Diflucan, 2 mg/ml 200 ml

Pharmacological group

The antifungal drug of the triazole series is a potent selective inhibitor of sterol synthesis in the fungal cell.

Pharmacological action

Fluconazole activity has been shown in vitro and in clinical infections against most of the following microorganisms: Candida alhicans, Candida glabrata (many strains are moderately sensitive), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans.

In vitro activity of fluconazole against the following microorganisms has been shown, but the clinical significance is unknown: Candida dubliniensis, Candida guilliermondii, Candida kefyr, Candida lusitaniae.

Pharmacodynamics

Fluconazole showed activity in various models of fungal infections in animals when administered orally and by IV administration. The activity of the drug was demonstrated in opportunistic mycoses, including those caused by Candida spp. (including generalized candidiasis in immunocompromised animals), Cryptococcus neoformans (including intracranial infections), Microsporum spp. and Trychoptyton spp. Fluconazole activity has also been established in models of endemic mycoses in animals, including infections caused by Blastomyces dermatitidis, Coccidioides immitis (including intracranial infections) and Histoplasma capsulatum in animals with normal and with reduced immunity.

Fluconazole has high specificity against cytochrome P450-dependent fungal enzymes. Fluconazole therapy at a dose of 50 mg/day for up to 28 days has no effect on plasma testosterone concentrations in men or steroid concentrations in women of childbearing age. Fluconazole at a dose of 200-400 mg/day had no clinically significant effect on endogenous steroid levels and their response to ACTH stimulation in healthy male volunteers.

Mechanisms of resistance to fluconazole

Resistance to fluconazole can develop in the following cases: a qualitative or quantitative change in the enzyme that targets fluconazole (lanosterol 14-α-demethylase), reduced access to target fluconazole, or a combination of these mechanisms.

Point mutations in the ERG11 gene, which encodes the target enzyme, lead to target alteration and decreased affinity for azoles. Increased expression of the ERG11 gene leads to the production of high concentrations of the target enzyme, which creates a need to increase fluconazole concentrations in the intracellular fluid to inhibit all enzyme molecules in the cell.

The second significant mechanism of resistance is the active excretion of fluconazole from the intracellular space through the activation of two types of transporters involved in the active excretion (efflux) of drugs from the fungal cell. These transporters include the main mediator encoded by the MDR (multiple drug resistance) genes and the ATP-binding cassette transporter superfamily encoded by the CDR (resistance genes of Candida spp. fungi to azole antimycotics) genes.

Hyperexpression of the MDR gene leads to resistance to fluconazole, while hyperexpression of CDR genes can lead to resistance to various azoles.

Resistance to Candida glabrata is usually mediated by CDR gene overexpression, which leads to resistance to many azoles. For those strains in which the MIC is defined as intermediate (16-32 µg/ml), maximum doses of fluconazole are recommended.

Candida krusei should be considered a pathogen resistant to fluconazole. The mechanism of resistance is associated with reduced sensitivity of the target enzyme to the inhibitory effects of fluconazole.

Pharmacokinetics

The pharmacokinetics of fluconazole are similar when administered by injection and when taken orally.

Eabsorption

Fluconazole is well absorbed after oral administration, its plasma levels (and overall bioavailability) exceed 90% of plasma levels of fluconazole when administered by IV. Simultaneous food intake has no effect on absorption when administered orally. C_max is reached 0.5-1.5 h after fluconazole administration on an empty stomach.

The plasma concentration is proportional to the dose.

Distribution

90% C_ss is reached by day 4-5 after initiation of therapy (when taken multiple times daily).

The administration of a shock dose (on day 1), 2 times the average daily dose, achieves C_ss 90% by day 2.

V_d approaches total body water content. Binding to plasma proteins is low (11-12%).

Fluconazole penetrates well into all body fluids. Fluconazole levels in saliva and sputum are similar to its concentrations in blood plasma.

In patients with fungal meningitis, fluconazole levels in the cerebrospinal fluid are about 80% of its plasma levels.

In the stratum corneum, epidermis, dermis and sweat fluid, high concentrations are reached that exceed serum levels. Fluconazole accumulates in the stratum corneum. When administered at a dose of 50 mg once daily, fluconazole concentrations were 73 µg/g after 12 days and only 5.8 µg/g after 7 days of discontinuation of treatment. When administered at a dose of 150 mg once/week, fluconazole concentrations in the stratum corneum were 23.4 µg/g on day 7 and 7 days after the second dose were 7.1 µg/g.

