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

Fluconazole, a representative of the class of triazole antifungal agents, has a highly specific effect, inhibiting the activity of enzymes of fungi, dependent on cytochrome P450. Blocking the conversion of lanosterol of fungal cells to ergosterol; increases the permeability of the cell membrane of fungi, disrupts its growth and replication. Fluconazole, being a highly selective inhibitor of cytochrome P450 fungi, practically does not inhibit these enzymes in the human body (in comparison with itraconazole, clotrimazole, econazole and ketoconazole to a lesser degree suppresses the oxidative processes dependent on cytochrome P450 in human liver microsomes).

Fluconazole, administered at a dose of 50 mg / day for up to 28 days, did not significantly affect the concentration of testosterone in the blood plasma in men or sex steroids in women of childbearing age. Fluconazole in doses of 200-400 mg / day does not have a clinically significant effect on the concentration in the blood of endogenous steroids and their response to stimulation with adrenocorticotropic hormone (ACTH) in healthy men. Ingestion fluconazole was active on various models of fungal infections in animals. The activity of the drug in opportunistic mycoses, including those caused by Candida spp., Was demonstrated. (including generalized candidiasis in animals with depressed immunity); Cryptococcus neoformans (including intracranial infections); Microsporum spp. and Trychophyton spp. Fluconazole activity was also established in the models of endemic mycoses in animals, including infections caused by Blastomyces dermatitides, Coccidioides immitis (including intracranial infections) and Histoplasma capsulatum in animals with normal and suppressed immunity.

In animal studies, a correlation was observed between the values of the minimum inhibitory concentration (MIC) and the efficacy against experimental mycoses caused by Candida spp. According to the results of clinical studies, there is an almost linear relationship between the area under the concentration-time curve (AUC) and the dose of fluconazole (close to 1: 1). There is also a direct, albeit inadequate, relationship between AUC or dose and a successful clinical response to oral candidiasis therapy and, to a lesser extent, candidemia. Likewise, there is a lower probability of fluconazole efficacy in cases of infections caused by strains that are characterized by a larger MIC of fluconazole.

Fungi of the genus Candida have developed a number of mechanisms of resistance to azole antifungal agents. Fluconazole demonstrates a high MIC for fungal strains that have formed one or more resistance mechanisms, which adversely affects the efficacy of the drug in vivo and in clinical practice.

Cases of superinfection with Candida species different from C. albicans are described, which are often not inherently susceptible to fluconazole (eg, Candida krusei). To treat such cases, alternative antifungal agents may be required.

Pharmacokinetics:

Fluconazole is a selective inhibitor of CYP2C9 and CYP3A4 isoenzymes, fluconazole is also an inhibitor of the isoenzyme CYP2C19. Fluconazole has similar pharmacokinetic properties when administered intravenously and when applied.

Suction

Fluconazole is well absorbed when taken orally, and its concentration in the blood plasma exceeds 90% of the concentration achieved by intravenous administration. The intake of food does not affect the absorption of the drug after ingestion. The maximum plasma concentration after taking an empty stomach is achieved after 0.5-1.5 hours.Concentrations in the blood plasma are proportional to the dose of the drug. 90% of the equilibrium concentration, is reached by the 4-5th day with the administration of the drug 1 time per day. The introduction of a shock dose (on day 1), which is twice the daily dose, ensures that 90% of the equilibrium plasma concentration reaches the second day of therapy.

Distribution

The apparent 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 content of the drug in saliva and sputum is similar to the concentration in the plasma. In patients with fungal meningitis, the level of fluconazole in the cerebrospinal fluid is about 80% of the corresponding concentration in the blood plasma.

High concentrations of fluconazole in the skin, which exceed the serum concentration, are observed in the stratum corneum, epidermis, dermis and sweat. Fluconazole accumulates in the stratum corneum. When administered at a dose of 50 mg once a day, the concentration of fluconazole after 12 days of therapy was 73 μg / g, and after 7 days after discontinuation of therapy it was still 5.8 μg / g. Using a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum on the 7th day of treatment was 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 administration at a dose of 150 mg once a week was 4.05 μg / g in healthy and 1.8 μg / g in diseased nails. The drug was still found in samples of nails taken 6 months after the completion of therapy.

