Diflucan, capsules 150mg, 12pcs

Composition

Solid gelatin capsules, No. 1, with turquoise lid and body, marked with the “Pfizer” and “FLU-150” logo in black; the contents of the capsules are white to pale yellow powder.

1 capsule contains:

Active ingredients:

fluconazole 150 mg.

Auxiliary substances:

lactose – 149.123 mg,

corn starch-49.5 mg,

colloidal silicon dioxide-0.352 mg,

magnesium stearate-3.173 mg,

sodium lauryl sulfate-0.352 mg.

Capsule shell composition:

titanium dioxide (E171) – 1.47%,

blue patent dye (E 131) – 0.03%,

gelatin – up to 100%.

Ink composition:

shellac glaze-63%, iron oxide black (E 172) – 25%, N-butyl alcohol-8.995%, industrial methylated alcohol 74 OP-2%, soy lecithin-1%, anti-foam component DC1510-0.005%.

In a blister of 1 or 4 capsules. In a package of 1 or 3 blisters.

Pharmacological action

Clinical and pharmacological group

Triazole antifungal drug is a powerful selective inhibitor of sterol synthesis in fungal cells.

Pharmacological action

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

Fluconazole has been shown to be active in vitro against the following microorganisms, but the clinical significance of this is unknown: Candida dubliniensis, Candida guilliermondii, Candida kefyr, Candida lusitaniae.

Pharmacodynamics

When taken orally and when administered intravenously, fluconazole was active in various models of fungal infections in animals. The drug has been shown to be active in opportunistic mycoses, including those caused by Candida spp. (including generalized candidiasis in animals with reduced immunity), Cryptococcus neoformans (including intracranial infections), Microsporum spp. and Trychoptyton spp. The activity of fluconazole was also 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 reduced immunity.

Fluconazole is highly specific for cytochrome P450-dependent fungal enzymes. Therapy with fluconazole 50 mg / day for up to 28 days does not affect the concentration of testosterone in plasma in men or the concentration of steroids in women of childbearing age. Fluconazole at a dose of 200-400 mg / day did not have a clinically significant effect on the levels of endogenous steroids and their response to ACTH stimulation in healthy male volunteers.

Mechanisms of development of resistance to fluconazole

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

Point mutations in the ERG11 gene encoding the target enzyme lead to a modification of the target and a decrease in affinity for azoles. An increase in the expression of the ERG11 gene leads to the production of high concentrations of the target enzyme, which creates the need to increase the concentration of fluconazole in the intracellular fluid to suppress all enzyme molecules in the cell.

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

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

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

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

Pharmacokinetics

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

Suction

After oral use, fluconazole is well absorbed, its plasma levels (and total bioavailability) exceed 90% of the plasma levels of fluconazole when administered intravenously. Simultaneous food intake does not affect oral absorption. Cmax is reached 0.5-1.5 hours after taking fluconazole on an empty stomach.

The concentration in the blood plasma is proportional to the dose.

The distribution

of 90% Css is achieved by the 4th-5th day after the start of therapy (with repeated use 1 time/day).

The introduction of a shock dose (on day 1),2 times higher than the average daily dose, allows you to achieve a Css of 90% by day 2.

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

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

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

In the stratum corneum, epidermis, dermis and sweat fluid, high concentrations are achieved that exceed serum levels. Fluconazole accumulates in the stratum corneum. When taken at a dose of 50 mg 1 time/day, the concentration of fluconazole after 12 days was 73 mcg/g, and 7 days after discontinuation of treatment – only 5.8 mcg/g. When applied at a dose of 150 mg 1 time/week, the concentration of fluconazole in the stratum corneum on day 7 was 23.4 mcg/g, and 7 days after the second dose-7.1 mcg/g.

The concentration of fluconazole in the nails after 4 months of use at a dose of 150 mg 1 time/week. It was 4.05 mcg/g in healthy and 1.8 mcg/g in affected nails; 6 months after the end of therapy, fluconazole was still detected in the nails.

