Fluconazole capsules 150mg №1×1

Name Fluconazole caps. Composition One capsule contains: active ingredient – fluconazole – 150 mg; excipients – lactose monohydrate, povidone K-17, sodium lauryl sulfate, magnesium stearate, potato starch. Capsule composition: gelatin, methyl parahydroxybenzoate E 218, titanium dioxide E 171, propyl parahydroxybenzoate E 216. Pharmacotherapeutic group Antifungal drugs for systemic use. ATX code: J02AC01. Pharmacological properties Pharmacodynamics Mechanism of action Fluconazole is an antifungal drug of the triazole group. The main mechanism of action of fluconazole is to inhibit the reaction of 14?-lanosterol-demethylation mediated by cytochrome P450, which is an integral step in the biosynthesis of fungal ergosterol. The accumulation of 14β-methylsterols correlates with the subsequent loss of ergosterol by the fungal cell membrane. This process may underlie the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various mammalian cytochrome P450 enzyme systems. The use of fluconazole at a dose of 50 mg / day for 28 days had no effect on plasma testosterone levels in men or plasma steroid levels in women of reproductive age. Fluconazole at a dose of 200-400 mg / day does not show a clinically significant effect on the level of endogenous steroids or response to ACTH stimulation in healthy male volunteers. Interaction studies with antipyrine have shown that the use of fluconazole at a dose of 50 mg single or multiple does not affect the metabolism of antipyrine. Sensitivity in vitro. Fluconazole in vitro exhibits antifungal activity against the most common Candida species in clinical practice (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows a wide range of sensitivity to fluconazole, while C. krusei is resistant to it. Fluconazole is also active in vitro against Cryptococcus neoformans and Cryptococcus gattii, as well as endemic molds Blastomyces dermatiditis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis. Dependence of parameters of pharmacokinetics and pharmacodynamics According to the results of experimental studies on animals, there is a correlation between the values of the minimum inhibitory concentration (MIC) and efficacy against experimental models of fungal infections caused by fungi of the genus Candida. According to clinical studies, there is an almost linear (almost 1:1) relationship between AUC and the dose of fluconazole. There is also a direct but not sufficient relationship between AUC or dose and positive clinical response to oral candidiasis and, to a lesser extent, candidemia. Similarly, the treatment of infections caused by strains for which fluconazole shows a higher MIC is less effective. Mechanisms of resistance development Fungi of the genus Candida implement numerous mechanisms for the development of resistance to antifungal agents from the azole group. It is known that fungal strains using 1 or more resistance mechanisms exhibit a high MIC of fluconazole, which has a negative impact on the efficacy of the drug in vivo and in clinical practice. There have been reports of superinfection caused by fungi of the genus Candida other than C. albicans, which are often inherently insensitive to fluconazole (eg Candida krusei). In such cases, alternative antifungal therapy is required. Breakpoints (EUCAST) Based on analysis of pharmacokinetic/pharmacodynamic (PK/PD) data, in vitro susceptibility and clinical response, EUCAST-AFST (European Committee for Antibacterial Susceptibility Testing – Subcommittee on Antifungal Susceptibility Testing) has developed susceptibility breakpoints to fluconazole for fungi of the genus Candida (“Justification for the use of fluconazole EUCAST (2007)” – edition 2). These breakpoints were divided into non-species-specific breakpoints (which were largely determined by PK/PD data and were independent of MIC species allocation) and species-specific breakpoints (which most often are the causative agents of infections in humans). Pharmacokinetics The pharmacokinetics of fluconazole are similar when administered intravenously and when taken orally. Absorption After oral administration, fluconazole is well absorbed and its plasma concentration (and total bioavailability) is more than 90% of its plasma concentration after intravenous administration. Simultaneous food intake does not affect the absorption of the drug when taken orally. The maximum plasma concentration is reached 0.5-1.5 hours after taking the drug on an empty stomach. Plasma concentrations of fluconazole are proportional to the dose of the drug