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

auxiliary substances: lactose monohydrate -23,50 mg, pregelatinized starch 71,10 mg, colloidal dioxide silicon -0,20 mg, magnesium stearate-5,00 mg, sodium lauryl sulfate -0.20 mg; shell capsules:

lid: dye blue patented (E 131) - 0.085%, iron oxide dye

yellow 0.0708%, titanium dioxide 3%, gelatin up to 100%;

body: titanium dioxide - 2%, gelatin - up to 100%, black ink *.

In 1 capsule 150 mg contains: active substance: fluconazole 150 mg;

auxiliary substances: lactose monohydrate 35.25 mg, pregelatinized starch 106.65 mg, colloidal colloidal silica 0.30 mg, magnesium stearate 7.50 mg, sodium lauryl sulfate 0.30 mg; shell capsules:

lid: dye blue patented (E 131) - 0.23%, titanium dioxide 3%, gelatin to 100%;

body: titanium dioxide - 2%, gelatin - up to 100%, black ink *.

* OPACODE BLACK (shellac, iron oxide black, n-butanol, purified water, propylene glycol, industrial methylated alcohol, isopropyl alcohol) or TekPrint ™ SW-9008 Black ink (shellac, absolute alcohol, butyl alcohol,

propylene glycol, purified water, ammonia solution concentrated, potassium hydroxide, iron oxide black).

Description:

Capsules 100 mg

Case: white opaque with black overprint "MYCO 100". Cap: blue, opaque.

Capsules 150 mg

Case: white opaque with black overprint "MYCO 150". Cap: blue, opaque.

The contents of the capsule are from almost white to white with a yellowish hue of color powder.

Pharmacotherapeutic group:Antifungal agent.

ATX: & nbsp

J.02.A.C Triazole derivatives

J.02.A.C.01 Fluconazole

Pharmacodynamics:

Fluconazole, a representative of the class of triazole antifungal agents, is a strong selective inhibitor of ergosterol synthesis in cell membranes of fungi. The mechanism of the antifungal action of fluconazole is the specific inhibition of the activity of the fungal isoenzyme system P 450, which leads to inhibition of the main stage of fungal ergosterol biosynthesis.

Fluconazole activity was demonstrated in vitro and in the clinic and in relation to most of the following microorganisms:Candida albicans, Candida glabrata (many strains are moderately sensitive), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans.

Fluconazole activity was demonstrated in vitro, a also for the following microorganisms, but the clinical significance of this is unknown: Candida dubliniensis, Candida guilliermondii, Candida kefyr, Candida lusitaniae.

The drug is effective in opportunistic mycoses, incl. caused by Candida spp., including generalized forms of candidiasis on background immunodepression; Cryptococcus neoformans, including intracranial

infection; Microsporum spp; Trichophyton spp. Fluconazole is also effective in

endemic mycoses caused by Blastomyces dermatitidis, Coccidioides

immitis, including intracranial infection, Histoplasma capsulatum (in number and immunodepression).

Fluconazole has high specificity in relation to the fungal isoenzymes of the P 450 system and has little effect on the isoenzymes of the P 450 system in humans.

With the administration of fluconazole at a dose of 50 mg per day for 28 days, there is no change in testosterone plasma concentrations in men or in concentrations of steroid homon in women of childbearing age. Besides fluconazole at a dose of 200-400 mg per day did not have a clinically significant effect on the concentrations of endogenous steroids or on the hormonal response to the introduction of ACTH in healthy male volunteers. Resistance to fluconazole can develop in the following cases: a qualitative or quantitative change in the enzyme that is the target for fluconazole (lanosteryl 14-a-demethylase), a decrease in access to the target of fluconazole, or a combination of these mechanisms.

Point mutations in the ERG11 gene encoding the target enzyme lead to a modification of the target and a decrease in the affinity for azoles. Increasing the expression of the ERG 11 gene results in the production of high concentrations of the target enzyme, which necessitates an increase in the concentration of fluconazole in the intracellular fluid to suppress all the enzyme molecules in the cell.

The second significant mechanism of resistance is active deducing fluconazole from the intracellular space by activating two types of transporter involved in the active excretion of drugs from the fungal cell. These transports include the main mediator, encoded by genes MDR (multiple drug resistance), and the superfamily of the ATP-binding cassette of the transporter, encoded by genes CDR (genes of resistance of fungi Candida to azole antifungal agents). Hyperexpression of the gene MDR leads to resistance to fluconazole, while at the same time overexpression of genes CDR can lead to resistance to various azoles.

Resistance to Candida glabrata is usually mediated by the overexpression of the gene CDR, which leads to resistance to many azoles. For those strains in which the minimum inhibitory concentration (MIC) is defined as an intermediate (16-32 μg / ml), it is recommended to apply the maximum doses of fluconazole.

Candida krusei should be considered as resistant to fluconazole. The mechanism of resistance is associated with a reduced sensitivity of the target enzyme to the inhibitory effect of fluconazole.

