Instructions Fluconazole-Health capsules 150 mg blister No. 3
Composition
active ingredient: fluconazole;
1 capsule contains 150 mg of fluconazole;
excipients: lactose, monohydrate; potato starch; povidone; calcium stearate; capsule shell contains black ink (in case of applying the company's trademark - ZT; contains shellac Glaze 45% solution in ethanol, black iron oxide (E 172), propylene glycol, concentrated ammonia solution) (all dosages), titanium dioxide (E 171), diamond blue (E 133), quinoline yellow (E 104), sunset yellow FCF (E 110), titanium dioxide (E 171), gelatin (dosage 150 mg).
Dosage form
The capsules are hard.
Main physical and chemical properties: hard gelatin capsules with opaque green body and cap (dosage 150 mg). The company's trademark - ZT - may be applied to the capsule. The contents of the capsules are white powder with a yellowish tinge. The presence of agglomerates of powder particles is allowed.
Pharmacotherapeutic group
Antifungal agents for systemic use. Triazole derivatives. ATX code J02A C01.
Pharmacological properties
Pharmacodynamics
Mechanism of action. Fluconazole is a triazole antifungal agent. Its primary mechanism of action is inhibition of fungal cytochrome P450 (CYP)-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 adrenocorticotropic hormone (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 susceptibility: Fluconazole has demonstrated antifungal activity in vitro against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata exhibits a broad 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.
Pharmacokinetic and pharmacodynamic relationship. Animal studies have shown a correlation between the minimum inhibitory concentration and efficacy against experimental models of fungal infections caused by Candida species. Clinical studies have shown a linear relationship between AUC and dose of fluconazole (approximately 1:1). There is also a direct but weak relationship between AUC or dose and a positive clinical response to the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, the treatment of infections caused by strains for which fluconazole exhibits a high minimum inhibitory concentration is less satisfactory.
Mechanism of resistance. Candida species have multiple mechanisms of resistance to azole antifungal agents. Fluconazole exhibits high minimum inhibitory concentrations against fungal strains that have one or more mechanisms of resistance, which negatively affects efficacy in vivo and in clinical practice. Superinfection with Candida spp. other than C. albicans, species that are often insensitive to fluconazole (e.g. C. krusei), has been reported. Alternative antifungal agents should be used in such cases.
Breakpoints (according to the recommendations of the European Committee for Antimicrobial Susceptibility Testing).
Based on a review of pharmacokinetic/pharmacodynamic information, in vitro susceptibility and clinical response, breakpoints for fluconazole have been established for Candida species. These have been divided into non-species-specific breakpoints, which are largely based on pharmacokinetic/pharmacodynamic information and are not dependent on species-specific MICs, and species-specific breakpoints, which are most commonly associated with human infections. These breakpoints are listed below.
Antifungal agent
Control points associated with a certain type S ≤/R >
Control points not associated with a specific speciesa 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 – non-species-specific breakpoints, which were determined largely on the basis of pharmacokinetic/pharmacodynamic information and do not depend on the distribution into specific species by minimum inhibitory concentration. They were studied only in microorganisms for which there is no specific breakpoint;
IE – there is insufficient evidence to support this species as a target for drug therapy.
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 on an empty stomach. Steady-state concentrations of 90% are reached by day 4–5 of multiple once-daily dosing. Plasma concentrations are dose-proportional. Steady-state concentrations of 90% are reached by day 2 of treatment with a loading dose of twice the usual daily dose given 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 those in serum, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum.
Biotransformation. Fluconazole is metabolized to a small extent. When a dose labeled with radioactive isotopes is administered, only 11% of fluconazole is excreted in the urine in an unchanged form. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes, as well as a potent inhibitor of CYP2C19 isoenzyme.
Excretion. T½ of fluconazole from blood plasma is about 30 hours. Most of the drug is excreted by the kidneys, with 80% of the administered dose being found in the urine unchanged. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.
The long T½ of the drug from blood plasma allows for a single use of the drug for vaginal candidiasis, as well as the use of the drug once a week for other indications.
Renal insufficiency. In patients with severe renal insufficiency (glomerular filtration rate < 20 ml/min), T½ 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, to a lesser extent by intraperitoneal dialysis. A 3-hour hemodialysis session reduces the level of fluconazole in the blood plasma by approximately 50%.
Lactation: Fluconazole passes into breast milk.
Children. After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, the AUC was approximately 38 μg*h/mL per 1 mg/kg dose. After multiple administration, the mean plasma half-life of fluconazole ranged between 15 and 18 hours; the volume of distribution was 880 mL/kg. A longer plasma half-life of approximately 24 hours was observed after a single dose of fluconazole.
Elderly patients: Changes in pharmacokinetics in elderly patients depend on renal function parameters.
