Instructions Fluconazole-Darnitsa solution for infusions 2 mg/ml bottle 100 ml No. 1
Composition
active ingredient: fluconazole;
1 ml of solution contains 2 mg of fluconazole;
Excipients: sodium chloride, water for injections.
Dosage form
Solution for infusion.
Main physicochemical properties: clear colorless liquid.
Pharmacotherapeutic group
Antifungal agents for systemic use. Triazole derivatives. ATX code J02A C01.
Pharmacological properties
Pharmacodynamics.
Mechanism of action.
Fluconazole, a triazole antifungal agent, is a potent, selective inhibitor of fungal enzymes required for ergosterol synthesis. Its primary mechanism of action is inhibition of fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. Accumulation of 14 alpha-methyl sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may be responsible for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various mammalian cytochrome P450 enzyme systems.
Fluconazole 50 mg daily for 28 days had no effect on plasma testosterone levels in men or on endogenous steroid levels in women of reproductive age. Fluconazole 200-400 mg daily had no clinically significant effect on endogenous steroid levels or on the response to ACTH stimulation in healthy male volunteers.
An interaction study with antipyrine demonstrated that single or multiple doses of 50 mg fluconazole did not affect the metabolism of antipyrine.
In vitro sensitivity.
Fluconazole has demonstrated antifungal activity in vitro against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata exhibits a wide range of susceptibility to fluconazole, while C. krusei is resistant to it.
Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against the endemic mold fungi Blastomices dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.
Pharmacodynamics–Pharmacokinetics.
According to the results of animal studies, there is a correlation between the minimum inhibitory concentration and the efficacy against experimental models of mycoses caused by Candida species. According to the results of clinical studies, there is a linear relationship between the AUC and the dose of fluconazole (approximately 1:1). There is also a direct, but insufficient relationship between the AUC or dose and a positive clinical response to the treatment of oral candidiasis and, to a lesser extent, candidemia. The similar treatment of infections caused by strains for which fluconazole shows a high minimum inhibitory concentration is less satisfactory.
Mechanism of resistance.
Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole exhibits a high minimum inhibitory concentration against fungal strains that possess one or more mechanisms of resistance, which has a negative impact on efficacy in vivo and in clinical practice. Superinfection with Candida spp., other than C. albicans, species that are often insensitive to fluconazole (e.g. Candida krusei) has been reported. Alternative antifungal agents should be used in such cases.
Pharmacokinetics.
The pharmacokinetic properties of fluconazole are similar after intravenous and oral administration.
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 studied body fluids. Fluconazole levels in saliva and sputum are similar to the drug concentration in blood plasma. In patients with fungal meningitis, fluconazole levels in cerebrospinal fluid reach 80% of the plasma concentration.
High concentrations of fluconazole in the skin, exceeding serum levels, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum. When a dose of 50 mg is used once a day, the concentration of fluconazole after 12 days of treatment was 73 μg/g, and 7 days after the end of treatment, the concentration was still 5.8 μg/g. When a dose of 150 mg is used once a week, the concentration of fluconazole on the 7th day of treatment was 23.4 μg/g; 7 days after the next dose, the concentration was still 7.1 μg/g.
The concentration of fluconazole in nails after 4 months of 150 mg once weekly administration was 4.05 μg/g in healthy volunteers and 1.8 μg/g in patients with nail diseases; fluconazole was detected in nail samples 6 months after the end of therapy.
Metabolism.
Fluconazole is metabolized to a small extent. When a dose labeled with radioactive isotopes is administered, only 11% of fluconazole is excreted unchanged in the urine. Fluconazole is a selective inhibitor of CYP2C9 and CYP3A4 isoenzymes, as well as an inhibitor of CYP2C19 isoenzyme.
The plasma half-life of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose being excreted unchanged in the urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.
The long half-life of the drug from blood plasma allows for its single use for vaginal candidiasis, as well as the use of the drug once a week for other indications.
Kidney failure.
In patients with severe renal insufficiency (glomerular filtration rate < 20 ml/min), the half-life increases from 30 hours to 98 hours. Therefore, the dose of fluconazole should be reduced in this category of patients. Fluconazole is removed by hemodialysis and, to a lesser extent, by intraperitoneal dialysis. A 3-hour hemodialysis session reduces the plasma level of fluconazole by approximately 50%.
