Fluconazole-Acti - instructions for use, dose, side effects, contraindications

Composition for:	1 ml	100 ml
active substance:
fluconazole	2.0 mg	200.0 mg
Excipients:
sodium chloride	9.0 mg	900.0 mg
water for injections	up to 1 ml	up to 100 ml

Description:Pcolorless or with a yellowish tinge solution.

Pharmacotherapeutic group:Antifungal agent

ATX: & nbsp

J.02.A.C Triazole derivatives

J.02.A.C.01 Fluconazole

Pharmacodynamics:

Fluconazole, a triazole antifungal agent, is a potent selective inhibitor of the synthesis of sterols in a fungal cell.

Fluconazole demonstrated activity in vitro and for most common species Candida: Candida albicans, Candida glabrata (many strains are moderately sensitive), Candida parapsilosis, Candida tropicalis.

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 Trichophyton spp. The activity of fluconazole on the models of endemic mycoses in animals, including infections caused by Blastomyces dermatitidis, Coccidioides immith (including intracranial infections) and Histoplasma capsulatum in 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 at 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 can develop in the following cases: a qualitative or quantitative change in the enzyme that is the target for fluconazole (lanosteryl 14-α-demethylase), decreased 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 azoles. Increasing the expression of the ERG11 gene results in the production of high concentrations of the target enzyme, which creates a need to increase the fluconazole concentration in the intracellular fluid to suppress all the enzyme molecules 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 oral administration. The concentration in the blood plasma is proportional to the dose and reaches a maximum (C_max) 0.5-1.5 hours after fasting fluconazole, 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)	Period 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 were administered intravenously at a dose of 6 mg / kg every third day prior to administration of a maximum of 5 doses while the children remained in the intensive care unit. The average half-life was 74 h (within 44-185 h) on day 1, 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 area under the concentration-time curve (AUC) was 271 μg.h / ml (within 173-385 μg.h / ml) on day 1, then increased to 490 μg.h / ml (within the range of 292-734 μg.h / ml) on the 7th day and decreased to an average of 360 μg.h / ml (within the range of 167-566 μg.h / ml) to the 13th 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 elderly patients aged 65 years and over, some of whom diuretics, FROM_m_Oh was achieved 1.3 hours after administration and was 1.54 μg / ml, the mean values AUC - 76.4 ± 20.3 μg h / 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 AUC and FROM_m_Oh.Creatinine clearance (74 ml / min), the percentage of fluconazole excreted unchanged by the kidneys (0-24 h, 22%) and renal clearance of fluconazole (0.124 ml / min / kg) in elderly patients is lower than in young patients.

Indications:

Fluconazole is indicated for the treatment of the following diseases in adults:

- cryptococcal meningitis;

- coccidioidomycosis;

- invasive candidiasis;

- Candidiasis of mucous membranes, incl. orofarengialnoy candidiasis, esophageal candidiasis, candiduria and chronic candidiasis of skin and mucous membranes;

- chronic atrophic candidiasis of the oral cavity (associated with the wearing of dentures), when compliance with oral hygiene or local treatment is not enough.

Fluconazole is indicated for the prevention of the following diseases in adults:

- recurrence of cryptococcal meningitis in patients with a high risk of recurrence;

- relapses of oropharyngeal candidiasis and esophageal candidiasis in HIV-infected patients with a high risk of recurrence;

- for the prevention of candidal infections in patients with prolonged neutropenia (such as patients with hemoblastoses undergoing chemotherapy, or patients,transplantation of hematopoietic stem cells.

Fluconazole is indicated for use in full-term newborns, infants, children and adolescents aged 0 to 18 years.

Fluconazole is used to treat candidiasis of the mucous membranes (oropharyngal candidiasis and esophageal candidiasis), invasive candidiasis, cryptococcal meningitis and the prevention of candidal infections in patients with a weakened immune system.

Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children with a high risk of recurrence.

Contraindications:

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

- congenital or identified lengthening interval QT on the electrocardiogram;

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

- simultaneous reception of terfenadine against the background of the continuous use of fluconazole at a dose of 400 mg / day or more.

Carefully:

- Impaired liver function;

- impaired renal function;

- the appearance of a rash against the background of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections;

- simultaneous use 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 balance disturbances and the associated concomitant therapy);

- simultaneous use of drugs with a narrow therapeutic profile, metabolized isoenzymes CYP2C9, CYP2C19, CYP3A4 (see section "Interaction with other medicinal products").

