Fluconazole-Vertex, 150 mg capsules

Pharmacotherapeutic group: antifungal agent.

CodeATH: J02AC01

Pharmacological properties

Pharmacodynamics

Fluconazole is a representative of the class of triazole antifungal agents and is a potent selective inhibitor of the fungal enzyme 14-α-demethylase. The drug prevents conversion of lanosterol into ergosterol – the main component of cell membranes of fungi.

The drug is effective against opportunistic mycoses, including those caused by Candida spp. (Candida albicans, Candida tropicalis), Cryptococcus neoformans, Microsporum spp. Fluconazole activity has also been shown in models of endemic mycoses, including infections caused by Blastomyces dermatidis, Coccidioides immitis and Histoplasma capsulatum. However, blastomycetes, histoplasmids, paracoccidioides and sporotrix are less sensitive to fluconazole than to other azoles.

Pharmacokinetics

Fluconazole is well absorbed after oral administration, its bioavailability is 90%. Maximum concentration (Cmax) after oral administration, on an empty stomach of 150 mg is 90% of the plasma content when administered intravenously at a dose of 2.5-3.5 mg/kg.

Concomitant ingestion does not affect absorption of the drug taken orally. Plasma concentrations reach a peak in 0.5-1.5 h (TSmax) after administration. Plasma concentrations are directly proportional to the dose. The 90% level of equilibrium concentration is reached by 4-5 days of treatment with the drug (when taken once daily).

The first day’s dosing of twice the usual daily dose allows the drug to reach a level in plasma equal to 90% of the equilibrium concentration by the second day. The apparent volume of distribution is close to the total volume of water in the body. Binding to plasma proteins is low – 11-12%.

Fluconazole penetrates well into all body fluids, including cerebrospinal fluid. The drug concentrations in saliva and sputum are similar to its content in plasma. In patients with fungal meningitis the content of fluconazole in cerebrospinal fluid reaches 80% of its level in plasma.

In the stratum corneum, epidermis, dermis and sweat fluid high concentrations are achieved that exceed serum levels.

Less than 5% of fluconazole is metabolized during first passage through the liver. The half-life (T1/2) of fluconazole is about 30 hours. The long T1/2 allows a single dose to be used for the treatment of vaginal candidiasis and allows once-daily administration for other indications. Fluconazole is mainly excreted by the kidneys; about 80% of the administered dose is excreted unchanged by the kidneys. Fluconazole clearance is proportional to creatinine clearance. No fluconazole metabolites were detected in peripheral blood.

Indications

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Active ingredient

Fluconazole

Composition

1 capsule contains:

The active ingredient:

fluconazole 50 mg or 150 mg.

Excipients:

corn starch, povidone (polyvinylpyrrolidone),

colloidal silicon dioxide (aerosil),

sodium lauryl sulfate,

calcium stearate,

lactose.

Solid gelatin capsules:

for dosage 50 mg – gelatin,

titanium dioxide,

dye azorubin,
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Sunset Yellow dye and for 150 mg dosage – gelatin,

titanium dioxide.

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, 400 mg is usually prescribed on the first day, and then treatment continues at a dose of 200 mg once daily. Depending on the response, the dose may be increased to 400 mg once daily.

The duration of treatment for cryptococcal infections depends on the clinical efficacy confirmed by microbiological testing. Recommended duration of treatment of initial therapy of cryptococcal meningitis is 10-12 weeks after a negative result of microbiological examination of cerebrospinal fluid sample.

In order to prevent a recurrence of cryptococcal meningitis in AIDS patients, fluconazole is given at a daily dose of 200 mg for an extended period after the completion of initial therapy.

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 per day; in severe systemic candidiasis, the dose may be increased to 800 mg per day. Duration of therapy depends on clinical efficacy; it should be continued for at least 2 weeks after obtaining of negative hemoculture or after disappearance of disease symptoms.

In oropharyngeal candidiasis the drug is usually prescribed 50-100 mg once daily; duration of treatment 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 the wearing of dentures, fluconazole is usually prescribed 50 mg once daily for 14 days in combination with topical antiseptics for denture treatment.

In other localizations of candidiasis (except genital candidiasis), such as esophagitis, non-invasive bronchopulmonary lesions, candiduria, candidiasis of skin and mucous membranes and so on, the effective dose is usually 50-100 mg daily for treatment duration of 14-30 days; in severe candidiasis of mucous membranes – 100-200 mg daily. For prophylaxis of oropharyngeal candidiasis relapses in AIDS patients after completion of complete course of initial therapy, the drug may be prescribed in dose of 150 mg once a week.

For vaginal candidiasis, fluconazole is taken orally once at 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 prescribed several days before the expected appearance of neutropenia; after an increase in neutrophil counts greater than 1000/mm3, treatment is continued for up to 7 days.

In mycoses of the skin, including mycoses of the feet, 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 rubella, 300 mg once a week for 2 weeks; some patients require a third dose of 300 mg a week, but in some cases a single dose of 300-400 mg is sufficient; alternatively, 50 mg once a day for 2-4 weeks.

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

In deep endemic mycoses, it may be necessary to use the drug at a dose of 200-400 mg per day for up to 2 years. The duration of therapy is determined individually; it may be 11-24 months for coccidiomycosis 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 per day. A shock dose of 6 mg/kg may be administered on the first day in order to reach equilibrium concentrations more quickly.

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

The maximum daily dose for children is 12 mg/kg.

Dosing for patients with renal failure

Fluconazole is excreted mainly by the kidneys unchanged. There is no need to change the dose if it is taken once.

