Fluzamed

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

Composition:

Active substance: fluconazole;

1 capsule contains 150 mg of fluconazole;

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

Capsule shell composition: azorubine (E 122), quinoline yellow (E 104), titanium dioxide (E 171), patent blue V (E 131), diamond black BN (E 151), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: hard gelatin capsules size №1, green cap, body white with yellowish tint, containing 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 is an antifungal agent of the triazole class. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation, mediated by cytochrome P450, 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 of mammals.

Administration of fluconazole at a dose of 50 mg once 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 have a clinically significant effect on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

Studies on interaction with antipyrine 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 reduced susceptibility to fluconazole, whereas C. krusei and C. auris are resistant.

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

Relationship between pharmacokinetic and pharmacodynamic properties.

According to animal studies, there is a correlation between the minimum inhibitory concentration (MIC) and efficacy against experimental models of mycoses caused by Candida species. Clinical studies have shown a linear relationship between the area under the pharmacokinetic concentration–time curve (AUC) and fluconazole dose (approximately 1:1). There is also a direct, but suboptimal, relationship between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, treatment of infections caused by strains exhibiting high minimum inhibitory concentrations to fluconazole is less effective.

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 impacts its in vivo efficacy and clinical effectiveness. Cases of superinfection with Candida spp. other than C. albicans have been reported, often involving strains with reduced susceptibility (e.g., C. glabrata) or resistance (e.g., C. krusei, C. auris) to fluconazole. Alternative antifungal agents should be used for the treatment of such cases.

Breakpoints (according to the recommendations of the European Committee on Antimicrobial Susceptibility Testing).

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species. These have been categorized into non-species-specific breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic data and not dependent on species-specific minimum inhibitory concentration distributions, and species-specific breakpoints, associated most commonly with human infections. These breakpoints are listed below.

Antifungal agent	Species-specific breakpoints S ≤ / R >					Non-species-specific breakpointsa S ≤ / R >
	Candida albicans	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	IE	--	2/4	2/4	2/4

S = sensitive;

R = resistant;

a – breakpoints not linked to a specific species, which were primarily determined based on pharmacokinetic/pharmacodynamic information and do not depend on species-specific minimal inhibitory concentration distributions. These were studied only in microorganisms lacking a specific breakpoint;

-- susceptibility testing is not recommended, as this organism is not a target for antimicrobial therapy;

IE – insufficient evidence to determine whether this organism is a target for antimicrobial therapy.

Pharmacokinetics.

The pharmacokinetic properties of fluconazole are similar following intravenous and oral administration.

Absorption.

Fluconazole is well absorbed after oral administration, and plasma fluconazole levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect the absorption of fluconazole when administered orally. Maximum plasma concentration (Cmax) is reached within 0.5–1.5 hours after oral administration of fluconazole on an empty stomach. Plasma fluconazole concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of fluconazole treatment with once-daily dosing. Steady-state 90% concentration is reached by day 2 of treatment when a loading dose twice the standard 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 investigated body fluids. Fluconazole levels in saliva and sputum are similar to plasma concentrations. In patients with fungal meningitis, fluconazole concentrations in cerebrospinal fluid reach 80% of plasma levels.

High fluconazole concentrations in skin, exceeding plasma levels, are achieved in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. After a daily dose of 50 mg, fluconazole concentration after 12 days of treatment was 73 µg/g, and 7 days after treatment completion, the concentration was still 5.8 µg/g. After a weekly dose of 150 mg, the fluconazole concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, the concentration remained at 7.1 µg/g.

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

Metabolism.

Fluconazole is minimally metabolized. After administration of radiolabeled dose, only 11% of fluconazole is excreted in urine as metabolites. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes and a potent inhibitor of the CYP2C19 isoenzyme.

Excretion.

The plasma elimination half-life (t1/2) is approximately 30 hours. The majority of fluconazole 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 t1/2 allows for single-dose administration of fluconazole in vaginal candidiasis and weekly dosing for other indications.

Use in patients with renal impairment.