Pregnancy and lactation:

Adequate and controlled studies of pregnant women have not been conducted. Cases of multiple congenital malformations in newborns whose mothers received high-dose fluconazole (400-800 mg / day) for coccidioidomycosis for most or all of the first trimester have been reported. 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 to the fetus.

Fluconazole is found in breast milk in concentrations close to plasma, so its appointment to women during breastfeeding is not recommended. If you need to use the drug during lactation, breastfeeding is discontinued.

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.

Fluconizole can be taken or administered intravenously by infusion at a rate of no 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 (container 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.

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.

When transferring a patient from an intravenous to an oral intake of the drug or vice versa, a daily dose change is not required.

The daily dose of fluconazole depends on the nature and severity of the fungal infection. In infections requiring repeated use of the drug, treatment should continue until the disappearance of clinical or laboratory signs of active fungal infection. In patients with HIV infection and cryptococcal meningitis or recurrent oropharyngeal candidiasis, supportive therapy forprevention of recurrence of infection.

Adults drug is prescribed in the following doses

Indications for use		Dose	Duration of therapy
Cryptococcosis	Treatment of cryptococcal meningitis and other localization infections	The initial dose on the first day is 400 mg, then 200-400 mg once daily	The duration of therapy depends on the clinical efficacy, confirmed by mycological examination; with meningitis usually 6-8 weeks.
Cryptococcosis	Prevention of recurrence of cryptococcal meningitis	200 mg once daily	Uncertainly long
Coccidioidomycosis		200-400 mg once a day. For some infections, especially with damage to the meninges, a dose of 800 mg per day	It is determined individually and is 11-24 months
Candidemia, disseminated candidiasis, invasive candidiasis		Depending on the severity of the disease, the initial dose on the first day is 400 or 800 mg, then 200 or 400 mg once daily	Treatment lasts at least 2 weeks after receiving negative blood culture or the disappearance of clinical manifestations of the disease.
Candidiasis of mucous membranes	Orofarengeal	The initial dose on the first day is 200 mg or 400 mg, then 100-200 mg once daily	7-21 days (until remission is achieved). Immunocompromised patients may require a longer treatment period.
	Candidiasis of the esophagus	The initial dose on the first day is 200 mg or 400 mg, then 100-200 mg once daily	14-30 days (until remission is achieved). Immunocompromised patients may require a longer treatment period.
	Candiduria	200-400 mg once daily	7-21 days. Immunocompromised patients may require a longer treatment period.
	Chronic atrophic candidiasis of the oral cavity, associated with the wearing of dentures	50 mg once daily	14 days in combination with local antiseptic denture treatment
	Skin and mucosa candidiasis	50-100 mg once daily	Up to 28 days (duration of therapy depends on the severity of the disease and the state of the immune system).
Deep endemic mycoses		200-400 mg once daily	It is determined individually and is 2-17 months with paracoccidioidomycosis, with sporotrichosis 1-16 months, with histoplasmosis - 3-17 months.

- For prevention of recurrence of oropharyngeal candidiasis in HIV-infected patients with a high risk of recurrence fluconazole apply 100-200 mg per day or 200 mg 3 times a week for an indefinite period of time in patients with chronically reduced immunity.

- For prevention of recurrent candidiasis of the esophagus in HIV-infected patients with a high risk of recurrence fluconazole apply 100-200 mg per day or 200 mg 3 times a week for an indefinite period of time in patients with chronically reduced immunity.

- For the prevention of candidal infections in patients with prolonged neutropenia the recommended dose of fluconazole is 200-400 mg once a day, depending on the degree of risk of fungal infection. For patients at high risk of generalized infection, such as severe or persistent neutropenia, the recommended dose is 400 mg once daily. Fluconazole apply a few 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.

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. Fluconazole apply daily once a day.

When candidiasis of mucous membranes the recommended dose of fluconazole 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 invasive candidiasis and cryptococcal meningitis 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 fluconazole is 6 mg / kg / day.