Pharmacokinetics:

After oral administration fluconazole well absorbed. Bioavailability of fluconazole is 90%. The maximum concentration of fluconazole in the blood plasma (Stach) after its intake in fasting at a dose of 150 mg is 90% of its concentration in the plasma with intravenous administration. Simultaneous food intake does not affect the absorption of the drug taken internally. After taking fluconazole, the inside of Stach is reached after 0.5-1.5 hours, its half-life (Tc) is about 30 hours. Concentrations in the blood plasma are in direct proportion to the dose. 90% of the equilibrium concentration is reached by 4 - 5 day of daily administration of fluconazole once a day.

The introduction on the first day of a shock dose, which is 2 times higher than the usual daily dose, allows reaching 90% of the equilibrium concentration by the second day.

Volume of distribution (Vd) is close to the total water content in the body. Binding to plasma proteins -11-12%. Fluconazole well penetrates into all body fluids. Concentrations of the drug in saliva and sputum are similar to its concentration in plasma blood. In patients with fungal meningitis, the fluconazole content in the cerebrospinal fluid reaches 80% of its concentration in the blood plasma.

In the stratum corneum, epidermis, dermis and fluids, high concentrations of fluconazole are achieved, which exceed its concentration in serum.

When fluconazole was taken 150 mg once a week, the fluconazole concentration in the stratum corneum was 23.4 μg / g, and 7 days after the second dose, 7.1 μg / g. The concentration of fluconazole in the nails after 4 months of admission at a dose of 150 mg once a week was 4.05 μg / g in healthy nails and 1.8 μg / g in the affected nails. Six months after the cessation of treatment in the nails, there is still a detectable concentration of fluconazole.

Fluconazole is excreted mainly by the kidneys; approximately 80% of the administered dose is excreted in the urine unchanged. The clearance of fluconazole is proportional to the clearance of creatinine (CC). Metabolites of fluconazole in peripheral blood were not detected.

Long-term T1/2 fluconazole from the plasma is the basis of a single application for vaginal candidiasis, as well as application once a day or once a week in connection with other indications. Pharmacokinetics in renal failure

In patients with severe renal failure (glomerular filtration rate <20 ml / min) T1/2 increased from 30 to 98 hours. Therefore, in the future, it is necessary to reduce the dose of the drug. Pharmacokinetics in children After taking 2-8 mg / kg fluconazole by children aged 9 months to 15 years AUC (the area under the concentration-time curve) was approximately 38 μg / hr / ml per mg / kg. Average T1/2 fluconazole from the blood plasma varied between 15 and 18 h, Vd was approximately 880 ml / kg after repeated administration. Higher T1/2 fluconazole from the plasma (approximately 24 h) was noted after a single dose. Vd in this age group was approximately 950 ml / kg.

Pharmacokinetics in elderly patients Pharmacokinetics was studied in 22 patients aged 65 years and older who took a single oral dose fluconazole in a dose of 50 mg, 10 of which at the same time took diuretics. FROM_max was 1.54 μg / ml and was achieved after 1.3 hours after taking the drug. Average AUC was 76.4 ± 20.3 μg / hr / ml, the mean terminal Tsh was 46.2 h. These pharmacokinetic parameters are higher than those described in normal healthy young volunteers. Simultaneous reception of diuretics did not significantly change AUC or Stach. Creatinine clearance (74 ml / min), the percentage of fluconazole found unchanged in urine (0-24 hours, 22%), and the renal clearance of fluconazole (0.124 ml / min / kg) in elderly patients was generally lower than in young volunteers.Therefore, a change in the distribution of fluconazole in elderly patients appears to be associated with a decreased renal function in this age group.

Indications:

Cryptococcosis, including cryptococcal meningitis and other localizations of this infection (including lungs, skin), both in patients with normal immune response, and
in patients with various forms of immunodepression (including those with acquired immune deficiency syndrome (AIDS), with organ transplantation); the drug can be used to prevent the recurrence of cryptococcal infection in AIDS patients.
Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis infections (peritoneal, endocardial, eye, respiratory and urinary tract infections, liver, spleen and other organs). Treatment can be performed in patients with malignant neoplasms, in intensive care units, in patients undergoing cytostatic or immunosuppressive therapy, and in the presence of other factors predisposing to the development of candidiasis.
Candidiasis of mucous membranes, incl. oral cavity and pharynx, esophagus, non-invasive bronchopulmonary candidiasis, candiduria,candidiasis skin in patients with normal immune system function and in patients with decreased immune system function; prevention of recurrence of oropharyngeal candidiasis in AIDS patients. Genital Candidiasis: vaginal candidiasis (acute and chronic
relapsing), prophylactic use to reduce the frequency of recurrences of vaginal candidiasis (3 or more episodes per year); candidiasis balanitis. Prevention of fungal infections in patients with malignant neoplasms that are predisposed to such infections as a result of chemotherapy with cytostatics or radiation therapy.
Mycosis of the skin, including mycosis of the feet, the body, the groin area; pityriasis lichen, onychomycosis; candidiasis of the skin.
Deep endemic mycoses, including coccidiomycosis, paracoccidiomycosis, sporotrichosis and histoplasmosis in patients with normal immunity.