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), t1/2 increases from 30 to 98 hours. Therefore, dose reduction of fluconazole is required in this patient population. 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%.

Use during breastfeeding.

Plasma and breast milk fluconazole concentrations were evaluated over 48 hours after a single 150 mg dose in a pharmacokinetic study involving 10 lactating women who temporarily or permanently discontinued breastfeeding. Fluconazole was detected in breast milk at an average concentration of approximately 98% of that in maternal plasma. The mean Cmax in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily fluconazole dose received by the infant via breast milk (assuming average milk intake of 150 mL/kg/day), calculated based on mean Cmax in milk of 0.39 mg/kg/day, corresponds to approximately 40% of the dose recommended for neonates (age < 2 weeks) or 13% of the dose recommended for infants for treatment of mucosal candidiasis.

Use in children.

Pharmacokinetic data were evaluated in 113 children across 5 studies: 2 single-dose studies, 2 multiple-dose studies, and 1 study in premature neonates.

After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, AUC was approximately 38 µg*h/mL per 1 mg/kg dose. After multiple dosing, the mean plasma t1/2 of fluconazole ranged between 15 and 18 hours; the volume of distribution was 880 mL/kg. A longer t1/2 of approximately 24 hours was observed after single-dose administration. This is comparable to the t1/2 of fluconazole after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours); mean birth weight was 900 g (range 750–1100 g). The study protocol was completed in 7 patients. Up to 5 intravenous injections of fluconazole at 6 mg/kg were administered every 72 hours. Mean t1/2 was 74 hours (44–185) on day 1, decreased to 53 hours (30–131) on day 7, and to 47 hours (27–68) on day 13. AUC (µg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. Volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7, and to 1328 (1040–1680) on day 13.

Use in elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged 65 years and older) who received 50 mg oral fluconazole. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after fluconazole administration. Mean AUC was 76.4±20.3 µg*h/mL. Mean t1/2 was 46.2 hours. These pharmacokinetic parameters are higher than those in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Creatinine clearance (74 mL/min), percentage of unchanged fluconazole excreted in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in this age group were also lower than in younger volunteers. Therefore, the observed changes in pharmacokinetics in elderly patients are clearly dependent on renal function parameters.

Clinical characteristics.

Indications.

• Acute vaginal candidiasis when topical therapy is not appropriate.
• Candidal balanitis when topical therapy is not appropriate.

Antifungal treatment may be initiated before obtaining results of culture and other laboratory tests; however, antifungal therapy should be adjusted accordingly once test results become available.

Official recommendations regarding appropriate use of antifungal agents should be taken into account.

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any excipients of the medicinal product.
• Concomitant administration of fluconazole and terfenadine to patients receiving repeated doses of fluconazole at 400 mg/day or higher (based on multiple-dose interaction study results).
• Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized via the CYP3A4 enzyme, such as cisapride, astemizole, pimozide, quinidine, and erythromycin (see sections "Interaction with other medicinal products and other types of interactions" and "Special warnings and precautions for use").

Interaction with other medicinal products and other types of interactions.

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

Cisapride.

Cardiac adverse reactions, including torsades de pointes-type paroxysmal ventricular tachycardia, have been reported in patients receiving fluconazole and cisapride concomitantly. A controlled study demonstrated that co-administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily significantly increased plasma levels of cisapride and prolonged the QT interval. Concomitant use of these agents is contraindicated (see section "Contraindications").

Terfenadine.

Due to cases of severe cardiac arrhythmias associated with QTc interval prolongation in patients receiving azole antifungal agents together with terfenadine, interaction studies were conducted. One study using fluconazole 200 mg daily showed no QTc prolongation. Another study using fluconazole at doses of 400 mg and 800 mg daily demonstrated that co-administration of fluconazole at doses ≥400 mg/day significantly increased plasma levels of terfenadine. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When fluconazole is used at doses below 400 mg/day together with terfenadine, careful patient monitoring is required.

Astemizole.