Children.
Pharmacokinetic data were evaluated in 113 children in 5 studies: 2 single-dose studies, 2 multiple-dose studies, and 1 study in premature infants.
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 varied 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. This is comparable to the plasma half-life of fluconazole after a single intravenous dose of 3 mg/kg to 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 of the infant at the time of the first dose was 24 hours (range 9 to 36 hours); the mean birth weight was 900 g (range 750 to 1100 g). Seven patients completed the study protocol. A maximum of 5 intravenous injections of fluconazole at a dose of 6 mg/kg were administered every 72 hours. The mean half-life was 74 hours (44–185) on the first day, then decreased to 53 hours (30–131) on the 7th day and to 47 (27–68) on the 13th day. The area under the curve (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. The 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.
Elderly patients.
A pharmacokinetic study was conducted in 22 patients (aged 65 years and older) who received 50 mg of fluconazole orally. 10 subjects were taking diuretics concomitantly. Cmax was 1.54 μg/mL and was reached within 1.3 hours after fluconazole administration. The mean AUC was 76.4 ± 20.3 μg × hour/mL. The mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher compared to those in healthy younger volunteers. Concomitant use of diuretics had no significant effect on Cmax and AUC. Also, creatinine clearance (74 mL/min), percentage of fluconazole excreted unchanged in urine (0–24 hours, 22%), and renal clearance of fluconazole (0.124 mL/min/kg) in patients of this age group were lower than those in younger volunteers. Therefore, changes in pharmacokinetics in elderly patients depend on renal function parameters.
Indication
Fluconazole-Darnitsa is indicated for the treatment of fungal infections in adults such as:
– cryptococcal meningitis;
– coccidioidosis;
– invasive candidiasis;
– candidiasis of the mucous membranes, including oropharyngeal candidiasis and esophageal candidiasis, candiduria, chronic candidiasis of the skin and mucous membranes;
– chronic atrophic candidiasis of the oral cavity (candidiasis caused by the use of dentures) with ineffective oral hygiene or local therapy.
Fluconazole-Darnitsa is indicated for the prevention of the following diseases in adults:
– recurrence of cryptococcal meningitis in patients at high risk of its development;
– recurrence of oropharyngeal or esophageal candidiasis in HIV patients at high risk of its development;
– prevention of candidal infections in patients with prolonged neutropenia (for example, in patients with malignant blood diseases receiving chemotherapy, or in patients undergoing hematopoietic stem cell transplantation).
Fluconazole-Darnitsa is used in children from birth 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.
Drug therapy may be initiated pending the results of culture and other laboratory tests; once results are available, antibiotic therapy should be adjusted accordingly.
Contraindication
Concomitant use of fluconazole and terfenadine in patients receiving fluconazole multiple times at doses of 400 mg/day and above (according to the results of a multiple-dose interaction study).
Concomitant use of fluconazole and other drugs that prolong the QT interval and are metabolized by the CYP3A4 enzyme (e.g. cisapride, astemizole, pimozide, quinidine 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. A controlled study demonstrated that concomitant administration of 200 mg of fluconazole once daily and 20 mg of cisapride four times daily resulted in significant increases in plasma cisapride levels and prolongation of the QT interval. Concomitant use of fluconazole and cisapride is contraindicated (see section 4.3).
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. One study with fluconazole 200 mg/day did not show any prolongation of the QTc interval. Another study with fluconazole 400 and 800 mg/day demonstrated that fluconazole at doses of 400 mg/day or higher significantly increased plasma levels of terfenadine when these drugs were administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section 4.3). When fluconazole is administered at doses below 400 mg/day with terfenadine, the patient should be closely monitored.
Astemizole. Concomitant use of fluconazole and astemizole may reduce the clearance of astemizole. The resulting increase in plasma concentrations of astemizole may lead to QT prolongation and, in rare cases, torsades de pointes. Concomitant use of fluconazole and astemizole is contraindicated.
