Instructions Fluconazole capsules 50 mg blister No. 10
Composition
active ingredient: fluconazole;
1 capsule contains fluconazole 50 mg;
excipients: lactose monohydrate; potato starch; magnesium stearate; colloidal anhydrous silicon dioxide;
capsule shell composition: gelatin, titanium dioxide (E 171), indigo carmine blue (E 132).
Dosage form
Capsules.
The main physical and chemical properties: hard gelatin capsules No. 2, cylindrical in shape with hemispherical edges, white body, cap for 50 mg blue capsules; the contents of the capsules are a white or almost white odorless powder.
Pharmacotherapeutic group
Antifungal agents for systemic use. Triazole derivatives. ATX code J02A C01.
Pharmacological properties
Pharmacodynamics
Mechanism of action.
Fluconazole, a triazole antifungal agent, is a potent, selective inhibitor of fungal enzymes required for ergosterol synthesis. Its primary mechanism of action is inhibition of fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. Accumulation of 14-alpha-methyl sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for the various mammalian cytochrome P450 enzyme systems.
Fluconazole 50 mg daily for 28 days had no effect on plasma testosterone levels in men or on endogenous steroid levels in women of reproductive age. Fluconazole 200-400 mg daily had no clinically significant effect on endogenous steroid levels or on the response to ACTH stimulation in healthy male volunteers.
An interaction study with antipyrine demonstrated that single or multiple doses of 50 mg fluconazole did not affect the metabolism of antipyrine.
In vitro sensitivity.
Fluconazole has demonstrated antifungal activity in vitro against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata exhibits a wide range of susceptibility to fluconazole, while C. krusei is resistant to it.
Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against the endemic mold fungi Blastomices dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.
Mechanism of resistance.
Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole exhibits high minimum inhibitory concentrations against fungal strains that possess one or more mechanisms of resistance, which negatively affects efficacy in vivo and in clinical practice. Superinfection with Candida spp. caused by species other than C. albicans, which are often insensitive to fluconazole (e.g. Candida krusei), has been reported. Alternative antifungal agents should be used in such cases.
Pharmacokinetics
The pharmacokinetic properties of fluconazole are similar after intravenous and oral administration.
Absorption.
Fluconazole is well absorbed after oral administration, and plasma levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect oral absorption. Peak plasma concentrations are reached 0.5-1.5 hours after administration. Plasma concentrations are dose-proportional. Steady-state concentrations of 90% are reached on the second day of treatment when a loading dose of twice the usual daily dose is administered on the first day.
Distribution.
The volume of distribution is approximately equal to the total body fluid content. Plasma protein binding is low (11-12%).
Fluconazole penetrates well into all body fluids tested. Fluconazole levels in saliva and sputum are similar to plasma concentrations. In patients with fungal meningitis, fluconazole levels in cerebrospinal fluid reach 80% of plasma concentrations.
High concentrations of fluconazole in the skin, exceeding serum levels, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum. When a dose of 50 mg is used once a day, the concentration of fluconazole after 12 days of treatment was 73 μg/g, and 7 days after the end of treatment, the concentration was still 5.8 μg/g. When a dose of 150 mg is used once a week, the concentration of fluconazole on the 7th day of treatment was 23.4 μg/g; 7 days after the next dose, the concentration was still 7.1 μg/g.
The concentration of fluconazole in nails after 4 months of 150 mg once weekly was 4.05 μg/g in healthy volunteers and 1.8 μg/g in nail diseases; fluconazole was detected in nail samples 6 months after the end of therapy.
Biotransformation.
Fluconazole is metabolized to a small extent. When a dose labeled with radioactive isotopes is administered, only 11% of fluconazole is excreted unchanged in the urine. Fluconazole is a selective inhibitor of CYP2C9 and CYP3A4 isoenzymes, as well as an inhibitor of CYP2C19 isoenzyme.
The plasma half-life of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose being excreted unchanged in the urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.