When comparing saliva and plasma concentrations after a single dose of 100 mg of fluconazole in the form of a capsule and oral suspension (rinsing and storing in the mouth for 2 minutes and swallowing), it was found that the Cmax of fluconazole in saliva after taking the suspension was observed after 5 minutes and 182 times higher than the Cmax in saliva after taking the capsule (reached after 4 hours). After approximately 4 hours, the salivary concentrations of fluconazole were the same. The mean salivary AUC0-96 was significantly higher with the suspension than with the capsules. There were no significant differences in the rate of salivary excretion or plasma pharmacokinetics when using fluconazole in the form of two Form of productions.

Metabolism and elimination

Fluconazole is mainly excreted by the kidneys; approximately 80% of the administered dose is found unchanged in the urine. The clearance of fluconazole is proportional to the CC. No circulating metabolites were detected.

T1 / 2 from plasma is about 30 hours. Long-term T1 / 2 from plasma allows you to take fluconazole once for vaginal candidiasis and 1 time/day or 1 time/week. for other indications.

Pharmacokinetics in special clinical cases

Table. Pharmacokinetic parameters of fluconazole in children

Age, dose T1/2 (h)AUC (µg×h/ml)for 11 days-11 mastroberte/3 mg/kg 23110,19 months-13 letodetrtro inside 2 mg/kg once inside 25,094,7 8 mg/kg 19,5362,55-15 latinoporno/in 2 mg/kg 17,4*67,4*multiple times in/at 4 mg/kg 15,2*139,1*multiple times in/at 8 mg/kg 17,6*196,1*the Average age of 7 latinoporno inside 3 mg/kg 15,541,6

* – indicator noted in the last day.

In preterm infants (approximately 28 weeks of development), fluconazole was administered intravenously at a dose of 6 mg / kg every 3rd day until a maximum of 5 doses were administered while the children remained in the ICU. The average T1/2 was 74 h (in the range 44-185 h) in the 1st day, with a decrease in 7-day average of 53 hours (in the range 30-131 h) and on the 13th day on the average up to 47 h (in the range 27-68 h).

AUC values were 271 µg×h/ml (within 173-385 µg×h/ml) in the 1st day, then increased to 490 µg×h/ml (within 292-734 µg×h/ml) on the 7th day and decreased to an average of 360 µg×h/ml (within 167-566 µg×h/ml) to the 13th day.

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

In patients of advanced age (65 years and older) in a single application of fluconazole at a dose of 50 mg orally (in some cases with concurrent use of diuretics) found that Cmax was achieved via 1,3 h after use and was 1.54 mcg/ml, the mean AUC values of 76.4±20.3 mcg×HR/ml, the average T1/2 was 46.2 per h.

the values of these pharmacokinetic parameters above, than in younger patients. Concomitant use of diuretics did not cause significant changes in AUC and Cmax. Creatinine clearance (74 ml / min), percentage of drug excreted unchanged in the urine (0-24 hours,22%), and renal clearance of fluconazole (0.124 ml/min/kg) are lower in elderly patients compared to young patients. Higher values of pharmacokinetic parameters in elderly patients taking fluconazole are probably associated with reduced renal function characteristic of the elderly.

Indications

Diflucan is used in adults and children:

• cryptococcosis, including cryptococcal meningitis and infections at other sites (e. g., lung, skin), including patients with normal immune response and AIDS patients, recipients of transplanted organs and patients with other forms of immunodeficiency; maintenance therapy to prevent relapse of cryptococcosis in AIDS patients;
• generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive Candida infections such as infection of the peritoneum, endocardium, eyes, respiratory and urinary tract infections, including patients with malignant tumors located in the ICU and receiving cytotoxic or immunosuppressive funds, as well as in patients with other predisposing factors to the development of Candida;
• candidiasis of the mucous membranes, including the mucous membranes of the oral cavity and pharynx, esophagus, non-invasive bronchopulmonary infections, candiduria, skin-mucous and chronic atrophic candidiasis of the oral cavity (associated with wearing dentures), including patients with normal and suppressed immune function; prevention of relapse of oropharyngeal candidiasis in patients with AIDS,
• genital candidiasis, acute or recurrent vaginal candidiasis; prophylaxis to reduce the frequency of recurrences of vaginal candidiasis (3 or more episodes per year); candidal balanitis;
• prevention of fungal infections in patients with malignant tumors, predisposed to such infections as a result of cytotoxic chemotherapy or radiotherapy;
• fungal skin infections, including athlete’s foot, body, groin, pityriasis versicolor, onychomycosis and the candidal skin infections;
• deep endemic mycoses in patients with normal immunity, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis.

