INSTRUCTION
for medical use of the preparation
ITRUNGAR

 
Composition.

Active substance: itraconazole; 1 capsule contains itraconazole 100 mg; 
Auxiliary substances: sucrose, hydroxypropyl methylcellulose, corn starch.  

Medicinal form. Capsules. 

Pharmacotherapeutical group. Antimycotic preparations for systemic use. Triazole derivatives. АТС code J02А С02. 

Clinical characteristics.

Indications.
Treatment of mycoses, caused by itraconazole-susceptible agents in patients without immune system disorders:
- gynaecological diseases: vulvovaginal candidiasis;
- dermatological diseases: dermatomycosis, pityriasis versicolor; 
- ophthalmological diseases: mycotic keratitis;
- oral candidiasis;
- onychomycoses, caused by dermatophytes, yeast, molds;
- systemic mycoses: systemic aspergillosis or candidiasis, cryptococcosis (including cryptococcal meningitis): patients with immune system disorders and all patients with cryptococcosis of the central nervous system the preparation is indicated only in case of ineffectiveness of the therapy with other atimycotic preparations;
- histoplasmosis, sporotrichosis, paracoccidioidomycosis, blastomycosis and other systemic mycoses, which occur very seldom, or tropical mycoses. 

Contraindications. Individual hypersensitivity to the preparation or its ingredients. Concomitant use of the preparations that metabolize with participation of CYP3A4 enzyme and able to increase QT-interval, such as astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, quinidine, pimozide, quinidine, sertindole and terfenadine. 

Itrungar should not be used in the patients with ventricular dysfunction, such as acute heart failure (AHF) or AHF in anamnesis except treatment of life-threatening or other serious infections (see Section “Peculiarities of use”). Itrungar should not be used during pregnancy unless there are vital indications. Period of lactation.

 
Way of administration and doses. For internal use. For optimal absorption the preparation capsules “Itrungar” should be used immediately after intake of high-caloric food.

Capsules should be swallowed as a whole. 

onychomycoses, caused by dermatophytes and/or yeast 

onychomycoses: there can be carried out continuous treatment or pulse-therapy. For continuous treatment the indication is itraconazole 200 mg a day for 3 months.

One course of pulse-therapy consists of taking two capsules “Itrungar” twice a day (200 mg twice a day) for 1 week. For treatment of mycotic lesions of hand nail plates 2 courses are recommended. For treatment of mycotic lesions of toe nail plates 3 courses of pulse-therapy are recommended. The interval between courses should be 3 weeks. 

Clinical results will manifest after the end of treatment with nail growth. Pulse-therapy regimen is given in the table.

Itraconazole excretion from skin tissue or nails is slower than from plasma. Therefore, optimal clinical and mycotic effects are achieved in 2 - 4 weeks after the end of the treatment course for skin infections and in 6 - 9 months after the end of the treatment course for nail plate infections.

Side effects. 

Most frequent adverse reactions to itraconazole were the reaction from the side of digestive tract: dyspepsia, nausea, abdominal pain, abdominal swelling, and constipation. Other possible side effects are: headache, allergic reactions (itch, rash, urticaria, and angioneurotic edema), Stevens-Johnson syndrome, rhinitis, sinusitis, infections of upper respiratory ways, congestive heart failure and pulmonary edema.
Very seldom there were reported the following side effects:
Lymphatic system and blood: leucopenia, neutropenia, thrombocytopenia.
Immune system: serum sickness, anaphylactic, anaphylactoid reactions.
Metabolic disorders: hypertriglyceridemia, hypokaliemia.
Nervous system: peripheral neuropathy, paresthesia, hypoesthesia, dizziness.
Sight organs: sight disorders, including diplopia, blurring of vision.
Hearing and vestibular apparatus: ear noise.
Gastrointestinal tract: vomiting, diarrhoea, dysgeusia.
Hepatobiliary system: serious hepatotoxicity (including single cases of acute and fatal hepatic insufficiency), hepatitis, reversible increase of liver enzymes activity.
Skin and subcutaneous tissues: toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, leukocytoplastic vasculitis, alopecia, photosensitivity.
Musculoskeletal  system and connective tissues: myalgia, arthralgia.
Kidneys and urinary system: pollakisuria, enuresis.
Reproductive system: menstrual cycle disorders, erectile dysfunction.