Biotransformation

Fluconazole is metabolized to a small extent. Only 11% of the dose labeled with a radioactive isotope was excreted in the changed form with urine.

Excretion

The half-life of fluconazole from the plasma is about 30 hours. Most of the drug is excreted through the kidneys, with about 80% of the injected drug found in the urine unchanged. The clearance of fluconazole is proportional to the creatinine clearance. No circulating metabolites were detected.

The long half-life of fluconazole from the plasma makes it possible to use it once for vaginal candidiasis, and also once a day and once a week with other indications.

Pharmacokinetics in renal dysfunction

In patients with chronic renal failure of moderate or severe severity (glomerular filtration rate (GFR) <20 ml / min), the half-life of the drug is increased from 30 to 98 hours, so a dose reduction is necessary. Fluconazole is derived by hemodialysis and, to a lesser extent, peritoneal dialysis. The hemodialysis session lasts 3 hours and reduces the plasma concentration of fluconazole by approximately 50%.

Pharmacokinetics in elderly patients

A pharmacokinetic study was conducted with the participation of 22 patients aged (> 65 years) who received 50 mg of fluconazole 50 mg once. Ten patients received diuretics at the same time. The maximum concentration in blood plasma (Cmax) was 1.54 μg / ml and was achieved 1.3 hours after the administration of the drug. The mean AUC was 76.4 ± 20.3 μg-h / ml, and the mean half-life (T1 / 2) was 46.2 hours. These pharmacokinetic parameters exceed similar values in healthy young men. The concomitant administration of diuretics to AUC or Cmax was not significantly affected. In addition, the creatinine clearance (74 ml / min), the percentage of the drug unchanged in the urine (0-24 h, 22%), and the renal clearance of fluconazole (0.124 ml / min / kg) in elderly patients were lower, than in younger volunteers. Thus, changes in the pharmacokinetics of fluconazole in elderly patients are obviously associated with a decreased renal function.

Indications:

Cryptococcosis, including cryptococcal meningitis and other localizations of this infection (including lungs, skin), both in patients with normal immune response, and in patients with various forms of immunosuppression (including those with AIDS, organ transplantation ); the drug can be used to prevent cryptococcal infection in AIDS patients;
generalized candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidiasis infections (with endocardial damage, abdominal organs, respiratory organs, eyes and urogenital organs). Treatment can be performed in patients with malignant neoplasms, in intensive care units, in patients undergoing cytostatic or immunosuppressive therapy, and in the presence of other factors predisposing to the development of candidiasis;
Candidiasis of mucous membranes, incl. oral cavity and pharynx (including atrophic candidiasis of the oral cavity, associated with the wearing of dentures), esophagus, non-invasive bronchopulmonary candidiasis, candiduria, candidiasis of the skin, prevention of recurrence of oropharyngeal candidiasis in AIDS patients;
genital candidiasis: vaginal candidiasis (acute and chronic
relapsing), prophylactic use to reduce the frequency of recurrences of vaginal candidiasis (3 or more episodes per year); Candidiasis balanitis;
prevention fungal infections in patients with malignant neoplasms that are predisposed to such infections as a result of chemotherapy with cytostatics or radiation therapy;
mycosis of the skin, including mycosis of the feet, the body, the groin area; pityriasis lichen, onychomycosis; cutaneous candidiasis infections;
Deep endemic mycoses, including coccidiomycosis, paracoccidiomycosis, sporotrichosis and histoplasmosis in patients with normal immunity.

Contraindications:

Hypersensitivity to the drug or a similar structure of azole compounds.

Simultaneous use of terfenadine (during repeated use of fluconazole at a dose of 400 mg per day or more).

Simultaneous use of cisapride, astemizole, erythromycin, pimozide and quinidine or other drugs that prolong the QT interval and increase the risk of severe cardiac rhythm disturbances.

Breastfeeding period.

Carefully:

In case of liver and / or kidney dysfunction, with fluconazole application in patients with superficial fungal infection and invasive / systemic fungal infections, when terfenadine and fluconazole are administered at a dose of less than 400 mg / day, potential pro-rhythmogenic conditions in patients with multiple risk factors (organic heart diseases, water-electrolyte balance disorders, simultaneous use of drugs causing arrhythmias), during pregnancy, with simultaneous ingestion of potentially hepatotoxic drugs, alcoholism.

