Diflucan - instructions for use, dose, side effects, contraindications

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

Fluconazole activity was demonstrated in vitro for the following microorganisms, however, the clinical significance of this is unknown: Candida dubliniensis, Candida guilliermondii, Candida kefyr, Candida lusitaniae.

With intravenous administration fluconazole was active on various models of fungal infections in animals. The activity of the drug was demonstrated for opportunistic mycoses, including those caused by Candida spp. (including generalized candidiasis in animals with depressed immunity); Cryptococcus neoformans (including intracranial infections); Microsporum spp. and Trychophyton spp. The activity of fluconazole on the models of endemic mycoses in animals, including infections caused by Blastomyces dermatitides, Coccidioides immitis (including intracranial infections) and Histoplasma capsulatum the animals with normal and suppressed immunity.

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

Mechanisms of development of resistance to fluconazole

Resistance to fluconazole may develop in the following cases: a qualitative or quantitative change in the enzyme that is the target for fluconazole (lanosterol 14-a-demethylase), a decrease in access to the target of fluconazole, or a combination of these mechanisms.

Point mutations in the gene ERG11, which encodes the target enzyme, lead to a modification of the target and a decrease in the affinity for the azoles. Increased gene expression ERG11 leads to the production of high concentrations of the target enzyme, which necessitates an increase in the concentration of fluconazole in the intracellular fluid for suppression of all molecules of the enzyme in the cell.

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

Hyperexpression of the gene MDR leads to resistance to fluconazole, while at the same time overexpression of genes CDR can lead to resistance to various azoles.

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

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

Pharmacokinetics:

Fluconazole is a selective inhibitor of isoenzymes CYP2C9 and CYP3A4, fluconazole is also an inhibitor of the isoenzyme CYP2C19. The pharmacokinetics of fluconazole is similar for intravenous administration and ingestion. The concentration in the blood plasma is proportional to the dose and reaches a maximum (C_m_Oh) 0.5-1.5 hours after taking fluconazole on an empty stomach, and the half-life is about 30 hours. 90% of the equilibrium concentration is reached by 4-5 days after the start of therapy (with repeated administration of the drug once a day).

The introduction of a shock dose (on day 1), twice the usual daily dose, makes it possible to achieve 90% of the equilibrium concentration by the 2nd day. The volume of distribution approximates the total water content in the body. Binding to plasma proteins is low (11-12%).

Fluconazole well penetrates into all body fluids. The concentrations of fluconazole in saliva and sputum are similar to those in plasma. In patients with fungal meningitis, fluconazole concentrations in the cerebrospinal fluid are about 80% of its concentrations in the blood plasma.

In the stratum corneum, the epidermis, the dermis and the sweat fluid, high concentrations are reached that exceed the serum levels. Fluconazole accumulates in the stratum corneum. When administered at a dose of 50 mg once a day, the concentration of fluconazole after 12 days is 73 μg / g, and after 7 days after discontinuation of treatment, only 5.8 μg / g.When applied at a dose of 150 mg once a week, the fluconazole concentration in the stratum corneum on day 7 is 23.4 μg / g, and 7 days after the second dose - 7,1 μg / g. The concentration of fluconazole in the nails after 4 months of use at a dose of 150 mg once a week is 4.05 μg / g in healthy and 1.8 μg / g in the affected nails; 6 months after completion of therapy fluconazole is still determined in the nails.

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

A long half-life from plasma allows fluconazole once a day or once a week - with other indications.

Pharmacokinetics in children

The following pharmacokinetic parameters were obtained in children.

Age	Dose (mg / kg)	Half-life (hour)	AUC (μg / ml)
11 days - 11 months	Once - in / in 3 mg / kg	23	110,1
5 years - 15 years	Repeatedly - in / in 2 mg / kg	17,4*	67,4*
5 years - 15 years	Repeatedly - iv 4 mg / kg	15,2*	139,1*
5 years - 15 years	Multiple - IV dose of 8 mg / kg	17,6*	196,7*

* the indicator marked on the last day

Preterm infants (about 28 weeks of development) fluconazole was administered intravenously at a dose of 6 mg / kg each The third day before the introduction of a maximum of 5 doses while the children remained in the intensive care unit. The mean half-life was 74 h (within 44-185 h) on the 1st day, with a decrease on the 7th day on average to 53 h (within 30-131 h) and on the 13th day on average to 47 h (within the limits of 27-68 hours).

