Itraconazole capsules 100 mg 14 pcs. (Itraconazole)

Release form

Capsules.

Pharmacological action

Pharmacotherapeutic group: antifungal.

ATX code: J02AC02.

Pharmacological properties of

Pharmacodynamics

Synthetic antifungal agent with a wide spectrum of action. Derivative of triazole. Suppresses the synthesis of ergosterol in the cell membrane of fungi. Active against dermatophytes (Trichophyton spp., Sficrosporum spp., Epidermophyton floccosum), yeast Candida spp. (including Candida albicans, Candida parapsilosis), molds (Cryptococcus neo / ormans, Aspergillus spp., Trichosporon spp., Geotrichum spp., Penicillium marneffei, Pseudallescheria boydii, Histoplasma spp., Coccidioides immitis, Paracoccidioides braziliensis. Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatidis), Sfalassezia spp.

Some strains may be resistant: Candida glabrata. Candida krusei, Candida tropicalis, Absidia spp., Fusarium spp. , Mucor spp., Rhizomucor spp., Rhizopus spp., Scedosporium proliferans, Scopulariopsis spp.

The effectiveness of treatment is assessed 2-4 weeks after discontinuation of therapy (with mycosis), after 6-9 months - with onychomycosis (as the nails change).

Pharmacokinetics

Absorbed from the gastrointestinal tract (GIT) quite well. Taking itraconazole in capsules immediately after a meal increases bioavailability. Reception in the form of a solution on an empty stomach leads to a higher rate of reaching maximum concentration (Cmax) and a higher value of the concentration of the equilibrium phase (Css) compared with the intake after meals (25%).

The time to reach the maximum concentration (TCmax) when taking capsules is about 3-4 hours. Css when taking 100 mg of the drug 1 time per day - 0.4 μg / ml when taking 200 mg once a day - 1.1 μg / ml , 200 mg 2 times a day - 2 μg / ml. TCmax when taking the solution - about 2 hours when taken on an empty stomach and 5 hours after eating. The time of onset of Css in plasma with prolonged use is 1-2 weeks. Communication with plasma proteins - 99.8%.

It penetrates well into tissues and organs (including the vaginal mucosa), is contained in the secretion of the sebaceous and sweat glands. The concentration of itraconazole in the lungs, kidneys, liver, bones, stomach, spleen, skeletal muscle is 2-3 times higher than its plasma concentration in tissues containing keratin - 4 times. The therapeutic concentration of itraconazole in the skin persists for 2-4 weeks after the termination of the 4-week course of treatment. The therapeutic concentration in nail keratin is achieved 1 week after the start of treatment and persists for 6 months after 3 months of treatment have been completed. Low concentrations are detected in the sebaceous and sweat glands of the skin. It is metabolized in the liver with the formation of active metabolites, including hydroxyitraconazole. It is an inhibitor of isofermites CYP3A4, CYP3A5 and CYP3A7.

Excretion from plasma is two-phase: by the kidneys for 1 week (35% as metabolites, 0.03% as unchanged) and through the intestines (3-18% unchanged). The half-life (T ) Is 1 - 1.5 days. It is not removed during dialysis.

Indications

Vulvovaginal candidiasis dermatomycosis, colorful lichen, candidiasis of the oral mucosa, keratomycosis onychomycosis caused by dermatophytes or yeast-like fungi systemic mycoses - systemic aspergillosis or candidiasis, cryptococcoccosis and cryptococcosis systems regardless of immune status with the failure of therapy of the 1st line histoplasmosis, blastomycosis, sporotrichosis, paracoccidioidosis, other rare si dark and tropical mycoses.

Contraindications

Hypersensitivity, chronic heart failure, including in the history (with the exception of the therapy of life-threatening conditions), the simultaneous administration of substrates of the CYP3A4 isoenzyme extending the QT interval (astemizole, bepridil, cisapride, dofetilide, levacetylmethadol, misolastatin, pimozide, quinidine, sertindole, terfenadin-3 metabolizin inhibitors), inhibitors , simvastatin) simultaneous oral administration of triazolam and midazolam, ergot alkaloids (dihydroergotamine, ergometrine, ergotamine, methylergotamine), nisoldipine, eletriptan pregnancy, lactation.

Precautions

Renal and hepatic failure, peripheral neuropathy, risk factors: chronic heart failure (coronary heart disease, damage to heart valves, severe lung diseases, including chronic obstructive pulmonary disease, conditions accompanied by edematous syndrome), hearing impairment, concomitant use of slow calcium channel blockers, childhood and old age.

Special instructions

Women of childbearing age who take Itraconazole need to use reliable methods of contraception throughout the course of treatment until the onset of the first menstruation after its completion.