Pregnancy and lactation:

Controlled studies on the use of the drug in 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.

Women of childbearing age should use contraception. Fluconazole is found in breast milk in concentrations close to the concentration in the blood plasma, therefore its administration to women during breast-feeding is not recommended.

Dosing and 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 the intravenous route of administration of the drug to oral administration or vice versa, a change in the daily dose is not required.

One vial of Fluconazole Zentiva is injected intravenously in at least 60 minutes, in children within 120 minutes. The infusion rate should not exceed 10 ml / min.

When choosing a dose, the results of inoculation and the severity of the fungal infection should be taken into account. Treatment of mycoses requiring repeated administration of the drug should be continued until the clinical indices or results of laboratory tests confirm the disappearance of mycosis. Inadequate duration of treatment can lead to a relapse of active infection.

Adult patients

Indications for use		Doses	Duration of therapy
Cryptococcosis	Treatment cryptococcal meningitis	Initial dose: 400 mg (200 ml) once. Follow-up dose: 200-400 mg (100-200 ml) / day	Usually 6-8 weeks. When life-threatening the daily dose can be increased to 800 mg (400 mL)
Cryptococcosis	Supportive therapy for the prevention of recurrence of cryptococcal meningitis in patients with a high risk of recurrence	200 mg (100 ml) / day	Indefinitely at a dose of 200 mg (100 ml) / day
Coccidioidomycosis		200-400 mg (100-200 ml) / day	11 to 24 months or longer, depending on the condition of the patient.With some infections and especially meningeal, it is possible to use a daily dose of 800 mg (400 ml)
Invasive candidiasis		Initial dose: 800 mg (400 ml) once. Subsequent doses: 400 mg (200 ml) / day	In general, the recommended PThe duration of therapy for candidemia is 2 weeks after the first negative blood culture is received and the signs and symptoms associated with candidemia are resolved
Treatment of candidiasis mucous shells	Oropharyngeal candidiasis	Initial dose: 200-400 mg (100- 200 ml) once. Subsequent doses: 100-200 mg (50-100 ml) / day	7-21 days (until remission achievements oropharyngeal candidiasis). Perhaps more prolonged treatment in patients with severe immunosuppression
	Candidiasis of the esophagus	The initial dose: 200-400 mg (100-200 ml) once. Subsequent doses: 100-200 mg (50-100 ml) / day	14-30 days (before reaching remission of esophageal candidiasis). Perhaps more prolonged treatment in patients with severe immunosuppression
	Candiduria	200-400 mg (100-200 ml) / day	7-21 days. Perhaps more prolonged treatment in patients with severe immunosuppression
	Chronic atrophic candidiasis	50 mg (25 ml) / day	14 days
	Chronic mucocutaneous candidiasis	50-100 mg (25-50 ml) / day	Up to 28 days.Perhaps a longer treatment, depending on the severity of the infection and reduce the immune response
Prevention candidiasis mucous shells in HIV- infected patients, prone to high risk recidivism	Oropharyngeal candidiasis	100-200 mg (50-100 ml) / day or 200 mg (100 ml) 3 times a week	Unlimited in patients with chronic immunosuppression
	Candidiasis of the esophagus	100-200 mg (50-100 ml) / day or 200 mg (100 ml) 3 times a week	Unlimited in patients with chronic immunosuppression
Genital Candidiasis	Acute vaginal candidiasis Candidiasis balanitis	150 mg (75 ml)	Once
Genital Candidiasis	Treatment and prevention recurrent vaginal candidiasis (> 4 episodes during of the year)	150 mg (75 ml) once every three days before the administration of 3 doses (days 1, 4 and 7), then the administration of a maintenance dose of 150 mg (30 ml) once a week	Supportive therapy - 6 months
Dermatomycosis	Dermatophytosis of the feet. Dermatophytosis torso. Dermatophytosis perineum. Candidiasis.	150 mg (75 ml) once a week or 50 mg (25 ml) once a day	2-4 weeks; to eliminate dermatophytosis stop may require treatment for up to 6 weeks
	Pearly (multi-colored) lichen	300-400 mg (150 - 200 ml) once a week	1-3 weeks
	Pearly (multi-colored) lichen	50 mg (25 ml) 1 time / day	2-4 weeks
	Dermatophyte onychomycosis	150 mg (75 ml) once a week	Treatment should continue until substitution infected nail (regrowth of uninfected). The growth of nails on the fingers and toes usually takes from 3-6 to 6-12 months. After successful treatment of long-term chronic infections, the nails sometimes remain deformed.
Prophylaxis of candidiasis in patients with protracted neutropenia		200-400 mg (100-200 ml) / day