Contraindications:

Simultaneous reception of terfenadine, if necessary, multiple administration of fluconazole at a dose of 400 mg per day or more, as well as other medications that can lengthen the interval QT and cause ventricular tachycardia, including ventricular pirouette tachycardia,the metabolism of which occurs with the cytochrome P 450 isoenzyme (CYP) ZA4, such as cisapride, astemizole, pimozide, quinidine and erythromycin. Hypersensitivity to fluconazole or structurally close to azole compounds, as well as the excipients of the drug and substances that form part of the capsule shell

Children with a body weight of less than 40 kg (for dosages of 100 mg and 150 mg)

Congenital intolerance of galactose, insufficiency of lactase, glucose-galactose malabsorption (due to the content of lactose in the formulation).

The period of breastfeeding.

Carefully:

Liver failure.

Renal failure (requires dose adjustment of fluconazole).

Potentially proaritmogenic states in patients with multiple risk factors (organic heart disease, water-electrolyte balance disturbances, simultaneous intake of drugs that cause arrhythmias).

Simultaneous reception of terfenadine with fluconazole in a dose of less than 400 mg per day.

Simultaneous reception of hypoglycemic agents for oral administration, sulfonylurea derivatives (increased risk of hypoglycemia,requires careful monitoring of the concentration of glucose in the blood, if necessary, correction of hypoglycemic therapy).

Pregnancy and lactation:

Adequate and controlled

studies of the use of fluconazole in pregnant women have not been conducted. During pregnancy, the use of fluconazole should be avoided, except in cases of severe and potentially life-threatening

fungal infections, when the expected benefit of treatment exceeds the possible risk to the fetus. Women of childbearing age should use

contraception. In the course of animal studies, reproductive toxicity was noted.

Breastfeeding period Fluconazole penetrates into breast milk, where it reaches concentrations below the plasma levels. The use of the drug in women during breast-feeding is not recommended

Dosing and Administration:

The drug is taken internally.

Capsules should be swallowed whole regardless of food intake.

Adults

When cryptococcal meningitis and cryptococcal infections of other localizations the first day, usually prescribed 400 mg, and then continue treatment at a dose of 200-400 mg once a day.The duration of treatment for cryptococcal infections depends on the clinical efficacy, confirmed by mycological examination; In cryptococcal meningitis, treatment usually lasts no less than 6-8 weeks.

For prevention of recurrence cryptococcal meningitis in patients with AIDS after completion of the full course of primary treatment fluconazole prescribe a dose of 200 mg per day for a long period of time.

When candidemia, disseminated candidiasis and other forms of invasive candidiasis infections on the first day 400 mg are prescribed, then continue treatment at a dose of 200 mg once a day. With insufficient clinical effectiveness, the dose of the drug can be increased to 400 mg per day. Typically, the recommended duration of treatment for candidemia is 2 weeks after the first negative result of blood culture and regression of symptoms of candidemia.

When candidiasis of the mouth and throat at usually appoint 100 mg of fluconazole 1 time / day; the duration of treatment is 7-14 days. If necessary, in patients with a marked decrease in immunity, treatment may be longer.

With other localizations of candidiasis (with the exception of genital candidiasis), for example, with esophagitis, noninvasive bronchopulmonary disease, candiduria, candidiasis of the skin and mucous membranes, etc., the effective dose is usually 100 mg per day, with a treatment duration of 14-30 days. To prevent the recurrence of oropharyngeal candidiasis in patients with AIDS after completing a full course of primary therapy, 150 mg once a week can be prescribed First day appoint 200 - 400 mg, then 100 - 200 mg once a day.

The duration of treatment is 7 to 21 days (until the remission of candidiasis of the oral cavity and pharynx).

When esophageal candidiasis on the first day, 200-400 mg is prescribed, then the treatment is continued at a dose of 100-200 mg once a day. The duration of treatment is 14-30 days (until the remission of candidiasis of the esophagus).

When candiduria prescribe 200 - 400 mg per day. The duration of treatment is 7-21 day.

If necessary, in patients with a marked decrease in immunity, the treatment of candidiasis of the mucous membranes (mouth and pharynx, esophagus), as well as candiduria, may be longer.

When chronic candidiasis of skin and mucous membranes prescribe 100 mg per day. Duration of treatment is up to 28 days. Depending on the severity of the infection or the existing depression of the immune system and infection, the duration of treatment may increase.

For prevention of recurrences of oral candidiasis, pharynx and esophagus in AIDS patients at high risk of recurrence, fluconazole is prescribed for 100-200 mg per day or 200 mg 3 times a week. For patients with chronic oppression of immunity duration of treatment is not established.

When acute vaginal candidiasis and candida balanitis fluconazole is taken once inside by 150 mg.

For treatment and prevention recurrent vaginal candidiasis (4 or more episodes per year), the drug is used at a dose of 150 mg every third day, in total 3 doses (days 1, 4, and 7), then take a maintenance dose of 150 mg once a week. The maintenance dose is taken within 6 months.

For the prevention of candidiasis in patients with long-lasting neutropenia the recommended dose is 200 - 400 mg once a day. Fluconazole appoint a few days before the expected appearance of neutropenia, after increasing the number of neutrophils more than 1000 / mm, the treatment is continued for another 7 days.

When skin mycoses, including epidermophytic feet, dermatomycosis smooth skin, inguinal dermatomycosis and candidiasis skin, the recommended dose is 150 mg once a week.

Duration of therapy in usual cases is 2-4 weeks, however, with epidermophytosis of the feet, longer therapy (up to 6 weeks) may be required.

