Fluconazole Sandoz, 150 mg capsules

Pharmacodynamics

Antifungal agent, has a highly specific action by inhibiting the activity of cytochrome P450-dependent fungal enzymes. It blocks conversion of fungi cells lanosterol into membrane lipid – ergosterol; increases cell membrane permeability, disrupts cell growth and replication.

Fluconazole is highly selective for cytochrome P450 of fungi, it actually 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 is active against 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).

Pharmacokinetics

After oral administration fluconazole is well absorbed, its bioavailability is 90%. Maximum concentration after oral administration on an empty stomach of 150 mg of the drug is90% of the plasma concentration when administered intravenously at a dose of 2.5-3.5 mg/l.

Concurrent intake of food has no effect on absorption of fluconazole taken orally. Time of maximum concentration after oral administration on an empty stomach of 150 mg of the drug is 0.5-1.5 hours. Concentration in plasma is in direct dependence on the dose.

The 90% level of equilibrium concentration is reached by 4-5 days of the drug treatment (when administered once daily). The “shock” dose (on the first day), twice as much as the usual daily dose, allows reaching the level of concentration corresponding to 90% of the equilibrium concentration by the second day.

The volume of distribution is close to the total body water content. Binding with blood plasma proteins is 11-12%. Fluconazole penetrates well into all body fluids. Concentration of active substance in breast milk, joint fluid, saliva, sputum and peritoneal fluid is similar to that in plasma.

Constant values in vaginal secretion are reached 8 hours after oral administration and maintained at this level for at least 24 hours. Fluconazole penetrates cerebrospinal fluid (CSF) well, in fungal meningitis the concentration in CSF is about 80% of its level in plasma.

In sweat fluid, epidermis and stratum corneum (selective accumulation) concentrations exceeding serum concentrations are achieved. On day 7 after oral intake of 150 mg fluconazole its concentration in stratum corneum is 23,4 mcg/g, 1 week after the second dose – 7,1 mcg/g. Concentration of fluconazole in healthy nails after 4 months of use in a dose of 150 mg once a week is 4.05 µg/g and 1.8 µg/g in affected nails.

It is an inhibitor of CYP2C9 isoenzyme in liver. No fluconazole metabolites were found in peripheral blood.

It is excreted mainly by the kidneys (80% – unchanged, 11% – as metabolites). Half-life of fluconazole is about 30 hours. Fluconazole clearance is proportional to creatinine clearance. After haemodialysis for 3 hours, plasma concentration of fluconazole decreases by 50%.

Indications

Active ingredient

Composition

Capsules:

1 capsule contains fluconazole – 150 mg.

How to take, the dosage

Ingestion. The daily dose depends on the nature and severity of the fungal infection.

In adults with cryptococcal meningitis and cryptococcal infections of other localizations the first day is usually prescribed 400 mg, and then treatment continues at a dose of 200-400 mg once a day. The duration of treatment in cryptococcal infections depends on the clinical efficacy confirmed by mycological examination; in cryptococcal meningitis it is usually continued for at least 6-8 weeks.

In order to prevent relapse of cryptococcal meningitis in AIDS patients, after completion of the full course of primary treatment, fluconazole is prescribed at a dose of 200 mg/day for an extended period of time.

In candidemia, disseminated candidiasis, and other invasive candidiasis infections, the dose is usually 400 mg in the first day and 200 mg thereafter. In case of insufficient clinical efficacy, the drug dose may be increased to 400 mg/day; in severe systemic candidiasis, the dose may be increased to 800 mg/day. Duration of therapy depends on clinical efficacy; it should be continued for at least 2 weeks after negative hemocultures or disappearance of symptoms.

In oropharyngeal candidiasis the drug is usually prescribed 50-100 mg once daily; duration of therapy is 7-14 days. If necessary, in patients with severe immune impairment the treatment may be longer (3 weeks).

In atrophic oral candidiasis associated with wearing dentures, fluconazole is usually prescribed 50 mg once daily for 14 days in combination with local antiseptics for denture treatment.

In other localizations of candidiasis (except genital candidiasis), such as esophagitis, noninvasive bronchopulmonary lesions, candiduria, candidiasis of the skin and mucous membranes, etc., the effective dose is usually 50-100 mg/day with a treatment duration of 14-30 days; in severe mucosal candidiasis, 100-200 mg/day.

To prevent relapses of oropharyngeal candidiasis in patients with AIDS after completion of the 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 once a month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may require more frequent use.

Fluconazole is given as a single oral dose of 150 mg for balanitis caused by Candida.

For prevention 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 anticipated 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 above 1000/mm, treatment is continued for another 7 days.

In cases of skin mycoses, including foot mycoses, skin of the groin, and candidiasis of the skin, the recommended dose is 150 mg once weekly or 50 mg once daily. 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.

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

In onychomycosis, the recommended dose is 150 mg once weekly. Treatment should be continued until the infected nail is replaced (the uninfected nail grows back). It normally takes 3-6 and 6-12 months, respectively, for re-growth of the nails on the fingers and feet.

In deep endemic mycoses, it may be necessary to use the drug at a dose of 200-400 mg/day for up to 2 years. The duration of therapy is determined individually; it may be 11-24 months for coccidiomycosis; 2-17 months for paracoccidiomycosis; 1-16 months for sporotrichosis and 3-17 months for histoplasmosis.

In children, as well 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 would exceed that of adults. The drug is used daily once a day.