taken. Equilibrium concentration (at the level of 90%) is achieved by 4-5 days of treatment with multiple doses of the drug 1 time per day. Taking the drug on the first day at a loading dose twice the average daily dose allows reaching an equilibrium concentration (at the level of 90%) by the second day of treatment. Distribution The apparent volume of distribution approximates the total body water content. The binding of fluconazole to plasma proteins is low (11-12%). Fluconazole penetrates well into all studied body fluids. Fluconazole concentrations in saliva and sputum are similar to those in plasma. In patients with fungal meningitis, fluconazole levels in the cerebrospinal fluid are approximately 80% of its plasma levels. In the stratum corneum, epidermis, dermis and sweat fluid, high concentrations of the drug are achieved, which exceed serum values. Fluconazole accumulates in the stratum corneum. When taking the drug at a dose of 50 mg once a day, the concentration of fluconazole after 12 days was 73 mcg / g, and after 7 days after stopping treatment – 5.8 mcg / g. When using the drug at a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum on the 7th day 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 using the drug at a dose of 150 mg once a week was 4.05 µg/g in healthy and 1.8 µg/g in affected nails; fluconazole was detected in nail samples 6 months after the end of therapy. Biotransformation Fluconazole is slightly metabolized. With the introduction of a dose labeled with radioactive isotopes, only 11% of fluconazole is excreted in the urine in an altered form. Fluconazole is a selective inhibitor of CYP2C9 and CYP3A4 isoenzymes (see the section “Interactions with other drugs”), as well as an inhibitor of the CYP2C19 isoenzyme. Withdrawal The plasma half-life of fluconazole is approximately 30 hours. The main route of elimination of the drug is renal excretion, with approximately 80% of the dose taken unchanged in the urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites were found. The long half-life of the drug from blood plasma allows you to take fluconazole once for the treatment of vaginal candidiasis and once a day or once a week for the treatment of other diseases. Pharmacokinetics in patients with impaired renal function In patients with severe renal insufficiency (GFR < 20 ml / min), the half-life of the drug increased from 30 hours to 98 hours. Therefore, this category of patients needs to reduce the dose of the drug. Fluconazole is removed by hemodialysis and, to a lesser extent, by peritoneal dialysis. A session of hemodialysis lasting 3 hours reduces the level of fluconazole in blood plasma by approximately 50%. Pharmacokinetics in children Pharmacokinetics were evaluated in 113 children in 5 studies: 2 single-dose studies, 2 multiple-dose studies and one study in preterm infants. Data from one study were not subject to interpretation due to a change in the method of administration of the drug during the study. During the charitable trial use of the drug, additional information was obtained. After administration of fluconazole at a dose of 2–8 mg/kg to children aged 9 months to 15 years, the AUC of fluconazole was about 38 µg h/ml per 1 mg/kg dose. After repeated administration of fluconazole, the mean plasma half-life of fluconazole ranged from 15 hours to 18 hours, and the volume of distribution was approximately 880 ml/kg. A longer plasma half-life of the drug (approximately 24 hours) was observed after a single dose of the drug, which is comparable to the plasma half-life of fluconazole after its single intravenous administration to children aged 11 days to 11 months at a dose of 3 mg / kg . The volume of distribution of the drug in patients of this age group was approximately 950 ml/kg. Experience with fluconazole in neonates is limited to pharmacokinetic studies involving 12 preterm infants with a gestational age of approximately 28 weeks. The mean age of the child at the first dose was 24 hours (range 9 hours to 36 hours); mean birth weight was 0.9 kg (range 0.75 to 1.10 kg). Seven patients completed the study according to the protocol. A maximum of 5 intravenous injections of fluconazole at a dose of 6 mg/kg was given every 72 hours. h) and on the thirteenth day on average up to 47 hours (within 27–68 hours). AUC values were 271 µg h/mL (range 173–385 µg h/mL) on day 1, then increased to 490 µg h/mL (range 292–734 µg h/mL) on day 7 and decreased to a median of 360 mcg h/ml (range 167–566 mcg h/ml) by day thirteen. The volume of distribution was 1183 ml/kg (range 1070-1470 ml/kg) on the first day, then increased over time to a mean of 1184 ml/kg (range 510-2130 ml/kg) on the seventh day and up to 1328 ml/kg. kg (range 1040–1680) on the thirteenth day. Pharmacokinetics in Elderly Patients Pharmacokinetic studies were performed in 22 patients aged 65 years and older who took fluconazole once orally at a dose of 50 mg. Ten patients were simultaneously taking diuretics. Cmax was 1.54 µg/ml and was reached 1.3 hours after taking the drug. The mean AUC was 76.4±20.3 µg h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameters are higher than those found in younger, healthy male volunteers. The simultaneous use of diuretics did not significantly affect the values of AUC and Cmax. In addition, creatinine clearance (74 ml/min), the percentage of fluconazole excreted in the urine unchanged (0–24 h, 22%), and renal clearance of fluconazole (0.124 ml/min/kg) were generally lower in the elderly. than those in younger volunteers. Thus, changes in the pharmacokinetics of fluconazole in elderly patients are likely to be associated with reduced renal function characteristic of the elderly. Indications for use The use of the drug Fluconazole, 150 mg capsules is indicated for the fungal infections listed below (see the Pharmacodynamics section). Fluconazole 150 mg capsules (packaged #1-1): acute vaginal candidiasis when topical therapy is not appropriate; candidal balanitis when topical therapy is not suitable Fluconazole 150 mg capsules (packaged #1-2): ringworm including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and candidal skin infections when systemic therapy is needed; tinea unguium (onychomycosis) when other drugs are not acceptable. results of the cultural method and other laboratory research methods. However, after these results become known, an appropriate correction in anti-infective therapy should be made. When using this drug, you must follow the official recommendations for the proper use of antifungal medicines. Contraindications Hypersensitivity to the active substance, azole substances similar to it in chemical structure, or to any of the excipients that make up the drug, indicated in the "Composition" section. According to a study of drug interactions with multiple doses of drugs, the simultaneous use of terfenadine during repeated use of fluconazole at a dose of 400 mg per day and above is contraindicated. Patients taking fluconazole are contraindicated in the simultaneous administration of drugs that prolong the QT interval and are metabolized by the cytochrome P450 isoenzyme CYP3A4, such as cisapride, astemizole, pimozide, quinidine and erythromycin (see sections "Precautions" and "Interaction with other drugs") . Side effects Most often (? 1/10) adverse reactions such as headache, abdominal pain, diarrhea, nausea, vomiting, increased levels of alanine aminotransferase, increased levels of aspartate aminotransferase, increased levels of alkaline phosphatase in the blood and rash were recorded. When taking the drug, the development of the following adverse reactions was observed with the following frequency: very often (?1/10), often (from?1/100 to <1/10), infrequently (from?1/1000 to <1/100), rare (?1/10,000 to <1/1000), very rare (<1/10,000) and unknown (cannot be determined from the available data). Children and adolescents Nature and frequency of adverse reactions, as well as abnormal laboratory results studies recorded in children and adolescents during clinical trials, with the exception of genital candidiasis, were comparable to those in adult patients. Reporting Suspected Adverse Reactions Reporting suspected adverse reactions after drug registration is important. This allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions using the national adverse reaction reporting system. Interaction with other medicinal products Co-administration of fluconazole and the following medicinal products is contraindicated: Cisapride: in patients who simultaneously took fluconazole and cisapride, the development of adverse reactions from the heart, including paroxysmal ventricular tachycardia of the pirouette type (torsade de pointes), was observed. In a controlled study, the simultaneous use of fluconazole at a dose of 200 mg 1 time per day and cisapride at a dose of 20 mg 4 times a day led to a significant increase in plasma concentrations of cisapride and a prolongation of the QTc interval. The simultaneous use of fluconazole and cisapride is contraindicated (see section "Contraindications"). Terfenadine: In connection with the development of