Pimozide and quinidine. Concomitant use of fluconazole and pimozide or quinidine may lead to inhibition of the metabolism of pimozide or quinidine, although in vitro and in vivo studies have not been conducted. Increased plasma concentrations of pimozide or quinidine may prolong the QT interval and, in rare cases, lead to the development of paroxysmal torsades de pointes. Concomitant use of fluconazole and pimozide or quinidine is contraindicated.
Erythromycin: Concomitant use of erythromycin and fluconazole may potentially increase the risk of cardiotoxicity (QT prolongation, torsades de pointes) and, as a result, 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 may increase the risk of cardiotoxicity (QT prolongation, torsades de pointes) and, as a result, sudden cardiac death. The combination of these drugs should be avoided.
Concomitant use of fluconazole and the following drugs requires caution and dose adjustment.
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.
Effect of other drugs on fluconazole.
Interaction studies have shown that oral administration of fluconazole with food, cimetidine, antacids, or subsequent total body irradiation for bone marrow transplantation has no clinically significant effect on the absorption of fluconazole.
Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% decrease in the half-life of fluconazole. Therefore, an increase in the dose of fluconazole should be considered in patients receiving rifampicin.
Hydrochlorothiazide: In a pharmacokinetic interaction study, co-administration of multiple hydrochlorothiazide to healthy volunteers receiving fluconazole increased the plasma concentrations of fluconazole by 40%. These interaction parameters do not require changes in the dosing regimen of fluconazole in patients receiving concomitant diuretics.
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/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9 and CYP3A4 when co-administered with fluconazole. Therefore, such drug combinations should be used with caution; patients should be closely monitored. The enzyme inhibitory effect of fluconazole persists for 4–5 days after administration due to its long half-life.
Alfentanil: Co-administration of alfentanil 20 mcg/kg and fluconazole 400 mg in healthy volunteers resulted in a two-fold increase in AUC10, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.
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 after 1 week. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.
Amphotericin B. Concomitant administration of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice resulted in a small additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism of the two drugs in systemic A. fumigatus infection. The clinical significance of the findings in these studies is unknown.
Anticoagulants: As with other azole antifungals, bleeding events (hematoma, epistaxis, gastrointestinal bleeding, haematuria and melena) in association with prolongation of prothrombin time have been reported with concomitant use of fluconazole and warfarin. A two-fold increase in prothrombin time has been observed with concomitant use of fluconazole and warfarin, presumably due to inhibition of warfarin metabolism by CYP2C9. Prothrombin time should be closely monitored in patients receiving concomitant coumarin anticoagulants. Dosage adjustment of warfarin may be necessary.
Short-acting benzodiazepines, e.g. midazolam, triazolam. Administration of fluconazole after oral midazolam resulted in a significant increase in midazolam concentrations and increased psychomotor effects. Concomitant administration of fluconazole 200 mg and midazolam 7.5 mg orally resulted in a 3.7- and 2.2-fold increase in AUC and half-life, respectively. Administration of fluconazole 200 mg daily and triazolam 0.25 mg orally resulted in a 4.4- and 2.3-fold increase in AUC and half-life, respectively. Potentiation and prolongation of the effects of triazolam were observed with concomitant administration of fluconazole and triazolam.
If a patient undergoing treatment with fluconazole is to be prescribed concomitant therapy with benzodiazepines, the dose of the latter should be reduced and appropriate monitoring of the patient's condition should be established.
Carbamazepine. Fluconazole inhibits the metabolism of carbamazepine and causes a 30% increase in serum carbamazepine levels. There is a risk of carbamazepine toxicity. The dose of carbamazepine may need to be adjusted depending on its concentration and the effect of the drug.
Calcium channel blockers. Some calcium antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by the CYP3A4 enzyme. Fluconazole has the potential to increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended.
Celecoxib: Concomitant administration of fluconazole (200 mg daily) and celecoxib (200 mg) increased celecoxib Cmax and AUC by 68% and 134%, respectively. A halving of the celecoxib dose may be necessary when celecoxib and fluconazole are coadministered.
