Gynekit

Pharmacological properties

gynecitis - a kit that consists of 3 drugs: azithromycin - an antimicrobial agent for systemic use, macrolide; secnidazole - an antiprotozoal drug of the nitroimidazole group with antibacterial effect; fluconazole is an antifungal agent for systemic use, a triazole derivative.

Azithromycin is a broad-spectrum antibiotic. It has a bactericidal effect on S. pyogenes, S. pneumoniae, H. influenzae, bacteriostatic effect against staphylococci and most aerobic gram-negative bacteria.

Active against such microorganisms:

aerobic gram-positive bacteria - Staphilococcus aureus, Streptococcus spp. (including Streptococcus pneumoniae, Streptococcus pyogenes / group A), Corynebacterium diphteriae;

aerobic gram-negative bacteria - Haemophilus (influenzae, parainfluenzae, ducreui), Moraxella catarrhalis, Escherichia coli, Salmonella, Shigella, Aeromonas, Bordetella (pertussis, parapertussis, burgdorferella, Campoella pepella, Campinolegella palma, Campina, Legissella campella

anaerobic bacteria - Bacteroides fragilis, Clostridium perfringens, Fusobacterium spp., Prevotella spp., Porphyromonas spp .;

active also with respect to Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, Mycoplasma hominis, Treponema pallidum, Toxoplasma gondi, Borrelia burgdorferi, Helicobacter pylori, Listeria spp., Mycobacterium avium, Complex ureticum

There is complete cross-resistance between erythromycin, azithromycin, other macrolides and lincosamides for Streptococcus pneumoniae, group A β-hemolytic streptococcus, Enterococcus faecalis and Staphylococcus aureus, including methicillin S. aureus (MRSA).

Azithromycin is less active than erythromycin and clarithromycin against enterococci sensitive to erythromycin.

Secnidazole - is characterized by a bactericidal (against gram-positive and gram-negative anaerobic bacteria) and amoebicidal (intra- and extraintestinal) effect. Secnidazole is especially active against Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia. Penetrating into the cell of the microorganism, secnidazole is activated as a result of the restoration of the 5-nitro group, due to which it interacts with cellular DNA. There is a violation of its spiral structure and destruction of filaments, inhibition of nucleotide synthesis and cell death.

Fluconazole is a triazole derivative with a fungistatic effect that specifically inhibits ergosterol synthesis in fungal cells, inhibiting the enzymes of the cytochrome P450 system. This leads, as I believe, to the occurrence of defects in the cell membrane. The range of its application covers a number of pathogens, including Candida albicans, Cryptococcus spp. and dermatophytes. Candida krusei, Candida glabrata are resistant to fluconazole. Fluconazole is ineffective in treating infections caused by Aspergillus species.

Pharmacokinetics

Azithromycin Quickly absorbed in the digestive tract. Concomitant use with food reduces the absorption of azithromycin.

Bioavailability is about 37%. C_max in blood plasma is achieved within 2-3 hours after taking the drug.

It is quickly distributed in tissues and body fluids. It penetrates well into the respiratory tract, organs and tissues of the urogenital tract, into the skin and soft tissues. It accumulates intracellularly, due to which the concentration of the drug in the tissues is almost 50 times higher than the concentration in the blood plasma. Azithromycin in large quantities accumulates in phagocytes and fibroblasts. Phagocytes transport the drug to the site of inflammation. Azithromycin persists in bactericidal concentrations in the focus of inflammation for 5–7 days after the last dose.

Binding to blood plasma proteins varies depending on the concentration - about 50% at 0.02-0.05 μg / ml and about 7% at 1 μg / ml. The average volume of distribution when a stable concentration is reached is 31.1 l / kg.

About 35% of azithromycin is metabolized in the liver by demethylation.

More than 59% is excreted in the bile and about 4.5% in urine unchanged.