When pityriasis the recommended dose is 300 to 400 mg once a week for 1 to 3 weeks.

When onychomycosis the recommended dose is 150 mg once a week. Treatment should continue until the full replacement of the affected nail is healthy. Usually this process lasts for 3-6 months, and when the nails of the big toes are damaged - within 6 to 12 months. The speed of nail growth is very individual and depends on the age of the patient. After curing a chronic nail infection, it is possible to preserve deformities of the nail plates.

When deep endemic mycoses may require the use of the drug at a dose of 200 - 400 mg per day for up to 2 years. The duration of therapy is determined individually; it can be 11 to 24 months with coccidioidomycosis; 2-17 months - with paracoccidioidomycosis; 1- 16 months - with sporotrichosis and 3 - 17 months - with histoplasmosis.

When coccidioidomycosis the dose is 200 to 400 mg, treatment lasts 11 to 24 months or longer, depending on the case. With some infections and, especially with damage to the meninges, it is possible to consider the use of fluconazole at a dose of 800 mg per day.

Children

In children, as with similar infections in adults, the duration of treatment depends on the clinical efficacy and sensitivity of fungi. Do not exceed the maximum dose of 400 mg per day.

The drug is used daily 1 time per day.

For treatment cryptococcal meningitis or invasive candidiasis the recommended dose is 6-12 mg / kg per day, depending on the severity of the disease.

In children with candidiasis of mucous membranes the recommended dose of fluconazole is 3 mg / kg per day. On the first day, a shock dose of 6 mg / kg may be prescribed to achieve a more rapid equilibrium equilibrium concentration.

For prevention of fungal infections the children with reduced immunity, who are at risk of developing infection due to neutropenia, developing as a result of cytotoxic chemotherapy or radiotherapy, the drug is prescribed at 3-12 mg / kg per day, depending on the severity and duration of preservation of induced neutropenia.

In the framework of maintenance treatment for the prevention of recurrence of cryptococcal meningitis in children with a high risk of recurrence, the drug is prescribed at 6 mg / kg per day, depending on the severity of the disease.

Adolescents (12-18 years)

The most suitable dose (for adults or children) should be selected depending on the body weight and maturity of the adolescent. Clinical evidence suggests that in children the clearance of fluconazole is higher than in adults. In order to achieve comparable systemic effects, 100, 200 and 400 mg for adults correspond to 3, 6 and 12 mg / kg for children.

The safety and effectiveness of the drug in the treatment of genital candidiasis in adolescents are not established. Available safety data for the drug in the context of other indications of adolescents are described in the section ("Side Effects"). With the expressed need for treatment genital candidiasis in adolescents (12 - 18 years) should use the same dose as in adults.

In children with impaired renal function, the daily dose of the drug should be reduced (in the same proportional relationship as in adults, according to the degree of renal failure, see below).

In elderly patients in the absence of violations of kidney function should follow the usual dosage regimen. Doses for elderly patients with renal insufficiency (CC less than 50 ml / min), see below.

In patients with impaired renal function fluconazole is excreted mainly by the kidneys in unchanged form. If you take it once, you do not need to change the dose. When taking a course of the drug, patients with impaired renal function should first enter a shock dose of 50 mg to 400 mg. If the SC is more than 50 ml / min, the usual dose of the drug (100% of the recommended dose) is used. With SC less than 50 ml / min without dialysis, a dose of 50% of the recommended dose is applied. Patients regularly on hemodialysis after each hemodialysis session should take the usual dose of the drug.

Side effects:

The frequency of occurrence of adverse adverse reactions (NDP), listed below, was determined by the classification of the frequency of occurrence of the NIR of the World Health Organization: often from more than 1/100 to less than 1/10, infrequently from more than 1/1000 to less than 1/100, from more than 1/10000 to less than 1/1000, an unknown frequency - according to available data to determine the incidence of adverse reactions is not possible.

Usually fluconazole well tolerated.

General disorders and disorders in place introduction of

Infrequently: weakness, fever, increased fatigue, anxiety.

Disturbances from the nervous system

Often: headache.

Infrequently: dizziness, convulsions, paresthesia, changes in taste, insomnia, drowsiness.

Rarely: tremor.

Hearing impairments and labyrinthine infringements infrequently: Vertigo.

Disturbances from the skin and subcutaneous fabrics

Often: skin rash.

Infrequently: itching, increased sweating, drug rash, hives.

Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioedema, edema of the face, alopecia.

Disorders from the gastro-intestinal tract

Often: nausea and vomiting, abdominal pain, diarrhea.

Infrequently: constipation, dyspepsia, flatulence, dryness of the oral mucosa.

Disorders from the side of the skeletal-muscular and connective tissue

Infrequently: myalgia.

Disorders from the liver and bile ducts

Often: a clinically significant increase in activity of alanine aminotransferase,aspartate aminotransferase, increased activity of alkaline phosphatase.

Infrequently: cholestasis, hyperbilirubinemia, jaundice.

Rarely: necrosis of liver cells, hepatic insufficiency, hepatitis, lesion of liver cells.

Unknown frequency: hepatotoxicity, in some cases with a fatal outcome.

Violations from the blood and lymphatic system

Infrequently: anemia.

Rarely: agranulocytosis, leukopenia, thrombocytopenia, neutropenia.