The long half-life of fluconazole from blood plasma allows for a single dose for vaginal candidiasis, as well as once-weekly dosing for other indications.
Kidney failure.
In patients with severe renal insufficiency (glomerular filtration rate < 20 ml/min), the half-life increases from 30 hours to 98 hours. Therefore, this category of patients requires a reduction in the dose of fluconazole. Fluconazole is removed by hemodialysis and, to a lesser extent, by intraperitoneal dialysis. A 3-hour hemodialysis session reduces the plasma level of fluconazole by approximately 50%.
Elderly patients.
The mean elimination half-life is 46.2 hours. These pharmacokinetic parameters are higher compared to those in healthy young volunteers. Concomitant use of diuretics had no significant effect on the maximum concentration (Cmax) and the area under the concentration-time curve (AUC). Creatinine clearance (74 ml/min), the percentage of fluconazole excreted unchanged in urine (0-24 hours, 22%), and renal clearance of fluconazole (0.124 ml/min/kg) in patients of this age group were lower than those in younger volunteers. Therefore, changes in pharmacokinetics in elderly patients depend on renal function parameters.
Indication
Treatment of diseases in adults such as:
cryptococcal meningitis; coccidioidomycosis; invasive candidiasis; candidiasis of the mucous membranes, including oropharyngeal candidiasis and esophageal candidiasis, candiduria, chronic candidiasis of the skin and mucous membranes; chronic atrophic candidiasis (candidiasis caused by the use of dentures) when local dental hygiene products are ineffective; vaginal candidiasis, acute or recurrent, when local therapy is not appropriate; candidal balanitis, when local therapy is not appropriate; dermatomycoses, including athlete's foot, smooth skin mycosis, inguinal dermatomycosis, lichen multicolor and candidal skin infections, when systemic therapy is indicated; dermatophyte onychomycosis, when the use of other drugs is not appropriate.
Prevention of diseases in adults such as:
Recurrence of cryptococcal meningitis in patients at high risk of developing it; Recurrence of oropharyngeal or esophageal candidiasis in HIV patients at high risk of developing it; Reduction of the frequency of recurrences of vaginal candidiasis (4 or more cases per year); Prevention of candidal infections in patients with prolonged neutropenia (e.g., patients with blood malignancies receiving chemotherapy or patients undergoing hematopoietic stem cell transplantation).
Children.
The drug in capsule form can be used in this category of patients when children are able to safely swallow the capsule, which is usually possible from the age of 5.
Fluconazole is used in children for the treatment of candidiasis of the mucous membranes (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis and for the prevention of candidal infections in patients with reduced immunity. The drug can be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of its development.
Fluconazole therapy may be initiated prior to the results of culture and other laboratory tests; once the results are available, antibacterial therapy should be adjusted accordingly.
Contraindication
Hypersensitivity to fluconazole, other azole compounds or to any of the excipients of the drug.
Concomitant use of fluconazole and terfenadine in patients receiving fluconazole multiple times at doses of 400 mg/day and above (according to the results of a multiple-dose interaction study).
Concomitant use of fluconazole and other drugs that prolong the QT interval and are metabolized by the CYP3A4 enzyme (e.g. cisapride, astemizole, pimozide, quinidine, amiodarone and erythromycin).
Interaction with other medicinal products and other types of interactions
The concomitant use of fluconazole and the following drugs is contraindicated.
Terfenadine. Due to cases of serious cardiac arrhythmias caused by prolongation of the QTc interval, drug-drug interaction studies have been conducted in patients receiving azole antifungals concomitantly with terfenadine. In one study, no prolongation of the QTc interval was observed with fluconazole at a dose of 200 mg/day. Another study with fluconazole at doses of 400 mg and 800 mg/day demonstrated that fluconazole at doses of 400 mg/day or higher significantly increased plasma levels of terfenadine when these drugs were administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section 4.3). When fluconazole is administered at doses below 400 mg/day with terfenadine, the patient should be closely monitored.