T_½ from blood plasma is 11-14 hours when measured in the range of 8-24 hours after taking a single dose; however, after applying multiple doses of T_½ approximately equal to T_½ from fabrics. T_½ from tissues - 2–4 days.

Secnidazole After oral administration, secnidazole is rapidly and completely absorbed in the digestive tract. Bioavailability is about 80%. Secnidazole passes through the BBB, passes into breast milk. T_½ secnidazole is about 25 hours, which allows to simplify the regimen of the drug, making it more convenient for patients.

FluconazoleAfter oral administration, fluconazole is well absorbed. Absolute bioavailability is about 90%. Eating does not affect the absorption of fluconazole. C_max in blood plasma is reached after 0.5-1.5 hours. An equilibrium concentration (at the level of 90%) is reached after 4-5 days when taken once a day.

T_½ is about 30 hours. The concentration of fluconazole in blood plasma is proportional to the dose. The distribution volume approaches the total fluid content in the body. Plasma protein binding is relatively low (11–12%).

Fluconazole penetrates well into all body fluids. Levels of the drug in saliva and sputum are the same as its concentration in blood plasma. A high concentration of fluconazole in the skin is higher than plasma indices, achieved in the stratum corneum, epidermis-dermis layer and sweat glands. Fluconazole accumulates in the stratum corneum.

Fluconazole is excreted mainly by the kidneys. About 80% of the administered dose is excreted unchanged in the urine. Fluconazole clearance is proportional to creatinine clearance. Circulating metabolites have not been established. T_½ from blood plasma is about 30 hours.

Elongated T_½ from blood plasma is the basis of low-dose therapy of vaginal candidiasis.

Pharmacokinetic parameters of fluconazole in the elderly. In people over the age of 65, the pharmacokinetic parameters are slightly higher than those recorded in young people. The difference in the accumulation of fluconazole in elderly patients is associated with reduced renal function in patients of this age category.

Indications

Treatment of diseases caused by drug-sensitive mixed microflora, which are transmitted sexually (acute nonspecific urethritis, cervicitis, colpitis, vaginitis).

Application

Tablets from the kit are taken as follows:

• in the morning - the first tablet With secnidazole (1 g) with meals;
• noon - the second pill With secnidazole (1 g) with meals;
• in the afternoon - tablet F fluconazole (150 mg) regardless of food intake;
• in the evening - tablet A azithromycin (1.0) 2 hours after a meal.

It is possible to use several sets of the drug for the treatment of sexually transmitted diseases. The doctor selects the number of doses of the drug Gynecitis and the treatment regimen individually.

The recommended treatment regimen for mixed infections, if Chlamidia is present in the composition, - taking Gynecit for 1-; 2-; 7-; 14th and 21st day.

The recommended treatment regimen for mixed infection, in which there is no Chlamidia (isolated Micoplasma / Ureaplasma urealiticum / Trichomonas vaginalis, etc.), - taking the drug Gynecitis on 1-; 3-; 5-; 7th and 14th day.

Contraindications

Increased individual sensitivity to azithromycin, secnidazole, fluconazole and other derivatives of nitroimidazole, azole, erythromycin, macrolide or ketolide antibiotics, as well as any excipients that make up the drug. the simultaneous use of fluconazole with other drugs that extend the q – t interval and are metabolized using the cyp 2a4 enzyme (for example, cisapride, astemizole, pimozide, quinidine and erythromycin). the simultaneous use of fluconazole and terfenadine in patients who use fluconazole repeatedly in doses of 400 mg / day and above (according to the results of studies of interaction with repeated use).

The simultaneous use of azithromycin with ergot derivatives due to the theoretical possibility of ergotism.

Pathological changes in the blood formula (severe leukopenia), including a history of. Acute cerebrovascular accident, parkinsonism, depression, severe liver dysfunction, giardiasis, organic diseases of the central nervous system.

Side effects

Azithromycin

On the part of the blood system: thrombocytopenia, leukopenia, hemolytic anemia, transient mild neutropenia is possible.