Indication
Treatment of the following fungal infections in adults (see section "Pharmacodynamics"):
cryptococcal meningitis (see section "Special instructions for use");
coccidioidomycosis (see section "Special instructions for use");
Invasive candidiasis; Mucosal candidiasis, including oropharyngeal and esophageal candidiasis; Candiduria, chronic candidiasis of the skin and mucous membranes; Chronic atrophic candidiasis (candidiasis caused by the use of dentures) when oral hygiene or topical therapy is ineffective; Vaginal candidiasis, acute or recurrent, when topical therapy is inappropriate; Candidal balanitis, when topical therapy is inappropriate; Dermatomycoses, including athlete's foot, smooth skin mycosis, inguinal dermatomycosis; Lichen multicolor and candidal skin infections, when systemic therapy is appropriate; Dermatophyte onychomycosis, when other drugs are inappropriate.
Prevention of the following diseases in adults:
Recurrence of cryptococcal meningitis in patients at high risk of developing it; Recurrence of oropharyngeal or esophageal candidiasis in HIV-infected 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) (see section "Pharmacological properties. Pharmacodynamics").
The drug 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.
Therapy with the drug can be initiated before the results of culture and other laboratory tests are available. Once the results are available, antibacterial therapy should be adjusted accordingly.
Contraindication
Hypersensitivity to any of the components of the drug/other azole compounds. Concomitant use of fluconazole and terfenadine in patients receiving fluconazole multiple times at doses of 400 mg/day and above. 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 and erythromycin).
Interaction with other medicinal products and other types of interactions
The concomitant use of fluconazole and the following drugs is contraindicated.
Cisapride: Cardiac adverse reactions, including torsades de pointes, have been reported in patients receiving fluconazole and cisapride concomitantly. Coadministration of fluconazole 200 mg once daily and cisapride 20 mg four times daily resulted in significant increases in plasma cisapride levels and QT prolongation. Concomitant use of fluconazole and cisapride 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. No prolongation of the QTc interval was observed with fluconazole at a dose of 200 mg/day. Fluconazole at doses of 400 mg/day or higher significantly increases plasma levels of terfenadine when these drugs are administered concomitantly. Concomitant use of fluconazole at doses of 400 mg/day or higher with terfenadine is contraindicated. 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 result in inhibition of the metabolism of pimozide or quinidine. Increased plasma concentrations of pimozide or quinidine may cause QT prolongation and, in rare cases, paroxysmal torsades de pointes. Concomitant use of fluconazole and pimozide or quinidine is contraindicated.
Erythromycin: Concomitant use of erythromycin and fluconazole increases the risk of cardiotoxicity (QT prolongation, torsades de pointes), which may result in sudden cardiac death. The combination of these drugs is contraindicated.
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 increases the risk of cardiotoxicity (QT prolongation, torsades de pointes), which may result in sudden cardiac death. The combination of these drugs should be avoided.
Concomitant use of fluconazole and the following drugs requires caution.
Amiodarone: Concomitant use of fluconazole with amiodarone may prolong the QT interval. Fluconazole should be used with caution with amiodarone, especially when high doses of fluconazole (800 mg) are prescribed.
Concomitant use of fluconazole and the following drugs requires caution and dose adjustment.
Effect of other medicinal products on fluconazole. Concomitant food intake, cimetidine, antacids, and radiation therapy to the whole body (in bone marrow transplantation) have no clinically significant effect on the absorption of fluconazole when administered orally.
Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% decrease in T½ of fluconazole. Therefore, an increase in the dose of fluconazole should be considered in patients receiving rifampicin.
Fluconazole effects on other medicinal products. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4. Fluconazole is also a potent inhibitor of the CYP2C19 isoenzyme. In addition to the interactions noted and 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 combinations of drugs should be used with caution; patients should be closely monitored. Due to the long T½ of fluconazole, its inhibitory effect on enzymes persists for 4–5 days.
Alfentanil: Concomitant administration of fluconazole 400 mg and alfentanil 20 mcg/kg resulted in a two-fold increase in AUC10 (possibly due to CYP3A4 inhibition). This necessitates a dose adjustment of alfentanil.
Amitriptyline, nortriptyline: Fluconazole potentiates the effects of amitriptyline and nortriptyline. It is recommended to measure the concentrations of 5-nortriptyline and/or S-amitriptyline at the beginning of combination therapy and 1 week after its start. If necessary, the dose of amitriptyline or nortriptyline should be adjusted.
Amphotericin B: Concomitant administration of fluconazole and amphotericin B to immunocompetent and immunocompromised infected 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 A. fumigatus infection. The clinical significance of these findings is unknown.
Anticoagulants: As with other azole antifungals, bleeding events (haematoma, epistaxis, gastrointestinal haemorrhage, haematuria and melena) have been reported with concomitant use of fluconazole and warfarin, in association with prolonged prothrombin time. 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 T½, 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 T½, respectively. Potentiation and prolongation of the effects of triazolam were observed when fluconazole and triazolam were co-administered.
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 metabolised by CYP3A4. Fluconazole may increase the systemic exposure of 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, but the risk of increased serum bilirubin and creatinine concentrations should be considered.
