Fungiflu (Capsules) Instructions for Use

Marketing Authorization Holder

Edge Pharma Private Limited (India)

Contact Information

Edge Pharma Private Limited CJSC (India)

ATC Code

J02AC01 (Fluconazole)

Active Substance

Fluconazole (Rec.INN registered by WHO)

Dosage Form

Fungiflu

Capsules 150 mg: 1 pc.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 2, with a white body and a pink cap; the capsule contents are a white or almost white powder.

Excipients: lactose – 27.8 mg, starch – 75 mg, colloidal silicon dioxide – 0.25 mg, sodium lauryl sulfate – 0.25 mg, magnesium stearate – 1.7 mg.

Capsule shell composition dye Floxin B – 0.138 mg, dye sunset yellow – 0.021 mg, titanium dioxide – 2.16 mg, gelatin – 60 mg.

1 pc. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Antifungal drugs for systemic use, triazole derivatives

Pharmacological Action

An antifungal agent, it has a highly specific action, inhibiting the activity of fungal enzymes dependent on cytochrome P450. It blocks the conversion of lanosterol in fungal cells to ergosterol; increases the permeability of the cell membrane, disrupts its growth and replication.

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 against 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.; against endemic mycoses caused by Blastomyces dermatitidis, Histoplasma capsulatum (including in immunosuppression).

Pharmacokinetics

Absorption is high (food does not affect the absorption rate), bioavailability is 90%. T_max in plasma after oral administration of 150 mg on an empty stomach is 0.5-1.5 hours and the maximum concentration C_max in plasma upon oral administration is 90% of the plasma concentration upon IV administration at a dose of 2.5-3.5 mg/kg.

Plasma protein binding is 11-12%. Plasma concentration is directly dependent on the dose. Steady-state concentration in blood is reached by day 4-5 of administration (when taken once daily). Administration of a “loading” dose (on the first day), twice the usual daily dose, allows achieving a concentration corresponding to 90% of the steady-state concentration by day 2. It penetrates well into all body fluids.

The concentration of the active substance in breast milk, synovial fluid, saliva, sputum, and peritoneal fluid is similar to that in plasma. Constant levels 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, epidermis, and the stratum corneum (selective accumulation), concentrations exceeding serum levels are achieved. After oral administration of 150 mg on day 7, the concentration in the skin stratum corneum is 23.4 mcg/g, and one week after the second dose – 7.1 mcg/g; concentration in nails after 4 months of use at a dose of 150 mg once a week is 4.05 mcg/g in healthy nails and 1.8 mcg/g in affected nails. The volume of distribution approaches the total body water content.

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). Fluconazole clearance is proportional to creatinine clearance (CrCl). The pharmacokinetics of fluconazole significantly depend on the functional state of the kidneys, with an inverse relationship between T_1/2 and CrCl. After hemodialysis for 3 hours, the plasma concentration of fluconazole decreases by 50%.

Indications

• Systemic lesions caused by Cryptococcus fungi, including meningitis, sepsis, lung and skin infections, both in patients with a normal immune response and in patients with various forms of immunosuppression (including patients with AIDS, organ transplantation);
• Prophylaxis of cryptococcal infection in AIDS patients;
• Generalized candidiasis: candidemia, disseminated candidiasis (with involvement of the endocardium, abdominal organs, respiratory organs, eyes, and genitourinary organs), including in patients receiving a course of cytotoxic or immunosuppressive therapy, as well as in the presence of other factors predisposing to their development – treatment and prophylaxis;
• Candidiasis of mucous membranes: oral cavity, pharynx, esophagus, non-invasive bronchopulmonary candidiasis, candiduria, mucocutaneous and chronic oral atrophic candidiasis (associated with wearing dentures);
• Genital candidiasis: vaginal (acute and recurrent), balanitis;
• Prophylaxis of fungal infections in patients with malignant tumors undergoing chemotherapy or radiation therapy;
• Prophylaxis of recurrence of oropharyngeal candidiasis in AIDS patients;
• Skin mycoses: feet, body, groin area, onychomycosis, pityriasis versicolor, cutaneous candidal infections;
• Deep endemic mycoses (coccidioidomycosis, sporotrichosis and histoplasmosis) in immunocompetent patients.

ICD codes

Dosage Regimen

The drug Fungiflu should be taken orally. For adults, for cryptococcal infections, candidemia, disseminated candidiasis, other invasive candidal infections, 400 mg is prescribed on day 1, then 200-400 mg once daily. The duration of treatment depends on the clinical and mycological response (for cryptococcal meningitis it is at least 6-8 weeks).