General disorders: edemas. Hypersensitivity, tinnitus, temporary or permanent loss of hearing, photosensitivity.

 
Overdose. 

There is no data as for the cases of overdose. Enhancement of side effects of the preparation is possible.
Treatment is symptomatic and supportive. There is no specific antidote for itraconazole. The active substance is not excreted at haemodialysis.

Use during pregnancy and lactation.

During pregnancy the preparation is indicated only for systemic mycoses that are life-threatening, when expected benefit for future mother overcomes the risk of negative influence on the fetus. Women of child-bearing age are recommended to use effective contraceptive agents during treatment with the preparation. In case of needed treatment with itraconazole during lactation period the women should discontinue breast-feeding.

Children.
As there is not enough clinical data as for the use of Itrungar in capsules in children, it is recommended to use itraconazole in such patients only when possible benefit significantly overcomes potential risk.

Peculiarities of use. 

It is estimated, that itraconazole has negative inotropic effect. There have been reports on cases of congestive heart failure, associated with itraconazole intake. Itrungar should not be taken by the patients with congestive heart failure or with presence of this disease in anamnesis unless those cases when possible benefit overcomes potential risk. At individual assessment of the ration benefit/risk the following factors should be taken into consideration: seriousness of indications, dose regimen and individual risk factors as for the development of congestive heart failure. The risk factors include the presence of heart diseases, such as coronary disease or valve lesions; serious lung diseases, such as obstructive lung lesions; renal insufficiency or other diseases, accompanied with edemas. Such patients should be informed about the signs and symptoms of congestive heart failure. The treatment should be carried out with caution. During treatment signs and symptoms of congestive heart failure should be monitored. In case of development of signs or symptoms during the course of treatment the intake of Itrungar should be discontinued.
Caution should be exercised at concomitant use of itraconazole and calcium channel-blocking agents.
At decreased gastric acidity the absorption of itraconazole in the bowels with Itrungar capsules worsens. The patients, receiving the preparations to decrease the acidity (such as aluminium hydroxide), should do it not earlier than 2 h after Itrungar intake. The patients with achlorhydria, for example, AIDS patients, or those, receiving Н2-blockers or proton pump inhibitors, are recommended to take Itrungar capsules with cola.

There are reports on the cases when at itraconazole use very seldom there developed severe hepatotoxicity, including cases of acute and fatal liver insufficiency. Those cases, which were registered, were observed in the patients, who previously had liver disease, received treatment on systemic indications and/or took preparations, which can cause hepatotoxic action. In some patients there were no evident risk factors from the side of the liver. Some of these cases were observed during the first month of treatment, including first weeks. That is why, it is recommended to monitor liver function in the patients, receiving Itrungar. The patients should be informed as for the necessity of urgent turning to the doctor in case of signs or symptoms of hepatitis, in particular: anorexia, nausea, vomiting, fatigue, abdominal pain or dark coloration of the urine. The patients with such symptoms should urgently discontinue the treatment and undergo liver function investigation. In the patients with increased level of liver enzymes, active liver diseases or those having experienced cases of liver toxicity at use of other preparations, the initiation of treatment is not recommended unless expected benefit from the use of the preparation overcomes the risk of liver dysfunction. In such cases monitoring of the level of liver enzymes is required.

