Pharmacological properties
Pharmacodynamics.
Mechanism of action. Fluconazole, a triazole antifungal agent, is a potent and 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 P450 enzymes than for the various mammalian cytochrome P450 enzyme systems.
Fluconazole 50 mg/day 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/day 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 susceptibility: Fluconazole has demonstrated antifungal activity in vitro against the most commonly detected 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.
Relationship between pharmacokinetics and pharmacodynamic properties
According to the results of animal studies, there is a correlation between the minimum inhibitory concentration (MIC) and the effectiveness 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 treatment of infections caused by strains for which fluconazole exhibits high MIC is less satisfactory.
Mechanism of resistance. Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole exhibits high MICs against fungal strains that possess one or more mechanisms of resistance, which negatively affects efficacy in vivo and in clinical practice. Superinfection of Candida spp. with species other than C. albicans, which are often insensitive to fluconazole (e.g. C. krusei), has been reported. Alternative antifungal agents should be used for treatment in such cases.
Pharmacokinetics. The pharmacokinetic properties of fluconazole are similar after intravenous and oral administration.
Absorption. Fluconazole is well absorbed after oral administration, and plasma levels and systemic bioavailability exceed 90% of the plasma levels achieved after intravenous administration. Concomitant food intake does not affect the absorption of the drug after oral administration. Cmax in plasma is achieved 0.5-1.5 hours after administration. Plasma concentrations are dose-proportional. Steady-state concentrations of 90% are achieved by day 2 of treatment with a loading dose of twice the usual daily dose administered on day 1.
Distribution: The volume of distribution is approximately equal to the total body fluid content. The degree of binding to plasma proteins is low (11-12%).
Fluconazole penetrates well into all body fluids tested. The drug level in saliva and sputum is similar to the drug concentration in blood plasma. In patients with fungal meningitis, the level of fluconazole in cerebrospinal fluid reaches 80% of the concentration in blood plasma.
High concentrations of fluconazole in the skin, exceeding those in blood plasma, are achieved in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum. When using a dose of 50 mg 1 time per 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 using a dose of 150 mg 1 time per 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 nail diseases; fluconazole was detected in nail samples 6 months after the end of therapy.
Biotransformation. Fluconazole is metabolized to a small extent. When a dose labeled with radioactive isotopes is administered, only 11% of fluconazole is excreted unchanged in the urine. Fluconazole is a selective inhibitor of CYP 2C9 and 3A4 isoenzymes, as well as an inhibitor of the CYP 2C19 enzyme.
Long T½ 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 failure. In patients with severe renal failure (glomerular filtration rate 20 ml/min) T ½ increases from 30 to 98 hours. Therefore, this category of patients requires a reduced 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 50%.
Elderly patients: Changes in pharmacokinetics in elderly patients appear to be dependent on renal function parameters.
Indication
Acute vaginal candidiasis when topical therapy is inappropriate. Candidal balanitis when topical therapy is inappropriate.
Application
The capsules should be swallowed whole. The drug is not dependent on food intake.
Adults: Take the drug orally at a dose of 150 mg once.
Elderly patients. In the absence of signs of renal dysfunction, the usual adult dose is used to treat this category of patients.
Renal impairment. Fluconazole is excreted mainly in the urine unchanged. With a single use of the drug, there is no need to adjust the dose for this category of patients.
Hepatic impairment: Fluconazole should be used with caution in patients with hepatic impairment, as there is insufficient information on the use of fluconazole in this patient population.
Contraindication
Hypersensitivity to fluconazole, other azole compounds or any of the excipients of the drug;
simultaneous use of fluconazole and terfenadine in patients who use fluconazole repeatedly 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 CYP 3A4 enzyme (e.g. cisapride, astemizole, pimozide, quinidine and erythromycin).
Side effects
The most frequently reported adverse reactions (1/10) were: headache, abdominal pain, diarrhea, nausea, vomiting, rash, increased ALT, AST and ALT levels in the blood.
To assess the frequency of adverse reactions, the following classification is used: very common (≥1/10), common (≥1/100 and 1/10), uncommon (≥1/1000 and 1/100), rare (≥1/10,000 and 1/1000), very rare (1/10,000) and frequency unknown (cannot be estimated from the available data).
From the blood and lymphatic system: infrequently - anemia; rarely - agranulocytosis, leukopenia, neutropenia, thrombocytopenia.
On the part of the immune system: rarely - anaphylaxis.
