INSTRUCTIONS FOR MEDICAL USE
Trade name of the drug: Candiflu® Neo
Active substance (INN): Fluconazole
Package name: 50 mg capsules
1 capsule contains:
active substance: Fluconazole – 50 mg;
Excipients: sugar, lactose, aerosil, potato or corn starch, calcium stearate or magnesium stearate
Description: Solid white gelatin capsules with white or almost white color powder, odorless.
Pharmacotherapeutic group: Antifungal agent.
ATX code: J02AC01
Fluconazole, a representative of a new class of triazole antifungal agents. It has a highly specific action by inhibiting the activity of cytochrome P450-dependent fungal enzymes. It blocks the conversion of fungal cell lanosterol into ergosterol; it increases cell membrane permeability, disrupts cell growth and replication. Fluconazole, being highly selective for cytochrome P450 of fungi, practically does not inhibit these enzymes in humans (in comparison with itraconazole, clotrimazole, econazole and ketoconazole it inhibits cytochrome P450 dependent oxidative processes in human liver microsomes to a lesser extent). It does not have antiadrogenic activity.
It is active in opportunistic mycoses, including those caused by Candida spp. (including generalized candidiasis against immunosuppression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp.; in endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including immunosuppression).
After oral administration, fluconazole is well absorbed. Simultaneous intake of food has no effect on the absorption rate (absorption) of the drug when taken orally. Time of maximum concentration achievement ( ТСmax) after oral use on an empty stomach of fluconazole 150 mg – 0.5-1.5 hours, and makes 90% of concentration in plasma in intravenous division of 2.5-3.5 mg/l.
Plasma concentration is in direct relation to the dose. Equilibrium plasma concentration (Css) of the drug is reached by day 4-5 of administration (when taken once daily). Administration of “shock” dose (on the first day), 2 times higher than the usual daily dose, allows achieving a concentration corresponding to 90% of Css by the second day.
Good penetration into all body fluids. Active substance concentrations in breast milk, joint fluid, saliva, sputum and peritoneal fluid are similar to those in plasma. Constant values in vaginal secretion are reached 8 hours after oral administration and are maintained at this level for at least 24 hours. It penetrates well into the cerebrospinal fluid (CSF); in fungal meningitis, the concentration in the CSF is about 85% of that in plasma. In sweat fluid, dermis and stratum corneum (selective accumulation) high concentrations exceeding serum concentrations are achieved. When administered at a dose of 50 mg once daily, fluconazole concentrations were 73 µg/g after 12 days and 5.8 µg/L after 7 days of discontinuation of treatment. After oral administration of 150 mg once a week. – on day 7, the concentration of fluconazole in the stratum corneum of the skin was 23.4 µg/g, and 7 days after the second dose was 7.1 µg/g.
Concentrations in the nails after 4 months of use at a dose of 150 mg once a week were: 4.05 µg/g in healthy nails and 1.8 µg/g in affected nails. Six months after completion of therapy, fluconazole was still detected in the nails.
The apparent volume of distribution (Vd) approached the total extracellular fluid content in the body. The binding to plasma proteins is low – 11-12%.
Metabolism and excretion
The elimination half-life (T1/2) is 30 hours. It is an inhibitor of CYP2C9 isoenzyme in the liver. It is eliminated mainly by the kidneys (80% – unchanged, 11% – as metabolites). Clearance of fluconazole is proportional to creatinine clearance.
Fluconazole pharmacokinetics depends significantly on the functional state of the kidneys, and there is an inverse relationship between T1/2 and creatinine clearance ( Cc). After hemodialysis, within 3 hours, plasma concentration of fluconazole decreases by 50%.
Fluconazole pharmacokinetics is similar when administered intravenously and when taken orally, which allows to easily switch from one type of administration to another.
Indications for use
Mucosal candidiasis: oral cavity, pharynx, esophagus, non-invasive bronchopulmonary candidiasis, candiduria, cutaneous-mucosal and chronic oral atrophic candidiasis (associated with wearing dentures).
Genital candidiasis: vaginal (acute and recurrent). Candida balanitis. Prophylactic use to reduce the frequency of recurrent vaginal candidiasis (three or more episodes per year).
Prophylaxis of fungal infections in patients with malignant tumors against the background of chemo- or radiation therapy; prevention of relapse of oropharyngeal candidiasis in AIDS patients.
Mycosis of the skin: feet, body, inguinal area, onychomycosis, pityriasis, cutaneous candida infections.
Dosage and administration
In cases of oropharyngeal andidosis, usually 50-100 mg once daily, treatment should be continued for 7-14 days. If necessary, in patients with severe immune impairment, treatment may be longer. For prophylaxis of oropharyngeal candidiasis relapses in AIDS patients after full course of primary therapy, the drug may be prescribed 150 mg once a week.
For vaginal candidiasis, fluconazole is taken once orally in a dose of 150 mg. To reduce the recurrence rate of vaginal candidiasis, the drug may be used in a dose of 150 mg. 1 time per month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may require more frequent use.
