Myconyl (Solution) Instructions for Use

Marketing Authorization Holder

Elda International, DMCC (United Arab Emirates)

Manufactured By

Claris Injectables, Ltd. (India)

ATC Code

J02AC01 (Fluconazole)

Active Substance

Fluconazole (Rec.INN registered by WHO)

Dosage Form

Myconyl

Infusion solution 200 mg/100 ml: vial 1 pc.

Dosage Form, Packaging, and Composition

100 ml – polyethylene vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal agent

Pharmacological Action

A representative of the triazole derivative class. It has a highly specific action, inhibiting the activity of fungal cytochrome P450. It blocks the conversion of lanosterol to ergosterol in fungal cells; it increases the permeability of the cell membrane.

Fluconazole, being highly selective for fungal cytochrome P450, practically does not inhibit these enzymes in the human body (compared to itraconazole, clotrimazole, econazole, and ketoconazole, it suppresses cytochrome P450-dependent oxidative processes in human liver microsomes to a lesser extent). It does not possess antiandrogenic activity.

It is active in opportunistic mycoses, including those caused by Candida spp. (including generalized forms of candidiasis against the background of immunosuppression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp.; in endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including in immunosuppression).

Pharmacokinetics

After IV administration, Fluconazole penetrates well into body tissues and fluids.

Distribution. The plasma concentration is in direct proportional dependence on the dose. The concentration of the active substance in breast milk, synovial fluid, saliva, sputum, and peritoneal fluid is similar to that in plasma.

In sweat fluid, epidermis, and the stratum corneum (selective accumulation), concentrations exceeding serum levels are achieved.

It penetrates well into the cerebrospinal fluid; in fungal meningitis, the concentration in the cerebrospinal fluid is about 85% of that in plasma.

90% equilibrium plasma concentration of fluconazole (C_ss) is reached by day 4-5. Administration of a “loading” dose (on the first day), twice the usual daily dose, allows achieving a concentration corresponding to 90% C_ss by day 2.

The apparent V_d approaches the total body water content. Plasma protein binding is low – 11-12%.

Metabolism and excretion. T_1/2 is 30 hours. It is an inhibitor of the CYP2C9 isoenzyme in the liver. It is excreted mainly by the kidneys (80% unchanged, 11% as metabolites). The clearance of fluconazole is proportional to the creatinine clearance. The pharmacokinetics of fluconazole significantly depend on the functional state of the kidneys, with an inverse relationship between T_1/2 and creatinine clearance (CrCl). After hemodialysis, within 3 hours, the plasma concentration of fluconazole decreases by 50%. The pharmacokinetics of fluconazole are similar for IV administration and oral intake, which allows for easy switching from one route of administration to the other.

Indications

• Cryptococcosis, including cryptococcal meningitis and infections of other locations (e.g., lungs, skin), both in patients with a normal immune response and in patients with various forms of immunosuppression (including patients with AIDS, organ transplantation); maintenance therapy to prevent relapse of cryptococcosis in patients with AIDS;
• Generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection, such as infections of the peritoneum, endocardium, eyes, bronchopulmonary system and urinary tract, including in patients with malignant tumors in intensive care units, patients receiving cytotoxic or immunosuppressive agents, as well as in patients with other factors predisposing to the development of candidiasis;
• Prophylaxis of candidiasis in the presence of a high risk of generalized infection, for example in patients with severe or prolonged neutropenia;
• Deep endemic mycoses (coccidioidomycosis and histoplasmosis) in immunocompetent patients;
• Oropharyngeal candidiasis, esophageal candidiasis and mucosal candidiasis in children.

ICD codes

Dosage Regimen

The solution for infusion is administered IV drip at a rate not exceeding 200 mg/hour. The daily dose of fluconazole depends on the nature and severity of the fungal infection. When switching from IV administration to the use of the drug in a form intended for oral administration, and vice versa, there is no need to change the daily dose.

The solution for infusion is compatible with 20% dextrose solution, Ringer’s solution, Hartmann’s solution, 5% dextrose and 0.9% potassium chloride solution, 4.2% sodium bicarbonate solution, 0.9% sodium chloride solution. Infusions can be carried out using standard transfusion sets, using one of the solvents listed above.