Use during pregnancy and lactation

Adequate and controlled studies of the safety of the drug in pregnant women have not been conducted. Cases of multiple congenital malformations in newborns whose mothers received high-dose fluconazole therapy (400-800 mg/day)for 3 months or more are described about coccidioidomycosis. The following developmental disorders were noted: brachycephaly, abnormal development of the facial part of the skull, abnormal formation of the cranial vault, cleft palate, curvature of the femur, thinning and elongation of the ribs, arthrogryposis and congenital heart defects. Currently, there is no evidence that these congenital disorders are associated with the use of low-dose fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy.

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

Fluconazole is found in breast milk at concentrations close to plasma, so the use of Diflucan® during lactation (breastfeeding) is not recommended.

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

Contraindications

Contraindication to the use of Diflucan is:

• couse of terfenadine during repeated use of fluconazole at a dose of 400 mg/day or more;
• concurrent use with drugs that increase the QT interval and are metabolized through CYP3A4 such as cisapride, astemizole, erythromycin, pimozide, and quinidine;
• deficiency of sucrase/isomaltase, fructose intolerance, glucose-galactose malabsorption (powder for suspension);
• galactose intolerance, lactase deficiency and malabsorption of glucose/galactose (for capsules);
• children up to age 3 years (for capsules);
• hypersensitivity to fluconazole, other components of the drug or azole substances with similar with fluconazole structure.

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

Side effects

When using the drug, you may::

The most common side effects were reported in clinical and post-marketing studies (*) of Diflucan®.

Nervous system disorders: headache, dizziness*, convulsions*, taste changes*, paresthesia, insomnia, drowsiness, tremor.

From the digestive system: abdominal pain, diarrhea, flatulence, nausea, dyspepsia*, vomiting*, dry oral mucosa, constipation, hepatotoxicity (in some cases fatal), increased bilirubin concentration, serum ALT and AST activity, alkaline phosphatase, impaired liver function*, hepatitis*, hepatocellular necrosis*, jaundice*, cholestasis, hepatocellular damage.

From the cardiovascular system*: increased QT interval on the ECG, arrhythmia, including ventricular tachysystolic “pirouette” type.

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

From the hematopoietic system*: leukopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

From the side of metabolism*: increased plasma cholesterol and triglycerides, hypokalemia.

Musculoskeletal disorders: myalgia. Allergic reactions*: anaphylactic reactions (including angioedema, facial edema, urticaria, pruritus).

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

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

Drug tolerance is usually very good.

Interaction

A single or multiple dose of fluconazole 50 mg does not affect the metabolism of phenazone (antipyrine) when taken simultaneously.

Concomitant use of fluconazole with the following medications is contraindicated

in Cisapride: concomitant use of fluconazole and cisapride may cause adverse reactions from the heart, including ventricular tachysystolic arrhythmia of the “pirouette” type. The use of fluconazole at a dose of 200 mg 1 time/day and cisapride at a dose of 20 mg 4 times/day leads to a pronounced increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Concomitant use of cisapride and fluconazole is contraindicated.