Use in children

Children should not exceed the maximum allowable daily dose of 400 mg.

As with similar infections in adults, the duration of therapy should be based on the clinical and mycological response. The drug Fluconazole Zentiva is administered once a day.

Concerning the use in children with impaired renal function - see "Patients with impaired renal function". The pharmacokinetics of fluconazole have not been studied in children with renal insufficiency (with respect to "term infants", in which the renal immaturity is often observed, see below).

Infants, children of preschool and primary school age (age from 28 days to 11 years)

Indication	Dose	Recommendations
Candidiasis of mucous membranes	Initial dose: 6 mg / kg Subsequent dose: 3 mg / kg / day	The initial dose can be used on the first day to achieve a more rapid equilibrium concentration of the drug
Invasive Candidiasis Cryptococcal meningitis	Dose: 6-12 mg / kg / day	Depending on the severity of the disease
Supportive therapy to prevent the recurrence of cryptococcal meningitis in children at high risk of meningitis	Dose: 6 mg / kg / day	Depending on the severity of the disease
Prevention of Candidiasis in Patients with Immune Deficiency	Dose: 3-12 mg / kg / day	Depending on the severity and duration of induced neutropenia (see Dosage in Adults)

Adolescents (12-17 years of age)

The most suitable dosage regimen (for adults or children) should be chosen taking into account the body weight and the stage of the child's sexual development. Clinical evidence suggests that the clearance of fluconazole in children exceeds that of adults. In children and adults, a comparable systemic exposure is provided by administering doses of 3, 6 and 12 mg / kg and 100, 200 and 400 mg, respectively.

The safety and efficacy of fluconazole therapy for genital candidiasis in children has not been established.Available data on the safety of the use of the drug for other indications in children are presented in the section "Side effect". If it is necessary to treat genital candidiasis in adolescents (age 12-17 years), the dosage should be the same as for adults.

Completed newborns (0-27 days)

In newborns fluconazole output slowly.

There are very limited pharmacokinetic data that could be used to justify the dosage in newborns (see the section "Pharmacokinetics").

Age Group	Dose	Recommendations
The dead	The same dose as for infants,	Do not exceed
newborns	children of preschool and younger	the maximum allowable
(0-14 days)	school age, should be entered every 72 hours	dose of 12 mg / kg for 72 hours
The dead	The same dose as for infants,	Do not exceed
newborns	children of preschool and younger	the maximum allowable
(15-27 days)	school age should be entered every 48 hours	dose 12 mg / kg for 48 hours

Patients in special categories Patients of advanced age

In the absence of signs of renal failure, the drug is used in a usual dose.Patients with renal insufficiency should be corrected in accordance with the instructions for use in patients with impaired renal function (see "Patients with impaired renal function").

Patients with impaired renal function

With the introduction of single doses, dose adjustment is not required. In patients (including children) with impaired renal function, who will take multiple doses of fluconazole, the initial dose should be 50-400 mg (depending on the daily dose recommended with the appropriate indication). After this dose, the daily dosage (in accordance with the indication) should be based on the following table:

Creatinine clearance (ml / min)	Percentage of recommended dose
>50	100%
<50 (without dialysis)	50%
Regular dialysis	100 % after each dialysis

Patients regularly undergoing dialysis should receive 100% of the recommended dose after each dialysis session; in days without dialysis, the dosage should be reduced in accordance with the patient's creatinine clearance.

Patients with impaired hepatic function

There are limited data on the use of the drug in patients with impaired hepatic function, so in people in this category fluconazole should be used with caution (See "With caution").