Adults. For cryptococcal meningitis and cryptococcal infections of other locations, on the first day, an average of 400 mg of fluconazole is prescribed, and then treatment is continued at a dose of 200-400 mg once a day. The duration of treatment for cryptococcal infections depends on clinical efficacy, confirmed by mycological examination; for cryptococcal meningitis, it is usually continued for at least 6-8 weeks.

To prevent relapse of cryptococcal meningitis in patients with AIDS after completing a full course of primary treatment, therapy with fluconazole at a dose of 200 mg/day can be continued for a very long period (a switch to the oral form is possible).

For candidemia, disseminated candidiasis and other invasive candidal infections, the dose is, on average, 400 mg on the first day, and then 200 mg per day. With insufficient clinical efficacy, the dose of fluconazole can be increased to 400 mg/day. The duration of therapy depends on clinical efficacy.

For the prophylaxis of candidiasis in the presence of a high risk of generalized infection, for example in patients with severe or prolonged neutropenia, the recommended dose is 400 mg once/day. Fluconazole is prescribed several days before the expected onset of neutropenia and after the neutrophil count increases above 1000/µl, treatment is continued for another 7 days.

For deep endemic mycoses, the use of the drug at a dose of 200-400 mg/day for up to 2 years may be required. The duration of therapy is determined individually; for coccidioidomycosis it is 11-24 months, for histoplasmosis it is 3-17 months (a switch to the oral form is possible).

Children. In children, as in similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be used in a daily dose that exceeds that in adults, i.e., no more than 400 mg per day. The drug is used daily once/day. If long-term therapy is necessary, a switch to the oral form of fluconazole is possible.

For cryptococcal meningitis and cryptococcal infections of other locations, as well as for generalized candidiasis in children, the recommended dose is 6-12 mg/kg/day, depending on the severity of the disease. The duration of therapy is 10-12 weeks (until laboratory confirmation of the absence of pathogens in the cerebrospinal fluid).

To prevent relapse of cryptococcal meningitis in children with AIDS, after completing a full course of primary treatment, therapy with fluconazole at a dose of 6 mg/kg/day can be continued for a long period.

For oropharyngeal candidiasis in children, the recommended dose is 6 mg/kg/day on the first day, then daily 3 mg/kg/day, as a single dose. The duration of therapy is at least 2 weeks.

For mucosal candidiasis in children, the recommended dose of fluconazole is 3 mg/kg/day. On the first day, a loading dose of 6 mg/kg may be prescribed to achieve steady-state concentrations more quickly. The duration of therapy is at least 3 weeks.

For esophageal candidiasis in children, Fluconazole is prescribed as a single dose of 3 mg/kg/day. On the first day, a loading dose of 6 mg/kg/day may be prescribed. Depending on the severity of the disease, the dose may be increased to 6-12 mg/kg/day. The duration of therapy is at least 3 weeks and for another 2 weeks after the regression of symptoms.

For the prophylaxis of fungal infections in children with reduced immunity, in whom the risk of infection is associated with neutropenia developing as a result of cytotoxic chemotherapy or radiation therapy, Fluconazole is prescribed as a single dose of 3-12 mg/kg/day. The duration of therapy is until the induced neutropenia resolves.

Use of the drug in children under 4 weeks of age. It should be borne in mind that in newborns, Fluconazole is excreted slowly. For the first 2 weeks of life, the drug is prescribed at the same dose (in mg/kg) as in older children, but with an interval of 72 hours. For children aged 3 and 4 weeks, the same dose is administered with an interval of 48 hours.

Elderly patients. In the absence of renal impairment, the usual dosing regimen of the drug should be followed.

Patients with renal impairment. If CrCl is less than 50 ml/min, adjustment of the dosing regimen is required.

Fluconazole is excreted mainly in the urine unchanged. With a single use, no dose change is required. In patients with renal impairment with multiple use of the drug, a loading dose of 50 mg to 400 mg should initially be administered, after which the daily dose (depending on the indications) is determined according to the following table.

