Flucoric

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUCORIC (FLUCORIC)

Composition:

Active substance: fluconazole;

1 capsule contains 150 mg of fluconazole;

Excipients: lactose monohydrate; corn starch; colloidal anhydrous silicon dioxide; magnesium stearate; sodium lauryl sulfate.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard two-piece gelatin capsules of size 1, blue/blue in color, with the inscription "RANBAXY" in black edible ink on both cap and body of the capsule; the capsules contain a white or almost white powder.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives. ATC code J02A C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Fluconazole, an antifungal agent of the triazole class, is a potent and selective inhibitor of fungal enzymes essential for ergosterol synthesis. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation, mediated by cytochrome P450, which is an essential step in the biosynthesis of fungal ergosterol. Accumulation of 14-alpha-methyl-sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may account for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various cytochrome P450 enzyme systems in mammals.

Administration of fluconazole at a dose of 50 mg daily for 28 days does not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily does not produce clinically significant effects on endogenous steroid levels or on the response to ACTH stimulation in healthy male volunteers.

Studies of interaction with antipyrine have demonstrated that single or repeated administration of 50 mg fluconazole does not affect antipyrine metabolism.

In vitro susceptibility.

Fluconazole demonstrates in vitro antifungal activity against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of susceptibility to fluconazole, whereas C. krusei is resistant.

Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against the endemic mould fungi Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.

Mechanism of resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimum inhibitory concentrations against fungal strains possessing one or more resistance mechanisms, which negatively affects efficacy in vivo and in clinical practice. Cases of superinfection with Candida spp. other than C. albicans, often insensitive to fluconazole (e.g., Candida krusei), have been reported. Alternative antifungal agents should be used for the treatment of such cases.

Pharmacokinetics.

Pharmacokinetic properties of fluconazole are similar following intravenous and oral administration.

Absorption.

Fluconazole is well absorbed after oral administration, and plasma drug levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect drug absorption following oral administration. Peak plasma concentration is reached within 0.5–1.5 hours after drug intake. Plasma drug concentration is proportional to the dose. Steady-state concentration reaches 90% by the second day of treatment when a loading dose twice the normal daily dose is administered on the first day.

Distribution.

The volume of distribution is approximately equal to total body water. Plasma protein binding is low (11–12%).

Fluconazole penetrates well into all studied body fluids. Drug 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. After administration of a 50 mg dose once daily, fluconazole concentration on day 12 of treatment was 73 µg/g, and 7 days after completion of treatment, the concentration was still 5.8 µg/g. With a dose of 150 mg once weekly, fluconazole concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, the concentration was still 7.1 µg/g.

Fluconazole concentration in nails after 4 months of treatment with 150 mg once weekly was 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disorders; fluconazole was detectable in nail samples 6 months after completion of therapy.

Biotransformation.

Fluconazole is minimally metabolized. After administration of a radiolabeled dose, only 11% of fluconazole is excreted in urine in altered form. Fluconazole is a selective inhibitor of CYP2C9 and CYP3A4 isoenzymes, as well as an inhibitor of the CYP2C19 isoenzyme.

Elimination.

The plasma elimination half-life of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.

The prolonged plasma elimination half-life allows for single-dose administration in vaginal candidiasis, as well as once-weekly dosing for other indications.

Renal impairment.

In patients with severe renal impairment (glomerular filtration rate <20 mL/min), the elimination half-life increases from 30 to 98 hours. Therefore, this patient group requires a reduced dose of fluconazole. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Geriatric patients.

Pharmacokinetic changes in elderly patients depend on renal function parameters.

Clinical characteristics.

Indications.

Acute vaginal candidiasis when local therapy is not appropriate.

Candidal balanitis when local therapy is not appropriate.

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients of the medicinal product.
• Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg/day or higher (based on results of multiple-dose interaction studies).
• Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized by the CYP2A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin).

Interaction with other medicinal products and other forms of interaction.