Mental disorders: aggressiveness, hyperactivity, anxiety and nervousness.

From the side of the nervous system: dizziness / vertigo, drowsiness, syncope, headache, cramps (it is also revealed that they are also caused by other macrolide antibiotics), changes in taste and smell, paresthesia, asthenia, insomnia, hypesthesia, psychomotor activity, myasthenia gravis.

On the part of the hearing organ: hearing loss, deafness and / or tinnitus.

From the cardiovascular system: reported palpitations, arrhythmias (including ventricular tachycardia) (it was found that they are also caused by other macrolide antibiotics). It is possible to lengthen the O – T interval and ventricular flutter / fibrillation, pirouette type arrhythmia, arterial hypotension.

From the digestive tract: nausea, vomiting, diarrhea, discomfort in the abdomen (pain / cramping), loose stools, flatulence, indigestion, anorexia, gastritis, constipation, discoloration of the tongue, pseudomembranous colitis, pancreatitis are possible.

From the liver: hepatitis and cholestatic jaundice, including pathological parameters of a functional liver test; there may be cases of necrotic hepatitis and liver dysfunction, which can be fatal; liver failure, fulminant hepatitis.

On the part of the skin: allergic reactions, including pruritus, rash, angioedema, urticaria; skin reactions, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis; photosensitivity.

From the musculoskeletal system: arthralgia.

From the urinary system: interstitial nephritis, acute renal failure.

Infections and infestations: oral and vaginal candidiasis, vaginal infections, candidiasis.

General disorders: fatigue, chest pain, weakness, asthenia, edema.

From the reproductive system: vaginitis.

From the side of the organ of vision: visual impairment.

Systemic disorders: hypersensitivity reactions, including anaphylaxis, anaphylactic reactions.

Laboratory studies: a decrease in the number of lymphocytes, an increase in the number of eosinophils and a decrease in the number of bicarbonates in the blood, an increase in the content of bilirubin, urea, creatinine in the blood plasma, an increase in the activity of AcAT, AlAT, changes in the potassium content in the blood. These changes were reversible.

Secnidazole

From the digestive tract: indigestion, nausea, pain in the stomach, vomiting, abdominal pain, glossitis, stomatitis.

From the sensory organs: metallic taste in the mouth.

On the part of the skin: urticaria, itching, rash on the skin.

From the blood system: leukopenia.

From the nervous system: dizziness, impaired coordination of movements, ataxia, paresthesia, polyneuropathy, headache.

From the immune system: hypersensitivity reactions.

Fluconazole

On the part of the blood system and lymphatic system: anemia, agranulocytosis, leukopenia, neutropenia, thrombocytopenia.

From the immune system: anaphylaxis.

Metabolic disorders: loss of appetite, hypertriglyceridemia, hypercholesterolemia, hypokalemia.

From the nervous system: headache, insomnia, drowsiness, cramps, dizziness, paresthesia, tremor.

On the part of the organ of hearing: vertigo.

From the cardiovascular system: paroxysmal ventricular tachycardia of the pirouette type, lengthening of the Q – T interval.

From the digestive tract: abdominal pain, diarrhea, nausea, vomiting, constipation, dyspepsia, flatulence, dry mouth.

On the part of the hepatobiliary system: increased levels of AlAT, AcAT, alkaline phosphatase, cholestasis, jaundice, increased levels of bilirubin, liver failure, hepatocellular necrosis, hepatitis, hepatocellular lesions.

On the part of the skin and subcutaneous tissue: rash, itching, drug dermatitis, urticaria, increased sweating, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, facial edema, angioedema, alopecia.

From the musculoskeletal system: myalgia.

Common disorders: fatigue, malaise, asthenia, fever.

special instructions

Before starting treatment with a gynecitis drug, it is necessary to sow and determine the sensitivity of microflora to the drugs that make up its composition.

Patients with infectious urethritis and cervicitis must undergo appropriate serological tests for syphilis before treatment with Gynecitis.

