Instructions for Fluzac tablets 150 mg No. 3
Composition
active ingredient: fluconazole;
1 tablet contains 50 mg, 150 mg or 200 mg of fluconazole;
excipients: calcium hydrogen phosphate, corn starch, colloidal anhydrous silicon dioxide, magnesium stearate, sodium starch glycolate (type A), sodium lauryl sulfate, methyl parahydroxybenzoate (E 218), propyl parahydroxybenzoate (E 216), talc, Ponceau 4R dye (E 124).
Dosage form
Pills.
Main physicochemical properties: flat, round, pink tablets with specks, with beveled edges, with a break line on one side and smooth on the other.
Pharmacotherapeutic group
Antifungal agents for systemic use. Triazole derivatives. ATX code J02A C01.
Pharmacological properties
Pharmacodynamics
Mechanism of action.
Fluconazole is an antifungal agent of the triazole class. 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 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 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.
The relationship between pharmacokinetic and pharmacodynamic properties.
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. Similarly, the 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 high minimum inhibitory concentrations against fungal strains that possess one or more mechanisms of resistance, which negatively affects efficacy in vivo and in clinical practice. Superinfection with Candida spp., other than C. albicans, has been reported, which are often insensitive to fluconazole (e.g. Candida krusei). Alternative antifungal agents should be used 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 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. Plasma concentrations are dose-proportional. Steady-state concentrations of 90% are reached on the second day of treatment when a loading dose of twice the usual daily dose is administered 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%).
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 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 CYP2C9 and CYP3A4 isoenzymes, as well as an inhibitor of CYP2C19 isoenzyme.
Breeding.
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 a single use of the drug 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, this category of patients requires a reduced dose of fluconazole. 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%.
Changes in pharmacokinetics in elderly patients apparently depend on renal function parameters.
Indication
Treatment of diseases 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 (candidiasis caused by the use of dentures), with ineffectiveness of local dental hygiene products;
– vaginal candidiasis, acute or recurrent, when local therapy is not appropriate;
– candidal balanitis, when local therapy is not appropriate;
– dermatomycoses, including athlete's foot, smooth skin mycosis, inguinal dermatomycosis, lichen planus and candidal skin infections, when systemic therapy is indicated;
– dermatophyte onychomycosis, when the use of other medications is not appropriate.
Prevention of diseases in adults such as:
– 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;
– reduction in the frequency of recurrences of vaginal candidiasis (4 or more cases per year);
– 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).
Children.
The drug in tablet form can be used in this category of patients when children are able to safely swallow a tablet, which is usually possible from the age of 5.
Fluzac 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 Fluzac may be initiated prior to the results of culture and other laboratory tests; once the results are available, antibacterial therapy should be adjusted accordingly.
Contraindication
– Hypersensitivity to fluconazole, other azole compounds or to any of the excipients of the drug.
– Concomitant use of fluconazole and terfenadine in patients taking 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, amiodarone and erythromycin).
Interaction with other medicinal products and other types of interactions
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. In one study, no prolongation of the QTc interval was observed with fluconazole at a dose of 200 mg/day. Another study with fluconazole at doses of 400 mg 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 increase the risk of cardiotoxicity (QT prolongation, torsades de pointes) and, as a result, sudden cardiac death. The combination of these drugs is contraindicated.
Amiodarone. Concomitant use of fluconazole with amiodarone may result in inhibition of amiodarone metabolism. An association between amiodarone use and QT prolongation has been observed. Concomitant use of fluconazole and amiodarone is contraindicated (see section 4.3).
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.
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 fluconazole plasma concentrations by 40%. These interaction parameters do not require changes in the fluconazole dosing regimen for patients receiving concomitant diuretics.
The effect of fluconazole on other drugs.
Fluconazole is a potent inhibitor of the cytochrome P450 (CYP) 2C9 isoenzyme and a moderate inhibitor of CYP3A4. Fluconazole is 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, CYP2C19 and CYP3A4 when co-administered with fluconazole. Therefore, such 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.