The concentration of fluconazole in the nails after 4 months of use at a dose of 150 mg once/week was 4.05 µg/g in healthy nails and 1.8 µg/g in affected nails; 6 months after completion of therapy, fluconazole was still detectable in the nails.

When comparing saliva and plasma concentrations after a single 100-mg dose of fluconazole in capsule form and oral suspension (rinsing and retained in the mouth for 2 min and swallowing), it was found that C_max of fluconazole in saliva after suspension administration was observed after 5 min and 182 times the C_max in saliva after capsule administration (reached after 4 h). After approximately 4 h, fluconazole concentrations in saliva were similar. The mean AUC_0-96 in saliva was significantly higher when taking the suspension than when taking the capsule. No significant differences in salivary excretion rates or plasma pharmacokinetics were found when fluconazole was administered as two release forms.

Metabolism and excretion

Fluconazole is excreted primarily by the kidneys; approximately 80% of the administered dose is found unchanged in the urine. Fluconazole clearance is proportional to CK. No circulating metabolites have been detected.

The T_1/2 from plasma is about 30 h. Prolonged T_1/2 from plasma allows fluconazole to be taken once for vaginal candidiasis and once/day or once/week for other indications.

Pharmacokinetics in Special Clinical Cases

Table. Pharmacokinetic parameters of fluconazole in children

* is the rate noted on the last day.

In premature infants (approximately 28 weeks of development), fluconazole was administered by IV at a dose of 6 mg/kg every 3rd day until a maximum of 5 doses were administered while children remained in the OIT. The mean T_1/2 was 74 h (range 44-185 h) on day 1, with decreases on day 7 averaging 53 h (range 30-131 h) and on day 13 averaging 47 h (range 27-68 h).

The AUC values were 271 µg×h/mL (range 173-385 µg×h/mL) on day 1, then increased to 490 µg×h/mL (range 292-734 µg×h/mL) on day 7 and decreased to an average of 360 µg×h/mL (range 167-566 µg×h/mL) by day 13.

The V_d was 1183 ml/kg (range 1070-1470 ml/kg) on day 1, then increased to an average of 1184 ml/kg (range 510-2130 ml/kg) on day 7 and to 1328 ml/kg (range 1040-1680 ml/kg) on day 13.

In elderly patients (65 years and older), a single oral dose of fluconazole 50 mg (in some cases with simultaneous use of a diuretic) found that C_max was reached 1.3 h after administration and was 1.54 mcg/mL, mean AUC values 76.4±20.3 µg×h/mL, and the mean T_1/2 was 46.2 h.

The values of these pharmacokinetic parameters are higher than in younger patients. Concomitant use of diuretics did not cause significant changes in AUC and C_max. CK (74 ml/min), the percentage of drug excreted unchanged in the urine (0-24 h, 22%) and the renal clearance of fluconazole (0.124 ml/min/kg) were lower in older patients compared to younger patients. The higher values of pharmacokinetic parameters in elderly patients taking fluconazole are probably related to the reduced renal function characteristic of older age.

Indications

Diflucan is used in adults and children:

Active ingredient

Composition

Intravenous solution is clear, colorless.

1 ml of the solution contains:

Active substances:

fluconazole 2 mg.

Associates:

Sodium chloride – 9 mg,

water d/i – up to 1 ml.

In a bottle of colorless glass 50, 100 or 200 ml of solution.

There is 1 vial in the carton pack.

How to take, the dosage

Principles of Use

How to use and dosages

Fluconazole can be taken orally (in the form of capsules and suspension) or intravenously (as an IV solution) by infusion at a rate of no more than 10 ml/min; the route of administration depends on the clinical condition of the patient. There is no need to change the daily dose when transferring a patient from IV to oral administration or vice versa.

The capsules should be swallowed whole.

When preparing the oral suspension, add 24 ml of water to the content of one bottle and shake well. Shake the suspension before each use.

The solution of the preparation for intravenous administration contains 0.9% sodium chloride solution; each 200 mg (100 ml bottle) contains 15 mmol Na+ and Cl-. Therefore, in patients who require sodium or fluid restriction, the rate of fluid administration should be considered.

The dosing regimen in different age groups and depending on symptoms

The treatment can be started before the results of culture and other laboratory tests. However, therapy should be changed accordingly when the results of these tests become known.