Azithromycin Since azithromycin is excreted primarily through the liver, in patients with severe liver diseases, the drug should be used with caution.

If patients have signs of impaired liver function, the use of the drug should be discontinued.

As with other antibiotics, it is necessary to monitor the possible manifestation of signs of superinfection caused by insensitive microorganisms, including fungi.

The likelihood of developing diarrhea associated with Clostridium difficile should be taken into account in all patients with diarrhea that occurs after antibiotic use. It is necessary to carefully analyze the history, since it was reported that Clostridium difficile-associated diarrhea can develop 2 months after taking antibacterial drugs.

In patients with severe renal failure (GRF 10 ml / min), an increase in systemic exposure of azithromycin by 33% was noted.

Elongation of cardiac repolarization and the Q – T interval, which were associated with a risk of developing cardiac arrhythmias and paroxysmal ventricular tachycardia such as pirouette, were identified during treatment with other macrolide antibiotics. A similar effect of azithromycin cannot be completely excluded in patients with an increased risk of prolonged cardiac repolarization; therefore, patients with congenital or registered Q-T prolongation should be prescribed with caution; receiving treatment with other active substances that are known to lengthen the Q – T interval, for example, class II and III antiarrhythmic drugs, cisapride and terfenadine; with a violation of electrolyte metabolism, especially in the case of hypokalemia and hypomagnesemia; with clinically relevant bradycardia, cardiac arrhythmias, or severe heart failure.

Secnidazole Secnidazole should not be prescribed to patients with a history of blood dyskrasia. During treatment with the drug, reversible neutropenia may occur. The white blood cell count is restored after cessation of treatment. During the use of the drug, alcohol should be avoided.

Fluconazole In rare cases, the use of fluconazole may be accompanied by toxic liver lesions, including fatalities (mainly they are noted in patients with severe concomitant diseases).

The hepatotoxic effect of fluconazole is usually reversible, the symptoms disappear after discontinuation of therapy. It is necessary to observe patients in whom liver function indicators are impaired during treatment with fluconazole in order to detect signs of more severe liver damage. If there are clinical signs of liver damage that may be associated with fluconazole, the drug must be discontinued.

During treatment with fluconazole in patients, exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis can very rarely be detected. AIDS patients are more likely to develop severe skin reactions when using a large number of drugs.If a patient with a superficial fungal infection develops a rash that can be associated with fluconazole, the drug should be discontinued.

In rare cases, as for other azoles, anaphylactic reactions may occur.

Halofantrine is a substrate of the CYP ZA4 enzyme and prolongs the O – Tc interval when used in recommended therapeutic doses. The simultaneous use of halofantrine and fluconazole is not recommended.

Fluconazole should be prescribed with caution to patients with a potential tendency to arrhythmias. Patients with liver, heart, and kidney disease should consult a physician before starting fluconazole treatment.

Cytochrome P450. Fluconazole is a potent inhibitor of the CYP 2C9 enzyme and a moderate inhibitor of the CYP ZA4 enzyme. Fluconazole is also an inhibitor of the CYP 2C19 enzyme. You should monitor the condition of patients simultaneously taking fluconazole and drugs with a narrow therapeutic window, metabolized with the participation of CYP 2C9, CYP 2C19 and CYP ZA4.

Terfenadine. Care should be taken to monitor the patients condition while using terfenadine and fluconazole at a dose of less than 400 mg / day.

The positive dynamics of symptoms usually begin after 24 hours. However, their complete disappearance can occur in a few days. If within a few days the patient does not show improvement, you should consult a doctor.

In patients with impaired renal function, the drug should be used with caution.

The excipients of azithromycin tablets include Ponce 411, which can cause hypersensitivity and severe allergic reactions.

With patients with a potential tendency to arrhythmias, fluconazole should be prescribed with caution.

Use during pregnancy and lactation. During pregnancy, the use of the drug is contraindicated. Breastfeeding during treatment should be discontinued.