severe cardiac arrhythmias caused by prolongation of the QTc interval, interaction studies of these drugs were conducted in patients who used azole antifungal drugs concomitantly with terfenadine. In one study, no prolongation of the QTc interval was found with fluconazole 200 mg/day. In another study using fluconazole at a dose of 400 mg / day and 800 mg / day, it was demonstrated that fluconazole at 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 or more with terfenadine is contraindicated (see section "Contraindications"). When using fluconazole at a dose of less than 400 mg / day simultaneously with terfenadine, careful monitoring of the patient's condition should be carried out. Astemizole: the combined use of fluconazole and astemizole may lead to a decrease in the clearance of astemizole. The resulting increase in the concentration of astemizole in the blood plasma can, in turn, lead to a prolongation of the QT interval and, in rare cases, to the development of paroxysmal ventricular tachycardia of the pirouette type (torsade de pointes). The simultaneous use of fluconazole and astemizole is contraindicated (see section "Contraindications"). Pimozide: Although no relevant in vitro or in vivo studies have been performed, it is believed that the combined use of fluconazole and pimozide may lead to inhibition of the metabolism of pimozide. In turn, an increase in the concentration of pimozide in the blood plasma can lead to a prolongation of the QT interval and, in rare cases, to the development of paroxysmal ventricular tachycardia of the pirouette type (torsade de pointes). The simultaneous use of fluconazole and pimozide is contraindicated (see section "Contraindications"). Quinidine: Although no relevant in vitro or in vivo studies have been conducted, it is believed that the combined use of fluconazole and quinidine may lead to inhibition of the metabolism of the latter. The use of quinidine was accompanied by a prolongation of the QT interval and, in rare cases, the development of paroxysmal ventricular tachycardia of the pirouette type (torsade de pointes). The simultaneous use of fluconazole and quinidine is contraindicated (see section "Contraindications"). Erythromycin: the simultaneous use of erythromycin and fluconazole increases the risk of developing cardiotoxicity (prolongation of the QT interval, the development of paroxysmal ventricular tachycardia of the torsade de pointes type) and, as a result, sudden coronary death. The simultaneous use of fluconazole and erythromycin is contraindicated (see section "Contraindications"). The concomitant use of fluconazole and the following medicinal products is not recommended: Halofantrine: fluconazole may increase plasma concentrations of halofantrine due to an inhibitory effect on CYP3A4. The simultaneous use of fluconazole and halofantrine may increase the risk of developing cardiotoxicity (prolongation of the QT interval, the development of paroxysmal ventricular tachycardia of the torsade de pointes type) and, as a result, sudden coronary death. The use of a combination of these drugs should be avoided (see section "Precautions"). Simultaneous use with the following drugs requires caution and dose adjustment: Effect of other drugs on fluconazole Rifampicin: the simultaneous use of fluconazole and rifampicin resulted in a 25% decrease in AUC and a 20% reduction in the half-life of fluconazole. In patients taking rifampicin, an increase in the dose of fluconazole should be considered. Interaction studies have shown that fluconazole administered orally at mealtimes, with cimetidine, antacids, or after total body irradiation (in preparation for bone marrow transplantation) has no clinically significant effect on fluconazole absorption. Effect of fluconazole on other drugs Fluconazole is a potent inhibitor of cytochrome P450 isoenzyme CYP2C9 and a moderate inhibitor of CYP3A4. In addition, fluconazole is an inhibitor of the CYP2C19 isoenzyme. In addition to the identified / established interactions (listed below), there is a risk of increasing plasma concentrations of other drugs that are metabolized by CYP2C9, CYP2C19 and CYP3A4 when they are used simultaneously with fluconazole. Therefore, such drug combinations should be used with caution; while it is necessary to carefully monitor the condition of patients. Due to the long half-life of fluconazole, its inhibitory effect on enzymes persists for 4-5 days after the end of treatment (see section "Contraindications"). Alfentanil: in healthy volunteers, the simultaneous use of fluconazole (at