Concomitant administration with fluconazole may reduce astemizole clearance. This increase in plasma astemizole concentration may lead to QT interval prolongation and, rarely, to torsades de pointes-type paroxysmal ventricular tachycardia. Concomitant use of these agents is contraindicated (see section "Contraindications").

Pimozide and quinidine.

Concomitant use with fluconazole may inhibit the metabolism of pimozide or quinidine, although specific in vitro and in vivo studies have not been conducted. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, rarely, lead to torsades de pointes-type paroxysmal ventricular tachycardia. Concomitant use of these agents is contraindicated (see section "Contraindications").

Erythromycin.

Concomitant use of erythromycin and fluconazole may increase the risk of cardiotoxicity (QT interval prolongation, torsades de pointes-type paroxysmal ventricular tachycardia) and, consequently, sudden cardiac death. Concomitant use of these agents is contraindicated (see section "Contraindications").

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

Halofantrine.

Concomitant use of fluconazole and halofantrine may increase halofantrine plasma concentrations due to CYP3A4 inhibition. This increase in halofantrine plasma concentration may increase the risk of cardiotoxicity (QT interval prolongation, torsades de pointes-type paroxysmal ventricular tachycardia) and, consequently, sudden cardiac death. Concomitant use of these agents should be avoided (see section "Special warnings and precautions for use").

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

Amiodarone.

Concomitant use of fluconazole and amiodarone may lead to QT interval prolongation. Concomitant use of these agents requires caution, especially when high-dose fluconazole (800 mg) is administered.

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

Effect of other medicinal products on fluconazole.

Interaction studies have shown that oral administration of fluconazole together with food, concomitant administration of cimetidine, antacids, or whole-body irradiation prior to bone marrow transplantation does not have a clinically significant effect on fluconazole absorption.

Rifampicin.

Concomitant use with rifampicin resulted in a 25% decrease in AUC and a 20% reduction in t1/2 of fluconazole. When these agents are used concomitantly, consideration should be given to increasing the fluconazole dose.

Hydrochlorothiazide.

In a pharmacokinetic interaction study, repeated concomitant administration of hydrochlorothiazide to healthy volunteers increased fluconazole plasma concentration by 40%. These interaction parameters do not require changes in fluconazole dosing regimen for patients receiving diuretics.

Effect of fluconazole on other medicinal products.

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is a potent inhibitor of CYP2C19 isoenzyme. In addition to observed/documentarily confirmed interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 when used concomitantly with fluconazole. Therefore, such agents should be used concomitantly with fluconazole with caution, and patients should be closely monitored. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after administration due to its long t1/2 (see section "Contraindications").

Alfentanil.

Concomitant administration of alfentanil (20 mcg/kg) to healthy volunteers resulted in a doubling of AUC10 of fluconazole (400 mg), possibly due to CYP3A4 inhibition. Dose adjustment of alfentanil may be necessary when these agents are used concomitantly.

Abrocitinib.

Concomitant use with fluconazole (an inhibitor of CYP2C19, 2C9, and 3A4) increases exposure to the active moiety of abrocitinib by 155%. When these agents are used concomitantly, the dose of abrocitinib should be reduced according to its medical instructions.

Amitriptyline, nortriptyline.

Concomitant use with fluconazole enhanced the effects of amitriptyline or nortriptyline. When these agents are used concomitantly, measurement of 5-nortriptyline and/or S-amitriptyline concentrations is recommended at the beginning of combination therapy and after 1 week. Dose adjustment of amitriptyline/nortriptyline may be necessary.

Amphotericin B.

Concomitant administration of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice showed the following results: slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism in systemic Aspergillus fumigatus infection. The clinical significance of these findings 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 when fluconazole was used concomitantly with warfarin. A twofold increase in prothrombin time was observed with concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be carefully monitored when fluconazole is used concomitantly with coumarin anticoagulants or indanediones. Dose adjustment of anticoagulants may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam.