Metabolic and nutritional disorders: infrequently - decreased appetite; rarely - hypertriglyceridemia, hypercholesterolemia, hypokalemia.
Mental disorders: infrequently - insomnia, drowsiness.
From the nervous system: often - headache; infrequently - convulsions, dizziness, paresthesia, taste disturbances; rarely - tremor.
From the side of the organs of hearing and vestibular apparatus: infrequently - vertigo.
On the part of the heart: rarely - paroxysmal ventricular tachycardia of the "pirouette" type, prolongation of the QT interval.
From the gastrointestinal tract: often - abdominal pain, diarrhea, nausea, vomiting; infrequently - constipation, dyspepsia, flatulence, dry mouth.
Hepatobiliary disorders: often - increased levels of ALT, AST, LF; infrequently - cholestasis, jaundice, increased bilirubin levels; rarely - liver failure, hepatocellular necrosis, hepatitis, hepatocellular damage.
Skin and subcutaneous tissue disorders: common: rash; uncommon: pruritus, drug dermatitis, urticaria, increased sweating; rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioedema, facial edema, alopecia.
Musculoskeletal and connective tissue disorders: uncommon - myalgia.
General disorders and administration site conditions: uncommon - fatigue, malaise, asthenia, fever.
Children: The frequency and nature of adverse reactions and laboratory abnormalities in clinical trials in children are comparable to those in adults.
Special instructions
Dermatophytosis. According to the results of a study of fluconazole for the treatment of dermatophytosis in children, fluconazole is not more effective than griseofulvin and its overall efficacy rate is 20%. Therefore, fluconazole should not be used for the treatment of dermatophytosis.
Cryptococcosis. There is insufficient evidence of the effectiveness of fluconazole for 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 regarding the dosage regimen for the treatment of such diseases.
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 individuals 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, and age of the patient. Fluconazole-induced hepatotoxicity is usually reversible and resolves 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 about 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 ECG. Cases of QT prolongation and paroxysmal torsades de pointes have been reported very rarely with fluconazole. These reports have been in patients with severe disease and multiple risk factors (structural heart disease, electrolyte disturbances, 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 QT interval and are metabolized by the cytochrome P450 enzyme CYP 3A4 is contraindicated.
Halofantrine is a substrate of the CYP 3A4 enzyme and causes QT prolongation at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended.
Dermatological reactions. Exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely with fluconazole. Patients with AIDS are more prone to developing severe skin reactions with many drugs. If a patient with a superficial fungal infection develops a rash that can be attributed to the use of fluconazole, further use of the drug should be discontinued. If a patient with an invasive/systemic fungal infection develops a skin rash, his health requires careful monitoring, and in the event of the development of a bullous rash or erythema multiforme, fluconazole should be discontinued.
Hypersensitivity: Anaphylactoid reactions have been reported in rare cases.
Cytochrome P450. Fluconazole is a potent inhibitor of CYP 2C9 and a moderate inhibitor of CYP 3A4. Fluconazole is also an inhibitor of CYP 2C19. Patients receiving fluconazole concomitantly with drugs with a narrow therapeutic window that are metabolized by CYP 2C9, 2C19, and 3A4 should be monitored.
Terfenadine: The patient's health should be carefully monitored during concomitant use of terfenadine and fluconazole at a dose of 400 mg/day.
Pregnancy and lactation. Data obtained with single or repeated use of fluconazole in usual doses (200 mg/day) in several hundred pregnant women in the first trimester did not demonstrate any undesirable effects on the fetus. Numerous congenital pathologies have been reported in newborns (including bradyphrenia, auricular dysplasia, excessive enlargement of the anterior fontanelle, hip curvature, brachio-ulnar synostosis) whose mothers used fluconazole in high doses (400-800 mg/day) for at least ≥ 3 months for the treatment of coccidioidomycosis. The relationship between the use of fluconazole and these cases has not been established.
Animal studies have shown reproductive toxicity.
Fluconazole should not be used in normal doses and short-term courses of fluconazole treatment during pregnancy, except when absolutely necessary.
Fluconazole should not be used in high doses and/or for long courses of fluconazole treatment during pregnancy, except for treatment of potentially life-threatening infections.
Fluconazole passes into breast milk and reaches concentrations lower than in plasma. Breastfeeding can be continued after a single dose of fluconazole, which is ≤200 mg.
Breastfeeding is not recommended with repeated use of fluconazole or when using fluconazole in high doses.