For balanitis caused by Candida spp., fluconazole is prescribed once in a dose of 150 mg orally. For prophylaxis of candidiasis, the recommended dose of fluconazole is 50-400 mg once daily, depending on the risk of fungal infection. If there is a high risk of generalized infection, such as in patients with expected severe or prolonged neutropenia, the recommended dose is 400 mg once daily. Fluconazole is administered several days before the expected appearance of neutropenia; after an increase in neutrophil count over 1000/mm for another 7 days.
For mycoses of the skin, including mycoses of the feet, skin of the groin, and candidiasis of the rut, the recommended dose is 150 mg once a week or 50 mg once a day. Duration of therapy in common cases is 2-4 weeks, but in case of mycoses of feet a longer therapy (up to 6 weeks) may be required.
For pityriasis – 300 mg once a week for 2 weeks, some patients need a third dose of 300 mg per week, while in some cases a single dose of 300 mg to 400 mg is sufficient; an alternative treatment regimen is 50 mg once a day for 2-4 weeks.
For onychomycosis, the recommended dose is 150 mg once a week. Treatment should be continued until the infected nail is replaced (uninfected nail grows back). It takes 3-6 months and 6-12 months, respectively, for the nails on the fingers and toes to re-grow. However, the rate of growth can vary widely from person to person and also depending on age.
For esophageal candidiasis in children, fluconazole is prescribed once in a daily dose of 3 mg/kg, in the following average doses: ages 3-6 years (body weight 15-20 kg) – 50 mg; ages 7-9 years (body weight 21-29 kg) – 50-100 mg; ages 10-12 years (body weight 30-40 kg) – 100-150 mg; ages 12-15 years (body weight 40-50 kg) – 100-150 mg. Duration of therapy – at least 3 weeks and for 2 more weeks after symptoms have regressed.
Forchildren with mucous membrane candidiasis, fluconazole is prescribed once in a daily dose of 3 mg/kg, in the following average doses: 3-6 years old (body weight 15-20 kg) – 100-150 mg on the 1st day, then – 50 mg; 7-9 years old (body weight 21-29 kg) – 100-200 mg on the 1st day, then – 100 mg: at the age of 10-12 years (body weight 30-40 kg) – on the 1st day 100-150 mg, then – by 50-100 mg; at the age of 12-15 years (body weight 40-50 kg) – on the 1st day 250-300 mg, then – by 100-150 mg. The therapy duration is at least 3 weeks.
For generalized candidiasis and cryptococcal infection (including meningitis) in children, fluconazole is indicated in a single daily dose of 6-12 mg/kg, with the following average doses: 3-6 years old (body weight 15-20 kg) – 100-250 mg; 7-9 years old (body weight 21-29 kg) – 100-300 mg; 10-12 years old (body weight 30-40 kg) – 200-350 mg; 12-15 years old (body weight 40-50 kg) – 250-400 mg. Duration of therapy – for 10-12 weeks (until laboratory confirmation of the absence of pathogens in the cerebrospinal fluid).
For prevention of fungal infections in immunocompromised children, in whom the risk of infection is associated with neutropenia, developed as a result of cytotoxic chemotherapy or radiotherapy, fluconazole is administered by 3-12 mg/kg/day, depending on the severity and duration of induced neutropenia, in the following average doses ages 3-6 years (body weight 15-20 kg) – 50-250 mg; ages 7-9 years (body weight 21-29 kg) – 50-300 mg; ages 10-12 years (body weight 30-40 kg) – 100-350 mg; ages 12-15 years (body weight 40-50 kg) – 100-400 mg. Duration of therapy – until elimination of induced neutropenia.
For 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.
For elderly patients with no renal impairment, the usual dosing regimen of the drug should be followed. In patients with renal failure (creatinine clearance less than 50 ml/min) the dosage regimen should be adjusted as described below.
Administration of the drug for patients with impaired renal function. Fluconazole is mainly excreted unchanged in the urine. It is not necessary to change the dose if it is administered once. In re-administration of the drug in patients with impaired renal function a “shock” dose of 50 mg to 400 mg should be given first. If creatinine clearance (CK) is 50 ml/min, the usual dose of the drug (100% of the recommended dose) is used once daily. If CK is 11 to 50 ml/min, a dose equal to 50% of the recommended dose is used. If patients are regularly on dialysis, one dose of the drug is administered after each session of hemodialysis.
Digestive system disorders: change of taste, vomiting, nausea, diarrhea, flatulence, abdominal pain, liver disorders (jaundice, hyperbilirubinemia, increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase activity, hepatitis, hepatocellular necrosis), including with lethal outcome.
Nervous system disorders: headache, dizziness, seizures.
Cardiovascular system: prolongation of the QT interval, ventricular fibrillation/rattling.
Blood organs: leukopenia, thrombocytopenia, neutropenia, agranulocytosis.
Allergic reactions: skin rash, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), anaphylactoid reactions (including angioedema, facial edema, urticaria, skin itching).
Other: impaired renal function, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Concomitant use of terfenadine (concomitantly with fluconazole at a dose of 400 mg/day or more), astemizole and other drugs that prolong the Q-T interval.