a dose of 400 mg) and alfentanil (at a dose of 20 μg / kg intravenously) led to a two-fold increase in the AUC10 of alfentanil (probably due to inhibition of the CYP3A4 isoenzyme). Dose adjustment of alfentanil may be required. Amitriptyline, nortriptyline: Fluconazole enhances the effect of amitriptyline and nortriptyline. Concentrations of 5-nortriptyline and/or S? amitriptyline is recommended to determine at the beginning of combination therapy and after the first week of treatment. If necessary, the dose of amitriptyline/nortriptyline should be adjusted. Amphotericin B: Co-administration of fluconazole and amphotericin B in immunocompromised and normal infected mice showed the following results: slight additive antifungal effect in systemic C. albicans infection; no interaction with intracranial infection caused by Cryptococcus neoformans; and two drug antagonism in systemic infection with Aspergillus fumigatus. The clinical significance of the results obtained in these studies is unknown. Anticoagulants: During the post-registration period, there have been reports of the development of bleeding (hematomas, epistaxis, gastrointestinal bleeding, hematuria and melena) due to prolongation of the prothrombin time with the simultaneous use of warfarin and fluconazole. Similar phenomena were observed with the use of other antifungal agents from the azole group. With the simultaneous use of fluconazole and warfarin, a twofold increase in prothrombin time was noted, probably due to inhibition of warfarin metabolism mediated by the CYP2C9 isoenzyme. In patients taking coumarin anticoagulants in conjunction with fluconazole, it is recommended to carefully monitor the prothrombin time. If necessary, the dose of warfarin should be adjusted. Short-acting benzodiazepines, such as midazolam and triazolam: After oral administration of midazolam and fluconazole, a significant increase in midazolam serum concentrations and an increase in psychomotor effects were observed. 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 a prolongation of the half-life of midazolam by 3.7 and 2.2 times, respectively. The simultaneous use of fluconazole at a dose of 200 mg / day and triazolam at a dose of 0.25 mg orally led to an increase in AUC and a prolongation of the half-life of triazolam by 4.4 and 2.3 times, respectively. With the simultaneous use of fluconazole and triazolam, potentiation and prolongation of the effects of triazolam were noted. If patients receiving fluconazole require concomitant benzodiazepine therapy, consideration should be given to reducing the dosage of the latter and establishing appropriate monitoring of the patient's condition. Carbamazepine: fluconazole inhibits the metabolism of carbamazepine and increases the concentration of carbamazepine in blood plasma by 30%, which, in turn, may be accompanied by the development of toxic effects of carbamazepine. It may be necessary to adjust the dose of carbamazepine depending on the level of its concentration in the blood and the severity of the therapeutic effect. Calcium channel blockers: Some calcium channel blockers (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by the CYP3A4 isoenzyme. Fluconazole is able to increase the systemic exposure of calcium channel blockers. Careful monitoring for adverse reactions is recommended. Celecoxib: With the simultaneous use of fluconazole (at a dose of 200 mg / day) and celecoxib (at a dose of 200 mg), there was an increase in the maximum concentration and AUC of celecoxib by 68% and 134%, respectively. Co-administration of celecoxib and fluconazole may require a halving of the celecoxib dose. Cyclophosphamide: The simultaneous use of cyclophosphamide and fluconazole leads to an increase in the level of bilirubin and creatinine in the blood serum. These drugs can be used simultaneously, taking into account the possible risk of increasing the concentration of bilirubin and creatinine in the blood serum. Fentanyl: One case of fatal fentanyl intoxication has been reported due to a possible interaction between fentanyl and fluconazole. In addition, in a study on healthy volunteers, it was demonstrated that fluconazole significantly slowed down the elimination of fentanyl. Increasing the concentration of fentanyl can lead to respiratory depression. Patients should be carefully monitored to identify potential risk of respiratory depression. Dose adjustment of fentanyl may be required. HMG-CoA reductase inhibitors: Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (such as atorvastatin and simvastatin) or HMG-CoA