Fentanyl: One fatal case of fentanyl intoxication has been reported due to a possible interaction between fentanyl and fluconazole. Fluconazole significantly slows 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.
Olaparib: Moderate CYP3A4 inhibitors such as fluconazole increase olaparib plasma concentrations; concomitant use is not recommended. If this combination cannot be avoided, olaparib should be limited to 200 mg twice daily.
Immunosuppressants (e.g., cyclosporine, everolimus, sirolimus, and tacrolimus).
Cyclosporine: Fluconazole significantly increases the concentration and AUC of cyclosporine. When fluconazole was administered concomitantly at a dose of 200 mg/day and cyclosporine at a dose of 2.7 mg/kg/day, a 1.8-fold increase in the AUC of cyclosporine was observed. These drugs can be used concomitantly, provided that the dose of cyclosporine is reduced depending on its concentration.
Everolimus: Fluconazole may increase serum concentrations of everolimus due to inhibition of CYP3A4.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus, possibly by inhibiting sirolimus metabolism by CYP3A4 and P-glycoprotein. These drugs can be used concomitantly, with dose adjustments of sirolimus based on concentration levels and drug effects.
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 conversion of losartan to its active metabolite (E-31 74). Continuous monitoring of blood pressure in patients is recommended.
Methadone: Fluconazole may increase the serum concentration of methadone. Methadone dose adjustment may be necessary when methadone and fluconazole are used concomitantly.
Nonsteroidal anti-inflammatory drugs: When co-administered with fluconazole, the Cmax and AUC of flurbiprofen were 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 were increased by 15% and 82%, respectively, compared to racemic ibuprofen alone.
Fluconazole has the potential to increase the systemic exposure of other nonsteroidal anti-inflammatory drugs (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 NSAIDs may be necessary.
Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. 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 treatment with 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 the hepatic metabolism of saquinavir by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may therefore be more pronounced. Saquinavir dose adjustment may be necessary.
Sulfonylureas: Concomitant use of fluconazole with oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) resulted in a prolongation of their T½. Frequent monitoring of blood sugar and appropriate reduction of the sulfonylurea dose are recommended when co-administered with fluconazole.
Tofacitinib: The exposure of tofacitinib is increased when co-administered with medicinal products that result in moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g. fluconazole). Therefore, it is recommended to reduce the dose of tofacitinib to 5 mg once daily in combination with these medicinal products.
Vinca alkaloids: Fluconazole, presumably through inhibition of CYP3A4, may increase plasma concentrations of vinca alkaloids (e.g. vincristine and vinblastine), leading to neurotoxic effects.
Vitamin A: A patient receiving all-trans retinoic acid (the acid form of vitamin A) and fluconazole was reported to have a central nervous system (CNS) adverse reaction in the form of pseudotumor cerebri that resolved after discontinuation of fluconazole. These drugs can be used concomitantly, but the risk of CNS adverse reactions should be considered.
Voriconazole (CYP2C9, CYP2C19, and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg q24h for 4 days) increased voriconazole Cmax and AUCτ by an average of 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 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 t½ 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: No significant pharmacokinetic interactions were observed with simultaneous oral administration of azithromycin and fluconazole at doses of 1200 mg and 800 mg, respectively.
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 by 3-fold and hydroxymethylivacaftor (M1) by 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. Fluconazole is not known to be superior to griseofulvin in the treatment of ringworm in children, and the overall efficacy is less than 20%. Therefore, fluconazole should not be used to treat 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 with prednisone is described in the section “Interaction with other medicinal products and other forms of interaction. Effects 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 fatal outcomes, 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 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.
Cardiovascular system. Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifier potassium channel (Ikr). QT prolongation caused by other drugs (e.g. amiodarone) may be potentiated by inhibition of the cytochrome P450 enzyme CYP3A4. Very rare cases of QT prolongation and paroxysmal torsades de pointes have been reported with fluconazole. These reports have been in severely ill patients with multiple risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant use of other drugs that affect the QT interval.
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 CYP3A4 enzyme 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 Lyell's syndrome 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.
CYP. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4. Fluconazole is also a potent inhibitor of CYP2C19. Patients receiving fluconazole concomitantly with 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.
This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking 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 using the drug. If such symptoms develop, it is not recommended to drive a car or operate other mechanisms.
Use during pregnancy or breastfeeding
There is an increased risk of spontaneous abortion in women who receive fluconazole during the first trimester of pregnancy. Multiple congenital anomalies (including brachycephaly, auricular dysplasia, excessive anterior fontanelle enlargement, hip dysplasia, brachio-ulnar synostosis) have been reported in newborns whose mothers received high doses of fluconazole (400-800 mg/day) for at least three or more months for the treatment of coccidiosis. The relationship between fluconazole use and these cases has not been established.
Animal studies have shown reproductive toxicity.
Normal doses of fluconazole and short-term use should not be used.
