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

Excipients: Neutral pellets (sugar balls), sucrose, hypromellose-E5 (HPME-E5), povidone K-30, propylene glycol 20000, methyl-, dimethylaminoethyl- and butyl methacrylate copolymer (eudragit E-100);

capsule shell: methyl parahydroxybenzoate, propyl parahydroxybenzoate, gelatin; lid (dyes): Ponso 4R (E 124), yellow "sunset sunset" (E 110), titanium dioxide (E 171); body (dyes): titanium dioxide (E 171)

Description:

Hard gelatin capsules №0 with a white body and a red lid containing pellets of white and white with a grayish shade of color.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A.C.02 Itraconazole

Pharmacodynamics:

Itraconazole, a derivative of triazole, 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 mameffei, as well as other yeast and mold fungi. Itraconazole violates the synthesis of ergosterol, which is an important component of the cell membrane of fungi, which causes the antifungal effect of the drug.

Pharmacokinetics:

When administered orally, the maximum bioavailability of itraconazole is noted when taking capsules immediately after meals. The maximum concentration in the plasma is reached within 3-4 hours after ingestion. The elimination from the plasma is biphasic with a finite half-life of 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 mcg / ml (100 mg when taken once a day), 1,1 mcg / ml (200 mg once daily) and 2.0 μg / ml (200 mg twice daily). 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 sweat.

Itraconazole is 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 is comparable with itraconazole antifungal action 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 full half-life of itraconazole and its plasma concentration in patients with cirrhosis is slightly increased, it may be necessary to adjust the dose (see section "Special instructions").

Indications:

- Dermatomycosis;

- fungal keratitis;

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

- 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 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 systemic or tropical mycoses;

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

- deep visceral candidiasis;

- pityriasis lichen.

Contraindications:

- Individual hypersensitivity to the drug or its constituents;

- simultaneous with itraconazole administration of the following drugs (see also the section "Interactions with other drugs"):

drugs metabolized by the enzyme CYP3A4, which can be prolonged QT interval such as terfenadine, astemizole, misolastine, cisapride, dofetilide, quinidine, pimozide, levomethadone, sertindole;
enzyme-cleavable CYP3A4 HMG-CoA reductase inhibitors, such as simvastatin and lovastatin;
midazolam for oral administration and triazolam;
preparations of ergot alkaloids, such as dihydroergotamine, ergometrine, ergotamine and methylergomethrin.

Carefully:

In cirrhosis, chronic renal failure, chronic heart failure, hypersensitivity to other azoles, in children and elderly patients (see also section "Special instructions").

Pregnancy and lactation:

Itraconazole should be prescribed during pregnancy only in life-threatening cases, when the expected positive effect exceeds the possible harm to the fetus.

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

Dosing and Administration:

For optimum absorption of the drug, it is necessary to take Itraconazole in capsules immediately after eating.

Capsules should be swallowed whole.

Indication	Dose	Duration treatment
Vulvovaginal candidiasis	200 mg twice a day or 200 mg once a day	1 day or 3 days
Peregrine lichen	200 mg once a day	7 days
Dermatomycosis smooth skin	200 mg once daily 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
Fungal keratitis	200 mg once a day	21 day Duration of treatment can be adjusted depending on the improvement of the clinical picture
Oral candidiasis	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.

Onychomycosis caused by dermatophytes and / or yeast and molds

Doses and duration of treatment

Onychomycosis - pulse therapy

One course of pulse therapy is a daily intake of 2 capsules of Itraconazole twice a day (200 mg twice a day) for one week.

Two courses are recommended for the treatment of fungal lesions of the nail plates of the brushes. For the treatment of fungal lesions of the nail plates of the feet, three 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

ned.

2nd

ned.

3rd

ned.

4th

ned.

5th

ned.

6th

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7th

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8th

ned.

9th

ned.

Lesions of the nail plates of the feet with or without defeat of the nail plates of the brushes

1st

course

Weeks free of course free from the intake of Itraconazole

2 nd

course

Weeks free of course free from the intake of Itraconazole

3rd

course

Lesion of the nail plates of brushes

1st

course

Weeks free of course free from the intake of Itraconazole

2 nd

course

Onychomycosis - continuous treatment

Dose

200 mg per day

Duration

treatment 3 months

Lesions of the nail plates of the feet with or without defeat of the nail plates of the brushes

Itraconazole removal from skin and nail tissue is slower than from plasma. Thus, optimal clinical and mycological effects are achieved in 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

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

Pediatric Use

Capsules Itraconazole should not be given to children unless the expected benefit exceeds the possible risk.

Side effects:

From the gastrointestinal tract: dyspepsia (nausea, vomiting, diarrhea, constipation, decreased appetite), abdominal pain.