In mucosal candidiasis the recommended dose of fluconazole is 3 mg/kg/day. On the first day, an initial loading dose of 6 mg/kg may be administered in order to achieve steady-state equilibrium concentrations more quickly.

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

For the prevention of fungal infections in immunocompromised children whose risk of infection is associated with neutropenia resulting from cytotoxic chemotherapy or radiation therapy, the drug is indicated at 3-12 mg/kg/day, depending on the severity and duration of induced neutropenia.

The maximum daily dose for children is 12 mg/kg. Due to the fact that it is not always possible to provide the required dosing regimen in mg/kg, it is recommended to use the drug in other dosage forms for children.

Dosing for patients with renal insufficiency. Fluconazole is excreted mainly by the kidneys in unchanged form. There is no need to change the dose if it is taken once.

Adult patients with impaired renal function should first be given an initial loading dose of 50 to 400 mg. Then, if the creatinine Cl is more than 50 ml/min, the usual dose of the drug (100% of the recommended dose) should be used. If creatinine Cl is 11 to 50 ml/min, a dose equal to 50% of the recommended dose is used, or the usual dose once every 2 days. For patients who are regularly on dialysis, one dose of the drug is used after each session of hemodialysis.

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 impairment the usual dosing regimen of the drug should be followed.

Interaction

In concomitant use with warfarin, fluconazole increases prothrombin time (by 12%), in connection with which bleeding may occur (hematomas, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants prothrombin time should be constantly monitored.

Fluconazole significantly increases midazolam concentration and psychomotor effects after oral administration of midazolam, and this effect is more pronounced after fluconazole oral administration than when it is used intravenously. If concomitant therapy with benzodiazepines is necessary, patients taking fluconazole should be monitored to reduce the benzodiazepine dose accordingly.

In concomitant use of fluconazole and cisapride, adverse cardiac reactions, including ventricular fibrillation/tripping (pirouette-type arrhythmia) are possible. The use of fluconazole in dose 200 mg once daily and cisapride in dose 20 mg four times daily causes significant increase of plasma concentration of cisapride and prolongation of QT interval on ECG. Simultaneous administration of cisapride and fluconazole is contraindicated.

In patients after kidney transplantation, the use of fluconazole at a dose of 200 mg/day leads to a slow increase in concentration of cyclosporine. However, no changes in cyclosporine concentrations were observed in bone marrow recipients when fluconazole was administered repeatedly at a dose of 100 mg/day. When concomitant use of fluconazole and cyclosporine it is recommended to monitor the concentration of cyclosporine in blood.

Multiple use of hydrochlorothiazide concomitantly with fluconazole leads to an increase in fluconazole plasma concentration by 40%. This increase does not require modification of the fluconazole dosing regimen in patients receiving concomitant diuretics, but this should be considered.

. No significant effects on hormone levels have been identified in concomitant administration of the combined oral contraceptive with fluconazole in a dose of 50 mg, while the AUCs of ethinylestradiol and levonorgestrel are increased by 40% and 24% respectively when taking fluconazole 200 mg daily, and the AUCs of ethinylestradiol and norethindrone are increased by 24% and 13% respectively when taking fluconazole 300 mg once weekly. Thus, repeated use of fluconazole at the indicated doses is unlikely to affect the efficacy of the combined oral contraceptive.

The concomitant use of fluconazole and phenytoin may be accompanied by clinically significant increases in phenytoin concentrations. In this combination, phenytoin concentrations should be monitored and the dose should be adjusted accordingly to ensure therapeutic serum concentrations.

The concomitant use of fluconazole and rifabutin may lead to increased serum concentrations of the latter. In concomitant use of fluconazole and rifabutin there have been described cases of uveitis. Patients receiving rifabutin and fluconazole concomitantly should be monitored closely.

Special Instructions

Caution is used with caution in patients with hepatic dysfunction when using fluconazole, with the occurrence of rash on fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections, with the simultaneous use of terfenadine and fluconazole at a dose less than 400 mg/day, in potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders).

Hepatotoxic effects of fluconazole were usually reversible; signs of these effects disappeared after discontinuation of therapy. Patients with impaired liver function during treatment with fluconazole should be monitored for signs of more serious liver damage. If there are clinical signs or symptoms of liver damage that may be associated with fluconazole, it should be discontinued.

AIDS patients are more prone to develop severe skin reactions with many drugs. If a patient treated for a superficial fungal infection presents with a rash that can be associated with fluconazole use, it should be discontinued. If rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be stopped if bullous lesions or erythema multiforme appear.

The concomitant use of fluconazole in doses less than 400 mg/day and terfenadine should be monitored closely.

When using fluconazole, QT interval prolongation and ventricular fibrillation/rattling have been observed very rarely in patients with multiple risk factors, such as organic heart disease, electrolyte disturbances, and concomitant therapy contributing to these disorders.

The therapy can be started before the results of culture and other laboratory tests. However, anti-infective therapy should be adjusted accordingly when the results of these tests become available.

There have been reports of cases of superinfections caused by Candida strains other than Candida albicans, which often do not show sensitivity to fluconazole (e.g., Candida krusei). In such cases, alternative antifungal therapy may be necessary.

Contraindications

With caution:

hepatic and/or renal impairment, rash on fluconazole in patients with superficial fungal infection and invasive/systemic fungal infections, concurrent administration of terfenadine and fluconazole at a dose of less than 400 mg/day, concurrent administration of potentially hepatotoxic drugs, alcoholism, potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte balance disorders, concurrent administration of medications that cause ar

Side effects

Overdose

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