Terfenadine: When azole antifungal agents are co-administered with terfenadine, serious arrhythmias may occur as a result of increased QT interval. When taking fluconazole at a dose of 200 mg / day, an increase in the QT interval was not established, but the use of fluconazole at doses of 400 mg / day and above causes a significant increase in the concentration of terfenadine in blood plasma. Concomitant use of fluconazole at doses of 400 mg / day or more with terfenadine is contraindicated. Treatment with fluconazole at doses of less than 400 mg / day in combination with terfenadine should be carefully monitored.

Astemizole: concomitant use of fluconazole with astemizole or other drugs that are metabolized by cytochrome P450 isoenzymes may be accompanied by an increase in serum concentrations of these agents. With an increase in the concentration of astemizole in blood plasma, it is possible to prolong the QT interval and in some cases develop ventricular tachysystolic arrhythmia “pirouette”. Concomitant use of astemizole and fluconazole is contraindicated.

Pimozide: Although no relevant in vitro or in vivo studies have been conducted, concomitant use of fluconazole and pimozide may lead to inhibition of pimozide metabolism. In turn, an increase in plasma concentrations of pimozide can lead to prolongation of the QT interval and, in some cases, to the development of ventricular tachysystolic arrhythmia of the “pirouette” type. Concomitant use of pimozide and fluconazole is contraindicated.

Quinidine: Although no relevant in vitro or in vivo studies have been conducted, 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 tachysystolic arrhythmia of the “pirouette” type.

Concomitant use of quinidine and fluconazole is contraindicated.

Erythromycin: concomitant use of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (prolongation of the QT interval, ventricular arrhythmia of the “pirouette” type) and, consequently, sudden cardiac death. Concomitant use of fluconazole and erythromycin is contraindicated.

Caution should be exercised and possibly dose adjustments should be made when the following medications and fluconazole are used concomitantly:

Drugs that affect fluconazole

Hydrochlorothiazide: Repeated use of hydrochlorothiazide concomitantly with fluconazole results in a 40% increase in the plasma concentration of fluconazole. The effect of this degree of severity does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time, but the doctor should take this into account.

Rifampicin: concomitant use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% decrease in T1 / 2 of fluconazole. In patients taking rifampicin concomitantly, it is necessary to consider the feasibility of increasing the dose of fluconazole.

Drugs affected by fluconazole

Fluconazole is a potent inhibitor of the CYP2C9 and CYP2C19 isoenzymes and a moderate inhibitor of the 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 taken concomitantly with fluconazole. In this regard, caution should be exercised when using these drugs simultaneously, and if necessary, such combinations. Patients should be under close medical supervision. It should be noted that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to prolonged T1/2.

Alfentanil: there is a decrease in clearance and Vd, an increase in T1/2 of alfentanil. This may be due to the inhibition of the CYP3A4 isoenzyme by fluconazole. You may need to adjust the dose of alfentanil.

Amitriptyline, nortriptyline: increased 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. If necessary, the dose of amitriptyline/nortriptyline should be adjusted.

Amphotericin B: in studies on mice (including those with immunosuppression), the following results were noted: a small additive antifungal effect in systemic infection caused by Candida 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 not clear.

Anticoagulants: like other azole – derived antifungal agents, fluconazole, when used concomitantly with warfarin, increases the prothrombin time (by 12%), which may lead to the development of bleeding (hematomas, nosebleeds and gastrointestinal tract, hematuria, melena). In patients receiving coumarin anticoagulants, prothrombin time should be constantly monitored. The feasibility of warfarin dose adjustment should also be evaluated.

Azithromycin: concomitant oral use of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg pronounced pharmacokinetic interaction was not established.

Benzodiazepines (short-acting): after oral use of midazolam, fluconazole significantly increases the concentration of midazolam and psychomotor effects, and this effect is more pronounced after oral use of fluconazole than when it is used intravenously. If concomitant benzodiazepine therapy is necessary, patients taking fluconazole should be monitored to assess whether appropriate benzodiazepine dose reduction is appropriate.

When triazolam is co-administered 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. You may need to adjust the dose of triazolam.

