Itraconazole capsules 100mg, 14pcs – AVVA

Composition

Each capsule contains Itraconazole pellets (22%) — 0.460 g. Composition of pellets: Active ingredient: itraconazole-0.100 g, excipients: hypromellose (hydroxypropylmethylcellulose E-5) – 0.1472 g, butylmethacrylate, dimethylaminoethylmethacrylate and methyl methacrylate copolymer [1: 2: 1] (eudrahyde E-100) – 0.0046 g, sucrose (sugar) – 0.2070 g. Capsule shell composition: body: gelatin, titanium dioxide (E 171), azorubin (carmoisine) E 122; cap: gelatin, titanium dioxide (E 171), indigo carmine-F D & C Blue 2 (E 132).

Pharmacological action

Pharmacotherapy group: antifungal agent. ATX code: J02AC02Pharmacological properties Pharmacodynamics ynthetic broad-spectrum antifungal agent. A triazole derivative. Inhibits the synthesis of ergosterol in the fungal cell membrane. Active against dermatophytes (Trichophyton spp., Spicrosporum spp., Epidermophyton floccosum), yeast fungi Candida spp. (including Candida albicans, Candida parapsilosis), mold fungi (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 evaluated 2-4 weeks after discontinuation of therapy (for mycoses),6-9 months – for onychomycosis (as the nails change). Pharmacokinetics Absorbed from the gastrointestinal tract (GIT) is quite complete. Taking itraconazole capsules immediately after a meal increases bioavailability. Taking it as a solution on an empty stomach leads to a higher rate of reaching the maximum concentration (Cmax) and a higher value of the equilibrium phase concentration (Css) compared to taking it after a meal (by 25%). The time to reach the maximum concentration (TMAX) when taking capsules is about 3-4 hours. Css when taking 100 mg of the drug 1 time a day – 0.4 mcg/ml; when taking 200 mg 1 time a day-1.1 mcg/ml,200 mg 2 times a day-2 mcg/ml. TSMAKH when taking the solution – about 2 hours when taken on an empty stomach and 5 hours after meals. The time of onset of Css in plasma with prolonged use is 1-2 weeks. Binding to plasma proteins is 99.8%. It penetrates well into tissues and organs (including the mucous membrane of the vagina), is contained in the secret of the sebaceous and sweat glands. The concentration of itraconazole in the lungs, kidneys, liver, bones, stomach, spleen, skeletal muscles is 2-3 times higher than its concentration in plasma; in tissues containing keratin-4 times. The therapeutic concentration of itraconazole in the skin is maintained for 2-4 weeks after discontinuation of the 4-week course of treatment. The therapeutic concentration in nail keratin is reached 1 week after the start of treatment and persists for 6 months after the end of a 3-month course of treatment. Low concentrations are detected in the sebaceous and sweat glands of the skin. It is metabolized in the liver to form active metabolites, including hydroxyitraconazole. It is an inhibitor of the CYP3A4, CYP3A5 and CYP3A7 isoenzymes. Elimination from plasma is biphasic: by the kidneys for 1 week (35% in the form of metabolites,0.03% in unchanged form) and through the intestine (3-18% in unchanged form). The half-life (half-life) is 1-1.5 days. It is not removed during dialysis.

Indications

Vulvovaginal candidiasis;dermatomycosis, multicolored lichen, candidiasis of the oral mucosa, keratomycosis;onychomycosis caused by dermatophytes or yeast — like fungi;systemic mycoses-systemic aspergillosis or candidiasis, cryptococcosis (including cryptococcal meningitis) in immunocompromised individuals and cryptococcosis of the central nervous system, regardless of the immune status, if the 1st-line therapy is ineffective;histoplasmosis blastomycosis, sporotrichosis, paracoccidioidosis; other rare systemic and tropical mycoses.

Contraindications

Hypersensitivity, chronic heart failure, including in the anamnesis (except for the treatment of life-threatening conditions); simultaneous use of substrates of the CYP3A4 isoenzyme that prolong the QT interval (astemizole, bepridil, cisapride, dofetilide, levacetylmethadol, mizolastatin, pimozide, quinidine, sertindol, terfenadine); HMG-CoA inhibitors reductases metabolized by the CYP3A4 isoenzyme (lovastatin, simvastatin); simultaneous oral use of triazolam and midazolam, ergot alkaloids (dihydroergotamine, ergometrine, ergotamine, methylergotamine), nisoldipine, eletriptan; pregnancy, lactation. With caution: Renal and hepatic insufficiency, peripheral neuropathy, risk factors: chronic heart failure (ischemic heart disease, heart valve damage, severe lung diseases, including chronic obstructive pulmonary disease, conditions accompanied by edematous syndrome), hearing impairment, simultaneous use of slow calcium channel blockers, children and the elderly.