Concomitant use with fluconazole significantly increased plasma concentrations of oral midazolam and enhanced psychomotor effects. Concomitant administration of 200 mg fluconazole and 7.5 mg oral midazolam increased AUC and t1/2 of midazolam by 3.7 and 2.2 times, respectively. Concomitant administration of 200 mg fluconazole daily and 0.25 mg oral triazolam increased AUC and t1/2 of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed with concomitant use of fluconazole and triazolam. When fluconazole is used concomitantly with benzodiazepines, benzodiazepine dose should be reduced and appropriate patient monitoring established.

Carbamazepine.

Concomitant use with fluconazole inhibits carbamazepine metabolism and increases plasma carbamazepine levels by 30%. There is a risk of carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary when these agents are used concomitantly, depending on its plasma concentration and effects.

Calcium channel blockers.

Some calcium antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole may potentially increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended when these agents are used concomitantly.

Celecoxib.

Concomitant use with fluconazole (200 mg daily) increased Cmax and AUC of celecoxib (200 mg) by 68% and 134%, respectively. Dose reduction of celecoxib by half may be necessary when these agents are used concomitantly.

Cyclophosphamide.

Concomitant use of cyclophosphamide and fluconazole leads to increased plasma levels of bilirubin and creatinine. These agents can be used concomitantly, considering the risk of increased plasma concentrations of bilirubin and creatinine.

Fentanyl.

One fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. Additionally, a study in healthy volunteers demonstrated that concomitant use with fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression. Close monitoring of the patient is required when these agents are used concomitantly. 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. When concomitant use of these agents is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels in plasma should be monitored. If significant increases in creatine kinase levels occur, or myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued.

Ivacaftor.

Concomitant use with fluconazole increases exposure to ivacaftor (a cystic fibrosis transmembrane conductance regulator potentiator) by 3 times and hydroxymethylivacaftor (M1) by 1.9 times. When moderate CYP3A inhibitors such as fluconazole and erythromycin are used concomitantly with ivacaftor, dose reduction to 150 mg once daily is recommended.

Ibrutinib.

Concomitant use with moderate CYP3A4 inhibitors such as fluconazole increases plasma concentrations of ibrutinib and may increase the risk of toxicity. If such combination cannot be avoided, the dose of ibrutinib should be reduced to 280 mg once daily to continue therapy, and continuous clinical monitoring should be ensured.

Olaparib.

Concomitant use with moderate CYP3A4 inhibitors such as fluconazole increases plasma concentrations of olaparib. Concomitant use of these agents is not recommended. If such combination cannot be avoided, olaparib intake should be limited to 200 mg twice daily.

Immunosuppressants (e.g., cyclosporine, everolimus, sirolimus, and tacrolimus).

Cyclosporine.

Concomitant use with fluconazole significantly increases cyclosporine concentration and AUC. When fluconazole 200 mg daily and cyclosporine 2.7 mg/kg/day were used concomitantly, cyclosporine AUC increased by 1.8 times. These agents can be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus.

Although in vitro and in vivo studies have not been conducted, it is known that fluconazole may increase plasma concentrations of everolimus by inhibiting CYP3A4.

Sirolimus.

Concomitant use with fluconazole increases sirolimus plasma concentration, likely by inhibiting sirolimus metabolism via CYP3A4 and P-glycoprotein. These agents can be used concomitantly provided sirolimus dose is adjusted based on concentration and effects.

Tacrolimus.

Concomitant use with fluconazole may increase plasma concentrations of tacrolimus up to 5 times with oral administration due to inhibition of tacrolimus metabolism by CYP3A4 in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. When these agents are used concomitantly, the oral dose of tacrolimus should be reduced based on its concentration.

Losartan.

Concomitant use with fluconazole inhibits losartan metabolism to its active metabolite (E-3174), which accounts for most of the angiotensin II receptor antagonism during losartan use. Continuous monitoring of blood pressure is recommended when these agents are used concomitantly.

Lurasidone.

Concomitant use with fluconazole (a moderate CYP3A4 inhibitor) may increase lurasidone plasma concentration. If such combination cannot be avoided, lurasidone dose should be reduced according to its medical instructions.

Methadone.