For the prophylaxis of cryptococcal meningitisin AIDS patients, therapy at a dose of 200 mg/day can be continued for a long time.

For oropharyngeal candidiasis – 50-100 mg once daily for 7-10 days, in patients with immunosuppression – 14 days or more.

For the prophylaxis of recurrence of oropharyngeal candidiasisin AIDS patients after completion of a full course of primary therapy – 150 mg once weekly.

For atrophic oral candidiasis associated with wearing dentures – 50 mg once daily for 14 days in combination with local antiseptic drugs for denture treatment.

For other candidal infections of mucous membranes (except genital candidiasis) – 50-100 mg/day, duration of treatment – 14-30 days.

For vaginal candidiasis – 150 mg as a single dose. To reduce the frequency of recurrences, 150 mg once monthly for 4-12 months is used, sometimes more frequent administration may be required.

For balanitis caused by Candida – 150 mg/day as a single dose.

For the prophylaxis of candidiasis, the recommended dose of the drug is 50-400 mg/day depending on the degree of risk of developing a fungal infection. In the presence of a high risk of generalized infection, for example in patients with expected severe or prolonged neutropenia, the recommended dose is 400 mg/day. The drug Fungiflu is prescribed several days before the expected onset of neutropenia; after the neutrophil count increases above 1 thousand/μL, treatment is continued for another 7 days. For skin lesions, including mycoses of the feet, skin of the groin area, and candidiasis – 150 mg once weekly or 50 mg once daily, duration of treatment – 2-4 weeks (up to 6 weeks for mycoses of the feet).

For pityriasis versicolor – 300 mg once weekly for 2 weeks, some patients require a third dose of 300 mg/week, while in some cases a single dose of 300-400 mg is sufficient; an alternative treatment regimen is 50 mg once daily for 2-4 weeks.

For onychomycosis – 150 mg once weekly; treatment continues until the infected nail is replaced. Normal regrowth of fingernails and toenails usually requires 3-6 months and 6-12 months, respectively.

For deep endemic mycoses – 200-400 mg/day for up to 2 years. The duration of therapy is determined individually; it can be 11-24 months for coccidioidomycosis, 2-17 months – for paracoccidioidomycosis, 1-16 months – for sporotrichosis and 3-17 months – for histoplasmosis.

For children, as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be used at a daily dose that would exceed that in adults. The drug is used daily once daily (special dosage forms for children are used). For childrenwith esophageal candidiasis, 3 mg/kg per day as a single dose is prescribed for at least 3 weeks and for 2 weeks after symptom regression; for candidiasis of mucous membranes – 3 mg/kg per day as a single dose for at least 3 weeks; when treating generalized candidiasis and cryptococcal infection (including meningitis) – 6-12 mg/kg per day for 10-12 weeks (until laboratory confirmation of the absence of pathogens in the CSF).

For the prophylaxis of fungal infectionsin children with reduced immunity, in whom the risk of infection is associated with neutropenia developing as a result of cytotoxic chemotherapy or radiation therapy – 3-12 mg/kg/day depending on the severity and duration of the induced neutropenia.

For newborn infants, the interval between drug administrations is 72 hours; for children aged 2-4 weeks, the same dose is administered at 48-hour intervals.

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

In elderly patients without impaired renal function, the usual dosing regimen of the drug should be followed. In patients with renal failure (CrCl less than 50 ml/min), the dosing regimen should be adjusted as indicated below.

For chronic renal failure, a “loading” dose of 50-400 mg is initially administered; for CrCl greater than 50 ml/min, the usual daily dose is prescribed; for CrCl 11-50 ml/min – 50% of the recommended dose or the usual dose once every 2 days; for patients on hemodialysis – 1 dose after each dialysis.

Adverse Reactions

From the digestive system: nausea, diarrhea, flatulence, abdominal pain, taste change, vomiting, rarely – impaired liver function (jaundice, hyperbilirubinemia, increased ALT, AST and ALP activity, hepatitis, hepatocellular necrosis), including fatal outcome.

From the nervous system: headache, dizziness, rarely – seizures.

From the hematopoietic organs: rarely – leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

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

From the cardiovascular system: increased QT interval duration, ventricular fibrillation/flutter.