The value of the area under the curve "concentration-time" (AUC) was 271 μg / mL (within 173-385 μg / mL) in 1 day, then increased to 490 μg / ml (within 292-734 μg / ml) on the 7th day and decreased to an average of 360 μg h / ml (within the range of 167-566 μg / ml) to the 13- day.

The volume of distribution was 1183 ml / kg (within 1070-1470 ml / kg) on day 1, then increased to an average of 1,184 ml / kg (range 510-2130 ml / kg) on day 7 and up to 1328 ml / kg (within 1040-1680 ml / kg) on the 13th day.

Pharmacokinetics in elderly patients

It was found that with a single application of fluconazole at a dose of 50 mg orally in elderly patients aged 65 years and older, some of whom concurrently took diuretics, the maximum concentration was achieved 1.3 hours after ingestion and was 1.54 μg / ml, the mean the area under the concentration-time curve is 76.4 ± 20.3 μg / ml, and the average half-life is 46.2 hours. The values of these pharmacokinetic parameters are higher than in young patients, which is probably associated with a decreased renal function characteristic of the elderly.Simultaneous reception of diuretics did not cause a pronounced change in the area under the concentration-time curve and maximum concentration. Creatinine clearance (74 ml / min), the percentage of fluconazole excreted by the kidneys unchanged (0-24 h, 22%) and the renal clearance of fluconazole (0.124 ml / min / kg) is lower in elderly patients than in young patients.

Indications:

- cryptococcosis, including cryptococcal meningitis and other localization infections (eg, lungs, skin), including those with normal immune response and AIDS patients, transplant recipients and patients with other forms of immunodeficiency; Supportive therapy for the prevention of recurrence of cryptococcosis in AIDS patients;

- generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis infection such as peritoneal, endocardial, eye, respiratory and urinary tract infections, including in patients with malignant tumors in intensive care units receiving cytotoxic or immunosuppressive agents, as well as in patients with other factors predisposing to the development of candidiasis;

- candidiasis of the mucous membranes, including oral and pharyngeal mucosa, esophagus, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic atrophic candidiasis of the oral cavity (associated with the wearing of dentures), including in patients with normal and suppressed immune function; prevention of recurrence of oropharyngeal candidiasis in AIDS patients;

- genital candidiasis; acute or recurrent vaginal candidiasis; prevention to reduce the frequency of recurrence of vaginal candidiasis (3 or more episodes a year); Candidiasis balanitis;

- prevention of fungal infections in patients with malignant tumors, predisposed to such infections as a result of cytotoxic chemotherapy or radiation therapy;

- mycosis of the skin, including mycosis of the feet, body, inguinal region, pityriasis, onychomycosis and cutaneous candidiasis infections;

- deep endemic mycoses in patients with normal immunity, coccidioidomycosis.

Contraindications:

- hypersensitivity to fluconazole, other components of the drug or azole substances with a similar fluconazole structure;

- simultaneous reception of terfenadine during multiple use of fluconazole at a dose of 400 mg / day or more (see section "Interaction with other drugs");

- simultaneous use with drugs that increase the interval QT and metabolized by isoenzyme CYP3A4, such as cisapride, astemizole, erythromycin, pimozide and quinidine (see section "Interaction with other drugs").

Carefully:

- violation of liver function;

- impaired renal function;

- the appearance of rashes on the background of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections;

- simultaneous application of terfenadine and fluconazole in a dose of less than 400 mg / day;

- potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy contributing to the development of such disorders).

Pregnancy and lactation:

Adequate and controlled studies of pregnant women have not been conducted. Cases of multiple congenital malformations in newborns are described,mothers of whom for most or all of the first trimester received fluconazole therapy in high doses (400-800 mg / day) for coccidioidomycosis. The following developmental disorders were noted: brachycephaly, development of the facial part of the skull, violation of the formation of the cranial vault, wolf mouth, bending of the femurs, thinning and lengthening of the ribs, arthrogryposis and congenital heart defects. At present, there is no evidence of a relationship of the listed congenital anomalies with the use of low doses of fluconazole (150 mg once for the treatment of vulvovaginal candidiasis) in the first trimester of pregnancy. During pregnancy, the use of fluconazole should be avoided, except in cases of severe and potentially life-threatening fungal infections, when the expected benefit of treatment for the mother exceeds the possible risk for the fetus.