The daily dose of fluconazole depends on the nature and severity of the fungal infection. For vaginal candidiasis, a single dose of the drug is effective in most cases. In infections requiring repeated administration of the antifungal drug, treatment should be continued until clinical or laboratory signs of fungal infection disappear. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually need maintenance therapy to prevent recurrence of infection.

In adults with cryptococcal meningitis and cryptococcal infections of other localizations, an average of 400 mg is prescribed on the first day and then treatment continues at a dose of 200-400 mg once daily. The duration of treatment of cryptococcal infections depends on the presence of clinical and mycological effects; in cryptococcal meningitis, treatment usually continues for at least 6-8 weeks.

In order to prevent relapse of cryptococcal meningitis in AIDS patients, fluconazole therapy at a dose of 200 mg/day may be continued for a very long period of time after completion of the full course of initial treatment.

In candidemia, disseminated candidiasis and other invasive candidiasis infections, the dose averages 400 mg the first day and then 200 mg/day. Depending on the severity of the clinical effect, the dose may be increased to 400 mg/day. The duration of therapy depends on clinical effectiveness.

In oropharyngeal candidiasis the drug is prescribed on average 50-100 mg 1 time per day for 7-14 days. If necessary, in patients with a marked decrease in immunity, treatment may be continued for a longer time. In atrophic oral candidiasis associated with wear of dentures, the drug is prescribed in an average dose of 50 mg 1 time per day for 14 days in combination with antiseptic local agents for denture treatment.

In other candida infections of the mucous membranes (except genital candidiasis), such as esophagitis, noninvasive bronchopulmonary infections, candiduria, candidiasis of the skin and mucous membranes, the effective dose is on average 50-100 mg/day for a treatment duration of 14-30 days.

For prevention of relapses of oropharyngeal candidiasis in AIDS patients after completion of the full course of primary therapy, fluconazole may be prescribed at 150 mg once a week.

For vaginal candidiasis, fluconazole is taken once orally in a dose of 150 mg.

In order to reduce the frequency of recurrence of vaginal candidiasis, the drug may be used in a dose of 150 mg once a month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may require more frequent use. It is not recommended to use the drug in a single dose in children under 18 years old and patients older than 60 years without prescription.

Fluconazole is indicated for balanitis caused by Candida spp. in a single oral dose of 150 mg.

For prevention of candidiasis, the recommended dose of fluconazole is 50-400 mg once daily depending on the risk of fungal infection. If there is a high risk of generalized infection, such as in patients with severe or prolonged neutropenia, the recommended dose is 400 mg once daily. Diflucan® is prescribed several days before the expected development of neutropenia and after increasing of neutrophil count more than 1000/µl the treatment is continued for 7 days.

In skin infections, including mycoses of the feet, smooth skin, inguinal area and candidiasis infections, the recommended dose is 150 mg once a week or 50 mg once a day. The duration of therapy in normal cases is 2-4 weeks, but in mycoses of the feet a longer therapy (up to 6 weeks) may be required.

In pityriasis the recommended dose is 300 mg once a day for 2 weeks; some patients require a third dose of 300 mg/week, while for some patients a single dose of 300-400 mg is sufficient. An alternative treatment regimen is to use 50 mg once daily for 2 to 4 weeks.

In onychomycosis the recommended dose is 150 mg once a week. Treatment should be continued until replacement of the infected nail (uninfected nail growth). It usually takes 3-6 months and 6-12 months, respectively, for nails on fingers and feet to re-grow. However, the growth rate can vary widely from person to person and also depending on age. After successful treatment of long-standing chronic infections, sometimes there is a change in the shape of the nails.

In deep endemic mycoses, the drug may need to be used at a dose of 200-400 mg/day for up to 2 years. Duration of therapy is determined individually; it is 11-24 months in coccidioidomycosis, 2-17 months in paracoccidioidomycosis, 1-16 months in sporotrichosis and 3-17 months in histoplasmosis.

In children, as well as in similar infections in adults, the duration of treatment depends on the clinical and mycological effect. The daily dose for children should not exceed that for adults. Diflucan® is used daily once a day.

In case of candidiasis of mucous membranes the recommended dose of Diflucan® is 3 mg/kg/day. On the first day, a shock dose of 6 mg/kg may be administered in order to achieve constant equilibrium concentrations more quickly.