Immune system disorders

Rarely: anaphylaxis.

Disorders from the metabolism and nutrition

Infrequently: decreased appetite.

Rarely: hypercholesterolemia, hypertriglyceridemia, hypokalemia. Disorders from the cardiovascular system

Rarely: ventricular tachycardia of the type "pirouette" (torsades de pointes), prolongation of the interval QT.

Adverse reactions were more often observed in patients infected with the human immunodeficiency virus (HIV) than in the rest of the patients.

Overdose:

Symptoms: hallucinations, paranoid behavior.

Treatment: symptomatic: gastric lavage, forced diuresis. Hemodialysis within 3 hours reduces the concentration of fluconazole in the blood plasma by approximately 50%.

Interaction:

Single and multiple administration of fluconazole at a dose of 50 mg does not affect the metabolism of phenazone.

Simultaneous application of with the following medicinal

contraindicated

Cisapride: There have been reports of adverse cardiac reactions, including ventricular pirouette torsades de pointes in patients simultaneously receiving fluconazole and cisapride. In controlled trials, it was found that simultaneous administration of fluconazole at a dose of 200 mg 1 time per day and cisapride 20 mg 4 times a day led to a significant increase in plasma concentrations of cisapride and an increase in the duration of the QT interval.

Simultaneous reception of cisapride in patients receiving fluconazole, contraindicated (cm. section "Contraindications").

Terfenadine: Some azoles in combination with terfenadine were associated with the occurrence of severe rhythm disturbances, including ventricular torsades de pointes, due to the prolongation of the QT interval on the electrocardiogram (ECG). Studies with fluconazole showed that a daily dose of fluconazole 200 mg did not show an extension of the QT interval.When fluconazole was administered at a dose of 400 or 800 mg, a significant increase in the plasma concentration of terfenadine was observed. The administration of fluconazole 400 mg or more in combination with terfenadine is contraindicated. Patients should be carefully observed while taking terfenadine and fluconazole at a dose of less than 400 mg per day.

Astemizole: simultaneous application of fluconazole and astemizole can lead to a decrease in the clearance of astemizole. As a result of increased plasma concentrations of astemizole, prolongation of the QT interval may occur and rarely a torsades de pointes ventricular tachycardia. Simultaneous administration of fluconazole and astemizole is contraindicated (see section "Contraindications").

Pimozide: Despite the lack of in vitro or in vivo studies, simultaneous administration of fluconazole and pimozide can lead to inhibition of the metabolism of pimozide. An increase in plasma concentrations of pimozide may lead to an elongation of the QT interval and rarely to ventricular torsades de pointes. The simultaneous administration of fluconazole and pimozide is contraindicated (see Section "Contraindications").

Quinidine: Despite the lack of in vitro or in vivo studies, simultaneous administration of fluconazole with quinidine may cause inhibition of quinidine metabolism.The use of quinidine was associated with prolongation of the QT interval and rarely with ventricular pirouette torsades de pointes. Simultaneous administration of fluconazole and quinidine is contraindicated (see the section "Contraindications"), Erythromycin: simultaneous administration of fluconazole and erythromycin may increase the risk of cardiotoxicity (prolongation of the QT interval, development of ventricular torsades de pointes) and, subsequently, to sudden cardiac death. Simultaneous administration of fluconazole and erythromycin is contraindicated (see section "Contraindications").

Simultaneous reception with the following drugs is not recommended

Hapofantrine: fluconazole may increase plasma concentrations of halofantrine due to oppression of the isoenzyme CYP3A4. Simultaneous use of fluconazole and halofantrine may increase the risk of cardiotoxicity (lengthening of the interval QT, the development of ventricular tachycardia such as "pirouette" (torsades de pointes)) and, subsequently, to sudden cardiac death. This combination of drugs is not recommended (see section "Special instructions").

In connection with the simultaneous use of the following medicines, compliance with measures precaution and dose selection

The effect of other drugs on fluconazole

Rifampicin: when fluconazole was combined with rifampicin, a decrease in T1 / 2 fluconazole by approximately 20%, plasma concentration by 25%. Therefore, patients receiving concomitantly rifampicin, it is advisable to increase the dose of fluconazole. Effect of fluconazole on other drugs Fluconazole is a potent inhibitor of the 2C9 isoenzyme cytochrome P 450 (SUR) and a moderate inhibitor of the isoenzyme CYP3A4. Also fluconazole is an inhibitor of the isoenzyme CYP2C19. In addition to the noted / documented interactions, there is a risk of increasing the plasma concentration of other substances metabolized by the CYP2C9 and CYP3A4 isoenzymes against a background of combined use with fluconazole. Therefore, when using these combinations, care should be taken and the condition of patients carefully monitored. The inhibition of enzymes with fluconazole persists for 4-5 days after discontinuation due to prolonged T1 / 2 (see the section "Contraindications"),

Alfentanil: when taking fluconazole (400 mg) and intravenous alfentanil (20 μg / kg) in healthy volunteers of AIH alfentanil increased 2-fold, possibly due to oppression of the isoenzyme CYP3A4. It may be necessary to select a dose of alfentanil.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. Concentrations of 5-nortriptyline and / or Samitriptyline can be measured at the beginning of the combined treatment and one week after its onset. If necessary, a dose of amitriptyline / nortriptyline should be chosen. Amphotericin B: with simultaneous administration of fluconazole and amphotericin B in the infected mice with normal immunity and suppression of immunity, the following results were noted: a slight additive antifungal effect in systemic lesions Candida albicans, absence of interaction with intracranial lesion Cryptococcus neoformans and antagonism of two drugs on the background of systemic lesion Aspergillus fumigatus. The clinical significance of the results noted during these studies is not clear.