Astemizole. Concomitant use of fluconazole and astemizole may reduce the clearance of astemizole. The resulting increase in plasma concentrations of astemizole may lead to QT prolongation and, in rare cases, torsades de pointes. Concomitant use of fluconazole and astemizole is contraindicated.
Pimozide and quinidine. Concomitant use of fluconazole and pimozide or quinidine may lead to inhibition of the metabolism of pimozide or quinidine, although in vitro and in vivo studies have not been conducted. Increased plasma concentrations of pimozide or quinidine may prolong the QT interval and, in rare cases, lead to the development of paroxysmal torsades de pointes. Concomitant use of fluconazole and pimozide or quinidine is contraindicated.
Erythromycin: Concomitant use of erythromycin and fluconazole may increase the risk of cardiotoxicity (QT prolongation, torsades de pointes) and, as a result, sudden cardiac death. The combination of these drugs is contraindicated.
Amiodarone. Concomitant use of fluconazole with amiodarone may result in inhibition of amiodarone metabolism. An association between amiodarone use and QT prolongation has been observed. Concomitant use of fluconazole and amiodarone is contraindicated (see section 4.3).
The concomitant use of fluconazole and the following medicines is not recommended.
Halofantrine: Fluconazole may increase plasma concentrations of halofantrine due to inhibition of CYP3A4. Concomitant use of these drugs may increase the risk of cardiotoxicity (QT prolongation, torsades de pointes) and, consequently, sudden cardiac death. The combination of these drugs should be avoided.
Concomitant use of fluconazole and the following drugs requires caution and dose adjustment.
Effect of other drugs on fluconazole.
Interaction studies have shown that oral administration of fluconazole with food, cimetidine, antacids, or subsequent total body irradiation for bone marrow transplantation has no clinically significant effect on the absorption of fluconazole.
Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% decrease in the half-life of fluconazole. Therefore, an increase in the dose of fluconazole should be considered in patients receiving rifampicin.
Hydrochlorothiazide: In a pharmacokinetic interaction study, co-administration of multiple hydrochlorothiazide to healthy volunteers receiving fluconazole increased fluconazole plasma concentrations by 40%. These interaction parameters do not require changes in the fluconazole dosing regimen for patients receiving concomitant diuretics.
The effect of fluconazole on other drugs.
Fluconazole is a potent inhibitor of the cytochrome P450 (CYP) 2C9 isoenzyme and a moderate inhibitor of CYP3A4. Fluconazole is an inhibitor of the CYP2C19 isoenzyme. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19 and CYP3A4 when co-administered with fluconazole. Therefore, such combinations should be used with caution; patients should be closely monitored. The enzyme inhibitory effect of fluconazole persists for 4-5 days after administration due to its long half-life.
Alfentanil: Co-administration of alfentanil 20 mcg/kg and fluconazole 400 mg in healthy volunteers resulted in a two-fold increase in AUC10, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.
Amphotericin B. Concomitant administration of fluconazole and amphotericin B to immunocompetent and immunocompromised mice showed a small additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic Aspergillus fumigatus infection. The clinical significance of these findings is unknown.
Anticoagulants: As with other azole antifungals, bleeding events (hematoma, epistaxis, gastrointestinal bleeding, hematuria, and melena) in association with prolonged prothrombin time have been reported with concomitant use of fluconazole and warfarin. A two-fold increase in prothrombin time has been observed with concomitant use of fluconazole and warfarin, presumably due to inhibition of warfarin metabolism by CYP2C9. Prothrombin time should be closely monitored in patients receiving concomitant coumarin anticoagulants or indanedione. Dosage adjustment of the anticoagulant may be necessary.
Short-acting benzodiazepines, e.g. midazolam, triazolam. Administration of fluconazole after oral midazolam resulted in a significant increase in midazolam concentrations and increased psychomotor effects. Concomitant administration of fluconazole 200 mg and midazolam 7.5 mg orally resulted in a 3.7- and 2.2-fold increase in AUC and half-life, respectively. Administration of fluconazole 200 mg/day and triazolam 0.25 mg orally resulted in a 4.4- and 2.3-fold increase in AUC and half-life, respectively. Potentiation and prolongation of the effects of triazolam were observed with concomitant administration of fluconazole and triazolam.