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 mice resulted in 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 Aspergillus fumigatus infection. The clinical significance of these findings is unknown.
Anticoagulants: As with other azole antifungals, bleeding events (hematoma, epistaxis, gastrointestinal bleeding, hematuria, 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 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 half-life, 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 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 effect.
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 may be used concomitantly, given 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. In addition, a study in healthy volunteers showed 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 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.
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: Fluconazole may increase serum concentrations of everolimus due to inhibition of CYP3A4.
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 metabolism of losartan to its active metabolite.
(E-31 74), which accounts for most of the antagonism to angiotensin II receptors during the use of losartan. It is recommended to carry out continuous monitoring of blood pressure in patients.
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.
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 NSAIDs 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 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 likely to have resulted in 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, leading to an increase in the AUC of rifabutin by up to 80%. Cases of uveitis have been reported with the simultaneous use of fluconazole and rifabutin. When using this combination of drugs, symptoms of rifabutin toxicity should be taken into account.
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 be more severe. Saquinavir dose adjustment may be necessary.
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: 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: Fluconazole, probably through inhibition of CYP3A4, may increase plasma concentrations of vinca alkaloids (e.g. vincristine and vinblastine), leading to neurotoxic effects.
Voriconazole (CYP2C9, CYP2C19 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) increased voriconazole Cmax and AUC by an average 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: 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 of zivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) enhancer, increased 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: A study of fluconazole for the treatment of ringworm in children found that fluconazole was not superior to griseofulvin in efficacy, and the overall efficacy rate was less than 20%. Therefore, Fluconazole should not be used for the treatment of 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 prednisone treatment is described in the section “Effect 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 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 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. 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 disturbances, and concomitant use of other drugs that affect the QT interval.
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. 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 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, the patient should be closely monitored and fluconazole should be discontinued if bullous rash or erythema multiforme develops. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has been reported.
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 should be monitored when concomitantly taking Fluzac and drugs with a narrow therapeutic window that are metabolized by CYP2C9, CYP2C19, and CYP3A4.
Terfenadine: The patient should be carefully monitored when terfenadine and fluconazole are used concomitantly at doses less than 400 mg/day.
Use during pregnancy or breastfeeding
Women of reproductive age
Before starting treatment, the patient should be informed of the potential risk to the fetus.
After a single dose, a fluconazole withdrawal period of approximately 1 week (corresponding to 5–6 half-lives) should be allowed before pregnancy occurs (see Pharmacokinetics).
For long-term treatment, women of reproductive age should consider using contraception throughout the treatment period and for 1 week after the last dose.
Pregnancy
Observational studies suggest an increased risk of spontaneous abortion in women who received fluconazole during the first and/or second trimester compared with women who did not receive fluconazole or received topical azoles during the same period.
The available epidemiological studies on the development of heart defects with fluconazole use during pregnancy have yielded conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester found a 1.8- to 2-fold increased risk of heart defects in infants compared with infants whose mothers did not use fluconazole and/or used topical azoles.
There have been reports of congenital malformations in infants whose mothers received high doses (400 to 800 mg/day) of fluconazole during pregnancy for 3 months or more for the treatment of coccidioidomycosis. Congenital malformations observed in these infants included brachycephaly, auricular dysplasia, excessive enlargement of the anterior fontanelle, femoral curvature, and radiohumeral synostosis. A causal relationship between fluconazole use and the congenital malformations has not been established.
Normal doses of fluconazole and short courses of fluconazole should not be used during pregnancy unless clearly necessary.
High doses of fluconazole and/or long courses of fluconazole treatment should not be used during pregnancy, except for the treatment of potentially life-threatening infections.
Fluconazole passes into breast milk and reaches lower concentrations than in blood plasma. Breastfeeding can be continued after a single dose of fluconazole, which is 200 mg or less.
Breastfeeding is not recommended during repeated use of fluconazole or when using high doses of fluconazole.
Fluconazole did not affect the fertility of male and female animals studied.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effects of the drug Flu