Women of childbearing age should use contraception. Fluconazole is found in breast milk in concentrations close to plasma, so its appointment to women during breastfeeding is not recommended.

Dosing and Administration:

Intravenous infusion.

Therapy can begin before the results of sowing and other laboratory tests. However, antifungal therapy must be changed accordingly when the results of these studies become known. Fluconazole can be taken or injected intravenously by infusion at a rate of not more than 10 ml / min; The choice of method of administration depends on the clinical condition of the patient. When transferring a patient from an intravenous to an oral intake of the drug or vice versa, a daily dose change is not required. In solution fluconazole for intravenous administration contains 0.9% solution of sodium chloride; in each 200 mg (vial per 100 ml) contains 15 mmol of sodium and chlorine ions. Therefore, in patients who need to limit the intake of sodium or liquid, it is necessary to take into account the rate of fluid administration.

The daily dose of Diflucan® depends on the nature and severity of the fungal infection. With vaginal candidiasis, in most cases, a single dose is effective. In infections requiring repeated use of an antifungal drug, treatment should continue until the disappearance of clinical or laboratory signs of an active fungal infection.People with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually need maintenance therapy to prevent recurrence of the infection.

Application in adults

- In cryptococcal meningitis and cryptococcal infections of other localization, 400 mg is usually administered on the first day, and then the treatment is continued at a dose of 200-400 mg once a day. The duration of treatment for cryptococcal infections depends on the presence of a clinical and mycological effect; In cryptococcal meningitis, treatment usually lasts at least 6-8 weeks.

To prevent the recurrence of cryptococcal meningitis in AIDS patients, after completing the full course of primary treatment, therapy with Diflucan® in a dose of 200 mg / day can continue indefinitely.

- With candidemia, disseminated candidiasis and other invasive candidiasis infections, the dose is usually 400 mg on day 1, then 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 clinical effectiveness.

- With oropharyngeal candidiasis, the drug is usually administered at 50-100 mg once a day for 7-14 days.If necessary, treatment with a pronounced suppression of immune function treatment can be continued for a longer time. With atrophic candidiasis of the oral cavity associated with the wearing of dentures, the drug is usually applied at a dose of 50 mg once a day for 14 days in combination with local antiseptic agents for prosthesis treatment.

In other candidal infections of mucous membranes (with the exception of genital candidiasis, see below), for example, esophagitis, non-invasive bronchopulmonary infections, candiduria, candidiasis of the skin and mucous membranes, etc., the effective dose is usually 50-100 mg / day with a treatment duration of 14-30 days.

To prevent the recurrence of oropharyngeal candidiasis in AIDS patients, after completion of the full course of primary therapy with Diflucan®, 150 mg once a week can be used.

- In vaginal candidiasis, Diflucan® is applied once inside at a dose of 150 mg. To reduce the frequency of recurrences of vaginal candidiasis, the drug can be used at a dose of 150 mg once a week. The duration of anti-relapse therapy is determined individually and, as a rule, is 6 months.The use of a single dose to children under 18 years of age and patients older than 60 years without a doctor's recommendation is not recommended.

With balanitis caused by Candida, Diflucan® is used once in a dose of 150 mg orally.

- For the prevention of candidiasis in patients with malignant tumors, the recommended dose of Diflucan is 50-400 mg once a day, depending on the degree of risk of fungal infection. For patients at high risk of generalized infection, for example, with severe or long-lasting neutropenia, the recommended dose is 400 mg once a day. Diflucan® is used several days before the expected development of neutropenia and, after an increase in the number of neutrophils more than 1000 in mm³, treatment continues for another 7 days.

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

With pityriasis, the recommended dose is 300 mg once a week for 2 weeks; some patients require a third dose of 300 mg per week, while as for some patients, a single dose of 300-400 mg is sufficient. An alternative treatment regimen is the use of the drug at 50 mg once a day for 2-4 weeks.

With onychomycosis, the recommended dose is 150 mg once a week. Treatment should continue until the replacement of the infected nail (growth of uninfected nail). For the repeated growth of nails on the fingers and toes, it usually takes 3-6 months and 6-12 months, respectively. However, the growth rate can vary widely among different people, and also depending on age. After successful treatment of long-lasting chronic infections, the shape of the nails is sometimes observed.