Side effects:

With the use of fluconazole, the following side effects may occur, which are separated according to the system-organ classes according to the classification of the Medical Dictionary of Regulatory Activities (MedDRA). The frequency of adverse reactions was determined according to the following gradation (classification of the World Health Organization):

- very frequent - more than 1/10,

- frequent - from more than 1/100 to less than 1/10,

- infrequent - from more than 1/1000 to less than 1/100,

- rare - from more than 1/10000 to less than 1/1000,

- very rare - from less than 1/10000, including individual messages.

General disorders and disorders at the site of administration: infrequent - weakness, increased fatigue, anxiety, fever.

Disorders from the nervous system: frequent - headache; infrequent - convulsions, dizziness, paresthesia, tremor; rare - change in taste.

Disorders of the psyche: infrequent - insomnia, drowsiness.

Hearing disorders and labyrinthine disturbances: infrequent vertex. Heart disorders: rare - QT interval elongation, polymorphic ventricular tachycardia such as "pirouette", arrhythmia.

Disturbances from the skin and subcutaneous tissues: frequent - skin rash, infrequent - itching, excessive sweating; rare - exfoliative skin diseases, including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, alopecia.

Disorders from the gastrointestinal tract: frequent - nausea, vomiting, abdominal pain, diarrhea; rare - constipation, dyspepsia, flatulence, dry mouth, hepatotoxicity, in some cases with a fatal outcome.

Disturbances from the liver and bile ducts: frequent - increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT) and alkaline phosphatase (APF); infrequent - cholestasis, jaundice, hyperbilirubinemia; rare - hepatic insufficiency, hepatitis, hepatocellular necrosis.

Disorders from the musculoskeletal and connective tissue: infrequent - myalgia.

Violations from the blood and lymphatic system: infrequent - anemia; rare - leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

Disorders from the immune system: infrequent - hives; rare - anaphylaxis (including angioedema, edema of the face, itching).

Disorders from the metabolism and nutrition: infrequent - reduced appetite; rare - hypercholesterolemia, hypertriglyceridemia, hypokalemia.

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.

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

Interaction:

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

Cisapride: described undesirable phenomena from the heart, incl. polymorphic ventricular tachycardia of the "pirouette" type in patients receiving parallel fluconazole and cisapride. In a controlled study, concomitant administration of fluconazole 200 mg once daily and cisapride 20 mg 4 times daily was associated with a significant increase in the plasma concentration of cisapride and an extension of the QT interval.The simultaneous use of fluconazole and cisapride is contraindicated.

Terfenadine: with the simultaneous use of azole antifungal agents and terfenadine, serious arrhythmias may occur as a result of an increase in the QT interval. When taking fluconazole at a dose of 200 mg per day, there is no increase in the QT interval, however, the use of fluconazole at doses of 400 mg per day and higher causes a significant increase in the concentration of terfenadine in the blood plasma. The simultaneous use of fluconazole at doses of 400 mg per day or more with terfenadine is contraindicated (see section "Contraindications"). Treatment with fluconazole at doses less than 400 mg per day in combination with terfenadine should be carefully monitored.

Astemizole: simultaneous application of fluconazole with astemizole or other drugs the metabolism of which the cytochrome P450 system may be accompanied by increased serum concentrations of these agents. Elevated concentrations of astemizole in the blood plasma can lead to lengthening of the QT interval and in some cases to the development of ventricular tachycardia as pirouette. The simultaneous use of fluconazole and astemizole is contraindicated.

Pimozide although corresponding study in vitro or in vivo have not been conducted, the concomitant administration of fluconazole and pimozide can lead to inhibition of the metabolism of the latter. An increase in the plasma concentration of pimozide may be the reason for the prolongation of the QT interval and the rare cases of ventricular pirouette tachycardia. Concomitant administration of fluconazole and pimozide is contraindicated.

Quinidine although corresponding study in vitro or in vivo have not been conducted, the concomitant administration of fluconazole and quinidine can lead to inhibition of the metabolism of the latter. When using quinidine, there are cases of prolongation of the QT interval and rare cases of polymorphic ventricular tachycardia such as "pirouette". The concomitant administration of fluconazole and quinidine is contraindicated.

