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

auxiliary substances that are part of pellets: sugar pellets 207.44 mg, hypromellose 130.11 mg, poloxamer 188 (lutrol) 25.94 mg, poloxamer 188 (lutrol) micronized 0.51 mg;

composition of the capsule: water (13-16%), dye sunset yellow (1%), titanium dioxide (1%), gelatin (up to 100%).

Description:

Hard gelatin capsules No. 0 in orange,containing spherical microgranules (pellets) from light yellow to yellowish-beige.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A.C.02 Itraconazole

Pharmacodynamics:

Itraconazole, 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 neoformans, Pityrosporum 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 fungi.

Itraconazole disrupts the synthesis of ergosterol, which is an important component of the cell membrane of fungi, which causes the antifungal effect of the drug.

Pharmacokinetics:

Taking itraconazole in capsules immediately after meals increases bioavailability. The maximum concentration in the plasma is reached within 3-4 hours after ingestion. The removal from the plasma is two-phase with a finite T_1/2 24-36 hours. At long reception the equilibrium concentration is reached within 1-2 weeks. The equilibrium concentration of itraconazole in the plasma 3-4 hours after taking the drug is 0.4 μg / ml (100 mg once daily), 1.1 μg / ml (200 mg once a day) and 2, 0 μg / ml (200 mg when taken twice a day). Itraconazole 99.8% is bound by plasma proteins. The concentration of itraconazole in the blood is 60% of the concentration in the plasma.

The accumulation of the drug in keratin tissues, especially in the skin, is about 4 times higher than the accumulation in the plasma, and the rate of its removal depends on the regeneration of the epidermis.

Unlike plasma concentrations that are not detectable within 7 days after cessation of therapy, therapeutic concentrations in the skin persist for 2-4 weeks after discontinuation of a 4-week course of treatment. Itraconazole is found in the nail keratin within one week after the start of treatment and is maintained for at least 6 months after the completion of the 3-month course of therapy. Itraconazole is also determined in sebum and to a lesser extent in the pose. Itraconazole well distributed in tissues that are prone to fungal lesions. Concentrations in the lungs, kidneys, liver, bones, stomach, spleen and muscles were two to three times higher than the corresponding concentrations in the plasma. Therapeutic concentrations in the tissues of the vagina persist for 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 a one-day course of treatment at a dose of 200 mg twice a day.

Itraconazole is metabolized by the liver with the formation of a large number of metabolites. One such metabolite is hydroxy-itraconazole, which has an antifungal action comparable to itraconazole in vitro. 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. Kidney excretion is less than 0.03% of the dose. Approximately 35% of the dose is excreted as metabolites in urine for 1 week.

Since the total T_1/2Itraconazole and its concentration in plasma in patients with renal insufficiency slightly enlarged, a dose adjustment may be required.

Since the total T_1/2Itraconazole and its concentration in plasma in patients with cirrhosis slightly enlarged, a dose adjustment may be required.

Indications:

- Dermatomycosis;

- fungal keratitis;

- onychomycosis caused by dermatophytes and / or yeast and mold fungi;

- Systemic fungal infections:

systemic aspergillosis and candidiasis,
cryptococcosis (including cryptococcal meningitis): in patients with immunodeficiency and in all patients with cryptococcosis of the central nervous system Itraconazole should be prescribed only in cases where the first-line drugs are not applicable in this case or are ineffective,
histoplasmosis,
sporotrichosis,
paracoccidioidomycosis,
blastomycosis,
other rare systemic or tropical mycoses;

- Candidami with skin or mucous membranes, including vulvovaginal candidiasis;

- pityriasis lichen.

Contraindications:

- Hypersensitivity to itraconazole and any of the components of the drug;

- simultaneous reception with Itraconazole capsules of the following preparations:

substrates of the isoenzyme CYP3A4, extending the interval QT (astemizole, bepridil, cisapride, dofetilide, levacetylmetadol, misolastine, pimozide, quinidine, sertindole, terfenadine);
inhibitors of HMG-CoA reductase metabolized by the isoenzyme CYP3A4 (lovastatin, simvastatin);
simultaneous oral administration of triazolam and midazolam, nisoldipine, eletriptan;
preparations of ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergomethrin;

- fructose intolerance, sugarase / isomaltase deficiency, glucose-galactose malabsorption;

- children under 3 years;

- pregnancy and lactation.

Carefully:

With cirrhosis of the liver, liver failure, chronic renal failure, periphyric neuropathy, chronic heart failure (CHD, damage to the heart valves, severe lung diseases, including COPD, conditions accompanied by edematous syndrome), hypersensitivity to other azoles, hearing impairment, with the simultaneous reception of blockers of "slow" calcium channels, children and the elderly.