- With deep endemic mycoses, it may be necessary to use the drug in a dose of 200-400 mg / day. Therapy can last up to 2 years. The duration of therapy is determined individually; it is 11-24 months with coccidioidomycosis.

Use in children

As with similar infections in adults, the duration of treatment depends on the clinical and mycological effect. For children, the daily dose of the drug should not exceed that for adults. The maximum daily dose is 400 mg.Diflucan® is used daily once a day.

In mucosal candidiasis, the recommended dose of Diflucan® is 3 mg / kg / day. On the first day, to achieve a more rapid equilibrium concentration, a shock dose of 6 mg / kg can be used.

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

For the prevention of fungal infections in patients with suppressed immunity, in which the risk of infection is associated with neutropenia, resulting from cytotoxic chemotherapy or radiation therapy, the drug is used at 3-12 mg / kg / day, depending on the severity and duration of preservation of induced neutropenia (cm dose for adults, for children with kidney failure - see the dose for patients with renal insufficiency).

Use in children aged 4 weeks and less

In newborns fluconazole output slowly. In the first 2 weeks of life, the drug is administered at the same dose (in mg / kg) as for older children, but at intervals of 72 hours.Children at the age of 3 and 4 weeks of the same dose administered at an interval of 48 hours.

Application in the elderly

In the absence of signs of renal failure, the drug is used in a usual dose. Patients with renal insufficiency (creatinine clearance <50 ml / min) dose of the drug is corrected, as described below.

Application the patients with renal insufficiency

With a single admission dose changes are not required. In patients (including children) with impaired renal function, repeated use of the drug should initially be given a shock dose of 50 mg to 400 mg, after which the daily dose (depending on the indication) is set according to the following table.

Creatinine clearance (ml / min)

Percent recommended dose

> 50

<50 (without dialysis) Routine dialysis

100 %

50 %

100% after each dialysis

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

Use in patients with liver failure

There are limited data on the use of fluconazole in patients with liver failure.In this regard, with the use of Diflucan ® in this category of patients should be careful.

Side effects:

Drug tolerance is usually very good.

In clinical and post-marketing (*) studies of Diflucan®, the following adverse reactions were noted.

From the nervous system: headache, dizziness *, convulsions *, taste change *, paresthesia, insomnia, drowsiness, tremor.

From the digestive system: abdominal pain, diarrhea, flatulence, nausea, dyspepsia *, vomiting *, dryness of the oral mucosa, constipation.

From the hepatobiliary system: hepatotoxicity, in some cases with fatal outcome, increased bilirubin concentration, serum activity of aminotransferases (alanine aminotransferase (ALT) and aspartate aminotransferase (ACT)), alkaline phosphatase, a violation of liver function *, hepatitis *, hepatocellular necrosis *, jaundice *, cholestasis, hepatocellular damage.

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

On the part of the organs of hematopoiesis and lymphatic system *: leukopenia, including neutropenia and agranulocytosis, thrombocytopenia, anemia.

From the immune system *: anaphylaxis (including angioedema, edema of the face, hives, itching).

From the cardiovascular system *: interval increase QT on the ECG, ventricular tachycardia as pirouette (see section "Special instructions").

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

From the musculoskeletal system: myalgia.

Other: weakness, asthenia, fatigue, fever, increased sweating, vertigo.

In some patients, especially with serious diseases such as AIDS or cancer, changes in blood counts, kidney and liver function were observed with Diflucan® and similar preparations (see section "Special instructions"), but the clinical significance of these changes and their relationship with treatment not established.

Overdose:

There are reports of an overdose of fluconazole, and in one case, a 42-year-old patient infected with human immunodeficiency virus received hallucinations and paranoid behavior after taking 8200 mg of the drug.The patient was hospitalized; his condition returned to normal within 48 hours.

In case of an overdose, symptomatic therapy (including supportive measures and gastric lavage) is performed.

Fluconazole is excreted mainly through the kidneys, so forced diuresis, probably, can speed up the elimination of the drug. The hemodialysis session lasting 3 hours reduces the concentration of fluconazole in blood plasma by approximately 50%.

Interaction:

A single or multiple application of fluconazole at a dose of 50 mg does not affect the metabolism of phenazone (Antipyrine) when they are used simultaneously.