Children. The use of the drug in children under the age of 18 is contraindicated.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Considering that sensitive patients may experience drowsiness and impaired coordination of movements, it is better to refrain from driving vehicles and mechanisms while taking the drug, and performing other work requiring attention.

Interactions

Azithromycin it should be used with caution in prescribing azithromycin to patients concurrently with other drugs, which may lengthen the interval of about.

Antacids: when studying the effect of the simultaneous use of antacids on the pharmacokinetics of azithromycin, generally no changes in bioavailability were detected, although plasma peak concentrations of azithromycin decreased by 30%. Azithromycin must be taken at least 1 hour before or 2 hours after taking antacid.

In a study of the pharmacokinetic interaction in healthy volunteers, carbamazepine azithromycin did not significantly affect plasma levels of carbamazepine or its active metabolites.

Cyclosporin: Some of the related macrolide antibiotics affect cyclosporin metabolism. Since there are no pharmacokinetic and clinical studies of possible interactions with the simultaneous administration of azithromycin and cyclosporine, the therapeutic situation should be carefully assessed before the simultaneous administration of these drugs. If combination treatment is considered warranted, careful monitoring of cyclosporine levels should be performed and the dose adjusted accordingly.

Coumarin anticoagulants. An increased tendency to bleeding has been reported in connection with the simultaneous use of azithromycin and warfarin or coumarin-like oral anticoagulants. Attention should be paid to the frequency of monitoring prothrombin time.

Digoxin: In some patients, certain macrolide antibiotics have been reported to affect digoxin metabolism in the intestines. Accordingly, in the case of simultaneous use of azithromycin and digoxin, one should remember about the possibility of increasing the concentrations of digoxin and monitor the level of digoxin.

Methylprednisolone: ​​in a study of the pharmacokinetic interaction in healthy volunteers, azithromycin did not significantly affect the pharmacokinetics of methylprednisolone.

Terfenadine: pharmacokinetic studies have not reported an interaction between azithromycin and terfenadine. As with other macrolide antibiotics, azithromycin should be used with caution in combination with terfenadine.

Theophylline azithromycin does not affect the pharmacokinetics of theophylline while taking azithromycin and theophylline in healthy volunteers. The combined use of theophylline and other macrolide antibiotics sometimes led to an increase in theophylline levels in blood plasma.

Zidovudine: 1000 mg single doses and 1200 or 600 mg multiple doses of azithromycin did not affect plasma pharmacokinetics and urinary excretion of zidovudine or its glucuronide metabolites. However, taking azithromycin increased the concentration of phosphorylated zidovudine, a clinically active metabolite in mononuclear cells in peripheral circulation. The clinical relevance of these data is inexplicable, but may be useful to patients.

Didanosine: with the simultaneous use of daily doses of 1200 mg of azithromycin with didanosine, there was no effect on the pharmacokinetics of didanosine compared with placebo.

Rifabutin: The simultaneous use of azithromycin and rifabutin did not affect the plasma concentrations of these drugs. Neutropenia was observed in patients taking both azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship with simultaneous administration with azithromycin has not been established.

Nelfinavir: the use of nelfinavir causes an increase in the concentration of azithromycin in blood plasma. Although dose adjustment of azithromycin with its simultaneous use with nelfinavir is not recommended, careful monitoring of the known side effects of azithromycin is warranted.

Ergot derivatives: given the theoretical possibility of ergotism, the simultaneous use of azithromycin with ergot derivatives is not recommended.

Macrolide antibiotics are known to react with astemizole, triazolam, midazolam, and alfentanil. Since there is no data on the interaction between azithromycin and the above drugs, it is recommended to carefully monitor patients if these drugs are used simultaneously.

The effect of azithromycin on cimetidine levels in the blood has not been reported.

Unlike most macrolide antibiotics, azithromycin has no effect on cytochrome P450, and there is currently no data on the interaction between azithromycin and the above drugs.