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

The drug solution contains 0.9% sodium chloride; each 100 ml vial contains 15 mmol of Na⁺ (sodium ions) and Cl^– (chloride ions), therefore, in patients who require restriction of sodium or fluid intake, it is necessary to take into account the rate of fluid administration.

Adverse Reactions

Fluconazole is generally well tolerated.

Depending on the frequency of occurrence, the following groups of side effects are distinguished: common – more than 1%, uncommon – 0.1-1%, rare – 0.01-0.1%; very rare – less than 0.01%.

Allergic reactions uncommon – skin rash, rare – multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), anaphylactoid reactions (including angioedema, facial edema, urticaria, skin itching).

From the central nervous system uncommon – headache, dizziness, rare – seizures.

From the gastrointestinal tract uncommon – nausea, diarrhea, flatulence, abdominal pain, taste change, vomiting, rare – impaired liver function (jaundice, hyperbilirubinemia, increased activity of ALT, AST and alkaline phosphatase, hepatitis, hepatocellular necrosis), including fatal outcome.

From the hematopoietic organs rare – leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

From the cardiovascular system rare – QT interval prolongation, very rare – ventricular fibrillation/flutter.

Other rare – impaired renal function, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Contraindications

Hypersensitivity to the components of the drug, as well as to other antifungal agents – azole derivatives; simultaneous use of terfenadine (against the background of continuous use of fluconazole at a dose of 400 mg/day or more) or astemizole; lactation period.

With caution. Hepatic insufficiency, appearance of rash during fluconazole use in patients with superficial fungal infection and invasive/systemic fungal infections, simultaneous use of terfenadine and fluconazole in a dose of less than 400 mg/day, potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalances, simultaneous use of drugs that cause arrhythmias, simultaneous intake with rifabutin and other cytochrome P450 inducers, acetylsalicylic acid), pregnancy.

Use in Pregnancy and Lactation

The use of fluconazole during pregnancy should be avoided, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of fluconazole use for the mother significantly outweighs the possible risk to the fetus. Since the concentration of fluconazole in breast milk and in plasma is the same, the use of the drug during breastfeeding is contraindicated.

Use in Hepatic Impairment

With caution: hepatic insufficiency.

Liver function should be monitored during treatment. If liver function impairment occurs, the use of the drug should be discontinued. In rare cases, the use of fluconazole was accompanied by toxic liver changes.

In the case of hepatotoxic effects associated with fluconazole, no dependence of their development on the total daily dose, duration of therapy, gender and age of the patient was noted. The hepatotoxic effect of fluconazole was usually reversible; its signs disappeared after discontinuation of therapy. If clinical signs of liver damage that may be associated with fluconazole appear, the drug should be discontinued.

Use in Renal Impairment

With caution in renal impairment. If CrCl is less than 50 ml/min, adjustment of the dosing regimen is required.

Renal function should be monitored during treatment. If renal function impairment occurs, the use of the drug should be discontinued.

Pediatric Use

Use is possible according to the dosing regimen.

Geriatric Use

In the absence of renal impairment in elderly patients, the drug should be prescribed in the usual dosing regimen.

Special Precautions

Treatment should be continued until clinical and hematological remission appears. Premature discontinuation of treatment leads to relapses.

Treatment can be started in the absence of culture results or other laboratory tests, but if they are available, appropriate correction of antifungal therapy is recommended.

During treatment, blood counts (cellular composition, coagulation), renal and liver function should be monitored. Monitoring of the prothrombin index is necessary when used concomitantly with indirect anticoagulants – coumarin derivatives. If renal and liver function impairment occurs, the use of the drug should be discontinued. In rare cases, the use of fluconazole was accompanied by toxic liver changes.