Side effects

– From the gastrointestinal tract: dyspepsia (nausea, vomiting, diarrhea, constipation, loss of appetite), abdominal pain. – From the side of the hepatobiliary system: reversible increase in “liver” enzymes, hepatitis, in very rare cases, severe toxic liver damage developed with the use of Itraconazole, including cases of acute liver failure with a fatal outcome. – Nervous system disorders: headache, dizziness, peripheral neuropathy. – From the immune system: anaphylactic, anaphylactoid and allergic reactions. – From the skin: in very rare cases – erythema multiforme (Stevens-Johnson syndrome) skin rash, pruritus, urticaria, angioedema, alopecia, photosensitivity. Others: menstrual disorders, hypokalemia, edematous syndrome, chronic heart failure and pulmonary edema.

Interaction

• Drugs that affect the absorption of itraconazole Drugs that reduce the acidity of the stomach reduce the absorption of itraconazole, which is associated with the solubility of the capsule shells.
• Drugs 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 potent 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. Concomitant use of itraconazole with these drugs, which are potential inducers of microsomal liver enzymes, is not recommended. Interaction studies with other inducers of microsomal liver enzymes, such as carbamazepine, phenobarbital, and isoniazid, have not been conducted, but similar results can be assumed. Potent inhibitors of the CYP3A4 isoenzyme, such as ritonavir, indinavir, clarithromycin, and erythromycin, may increase the bioavailability of itraconazole.
• Effect of itraconazole on the metabolism of other drugs. Itraconazole can inhibit the metabolism of drugs broken down by the CYP3A4 isoenzyme. 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 metabolic pathways of this drug, indicated in the instructions for medical use. After discontinuation of treatment, plasma concentrations of itraconazole decrease gradually depending on the dose and duration of treatment (see section Pharmacokinetics). This should be taken into account when discussing the migratory effect of itraconazole on concomitant medications.

Examples of such medications are:

Medications that should not be administered concomitantly with itraconazole:

• Terfenadine, astemizole, mizolastine, cisapride, dofetilide, quinidine, pimozide, levacetylmetadol, sertindol-the combined use of these drugs with itraconazole may cause an increase in the concentration of these substances in plasma and increase the risk of prolongation of the QT interval and, in rare cases, the occurrence of atrial fibrillation of the ventricles (torsade de pointes).
• CYP3A4-metabolized HMG – CoA reductase inhibitors such as simvastatin and lovastatin,
• oral midazolam and triazolam,
• ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergometrine,
• Slow calcium channel blockers – in addition to the possible pharmacokinetic interaction associated with a common pathway of metabolism involving the CYP3A4 isoenzyme, slow calcium channel blockers may have a negative inotropic effect, which is enhanced when co-administered with itraconazole.

Drugs that require monitoring of their plasma concentrations, effects, and side effects. In the case of concomitant use with itraconazole, the dose of these drugs should be reduced, if necessary.

• Indirect anticoagulants;
• HIV protease inhibitors, such as ritonavir, indinavir, saquinavir;
• Some antitumor drugs, such as pink periwinkle alkaloids, busulfan, docetaxel, trimetrexate;
• CYP3A4-metabolized slow calcium channel blockers, such as verapamil and dihydropyridine derivatives;
• Some immunosuppressive agents: cyclosporine, tacrolimus, sirolimus (also known as rapamycin);
• Some HMG – CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme, such as atorvastatin;
• Some glucocorticosteroids, such as budesonide, dexamethasone, and methylprednisolone;
• Other medications: digoxin, carbamazepine, buspirone alfentanil, alprazolam, brotisolam, midazolam for intravenous use, rifabutin, Ebastine, reboxetin, cilostazol, disoliramide, eletriptan, halofantrin, repaglinide.

There was no interaction between itraconazole and zidovudine and fluvastatin.

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

Effect on plasma protein binding.

In vitro studies have shown no interaction between itraconazole and drugs such as imipramine, propranolol, diazepam, cimetidine, Indometacin, tolbutamide, and sulfamethazine when binding to plasma proteins.

How to take, course of use and dosage

Inside. Immediately after eating. Capsules are swallowed whole.

Elimination of itraconazole from the skin and nail tissue is slower 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 for nail infections.

The duration of treatment can be adjusted depending on the clinical picture of the treatment:

