INSTRUCTIONS FOR MEDICAL USE
Trade name of the drug: Candiflu® Neo
Active substance (INN): Fluconazole
Dosage form: solution for infusion.
100 ml of the solution contains:
active substance: fluconazole – 200 mg.
Excipients: sodium chloride – 900 mg, water for injections up to 100 ml.
Description: clear, colorless or light yellow liquid.
Pharmacotherapeutic group: Antifungal agent.
ATX code: J02AC01
Fluconazole is representative of the class of triazole derivatives, it is a selective inhibitor of sterol synthesis in fungal cells. It blocks conversion of lanosterol of fungal cells to ergosterol; it increases cell membrane permeability. Fluconazole, being highly selective for cytochrome P450 of fungi, does not suppress cytochrome P450 system in humans (compared to itraconazole, clotrimazole, econazole and ketoconazole it suppresses cytochrome P450 dependent oxidation processes in human liver microsomes to a lesser extent). It has no androgenic activity. The drug is active in mycosis caused by Candida spp., Cryptococcus neoformans, Microsporum spp., Trichophyton spp., Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum.
After intravenous administration fluconazole penetrates well into tissues and body fluids. Drug concentrations in saliva and sputum are similar to its levels in plasma. In patients with fungal meningitis fluconazole content in cerebrospinal fluid reaches 80% of the corresponding levels in plasma. Plasma concentrations are in direct proportional relationship to the dose. 90% of the equilibrium concentration level is reached by day 4-5 after several injections of one dose per day.
Using a dose twice the usual daily dose on the first day allows achieving such plasma levels of the drug that are close to 90% of the equilibrium concentrations by the second day. The apparent volume of distribution is close to the total body fluid volume. A small part of fluconazole (11-12%) is bound to plasma proteins. The elimination half-life is long (30 hours).
Fluconazole is excreted mainly by the kidneys; approximately 80% of the administered dose is excreted unchanged. Fluconazole clearance is in direct proportion to creatinine clearance. No metabolites were detected in peripheral blood.
Indications for use
Cryptococcosis: cryptococcal meningitis, cryptococcal infections of the lungs and skin: prevention of recurrent cryptococcosis in patients with AIDS, in organ transplants or in other cases of immunodeficiency;
generalized candidiasis: candidemia, disseminated candidomycosis and other forms of invasive candidiasis infections (abdominal, endocardial, eye, respiratory and urinary tract infections);
candidiasis of mucous membranes: oral cavity, pharynx, esophagus and non-invasive bronchopulmonary infections, candiduria;
Vaginal candidiasis – acute or chronic recurrent form;
prevention of fungal infections in patients with malignant neoplasms that are predisposed to such infections as a result of cytostatic chemotherapy or radiation therapy;
genital candidiasis, acute or recurrent vaginal candidiasis, prophylaxis to reduce the frequency of recurrent vaginal candidiasis (3 or more episodes per year), candidal balanitis;
Mycoses of the skin, including mycoses of the feet, body, groin area, pityriasis, onychomycosis, and cutaneous candidiasis;
deep endemic mycoses in patients with normal immunity, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis.
Dosage and administration
Fluconazole in the form of infusion solution is administered intravenously by drip at a rate not exceeding 20 mg (10 ml) min. There is no need to change the daily dose when transferring from intravenous administration to capsule administration and vice versa.
The solution for infusion is compatible with the following solvents: 20% glucose solution, Ringer’s solution, Hartmann’s solution, potassium chloride solution in glucose, aminofusin, isotonic sodium chloride solution.
Fluconazole infusions can be given with conventional transfusion kits using one of the fluids listed above.
Use for adults
For cryptococcal infections the usual dose of fluconazole is 400 mg once a day on the first day of treatment and 200-400 mg once a day thereafter. The duration of treatment for cryptococcal infections depends on the clinical efficacy confirmed by mycological examination, usually ranging from 6 to 8 weeks.
For prophylaxis of recurrence of cryptococcal meningitis in AIDS patients after the completion of the initial complete course of therapy, fluconazole is prescribed in doses not less than 200 mg/day for a long period.
For candidemia, disseminated candidiasis, and other invasive, candida infections, the daily dose is 400 mg in the first day and 200 mg in subsequent days. Depending on the clinical efficacy of the drug, the dose may be increased up to 400 mg/day. Treatment duration depends on clinical efficacy.
For oropharyngeal candidiasis, including patients with immune impairment, the usual dose is 50-100 mg once daily for 7-14 days. If necessary, treatment may be prolonged, especially in severe immune disorders.
For other candidal infections, such as esophagitis, non-invasive bronchopulmonary infections, candiduria, candidiasis of skin and mucous membranes, the usual daily dose is 50-100 mg for 14-30 days.
For prophylaxis of fungal infections in patients with malignant neoplasms, a dose of fluconazole should be 50 mg once a day for as long as the patient is at high risk due to cytostatic therapy or radiotherapy.
Use for children
As with similar infections in adults, the duration of treatment depends on clinical and mycological effects. For children, the daily dose of the drug should not exceed that of adults. Fluconazole is used daily once a day.
In candidiasis of mucous membranes, the recommended dose of fluconazole is 3 mg/kg/day. On the first day, a shock dose of 6 mg/kg may be administered in order to achieve constant equilibrium concentrations more quickly.
For treatment of generalized candidiasis and cryptococcal infection, the recommended dose is 6-12 mg/kg/day depending on the severity of the disease.
For prophylaxis of fungal infections in immunocompromised children at risk of infection due to neutropenia resulting from cytotoxic chemotherapy or radiation therapy, the drug is prescribed 3-12 mg/kg/day depending on the severity and duration of induced neutropenia.
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 severity of renal failure.