Erythromycin: Combination of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolongation of QT interval, polymorphic ventricular tachycardia type "pirouette"), and hence, sudden cardiac death. Concomitant administration of fluconazole and erythromycin is contraindicated.

Drugs affecting fluconazole:

Hydrochlorothiazide: the repeated 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.

Rifampin: simultaneous application of fluconazole and rifampicin leads to a 25% reduction in AUC and a 20% decrease in the half-life of fluconazole. In patients who simultaneously take rifampicin, it is necessary to consider the advisability of increasing the dose of fluconazole.

Drugs affected by fluconazole:

Fluconazole is a potent inhibitor of the CYP2C9 isoenzyme cytochrome P450 and a moderate inhibitor of the CYP3A4 isoenzyme. In addition, in addition to the effects listed below, there is a risk of an increase in plasma concentrations and other drugs metabolized by the CYP2C9 and CYP3A4 isoenzymes while being used with fluconazole. In this regard, caution should be exercised when using these drugs at the same time, and if necessary, such combinations should be carefully monitored by patients.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 in clearance and volume of distribution, an increase in the half-life of alfentanil. Perhaps this is due to the inhibition of the isoenzyme CYP3A4 by fluconazole. Alfventanyl dosage adjustment may be required.

Amitriptyline, nortriptyline: fluconazole enhances the effect of amitriptyline and nortriptyline. The concentration of 5-nortriptyline and / or S-amitriptyline should be determined at the beginning of the combination therapy and one week after. If necessary, the dose of amitriptyline / nortriptyline should be adjusted.

Amphotericin B: concomitant administration of fluconazole and amphotericin B the following results were obtained in infected mice with normal and depressed immunity: a slight additive antifungal effect in systemic infection caused by C. albicans, lack of interaction with intracranial infection caused by Cryptococcus neoformans, and antagonism of drugs used in systemic infection caused by A. fumigatus.The clinical significance of the results of these studies is unknown.

Anticoagulants: like other antifungal agents - azole derivatives, fluconazole, with simultaneous application with warfarin, can increase prothrombin time up to 2-fold, in connection with which, 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.

Benzodiazepines (short-acting), i.e. midazolam, triazolam: fluconazole caused a significant increase in the concentrations of midazolam and increased psychomotor effects when administered orally. The concomitant use of fluconazole 200 mg and midazolam 7.5 mg increased the AUC and midazolam half-life in 3.7 and 2.2 times, respectively. With the concomitant use of fluconazole 200 mg per day and the administration of triazolam 0.25 mg AUC and the half-life of triazolam increased by 4.4 and 2.3 times, respectively. There were observed enhanced and prolonged effects of triazolam, used in combination with fluconazole.In patients who require concomitant use of benzodiazepines and fluconazole, a reduction in the dose of benzodiazepine should be assessed, and such patients should be closely monitored.

Carbamazepine: fluconazole inhibits the metabolism of carbamazepine, and an increase in the concentration of carbamazepine in serum by 30% was observed. 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 and felodipine) are metabolized by CYP3A4. Fluconazole increased the systemic exposure of antagonists of calcium channels. It is recommended to monitor frequently unwanted phenomena.

Non-steroidal anti-inflammatory drugs (NSAIDs): C max and AUC of flurbiprofen are increased by 23 % and 81 %, respectively. Similarly, Cmax and AUC of the pharmacologically active isomer [S - (+) - ibuprofen] increased by 15% and 82%, respectively, while fluconazole was simultaneously administered with racemic ibuprofen (400 mg).

With the simultaneous use of fluconazole at a dose of 200 mg per day and celecoxib at a dose of 200 mg of Cmax and AUC of celecoxib are increased by 68% and 134%, respectively. In this combination, a dose reduction of celecoxib can be halved.

Despite the lack of targeted research fluconazole can increase the systemic exposure of other NSAIDs metabolized by the CYP2C9 isoenzyme (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 carefully monitored to detect and control adverse events and toxicity associated with NSAIDs.