If a patient undergoing treatment with fluconazole is to be prescribed concomitant therapy with benzodiazepines, the dose of the latter should be reduced and appropriate monitoring of the patient's condition should be established.
Carbamazepine. Fluconazole inhibits the metabolism of carbamazepine and causes a 30% increase in serum carbamazepine levels. There is a risk of carbamazepine toxicity. The dose of carbamazepine may need to be adjusted depending on its concentration and effect.
Calcium channel blockers. Some calcium antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by the CYP3A4 enzyme. Fluconazole has the potential to increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended.
Celecoxib: Concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg) increased celecoxib Cmax and AUC by 68% and 134%, respectively. A halving of the celecoxib dose may be necessary when celecoxib and fluconazole are coadministered.
Cyclophosphamide: Concomitant use of cyclophosphamide and fluconazole has been shown to increase serum bilirubin and creatinine levels. These drugs may be used concomitantly, given the risk of increased serum bilirubin and creatinine concentrations.
Fentanyl. One fatal case of fentanyl intoxication has been reported due to a possible interaction between fentanyl and fluconazole. In addition, a study in healthy volunteers showed that fluconazole significantly delayed the elimination of fentanyl. Increased fentanyl concentrations may lead to respiratory depression, so the patient should be closely monitored. Fentanyl dosage adjustment may be necessary.
HMG-CoA reductase inhibitors. Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin) or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin) increases the risk of myopathy and rhabdomyolysis. If concomitant use of these drugs is necessary, the patient should be closely observed for symptoms of myopathy and rhabdomyolysis and creatine kinase levels should be monitored. In the event of a significant increase in creatine kinase levels, as well as when myopathy/rhabdomyolysis is diagnosed or suspected, the use of HMG-CoA reductase inhibitors should be discontinued.
Immunosuppressants (e.g. cyclosporine, everolimus, sirolimus and tacrolimus).
Cyclosporine. Fluconazole significantly increases the concentration and AUC of cyclosporine. With simultaneous use of fluconazole at a dose of 200 mg/day and cyclosporine at a dose of 2.7 mg/kg/day, an increase in the AUC of cyclosporine by 1.8 times was observed. These drugs can be used simultaneously, provided that the dose of cyclosporine is reduced depending on its concentration.
Everolimus: Although in vitro and in vivo studies have not been performed, it is known that fluconazole may increase serum concentrations of everolimus due to inhibition of CYP3A4.
Tacrolimus: Fluconazole may increase the serum concentrations of tacrolimus up to 5-fold when administered orally due to inhibition of tacrolimus metabolism by the CYP3A4 enzyme in the intestine. No significant changes in pharmacokinetics have been observed with intravenous administration of tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. The oral dose of tacrolimus should be reduced depending on tacrolimus concentrations.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which accounts for most of the angiotensin II receptor antagonism during the use of losartan. Continuous monitoring of blood pressure in patients is recommended.
Methadone: Fluconazole may increase the serum concentration of methadone. Methadone dosage adjustment may be necessary when methadone and fluconazole are used concomitantly.
Non-steroidal anti-inflammatory drugs (NSAIDs). When co-administered with fluconazole, the Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared to flurbiprofen alone. Similarly, when co-administered with racemic ibuprofen (400 mg), the Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen increased by 15% and 82%, respectively, compared to racemic ibuprofen alone.
Although no specific studies have been performed, fluconazole may increase the systemic exposure of other NSAIDs metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse reactions and toxicities associated with NSAIDs is recommended. Dose adjustment of the NSAID may be necessary.
Phenytoin. Fluconazole inhibits the metabolism of phenytoin in the liver. Simultaneous multiple administration of 200 mg of fluconazole and 250 mg of phenytoin intravenously leads to an increase in phenytoin AUC24 by 75% and Cmin by 128%. When these drugs are used simultaneously, phenytoin serum concentrations should be monitored to avoid the development of phenytoin toxicity.