Liver dysfunction. Itraconazole is mainly metabolized in the liver. The half-life of itraconazole in the patients with liver cirrhosis is somewhat increased. The bioavailability of the preparation at oral use in the patients with liver cirrhosis is somewhat decreased. In this case dose adjustment can be considered.
Renal dysfunction. The bioavailability of the preparation at oral use in the patients with renal insufficiency can be decreased. In this case dose adjustment can be considered.In case of peripheral neuropathy development, caused by the intake of the preparation, the treatment should be discontinued.
Use in elderly patients. As there is not enough clinical data as for the use of the preparation in elderly patients, itraconazole can be indicated to such patients only when possible benefit significantly overcomes potential risk.
Prevention in neutropenia patients. In clinical studies the most frequent side effect of itraconazole was diarrhea. Such gastric disorder can lead to decreased absorption and can change microbiological flora, potentially promoting mycotic colonization. Caution should be exercised and in such cases the treatment should be discontinued.
Cross-sensitivity. There is no information as for cross hypersensitivity between itraconazole and other azole antimycotic preparations, however, caution should be exercised when indicating Itrungar to the patients with hypersensitivity to other azole preparations.
Loss of hearing. There were reports on temporary or stable loss of hearing in the patients, receiving itraconazole. In some cases the loss of hearing occurred against the background of concomitant use with quinidine, which is contraindicated (see Sections “Contraindications” and “Interaction with other medicinal preparations and other forms of interaction”). Hearing usually restores after the end of the therapy with the preparation, but in some patients the loss of hearing is irreversible.

Ability to influence the rate of reaction when driving or operating other mechanisms. 

There are no reports on the influence of the preparation the capacity to drive or operate technical devices. If during treatment with the preparation there occur sight disorder, sleepiness, dizziness, one should abstain from driving or operating complicated technical devices. 

Interaction with other medicinal preparations and other forms of interaction.
1. Medicinal preparations that influence the metabolism of itraconazole.
During the study of medicinal interaction with rifampicin, rifabutin and phenytoin there was established that in these cases the bioavailability of itraconazole and hydroxiitraconazole decrease significantly, which leads to significant decrease of the effectiveness of the preparation. Therefore, concomitant use of itraconazole with these preparations, which are potential enzyme-reducers, is not recommended. The study of interaction of itraconazole with other enzyme-reducers, such as carbamazepine, phenobarbital and isoniazid, has not been carried out, but similar interactions can be expected.

As itraconazole is mainly broken down by CYP3А4 enzyme, potential inhibitors of this enzyme can increase the bioavailability of itraconazole. The examples can be ritonavir, indinavir, clarithromycin and erythromycin.

2. Influence of itraconazole on the metabolism of other medicinal preparations.

Itraconazole can inhibit the metabolism of medicinal preparations, which break down with the enzymes of cytochrome 3А family. As a result there can occur increase or prolongation of their action, including side effects. After the discontinuation of the treatment the levels of plasma itraconazole decrease slowly due to the dose and duration of the treatment. It should be taken into consideration when estimating inhibiting effect of itraconazole on the metabolism of the preparations, which are indicated concomitantly.

The examples of such medicinal preparation are: 
Medicinal preparations that should not be indicated during treatment with itraconazole. 

Astemizole, Bepridil, Cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, quinidine, pimozide, sertindole and terfenadine are contraindicated for concomitant use with the preparation, as it can lead to increased plasma concentrations of these substrates, which, in its turn, can lead to prolongation of QT intervals and in rare cases – to torsade de pointes.

Preparations, broken down by CYP3А4 enzyme are inhibitors of HMG-CoA reductase, such as atorvastatin, simvastatin andlovastatin.

Triazolam and oral midazolam.

Ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (metilergonovin).

Eletriptan. 

Nisoldipine.

At concomitant use of itraconazole and calcium channel-blocking agents, caution should be exercised due to increased risk of congestive heart failure. In addition to possible pharmakc kinetic interaction with participation of metabolizing CYP3А4 enzyme calcium channel-blocking agents can cause negative inotropic effect, which can enhance similar effect of itraconazole.