Pregnancy and lactation:

Pregnancy is an absolute contraindication for the use of the drug Itraconazole.

Because the itraconazole can penetrate into breast milk, if it is necessary to use during the lactation period, women who use itraconazole capsules should stop breastfeeding.

Dosing and Administration:

For optimal absorption of the drug, it is necessary to take Itraconazole capsules immediately after meals. Capsules should be swallowed whole.

Indication				Dose				Duration of treatment
Vulvovaginal candidiasis			200 mg twice daily or 200 mg once daily					1 day or 3 days
Multicolored lichen			200 mg once a day					7 days
Dermatomycosis smooth skin			200 mg once a day or 100 mg once a day					7 days or 15 days
Defeats high-keratinized areas of the skin, such as hands and feet			200 mg 2 times a day or 100 mg once a day					7 days or 30 days
Candidiasis of the oral mucosa			100 mg once a day					15 days
Bioavailability of itraconazole for oral administration may be reduced in some patients with impaired immunity, for example, in patients with neutropenia, AIDS patients or organ transplants. Therefore, a double dose increase may be required.
Fungal keratitis			200 mg once a day					21 day Duration of treatment can be adjusted depending on the improvement of the clinical picture
Onychomycosis caused by dermatophytes and / or yeast-like and mold fungi
Onychomycosis - pulse therapy	Doses and duration of treatment
	One course of pulse therapy is a daily intake of 2 capsules of the drug 2 times a day for 1 week. For treatment of fungal lesions of the nail plates of the brushes, 2 courses are recommended. For treatment of fungal lesions of the nail plates of the feet, 3 courses are recommended. The gap between the courses during which you do not need to take the drug is 3 weeks.Clinical results will become evident after the end of treatment, as the nails grow.
Localization onychomycosis	1st week	2 nd week		3rd week	4th week	5th week	6th week		7th week	8th week	9th week
Lesion of the nail plates of the toes with or without defeat of the nail plates of the fingers	1st year	Weeks free from taking the drug				2 nd year	Weeks free from taking the drug				3rd year
Defeat nail records brushes	1st year	Weeks free from taking the drug				2 nd year
Onychomycosis continuous treatment		Dose					Duration of treatment
Lesions of the nail plates of the feet with or without defeat of the nail plates of the brushes		200 mg per day					3 months

The removal of itraconazole from the skin and nail tissue is slower than from the plasma. Thus, optimal clinical and mycological effects are achieved after 2-4 weeks after the end of treatment for skin infections and 6-9 months after the end of treatment for nail infections.

Systemic mycoses
Indication	Dose	Average Duration treatment *	Remarks
Aspergillosis	200 mg once a day	2-5 months	Increase the dose to 200 mg twice a day for invasive or disseminated disease
Candidiasis	100-200 mg once a day	from 3 weeks to 7 months	Increase the dose to 200 mg twice a day for invasive or disseminated disease
Cryptococcosis (except meningitis)	200 mg once a day	from 2 months to 1 year
Cryptococcal meningitis	200 mg twice daily	from 2 months to 1 year	Maintenance therapy, see section "Special instructions"
Histoplasmosis	from 200 mg once a day to 200 mg twice a day	8 months
Blastomycosis	from 100 m g once a day to 200 mg twice a day	6 months
Sporotrichosis	100 mg once a day	3 months
Paracoccidioidomycosis	100 mg once a day	6 months	Data on the effectiveness of this dosage for the treatment of paracoccidioidomycosis in AIDS patients are absent
Chromomycosis	100-200 mg once a day	6 months

* - duration of treatment can be adjusted depending on the clinical picture of the treatment.

Dosing regimen in pediatric practice: since data on the use of itraconazole in children is not enough, 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 administered to children aged 3 to 16 years at a dosage of 100 mg once a day for the treatment of systemic fungal infections, no side effects were observed.

Side effects:

From the digestive system: dyspepsia (nausea, vomiting, diarrhea, constipation, decreased appetite), abdominal pain, eating disorders, hyperbilirubinemia, hepatic enzyme activity, hepatitis, acute hepatic insufficiency, hepatotoxicity.

From the nervous system: headache, dizziness, peripheral neuropathy, paresthesia, hypoesthesia.

Allergic reactions: anaphylactic and anaphylactoid reactions, serum sickness, skin rash, itching, urticaria, angioedema, multiforme exudative erythema (Stevens-Johnson syndrome), polymorphic erythema.