Concomitant use of fluconazole and the following medicinal products is contraindicated.

Cisapride: cases of cardiac adverse reactions, including paroxysmal ventricular tachycardia of the "torsade de pointes" type, have been reported in patients receiving fluconazole and cisapride concomitantly. Concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily resulted in a significant increase in cisapride plasma levels and QT interval prolongation. Concomitant use of fluconazole and cisapride is contraindicated (see section "Contraindications").

Terfenadine: due to cases of severe cardiac arrhythmias caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine. Administration of fluconazole at a dose of 200 mg daily did not result in QTc interval prolongation. However, administration of fluconazole at doses of 400 mg and 800 mg daily demonstrated that fluconazole doses of 400 mg daily or higher significantly increase terfenadine plasma levels when both agents are administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is administered at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

Astemizole: concomitant use of fluconazole and astemizole may reduce astemizole clearance. The resulting increase in astemizole plasma concentration may lead to QT interval prolongation and, in rare cases, to paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole and astemizole is contraindicated.

Pimozide and quinidine: concomitant use of fluconazole and pimozide or quinidine may lead to inhibition of pimozide or quinidine metabolism. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, in rare cases, lead to paroxysmal ventricular tachycardia of the "torsade de pointes" type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated.

Erythromycin: concomitant use of erythromycin and fluconazole may potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsade de pointes" type) and, as a consequence, sudden cardiac death. The use of this combination of medicinal products is contraindicated.

Amiodarone: concomitant use of fluconazole with amiodarone may lead to inhibition of amiodarone metabolism. An association between amiodarone use and QT interval prolongation has been observed. Concomitant use of fluconazole and amiodarone is contraindicated (see section "Contraindications").

Concomitant use of fluconazole and the following medicinal products is not recommended.

Halofantrine: fluconazole may increase halofantrine plasma concentrations by inhibiting CYP3A4. Concomitant use of these medicinal products may potentially increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the "torsade de pointes" type) and, as a consequence, sudden cardiac death. The use of this combination of medicinal products should be avoided.

Concomitant use of fluconazole and the following medicinal products requires caution and dose adjustment.

Effect of other medicinal products on fluconazole.

Oral administration of fluconazole concomitantly with food, administration of cimetidine, antacids, or total body irradiation for bone marrow transplantation does not have a clinically significant effect on fluconazole absorption.

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% reduction in the elimination half-life of fluconazole. Therefore, for patients receiving rifampicin, consideration should be given to increasing the fluconazole dose.

Hydrochlorothiazide: in a pharmacokinetic interaction study, repeated concomitant administration of hydrochlorothiazide in healthy volunteers receiving fluconazole increased fluconazole plasma concentrations by 40%. Such interaction parameters do not require changes in the fluconazole dosing regimen for patients receiving diuretics concomitantly.

Effect of fluconazole on other medicinal products.

Fluconazole is a potent inhibitor of the cytochrome P450 (CYP) 2C9 isoenzyme and a moderate inhibitor of CYP3A4. Fluconazole is also an inhibitor of CYP2C19. In addition to the observed/documentarily confirmed interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9 and CYP3A4 when administered concomitantly with fluconazole. Therefore, such combinations of medicinal products should be used with caution; careful monitoring of patients is necessary. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after its administration due to its long elimination half-life.

Alfentanil: during concomitant administration of alfentanil at a dose of 20 mcg/kg and fluconazole at a dose of 400 mg, a twofold increase in AUC was observed, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.

• Amitriptyline, nortriptyline:* fluconazole enhances the effect of amitriptyline and nortriptyline. Measurement of 5-nortriptyline and/or S-amitriptyline concentrations is recommended at the beginning of combination therapy and after 1 week. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B: concomitant use of fluconazole and amphotericin B in infected immunocompetent mice and infected immunocompromised mice resulted in the following findings: slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic A. fumigatus infection. The clinical significance of these study results is unknown.