Concomitant use of cisapride.
Hypersensitivity to the drug or similar azole compounds.
Lactose intolerance, lactase deficiency or glucose-galactase malabsorption.
Children under 3 years of age (for this dosage form).
With caution: hepatic and/or renal insufficiency, the appearance of rash against the background of fluconazole administration in patients with superficial fungal infection and invasive/systemic fungal infections, potentially proarrhythmogenic conditions in patients with multiple risk factors (organic heart disease, electrolyte balance disorders, simultaneous use of drugs that cause arrhythmias), simultaneous use of potentially hepatotoxic agents, alcoholism. Simultaneous use of terfenadine and fluconazole in dose less than 400 mg/day.
Anticoagulants. Fluconazole increases prothrombin time of coumarin anticoagulants (e.g., warfarin) by 12% on average, therefore it is necessary to monitor prothrombin time of patients receiving fluconazole and coumarin anticoagulants carefully.
Sulfonylureas. When concomitant administration of fluconazole and oral sulfonylurea drugs (chlorpropamide, glibenclamide, glipizide and tolbutamide) the elimination half-life of the latter is prolonged, which may lead to hypoglycemia. Blood glucose concentration should be periodically monitored and, if necessary, the dose of hypoglycemic drugs should be adjusted.
Hydrochlorothiazide increases fluconazole plasma concentration by 40%, but it does not require changing the dosing regimen of fluconazole in patients receiving concomitant diuretics.
Phenytoin. Concomitant administration of fluconazole and phenytoin is accompanied by an increase in concentrations of the latter to a clinically significant degree. Therefore, it is necessary to monitor phenytoin levels and dose selection to ensure therapeutic concentration in serum.
Oral contraceptives. Repeated use of fluconazole (in doses of 50-200 mg) has no effect on the effectiveness of the combined contraceptive.
Rifampicin. Concomitant use of fluconazole and rifampicin decreased the area under the curve “concentration – time” by 25% and the half-life of fluconazole by 20%. It is necessary to increase fluconazole dose if they are concomitantly administered.
Cyclosporine. When treating with fluconazole at a dose of 200 mg/day, cyclosporine blood concentrations are increased.
Theophylline. Fluconazole prolongs the half-life of theophylline and increases the risk of intoxication (its dose should be corrected).
Terfenadine. Concomitant administration of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg/day. In combination with terfenadine should be performed under close medical supervision.
Cisapride. When concomitant administration of fluconazole and cisapride, adverse cardiac reactions, including paroxysms of ventricular tachycardia (torsades depointes).
Nifabutin. Cases of uveitis have been described.
Tacrolimus. Increases the concentration of tacrolimus, therefore increasing the risk of nephrotoxic effects.
Zidovudine. In patients receiving a combination of fluconazole and zidovudine, an increase in zidovudine concentration is observed, which is caused by a decrease in conversion of the latter to its main metabolite, so an increase in side effects of zidovudine should be expected.
Midazolam. Increases the concentration of midazolam, and therefore, the risk of psychomotor effects increases (most pronounced when fluconazole is administered orally than intravenously).
Treatment should be continued until clinical and hematological remission occurs. Premature discontinuation of treatment leads to relapses.
Treatment can be started in the absence of results of culture or other laboratory tests, but if they are available, appropriate correction of fungicidal therapy is recommended.
Blood counts, kidney and liver function should be monitored during treatment. If renal and liver function abnormalities occur, 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 clear dependence on the total daily dose, duration of therapy, sex, and age of the patient was noted. Hepatotoxic effects of fluconazole are usually reversible; their signs disappeared after discontinuation of therapy. If clinical signs of liver damage appear, which may be associated with fluconazole, the drug should be discontinued.
AIDS patients are more prone to develop severe skin reactions when using many drugs. In cases where patients with superficial fungal infection develop a rash and it is considered to be definitely related to fluconazole, the drug should be discontinued. If rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous changes or erythema multiforme appear.
Use in pregnancy and during breastfeeding
It is not advisable to use the drug in pregnant women, with the exception of severe or life-threatening forms of fungal infections, if the anticipated benefits to the mother exceed the possible risks to the fetus.
Fluconazole is in breast milk at the same concentration as in plasma, therefore its administration during lactation is not recommended.
Influence on the ability to drive motor transport and operate machinery
In case of adverse reactions on the nervous system side, patients are recommended to refrain from driving a vehicle and other mechanisms as well as to be cautious while carrying out activities requiring high concentration and quick psychomotor reactions.
There was described a case of hallucinations and paranoid behavior after 8.2 g of drug administration. The patient was hospitalized and his condition normalized within 48 hours. In case of overdose, gastric lavage, forced diuresis and symptomatic treatment should be administered. After 3-hour session of hemodialysis the drug concentration in plasma is decreased by 50%.
Form of production
Capsules of 50 mg in a contour cellular pack.
Store in a dry, dark place at a temperature not exceeding 25°C.
Keep out of the reach of children!
3 years. Do not use after the expiration date.
Conditions of dispensing from pharmacies.
Reliased by a doctor’s prescription