Anticoagulants, as well as when using other azole antifungal agents, during post-marketing application bleeding (formation of hematomas, bleeding from the nose or gastrointestinal tract, hematuria and melena) has been described in connection with the increase prothrombin time in patients taking fluconazole together with warfarin. With the simultaneous administration of fluconazole with warfarin, an increase in prothrombin time by a factor of 2 was observed, possibly due to the suppression of isoenzyme by fluconazole CYP2C9, by means of which it is metabolized warfarin. In patients who simultaneously receive anticoagulants (coumarin derivatives) with fluconazole, careful monitoring of prothrombin time is required. There may be a need for a dose of warfarin.

Benzodiazepines (short-acting), for example, midazolam, triazolam: after taking midazolam orally fluconazole significantly increased the concentration of midazolam, which can lead to a change in the psychomotor function. Simultaneous oral administration of fluconazole at a dose of 200 mg and midazolam at a dose of 7.5 mg increased AUC Midazolam in 3,7 times and Ti/2 in 2,2 times. Fluconazole in a dose of 200 mg per day together with oral triazolam at a dose of 0.25 mg increased AUC triazolam 4.4 times, Tsh - 2.3 times. Against the background of simultaneous application of fluconazole, the increase and lengthening of the action of triazolam was noted. If it is necessary to simultaneously treat benzodiazepines with patients taking fluconazole, it is necessary take into account the reduction in the dose of benzodiazepine, also the patients should be monitored accordingly. Carbamazepine: fluconazole inhibits the metabolism of carbamazepine, there was an increase in the concentration of carbamazepine in blood plasma by 30%. There is a risk of carbamazepine intoxication. It may be necessary to select a dose of carbamazepine depending on the concentration / effect estimate.

Blocks of "slow" calcium channels: metabolism of some calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) occurs by means of isoenzyme CYP3A4. Fluconazole may increase the systemic effect of calcium channel antagonists. Recommended frequent control of occurrence of undesirable phenomena.

Celecoxib: during simultaneous treatment with fluconazole (200 mg per day) and celecoxib (200 mg) C_max and AUC celecoxib increased by 68% and 134%, respectively. When co-administered with fluconazole, half the dose of celecoxib may be required.

Cyclophosphamide: simultaneous application of fluconazole and cyclophosphamide led to an increase in the concentration of bilirubin and creatinine in the blood plasma.This combination is acceptable taking into account the risk of increasing concentrations of bilirubin and creatinine. Fentanyl: One case of fentanyl intoxication with a fatal outcome has been described because of the possible interaction of fentanyl with fluconazole. In addition, in healthy volunteers fluconazole led to a pronounced delay in the excretion of fentanyl. Increased concentrations of fentanyl may lead to respiratory depression. Patients should be closely monitored because of the possible risk of respiratory depression. It may be necessary to select a dose of fentanyl.

HMG-CoA reductase inhibitors: the risk of developing myopathy and rhabdomyolysis increases with the combined use of fluconazole with HMG-CoA reductase inhibitors, the metabolism of which occurs with the CYP3A4 isoenzyme (atorvastatin and simvastatin) or with the aid of the CYP2C9 isoenzyme (fluvastatin). If joint treatment is necessary, patients should be monitored for symptoms of myopathy and rhabdomyolysis, and the concentration of creatine kinase should also be checked. The intake of HMG-CoA reductase inhibitors should be discontinued with a marked increase in creatine kinase,as well as the development of myopathy / rhabdomyolysis or suspected of them.

Immunosuppressors (ciclosporin, everolimus, sirolimus and tacrolimus): Cyclosporin: in patients with kidney transplantation with fluconazole at a dose of 200 mg / day, a slight increase in the concentration of cyclosporine in the blood was observed. This combination of drugs can be used to reduce the dose of cyclosporine depending on its concentration.

Everolimus: despite the lack of in vivo or in vitro studies, fluconazole can increase the concentration of everolimus in blood plasma by inhibiting the isoenzyme CYP3A4.

Sirolimus: fluconazole increases plasma concentrations of sirolimus, possibly by inhibiting the metabolism of sirolimus by means of the isoenzyme CYP3A4 and P-glycoprotein. This combination of drugs can be used against the background of choosing a dose of sirolimus depending on the concentration / efficacy assessment.

Tacrolimus: fluconazole can increase the concentration of tacrolimus in the blood plasma after oral administration up to 5 times because of inhibition of tacrolimus metabolism through the isoenzyme CYP3A4 in the intestine. Against the background of intravenous tacrolimus, no significant changes in pharmacokinetics were noted. An increase in tacrolimus concentrations was associated with nephrotoxicity.The dose of tacrolimus when taken orally should be reduced depending on the concentration of tacrolimus in the blood.