From the hematopoiesis: infrequently - leukopenia, neutropenia, thrombocytopenia.

From the side of metabolism: hypertriglyceridemia, hypokalemia.

From the sense organs: impaired vision, including vagueness and diplopia; noise in the ears, transient or permanent deafness.

From the side of the cardiovascular system: acute heart failure.

From the respiratory system: pulmonary edema.

From the skin: exfoliative dermatitis, leukoclastic vasculitis.

From the side of the musculoskeletal system: myalgia, arthralgia.

From the genitourinary system: pollakiuria, incontinence, erectile dysfunction, menstrual irregularities.

Other: alopecia, edematous syndrome, photosensitivity.

Overdose:

There are limited data that when taking itraconazole in capsules at a dose above 3000 mg, the same side effects were observed as with the administration of itraconazole in therapeutic doses.

Itraconazole is not removed from the body during hemodialysis. There is no specific antidote. In case of an overdose, supportive therapy should be performed, a gastric lavage with sodium bicarbonate solution should be done, Activated carbon.

Interaction:

1. Medicines that affect the absorption of itraconazole.

Drugs that reduce the acidity of gastric juice, reduce the absorption of itraconazole, which is associated with the solubility of capsule shells.

2. Medicines that affect the metabolism of itraconazole.

Itraconazole mainly is isoenzyme CYP3A4. The interaction of itraconazole with rifampicin, rifabutin and phenytoin, which are potent inducers of the isoenzyme CYP3A4.The study found that in these cases, the bioavailability of itraconazole and hydroxy-itraconazole is significantly reduced, which leads to a significant decrease in the effectiveness of the drug. Simultaneous application of itraconazole with these drugs, which are potential inducers of microsomal liver enzymes, is not recommended. Studies of interaction with other inducers of microsomal liver enzymes, such as carbamazepine, phenobarbital and isoniazid, were not conducted, however, similar results can be assumed.

Powerful inhibitors of isoenzyme CYP3A4, such as ritonavir, indinavir, clarithromycin and erythromycin, can increase the bioavailability of itraconazole.

3. Effect of itraconazole on the metabolism of other drugs.

Itraconazole can inhibit the metabolism of drugs cleaved by an isoenzyme CYP3A4. 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 ways of metabolism of this drug, indicated in the instructions for medical use.After discontinuation of treatment, the concentrations of itraconazole in the plasma are reduced gradually depending on the dose and duration of treatment. This need to be taken into account when discussing the inhibitory effect of itraconazole on concomitant medications.

Examples of such medicines are:

Drugs that can not be administered simultaneously with itraconazole:

terfenadine, astemizole, misolastine, cisapride, dofetilide, quinidine, pimozide, levomethadone, sertindole - the combined use of these drugs with itraconazole may cause an increase in the concentration of these substances in the plasma and increase the risk of prolongation of the QT interval and, in rare cases, the occurrence of atrial fibrillation (torsade des pointes);
CYP3A4 cleavage inhibitors of HMG-CoA reductase, such as simvastatin and lovastatin;
midazolam for oral administration and triazolam;
ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergomethrin;
in addition to the possible pharmacokinetic interaction associated with a common metabolic pathway involving the enzyme CYP3A4, slow calcium channel blockers may have a negative inotropic effect, which is enhanced by simultaneous administration with itraconazole.

Preparations, in the appointment of which it is necessary to monitor their concentrations in plasma, action, side effects

In the case of simultaneous administration with itraconazole dose of these drugs, if necessary, should be reduced:

indirect anticoagulants;
HIV protease inhibitors, such as ritonavir, indinavir, saquinavir;
Some anti-tumor drugs, such as vinca alkaloids pink, busulfan, docetaxel, trimetrexate;
CYP3A4 digested enzyme "slow" calcium channel blockers, such as verapamil and dihydropyridine derivatives;
some immunosuppressive agents: ciclosporin, tacrolimus, sirolimus Some CYP3A4 cleavable HMG-CoA reductase inhibitors, such as atorvastatin;
Some glucocorticosteroids, such as budesonide, dexamethasone and methylprednisolone;
other drugs: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotisolam, midazolam for intravenous administration, rifabutin, ebastia, reboxetine, cilostazol, disopyramide, eletriptan, halofantrine, repaglinide.

Interactions between itraconazole and zidovudine and fluvastatin were not detected.

There was no effect of itraconazole on the metabolism of ethinylestradiol and norethisterone.

4. Effect on the connection with plasma proteins.

Research in vitro demonstrated lack of interaction between itraconazole and such drugs as imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfadiazine when binding to plasma proteins.