Medicinal preparations that should be indicated under control of the level of their plasma concentration, action and side effects (at their concomitant use with itraconazole the dose of the indicated preparations should be decreases if required): 
- oral anticoagulants;

- HIV- protease inhibitors, such as ritonavir, indinavir, saquinavir;

- some antitumor preparations, such as pink colorant alkaloids (Vinca), busulfan, docetaxel and trimetrexate;

- calcium channel-blocking agents, broken down by CYP3А4 enzyme, such as dihydropyridine and verapamil;

- some immunosuppressive agents: ciclosporin, tacrolimus, rapamycin (also known as  sirolimus);

- other preparations: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, methylprednisolone, ebastin, reboksetin, budezonid, dexamethasone, fluticasone, methylprednisolone.

Interaction of itraconazole with AZT (azidothymidine) and fluvastatin has not been estimated.

No influence of itraconazole on metabolism of etinilestradiol and norethisterone has been observed.

Influence on protein binding.

Studies in vitro demonstrated no interaction at binding with plasma proteins between itraconazole and such preparations as imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide, sulfametazin. 

Pharmacological properties. 
Pharmacodynamics. Triazole derivative, synthetic antimycotic agent, active as for wide spectrum of causative agents. The mechanism of action is conditioned by inhibition of ergosterol synthesis – important component of mycotic cellular membrane. Preparation-susceptible are: Trichophyton spp., Epidermophyton floccosum, Microsporum spp., Candida spp. (including C. albicans, C. glabrata and C. krusei), Cryptococcus neoformans,  Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatidis as well as some other microorganisms. Clinical effect of the preparation is fully manifested in 2–4 weeks after the end of therapy in patients with skin mycosis and in 6–9 months after the end of therapy in patients with onychomycosis (with nail growth).

Pharmacokinetics.
Absorption: maximal bioavailability of itraconazole is observed at intake of the preparation immediately after meals. After single intake of the preparation maximal plasma concentration of itraconazole is observed in 2.5 h. At long-term use the stable plasma concentration of itraconazole is achieved in 1–2 weeks and in 3–4 h after the intake of the last dose of the preparation is: 0.4 µg/ml – at the intake of 0.1 g of the preparation once a day; 1.1 µg/ml – at the intake of 0.2 g of the preparation once a day, 2 µg/ml at the intake of 0.2 g of the preparation twice a day.  
Distribution: 99.8% of the active substance is bound to plasma proteins. Itraconazole distributes in different tissues of the organism, and the concentration in lungs, kidneys, liver, bones, stomach, spleen, skeletal muscles 2 – 3 times exceeds plasma concentration of itraconazole. The concentration of itraconazole in keratin-containing tissues, especially in skin, 4 times exceeds plasma concentration. Therapeutic concentration of itraconazole in skin preserves for 2 – 4 weeks after the end of 4-week course of treatment. Therapeutic concentration of itraconazole in nail keratin is achieved in 1 week after the initiation of treatment and preserves at least for 6 months after the end of 3-month course of treatment. Itraconazole also penetrates into sebaceous and perspiratory (to a less degree) glands of the skin.

Metabolism: itraconazole is metabolized in the liver with formation of numerous derivatives, one of which – hydroxiitraconazole – has comparative with itraconazole antimycotic action in vitro.
Excretion: the excretion of itraconazole from plasma is biphasic with final half-life of 1 – 1.5 days. About 35% of the taken dose of the preparation is excreted with urine as metabolites for 1 week, from which in unchanged state – less than 0.03%. About 3 – 18% of the taken dose of the preparation is excreted with feces in unchanged state. 

Pharmacokinetics in special clinical cases: in the patients with renal and hepatic insufficiency, as well as in some patients with immunosuppression (for example, with AIDS, neutropenia, after organ transplantation) the bioavailability of itraconazole can decrease.
Pharmaceutical characteristics.
Main physical and chemical properties:
Solid gelatine capsules with yellow shell and green cap or vice versa (size 0); content of the capsule – pellets of white to grey colour.

Shelf life. 2 years. 

Storage conditions. Keep out of the reach of children in the original package at temperature below 25єC. 
Packing. 4 or 15 capsules in a blister, 1 blister in a package.  

Name and Address of the Manufacturer. Ananta Medicare Ltd.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom. 

Terms of dispensing. On prescription.