Concomitant use with fluconazole may increase methadone plasma concentration. Dose adjustment of methadone may be necessary when these agents are used concomitantly.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

Concomitant use with fluconazole increased Cmax and AUC of flurbiprofen by 23% and 81%, respectively, compared to flurbiprofen alone. Similarly, concomitant use of fluconazole with racemic ibuprofen (400 mg) increased Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer by 15% and 82%, respectively, compared to racemic ibuprofen alone. Although specific studies have not been conducted, fluconazole may increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for NSAID-related adverse reactions is recommended when these agents are used concomitantly. Dose adjustment of NSAIDs may be needed.

Phenytoin.

Fluconazole inhibits hepatic metabolism of phenytoin. Repeated concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin increases AUC24 of phenytoin by 75% and Cmin by 128%. Plasma phenytoin concentration should be monitored when these agents are used concomitantly to avoid toxic effects.

Prednisone.

A case has been reported of acute adrenal insufficiency developing in a liver transplant patient receiving prednisone after discontinuation of a 3-month course of fluconazole therapy. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Careful monitoring of patients is recommended when these agents are used concomitantly long-term to prevent adrenal insufficiency after stopping fluconazole.

Rifabutin.

Concomitant use with fluconazole increases rifabutin plasma concentration, leading to up to an 80% increase in AUC of rifabutin. Cases of uveitis have been reported with concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when these agents are used concomitantly.

Saquinavir.

Concomitant use with fluconazole increases AUC and Cmax of saquinavir by approximately 50% and 55%, respectively, due to inhibition of saquinavir metabolism in the liver by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied, so they may be more pronounced. Dose adjustment of saquinavir may be necessary when these agents are used concomitantly.

Sulfonylurea derivatives.

Concomitant use with fluconazole prolongs t1/2 of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) in healthy volunteers. Frequent blood glucose monitoring and appropriate dose reduction of sulfonylurea derivatives are recommended when these agents are used concomitantly.

Theophylline.

In a placebo-controlled interaction study, administration of fluconazole 200 mg for 14 days reduced the average plasma clearance of theophylline by 18%. When these agents are used concomitantly, 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 if signs of toxicity appear.

Tofacitinib.

Exposure to tofacitinib increases when used concomitantly with medicinal products causing moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). When used concomitantly with such agents, dose reduction of tofacitinib to 5 mg once daily is recommended.

Tolvaptan.

Concomitant use with fluconazole (a moderate CYP3A4 inhibitor) significantly increases exposure to tolvaptan (a CYP3A4 substrate) (200% AUC; 80% Cmax), thereby increasing the risk of adverse reactions such as enhanced diuresis, dehydration, and acute kidney injury. When these agents are used concomitantly, the dose of tolvaptan should be reduced according to its medical instructions, and patients should be monitored for adverse reactions.

Vinca alkaloids.

Although specific studies have not been conducted, fluconazole, likely via CYP3A4 inhibition, may increase plasma concentrations of vinca alkaloids (e.g., vincristine, vinblastine), leading to neurotoxic effects.

Vitamin A.

A case has been reported of central nervous system (CNS) adverse reactions (pseudotumor cerebri) in a patient receiving all-trans retinoic acid (the acid form of vitamin A) concomitantly with fluconazole; this effect resolved after discontinuation of fluconazole. These agents can be used concomitantly, but the risk of CNS adverse reactions should be kept in mind.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4).

Oral concomitant 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 8 healthy male volunteers resulted in mean increases in Cmax and AUCτ of voriconazole 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 voriconazole-associated adverse reactions is recommended.

Zidovudine.

Concomitant use with fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to approximately 45% reduction in zidovudine clearance after oral administration. t1/2 of zidovudine was also prolonged by approximately 128% after co-administration of fluconazole and zidovudine. Monitoring for zidovudine-related adverse reactions is recommended when these agents are used concomitantly. Dose reduction of zidovudine may be considered.

Azithromycin.

No significant pharmacokinetic interactions were observed after single oral co-administration of azithromycin 1200 mg and fluconazole 800 mg.