Secnidazole

Anticoagulants: secnidazole with simultaneous use enhances the effect of indirect anticoagulants (coumarin and indandion derivatives), the risk of bleeding increases.

Disulfiram: combined with secnidazole can cause paranoid reactions and psychoses.

Alcohol: combination with alcohol causes symptoms of a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headache, flushing), delirious seizures and dizziness are possible.

Lithium preparations: with simultaneous use with secnidazole, the concentration of lithium in the blood plasma increases.

Non-depolarizing muscle relaxants (vecuronium bromide): not recommended for combination with secnidazole.

Amoxicillin: when used with secnidazole, Helicobacter pylori activity increases (amoxicillin inhibits the development of resistance).

FluconazoleThe combined use of fluconazole with the following drugs is contraindicated.

Cisapride: The development of adverse reactions from the heart, including paroxysmal ventricular tachycardia of the pirouette type in patients simultaneously taking fluconazole and cisapride, has been reported. A controlled study showed that the simultaneous use of 200 mg of fluconazole 1 time per day and 20 mg of cisapride 4 times a day led to a significant increase in the level of cisapride in blood plasma and lengthening of the Q – T interval. The simultaneous use of fluconazole and cisapride is contraindicated (see CONTRAINDICATIONS).

Terfenadine: due to cases of severe cardiac arrhythmias caused by lengthening of the Q – Tc interval in patients using azole antifungal drugs simultaneously with terfenadine, studies of the interaction of these drugs have been conducted. In the course of studies using fluconazole at a dose of 200 mg / day, no prolongation of the Q – T interval was revealed. Another study using fluconazole in doses of 400 and 800 mg / day demonstrated that the use of fluconazole in doses of 400 mg / day or higher significantly increases the level of terfenadine in blood plasma while using these drugs. The combined use of fluconazole in doses of ≥400 mg with terfenadine is contraindicated (see CONTRAINDICATIONS). When using fluconazole in doses of 400 mg / day at the same time as terfenadine, careful monitoring of the patients condition should be carried out.

Astemizole: The combined use of fluconazole and astemizole can reduce the clearance of astemizole. The increase in astemizole concentration in blood plasma caused by this can lead to a prolongation of the Q – T interval and, in rare cases, to paroxysmal ventricular tachycardia of the pirouette type. The simultaneous use of fluconazole and astemizole is contraindicated.

Pimoside and quinidine: the simultaneous use of fluconazole and pimoside or quinidine can inhibit the metabolism of pimoside or quinidine, although no relevant in vitro or in vivo studies have been performed. An increase in the concentration of pimozide or quinidine in blood plasma can cause an extension of the Q – T interval and, in rare cases, lead to the development of paroxysmal ventricular tachycardia such as pirouette. The simultaneous use of fluconazole and pimozide or quinidine is contraindicated.

Erythromycin: the simultaneous use of erythromycin and fluconazole can potentially lead to an increased risk of cardiotoxicity (prolongation of the Q – T interval, paroxysmal ventricular tachycardia such as pirouette) and, as a result, sudden cardiac death. The use of a combination of these drugs is contraindicated.

The simultaneous use of fluconazole and the following medicines is not recommended.

Halofantrine: fluconazole may cause an increase in plasma halofantrine concentration due to inhibition of CYP 3A4. The simultaneous use of these drugs can lead to an increased risk of cardiotoxicity (prolongation of the Q – T interval, paroxysmal ventricular tachycardia such as pirouette) and, as a result, sudden cardiac death. A combination of these medicines should be avoided.

The combined use of fluconazole and the following medicines requires caution and dose adjustment.

The effect of other drugs on fluconazole. Interaction studies have shown that concomitant use of food, cimetidine, antacids, or prolonged whole-body irradiation for bone marrow transplantation does not have a clinically significant effect on the absorption of fluconazole when administered orally.