Itraconazole has been found to have a negative inotropic effect. With the simultaneous administration of itraconazole and calcium channel blockers, which may have the same effect, caution must be exercised. Cases of chronic heart failure associated with taking Itraconazole have been reported. Itraconazole 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. An individual assessment of the benefit-risk ratio should take into account factors such as the severity of the indications, dosing regimen and individual risk factors for the occurrence of chronic heart failure. Risk factors include the presence of heart disease, such as coronary heart disease or valve damage, serious lung disease, 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 done with caution, it is necessary to monitor the patient for symptoms of congestive heart failure. When they appear, taking Itraconazole must be discontinued.

In case of reduced acidity of the stomach: in this condition, the absorption of itraconazole from the capsules is impaired. Patients taking antacids (e.g. aluminum hydroxide) are advised to use them no earlier than 2 hours after taking Itraconazole capsules. Patients with achlorhydria or using H2 histamine receptor blockers and proton pump inhibitors are advised to take Itraconazole capsules with drinks containing cola.

In very rare cases, the use of Itraconazole developed severe toxic liver damage, 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 according to 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 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 an increased concentration of "liver" enzymes or liver disease in the active phase, or with toxic liver damage while taking other drugs should not be prescribed Itraconazole treatment unless the expected benefit justifies the risk of liver damage. In these cases, it is necessary to monitor the concentration of “liver” enzymes during treatment.

Impaired liver function: Itraconazole is metabolized primarily in the liver. Since in patients with impaired liver function, the total half-life of itraconazole is slightly increased, it is recommended to monitor the concentration of itraconazole in plasma and, if necessary, adjust the dose of the drug.

Renal dysfunction: Since in patients with renal failure the total elimination half-life of itraconazole is slightly increased, it is recommended to monitor the plasma concentration of itraconazole and adjust the dose if necessary.

Immunodeficiency Patients: The oral bioavailability of itraconazole may be reduced in some immunocompromised patients, such as patients with neutropenia, AIDS patients, or undergoing organ transplant surgery.

Patients with life-threatening systemic fungal infections: due to pharmacokinetic characteristics, itraconazole in capsule form is not recommended for starting treatment of systemic fungal infections that pose a threat to the life of patients.

AIDS patients.

The attending physician should evaluate the need for prescribing supportive care for AIDS patients who have previously received treatment for systemic fungal infections, such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (both meningeal and non-meningeal), which are at risk of relapse.

Clinical data on the use of Itraconazole capsules in pediatric practice are limited. Itraconazole capsules should not be prescribed to children, unless the expected benefit outweighs the potential risk.

Treatment should be discontinued if peripheral neuropathy occurs, which may be associated with taking itraconazole capsules.

There is no evidence of cross-sensitivity to itraconazole and other azole antifungal drugs.

Impact on the ability to drive and operate

Itraconazole may cause dizziness and other side effects that may affect the ability to drive vehicles and other machinery that require increased attention when working.



Composition Each capsule contains pellets of itraconazole (22%) - 0.460 g

composition pellets:

active substance: itraconazole - 0.100 g,

excipients: hypromellose (hydroxypropyl methylcellulose E-5 ) - 0.1472 g, butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate copolymer [1: 2: 1] (Eudragide E-100) - 0 , 0046 g, sucrose (sugar) - 0.2070 g.

Capsule shell composition:

shell: gelatin, titanium dioxide (E 171), azorubine (carmuazine) E 122

cap: gelatin, titanium dioxide (E 171), indigo carmine - F D&C Blue 2 (E 132).

Dosage and Administration

Inside. Immediately after a meal. Capsules are swallowed whole.

Itraconazole is eliminated 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.

Duration of treatment can be adjusted depending on the clinical picture of treatment:

with vulvovaginal candidiasis - 200 mg 2 times a day for 1 day or 200 mg 1 time per day for 3 days

with dermatomycosis - 200 mg 1 time per day for 7 days or 100 mg 1 time per day for 15 days

lesions of highly keratinized skin areas (dermatophytosis of the feet and hands) -200 mg 2 times a day for 7 days or 100 mg 1 time per day for 30 days

with pityriasis versicolor - 200 mg 1 time per day for 7 days

with candidiasis of the oral mucosa - 100 mg 1 time per day for 15 days (in some cases, immunocompromite In those who are not, the bioavailability of itraconazole may decrease, which sometimes requires doubling the dose)

with keratomycosis - 200 mg 1 time per day for 21 days (the duration of treatment depends on the clinical response)

with onychomycosis - 200 mg 1 time per day for 3 months or 200 mg 2 times a day for 1 week on the

course with damage to the toenails (regardless of the presence of damage to the nails on the hands), 3 courses are conducted with an interval of 3 weeks. In case of nail damage only on the hands, 2 courses are carried out with an interval of 3 weeks

elimination of itraconazole from the skin and nails slow optimal clinical response with dermatomycosis is achieved 2-4 months after completion of treatment, with onychomycosis - 6-9 months

with systemic aspergillosis - 200 mg / day for 2-5 months with the progression and dissemination of the disease, the dose is increased to 200 mg 2 times a day

with systemic candidiasis - 100-200 mg 1 time per day within 3 weeks - 7 months, with the progression and dissemination of the disease, the dose is increased to 200 mg 2 times a day

with systemic cryptococcosis without signs of meningitis - 200 mg 1 time per day for 2-12 months. With cryptococcal meningitis - 200 mg 2 times a day for 2-12 months.