The simultaneous use of fluconazole with the following drugs is contraindicated:

Cisapride: with the simultaneous use of fluconazole and cisapride, unwanted reactions from the heart are possible, including arrhythmia of the ventricular tachysystolic type "pirouette" (torsade de pointes). The use of fluconazole at a dose of 200 mg 1 time per day and cisapride in a dose of 20 mg 4 times a day leads to a pronounced increase plasma concentrations of cisapride and increase the interval QT on the ECG. Simultaneous use of cisapride and fluconazole is contraindicated.

Terfenadine: with the simultaneous use of azole antifungal agents and terfenadine, serious arrhythmias can occur as a result of an increase in the interval QT. When using fluconazole at a dose of 200 mg / day of increasing the interval QT is not established, however, the use of fluconazole at doses of 400 mg / day and higher causes a significant increase in the concentration of terfenadine in the blood plasma. The simultaneous use of fluconazole 400 mg / day or more with terfenadine is contraindicated (see the section "Contraindications"). Treatment with fluconazole at doses less than 400 mg / day in combination with terfenadine should be carefully monitored.

Astemizole: the simultaneous use of fluconazole with astemizole or other drugs metabolized by the cytochrome P450 system may be accompanied by an increase in the serum concentrations of these agents. Elevated concentrations of astemizole in the blood plasma can lead to lengthening of the interval QT and in some cases to the development of ventricular arrhythmia tahisystolic type "pirouette" (torsade de pointes). Simultaneous use of astemizole and fluconazole is contraindicated.

Pimozide: Despite the fact that no relevant studies have been carried out in vitro or in vivo, simultaneous application of fluconazole and pimozide can lead to inhibition of the metabolism of pimozide. In turn, an increase in plasma concentrations of pimozide can lead to an elongation of the interval QT and in some cases to the development of arrhythmia of the ventricular tachysystolic type "pirouette" (torsade de pointes). Simultaneous use of pimozide and fluconazole is contraindicated.

Quinidine: Despite the fact that no relevant studies have been carried out in vitro or in vivo, simultaneous application of fluconazole and quinidine may also lead to inhibition of quinidine metabolism. The use of quinidine is associated with lengthening the interval QT and in some cases with the development of arrhythmia of the ventricular tachysystolic type "pirouette" (torsade de pointes). Simultaneous use of quinidine and fluconazole is contraindicated.

Erythromycin: simultaneous application of fluconazole and erythromycin potentially leads to an increased risk of cardiotoxicity (lengthening of the interval QT, torsade de pointes) and, as a result, sudden cardiac death. The simultaneous use of fluconazole and erythromycin is contraindicated.

Care should be taken and, possibly, dose adjustments should be made while using the following drugs and fluconazole:

Drugs affecting fluconazole:

Hydrochlorothiazide: multiple use of hydrochlorothiazide simultaneously with fluconazole leads to an increase in the concentration of fluconazole in the blood plasma by 40%. The effect of this degree of expression 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: simultaneous application of fluconazole and rifampicin leads to a decrease the values of the area under the curve "concentration-time" by 25% and the duration of the half-life of fluconazole by 20%. In patients, simultaneously host rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.

Drugs affected by fluconazole:

Fluconazole is a potent inhibitor of isoenzyme CYP2C9 and CYP2C19 cytochrome P450 and a moderate isoenzyme inhibitor CYP3A4. In addition, in addition to the effects listed below, there is a risk of an increase in plasma concentrations and other drugs metabolized isoenzymes CYP2C9, CYP2C19 and CYP3A4 with simultaneous application with fluconazole. In this regard, care should be taken when simultaneous application listed drugs, and if necessary, such combinations patients should be under careful medical supervision. It should be borne in mind that the inhibitory effect of fluconazole persists for 4-5 days after discontinuation of the drug due to a prolonged half-life.

Alfentanil: there is a decrease clearance and volume distribution, an increase in the half-life of alfentanil. Perhaps this is due to inhibition of the isoenzyme CYP3A4 fluconazole. Alfventanyl dosage adjustment may be required.

Amitriptyline, nortriptyline: increase in effect. The concentration of 5-nortryptiline and / or S-amitriptyline can be measured at the beginning combined therapy with fluconazole and a week after the onset. If necessary, adjust the dose amitriptyline / nortriptyline.

Amphotericin B: in studies on mice (including, with immunosuppression), the following results were noted: small additive antifungal effect in systemic infection caused by C. albicans, lack of interaction with intracranial infection caused by Cryptococcus neoformans and antagonism in case of systemic infection caused by A. fumigatus. The clinical significance of these results is not clear.