For the prevention of fungal infections in children with depressed immunityIn which the risk of infection associated with neutropenia that develops as a result of cytotoxic chemotherapy or radiation therapy, the drug is used at 3-12 mg / kg / day, depending on the severity and duration of preservation-induced neutropenia (see dosage for adults. Children with renal insufficiency - see dose for patients with renal insufficiency).

Adolescents (12 to 18 years of age)

Depending on the weight and age, the optimal dose is selected. According to pharmacokinetics in children, a higher clearance of fluconazole than in adults. The dose of 100, 200 and 400 mg in adults corresponds to a dose of 3, 6 and 12 mg / kg in children to obtain a comparable systemic effect.

Use in children aged 0 to 27 days

In newborns fluconazole output slowly.

In the period from 0 to 14 days of life The drug is used in the same dose (in mg / kg) as for older children, but at intervals of 72 hours (the maximum dose of 12 mg / kg should not be exceeded).

Children aged from 14 to 27 days the same dose is administered at an interval of 48 hours (maximum dose of 12 mg / kg should not be exceeded).

Application in the elderly

In the absence of impaired renal function, the usual dosage regimen should be followed.

Patients with impaired renal function

When creatinine clearance (CK) is less than 50 ml / min, correction of the dosing regimen is required. In patients with impaired renal function with repeated administration of the drug, a "shock" dose of 50 to 400 mg should be initially administered. After that, the daily dose (depending on the indications) is determined according to the following table:

CK (ml / min)	Percent recommended dose
>50	100%
≤50 (without dialysis)	50%
Regular dialysis	100% after each dialysis session

In children with impaired renal function The daily dose of the drug should be reduced (in the same proportional relationship as in adults) according to the degree of renal insufficiency.

Patients with impaired hepatic function

The drug should be used with caution in this category of patients.

Side effects:

Drug tolerance is usually very good.

In clinical and post-marketing studies of fluconazole, the following adverse reactions were noted:

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

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

From the hepatobiliary system: hepatotoxicity, in some cases fatal, 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 injury.

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

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

From the immune system: anaphylactic reactions, angioedema, facial edema, hives, itching of the skin.

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

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

From the musculoskeletal system: myalgia.

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

Overdose:

Symptoms: hallucinations, paranoid behavior.

Treatment: forced diuresis, symptomatic therapy. Hemodialysis within 3 hours reduces the plasma fluconazole concentration by approximately 50%.

Interaction:

The simultaneous use of fluconazole with the following drugs 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 QT interval. With the use of fluconazole at a dose of 200 mg / day, the increase in the QT interval is not established, but the use of fluconazole at doses of 400 mg / day and higher causes a significant increase in the concentration of terfenadine in the plasma.

The simultaneous use of fluconazole in doses of 400 mg and more with terfenadine is contraindicated. Care should be taken when using fluconazole in doses less than 400 mg with terfenadine.

Cisapride: with simultaneous application with fluconazole may be unwanted reactions from the heart, including. ventricular tachycardia as pirouette.

The use of fluconazole at a dose of 200 mg / day and cisapride at a dose of 20 mg 4 times a day leads to a marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. The simultaneous use of these drugs is contraindicated.

Astemirol: the simultaneous use of fluconazole with astemizole or other drugs metabolized by the cytochrome P450 system may be accompanied by an increase in the plasma concentrations of these substances. Elevated concentrations of astemizole may lead to lengthening of the interval QT and in some cases to the development of ventricular tachycardia of the pirouette type. Simultaneous use of astemizole and fluconazole is contraindicated.

Amiodarone: The combined use of fluconazole and amiodarone may lead to inhibition of amiodarone metabolism.The use of amiodarone was associated with the prolongation of the QT interval. The simultaneous use of fluconazole and amiodarone is contraindicated (see section "Contraindications").

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 the plasma condensation of pimozide can lead to an elongation of the QT interval and, in some cases, to the development of a ventricular tachycardia of the pirouette type. 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, the simultaneous use of fluconazole and quinidine can lead to inhibition of quinidine metabolism. In turn, the increase in plasma concentrations of quinidine may lead to QT prolongation, and in some cases, to the development of ventricular tachycardia type "pirouette". Simultaneous use of quinidine and fluconazole is contraindicated.

Erythromycin: simultaneous application of fluconazole and erythromycin may lead to a lengthening of QT interval, and in some cases to the development of ventricular tachycardia type "pirouette".The simultaneous use of erythromycin and fluconazole is contraindicated.