Cyclophosphamide: with the simultaneous use of cyclophosphamide and fluconazole, there is an increase in the concentrations of bilirubin and creatinine in serum. 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 administration 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 3-hydroxy-3-methylglutaryl-coenzyme A (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. If it is necessary to simultaneously treat these drugs, patients should be observed to identify the symptoms of myopathy and rhabdomyolysis. It is necessary to monitor the concentration of creatinine kinase. In the case of a significant increase in the concentration of creatinine kinase or a suspected development of myopathy or rhabdomyolysis, therapy with HMG-CoA reductase inhibitors should be discontinued.

Losartan: fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which is responsible for most of the effects,associated with the antagonism of angiogenesin-P receptors. Regular monitoring of blood pressure is necessary.

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

Oral contraceptives: while simultaneous application of a combined oral contraceptive with fluconazole at a dose of 50 mg, there is no significant effect on the level of hormones, whereas with a daily intake of 200 mg of fluconazole, the AUC of ethinylestradiol and levonorgestrel is increased by 40% and 24% respectively, and 300 mg of fluconazole once a week , AUC of ethinyl estradiol 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 oral contraceptive.

Phenytoin: simultaneous use 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 on the background of the cancellation of fluconazole after a three-month course of therapy. Presumably, discontinuation of fluconazole therapy caused an increase in the activity of the isoenzyme CYP3A4, which led to an increased metabolism of prednisone. Patients receiving combination therapy with prednisone and fluconazole should be under close medical supervision with the withdrawal of fluconazole 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%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis are described. Patients simultaneously receiving rifabutin and fluconazole, must be carefully observed.

Saquinavir: AUC increases by approximately 50%, Cmax by 55%, saquinavir clearance 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.

Cyclosporine: fluconazole significantly increases the concentration and PPC of cyclosporine. With concomitant therapy with fluconazole (200 mg per day) and cyclosporine (2.7 mg / kg per day), a 1.8-fold increase in cyclosporine AUC was noted. Use of this combination is possible provided that the dose of cyclosporine is reduced depending on its serum concentration.

Sirolimus: an increase in the concentration of sirolimus in the blood plasma, presumably due to the inhibition of the metabolism of sirolimus 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 admission, leads to an increase in the half-life of oral preparations of sulfonylurea (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes mellitus may be prescribed joint use of fluconazole and oral sulfonylureas, but this 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 (oral) leads to higher concentrations in the serum last up to 5 times by inhibiting the metabolism of tacrolimus, which occurs in the intestine by 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: with 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 in patients at increased risk of developing the toxic effect of theophylline, the symptoms of an overdose of theophylline should be monitored and, if necessary, adjusted accordingly.

Tofacitinib: When applied simultaneously with fluconazole tofacitinib, exposure tofacitinib (metabolized by the action of the isoenzyme CYP3A4) increases.The simultaneous use of fluconazole (a moderate inhibitor of the isoenzyme CYP3A4, as well as a potent inhibitor of the isoenzyme CYP2C19) increases AUC and Stach tofacitinib, so a dose correction of tofacitinib may be necessary.

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 development of unwanted reactions from the central nervous system (CNS) in the form of a pseudotumor of the brain with the simultaneous use of polytransretinic acid (acid form of vitamin A) 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 CNS.

Zidovudine: when used concomitantly 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.The half-life of zidovudine increased approximately 128% after administration in combination with fluconazole. Patients receiving this combination should be observed to identify side effects of zidovudine.

Azithromycin: in an open, randomized, three-group, crossover study involving 18 healthy volunteers, the effect of a single oral dose of 1200 mg of azithromycin on the pharmacokinetics of a single oral dose of 800 mg fluconazole was assessed, as well as the effect of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Phenazone (antipyrine): Investigations of inter-drug interaction with the use of antipyrin suggest that single or multiple doses of fluconazole 50 mg per metabolism of this compound do not affect.

Voriconazole (inhibitor of isoenzymes CYP2C9, CYP2C19 and 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 per day for 4 days) leads to an increase of Cmax and AUC of voriconazole by 57% and 79%, respectively.It was shown that this effect persists with a decrease in the dose and / or a decrease in the frequency of application of any of the drugs. In the case of sequential administration of voriconazole and fluconazole, it is recommended to monitor possible adverse events associated with voriconazole.

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

The listed interactions are established at repeated application of fluconazole, interaction with medicines as a result of single reception fluconazole, are unknown.