Anticoagulants: as with other azole antifungal agents, cases of bleeding (hematomas, epistaxis, gastrointestinal bleeding, hematuria, and melena) associated with prolonged prothrombin time have been reported during concomitant use of fluconazole and warfarin. A twofold increase in prothrombin time was observed during concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be carefully monitored in patients receiving coumarin anticoagulants concomitantly. Dose adjustment of the anticoagulant may be necessary.

Benzodiazepines of short duration of action, e.g., midazolam, triazolam: administration of fluconazole after oral administration of midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant administration of fluconazole at a dose of 200 mg and midazolam at a dose of 7.5 mg orally resulted in a 3.7-fold and 2.2-fold increase in AUC and elimination half-life, respectively. Administration of fluconazole at a dose of 200 mg/day and 0.25 mg triazolam orally resulted in a 4.4-fold and 2.3-fold increase in AUC and elimination half-life, respectively. Potentiation and prolongation of triazolam effects were observed during concomitant use of fluconazole and triazolam.

If a patient undergoing fluconazole treatment needs to be prescribed benzodiazepines concomitantly, the dose of the latter should be reduced and appropriate patient monitoring established.

Carbamazepine: fluconazole inhibits carbamazepine metabolism and causes a 30% increase in serum carbamazepine levels. There is a risk of carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on its concentration and effect.

Calcium channel blockers: some calcium antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by the CYP3A4 enzyme. Fluconazole may potentially increase systemic exposure to calcium channel blockers. Careful monitoring for adverse reactions is recommended.

Celecoxib: during concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg), Cmax and AUC of celecoxib increased by 68% and 134%, respectively. When celecoxib is used concomitantly with fluconazole, a reduction in celecoxib dose by half may be necessary.

Cyclophosphamide: concomitant use of cyclophosphamide and fluconazole leads to increased serum bilirubin and creatinine levels. These drugs can be used concomitantly, considering the risk of increased serum bilirubin and creatinine levels.

Fentanyl: one fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. In addition, fluconazole was shown to significantly slow fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, careful monitoring of the patient is required. Dose adjustment of fentanyl 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, careful monitoring of the patient for symptoms of myopathy and rhabdomyolysis and monitoring of creatine kinase levels should be performed. If a significant increase in creatine kinase levels occurs, or if 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 cyclosporine concentration and AUC. During concomitant use of fluconazole at a dose of 200 mg/day and cyclosporine at a dose of 2.7 mg/kg/day, a 1.8-fold increase in cyclosporine AUC was observed. These drugs can be used concomitantly provided the cyclosporine dose is reduced depending on its concentration.

Everolimus: fluconazole may increase everolimus serum concentration by inhibiting CYP3A4.

Sirolimus: fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism by the CYP3A4 enzyme and P-glycoprotein. These drugs can be used concomitantly provided the sirolimus dose is adjusted depending on its concentration and effects.

Tacrolimus: fluconazole may increase tacrolimus serum concentrations up to 5-fold with oral administration due to inhibition of tacrolimus metabolism by the CYP3A4 enzyme in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus administration. Elevated tacrolimus levels are associated with nephrotoxicity. The oral tacrolimus dose should be reduced depending on tacrolimus concentration.

Losartan: fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which accounts for most of the angiotensin II receptor antagonism during losartan use. Continuous monitoring of blood pressure in patients is recommended.

Methadone: fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary during concomitant use of methadone and fluconazole.

Nonsteroidal anti-inflammatory drugs (NSAIDs): during concomitant use with fluconazole, Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared to corresponding values when flurbiprofen was used alone. Similarly, during concomitant use of fluconazole with racemic ibuprofen (400 mg), Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen increased by 15% and 82%, respectively, compared to corresponding values when only racemic ibuprofen was used.