Oral contraceptives.

No effect on hormone levels was observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg daily increased AUC of ethinylestradiol by 40% and levonorgestrel by 24%. This suggests that repeated administration of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use

Use in infections caused by Candida species

Studies have shown an increased prevalence of infections caused by Candida species other than C. albicans. These species are often resistant (e.g., C. krusei, C. auris) or have reduced susceptibility to fluconazole (C. glabrata). Alternative antifungal agents should be used for the treatment of such infections. When prescribing fluconazole, the prevalence of resistance among different Candida species to fluconazole should be taken into account.

Use in dermatophytosis

According to clinical studies evaluating fluconazole for the treatment of dermatophytosis in children, fluconazole is not superior to griseofulvin in efficacy, with an overall efficacy rate of less than 20%. Therefore, the drug should not be used for the treatment of dermatophytosis.

Use in 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 provided for treatment of these conditions.

Use in 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 provided for treatment of these conditions.

Renal effects

The drug should be used with caution in patients with impaired renal function (see section "Dosage and administration").

Adrenal insufficiency risk

Ketoconazole is known to cause adrenal insufficiency, and this may also occur with fluconazole, although rarely. Cases of adrenal insufficiency associated with concomitant prednisone therapy are described in the section "Interaction with other medicinal products and other forms of interaction".

Hepatic effects

The drug should be used with caution in patients with impaired liver function. Fluconazole has been associated with rare cases of severe hepatotoxicity, including fatal outcomes, primarily in patients with serious underlying diseases. In cases where hepatotoxicity was linked to fluconazole use, there was no clear correlation with total daily dose, duration of therapy, sex, or age of the patient. Hepatotoxicity caused by fluconazole is usually reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormal liver function test results during fluconazole treatment should be closely monitored for the development of 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, the drug should be discontinued immediately and medical advice sought.

Cardiovascular effects

Some azoles, including fluconazole, have been associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifier potassium channel (Ikr). QT interval prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated due to inhibition of the CYP3A4 enzyme of cytochrome P450. Very rare cases of QT interval prolongation and torsades de pointes ventricular tachycardia have been reported with fluconazole use. These reports involved patients with severe underlying conditions and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other QT-prolonging drugs.

Patients with hypokalemia and advanced heart failure are at increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

The drug should be used with caution in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 enzyme of cytochrome P450 is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Interaction with halofantrine

Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when administered at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Skin reaction risk

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

Hypersensitivity risk

Anaphylactic reactions have been reported rarely during fluconazole use (see section "Contraindications").

Interaction with cytochrome P450 enzymes

Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 enzymes. It is also a potent inhibitor of the CYP2C19 enzyme. Patients receiving fluconazole concomitantly with drugs having a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with terfenadine

Careful monitoring is required when terfenadine and fluconazole are used concomitantly at fluconazole doses below 400 mg daily (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Special warnings regarding excipients

The medicinal product contains lactose. It should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

The medicinal product also contains carmoisine (E 122) and brilliant black BN (E 151), which may cause allergic reactions.

The product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Women of childbearing potential

Before initiating treatment, the patient 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 pregnancy (see section "Pharmacokinetics").

For prolonged 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 compared to women who did not take fluconazole or received topical azoles during the same period.

Data from several hundred pregnant women who received a cumulative dose of fluconazole ≤ 150 mg during the first trimester do not indicate an increased risk of fetal malformations. An observational cohort study showed a slight increase in musculoskeletal malformations (approximately 1 additional case per 1000 women) with fluconazole cumulative doses ≤ 450 mg during the first trimester compared to women receiving topical azoles, and approximately 4 additional cases per 1000 women with cumulative doses > 450 mg. The adjusted relative risk was 1.29 (95% CI 1.05–1.58) for a 150 mg oral dose of fluconazole and 1.98 (95% CI 1.23–3.17) for doses exceeding 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 congenital heart defects in infants compared to infants of mothers who did not receive fluconazole and/or used topical azoles.