Losartan: fluconazole inhibits the metabolism of losartan with the formation of an active metabolite (E-31 74), responsible for most of the inhibition of angiotensin II receptors, which occurs during treatment with losartan. Patients should constantly monitor blood pressure. Methadone: fluconazole can increase the concentration of methadone in the blood plasma. There may be a need for a dose of methadone.

Non-steroidal anti-inflammatory drugs (NSAIDs): Stach and AUC of flurbiprofen increased by 23% and 81% against a background of combined use of fluconazole compared to flurbiprofen monotherapy. Similarly, Stach and AUC of the pharmacologically active isomer of [8 - (+) - ibuprofen] increased by 15% and 82% against a background of co-administration of fluconazole with racemic ibuprofen (400 mg) compared with monotherapy with racemic ibuprofen.

Despite the absence of special studies, fluconazole can enhance the systemic effect of other non-steroidal anti-inflammatory drugs, the metabolism of which occurs with the isoenzyme CYP2C9 (eg, naproxen, lornoxicam, meloxicam, diclofenac).Recommended frequent control of adverse events and signs of toxicity NSAIDs. It may be necessary to select a dose of NSAIDs. Phenytoin: simultaneous application of fluconazole and phenytoin clinically significantly increases the concentration of phenytoin in the blood. It is necessary to monitor the concentration of phenytoin in the blood and, if necessary, adjust the dose of phenytoin in order to maintain its concentration in the blood within the therapeutic range. Prednisone: A report was received that the patient who underwent a liver transplant and received prednisone, acute adrenocortical failure occurred after the cessation of a three-month treatment with fluconazole. The discontinuation of fluconazole probably led to an increase in the activity of the isoenzyme CYP3A4, which led to an increase in the metabolism of prednisone. The condition of long-term patients fluconazole and prednisone, should be carefully monitored for the occurrence of adrenocortical insufficiency after the discontinuation of fluconazole.

Rifabutin: simultaneous application of fluconazole and rifabutin may increase the plasma concentration of rifabutin up to 80%.In patients who simultaneously take fluconazole and rifabutin, it is possible to develop uveitis. When combined therapy should take into account the symptoms of rifabutin toxicity and monitor the condition of patients.

Saquinavir: fluconazole increases AUC and Saquinavir stach by approximately 50% and 55%, respectively, due to the inhibition of hepatic metabolism of saquinavir with the participation of the isoenzyme CYP3A4 and P-glycoprotein. Interactions with saquinavir / ritonavir have not been studied, it may be more pronounced. There may be a need for a dose of saquinavir.

Hypoglycemic agents for oral administration (sulfonylureas derivatives): it has been demonstrated that fluconazole increases the plasma concentration and increases T1 / 2 simultaneously taken chlorpropamide, glibenclamide, glipizide and tolbutamide. Simultaneous use of fluconazole and hypoglycemic agents for oral administration (sulfonylureas derivatives) is possible, but the likelihood of hypoglycemia should be considered, and the concentration of glucose in the blood should be carefully monitored; in rare cases, a dose reduction may be requireda hypoglycemic agent for oral administration, a sulfonylurea derivative.

Theophylline: fluconazole increases the plasma concentrations of theophylline. The use of fluconazole at a dose of 200 mg for 14 days resulted in an 18% decrease in the average plasma clearance values of theophylline. Patients who receive high doses of theophylline or who are at risk of developing the toxic effects of theophylline should be monitored for the early detection of symptoms of theophylline overdose. When signs of toxicity appear, treatment should be changed.

Vinca alkaloids: although no studies have been carried out, fluconazole can increase plasma concentrations of vinca alkaloids (vincristine, vinblastine) and cause a neurotoxicity, which is possibly associated with inhibition of the CYP3A4 isoenzyme.

Vitamin A: Based on the case report of one patient receiving a combination of fully trans-retinoic acid (acidic form of vitamin A) and fluconazole, unwanted effects from the central nervous system developed in the form of benign intracranial hypertension that disappeared after discontinuation of fluconazole treatment.This combination of drugs can be used, however, the frequency of undesirable effects from the central nervous system should be taken into account.

Voriconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4): simultaneous oral administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral administration of fluconazole (400 mg per day, then 200 mg every 24 hours for 4 days) in 8 healthy male subjects led to an increase in Stach and AUCt voriconazole by an average of 57% (90% confidence interval: 20%, 107%) and 79% (90% confidence interval: 40% , 128%), respectively. The effect of dose reduction and / or the frequency of administration of voriconazole and fluconazole on this effect has not been established. When taking voriconazole after fluconazole, it is recommended to control undesirable phenomena associated with voriconazole. Zidovudine: fluconazole increases Stach and AUC of zidovudine by 84% and 74% due to approximately 45% reduction in zidovudine clearance after oral administration. T1 / 2 zidovudine also elongated by about 128% after combined treatment with fluconazole. The condition of patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.Consideration should be given to reducing the dose of zidovudine.

Azithromycin: no significant pharmacokinetic interaction was observed between fluconazole and azithromycin.

Hydrochlorothiazide: in patients receiving hydrochlorothiazide, with the simultaneous administration of fluconazole, an increase in plasma concentrations of fluconazole by 40% is possible. This effect should not affect the dose of fluconazole.