Prednisone. A case report has been made of a liver transplant patient receiving prednisone who developed acute adrenal insufficiency after discontinuation of a three-month course of fluconazole. Discontinuation of fluconazole is thought to have increased CYP3A4 activity, leading to increased metabolism of prednisone. Patients receiving long-term concomitant fluconazole and prednisone should be carefully monitored for the development of adrenal insufficiency after discontinuation of fluconazole.
Rifabutin. Fluconazole increases the serum concentration of rifabutin, resulting in an increase in the AUC of rifabutin by up to 80%. Cases of uveitis have been reported with the concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when using this combination of drugs. Saquinavir. Fluconazole increases the AUC and Cmax of saquinavir by approximately 50% and 55%, respectively, due to inhibition of saquinavir metabolism in the liver by the CYP3A4 enzyme and inhibition of P-glycoprotein. The interaction between fluconazole and saquinavir/ritonavir has not been studied and may therefore be more pronounced. Saquinavir dose adjustment may be necessary.
Sulfonylureas: Fluconazole prolongs the elimination half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide, and tolbutamide) when administered concomitantly to healthy volunteers. Frequent monitoring of blood sugar levels and appropriate dose reduction of sulfonylureas is recommended when co-administered with fluconazole.
Theophylline: In a drug interaction study, fluconazole 200 mg for 14 days decreased the mean plasma clearance of theophylline by 18%. Patients receiving high doses of theophylline or who are otherwise at increased risk of theophylline toxicity should be monitored for signs of theophylline toxicity. Therapy should be changed if signs of toxicity occur.
Vinca alkaloids: Although not studied, fluconazole, possibly through inhibition of CYP3A4, may increase plasma concentrations of vinca alkaloids (e.g. vincristine and vinblastine), leading to neurotoxic effects.
Voriconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor). Co-administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male volunteers resulted in an increase in voriconazole Cmax and AUC by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is not known whether reducing the dose and/or frequency of voriconazole or fluconazole would eliminate this effect. When voriconazole is administered after fluconazole, monitoring for adverse events associated with voriconazole should be performed.
Zidovudine. Fluconazole increased the Cmax and AUC of zidovudine by 84% and 74%, respectively, due to a decrease in zidovudine clearance by approximately 45% when administered orally. The half-life of zidovudine was also prolonged by approximately 128% after the combination of fluconazole and zidovudine. Patients receiving this combination should be monitored for adverse reactions associated with zidovudine. A reduction in the dose of zidovudine may be considered.
Azithromycin: Studies have evaluated the effects of azithromycin and fluconazole on the pharmacokinetics of each other when administered orally at single doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were observed.
Oral contraceptives. Fluconazole 50 mg had no effect on hormone levels, while fluconazole 200 mg daily increased the AUC of ethinylestradiol by 40% and levonorgestrel by 24%. This suggests that multiple doses of fluconazole are unlikely to affect the efficacy of a combined oral contraceptive.
Ivacaftor: Co-administration with ivacaftor, a cystic fibrosis transmembrane conductance regulator enhancer, increases ivacaftor exposure 3-fold and hydroxymethylivacaftor (M1) exposure 1.9-fold. For patients concomitantly taking moderate CYP3A inhibitors such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.
Application features
Ringworm. According to the results of a study of fluconazole for the treatment of ringworm in children, fluconazole is not superior to griseofulvin in efficacy and the overall efficacy rate is less than 20%. Therefore, fluconazole should not be used for the treatment of ringworm.
Cryptococcosis. There is insufficient evidence of fluconazole efficacy in the treatment of cryptococcosis of other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis), and therefore no dosage recommendations can be made for these conditions.
Deep endemic mycoses. Evidence of the effectiveness of fluconazole for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis and cutaneous-lymphatic sporotrichosis, is insufficient, therefore there are no recommendations for a dosage regimen for the treatment of such diseases.