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

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

Cyclosporine: in patients with a kidney transplant, the use of fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine. However, with repeated use of fluconazole at a dose of 100 mg / day, no changes in the concentration of cyclosporine in bone marrow recipients were observed. With the simultaneous use of fluconazole and cyclosporine, it is recommended to monitor the concentration of cyclosporine in the blood.

Cyclophosphamide: When cyclophosphamide and fluconazole are co-administered, serum bilirubin and creatinine concentrations are increased. This combination is acceptable given the risk of increased bilirubin and creatinine concentrations.

Fentanyl: One fatal event has been reported, possibly related to concomitant use of fentanyl and fluconazole. It is assumed that the violations are associated with fentanyl intoxication. Fluconazole has been shown to significantly extend the elimination time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl can lead to respiratory depression.

Halofantrine: fluconazole may increase the concentration of halofantrine in blood plasma due to inhibition of the CYP3A4 isoenzyme.

HMG-CoA reductase inhibitors: concomitant use of fluconazole with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or the CYP2D6 isoenzyme (such as fluvastatin) increases the risk of myopathy and rhabdomyolysis. If concomitant therapy with these drugs is necessary, patients should be monitored for symptoms of myopathy and rhabdomyolysis. It is necessary to monitor the concentration of creatinine kinase. If there is a significant increase in creatinine kinase concentration or if myopathy or rhabdomyolysis is diagnosed or suspected, therapy with HMG-CoA reductase inhibitors should be discontinued.

Losartan: fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which is responsible for most of the effects associated with angiotensin II receptor antagonism. Regular blood pressure monitoring is required.

Methadone: fluconazole may increase the plasma concentration of methadone. You may need to adjust the dose of methadone.

NSAIDs: Cmax and AUC of flurbiprofen 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 co-administered with racemic ibuprofen (400 mg). Concomitant use of fluconazole 200 mg / day and celecoxib 200 mg increased the cmax and AUC of celecoxib by 68% and 134%, respectively. In this combination, it is possible to reduce the dose of celecoxib by half.

Despite the lack of targeted studies, fluconazole may increase the systemic exposure of other NSAIDs metabolized by the CYP2C9 isoenzyme (for example, naproxen, lornoxicam, meloxicam, diclofenac). You may need to adjust the dose of NSAIDs.

Patients with concomitant use of NSAIDs and fluconazole should be closely monitored to detect and control adverse reactions and toxicity associated with NSAIDs.

Oral contraceptives: concomitant use of a combined oral contraceptive with fluconazole at a dose of 50 mg did not significantly affect hormone levels, whereas with daily use of 200 mg of fluconazole, the AUC of ethinyl estradiol and levonorgestrel increases by 40% and 24%, respectively, and with 300 mg of fluconazole 1 time/week. The AUC of ethinyl estradiol and norethindrone increases by 24% and 13%, respectively. Thus, repeated use of fluconazole at these doses is unlikely to affect the effectiveness of the combined oral contraceptive.

Phenytoin: concomitant use of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. If it is necessary to use both drugs simultaneously, the concentration of phenytoin should be monitored and its dose adjusted accordingly in order to ensure therapeutic concentration in blood plasma.

Prednisone: Acute adrenal insufficiency has been reported in a patient after liver transplantation after discontinuation of fluconazole after a 3-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the CYP3A4 isoenzyme, which led to an increase in prednisone metabolism.

Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision when discontinuing fluconazole to assess the condition of the adrenal cortex.

Rifabutin: concomitant use of fluconazole and rifabutin may lead to an increase in the plasma concentration of the latter by up to 80%. Cases of uveitis have been reported with concomitant use of fluconazole and rifabutin. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.

Saquinavir: AUC increases by approximately 50%, Cmax-by 55%, clearance of saquinavir decreases by approximately 50% due to inhibition of hepatic metabolism of the CYP3A4 isoenzyme and inhibition of P-glycoprotein. You may need to adjust the dose of saquinavir.