In elderly patients with no renal dysfunction the drug is used according to the usual dosing regimen.
In patients with impaired renal function, if administered once a day, no change in the drug dosage is required. When administering the drug repeatedly at a CKR of more than 50 ml/min, the drug is administered in a medium dose. In CKR of 11 to 50 ml/min, a shock dose of 50 mg to 400 mg should be administered first, followed by a dose equal to 50% of the recommended dose. Patients who are regularly on dialysis are prescribed one dose of the drug after each hemodialysis session.
Digestive system: change of taste, vomiting, nausea, diarrhea, flatulence, abdominal pain; rarely – liver dysfunction (jaundice, hepatitis, hepatonecrosis, hyperbilirubinemia, increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase activity).
Nervous system disorders: headache, dizziness, rarely convulsions.
Blood organs: rarely – leukopenia, thrombocytopenia, neutropenia, agranulocytosis.
Cardiovascular system: prolongation of Q-T interval; ventricular fibrillation, torsade de pointes.
Allergic reactions: skin rash, rare – malignant erythema exudative (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), anaphylactoid reactions.
Other: rarely – renal dysfunction, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.
- Concomitant use of terfenadine (concomitant use of fluconazole at a dose of 400 mg/day or more) or astemizole and other drugs that prolong Q-T interval.
- Hypersensitivity to the drug or similar azole compounds.
- Children under 1 year of age.
- Pregnancy, lactation.
Caution hepatic or renal failure, concomitant use of potentially hepatotoxic drugs, alcoholism, proarrhythmogenic states in patients with multiple risk factors (organic heart disease, electrolyte imbalance, concomitant use of drugs that cause arrhythmias).
The use of the drug in pregnant women is inappropriate, except for severe or life-threatening forms of fungal infections, if the expected effect exceeds the possible risk to the fetus. Fluconazole is in breast milk in the same concentration as in plasma, therefore its administration during lactation is not recommended.
When fluconazole is used with warfarin, an increase in prothrombin time by 12% has been noted. In this regard, it is recommended to monitor prothrombin time in patients receiving this drug in combination with coumarin anticoagulants. Co-administration of fluconazole increases T1/2 of oral hypoglycemic drugs – sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide and tolbutamide). Concomitant administration of fluconazole and oral hypoglycemic agents is allowed, but the possibility of hypoglycemia should be taken into account.
Concomitant use of fluconazole and phenytoin may be accompanied by an increase in phenytoin concentrations to a clinically significant degree. Therefore, if concomitant use of these drugs is necessary, phenytoin concentrations should be monitored and the dose should be adjusted to ensure therapeutic plasma concentrations.
Concomitant use of fluconazole and rifampicin decreases the area under the curve “concentration – time” (AUC) by 25% and shortens the T1/2 of fluconazole from plasma by 20%. Therefore, it is recommended to increase the dose of fluconazole in patients receiving simultaneously rifampicin. It is recommended to monitor the blood concentration of cyclosporine in patients receiving fluconazole, because when using fluconazole and cyclosporine in patients with kidney transplantation, fluconazole administration at a dose of 200 mg/day leads to a slow increase in plasma concentration of cyclosporine.
Patients receiving theophylline in high doses, or who are likely to develop theophylline intoxication, should be monitored for early detection of symptoms of theophylline overdose, because concomitant administration of fluconazole leads to a decrease in the average rate of clearance of theophylline from plasma.
When concomitant use of fluconazole and terfenadine or cisapride, cases of adverse cardiac reactions, including paroxysms of ventricular tachycardia (arrhythmias of the type “pirouette”) have been described. There have been reports of interaction of fluconazole and rifabutin, accompanied by increased serum levels of the latter. When concomitant use of fluconazole and rifabutin, cases of uveitis have been described. Patients receiving rifabutin and fluconazole concomitantly should be closely monitored.
During concomitant use of fluconazole and zidovudine, an increase in plasma concentrations of zidovudine is noted, which is caused by a decrease in the conversion of the latter to its metabolite.
Concomitant use of fluconazole with midazolam increases the risk of psychomotor effects, with tacrolimus – increased risk of nephrotoxicity.
In rare cases fluconazole use was accompanied by toxic liver changes, including fatal, mainly in patients with severe comorbidities. 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 were 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.
For patients with impaired renal function, no dose adjustment is required during a single use of the drug. When repeated use it is guided by CKD. If CKR is more than 50 ml/min, in case of CKR 11 to 20 ml/min the dose adjustment is not required, 33% of usual dose is taken at 72 hours interval. If CK of 21 to 40 ml/min, half the usual dose is taken at 48-hour intervals. For patients who are regularly on dialysis, one dose is taken after each session of hemodialysis.
Caution should be exercised when concomitant administration of fluconazole with cisapride, rifabutin or other drugs metabolized by cytochrome P450 system.
Treatment should be continued until clinical and hematological remission occurs, since premature discontinuation leads to relapses.
Use only clear solution in an intact vial! Failure to observe the storage and transportation conditions can lead to the formation of micro-cracks on the vial, thereby increasing the risk of microbial contamination of the solution.
For single-use sampling only!
Do not freeze or heat!
Hallucinations and paranoid behavior have been described. In case of overdose, gastric lavage, forced diuresis and symptomatic treatment should be administered. After a 3-hour session of hemodialysis the drug concentration in plasma is decreased by 50%.
Form of production
Infusion solution 200 mg/100 ml or 400 mg/200 ml in 100 ml or 200 ml vials.
Store in a dry, dark place at a temperature not exceeding 25°C. Keep out of the reach of children!
2 years. Do not use after the expiration date.
Conditions of dispensing from pharmacies
Released by a doctor’s prescription.