Rifampicin: concomitant use of fluconazole and rifampicin led to a 25% decrease in AUC and a decrease in T_½ fluconazole by 20%. Therefore, for patients taking rifampicin, the feasibility of increasing the dose of fluconazole should be considered.

The effect of fluconazole on other drugs. Fluconazole is a potent inhibitor of the 2C9 isoenzyme cytochrome P450 (CYP) and a moderate inhibitor of CYP 3A4. Fluconazole is also an inhibitor of CYP 2C19. In addition to the noted / documented interactions described below, when used simultaneously with fluconazole, there is a risk of increased plasma concentrations of other compounds that are metabolized by CYP 2C9 and CYP 3A4. Therefore, use such combinations of drugs with caution; it is necessary to carefully monitor the condition of the patients. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after its use in connection with its long T_½.

Alfentanil: with the simultaneous use of alfentanil at a dose of 20 μg / kg body weight and fluconazole at a dose of 400 mg in healthy volunteers, a double increase in AUC was noted, possibly due to inhibition of CYP3 A4. A dose adjustment of alfentanil may be required.

Amitriptyline, nortriptyline: fluconazole enhances the effects of amitriptyline and nortriptyline. It is recommended to measure the concentrations of 5-nortriptyline and / or S-amitriptyline at the beginning of combination therapy and after 1 week. If necessary, the dose of amitriptyline / nortriptyline should be adjusted.

Amphotericin B: according to research data, the simultaneous use of fluconazole and amphotericin led to the following results: a small additive antifungal effect in case of systemic infection of C. albicans, lack of interaction in case of intracranial infection of Cryptococcus neoformans and antagonism of two drugs in case of systemic infection of A. fumigatus. The clinical significance of the results obtained during the studies is unknown.

Anticoagulants: as with other azole antifungal agents, with the simultaneous use of fluconazole and warfarin, cases of the development of bleeding (hematomas, nosebleeds, gastrointestinal bleeding, hematuria and melena) in combination with an extension of prothrombin time have been reported. With the simultaneous use of fluconazole and warfarin, a twofold increase in prothrombin time was detected, probably due to inhibition of warfarin metabolism by CYP 2C9. Prothrombin time should be carefully monitored in patients simultaneously taking coumarin-type anticoagulants. A dose adjustment of warfarin may be required.

Short-acting benzodiazepines, for example midazolam, triazolam: the administration of fluconazole after oral administration of midazolam led to a significant increase in the concentration of midazolam and increased psychomotor effects. The simultaneous use of fluconazole at a dose of 200 mg and midazolam at a dose of 7.5 mg orally led to an increase in AUC and T_½ 3.7 and 2.2 times, respectively. The use of fluconazole at a dose of 200 mg / day and 0.25 mg of triazolam orally led to an increase in AUC and T_½ 4.4 and 2.3 times, respectively. With the simultaneous use of fluconazole and triazolam, potentiation and prolongation of the effects of triazolam were revealed.

If a patient who received fluconazole treatment should be prescribed benzodiazepine therapy at the same time, the dose of the latter should be reduced and proper monitoring of the patients condition should be established.

Carbamazepine: fluconazole inhibits the metabolism of carbamazepine and causes an increase in the level of carbamazepine in blood plasma by 30%. There is a risk of toxicity from carbamazepine. A dose adjustment of carbamazepine may be necessary depending on the level of its concentration and the effect of the drug.

Calcium channel blockers: some calcium antagonists (nifedipine, isradipine, amlodipine and felodipine) are metabolized by the enzyme CYP 3A4. Fluconazole may increase the systemic exposure of calcium channel blockers. Careful monitoring of the development of adverse reactions is recommended.

Celecoxib: with the simultaneous use of fluconazole (200 mg / day) and celecoxib (200 mg) C_max and celecoxib AUC increased by 68 and 134%, respectively. With the simultaneous use of celecoxib and fluconazole, a dose reduction of celecoxib by 2 times may be required.