Renal system: The drug should be used with caution in patients with impaired renal function (see section "Method of administration and dosage").
Adrenal insufficiency: Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although it is rare. Adrenal insufficiency associated with concomitant treatment is described in the section “Effect of fluconazole on other medicinal products”.
Hepatobiliary system. The drug should be used with caution in patients with impaired liver function. The use of fluconazole has been associated with rare cases of severe hepatotoxicity, including fatalities, mainly in patients with severe underlying diseases. In cases where hepatotoxicity has been associated with the use of fluconazole, there has been no clear relationship between the total daily dose of the drug, duration of therapy, gender or age of the patient. Usually, hepatotoxicity caused by fluconazole is reversible and its manifestations disappear after discontinuation of therapy.
Patients who develop abnormal liver function tests while taking fluconazole should be closely monitored for the development of more severe liver damage.
Patients should be informed of symptoms that may indicate serious liver effects (severe asthenia, anorexia, persistent nausea, vomiting and jaundice). In such cases, fluconazole should be discontinued immediately and a doctor should be consulted.
Fluconazole should be used with caution in patients at risk of arrhythmias. Concomitant use with drugs that prolong the QTc interval and are metabolized by the cytochrome P450 enzyme CYP3A4 is contraindicated.
Halofantrine: Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended.
Dermatological reactions. Exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely with fluconazole. Patients with AIDS are more prone to developing severe skin reactions with many drugs. If a patient with a superficial fungal infection develops a rash that can be attributed to the use of fluconazole, further use of the drug should be discontinued. If a patient with an invasive/systemic fungal infection develops a skin rash, his condition should be closely monitored, and in the event of the development of bullous rashes or erythema multiforme, fluconazole should be discontinued.
Hypersensitivity: Anaphylactic reactions have been reported in rare cases.
Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole is also an inhibitor of the CYP2C19 enzyme. Patients who are concomitantly treated with Fluconazole and drugs with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be monitored.
Terfenadine: The patient should be carefully monitored when terfenadine and fluconazole are used concomitantly at doses less than 400 mg/day.
Excipients: This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of Fluconazole on the ability to drive or operate other mechanisms have not been conducted.
Patients should be informed about the possibility of dizziness or convulsions while taking Fluconazole. If such symptoms occur, it is not recommended to drive or operate machinery.
Use during pregnancy or breastfeeding
Numerous congenital anomalies (including brachycephaly, auricular dysplasia, excessive anterior fontanelle enlargement, hip dysplasia, brachioradial synostosis) have been reported in newborns whose mothers received high doses of fluconazole (400-800 mg/day) for at least three months or more for the treatment of coccidioidomycosis. The relationship between fluconazole use and these cases has not been established.
Animal studies have shown reproductive toxicity.
Data obtained during single or repeated administration of fluconazole at usual doses (< 200 mg/day) to several hundred pregnant women during the first trimester of pregnancy have not demonstrated an increased risk of adverse reactions in the fetus.
Normal doses of fluconazole and short courses of fluconazole should not be used during pregnancy unless clearly necessary.
High doses of fluconazole and/or long courses of fluconazole treatment should not be used during pregnancy, except for the treatment of potentially life-threatening infections.
Fluconazole passes into breast milk and reaches lower concentrations than in blood plasma. Breastfeeding can be continued after a single dose of fluconazole, which is 200 mg or less.
Breastfeeding is not recommended during repeated use of fluconazole or when using high doses of fluconazole.
Method of administration and doses
The daily dose of fluconazole depends on the type and severity of the fungal infection. For most cases of vaginal candidiasis, a single dose is sufficient.
If repeated use of the drug is necessary, treatment of infections should be continued until the disappearance of clinical and laboratory manifestations of fungal infection activity. Insufficient duration of treatment may lead to the resumption of the active infectious process.
Fluconazole is administered, depending on the dosage form, orally or intravenously by infusion. The method of administration of the drug depends on