In the case of hepatotoxic effects associated with fluconazole, no dependence of their development on the total daily dose, duration of therapy, gender and age of the patient was noted. The hepatotoxic effect of fluconazole was usually reversible; its signs disappeared after discontinuation of therapy. If clinical signs of liver damage that may be associated with fluconazole appear, the drug should be discontinued. AIDS patients are more prone to developing severe skin reactions when using many drugs. In cases where a rash develops in patients with superficial fungal infection and it is assessed as definitely associated with fluconazole, the drug should be discontinued. If a rash appears in patients with systemic fungal infections, patients should be carefully monitored and if bullous changes or multiform erythema appear, Fluconazole must be discontinued.

It is recommended to monitor the blood concentration of cyclosporine in patients receiving Fluconazole, since in patients with kidney transplants, the use of fluconazole at a dose of 200 mg/day leads to a slow increase in cyclosporine plasma concentration. Caution should be exercised when using fluconazole concomitantly with cisapride, rifabutin or other drugs metabolized by the cytochrome P450 system.

Effect on ability to drive vehicles and mechanisms. During the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms hallucinations, paranoid behavior.

Treatment symptomatic, forced diuresis. Hemodialysis for 3 hours reduces the plasma concentration by approximately 50%.

Drug Interactions

Anticoagulants. Fluconazole increases the prothrombin time of indirect anticoagulants – coumarin derivatives (for example, warfarin) by an average of 12%, therefore careful monitoring of prothrombin time is necessary in patients taking Fluconazole and indirect anticoagulants – coumarin derivatives.

Oral hypoglycemic drugs, sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide and tolbutamide). When used simultaneously with fluconazole, the T_1/2 of oral hypoglycemic drugs, sulfonylurea derivatives, is prolonged, which can lead to the development of hypoglycemia. Blood glucose concentration should be periodically monitored and, if necessary, the dose of hypoglycemic drugs should be adjusted.

Hydrochlorothiazide increases the plasma concentration of fluconazole by 40%, but this does not require a change in the fluconazole dosage regimen in patients simultaneously receiving diuretics.

Phenytoin. Simultaneous use of fluconazole and phenytoin is accompanied by an increase in the concentration of the latter to a clinically significant degree. Therefore, it is necessary to monitor the concentration of phenytoin and adjust its dose to ensure a therapeutic plasma concentration.

Oral contraceptives. Multiple use of fluconazole (in doses of 50-200 mg) does not affect the effectiveness of combined oral contraceptives.

Rifampicin. Simultaneous use of fluconazole and rifampicin led to a 25% decrease in AUC and a 20% decrease in the duration of T_1/2 of fluconazole. When using rifampicin and fluconazole simultaneously, the dose of fluconazole must be taken into account.

Cyclosporine. When treating with fluconazole, it is recommended to monitor the blood concentration of cyclosporine.

Theophylline. Fluconazole prolongs the half-life of theophylline and increases the risk of intoxication (its dose adjustment is necessary).

Terfenadine. Simultaneous use of fluconazole in doses of 400 mg/day and higher is contraindicated. Treatment with fluconazole in doses of less than 400 mg/day in combination with terfenadine should be carried out under the careful supervision of a physician.

Cisapride. When fluconazole and cisapride are used simultaneously, adverse cardiac reactions, including paroxysms of ventricular tachycardia (torsade de pointes).

Rifabutin. Simultaneous use of fluconazole and rifabutin may lead to an increase in the plasma concentrations of the latter. Cases of uveitis have been described with the simultaneous use of fluconazole and rifabutin. Patients simultaneously receiving rifabutin and Fluconazole should be carefully monitored.

Tacrolimus. Fluconazole increases the plasma concentration of tacrolimus, thereby increasing the risk of nephrotoxic effects.

Zidovudine. In patients receiving a combination of fluconazole and zidovudine, an increase in the plasma concentration of zidovudine is observed, which is caused by a decrease in its conversion to its main metabolite, therefore, an increase in the side effects of zidovudine should be expected.

Midazolam. Fluconazole increases the plasma concentration of midazolam, thereby increasing the risk of psychomotor effects (most pronounced when fluconazole is used orally than intravenously).

Storage Conditions

The drug should be stored in a dry place, protected from light, at a temperature not exceeding 30°C (86°F). Do not freeze. Keep out of reach of children.

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.