Special instructions:

- Women of childbearing age, taking capsules of Itraconazole, it is necessary to use adequate contraceptive methods throughout the course of treatment until the onset of the first menstrual period after its completion.

- It was found that itraconazole possesses negative inotropic effect. With simultaneous administration of itraconazole and blockers of "slow" calcium channels, which can have the same effect, care must be taken. Cases of congestive heart failure associated with taking itraconazole have been reported. Itraconazole Do not take patients with chronic heart failure or the presence of this disease in history, except when the possible benefits far exceed the potential risk.

When assessing the benefit / risk ratio individually, one should take into account such factors as the severity of the indications,dosage regimen and individual risk factors for congestive heart failure. Risk factors include the presence of heart disease, such as ischemic heart disease or valve lesions; serious lung diseases, such as obstructive pulmonary disease; renal failure or other diseases accompanied by edema. Such patients should be informed about the signs and symptoms of congestive heart failure. Treatment should be done with caution, while monitoring the patient for symptoms of congestive heart failure. When they appear, taking Itraconazole capsules should be stopped.

- With reduced acidity of gastric juice: in this condition, the absorption of itraconazole from the capsules is impaired. Patients taking antacid preparations (for example, aluminum hydroxide), it is recommended to use them not earlier than 2 hours after taking the capsules of Itraconazole. Patients with achlorhydria or using blockers H₂-gistaminovyh receptors and proton pump inhibitors, it is recommended to take capsules of Itraconazole with cola.

- In very rare cases, with the use of itraconazole, severe toxic liver damage, including cases of acute hepatic insufficiency with a fatal outcome. In most cases, this was noted in patients who already had liver disease, in patients with other serious illnesses who received itraconazole therapy but systemic indications, as well as in patients receiving other drugs with a hepatotoxic effect. In some patients, there were no 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 therapy. Patients should be warned about the need to immediately contact their doctor if symptoms occur that suggest hepatitis, namely: anorexia, nausea, vomiting, weakness, abdominal pain and darkening of the urine. In the case of such symptoms it is necessary to immediately stop therapy and conduct a study of liver function.Patients with increased hepatic enzyme activity or liver disease in the active phase, or with transferred toxic liver damage with other medications should not be treated with Itraconazole, unless the expected benefit justifies the risk of liver damage. In these cases it is necessary during the treatment to monitor the activity of liver enzymes.

- Dysfunction of the liver: itraconazole it is metabolized primarily in the liver. Since in patients with impaired liver function complete T_1/2itraconazole is slightly increased, it is recommended to monitor the concentrations of itraconazole in the plasma and, if necessary, adjust the dose of the drug.

- Impaired renal function: Since in patients with renal insufficiency complete T_1/2itraconazole is slightly increased, it is recommended to monitor the concentrations of itraconazole in the plasma and, if necessary, adjust the dose of the drug.

- Patients with immunodeficiency: the bioavailability of itraconazole for oral administration may be reduced in some immunocompromised patients, for example, in patients with neutropenia who have AIDS or who underwent an organ transplant operation.

- Patients with systemic fungal infections that are life-threatening: due to the pharmacokinetic characteristics of itraconazole in the form of capsules is not recommended for the initiation of treatment of systemic mycoses that pose a threat to the lives of patients.

- AIDS patients: the attending physician should evaluate the need to prescribe supportive therapy for people with AIDS who have previously been treated for systemic fungal infections, such as sporotrichosis, blastomycosis, histoplasmosis, or cryptococcosis (both meningeal and non-meninge) who are at risk of recurrence,

- Treatment should be discontinued when peripheral neuropathy, which may be associated with the administration of Itraconazole capsules.

- No data about cross-over-hypersensitivity to itraconazole and other azole antifungal agents.

Effect on the ability to drive transp. cf. and fur:

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.

Form release / dosage:

Capsules, 100 mg.

Packaging:

For 5, 6 or 7 capsules in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 1, 2 or 3 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Storage conditions:

In a place protected from moisture and light, at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LS-001607

Date of registration:14.10.2011 / 12.04.2013

Expiration Date:Unlimited

The owner of the registration certificate:AVVA RUS, OJSC AVVA RUS, OJSC Russia

Manufacturer: & nbsp

AVVA RUS, OJSC Russia

Laboratorios LICONSA, S.A. Spain

Representation: & nbspAVVA ENG JSC AVVA ENG JSC Russia

Information update date: & nbsp28.11.2017

Illustrated instructions

Instructions

Itraconazole (Itraconazole)