Cyclophosphamide: Concomitant use of cyclophosphamide and fluconazole has been shown to increase serum bilirubin and creatinine levels. These drugs can be used concomitantly despite the risk of increased serum bilirubin and creatinine concentrations.
HMG-CoA reductase inhibitors. Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin) or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin) increases the risk of myopathy and rhabdomyolysis. If concomitant use of these drugs is necessary, the patient should be closely observed for symptoms of myopathy and rhabdomyolysis and creatine kinase levels should be monitored. In the event of a significant increase in creatine kinase levels, as well as when myopathy/rhabdomyolysis is diagnosed or suspected, the use of HMG-CoA reductase inhibitors should be discontinued.
Olaparib: Moderate CYP3A4 inhibitors, such as fluconazole, increase olaparib plasma concentrations; concomitant use is not recommended. If the 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. With simultaneous use of fluconazole at a dose of 200 mg/day and cyclosporine at a dose of 2.7 mg/kg/day, an increase in the AUC of cyclosporine by 1.8 times was observed. These drugs can be used simultaneously, provided that the dose of cyclosporine is reduced depending on its concentration.
Everolimus: Although in vitro and in vivo studies have not been conducted, fluconazole may increase serum concentrations of everolimus due to inhibition of CYP3A4.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus, presumably by inhibiting sirolimus metabolism by CYP3A4 and P-glycoprotein. These drugs can be used concomitantly, with dose adjustments of sirolimus based on drug levels and effects.
Tacrolimus: Fluconazole may increase the serum concentration of tacrolimus up to 5-fold when administered orally due to inhibition of tacrolimus metabolism by the CYP3A4 enzyme in the intestine. No significant changes in pharmacokinetics have been observed with intravenous administration of tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. The oral dose of tacrolimus should be reduced depending on tacrolimus concentrations.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which accounts for most of the angiotensin II receptor antagonism during the use of losartan. Continuous monitoring of blood pressure in patients is recommended.
Methadone: Fluconazole may increase the serum concentration of methadone. Methadone dosage adjustment may be necessary when methadone and fluconazole are used concomitantly.
Non-steroidal anti-inflammatory drugs (NSAIDs). When co-administered with fluconazole, the Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared to flurbiprofen alone. Similarly, when co-administered with racemic ibuprofen (400 mg), the Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen increased by 15% and 82%, respectively, compared to racemic ibuprofen alone.
Although no specific studies have been conducted, fluconazole has the potential to increase the systemic exposure of other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse reactions and toxicities associated with NSAIDs is recommended. Dose adjustment of the NSAID may be necessary.
Phenytoin. Fluconazole inhibits the metabolism of phenytoin in the liver. Simultaneous multiple administration of 200 mg of fluconazole and 250 mg of phenytoin intravenously leads to an increase in phenytoin AUC24 by 75% and Cmin by 128%. When these drugs are used simultaneously, phenytoin plasma concentrations should be monitored to avoid the development of phenytoin toxicity.
Prednisolone. A case report has been made of a liver transplant patient receiving prednisolone 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 prednisolone. Patients receiving long-term concomitant fluconazole and prednisolone should be carefully monitored for the development of adrenal insufficiency after discontinuation of fluconazole.
Rifabutin. Fluconazole increases the serum concentration of rifabutin, leading to 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.
Sulfonylureas: Fluconazole prolongs the elimination half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide, and tolbutamide) when administered concomitantly to healthy volunteers. Frequent monitoring of blood sugar levels and appropriate dose reduction of sulfonylureas is recommended when co-administered with fluconazole.
Theophylline: In a placebo-controlled drug interaction study, fluconazole 200 mg for 14 days decreased the mean plasma clearance of theophylline by 18%. Patients receiving high doses of theophylline or who are otherwise at increased risk of theophylline toxicity should be monitored for signs of theophylline toxicity. Therapy should be changed if signs of toxicity occur.
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: Although not studied, fluconazole, possibly through inhibition of CYP3A4, may increase plasma concentrations of vinca alkaloids (e.g. vincristine and vinblastine), leading to neurotoxic effects.