Other: rarely – impaired renal function, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Contraindications

• Hypersensitivity (including to other azole antifungal drugs in the medical history);
• Concomitant use of terfenadine (while taking fluconazole continuously at a dose of 400 mg/day and higher) and astemizole;
• Lactation period.

With caution: hepatic failure; appearance of rash during the use of fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections; concomitant use of terfenadine and fluconazole at a dose of less than 400 mg per day; potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance, concomitant use of drugs causing arrhythmias); pregnancy.

Use in Pregnancy and Lactation

Use with caution during pregnancy.

Contraindicated during lactation.

Use in Hepatic Impairment

With caution: hepatic failure.

Use in Renal Impairment

For chronic renal failure, a “loading” dose of 50-400 mg is initially administered; for CrCl greater than 50 ml/min, the usual daily dose is prescribed; for CrCl 11-50 ml/min – 50% of the recommended dose or the usual dose once every 2 days; for patients on hemodialysis – 1 dose after each dialysis.

Pediatric Use

For children, as with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. In children, the drug should not be used at a daily dose that would exceed that in adults. The drug is used daily once daily (special dosage forms for children are used). For childrenwith esophageal candidiasis, 3 mg/kg per day as a single dose is prescribed for at least 3 weeks and for 2 weeks after symptom regression; for candidiasis of mucous membranes – 3 mg/kg per day as a single dose for at least 3 weeks; when treating generalized candidiasis and cryptococcal infection (including meningitis) – 6-12 mg/kg per day for 10-12 weeks (until laboratory confirmation of the absence of pathogens in the CSF).

For the prophylaxis of fungal infectionsin children with reduced immunity, in whom the risk of infection is associated with neutropenia developing as a result of cytotoxic chemotherapy or radiation therapy – 3-12 mg/kg/day depending on the severity and duration of the induced neutropenia.

For newborn infants, the interval between drug administrations is 72 hours; for children aged 2-4 weeks, the same dose is administered at 48-hour intervals.

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

Geriatric Use

In elderly patients without impaired renal function, the usual dosing regimen of the drug should be followed

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 fungicidal therapy is recommended. During treatment, blood counts, renal and liver function should be monitored. If impaired renal or liver function occurs, the drug should be discontinued. The hepatotoxic effect of fluconazole is usually reversible, symptoms disappear after discontinuation of therapy.

During the use of the drug, rare cases of exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been observed in patients. AIDS patients and patients with malignant neoplasms are more prone to developing severe skin reactions when using many drugs. If a rash appears in a patient during treatment for a superficial fungal infection that can be associated with the use of fluconazole, the drug should be discontinued. If a rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and Fluconazole should be discontinued if bullous lesions or erythema multiforme occur.

Monitoring of the prothrombin index is necessary when used concomitantly with coumarin anticoagulants.

It is recommended to monitor the concentration of cyclosporine in the blood in patients receiving Fluconazole, because in kidney transplant patients, taking fluconazole at a dose of 200 mg/day leads to a slow increase in cyclosporine plasma concentration.

Overdose

Symptoms: hallucinations, paranoid behavior.

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

Drug Interactions

It increases the effectiveness of coumarin anticoagulants (an increase in prothrombin time when using warfarin – by an average of 12%), the concentration of zidovudine (an increase in the side effects of zidovudine), cyclosporine (when using fluconazole at a dose of 200 mg/day), rifabutin (cases of uveitis have been described with simultaneous use) and phenytoin to a clinically significant extent (when used in combination, monitoring of phenytoin plasma concentration is necessary).

It prolongs the T_1/2 of theophylline and increases the risk of intoxication (a dose adjustment is necessary).

It increases the concentration of midazolam – an increased risk of psychomotor effects (more pronounced when fluconazole is administered orally than intravenously); tacrolimus – the risk of nephrotoxicity.

When taken simultaneously with sulfonylurea derivatives (chlorpropamide, glibenclamide, glipizide and tolbutamide), blood glucose levels should be periodically monitored and, if necessary, the dose of hypoglycemic drugs should be adjusted (since Fluconazole prolongs T_1/2).

Hydrochlorothiazide increases the plasma concentration of fluconazole by 40%, rifampicin reduces T_1/2 by 20% and the area under the concentration-time curve (AUC) by 25%. Terfenadine and cisapride increase the risk of arrhythmias, including paroxysms of ventricular tachycardia (torsades de pointes).

Storage Conditions

Store in a place inaccessible to children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

Over-the-counter.

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.