Ability to influence the reaction rate when driving vehicles or working with other mechanisms. Studies of the effect of the drug Ryativnik on the ability to drive vehicles or work with other mechanisms have not been conducted. Patients should be informed about the possibility of developing dizziness or convulsions during the use of fluconazole. If such symptoms develop, it is not recommended to drive vehicles or work with other mechanisms.
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. Studies have shown 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 administration of fluconazole and cisapride is contraindicated (see Adverse Reactions).
Terfenadine: Due to cases of severe arrhythmias caused by QT prolongation in patients receiving azole antifungals concomitantly with terfenadine, drug interaction studies have been conducted. One study with fluconazole 200 mg/day did not show any QT prolongation. Another study with 400 and 800 mg/day demonstrated that ≥400 mg/day significantly increased plasma terfenadine levels when these drugs were administered concomitantly. Concomitant administration of fluconazole ≥400 mg with terfenadine is contraindicated (see Adverse Reactions). Careful monitoring of the patient's health is recommended when 400 mg/day is administered concomitantly with terfenadine.
Astemizole: Concomitant administration of fluconazole may reduce the clearance of astemizole. The resulting increase in plasma astemizole concentrations may lead to QT prolongation and rarely torsades de pointes. Concomitant administration of fluconazole is contraindicated.
Pimozide and quinidine: Concomitant use of fluconazole and pimozide or quinidine may result in 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 cause QT prolongation and rarely lead to paroxysmal torsades de pointes. Concomitant use of fluconazole and pimozide or quinidine is contraindicated.
Erythromycin Concomitant use of erythromycin and fluconazole may potentially lead to an increased risk of cardiotoxicity (QT prolongation, torsades de pointes) and, as a consequence, sudden fatal cardiovascular events. The use of this combination of 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 CYP 3A4. Concomitant use of these medicinal products may potentially lead to an increased risk of cardiotoxicity (QT prolongation, torsades de pointes) and, as a result, sudden cardiac death. The combination of these medicinal products should be avoided.
The combined use of fluconazole and the following drugs requires caution and dose adjustment.
Effects of other drugs on fluconazole
Interaction studies have shown that concomitant administration of food, cimetidine, antacids, or subsequent total body irradiation for bone marrow transplantation has no clinically significant effect on the absorption of oral fluconazole.
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.
Effect of fluconazole on other drugs
Fluconazole is a potent inhibitor of the cytochrome P450 (CYP) 2C9 isoenzyme and a moderate inhibitor of CYP 3A4. Fluconazole is an inhibitor of CYP 2C19. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP 2C9, 2C19 and 3A4 when co-administered with fluconazole. Therefore, such combinations should be used with caution; patients should be closely monitored. The inhibitory effect of fluconazole on enzymes persists for 4-5 days after administration due to its long T ½.
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 infected immunocompetent and immunocompromised 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 Aspergillus fumigatus infection. The clinical significance of these findings is unknown.
Anticoagulants: As with other azole antifungals, bleeding events (hematomas, epistaxis, gastrointestinal bleeding, haematuria and melena) in association with prolonged prothrombin time have been reported with concomitant use of fluconazole and warfarin. A two-fold increase in prothrombin time has been observed with concomitant use of fluconazole and warfarin, probably due to inhibition of warfarin metabolism by CYP 2C9. Prothrombin time should be closely monitored in patients receiving concomitant coumarin anticoagulants. The dose of warfarin may need to be adjusted.
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 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 health should be established.
Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and causes an increase in carbamazepine plasma levels by 30%. 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 metabolised by CYP3A4. 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/day) and celecoxib (200 mg) increased celecoxib Cmax and AUC by 68% and 134%, respectively. Concomitant administration of celecoxib and fluconazole may require a 2-fold reduction in the celecoxib dose.
Cyclophosphamide: Concomitant use of cyclophosphamide and fluconazole has been shown to increase serum bilirubin and creatinine levels. These drugs may be used concomitantly, taking into account the risk of increased serum bilirubin and creatinine concentrations.
Fentanyl: One fatal case of fentanyl intoxication has been reported due to a possible interaction between fentanyl and fluconazole. Studies have shown that fluconazole significantly delayed the elimination of fentanyl. Increased fentanyl concentrations may lead to respiratory depression, so the patient should be closely monitored. Fentanyl dosage adjustment may be necessary.
HMG-CoA reductase inhibitors: Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP 3A4 (atorvastatin and simvastatin) or HMG-CoA reductase inhibitors metabolized by CYP 2C9 (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. If creatine kinase levels are significantly elevated, or if myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued.