• when vulvovaginal candidiasis is 200 mg 2 times a day for 1 day or 200 mg 1 time per day for 3 days;
• for ringworm – 200 mg 1 time per day for 7 days or 100 mg 1 time per day for 15 days;
• defeat vysokokvalifitsirovannykh areas of the skin (tinea of feet and hands) -200 mg 2 times a day for 7 days or 100 mg 1 time per day for 30 days;
• in pityriasis lichen – 200 mg 1 time a day for 7 days;
• candidiasis of the mucous membrane of the oral cavity – 100 mg 1 time a day for 15 days (in some cases immunocompromising individuals bioavailability of Itraconazole may be reduced, which sometimes requires a doubling dose);
• if keratomycosis – 200 mg 1 time per day for 21 days (the duration of treatment depends on clinical response);
• onychomycosis – 200 mg 1 time per day for 3 months or 200 mg 2 times a day for 1 week on the course;
• if it affects the toenails (regardless of the presence of lesions of the nails on the hands) hold 3 courses with an interval of 3 weeks. With the defeat of the nails on his hands only spend 2 courses with an interval of 3 weeks;
• elimination of Itraconazole from skin and nail is slow, optimal clinical response for ringworm is achieved in 2-4 months after completion of treatment, when onychomycosis – 6-9 months
• in the systemic aspergillosis – 200 mg/day for 2-5 months; with the progression and dissemination of the disease, increase the dose to 200 mg 2 times a day;
• in a systemic candidiasis – 100-200 mg 1 time per day for 3 weeks – 7 months with the progression and dissemination of the disease, increase the dose to 200 mg 2 times a day;
• with systemic cryptococcosis without signs of meningitis 200 mg 1 time per day for 2-12 months. For cryptococcal meningitis – 200 mg 2 times a day for 2-12 months.
• treatment of histoplasmosis start with 200 mg 1 time per day, maintenance dose – 200 mg 2 times a day for 8 months;
• when blastomycosis – 100 mg 1 time a day, maintenance dose – 200 mg 2 times a day for 6 months;
• when sporotrichosis – 100 mg 1 time per day for 3 months;
• if paracoccidioides – 100 mg 1 time per day for 6 months;
• when chromatose -100-200 mg 1 time per day for 6 months.
• children shall, if the expected benefit outweighs the potential risk.

Overdose

No data available. In case of accidental overdose, supportive measures should be applied. During the first hour, perform gastric lavage and, if necessary, prescribe activated charcoal. Itraconazole is not eliminated by hemodialysis. There is no specific antidote.

Special instructions

Women of childbearing age taking Itraconazole should use reliable methods of contraception throughout the entire course of treatment up to the onset of the first menstrual period after its completion.

Itraconazole was found to have a negative inotropic effect. Caution should be exercised when taking itraconazole and calcium channel blockers at the same time, which may have the same effect. Cases of chronic heart failure associated with Itraconazole have been reported.

Itraconazole should not be used in patients with chronic heart failure or a history of heart failure, unless the potential benefit significantly outweighs the potential risk. Individual assessment of the benefit-risk ratio should take into account factors such as the severity of indications, dosage regimen, and individual risk factors for chronic heart failure.

Risk factors include the presence of heart disease, such as coronary heart disease or valve damage; serious lung diseases, such as obstructive pulmonary disease; kidney failure or other diseases accompanied by edema. These patients should be informed about the signs and symptoms of congestive heart failure. Treatment should be carried out with caution, and the patient should be monitored for symptoms of congestive heart failure. If they occur, Itraconazole should be discontinued.

With low stomach acidity: in this condition, the absorption of itraconazole from capsules is disrupted. Patients taking antacid medications (for example, 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 cola-containing beverages.

In very rare cases, severe toxic liver damage has occurred with Itraconazole, including cases of acute liver failure with a fatal outcome. In most cases, this was observed in patients who already had liver diseases, in patients with other serious diseases who received itraconazole therapy for systemic indications, as well as in patients who received other drugs that have a hepatotoxic effect.

In some patients, no obvious risk factors for liver damage were identified. Some of these 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 to contact their doctor immediately if they experience symptoms that suggest hepatitis, such as anorexia, nausea, vomiting, weakness, abdominal pain, and dark urine.

If such symptoms occur, you should immediately stop therapy and conduct a liver function study. Patients with elevated concentrations of” liver ” enzymes or active liver disease, or with a history of toxic liver damage while taking other medications, should not be treated with Itraconazole 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 primarily metabolized in the liver. Since the total half-life of itraconazole is slightly increased in patients with impaired liver function, it is recommended to monitor the concentration of itraconazole in plasma and, if necessary, adjust the dose of the drug.

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

Immunodeficient patients: Oral bioavailability of itraconazole may be reduced in some immunocompromised patients, such as those with neutropenia, AIDS patients, or those undergoing organ transplantation.

Patients with life-threatening systemic fungal infections: Due to the pharmacokinetic characteristics, Itraconazole capsules are not recommended for starting treatment of life-threatening systemic mycoses.

People with AIDS.

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

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

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

There are no data on cross-hypersensitivity to itraconazole and other azole antifungal drugs.

Impact on the ability to drive a car and work with machinery

Itraconazole can cause dizziness and other side effects that can affect the ability to drive vehicles and other equipment that requires increased attention when working.

Form of production

Capsules.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25 °C. Keep out of reach of children.

Shelf

life is 3 years.

Active ingredient

Itraconazole

Conditions of release from pharmacies

By prescription

Dosage form

Capsules