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

Sulfonylureas: concomitant use of fluconazole leads to an increase in T1 / 2 of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide, and tolbutamide). Patients with diabetes mellitus can be prescribed simultaneously fluconazole and sulfonylureas for oral use, but the possibility of hypoglycemia should be taken into account, in addition, regular monitoring of blood glucose and, if necessary, dose adjustment of sulfonylureas is necessary.

Tacrolimus: concomitant use of fluconazole and tacrolimus (orally) 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 the CYP3A4 isoenzyme. No significant changes in the pharmacokinetics of drugs were observed with the use of tacrolimus iv. Cases of nephrotoxicity are described. Patients receiving concomitant oral use of tacrolimus and fluconazole should be closely monitored. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood.

Theophylline: when used concomitantly with fluconazole at a dose of 200 mg for 14 days, the average rate of plasma clearance of theophylline decreases by 18%. When prescribing fluconazole to patients taking theophylline in high doses, or patients with an increased risk of developing toxic effects of theophylline, the appearance of symptoms of overdose of theophylline should be monitored and, if necessary, therapy should be adjusted accordingly.

Tofacitinib: exposure to tofacitinib increases when co-administered with drugs that are both moderate inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (for example, fluconazole). You may need to adjust the dose of tofacitinib.

Periwinkle alkaloid: despite the lack of targeted studies, it is suggested that fluconazole may increase the concentration of periwinkle alkaloids (for example, vincristine and vinblastine) in blood plasma and, thus, lead to neurotoxicity, which may possibly be associated with inhibition of the CYP3A4 isoenzyme.

Vitamin A: one case of CNS adverse reactions in the form of a pseudotumor of the brain has been reported with the simultaneous use of completely transretinoic acid and fluconazole, which disappeared after discontinuation of fluconazole. The use of this combination is possible, but it should be remembered about the possibility of adverse reactions from the central nervous system.

Zidovudine: when used simultaneously 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, patients with AIDS and ARC (AIDS-related complex) showed a significant increase in the AUC of zidovudine (20%).

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 twice daily on the first day, then 200 mg twice daily for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg/day for 4 days) leads to an increase in the concentration and AUC of voriconazole by 57% and 79%, respectively. It has been shown that this effect persists with a decrease in the dose and / or a decrease in the frequency of taking any of the drugs. Concomitant use of voriconazole and fluconazole is not recommended.

Studies of the interaction of oral forms of fluconazole when administered concomitantly with food, cimetidine, antacids, as well as after total body irradiation to prepare for bone marrow transplantation have shown that these factors do not have a clinically significant effect on the absorption of fluconazole.

The listed interaction was established with repeated use of fluconazole; interaction with drugs as a result of a single dose of fluconazole is unknown. Doctors should keep in mind that interactions with other drugs have not been specifically studied, but they are possible.

Pharmaceutical interaction

Diflucan® – solution for intravenous use 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, aminofuzine, isotonic saline solution. Diflucan® can be administered into the infusion system together with one of the solutions listed above. Although cases of specific incompatibility of fluconazole with other drugs are not described, however, it is not recommended to mix it with any other drugs before infusion.

How to take, course of use and dosage

Rules for using the drug

Dosage and

use Fluconazole can be taken orally (in the form of capsules and suspensions) or administered intravenously (in the form of a solution for intravenous use) by infusion at a rate of no more than 10 ml/min; the choice of route of use depends on the clinical condition of the patient. When transferring a patient from intravenous use to oral use or vice versa, no change in the daily dose is required.

Capsules should be swallowed whole.

When preparing the suspension for oral use, add 24 ml of water to the contents of one bottle and shake thoroughly. The suspension should be shaken before each application.

The solution of the drug for intravenous use contains 0.9% sodium chloride solution; each 200 mg (bottle per 100 ml) contains 15 mmol of Na+ and Cl-. Therefore, in patients who need to limit their sodium or fluid intake, the rate of fluid use should be considered.

Dosage regimen for different age groups and depending on symptoms

Treatment can be started before receiving the results of seeding and other laboratory tests. However, therapy needs to be changed accordingly when the results of these studies become known.