Vitamin A. A patient receiving all-trans retinoic acid (the acid form of vitamin A) and fluconazole was reported to have a CNS-related pseudotumor cerebri that resolved after discontinuation of fluconazole. These drugs can be used concomitantly, but the risk of CNS-related adverse reactions should be considered.
Voriconazole (CYP2C9 and CYP3A4 inhibitor). Co-administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male volunteers resulted in an average increase in voriconazole Cmax and AUCτ of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is not known whether reducing the dose and/or frequency of voriconazole or fluconazole would eliminate this effect. When voriconazole is administered after fluconazole, monitoring for adverse events associated with voriconazole should be performed.
Zidovudine. Fluconazole increased the Cmax and AUC of zidovudine by 84% and 74%, respectively, due to a decrease in zidovudine clearance by approximately 45% when administered orally. The half-life of zidovudine was also prolonged by approximately 128% after the combination of fluconazole and zidovudine. Patients receiving this combination should be monitored for adverse reactions associated with zidovudine. A reduction in the dose of zidovudine may be considered.
Azithromycin: In an open-label, randomized, three-way crossover study in 18 healthy volunteers, the effects of azithromycin and fluconazole on the pharmacokinetics of each other were evaluated when they were co-administered as single oral doses of 1200 and 800 mg, respectively. No significant pharmacokinetic interactions were observed.
Oral contraceptives. Two pharmacokinetic studies have been conducted with multiple doses of fluconazole and a combined oral contraceptive. Fluconazole 50 mg had no effect on hormone levels, while fluconazole 200 mg daily increased the AUC of ethinylestradiol by 40% and levonorgestrel by 24%. This suggests that multiple doses of fluconazole are unlikely to affect the efficacy of a combined oral contraceptive.
Ivacaftor: Co-administration with ivacaftor, a cystic fibrosis transmembrane conductance regulator enhancer, increases ivacaftor exposure 3-fold and hydroxymethylivacaftor (M1) exposure 1.9-fold. For patients concomitantly taking moderate CYP3A inhibitors such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.
Application features
Ringworm. According to the results of a study of fluconazole for the treatment of ringworm in children, fluconazole is not superior to griseofulvin in terms of efficacy and the overall efficacy rate is less than 20%. Therefore, the drug should not be used for the treatment of ringworm.
Cryptococcosis: There is insufficient evidence of the efficacy of fluconazole 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.
Adrenal insufficiency. Ketoconazole, which is known to cause adrenal insufficiency, may also cause fluconazole insufficiency, although this is rare. Adrenal insufficiency associated with concomitant prednisolone treatment 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 fatalities, mainly in patients with severe underlying diseases. In cases where hepatotoxicity has been associated with fluconazole, there has been no clear relationship between the total daily dose of the drug, duration of therapy, gender, or age of the patient. Fluconazole-induced hepatotoxicity is usually reversible and disappears after discontinuation of therapy.
Patients who develop abnormal liver function tests while taking fluconazole should be closely monitored for the development of more severe liver damage.
Patients should be informed of symptoms that may indicate serious liver effects (severe asthenia, anorexia, persistent nausea, vomiting and jaundice). In such cases, fluconazole should be discontinued immediately and a doctor should be consulted.
Cardiovascular system. Some azoles, including fluconazole, are 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 torsades de pointes have been reported with the drug. These reports have been in patients with severe medical conditions and multiple risk factors, such as structural heart disease, electrolyte disturbances and concomitant use of other drugs that affect the QT interval. Patients with hypokalemia and progressive 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 drugs that prolong the QTc interval and are metabolized by the cytochrome P450 enzyme CYP3A4 is contraindicated.
Halofantrine: Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended.
Dermatological reactions. Exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely with fluconazole. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported. AIDS patients are more prone to severe skin reactions with many drugs. If a patient with a superficial fungal infection develops a rash that may be related to 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 if bullous rashes or erythema multiforme develop, fluconazole should be discontinued.
Hypersensitivity: Anaphylactic reactions have been reported in rare cases.
Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole is also an inhibitor of the CYP2C19 enzyme. Patients 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.
Important information about excipients. The medicinal product contains 0.9% sodium chloride solution. Each 200 mg (100 ml vial) contains 15 mmol sodium ions (0.145 mM