treatment of histoplasmosis begins with 200 mg once a day, a maintenance dose of 200 mg 2 times a day for 8 months

with blastomycosis - 100 mg once a day, maintenance dose - 200 mg 2 times a day for 6 months

for sporotrichosis - 100 mg 1 time per day for 3 months

for paracoccidioidosis - 100 mg once a day for 6 months

for chromomycosis -100-200 mg 1 once a day for 6 months,

is prescribed for children if the expected benefit outweighs the potential risk.

Side effects of

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

From the hepatobiliary system: a reversible increase in "liver" enzymes, hepatitis, in very rare cases, when itraconazole was used, severe toxic liver damage developed, including cases of acute liver failure with a fatal outcome.

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

From the side of the immune system: anaphylactic, anaphylactoid and allergic reactions.

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

Other: menstrual irregularities, hypokalemia, edema syndrome, chronic heart failure, and pulmonary edema.

Drug Interactions

Medicines, affecting the absorption of itraconazole Medicines that reduce the acidity of the stomach, reduce the absorption of itraconazole, which is associated with the solubility of the capsule shells.

Medicines that affect the metabolism of itraconazole. Itraconazole is mainly metabolized by the CYP3A4 isoenzyme. The interaction of itraconazole 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 and hydroxyitraconazole is significantly reduced, which leads to a significant decrease in the effectiveness of the drug. The simultaneous use of itraconazole 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, however, similar results can be assumed. Potent inhibitors of the CYP3A4 isoenzyme, such as ritonavir, indinavir, clarithromycin, and erythromycin, can increase the bioavailability of itraconazole.

Effect of itraconazole on the metabolism of another drugfunds. Itraconazole can 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. Before taking concomitant medications, you should consult your doctor about the metabolic pathways of this drug indicated in the instructions for medical use. After discontinuation of treatment, plasma concentrations of itraconazole gradually decrease depending on the dose and duration of treatment (see Pharmacokinetics section). This must be taken into account when discussing the migratory effect of itraconazole on concomitant medications.

Examples of such drugs are:

Drugs that cannot be prescribed at the same time as itraconazole: terfenadine, astemizole, misolastine, cisapride, dofetilide, quinidine, pimozide, levacetylmethadol, sertindole - the combined use of these drugs with itraconazole can increase the concentration of these substances in the plasma and increase the risk of lengthening the QT interval and, in rare cases, the occurrence of atrial fibrillation (torsade de pointes).

metabolized by the CYP3A4 isoenzyme inhibitors of HMG-CoA reductase, such as simvastatin and lovastatin,

midazolam for oral administration and triazolam,

ergot alkaloids such as dihydroergotamine, ergometrin, ergometrin, calc the interaction associated with the general pathway of metabolism involving the CYP3A4 isoenzyme, blockers of "slow" calcium channels can have a negative inotropic effect, which is enhanced while taking itraconazole.

Drugs for which it is necessary to monitor their plasma concentration, action, side effects. In the case of simultaneous administration with itraconazole, the dose of these drugs, if necessary, should be reduced.

Indirect anticoagulants

HIV protease inhibitors, such as ritonavir, indinavir, saquinavir

Some antitumor drugs, such as pink vinca alkaloids, busulfan, docetaxel, sirdlkp trimerexate metabolizable drugs, are metabolizable drugs Some immunosuppressive drugs: cyclosporine, tacrolimus, sirolimus (also known as rapamycin)

Some inhibitors of the HMG-CoA reductase metabolized by the CYP3A4 isoenzyme such as atorvastatins

Some glucocorticosteroids such as budesonide, dexamethasone and methylprednisoline, birzolzolfinzoline, bizolzolfrazine alfazolzinfrazine alfazolprazindrazolina administration, rifabutin, ebastin, reboxetine, cilostazole, disoliramide, eletriptan, halofantrine, repaglinide.

No interaction was found between itraconazole and zidovudine and fluvastatin.

No effect of itraconazole on the metabolism of ethinyl estradiol and norethisterone was observed.

Effect on plasma protein binding.

In vitro studies have shown a lack of interaction between itraconazole and drugs such as imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfamethazine when bound to plasma proteins.

Overdose

Data not available. In case of accidental overdose, supportive measures should be applied. During the first hour, carry out a gastric lavage and, if necessary, prescribe activated charcoal. Itraconazole is not excreted during hemodialysis. There is no specific antidote.

Storage conditions

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

The Expiration of

is 3 years.

Deystvuyuschee substances

Itraconazole

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Dosage form

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