bepridil, cisapride, dofetilide, levacetylmethadol, misolastine, pimozide, quinidine, sertindole, terfenadine); HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (lovastatin, simvastatin);
simultaneous oral administration of triazolam and midazolam, nisoldipine, eletriptan; ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergometrine;
- fructose intolerance, sucrose / isomaltase deficiency, glucose-galactose malabsorption; - children's age up to 3 years; - pregnancy and lactation.
With caution: With cirrhosis, liver failure, chronic renal failure, peripheral neuropathy, chronic heart failure (IHD, damage to the heart valves, severe lung diseases, including COPD, conditions accompanied by edema syndrome), hypersensitivity to other azoles, hearing impairment, while taking blockers of "slow" calcium channels, children and the elderly. Pregnancy and lactation: Pregnancy is an absolute contraindication for the use of Itraconazole Oral. Since antifungal agent Oral can pass into breast milk, if it is necessary to use it during lactation, women who use antifungal agent capsules should stop breast-feeding.
Drug Interactions Itraconazole:
Medicines that affect the absorption of Itraconazole Oral. Medicines that reduce the acidity of gastric juice, reduce the absorption of antifungal agent, which is associated with the solubility of the capsule shells.
Medicines that affect the metabolism of Itraconazole Oral.
Itraconazole is mainly cleaved by the CYP3A4 isoenzyme. The interaction of Itraconazole Oral with rifampicin, rifabutin and phenytoin, which are powerful inducers of the CYP3A4 isoenzyme, was studied.
The study found that in these cases the bioavailability of Itraconazole Oral and hydroxy antifungal agent is significantly reduced, which leads to a significant decrease in the effectiveness of the drug. The simultaneous use of Itraconazole Oral with these drugs, which are potential inducers of microsomal liver enzymes, is not recommended. Studies of interactions with other inducers of microsomal liver enzymes, such as carbamazepine, phenobarbital and isoniazid, have not been conducted, but similar results can be assumed.
Powerful inhibitors of the CYP3A4 isoenzyme, such as ritonavir, indinavir, clarithromycin, and erythromycin, can increase the bioavailability of Itraconazole Oral.
The effect of antifungal agent on the metabolism of other drugs.
Itraconazole Oral may inhibit the metabolism of drugs cleaved by the CYP3A4 isoenzyme. The result of this may be an increase or prolongation of their action, including side effects. With the simultaneous use of other drugs, it is necessary to consult with your doctor about the metabolic pathways of this drug indicated in the instructions for medical use.
After discontinuation of treatment, plasma concentrations of Itraconazole Oral decrease gradually depending on the dose and duration of treatment. This must be taken into account when discussing the inhibitory effect of pills on concomitant medications. Examples of such drugs are:
Drugs that cannot be prescribed simultaneously with Itraconazole Oral: terfenadine, astemizole, misolastine, cisapride, dofetilide, quinidine, pimozide, levomethadone, sertindole - the combined use of these drugs with antifungal agent can cause an increase in the concentration of these substances in plasma and increase the risk lengthening of the QT interval and in rare cases - the occurrence of atrial fibrillation of the ventricles (torsade des pointes); HMG-CoA reductase inhibitors cleaved by the CYP3A4 enzyme, such as simvastatin and lovastatin; midazolam for oral administration and triazolam; ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergometrine; in addition to the possible pharmacokinetic interaction associated with a common metabolic pathway involving the CYP3A4 enzyme, “slow” calcium channel blockers can have a negative inotropic effect, which is enhanced when taken with itraconazole. Drugs, the appointment of which is necessary to monitor their plasma concentrations, action, side effects
In the case of simultaneous administration with Itraconazole Oral, the dose of these drugs, if necessary, should be reduced: indirect anticoagulants; HIV protease inhibitors such as ritonavir, indinavir, saquinavir; some anticancer drugs, such as pink vinca alkaloids, busulfan, docetaxel, trimerexate; CYP3A4 enzyme-cleavable “slow” calcium channel blockers, such as verapamil and dihydropyridine derivatives; some immunosuppressive drugs: cyclosporine, tacrolimus, sirolimus; Some enzymes cleaved by CYP3A4, HMG-CoA reductase inhibitors, such as atorvastatin; certain glucocorticosteroids such as budesonide, dexamethasone and methylprednisolone; other drugs: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam for intravenous administration, rifabutin, ebastia, reboxetine, cilostazol, disopyramide, eletriptan, halofantrine, repaglinide. No interaction between antifungal agent and zidovudine and fluvastatin was found.
No effect of Itraconazole Oral on the metabolism of ethinyl estradiol and norethisterone was noted. 4. Effect on communication with plasma proteins. In vitro studies have shown a lack of interaction between Itraconazole Oral and drugs such as imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfadiazine when bound to plasma proteins.
Dosage Itraconazole:
For optimal absorption of the drug, Itraconazole capsules should be taken immediately after meals. Capsules should be swallowed whole. Vulvovaginal candidiasis - 200 mg 2 times a day or 200 mg 1 time per day - 1 day or 3 days Multi-colored lichen - 200 mg 1 time per day - 7 days Dermatomycosis of smooth skin - 200 mg 1 time per day or 100 mg 1 time per day - 7 days or 15 days
Lesions of highly keratinized areas of the skin, such as hands and feet - 200 mg 2 times a day or 100 mg 1 time per day - 7 days or 30 days Candidiasis of the oral mucosa - 100 mg 1 time per day - 15 days Bioavailability of pills with oral administration may be reduced in some immunocompromised patients, for example, patients with neutropenia, AIDS patients, or with transplanted organs. Therefore, a double dose increase may be required. Fungal keratitis - 200 mg once a day - 21 days. The duration of treatment can be adjusted depending on the improvement of the clinical picture of Onychomycosis caused by dermatophytes and / or yeast-like and mold fungi Onychomycosis - pulse therapy
- One course of pulse therapy consists in daily intake of 2 capsules of the drug 2 times a day for 1 week. For the treatment of fungal lesions of the nail plates of the hands, 2 courses are recommended. For the treatment of fungal infections of the nail plates of the feet, 3 courses are recommended. The interval between courses, during which you do not need to take the drug, is 3 weeks. Clinical results will become apparent after treatment, as the nails grow (see instructions). antifungal agent is removed from the skin and nail tissue more slowly than from plasma. Thus, optimal clinical and mycological effects are achieved 2-4 weeks after the end of treatment for skin infections and 6-9 months after the end of treatment of nail infections. (see instructions) Dosage regimen in pediatric practice: since there are insufficient data on the use of itraconazole in children, it is recommended to prescribe the drug to children only if the possible benefit exceeds the potential risk. It is known that the drug was prescribed for children aged 3 to 16 years old at a dosage of 100 mg once a day for the treatment of systemic fungal infections, with no side effects observed.
Overdose Itraconazole:
There is limited evidence that when taking in capsules a dose above 3000 mg, the same side effects were observed as when taking pills in therapeutic doses.
antifungal agent is not removed from the body during hemodialysis. There is no specific antidote. In case of an overdose, maintenance therapy should be carried out, gastric lavage should be done with sodium bicarbonate solution, and activated charcoal should be taken.