For the treatment of generalized candidiasis and cryptococcal infection, the recommended dose is 6-12 mg/kg/day depending on the severity of the disease.

For suppression of relapsed cryptococcal meningitis in children with AIDS, the recommended dose of Diflucan® is 6 mg/kg/day.

For the prevention of fungal infections in immunocompromised patients whose risk of infection is associated with neutropenia resulting from cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg/kg/day, depending on the severity and duration of persistence of induced neutropenia.

When using the drug in children aged 4 weeks or less it should be borne in mind that in newborns fluconazole is excreted slowly.

In the first 2 weeks of life, the drug is given in the same dose (in mg/kg) as in older children, but at 72-hour intervals.

In children aged 3 and 4 weeks of life the same dose is given at 48-hour intervals.

Dosing regimen in special clinical cases

In elderly patients in the absence of signs of renal failure, the drug is administered in a medium dose. In elderly patients with renal insufficiency (CKR < 50 ml/min) a correction of the dosage regimen is required.

Fluconazole is mainly excreted unchanged in the urine. No dosage adjustment is required when administered once daily. In patients (including children) with impaired renal function a shock dose of 50 mg to 400 mg should be administered initially, after which the daily dose (depending on indications) is determined according to the following table.

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis session. Patients should receive a reduced (depending on CK) dose of the drug on the day they are not on dialysis.

There are limited data on the use of fluconazole in patients with impaired liver function. Therefore, caution should be exercised when using Diflucan® in this category of patients.

Interaction

Single or multiple administration of fluconazole in a dose of 50 mg does not affect the metabolism of fenazone (antipyrine) when they are taken simultaneously.

The concomitant use of fluconazole with the following drugs is contraindicated

Cisapride: concomitant use of fluconazole and cisapride may cause adverse reactions in the heart, including ventricular tachycardia of “pirouette” type. Fluconazole administration in dose 200 mg 1 time per day and cisapride in dose 20 mg 4 times per day leads to significant increase of plasma concentration of cisapride and QT interval prolongation on ECG. Simultaneous administration of cisapride and fluconazole is contraindicated.

Terfenadine: Concomitant use of azole antifungal agents and terfenadine may cause serious arrhythmias due to prolongation of the QT interval. It has not been established that fluconazole administration at a dose of 200 mg/day increases QT interval, but fluconazole administration at doses of 400 mg/day and higher causes a significant increase in terfenadine plasma concentrations. Concomitant administration of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg/day in combination with terfenadine should be performed under close supervision.

Astemizole: Concomitant use of fluconazole with astemizole or other drugs metabolized by cytochrome P450 isoenzymes may be accompanied by increased serum concentrations of these drugs. Increased plasma concentrations of astemizole may cause prolongation of the QT interval and, in some cases, development of ventricular tachycardia “pirouette”. Simultaneous use of astemizole and fluconazole is contraindicated.

Pimozide: Although no relevant in vitro or in vivo studies have been performed, concomitant use of fluconazole and pimozide may lead to inhibition of pimozide metabolism. In turn, increased plasma concentrations of pimozide may lead to prolongation of the QT interval and, in some cases, the development of ventricular tachycardia of the “pirouette” type. Simultaneous use of pimozide and fluconazole is contraindicated.

Hinidine: Although there have been no appropriate in vitro or in vivo studies, concomitant use of fluconazole and quinidine may also lead to inhibition of quinidine metabolism. The use of quinidine is associated with prolongation of the QT interval and in some cases with the development of ventricular tachycardic arrhythmias of the “pirouette” type.

The concomitant use of quinidine and fluconazole is contraindicated.

Eritromycin: Concomitant use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (prolongation of QT interval, ventricular pirouette arrhythmia) and, consequently, sudden cardiac death. Simultaneous use of fluconazole and erythromycin is contraindicated.

Caution should be exercised and doses may need to be adjusted if the following drugs and fluconazole are used concomitantly

Drugs affecting fluconazole

Hydrochlorothiazide: Repeated use of hydrochlorothiazide concomitantly with fluconazole results in a 40% increase in plasma fluconazole concentrations. This effect does not require a change in fluconazole dosing regimen in patients receiving concomitant diuretics, but the physician should consider this.

Rifampicin: simultaneous use of fluconazole and rifampicin causes decrease in AUC by 25% and decrease in T1/2 of fluconazole by 20%. In patients simultaneously taking rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.