Anticoagulants: like the others antifungal agents (azole derivatives), fluconazole, with simultaneous application with warfarin, increases prothrombin time (by 12%), which is why bleeding may develop (hematomas, nosebleeds and gastrointestinal tract, hematuria, melena). Patients receiving coumarin anticoagulants should constantly monitor prothrombin time. Also, the appropriateness of correcting the dose of warfarin should be evaluated.

Azithromycin: with simultaneous application of fluconazole in a single dose of 800 mg with azithromycin in a single dose of 1200 mg expressed pharmacokinetic interaction between both drugs is not established.

Benzodiazepines (short-acting): after ingestion of midazolam, fluconazole significantly increases the concentration of midazolam and psychomotor effects, and this effect is more pronounced after taking fluconazole orally than with its use intravenously. If necessary concomitant therapy with benzodiazepines of patients, host fluconazole, it follows that To observe with the purpose of an estimation of expediency of corresponding reduction of a dose of benzodiazepine. With the simultaneous use of a single dose of triazolam, fluconazole increases the the area under the concentration-time curve and the maximum concentration triazolam approximately 50% and 25-32%, respectively, half-life - by 25-50% due to oppression metabolism of triazolam. Can dosage adjustment is needed triazolam.

Carbamazepine: fluconazole depresses metabolism of carbamazepine and increases serum concentration carbamazepine by 30%. Required take into account the risk of development of toxicity of carbamazepine. It is necessary to evaluate the need for correcting the dose of carbamazepine as a function of concentration / effect.

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

Cyclosporine: In patients with a transplanted kidney, 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, changes in the concentration of cyclosporin in bone marrow recipients were not observed. With the simultaneous use of fluconazole and cyclosporine, it is recommended to monitor the concentration of cyclosporine in the blood.

Cyclophosphamide: with the simultaneous use of cyclophosphamide and fluconazole, there is an increase in serum bilirubin concentrations and creatinine. This combination is acceptable given the risk of increasing concentrations of bilirubin and creatinine.

Fentanyl: there is a report of one fatal outcome, possibly associated with simultaneous use of fentanyl and fluconazole. It is assumed that the violations are associated with intoxication with fentanyl. It was shown that fluconazole significantly prolongs the excretion time of fentanyl. It should be borne in mind that an increase in the concentration of fentanyl may lead to inhibition of respiratory function.

Halofantrine: fluconazole can increase the concentration of halophanthin in the blood plasma in connection with the inhibition of the isoenzyme CYP3A4.

Inhibitors of HMG-CoA reductase: at simultaneous application of fluconazole with inhibitors of HMG-CoA reductase,metabolized isoenzyme CYP3A4 (such as atorvastatin and simvastatin) or isoenzyme CYP2D6 (such as fluvastatin), the risk of developing myopathy and rhabdomyolysis increases. In case of need for simultaneous therapy with these drugs, patients should be observed to identify the symptoms of myopathy and rhabdomyolysis. Required control concentration creatinine kinase. When significant increase in the concentration of creatinine kinase or if is diagnosed or suspected of developing myopathy or rhabdomyolysis, therapy inhibitors HMG-CoA reductase should be discontinued.

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

Methadone: fluconazole can increase the plasma concentration of methadone. Methadone dose adjustment may be necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs): the area under the concentration-time curve and the maximum concentration of flurbiprofen increased by 81% and 23%, respectively. Similarly the area under the concentration-time curve and the maximum concentration pharmacologically active isomer [8 - (+) - ibuprofen] increased by 82% and 15%, respectively, with simultaneous application of fluconazole with racemic ibuprofen (400 mg). With the simultaneous use of fluconazole at a dose of 200 mg / day and celecoxib at a dose of 200 mg, the maximum concentration and area under the curve "concentration-time" celecoxib increased by 68% and 134%, respectively. In this combination, a dose reduction of celecoxib can be halved.

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

With the simultaneous use of NSAIDs and fluconazole, patients should be under careful medical surveillance to identify and control unwanted phenomena and manifestations of toxicity, associated with NSAIDs.