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

Special instructions:

Treatment should continue until the appearance of clinical-hematologic remission. Premature termination of treatment leads to relapse.

Treatment can be started in the absence of seeding results or other laboratory tests,but when they appear, if necessary, appropriate correction of fungicidal therapy is recommended.

The use of fluconazole for the treatment of trichophytosis of the scalp in children (Tinea capitis) was investigated. The drug did not provide more efficacy in comparison with griseofulvin, and the overall efficacy index did not exceed 20%. Therefore, it is not necessary to use Fluconazole Zentiva for the treatment of trichophytosis of the scalp.

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

In the course of treatment, it is necessary to monitor blood counts, kidney and liver function. Fluconazole Zentiva should be used with caution in patients with impaired renal function.

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 fluconazole, there was no apparent dependence on the total daily dose, duration of therapy, sex, and age of the patient.The hepatotoxic effect of fluconazole was usually reversible; signs of it disappeared after discontinuation of therapy. If there are clinical signs of liver damage that may be associated with fluconazole, the drug should be discontinued.

Like other azoles, fluconazole can cause an increase in the QT interval on the ECG. With fluconazole, an increase in the QT interval and fibrillation / flutter of the ventricles were very rare in seriously ill patients with multiple risk factors, such as organic heart disease, water-electrolyte balance disorders, and concomitant therapy contributing to the development of such disorders. Therefore, in such patients with potentially proarrhythmic conditions, fluconazole with caution.

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

Against the background of the use of the drug in patients, there were rare cases of development of exfoliative skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Patients with AIDS are more likely to develop severe skin reactions with many drugs.In those cases when the rash develops in patients with superficial fungal infection and it is regarded as definitely associated with fluconazole, the drug should be discontinued. When rashes appear in patients with invasive / systemic fungal infections, they should be carefully monitored and canceled fluconazole when there are bullous changes or erythema multiforme. It is necessary to control the prothrombin index while using the coumarinic anticoagulants simultaneously.

It is recommended to monitor the concentration of cyclosporine in the blood in patients receiving fluconazole, since in patients with kidney transplantation the use of fluconazole at a dose of 200 mg per day leads to a slow increase in the concentration of cyclosporine in the plasma.

When fluconazole 150 mg is used for vaginal candidiasis, patients should be warned that symptom improvement usually occurs after 24 hours, but it often takes several days to completely disappear. If symptoms persist for several days, you should consult your doctor.

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

In 100 ml of the preparation Fluconazole Zentiva contains 15.4 mmol of sodium ions and 15.4 mmol of chloride ions, which should be taken into account in patients who observe a salt-free diet or should limit the intake of liquid. It is necessary to monitor the total volume of the solution administered.

To a solution of the drug Fluconazole Zentiva should not be added any other solutions or medicines.

The drug Fluconazole Zentiva is compatible with the following solutions:

20% glucose solution;

Ringer's solution;

Hartman solution

potassium chloride in glucose solution;

sodium bicarbonate 4.2%;

aminofusine;

sodium chloride 9 mg / ml (0.9%).

All unused preparations or waste should be disposed of in accordance with local regulations, should not be placed in the refrigerator,keep frozen or otherwise store for future use.

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

There were no studies of the effect of Fluconazole Zentiva on the ability to drive vehicles and mechanisms. Patients should be warned about the possibility of dizziness or seizures during therapy with the drug Fluconazole Zentiva and are instructed to refrain from driving or working with mechanisms in the event of such symptoms.

Form release / dosage:

Solution for infusion, 2 mg / ml.

Packaging:

For 100 ml of the drug in a vial of colorless glass, ukuporenny rubber stopper, zavaltsovannaya under the break-in with a lid type "flip off". Each vial with instructions for use is placed in a cardboard box.

Storage conditions:

In a dry, protected from light place at a temperature of 10-25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N013252 / 03

Date of registration:30.07.2007

Date of cancellation:2017-11-14

The owner of the registration certificate:Zentiva c.s.Zentiva c.s. Czech Republic

Manufacturer: & nbsp

ZENTIVA, k.s. Czech Republic

Information update date: & nbsp14.11.2017

Illustrated instructions

Instructions

Fluconazole Zentiva (Fluconazole Zentiva)