Care should be taken and, possibly, dosage adjustments should be made, with simultaneous use of the following drugs and fluconazole

Drugs affecting fluconazole

Rifampicin: decreases T_1/2by 20% and AUC by 25% fluconazole. In patients taking both rifampicin and fluconazole, it is necessary to consider the advisability of increasing the dose of fluconazole.

Hydrochlorothiazide: repeated use of hydrochlorothiazide simultaneously with fluconazole leads to an increase in the concentration of fluconazole in plasma by 40%. Such a change does not require a correction of the dosing regimen, but this change should be taken into account.

Drugs affected by fluconazole

Fluconazole is a potent inhibitor of isoenzyme CYP2C9 and CYP2C19 cytochrome P450 and a moderate inhibitor of the isoenzyme CYP3A4. In addition, in addition to the effects listed below, there is a risk of increased plasma concentrations and other drugs metabolized by the CYP2C9, CYP2C19 and CYP3A4 isoenzymes when used concurrently with fluconazole. Therefore, care should be taken when using these drugs at the same time,and if necessary, these combinations patients should be under close medical supervision. It should be borne in mind that the inhibitory effect of fluconazole persists for 4-5 days after drug withdrawal due to a long half-life.

Alfentanil: there is a decrease in clearance and volume of distribution, an increase T_1/2alfentanil. Perhaps this is due to the inhibition of the isoenzyme CYP3A4 by fluconazole. Alfventanyl dosage adjustment may be required.

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

Amphotericin B: in studies in animals, a slight additive effect was observed with respect to Candida ablicans, lack of interaction with infection caused by Cryptococcus neoformans and antagonism, with systemic infection caused by A. fumigates.

Anticoagulants: like other 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).In patients receiving coumarone anticoagulants, it is necessary to constantly monitor prothrombin time during therapy and for 8 days after simultaneous use. Also, the appropriateness of correcting the dose of warfarin should be evaluated.

Azithromycin: with the simultaneous administration of fluconazole at a dose of 800 mg once with azithromycin in a single dose of 1200 mg of pronounced pharmacokinetic interaction is not established.

Benzodiazepines (short-acting): fluconazole significantly increases the concentration of midazolam, and this effect is more pronounced when fluconazole is taken orally than with intravenous administration. If necessary, joint use of patients should be monitored in order to appropriately reduce the dose of benzodiazepine. With the simultaneous use of a single dose of triazolam fluconazole increases the AUC of triazolam by approximately 50%, C_max - by 25-32%, T_1/2by 25-50% by inhibiting the metabolism of triazolam. A dose adjustment of triazolam may be required.

Carbamazepine: fluconazole inhibits the metabolism of carbamazepine and increases the plasma concentration of carbamazepine by 30%.It is necessary to consider 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, felodipine) are metabolized by the isoenzyme CYP3A4. Fluconazole increases the systemic exposure of calcium channel antagonists. It is necessary to control the development of side effects.

Cyclosporine: the use of fluconazole at a dose of 200 mg / day in patients after kidney transplantation 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 cyclosporine and fluconazole, it is recommended to monitor the concentration of cyclosporin in the blood.

Cyclophosphamide: while simultaneous use of cyclophosphamide and fluconazole increased plasma concentrations of bilirubin and creatinine. This combination is acceptable in view of the risk of increasing the concentration of bilirubin and creatinine.

Fentanyl: fluconazole significantly prolongs the time of removal 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. With simultaneous use with fluconazole, as with other antifungal azole agents, it is possible to develop a ventricular tachycystolic type of arrhythmia "pirouette", so joint application is not recommended.

Inhibitors of HMG-CoA reductase: with the simultaneous use of fluconazole with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme (such as atorvastatin and simvastatin) or the 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. It is necessary to monitor the activity of creatine kinase. In the case of a significant increase in the activity of creatine kinase, as well as if there is a diagnosis or suspected development of myopathy orrhabdomyolysis, 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 the antagonism of angiotesin 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): FROM_m_Oh and AUC of flurbiprofen increased by 23% and 81%, respectively. Similarly, C_max and the AUC of the pharmacologically active isomer [S - (+) + ibuprofen] increased by 15% and 82%, respectively, while fluconazole was administered with racemic ibuprofen (400 mg).