Drugs affected by fluconazole

Fluconazole is a potent inhibitor of CYP2C9 and CYP2C19 isoenzymes and a moderate inhibitor of CYP3A4 isoenzyme. In addition, in addition to the effects listed below, there is a risk of increased plasma concentrations of other drugs metabolized by CYP2C9, CYP2C19 and CYP3A4 isoenzymes when concomitantly administered with fluconazole. In this regard, caution should be exercised when concomitant use of these drugs and, if necessary, such combinations. Patients should be under close medical supervision. It should be taken into account that the inhibitory effect of fluconazole persists for 4-5 days after drug withdrawal due to the long T1/2.

Alfentanil: decreased clearance and Vd, increased T1/2 alfentanil are noted. This may be due to inhibition of CYP3A4 isoenzyme by fluconazole. Dose adjustment of alfentanil may be required.

Amitriptyline, nortriptyline: increase in effect. The concentration of 5-nortriptyline and/or S-amitriptyline can be determined at the beginning of combination therapy with fluconazole and one week after the start. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B: In studies in mice (including immunosuppressed mice) the following results were noted: slight additive antifungal effect in systemic infection caused by Сandida albicans, no interaction in intracranial infection caused by Cryptococcus neoformans and antagonism in systemic infection caused by A. fumigatus. The clinical significance of these results is unclear.

Anticoagulants: as well as other antifungal agents – azole derivatives, fluconazole with warfarin increases prothrombin time (by 12%), in connection with which bleeding may develop (hematoma, bleeding from the nose and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, prothrombin time should be constantly monitored. The appropriateness of warfarin dose adjustment should also be evaluated.

Asitromycin: No significant pharmacokinetic interaction was found in concomitant oral administration of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg.

Benzodiazepines (short-acting): after oral administration of midazolam, fluconazole significantly increases midazolam concentration and psychomotor effects, and this effect is more pronounced after fluconazole oral administration than after its intravenous administration. If concomitant therapy with benzodiazepines is necessary, patients taking fluconazole should be monitored to assess the appropriateness of appropriate benzodiazepine dose reduction.

When concomitant administration of triazolam in a single dose, fluconazole increases the AUC of triazolam by approximately 50%, Cmax by 25-32% and T1/2 by 25-50% due to inhibition of triazolam metabolism. Dose adjustment of triazolam may be necessary.

Carbamazepine: fluconazole inhibits the metabolism of carbamazepine and increases the plasma concentration of carbamazepine by 30%. The risk of carbamazepine toxicity should be considered. The need to adjust the dose of carbamazepine depending on the concentration/effect should be assessed.

Calcium channel blockers: some calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4 isoenzyme. Fluconazole increases systemic exposure to calcium channel antagonists. It is recommended to control the development of side effects.

Cyclosporine: in patients with transplanted kidney the use of fluconazole at a dose of 200 mg/day leads to a slow increase in concentration of cyclosporine. However, no changes in cyclosporine concentrations were observed in bone marrow recipients when fluconazole was administered repeatedly at a dose of 100 mg/day. When concomitant use of fluconazole and cyclosporine it is recommended to monitor the concentration of cyclosporine in blood.

Cyclophosphamide: in concomitant use of cyclophosphamide and fluconazole an increase in serum concentrations of bilirubin and creatinine has been observed. This combination is acceptable taking into account the risk of increased bilirubin and creatinine concentrations.

Fentanyl: One fatality has been reported, possibly related to concomitant administration of fentanyl and fluconazole. The abnormalities are thought to be related to fentanyl intoxication. Fluconazole has been shown to significantly prolong fentanyl elimination time. Note that increased fentanyl concentrations may result in respiratory depression.

Halofantrine: Fluconazole may increase plasma concentrations of halofantrine due to inhibition of the CYP3A4 isoenzyme.

HMG-CoA reductase inhibitors: co-administration of fluconazole with HMG-CoA reductase inhibitors metabolized by CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or CYP2D6 isoenzyme (such as fluvastatin) increases the risk of myopathy and rhabdomyolysis. If concomitant therapy with these drugs is necessary, patients should be monitored to detect symptoms of myopathy and rhabdomyolysis. Creatinine kinase concentration should be monitored. In case of significant increase in creatinine kinase concentration or if myopathy or rhabdomyolysis is diagnosed or suspected, therapy with HMG-CoA reductase inhibitors should be stopped.

Lozartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which is responsible for most of the effects associated with antagonism to angiotensin II receptors. Regular BP control is necessary.

Methadone: Fluconazole may increase the plasma concentration of methadone. Correction of methadone dose may be necessary.

NSAIDs: Cmax and AUC of flurbiprofen are increased by 23% and 81%, respectively. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was used concomitantly with racemic ibuprofen (400 mg). Concomitant administration of fluconazole at a dose of 200 mg/day and celecoxib at a dose of 200 mg increased Cmax and AUC of celecoxib by 68% and 134%, respectively. In this combination, it is possible to reduce the dose of celecoxib by half.

While there are no focused studies, fluconazole may increase systemic exposure to other NSAIDs metabolized by CYP2C9 isoenzyme (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Dose adjustment of NSAIDs may be necessary.

If NSAIDs and fluconazole are used concomitantly, patients should be closely monitored by physicians for the identification and control of adverse reactions and manifestations of NSAID-related toxicity.

Peroral contraceptives: No significant effect on hormone levels was found when using combined oral contraceptives with fluconazole at a dose of 50 mg, whereas the AUC of ethinylestradiol and levonorgestrel increased by 40% and 24%, respectively, when taking fluconazole 300 mg once/week. AUC of ethinylestradiol and norethindrone increases by 24% and 13%, respectively. Thus, repeated use of fluconazole at the indicated doses is unlikely to affect the efficacy of the combined oral contraceptive.

Phenytoin: Concomitant use of fluconazole and phenytoin may be accompanied by clinically significant increases in phenytoin concentrations. In case of necessity of concomitant use of both drugs, phenytoin concentrations should be monitored and the dose should be adjusted accordingly to ensure therapeutic blood plasma concentrations.

Prednisone: There is a report of acute adrenal insufficiency in a patient after liver transplantation after withdrawal of fluconazole after 3 months of therapy. Presumably, discontinuation of fluconazole therapy caused increased CYP3A4 isoenzyme activity, which resulted in increased metabolism of prednisone.

Patients receiving combined therapy with prednisone and fluconazole should be closely monitored during discontinuation of fluconazole to assess the adrenal cortex.

Rifabutin: Concomitant use of fluconazole and rifabutin may increase plasma concentrations of the latter up to 80%. There have been cases of uveitis when concomitant use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly should be monitored closely.

Saquinavir: AUC increases by approximately 50%, Cmax increases by 55%, clearance of saquinavir decreases by approximately 50% due to inhibition of hepatic metabolism of CYP3A4 isoenzyme and inhibition of P-glycoprotein. Dose adjustment of saquinavir may be necessary.

Syrolimus: increased plasma concentrations of sirolimus, presumably due to inhibition of sirolimus metabolism through inhibition of CYP3A4 isoenzyme and P-glycoprotein. This combination can be used with appropriate dose adjustment of sirolimus depending on the effect/concentration.

Sulfonylurea drugs: Fluconazole concomitantly causes an increase in T1/2 of oral sulfonylurea drugs (chlorpropamide, glibenclamide, glipizide and tolbutamide). People with diabetes may use fluconazole concomitantly with oral sulfonylureas, but they should consider the possibility of hypoglycemia, and the blood glucose should be monitored regularly, and the dose of sulfonylureas should be adjusted if necessary.

Tacrolimus: Concomitant use of fluconazole and tacrolimus (oral) leads to an increase in serum concentrations of the latter up to 5 times due to inhibition of tacrolimus metabolism, which occurs in the intestine by CYP3A4 isoenzyme. No significant changes in pharmacokinetics of the drugs were observed when using tacrolimus by IV. Cases of nephrotoxicity have been described. Patients receiving tacrolimus and fluconazole concomitantly require close monitoring. The dose of tacrolimus should be adjusted according to the degree of increase in its blood concentration.

Theophylline: In concomitant use with fluconazole in dose of 200 mg for 14 days average plasma clearance rate of theophylline decreases by 18%. When fluconazole is administered to patients taking high doses of theophylline, or to patients with increased risk of development of toxic effect of theophylline it is necessary to monitor the appearance of symptoms of theophylline overdose and, if necessary, to correct therapy accordingly.

Tofacitinib: Exposure to tofacitinib is increased when co-administered with drugs that are both moderate CYP3A4 isoenzyme inhibitors and potent CYP2C19 isoenzyme inhibitors (e.g., fluconazole). It may be necessary to adjust the dose of tofacitinib.