Congenital malformations have been reported in infants whose mothers received high doses (400–800 mg/day) of fluconazole for 3 months or more during pregnancy for treatment of coccidioidomycosis. Malformations observed in these infants include brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

The drug should not be used during pregnancy at usual doses or for short-term treatment unless absolutely necessary. The drug should also not be used at high doses and/or for prolonged treatment courses unless for life-threatening infections.

Lactation

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma (see section "Pharmacokinetics"). Breastfeeding may continue after a single standard dose of 150 mg. Breastfeeding is not recommended with repeated administration of the drug or with high-dose regimens. The benefit of breastfeeding for the infant's development and health, the mother's clinical need for the drug, and any potential adverse effects of fluconazole or the mother's underlying condition on the breastfed infant should be carefully considered.

Fertility

Fluconazole did not affect fertility in male and female rats.

Ability to drive and use machines

Studies on the effect of fluconazole on the ability to drive or operate machinery have not been conducted.

Patients should be informed about the possibility of dizziness or seizures (see section "Adverse reactions") during treatment. If such symptoms occur, driving or operating machinery is not recommended.

Dosage and Administration

The medicinal product is intended for oral use. Capsules should be swallowed whole. Administration of the medicinal product is independent of food intake.

Adults.

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

Elderly patients.

In the absence of signs of renal impairment, this patient category should receive the standard adult dose.

Renal impairment.

Fluconazole is primarily excreted unchanged in urine. Dose adjustment is not required in this patient category following single-dose administration.

Hepatic impairment.

The medicinal product should be used with caution in patients with hepatic impairment due to insufficient data on fluconazole use in this patient population (see sections "Special precautions" and "Adverse reactions").

Children.

The efficacy and safety of fluconazole for the treatment of genital candidiasis in children have not been established. Available information is presented in the section "Adverse reactions." If there is an urgent need to administer the medicinal product to adolescents (aged 12 to 17 years), standard adult doses should be used.

Overdose.

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

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

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

Side effects

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

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

Blood and lymphatic system disorders:

Uncommon – anemia; rare – agranulocytosis, leukopenia, thrombocytopenia, neutropenia.

Immune system disorders:

Rare – anaphylaxis.

Metabolism and nutrition disorders:

Uncommon – decreased appetite; rare – hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Psychiatric disorders:

Uncommon – insomnia, somnolence.

Nervous system disorders:

Common – headache; uncommon – convulsions, paraesthesia, dizziness, taste disturbance; rare – tremor.

Ear and labyrinth disorders:

Uncommon – vertigo.

Cardiac disorders:

Rare – paroxysmal torsades de pointes ventricular tachycardia, QT interval prolongation (see section "Special precautions").

Gastrointestinal disorders:

Common – abdominal pain, nausea, diarrhea, vomiting; uncommon – constipation, dyspepsia, flatulence, dry mouth.

Hepatobiliary disorders:

Common – increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased alkaline phosphatase levels (see section "Special precautions"); uncommon – cholestasis, jaundice, increased bilirubin levels (see section "Special precautions"); rare – hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special precautions").

Skin and subcutaneous tissue disorders:

Common – rash (see section "Special precautions"); uncommon – drug eruption (including fixed drug eruption), urticaria, pruritus, increased sweating (see section "Special precautions"); rare – toxic epidermal necrolysis, Stevens–Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia (see section "Special precautions"); 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 – fatigue, malaise, asthenia, pyrexia.

Children

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

Cases of drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) associated with fluconazole treatment have been reported (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life

4 years.

Storage conditions

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging

1 hard capsule in a blister; 1 or 2 blisters in a cardboard box.

Prescription status

Capsules No. 1 – over-the-counter. Capsules No. 2 – prescription only.

Manufacturer

K.O. Rompharm Company S.R.L. /
S.C. Rompharm Company S.R.L.

Manufacturer's address and location of operations

Otopeni city, Eroilor str. № 1A, 075100, jud. Ilfov, Romania.

Marketing Authorization Holder

LLC "WORLD MEDICINE", Ukraine /
WORLD MEDICINE, LLC, Ukraine.