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

Adults with cryptococcal meningitis and cryptococcal infections of other localization are prescribed an average of 400 mg on the first day, and then continue treatment at a dose of 200-400 mg 1 time/day. The duration of treatment for cryptococcal infections depends on the presence of clinical and mycological effects; for cryptococcal meningitis, treatment is usually continued for at least 6-8 weeks.

To prevent recurrence of cryptococcal meningitis in AIDS patients, after completing the full course of primary treatment, fluconazole therapy at a dose of 200 mg / day can be continued for a very long time.

For candidaemia, disseminated candidiasis, and other invasive candida infections, the average dose is 400 mg on the first day, followed by 200 mg/day. Depending on the severity of the clinical effect, the dose can be increased to 400 mg/day. The duration of therapy depends on the clinical efficacy.

With oropharyngeal candidiasis, the drug is prescribed on average 50-100 mg 1 time/day for 7-14 days. If necessary, in patients with a marked decrease in immunity, treatment can be continued for a longer time. In case of atrophic candidiasis of the oral cavity associated with wearing dentures, the drug is prescribed in an average dose of 50 mg 1 time/day for 14 days in combination with local antiseptics for the treatment of the prosthesis.

For other candida infections of the mucous membranes (with the exception of genital candidiasis), for example, esophagitis, non-invasive bronchopulmonary infections, candiduria, candidiasis of the skin and mucous membranes, the effective dose is on average 50-100 mg / day with a treatment duration of 14-30 days.

To prevent relapses of oropharyngeal candidiasis in AIDS patients after completing the full course of primary therapy, fluconazole can be prescribed 150 mg 1 time/week.

With vaginal candidiasis, fluconazole is taken once orally at a dose of 150 mg.

To reduce the frequency of relapses of vaginal candidiasis, the drug can be used at a dose of 150 mg 1 time/month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may require more frequent use. The use of the drug in a single dose in children under 18 years of age and patients over 60 years of age without a doctor’s prescription is not recommended.

With balanitis caused by Candida spp., fluconazole is prescribed once in a dose of 150 mg orally.

For the prevention of candidiasis, the recommended dose of fluconazole is 50-400 mg 1 time / day, depending on the degree of risk of fungal infection. If there is a high risk of generalized infection, for example, in patients with severe or long-term neutropenia, the recommended dose is 400 mg 1 time / day. Diflucan® is prescribed a few days before the expected development of neutropenia and after an increase in the number of neutrophils more than 1000/µl, treatment is continued for another 7 days.

For skin infections, including mycoses of the feet, smooth skin, groin and candida infections, the recommended dose is 150 mg 1 time / week. or 50 mg 1 time/day. The duration of therapy in normal cases is 2-4 weeks, however, with mycoses of the feet, longer therapy may be required (up to 6 weeks).

For pityriasis versicolor, the recommended dose is 300 mg once a week. within 2 weeks; some patients require a third dose of 300 mg / week., while for some patients, a single dose of 300-400 mg of the drug is sufficient. An alternative treatment regimen is the use of the drug 50 mg 1 time/day for 2-4 weeks.

For onychomycosis, the recommended dose is 150 mg once a week. Treatment should be continued until the infected nail is replaced (uninfected nail regrowth). It usually takes 3-6 months and 6-12 months, respectively, for the nails to regrow on the fingers and feet. However, the rate of growth can vary widely in different people, as well as depending on age. After successful treatment of long-term chronic infections, sometimes there is a change in the shape of the nails.

Deep endemic mycoses may require the use of the drug at a dose of 200-400 mg / day for up to 2 years. The duration of therapy is determined individually; it is 11-24 months for coccidioidomycosis,2-17 months for paracoccidioidomycosis,1-16 months for sporotrichosis, and 3-17 months for histoplasmosis.

In children, as with 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 1 time/day.

For mucosal candidiasis, the recommended dose of Diflucan is 3 mg / kg / day. On the first day, a shock dose of 6 mg/kg may be prescribed 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.