The periwinkle alkaloid: Although there are no focused studies, it is suggested that fluconazole may increase plasma concentrations of periwinkle alkaloids (e.g., vincristine and vinblastine) and thus lead to neurotoxicity, which may be due to inhibition of the CYP3A4 isoenzyme.

Vitamin A: there has been a report of one case of adverse CNS reactions in the form of pseudotumor cerebri when using completely transretinoic acid and fluconazole at the same time, which disappeared after withdrawal of fluconazole. The use of this combination is possible, but it should be remembered about the possibility of adverse reactions from the CNS.

Zidovudine: in concomitant use with fluconazole there is an increase in Cmax and AUC of zidovudine by 84% and 74%, respectively. This effect is probably due to a decrease in the metabolism of the latter to its main metabolite. Before and after therapy with fluconazole at a dose of 200 mg/day for 15 days in patients with AIDS and ARC (AIDS-related complex) a significant increase in the AUC of zidovudine (20%) was found.

Patients receiving this combination should be monitored for side effects of zidovudine.

Voriconazole (inhibitor of CYP2C9, CYP2C19 and CYP3A4 isoenzymes): concomitant use of voriconazole (400 mg 2 times daily on the first day, then 200 mg 2 times daily for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg/day for 4 days) increased voriconazole concentration and AUC by 57% and 79%, respectively. This effect has been shown to persist with dose reduction and/or reduction in the frequency of administration of either drug. Simultaneous use of voriconazole and fluconazole is not recommended.

The studies of oral fluconazole interaction with food, cimetidine, antacids and after total body irradiation in preparation for bone marrow transplantation showed that these factors have no clinically significant effect on fluconazole absorption.

The listed interactions have been established with multiple uses of fluconazole; drug interactions resulting from a single dose of fluconazole are unknown. Physicians should note that interactions with other medicinal products have not been specifically studied, but are possible.

Pharmaceutical interaction

Diflucan® – solution for IV administration is compatible with the following solutions: 20% glucose solution, Ringer’s solution, Hartmann’s solution, potassium chloride solution in glucose, 4.2% sodium bicarbonate solution, aminofusin, isotonic saline solution. Diflucan® may be administered in an infusion system together with one of the above solutions. Although no cases of specific incompatibility of fluconazole with other agents have been described, it is nevertheless not recommended to mix it with any other drugs before infusion.

Special Instructions

Precautionary measures when taking the drug

There have been reports of superinfections caused by Candida aibicans strains other than Candida, which often have natural resistance to fluconazole (e.g., Candida krusei). In such cases, alternative antifungal therapy may be required.

In rare cases the use of fluconazole has been accompanied by toxic liver changes, including fatalities, mainly in patients with serious comorbidities. No clear dependence of hepatotoxic effects of fluconazole on the total daily dose, duration of therapy, sex and age of the patient was noted. Hepatotoxic effects of fluconazole were usually reversible; their signs disappeared after discontinuation of therapy. Patients with impaired liver function during treatment with fluconazole should be monitored for signs of more serious liver damage. If there are clinical signs or symptoms of liver damage that may be associated with fluconazole, the drug should be discontinued.

During treatment with fluconazole, patients have rarely developed exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. AIDS patients are more prone to develop severe skin reactions when using many drugs. If a patient treated for a superficial fungal infection develops a rash that can be associated with fluconazole use, the drug should be discontinued. Patients with invasive/systemic fungal infections should be monitored closely and fluconazole should be stopped if bullous lesions or erythema multiforme appear.

As with other azoles, fluconazole may cause anaphylactic reactions in rare cases.

The concomitant use of fluconazole in doses less than 400 mg/day and terfenadine should be carefully controlled.

Like other azoles, fluconazole may cause QT interval prolongation on ECG. During fluconazole use, QT interval prolongation and ventricular fibrillation/rattling have been observed very rarely in patients with multiple risk factors, such as organic heart disease, electrolyte imbalances and concomitant therapy contributing to these disorders. Therefore, these patients with potentially proarrhythmic conditions should use fluconazole with caution.

Patients with liver, heart and kidney disease should consult a physician before using Diflucan®. When using Diflucan® 150 mg for vaginal candidiasis, patients should be warned that improvement of symptoms is usually seen within 24 hours, but it sometimes takes several days for symptoms to disappear completely. If symptoms persist for several days, a physician should be consulted.