Oral contraceptives: at simultaneous application combined oral contraceptive with fluconazole at a dose of 50 mg has no significant effect on the level of hormones, whereas with daily use of 200 mg fluconazole values the area under the concentration-time curve of ethinyl estradiol and levonorgestrel is increased by 40% and 24%, respectively, and when 300 mg of fluconazole is administered once a week, the area under the concentration-time curve of ethinylestradiol and norethindrone increases by 24% and 13% respectively. Thus, the repeated use of fluconazole at these doses is unlikely to have an effect on the efficacy combined oral contraceptive.

Phenytoin: simultaneous application of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. If simultaneous use of both drugs is necessary, the concentration of phenytoin should be monitored and its dose adjusted accordingly to ensure therapeutic serum concentration.

Prednisone: there is a report on the development of acute adrenal insufficiency in the patient after liver transplantation with a fluconazole withdrawal after a three-month course of therapy.Presumably, discontinuation of fluconazole therapy caused an increase in isoenzyme activity CYP3A4, which led to an increased metabolism of prednisone. Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision when fluconazole is withdrawn in order to assess the state of the adrenal cortex.

Rifabutin: simultaneous application of fluconazole and rifabutin can lead to an increase in serum concentrations of the latter up to 80%. When the simultaneous use of fluconazole and rifabutin described cases of uveitis. Patients receiving concurrently rifabutin and fluconazole, must be carefully observed.

Saquinavir: the area under the "concentration-time" curve increases approximately 50%, the maximum concentration - by 55%, clearance of saquinavir decreases by approximately 50% due to inhibition of hepatic isoenzyme metabolism CYP3A4 and inhibition of P-glycoprotein.

You may need to adjust the dose of saquinavir.

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

Sulfonylurea preparations: fluconazole, with simultaneous application, leads to an increase in the half-life of oral sulfonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes can be assigned joint use of fluconazole and oral sulfonylureas, but it should take into account the possibility of developing hypoglycemia, in addition, regular monitoring of blood glucose and, if necessary, dose adjustment of sulfonylureas.

Tacrolimus: simultaneous application of fluconazole and tacrolimus (inward) leads to an increase in serum concentrations of the latter up to 5 times by inhibiting the metabolism of tacrolimus occurring in the intestine through isoenzyme CYP3A4. Significant changes in the pharmacokinetics of drugs have not been observed with tacrolimus intravenously. Cases of nephrotoxicity are described. Patients who simultaneously take tacrolimus inside and fluconazole, should be carefully observed. The dose of tacrolimus should be adjusted depending on the degree of increase in its concentration in the blood.

Theophylline: while simultaneous application with fluconazole at a dose of 200 mg for 14 days, the average plasma clearance rate of theophylline is reduced by 18%. In the administration of fluconazole to patients receiving theophylline in high doses, or patients with an increased risk of developing toxic effects theophylline, one should observe the appearance of symptoms of an overdose of theophylline and, if necessary, adjust the therapy accordingly.

Tofacitinib: the exposure of tofacitinib increases with its simultaneous use with drugs that are both moderate inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (for example, fluconazole). It may be necessary to correct the dose of tofacitinib.

Vinca alkaloid: Despite the lack of targeted research, it is assumed that fluconazole can increase the concentration of vinca alkaloids (eg, vincristine and vinblastine) in the blood plasma and, thus, lead to neurotoxicity, which may possibly be due to inhibition of the CYP3A4 isoenzyme.

Vitamin A: there is a report of one case of the development of unwanted reactions from the side of the CNS in the form of a pseudotumor of the brain with simultaneous application of all transretinic acid and fluconazole that disappeared after the withdrawal of fluconazole. The use of this combination is possible, but should be aware of the possibility of undesirable reactions from the side of the central nervous system.

Zidovudine: with simultaneous with fluconazole values of the maximum concentration of the area under the curve "concentration-time" 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 200 mg / day for 15 days with AIDS and ARC (AIDS-related complex), a significant increase the values of the area under the curve "concentration-time" zidovudine (20%). Patients, receiving such a combination should be observed to identify side effects zidovudine.

Voriconazole (inhibitor of isoenzymes CYP2C9. CYP2C19 and CYP3A4): simultaneous application voriconazole (400 mg twice a day on the first day,then 200 mg twice a day for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg per day for 4 days) leads to an increase in the concentration and the values of the area under the curve "concentration-time" voriconazole by 57% and 79%, respectively. It was shown that this effect persists with a reduction in the dose and / or a decrease in the frequency of administration of any of the drugs. Simultaneous use of voriconazole and fluconazole is not recommended.