To suppress the recurrence of cryptococcal meningitis in children with AIDS, the recommended dose of Diflucan® is 6 mg / kg / day.

For the prevention of fungal infections in patients with reduced immunity, whose risk of infection is associated with neutropenia, developing as a result of cytotoxic chemotherapy or radiation therapy, the drug is prescribed at 3-12 mg / kg / day, depending on the severity and duration of preservation of induced neutropenia.

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

In the first 2 weeks of life, the drug is prescribed in the same dose (in mg / kg) as older children, but with an interval of 72 hours.

Children aged 3 and 4 weeks of life are given the same dose at intervals of 48 hours.

Dosage regimen in special clinical cases

In elderly patients with no signs of renal failure, the drug is prescribed in an average dose. Elderly patients with renal insufficiency (CC

Fluconazole is mainly excreted unchanged in the urine. With a single dose, no dose change is required. In patients (including children) with impaired renal function with repeated use of the drug, a shock dose of 50 mg to 400 mg should be initially administered, after which the daily dose (depending on the indications) is determined according to the following table.

KK (ml / min)Recommended dose percentage> 50100%≤ 50 (without dialysis)50%Regular dialysis 100% after each dialysis session

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis session. On the day when dialysis is not performed, patients should receive a reduced dose of the drug (depending on the creatinine clearance).

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

Overdose

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

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

Fluconazole is mainly excreted in the urine, so forced diuresis can probably accelerate its elimination. A 3-hour hemodialysis session reduces the plasma level of fluconazole by approximately 50%.

Special instructions

Precautions when taking the drug

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

In rare cases, the use of fluconazole was accompanied by toxic changes in the liver, including with a fatal outcome, mainly in patients with serious concomitant diseases. There was no obvious dependence of the hepatotoxic effects of fluconazole on the total daily dose, duration of therapy, gender and age of the patient. The hepatotoxic effect of fluconazole was usually reversible; signs of it disappeared after discontinuation of therapy. Patients who have 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 rarely developed exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. People with AIDS are more likely to develop severe skin reactions when using many medications. If a patient receiving treatment for a superficial fungal infection develops a rash that may be associated with the use of fluconazole, the drug should be discontinued. If a rash appears in patients with invasive / systemic fungal infections, they should be carefully monitored and discontinue fluconazole if bullous lesions or erythema multiforme occur.

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

Concomitant use of fluconazole at doses less than 400 mg / day and terfenadine should be carefully monitored.

Like other azoles, fluconazole can cause an increase in the QT interval on the ECG. When using fluconazole, increased QT interval and ventricular fibrillation/flutter were observed very rarely in patients with multiple risk factors, such as organic heart disease, electrolyte imbalance, and concomitant therapy that contributes to the development of such disorders. Therefore, such patients with potentially proarrhythmic conditions should use fluconazole with caution.

Patients with liver, heart and kidney diseases should consult their doctor before using Diflucan®. When using Diflucan® 150 mg for vaginal candidiasis, patients should be warned that symptoms usually improve after 24 hours, but sometimes it takes several days for them to completely disappear. If symptoms persist for several days, you should consult a doctor.

Evidence for the efficacy of fluconazole in the treatment of other endemic mycoses, such as paracoccidioidomycosis, sporotrichosis, and histoplasmosis, is limited, making it impossible to determine specific dosage recommendations.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Experience with the use of Diflucan® indicates that deterioration of the ability to drive a car and mechanisms associated with the use of the drug is unlikely.

Interaction with alcohol

There are no data on interaction with alcohol.

Conditions of release from pharmacies

The drug is available on prescription.

The drug in the form of 150 mg capsules is allowed for use as an over-the-counter medication (only for the treatment of vaginal candidiasis previously confirmed by a doctor).

Form of production

Capsules

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

5 years

Active ingredient

Fluconazole

Conditions of release from pharmacies

By prescription

Dosage form

Capsules

Purpose

For adults and children as prescribed by a doctor

Indications

Fungus, Skin Fungus, Nail Fungus, Thrush