With the simultaneous use of fluconazole at a dose of 200 mg and celecoxib in a dose of 200 mg C_mOh and AUC celecoxib increased by 68% and 134%, respectively. In this combination, a dose reduction of celecoxib can be doubled.

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

With the simultaneous use of NSAIDs and fluconazole, patients should be carefully monitored to detect and control adverse events and toxicity associated with NSAIDs.

Oral contraceptives: with simultaneous application of combined oral contraceptive with fluconazole at a dose of 50 mg, there is no significant effect on the concentration of hormones, whereas with daily administration of 200 mg of fluconazole AUC of ethinylestradiol and levonorgestrel are increased by 40% and 24% respectively, and with 300 mg of fluconazole 1 time per week AUC of ethinylestradiol and norethindrone increase by 24% and 13%, respectively. Thus, the repeated use of fluconazole at these doses is unlikely to affect the effectiveness of the combined contraceptive.

Phenytoin: simultaneous application of fluconazole and phenytoin may be accompanied by a clinically significant increase in the concentration of phenytoin. In case of necessity of simultaneous application of these preparations, it is necessary to control the concentration of phenytoin in the plasma and to correct its dose.

Prednisone: cessation of therapy with fluconazole may cause an increase in the activity of the isoenzyme CYP3A4, which leads to an increase in the metabolism of prednisone. Patients receiving combination therapy with these drugs should be under careful medical supervision when the application of fluconazole is canceled to assess the state of the adrenal cortex.

Rifabutin: simultaneous application of fluconazole and rifabutin can lead to an increase in the plasma concentration of rifabutin up to 80%, in connection with which the risk of uveitis increases. Patients simultaneously applying fluconazole and rifabutin must be carefully observed.

Saquinavir: AUC is increased by approximately 50%, C_mOh- by 55%, saquinavir clearance is reduced by approximately 50% due to inhibition of hepatic metabolism of the CYP3A4 isoenzyme and inhibition of P-glycoprotein. It may be necessary to adjust the dose of saquinavir.

Sirolimus: an increase in the concentration of sirolimus in the blood plasma, presumably due to the inhibition of sirolimus metabolism through inhibition of the 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 T_1/2Sulfonylurea preparations (chlorpropamide, glibenclamide, glipizide and tolbutamide) for oral administration. Patients with diabetes mellitus can be assigned joint use of fluconazole and these drugs, but the possibility of developing hypoglycemia should be considered. It is necessary to periodically monitor the concentration of glucose in the blood and, if necessary, to correct the dose of hypoglycemic drugs.

Tacrolimus: simultaneous application of fluconazole and tacrolimus (inward) leads to an increase in plasma concentrations of the latter up to 5 times by inhibiting the metabolism of tacrolimus occurring in the intestine through isoenzyme CYP3A4 (cases of nephrotoxicity are described). Significant changes in the pharmacokinetics of drugs have not been observed with tacrolimus intravenously. Patients simultaneously applying 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: when used simultaneously with fluconazole at a dose of 200 mg for 14 days, the average plasma clearance rate of theophylline is reduced by 18%. When fluconazole is used simultaneously with high doses of theophylline or in patients with an increased risk of developing the toxic effect of theophylline, symptoms of an overdose of theophylline should be observed and, if necessary, a correction of the theophylline dose should be made.

Vinca alkaloid: it is assumed that fluconazole can increase the concentration of vinca alkaloids (vincristine, vinblastine) in blood plasma (presumably due to inhibition of the isoenzyme CYP3A4) and, thus, lead to the development of nephrotoxicity.

Vitamin A: there are reports of the development of the pseudotumor of the brain with the simultaneous use of a full transretinic acid and fluconazole, which disappeared after the withdrawal of fluconazole. The use of this combination is possible, but one should remember about the possibility of undesirable reactions from the central nervous system.

Zidovudine: with the simultaneous use of fluconazole and zidovudine increased C_mOh and AUC zidovudine by 84% and 74%, respectively.This effect is probably due to a decrease in the metabolism of the latter to its main metabolite. Patients using this combination should be monitored to identify side effects of zidovudine.