Immunosuppressants (e.g. cyclosporine, everolimus, sirolimus and tacrolimus)
Cyclosporine: Fluconazole significantly increases the concentration and AUC of cyclosporine. With simultaneous use of fluconazole at a dose of 200 mg/day and cyclosporine at a dose of 2.7 mg/kg/day, an increase in the AUC of cyclosporine by 1.8 times was observed. These drugs can be used simultaneously, provided that the dose of cyclosporine is reduced depending on its concentration.
Everolimus: Although in vitro and in vivo studies have not been conducted, fluconazole may increase the plasma concentration of everolimus due to inhibition of CYP 3A4.
Tacrolimus: Fluconazole may increase the plasma concentration of tacrolimus up to 5-fold when administered orally due to inhibition of tacrolimus metabolism by the CYP 3A4 enzyme in the intestine. No significant changes in pharmacokinetics were 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 (E3174), which accounts for much of the angiotensin II receptor antagonism of losartan. It is recommended that patients' blood pressure be monitored closely.
Methadone: Fluconazole may increase the plasma concentration of methadone. Methadone dose adjustment may be required when methadone and fluconazole are used concomitantly.
NSAIDs: When co-administered with fluconazole, the Cmax and AUC of flurbiprofen increased by 23 and 81%, respectively, compared with those obtained with 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 with those obtained with racemic ibuprofen alone.
Although no specific studies have been conducted, fluconazole has the potential to increase systemic exposure to other NSAIDs metabolized by CYP 2C9 (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 IV leads to an increase in AUC 24 of phenytoin by 75% and C min by 128%. With simultaneous use of these drugs, monitoring of phenytoin plasma concentrations should be carried out in order 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 likely to have induced increased CYP 3A4 activity, leading to increased metabolism of prednisone. Patients receiving long-term concomitant fluconazole and prednisone should be carefully monitored for the development of adrenal insufficiency after discontinuation of fluconazole.
Rifabutin: Fluconazole increases the plasma concentration of rifabutin, resulting in an increase in the AUC of rifabutin by up to 80%. Cases of uveitis have been reported with the concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when using this combination of drugs.
Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir by approximately 50 and 55%, respectively, due to inhibition of saquinavir metabolism in the liver by the enzyme CYP 3A4 and through 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: Fluconazole prolongs the half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide, and tolbutamide) when administered concomitantly to healthy volunteers. Frequent monitoring of plasma glucose and appropriate dose reduction of sulfonylureas is recommended when co-administered with fluconazole.
Theophylline: In drug interaction studies, fluconazole 200 mg for 14 days decreased the mean plasma clearance of theophylline by 18%. Patients receiving high doses of theophylline or who are otherwise at increased risk of theophylline toxicity should be monitored for signs of theophylline toxicity. Therapy should be changed if signs of toxicity occur.
Vinca alkaloids: Although no relevant studies have been conducted, fluconazole, probably through inhibition of CYP 3A4, may cause an increase in plasma concentrations of vinca alkaloids (e.g. vincristine and vinblastine), leading to the development of neurotoxic effects.
Voriconazole (CYP 2C9, 2C19, and 3A4 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) in 8 healthy male volunteers resulted in an average increase in voriconazole Cmax and AUCt 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 events associated with zidovudine. A reduction in the dose of zidovudine may be considered.
Azithromycin: in studies evaluating the effect of azithromycin and fluconazole on the pharmacokinetics of each other during their simultaneous oral single administration at a dose of 1200 and 800 mg, respectively, no significant pharmacokinetic interactions were found.
Oral contraceptives: Fluconazole 50 mg had no effect on hormone levels, while fluconazole 200 mg/day 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 hydroxymethyl ivacaftor (M1) by 1.9-fold. For patients concomitantly taking moderate CYP 3A inhibitors such as fluconazole and erythromycin, a dose reduction of ivacaftor to 150 mg once daily is recommended.
Overdose
Cases of hallucinations and paranoid behavior have been reported with fluconazole overdose. In case of overdose, immediate gastric lavage and symptomatic treatment (including supportive measures) are recommended.
Fluconazole is excreted in the urine, so forced diuresis may accelerate the elimination of the drug. A 3-hour hemodialysis session reduces the plasma level of fluconazole by approximately 50%.
Storage conditions
In the original packaging at a temperature not exceeding 25 °C.