Fluconazole may potentially increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring of adverse reactions and toxic effects associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin: fluconazole inhibits hepatic metabolism of phenytoin. Repeated concomitant administration of 200 mg fluconazole and 250 mg phenytoin intravenously results in a 75% increase in phenytoin AUC24 and a 128% increase in Cmin. Monitoring of phenytoin serum concentration should be performed during concomitant use of these medicinal products to avoid phenytoin toxicity.

Prednisone: a case has been reported where a patient after liver transplantation developed acute adrenal insufficiency following discontinuation of a three-month course of fluconazole therapy while receiving prednisone. Discontinuation of fluconazole may have led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients receiving long-term concomitant fluconazole and prednisone should be carefully monitored to prevent adrenal insufficiency after discontinuation of fluconazole.

Rifabutin: fluconazole increases rifabutin serum concentration, leading to an up to 80% increase in rifabutin AUC. Cases of uveitis have been reported during concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when using this combination of medicinal products.

Saquinavir: fluconazole increases AUC and Cmax of saquinavir by approximately 50% and 55%, respectively, due to inhibition of hepatic metabolism of saquinavir by the CYP3A4 enzyme and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Dose adjustment of saquinavir may be necessary.

Sulfonylurea derivatives: fluconazole prolongs the elimination half-life of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) when used concomitantly. Frequent blood glucose monitoring is recommended, and the dose of sulfonylurea derivatives should be reduced accordingly when used concomitantly with fluconazole.

Theophylline: administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the average plasma clearance of theophylline. Patients receiving high-dose theophylline or those at increased risk of theophylline toxicity for other reasons should be monitored for signs of theophylline toxicity. Therapy should be modified upon signs of toxicity.

Vinca alkaloids: fluconazole, likely via inhibition of CYP3A4, may increase plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A: a case has been reported where a patient receiving all-trans retinoic acid (the acid form of vitamin A) concomitantly with fluconazole developed central nervous system adverse reactions in the form of pseudotumor cerebri, which resolved after discontinuation of fluconazole. These medicinal products can be used concomitantly, but the risk of central nervous system adverse reactions should be kept in mind.

Voriconazole (inhibitor of CYP2C9 and CYP3A4): concomitant oral administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to male volunteers resulted in an average increase in voriconazole Cmax and AUCτ by 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is used after fluconazole, monitoring for adverse effects associated with voriconazole is recommended.

Zidovudine: fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to a decrease in zidovudine clearance of approximately 45% after oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128% after administration of the fluconazole and zidovudine combination. Patients receiving this combination of medicinal products should be monitored for adverse reactions associated with zidovudine use. Consideration may be given to reducing the zidovudine dose.

Azithromycin: no significant pharmacokinetic interactions between azithromycin and fluconazole have been identified.

Oral contraceptives: no effect on hormone levels was observed with fluconazole at a dose of 50 mg, whereas administration of fluconazole at a dose of 200 mg daily resulted in a 40% increase in AUC of ethinylestradiol and a 24% increase in levonorgestrel. This indicates that repeated administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Ivacaftor: concomitant use with ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, increases exposure to ivacaftor by 3 times and to hydroxymethylivacaftor (M1) by 1.9 times. For patients concomitantly receiving moderate CYP3A inhibitors such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.

Special precautions for use.

Dermatophytosis. According to clinical studies on fluconazole for the treatment of dermatophytosis in children, fluconazole is not superior to griseofulvin in efficacy, and the overall response rate is less than 20%. Therefore, fluconazole should not be used for the treatment of dermatophytosis.

Cryptococcosis. There is insufficient evidence of fluconazole efficacy in treating cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis); therefore, no dosage recommendations can be made for the treatment of these infections.

Deep endemic mycoses. There is insufficient evidence of fluconazole efficacy in treating other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis; therefore, no dosage recommendations can be made for the treatment of these infections.