Voriconazole (inhibitor of isoenzymes CYP2C9, CYP2C19, CYP3A4): simultaneous application of voriconazole (400 mg twice a day on the first day, then 200 mg twice daily for 2.5 days) and fluconazole (400 mg on the first day, then 200 mg for 4 days) leads to an increase in the concentration and AUC 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. Patients using voriconazole after fluconazole, should be observed in order to identify side effects of voriconazole.

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

Iwafaff. When used simultaneously with ivakaftorom, stimulant cystic fibrosis regulator of transmembrane conductivity (CFTR), an increase in the exposure of ivakaftora 3 times and exposure of hydroxymethyl-ivacafluor (M1) in 1,9 times. Patients concurrently taking moderate CYP3A inhibitors, such as fluconazole and erythromycin, it is recommended to reduce the dose of ivacafluor up to 150 mg once a day.

The above interactions were established with repeated application of fluconazole; interactions with drugs as a result of a single administration of fluconazole are not known.

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

Special instructions:

Treatment with fluconazole can begin if there are no results of sowing or other laboratory tests. After receiving mycological data, appropriate correction of fungicidal therapy is recommended. Premature termination of treatment leads to relapse.

There are 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.

Evidence of the efficacy of fluconazole in the treatment of other endemic mycoses such as paracoccidioidomycosis, sporotrichosis and histoplasmosis is limited, which does not allow the determination of specific dosage recommendations.

In rare cases, the use of fluconazole was accompanied by hepatotoxicity, in some cases with a fatal outcome, mainly in patients with serious concomitant diseases. In the case of hepatotoxicity, there was no apparent dependence on the daily dose of fluconazole, the duration of therapy, the sex and age of the patient. 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 liver function tests, should be monitored in order to identify signs of more serious liver damage. If there are clinical signs or symptoms of liver damage associated with the use of fluconazole, the drug should be discontinued.

During the administration of fluconazole, anaphylactic reactions and exfoliative skin lesions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, rarely developed in patients. HIV-infected people are more likely to develop severe skin reactions with many drugs. When a patient with a superficial fungal infection appears during treatment for a rash that can be associated with fluconazole, the drug should be discarded. When rashes appear in patients with invasive or systemic mycoses, they should be carefully monitored and discontinued if bulleous lesions or erythema multiforme occur.

The simultaneous use of fluconazole in doses less than 400 mg and terfenadine should be carefully monitored.

Fluconazole - solution for infusions is compatible with the following solutions:

- 20% dextrose solution

- Ringer's solution

- Hartman solution

- potassium chloride solution in dextrose

- 4.2% solution of sodium bicarbonate

- aminofusine

- 0.9% solution of sodium chloride.

Fluconazole 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.

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.

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 fluttering of the ventricles was very rare in patients with severe diseases with multiple risk factors, such as organic heart disease, electrolyte imbalance, and concomitant therapy contributing to the development of such disorders. Therefore, patients with potentially proarrhythmic conditions fluconazole with caution.

It is necessary to monitor prothrombin time with simultaneous application with indirect anticoagulants.

Women of childbearing age should use contraception.

Pharmaceutical compatibility

The drug is compatible with 20% dextrose solution, Ringer's solution, Hartman's solution, potassium chloride solution in dextrose, 4.2% sodium bicarbonate solution, 0.9% sodium chloride solution.

Mixing fluconazole solution for infusions with any other drugs is not recommended.

Single or multiple use of fluconazole at a dose of 50 mg does not affect metabolism of phenazone (Antipyrine) when they are used simultaneously.

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

In connection with the possible occurrence of side effects of the drug (dizziness, cramp), care should be taken when driving vehicles and when engaging in other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Solution for infusion, 2 mg / ml.

Packaging:

To 100 ml in containers polymeric (polyvinyl chloride) for infusion solutions.

Each polymer container together with instructions for medical use is placed in a separate transparent bag made of high pressure polyethylene.

For hospitals: each polymer container is placed in a transparent a polyethylene bag and placed in boxes of cardboard corrugated for 100 packages together with instructions for medical use in an amount corresponding to number of polymer containers.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-004025

Date of registration:14.12.2016

Expiration Date:14.12.2021

The owner of the registration certificate:Aktifarm, OOOAktifarm, OOO Russia

Manufacturer: & nbsp

FARMLEND JV, LLC Republic of Belarus

Information update date: & nbsp25.01.2017

Illustrated instructions

Instructions

Fluconazole-Acti (Fluconazole-Akti)