The evidence for the effectiveness of fluconazole in treating other endemic mycoses such as paracoccidioidomycosis, sporotrichosis and histoplasmosis is limited, making it impossible to determine specific dosing recommendations.

Impact on the ability to drive vehicles and other mechanisms requiring increased concentration

The experience with Diflucan® indicates that impairment of the ability to drive and operate vehicles associated with the use of the drug is unlikely.

Interaction with alcohol

There are no data on interaction with alcohol.

Prescription conditions in pharmacies

The drug is available with a prescription.

The product in the form of capsules 150 mg is approved for over-the-counter use (only for therapy of vaginal candidiasis previously confirmed by a physician).

Contraindications

The contraindication to the use of Diflucan is:

With caution: Prescribe the drug in impaired liver function parameters, in impaired renal function, in the occurrence of rash on the background of fluconazole use in patients with superficial fungal infection and invasive/systemic fungal infections, in the simultaneous use of terfenadine and fluconazole at a dose less than 400 mg/day, in potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte balance disorders and contributing to such disorders concomitant therapy).

Side effects

When using the drug, the most common side effects were reported in clinical and post-marketing (*) studies of Diflucan®.

Nervous system disorders: headache, dizziness*, seizures*, change in taste*, paresthesia, insomnia, somnolence, tremor.

Digestive system disorders: Abdominal pain, diarrhea, flatulence, nausea, dyspepsia*, vomiting*, dry oral mucosa, constipation, hepatotoxicity (in some cases with fatal outcome), increased bilirubin concentration, serum ALT and AST activity, ALF, liver function disorder*, hepatitis*, hepatocellular necrosis*, jaundice*, cholestasis, hepatocellular damage.

Cardiovascular system disorders*: prolongation of the QT interval on ECG, arrhythmia, including ventricular tachycardia of the “pirouette” type.

Skin disorders: rash, alopecia*, exfoliative skin disorders* including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, increased sweating, drug rash.

Hematopoietic system disorders*: leukopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

Metabolism disorders*: increase in plasma cholesterol and triglyceride levels, hypokalemia.

Muscular system disorders: myalgia. Allergic reactions*: anaphylactic reactions (including angioedema, facial edema, urticaria, itching).

Others: weakness, asthenia, increased fatigue, fever, vertigo.

In some patients, especially those with serious diseases (AIDS, malignant tumors) during treatment with Diflucan® and similar drugs changes in blood parameters, kidney and liver function have been observed, but the clinical significance of these changes and their relation to the treatment have not been established.

Tolerability of the drug is usually very good.

Overdose

In one case of fluconazole overdose, a 42-year-old HIV patient experienced hallucinations and paranoid behavior after taking 8200 mg of fluconazole. The patient was hospitalized and his condition normalized within 48 hours.

Treatment: in case of overdose, symptomatic therapy (including supportive measures and gastric lavage) is administered.

Fluconazole is mainly excreted with the urine, so forced diuresis is likely to hasten its excretion. A hemodialysis session of 3 h reduces plasma levels of fluconazole by approximately 50%.

Pregnancy use

There have been no adequate and controlled safety studies of the drug in pregnant women. There have been cases of multiple birth defects in infants whose mothers received high-dose fluconazole therapy (400-800 mg/day) for coccidioidomycosis for 3 months or more. The following developmental abnormalities were noted: brachycephaly, developmental disorder of the facial part of the skull, disorders of the cranial vault formation, cleft palate, curvature of the femur bones, thinning and elongation of the ribs, arthrogryposis and congenital heart defects. Currently, there is no evidence to link these congenital abnormalities to the use of fluconazole at low doses (150 mg once for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy.

The use of fluconazole in pregnancy should be avoided except in cases of severe and potentially life-threatening fungal infections, when the expected benefits of treatment exceed the possible risk to the fetus. Therefore, women of childbearing age should use reliable contraception.

Fluconazole is detected in breast milk in concentrations close to plasma concentrations, therefore it is not recommended to use Diflucan® during lactation (breast-feeding).

When using the drug in children aged 4 weeks or less it should be noted that in newborns fluconazole is excreted slowly. In the first 2 weeks of life the drug is given in the same dose (mg/kg) as in older children but with an interval of 72 hours. In children at the age of 3 and 4 weeks of life the same dose is administered at intervals of 48 hours.

Similarities