Candidiasis. Clinical studies have shown an increasing prevalence of infections caused by Candida species other than Candida albicans. These species are often intrinsically resistant (e.g., Candida krusei and Candida auris) or exhibit reduced susceptibility to fluconazole (Candida glabrata). Such infections may require alternative antifungal therapy. Therefore, it is recommended to consider the prevalence of resistance among different Candida species to fluconazole.

Renal system. Fluconazole should be used with caution in patients with impaired renal function (see section "Dosage and administration").

Hepatobiliary system. Fluconazole should be used with caution in patients with impaired liver function. Rare cases of severe hepatotoxicity, including fatal outcomes, have been associated with fluconazole use, primarily in patients with serious underlying conditions. In cases where hepatotoxicity was linked to fluconazole, no clear relationship was observed with the total daily dose, duration of therapy, sex, or age of the patient. Hepatotoxicity associated with fluconazole is usually reversible, and symptoms typically resolve after discontinuation of therapy.

Patients who develop abnormalities in liver function tests during fluconazole treatment should be closely monitored for progression to more severe liver injury.

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole should be discontinued immediately and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, have been associated with QT interval prolongation on electrocardiogram. Very rare cases of QT interval prolongation and paroxysmal ventricular tachycardia of the torsades de pointes type have been reported during fluconazole use. These reports involved patients with severe underlying diseases and multiple risk factors, such as structural heart disease, electrolyte imbalances, and concomitant use of other drugs affecting the QT interval.

Fluconazole should be used cautiously in patients at risk of arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 enzyme of the cytochrome P450 system is contraindicated.

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when used at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended.

Cutaneous reactions. Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole use. Patients with AIDS are more prone to developing severe skin reactions when taking various medicinal products. If a patient with superficial fungal infection develops a rash that may be related to fluconazole use, further treatment with the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole should be discontinued in case of bullous eruptions or erythema multiforme. Drug reactions with eosinophilia and systemic symptoms (DRESS syndrome) have also been reported.

Resistance. Available data on fluconazole resistance are provided.

Hypersensitivity. Rare cases of anaphylactic reactions have been reported.

Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of CYP3A4. Fluconazole also inhibits CYP2C19. Patients receiving concomitant fluconazole and drugs with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, or CYP3A4 should be closely monitored.

Terfenadine. Careful monitoring is required when terfenadine is used concomitantly with fluconazole at doses below 400 mg per day.

Excipients. The medicinal product contains lactose. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

Before initiating treatment, patients should be informed about the potential risk to the fetus.

After a single dose, a washout period of approximately 1 week (corresponding to 5–6 elimination half-lives) should be observed before attempting conception (see section "Pharmacokinetics").

For longer treatment courses, women of childbearing potential should consider using contraception throughout the treatment period and for 1 week after the last dose.

Pregnancy.

Observational studies indicate an increased risk of spontaneous abortion in women who received fluconazole during the first and/or second trimester of pregnancy compared to women who did not take fluconazole or received topical azoles during the same period.

Data from several thousand women who received a cumulative dose of ≤150 mg of fluconazole during the first trimester of pregnancy do not indicate an increased overall risk of fetal malformations. In one large observational cohort study, oral fluconazole use during the first trimester was associated with a small increased risk of musculoskeletal abnormalities, corresponding to approximately 1 additional case per 1000 women receiving a cumulative therapeutic dose ≤450 mg compared to women receiving topical azoles, and approximately 4 additional cases per 1000 women receiving cumulative doses above 450 mg. The relative risk was 1.29 (95% CI 1.05–1.58) for a 150 mg dose of oral fluconazole and 1.98 (95% CI 1.23–3.17) for doses above 450 mg.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy have yielded conflicting results. However, a meta-analysis of five observational studies involving several thousand pregnant women who received fluconazole during the first trimester showed a 1.8- to 2-fold increased risk of cardiac malformations compared to no fluconazole use or use of topical azoles.

Case reports describe congenital malformations in infants whose mothers received high doses (400–800 mg/day) of fluconazole during pregnancy for more than three months for the treatment of coccidioidomycosis. The observed congenital abnormalities included brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

Standard doses and short-term fluconazole treatment should not be used during pregnancy unless absolutely necessary.