Oral contraceptives: with simultaneous application of fluconazole at a dose of 50 mg and oral contraceptives, there were no significant changes in plasma concentrations of ethinylestradiol and levonorgestrel, but with 200 mg of fluconazole, there was an increase in ethinylestradiol AUC by 40% and levonorgestrel by 24%. Therefore, the effect of fluconazole on the efficacy of combined oral contraceptives is not expected.

The attending physicians should keep in mind that studies on drug interactions with other drugs have not been conducted, but the development of such interactions is possible.

Interaction studies have shown that with simultaneous intake of food, cimetidine,antacids or whole-body irradiation for bone marrow transplantation, there was no clinically significant deterioration in the absorption of fluconazole.

Special instructions:

The dose should be selected taking into account the pathogen and the severity of the fungal infection. For all indications, treatment with the drug should be continued until the onset of clinical and laboratory remission. Premature termination of treatment leads to relapse.

During the treatment it is necessary to monitor hematological parameters, kidney and liver function.

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, including fatalities, mainly in patients with serious concomitant diseases. In the case of hepatotoxic effects associated with fluconazole, there was no apparent dependence on the total daily dose, duration of therapy, sex and age of the patient. Hepatotoxic effect of fluconazole was usually reversible, signs of it disappeared after discontinuation of therapy. The patient should be informed of possible clinical symptoms of liver damage (asthenia, anorexia, persistent nausea, vomiting and jaundice).If they occur, treatment with fluconazole should be stopped immediately, the patient should consult a doctor.

The drug Mikomaks® should be administered with caution to patients with impaired renal function. If there are violations of the kidneys, you also need to cancel the drug.

Patients with AIDS are more likely to develop severe skin reactions with many drugs. In those cases where the rash develops in patients with superficial fungal infection and it is regarded as definitely associated with fluconazole, the drug should be discontinued. When rashes appear in patients with invasive / systemic fungal infections, they should be carefully monitored and canceled fluconazole when there are bullous changes or erythema multiforme. In rare cases, during treatment with fluconazole, exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis occurred in patients. In rare cases, anaphylaxis has been described.

Caution should be exercised while taking fluconazole with rifabutin or other drugs metabolized by the P 450 isoenzyme system. Fluconazole is a strong inhibitor of the isoenzyme CYP2C9 and a moderate inhibitor of the isoenzyme CYP3A4. Also fluconazole is an inhibitor of the isoenzyme CYP2C19. It should be monitored the condition of patients taking the drug Mikomaks ® together with drugs with a narrow therapeutic index, the metabolism of which occurs with the isozymes CYP2C9, CYP2C19 and CYP3A4.

Some azoles, including fluconazole, were associated with the prolongation of the QT interval on the ECG. During the post-marketing use of the drug, there were reported rare cases of prolongation of the QT interval and the development of ventricular pirouette tachycardia during treatment with fluconazole. This effect was more often observed in patients with severe cardiac pathology and multiple risk factors, such as structural changes in the heart, abnormal water-electrolyte balance, and simultaneous use of drugs that may contribute to the occurrence of rhythm disturbances. The drug Mikomaks® should be taken with caution to patients with possible pro-arrhythmogenic conditions. Simultaneous use of other drugs that extend the QT interval and are metabolized by cytochrome P 450 isoenzymeCYP3A4, is contraindicated.

Halophthrin in the recommended therapeutic doses extended the QTc interval. It is a substrate of the isoenzyme CYP3A4. Therefore, the simultaneous use of fluconazole and halofantrine is not recommended.

When co-administration of fluconazole at doses below 400 mg / day with terfenadine should carefully monitor the condition of patients.

Mikomax® capsules contain lactose. Patients with rare hereditary intolerance to galactose, deficiency of lactase, glucose galactose malabsorption should not take this drug.

Evidence of the efficacy of fluconazole in the treatment of other endemic mycoses such as paracoccidioidomycosis, sporotrichosis and histoplasmosis is limited, which does not allow the determination of specific dosage recommendations. When fluconazole 150 mg is used for vaginal candidiasis, patients should be warned that symptom improvement usually occurs after 24 hours, but it often takes several days to completely disappear. If symptoms persist for several days, consult a doctor.

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

Study of the effect of the drug Mikomaks® on the ability to drive vehicles or machinery equipment was not conducted. Patients should be aware of the possible risk of dizziness or seizures during the administration of Mikomax®. If any of these symptoms occur, do not drive vehicles or machinery.

Form release / dosage:Capsules 100 mg.

Capsules 150 mg.

Packaging:

7 capsules per blister of A1 / PVC / PE / PVDC. For 1, 4 or 10 blisters together with instructions for use are placed in a cardboard box.

1 or 3 capsules per blister of A1 / PVC / PE / PVDC. Each blister along with instructions for use is placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiration date

Terms of leave from pharmacies:Without recipe

Registration number:П N013252 / 01

Date of registration:19.01.2012

The owner of the registration certificate:Zentiva c.s.Zentiva c.s. Czech Republic

Manufacturer: & nbsp

ZENTIVA, k.s. Czech Republic

Representation: & nbspZENTIVA PHARMA, LLCZENTIVA PHARMA, LLC

Information update date: & nbsp27.09.2015

Illustrated instructions

Instructions

Mycomomax® (Mycomax®)