Investigations of the interaction of oral forms of fluconazole with its simultaneous administration with food, cimetidine, antacids, and after total body irradiation for the preparation of bone marrow transplantation showed that these factors do not have a clinically significant effect on the absorption of fluconazole.

The above interactions were established with repeated application of fluconazole; interactions with drugs as a result of a single dose of fluconazole are unknown.

Doctors should take into account that interaction with other drugs has not been specifically studied, but it is possible.

Special instructions:

There have been reports of cases of superinfection caused by Candida albicans strains Candida, which often have a 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 fatalities, mainly in patients with serious concomitant diseases. In the case of hepatotoxic effects associated with the use of fluconazole, their apparent dependence on the total daily dose of the drug, the duration of therapy, the sex and age of the patient was not noted. The hepatotoxic effect of the drug was usually reversible; signs of it disappeared after discontinuation of therapy.

Patients who, at the time of drug treatment, are impaired by function indicators liver, it is necessary to observe in order to reveal signs of more serious liver damage. If there are clinical signs or symptoms of liver damage that may be associated with the use of fluconazole, the drug should be discarded.

As with the use of other azoles, fluconazole in rare cases can cause anaphylactic reactions.

During treatment with fluconazole, exfoliative skin lesions developed rarely in patients, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients with AIDS are more likely to develop severe skin reactions with many drugs. When the patient develops a superficial fungal infection of the rash during treatment, which can be associated with the use of fluconazole, the drug should be discarded. When rashes appear in patients with invasive or systemic fungal infections, they should be carefully monitored and canceled the drug with the appearance of bullous lesions or multiforme exudative erythema.

Simultaneous use of fluconazole in doses less than 400 mg / day and terfenadine should be carried out under close supervision (see section "Interaction with other drugs").

Like other azoles, fluconazole may cause an increase in the interval QT on the ECG. When using fluconazole, the increase in the interval QT and fibrillation or flutter of the ventricles was very rare in patients with severe diseases with multiple risk factors, such as organic heart disease, electrolyte imbalance, and accompanying therapy contributing to the development of such disorders.Therefore, in such patients with potentially proarrhythmic conditions, fluconazole with caution.

Patients with diseases of the liver, heart and kidneys are advised to consult a doctor before using the drug. When fluconazole 150 mg is used for vaginal candidiasis, patients should be warned that symptom improvement usually occurs after 24 hours, but to completely disappear, it sometimes takes several days. If symptoms persist for several days, consult a doctor.

Diflucan® - solution for intravenous administration is compatible with the following solutions:

- 20% dextrose solution

- Ringer's solution

- Hartmann's solution

- potassium chloride solution in dextrose

- 4.2% solution of sodium bicarbonate

- aminofusine

- 0.9% solution of sodium chloride.

Diflucan® can be injected into the infusion system together with one of the solutions listed above. Although cases of specific incompatibility of fluconazole with other agents are not described, nevertheless, it is not recommended to mix it with any other drugs before infusion.

Evidence of the effectiveness of fluconazole in the treatment of other endemic mycoses such as paracoccidioidomycosis,sporotrichosis and histoplasmosis are limited, which does not allow to determine specific recommendations for dosing. Fluconazole is a potent inhibitor of isoenzyme CYP2C9 and a moderate isoenzyme inhibitor CYP3A4. Fluconazole is also an inhibitor of the isoenzyme CYP2C19. With simultaneous therapy with drugs with a narrow therapeutic profile, metabolized isoenzymes CYP2C9, CYP2C19 and CYP3A4, caution is recommended.

Effect on the ability to drive transp. cf. and fur:

When using the drug, the possibility of developing dizziness and seizures.

Form release / dosage:Solution for intravenous administration 2 mg / ml.

Packaging:

Solution for intravenous administration 2 mg / ml; 25 ml, 50 ml, 100 ml or 200 ml solution in a transparent type I colorless glass bottle capped with a rubber stopper and crimped with an aluminum cap with a plastic insert type "flip off". The bottle is equipped with a plastic holder. One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

At temperatures not higher than 30 ° C, out of reach of children. Do not freeze.

Shelf life:

5 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013546 / 03

Date of registration:06.11.2007

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

Fareva Amboise France

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp05.05.2015

Illustrated instructions

Instructions

Diflucan® (Diflucan®)