Adult patients with impaired renal function should first be given a “shock” dose of 50 mg to 400 mg when re prescribing the drug. If the creatinine clearance (CK) is greater than 50 mL/min, the normal dose of the drug (100% of the recommended dose) should be used.

If the CK is between 11 and 50 mL/min, then a dose equal to 50% of the recommended dose or the usual dose once every 2 days is used. For patients who are regularly on dialysis, one dose of the drug is administered 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 adhered to.

Special Instructions

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

By treatment, blood parameters, renal and hepatic function should be monitored. If renal and hepatic function abnormalities occur, the drug should be discontinued.

In rare cases the use of fluconazole has been 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, gender and age of the patient was noted.

Hepatotoxic effects of fluconazole were usually reversible; symptoms 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 with many drugs. In cases where patients with superficial fungal infections develop a rash and it is considered definitely related to fluconazole, the drug should be discontinued. If a rash develops in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous changes or erythema multiforme appear.

Caution should be exercised when fluconazole is taken concomitantly with cisapride, rifabutin or other drugs metabolized by the cytochrome P 450 system.

Contraindications

Hypersensitivity to fluconazole, other drug components or other azole compounds; concomitant use of terfenadine (with continuous use of fluconazole at a dose of 400 mg or more per day), cisapride or astemizole and other drugs prolonging the Q-T interval and increasing the risk of severe rhythm disturbances; lactose intolerance; lactase deficiency; glucose-galactose malabsorption; lactation; children under 3 years of age (for this dosage form).

With caution: hepatic and/or renal insufficiency, occurrence of rash on the pho of fluconazole administration in patients with superficial fungal infection and invasive/systemic fungal infections, simultaneous administration of terfenadine and fluconazole at a dose less than 400 mg daily, potentially proarrhythmogenic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalances, simultaneous administration of drugs that cause arrhythmias); Patients with intolerance to acetylsalicylic acid, pregnancy.

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Side effects

Digestive system disorders: decreased appetite, changes in taste, abdominal pain, vomiting, nausea, diarrhea, flatulence, rarely – liver function disorders (jaundice, hepatitis, hepatonecrosis, hyperbilirubinemia, increased alanine aminotransferase activity, aspartate aminotransferase activity, increased alkaline phosphatase activity, hepatocellular necrosis), including severe.

Nervous system disorders: headache, dizziness, excessive fatigue, rarely – seizures.

Hematopoietic organs: rarely – leukopenia, thrombocytopenia (bleeding, petechias), neutropenia, agranulocytosis.

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

Cardiovascular system disorders: prolongation of the QT interval, ventricular fibrillation/thrash.

Others: rarely – renal dysfunction, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Overdose

Symptoms: nausea, vomiting, diarrhea, in severe cases seizures, hallucinations, paranoid behavior may be noted.
Treatment: symptomatic, gastric lavage; since fluconazole is excreted by the kidneys forced diuresis is recommended. Hemodialysis for 3 hours reduces concentration in plasma by 2 times.

Interaction with other medicinal products
A single dose of fluconazole in the treatment of vaginal candidiasis is not associated with significant interactions. However, the following drug interactions are possible when multiple or higher doses of the drug are used concomitantly with other medicinal products:

• Interaction of fluconazole with terfenadine, cisapride, and astemizole may lead to increased plasma concentrations of these drugs, which in turn may cause Q-T interval prolongation and lead to serious heart rhythm disturbances. Fluconazole inhibits P450 enzymes in the liver, thus reducing the metabolism of terfenadine, cisapride and astemizole. Concomitant use of fluconazole and these drugs is contraindicated.
• Warfarin and fluconazole together lead to prolongation of pro-thrombin time. In this regard, prothrombin time should be controlled in patients receiving fluconazole and coumarin anticoagulants concomitantly.
• Fluconazole prolongs T1/2 of oral hypoglycemic agents (sulfonylurea derivatives). In diabetic patients it is possible to simultaneously prescribe fluconazole and sulphonylurea derivatives, however it is necessary to take into consideration the possible risk of hypoglycemia.
• Monitoring of hydrochlorothiazide with fluconazole may increase fluconazole plasma concentrations. The dose of fluconazole should be increased accordingly with concomitant use.
• In patients who have undergone a renal transplant, fluconazole may increase the plasma concentration of cyclosporine. It is therefore recommended that cyclosporine concentrations be monitored in patients receiving cyclosporine and fluconazole concomitantly.
• Fluconazole increases plasma concentrations of theophylline. It is therefore recommended that theophylline concentrations be monitored in patients receiving theophylline and fluconazole concomitantly.
• Fluconazole may increase plasma concentrations of indinavir and midazolam. If these drugs are co-administered with fluconazole the dose should be reduced accordingly.”
• Clinical studies have shown that as a result of the delayed metabolism of zidovudine, its plasma concentration may increase with fluconazole. It is necessary to monitor patients receiving both drugs at the same time, because in this case the frequency of side effects of zidovudine may increase.
• Enhances tacrolimus concentration – risk of nephrotoxicity.
• Physicians should note that interaction with other medicinal products has not been specifically studied, but it is possible.

Pregnancy use

The use of the drug in pregnant women is not advisable, except for severe or life-threatening forms of fungal infections, if the expected effect exceeds the possible risk to the fetus.

Fluconazole is found in breast milk at the same concentration as in plasma, so its administration during lactation is not recommended.

Similarities

Diflucan, Flucostat, Mycosist, Mycomax, Fluconazole-Teva, Fluconazole, Fluconazole Stada, Fluconazole Sandoz