From the hepatobiliary system: reversible increase in hepatic enzymes, hepatitis, in very rare cases with the use of Itraconazole developed severe toxic liver damage, including cases of acute hepatic insufficiency with a fatal outcome.

From the nervous system: headache, dizziness, peripheral neuropathy

On the part of the immune system, anaphylactic, anaphylactoid and allergic reactions

From the skin: in very rare cases - multiforme exudative erythema (Stevens-Johnson syndrome) skin rash, itchy skin, hives, angioedema, alopecia, photosensitivity

Other: disorders of the menstrual cycle, hypokalemia, edematous syndrome, congestive heart failure and pulmonary edema, hypercreatininaemia, staining of urine in a dark color.

Overdose:

No data available. In case of an accidental overdose, supportive measures should be used. During the first hour, wash the stomach and, if necessary, assign Activated carbon. Itraconazole not excreted by hemodialysis.

There is no specific antidote.

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 is mainly digested with an enzyme CYP3A4. The interaction of itraconazole with rifampicin, rifabutin and phenytoin, which are potent inducers of the enzyme 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 use of itraconazole with these drugs, which are potential inducers of hepatic enzymes, is not recommended. Investigations of interaction with other inducers of hepatic enzymes, such as carbamazepine, phenobarbital and isoniazid, were not conducted, however, similar results can be assumed.

Strong inhibitors of the enzyme 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 enzyme-cleavable drugs CYP3A4. The result of this may be an increase or prolongation of their action, including side effects. Before starting to take concomitant medications, you should consult 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 decrease gradually depending on the dose and duration of treatment (see the section "Pharmacokinetics "). 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 level of these substances in the plasma and increase the risk of prolonging the QT interval and, in rare cases, the occurrence of atrial fibrillation (torsade de 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;
calcium channel blockers - in addition to the possible pharmacokinetic interaction associated with a common metabolic pathway involving the enzyme CYP3A4, calcium channel blockers can 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, the dose of these drugs, if necessary, should be reduced;

oral anticoagulants;
HIV protease inhibitors, such as ritonavir, indinavir, saquinavir;
Some anti-tumor drugs, such as vinca alkaloids pink, busulfan, docetaxel, trimetrexate;
digestible by the enzyme CYP3A4 calcium channel blockers, such as verapamil and dihydropyridine derivatives;
some immunosuppressive agents: ciclosporin, tacrolimus, rapamycin;
some CYP3A4 enzyme-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, ebastine, 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 protein binding.

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

Special instructions:

- Women of childbearing age, host Itraconazole, it is necessary to use adequate methods of contraception throughout the course of treatment until the onset of the first menstruation after its completion.

- When studying the drug form of the drug Itraconazole for intravenous administration, conducted on healthy volunteers, there was a transient asymptomatic reduction of left ventricular ejection fraction, normalized until the next infusion of the drug. The clinical significance of the data obtained for oral dosage forms is unknown.

- It was found that itraconazole possesses negative inotropic effect. With the simultaneous administration of itraconazole and calcium channel blockers, which may have the same effect, care must be taken. Cases of congestive heart failure associated with taking Itraconazole have been reported.

Itraconazole should not be taken patients with chronic heart failure or with the presence of this disease in the history, except when the possible benefits far exceed the potential risk. When assessing the benefit-risk ratio individually, factors such as the severity of the indications, the dosage regimen, and individual risk factors for congestive heart failure should be taken into account. 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, the intake of Itraconazole should be discontinued.

- 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. Patients with achlorhydria or using H₂-blocks or 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 diseases who received itraconazole therapy for systemic indications, as well as for patients receiving other drugs with 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 elevated levels of hepatic enzymes or liver disease in the active phase, or with transferred toxic liver damage when taking other medications should not be prescribed treatment with Itraconazole forexcept when the expected benefit justifies the risk of liver damage. In these cases, it is necessary to control the level of hepatic enzymes during treatment.

- Dysfunction of the liver: itraconazole it is metabolized primarily in the liver. Since in patients with impaired liver function the full half-life of itraconazole 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 patients with renal insufficiency complete the half-life of itraconazole slightly increased, it is recommended to monitor the concentrations of itraconazole in 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 pharmacokinetic characteristics 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:

Not observed.

Form release / dosage:Capsules, 100 mg.

Packaging:

For 15 capsules in a blister of PVC / aluminum, one blister, along with instructions for use in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LS-002112

Date of registration:12.03.2012 / 07.04.2017

Expiration Date:Unlimited

The owner of the registration certificate:Roushan Pharma Co., Ltd.Roushan Pharma Co., Ltd. India

Manufacturer: & nbsp

RUSAN PHARMA, Ltd. India

Representation: & nbspRoushan Pharma Co., Ltd.Roushan Pharma Co., Ltd.

Information update date: & nbsp28.11.2017

Illustrated instructions

Instructions

Itraconazole (Itraconazole)