High-dose and/or long-term fluconazole treatment should not be used during pregnancy except for life-threatening infections.

Breastfeeding.

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma. Breastfeeding may be continued after a single standard dose of fluconazole (200 mg or less).

Breastfeeding is not recommended during repeated or high-dose fluconazole treatment. The benefit of breastfeeding for the child's development and health, the mother's clinical need for the drug, and any potential adverse effects of the drug or the mother's underlying condition on the breastfed infant should be carefully evaluated.

Fertility.

Fluconazole had no effect on fertility in male and female rats.

Effect on ability to drive and use machines.

No studies have been conducted on the effect of the medicinal product on the ability to drive or operate machinery.

Patients should be informed about the possibility of developing dizziness or seizures during treatment. If such symptoms occur, patients should refrain from driving or operating machinery.

Dosage and Administration

Capsules should be swallowed whole. The administration of the drug is not affected by food intake.

Adults.

The drug should be administered orally as a single 150 mg dose.

Elderly patients.

In the absence of signs of impaired renal function, the usual adult dose should be used for treatment of this patient group.

Renal impairment.

Fluconazole is mainly excreted unchanged in the urine. Dose adjustment is not required in this patient group when the drug is administered as a single dose.

Hepatic impairment.

Fluconazole should be used with caution in patients with hepatic dysfunction, as information regarding the use of fluconazole in this patient group is limited.

Children.

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established, despite adequate data on the use of the drug in pediatric patients. If there is an urgent need to administer the drug to adolescents (aged 12 to 17 years), the usual adult doses should be used.

Overdose.

Cases of fluconazole overdose have been reported, with concomitant hallucinations and paranoid behavior.

In case of overdose, symptomatic and supportive therapy should be administered, and gastric lavage should be performed if necessary.

Fluconazole is substantially excreted in the urine; forced diuresis may accelerate drug elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Adverse Reactions

The most commonly reported adverse reactions (> 1/10) are: headache, abdominal pain, diarrhea, nausea, vomiting, rash, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase in blood.

A drug reaction with eosinophilia and systemic symptoms (DRESS) associated with fluconazole treatment has been reported.

The following classification is used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: anemia.

Rare: agranulocytosis, leukopenia, neutropenia, thrombocytopenia.

Immune system disorders

Rare: anaphylaxis.

Metabolism and nutrition disorders

Uncommon: decreased appetite.

Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia.

Psychiatric disorders

Uncommon: insomnia, somnolence.

Nervous system disorders

Common: headache.

Uncommon: seizures, dizziness, paraesthesia, taste disturbance.

Rare: tremor.

Ear and labyrinth disorders

Uncommon: vertigo.

Cardiac disorders

Rare: paroxysmal ventricular tachycardia of the torsades de pointes type, QT interval prolongation.

Gastrointestinal disorders

Common: abdominal pain, diarrhea, nausea, vomiting.

Uncommon: constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders

Common: increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase.

Uncommon: cholestasis, jaundice, increased bilirubin levels.

Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury.

Skin and subcutaneous tissue disorders

Common: rash.

Uncommon: pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating.

Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia.

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders

Uncommon: myalgia.

General disorders and administration site conditions

Uncommon: increased fatigue, malaise, asthenia, fever.

Children

The frequency and nature of adverse reactions and laboratory abnormalities observed in clinical trials involving children are comparable to those in adults.

Shelf life. 3 years.

Storage conditions. Store in a dry place, out of reach of children, at a temperature not exceeding 25 °C.

Packaging. 1 capsule in a blister; 1 blister per cardboard box.

Prescription status. Over-the-counter (without prescription).

Manufacturer. Sun Pharmaceutical Industries Limited.

Manufacturer's address. Industrial Area 3, Dewas - 455001, India.