reductase inhibitors metabolized by CYP2C9 (such as fluvastatin) increases the risk of myopathy and rhabdomyolysis . If necessary, the simultaneous use of these drugs should be carefully monitored for symptoms of myopathy and rhabdomyolysis and monitor the level of creatine kinase. With a pronounced increase in the level of creatine kinase, as well as with suspicion or detection of myopathy / rhabdomyolysis, you should stop taking HMG-CoA reductase inhibitors. Immunosuppressants (eg, cyclosporine, everolimus, sirolimus, and tacrolimus): Cyclosporine: Fluconazole significantly increases the concentration and AUC of cyclosporine. With the simultaneous use of fluconazole at a dose of 200 mg / day and cyclosporine (at a dose of 2.7 mg / kg / day), an increase in the AUC of cyclosporine by 1.8 times was noted. These drugs can be used simultaneously, provided that the dose of cyclosporine is reduced depending on its concentration. Everolimus: Although no relevant in vivo and in vitro studies have been performed, fluconazole is believed to be able to increase everolimus serum concentrations by inhibiting CYP3A4. Sirolimus: Fluconazole increases plasma concentrations of sirolimus, probably by inhibiting the metabolism of sirolimus by CYP3A4 and P-glycoprotein. This combination can be used subject to adjustment of the dose of sirolimus depending on the level of concentration and the severity of the therapeutic effect. Tacrolimus: Fluconazole is able to increase serum concentrations of tacrolimus up to 5-fold when administered orally by inhibiting the metabolism of tacrolimus by the CYP3A4 enzyme in the intestine. With intravenous use of tacrolimus, significant changes in pharmacokinetics were noted. An increase in the concentration of tacrolimus in the blood serum was associated with the development of nephrotoxicity. The dose of tacrolimus for oral administration should be reduced depending on its concentration in the blood. Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which is responsible for most of the effects associated with angiotensin II receptor antagonism when taking losartan. It is recommended to carry out continuous monitoring of blood pressure in patients during the entire period of treatment. Methadone: fluconazole is able to increase the concentration of methadone in the blood serum. Dose adjustment of methadone may be required. Non-steroidal anti-inflammatory drugs (NSAIDs): when used simultaneously with fluconazole, Cmax and AUC of flurbiprofen increased by 23% and 81%, respectively, compared with similar indicators when flurbiprofen alone was used. Similarly, with the simultaneous use of fluconazole and racemic ibuprofen (at a dose of 400 mg), Cmax and AUC of the pharmacologically active isomer S-(+)-ibuprofen increased by 15% and 82%, respectively, compared with similar indicators when using racemic ibuprofen alone. ibuprofen. Despite the lack of targeted studies, it is known that fluconazole is able to increase the systemic exposure of other NSAIDs that are metabolized by the CYP2C9 isoenzyme (for example, naproxen, lornoxicam, meloxicam, diclofenac). In the case of the joint use of these drugs, it is recommended to conduct frequent monitoring to identify adverse reactions and toxic manifestations associated with the use of NSAIDs. Dose adjustment of NSAIDs may be required. Phenytoin: Fluconazole inhibits the metabolism of phenytoin in the liver. Simultaneous repeated use of fluconazole at a dose of 200 mg and phenytoin at a dose of 250 mg intravenously led to an increase in AUC24 and Cmin of phenytoin by 75% and 128%, respectively. With the simultaneous use of these drugs, the concentration of phenytoin in the blood plasma should be monitored to exclude the development of the toxic effect of phenytoin. Prednisone: There is a report of the development of acute adrenal insufficiency in a patient after liver transplantation against the background of fluconazole withdrawal after a 3-month course of therapy. Presumably, the cessation of fluconazole therapy caused an increase in the activity of the CYP3A4 isoenzyme, which led to an increase in the metabolism of prednisone. Patients receiving long-term combination therapy with prednisone and fluconazole should be under close medical supervision when fluconazole is discontinued in order to detect adrenal insufficiency. Rifabutin: fluconazole increases the concentration of rifabutin in the blood serum, which leads to an increase in the AUC of rifabutin up to 80%. With the simultaneous use of fluconazole and rifabutin, cases of uveitis have been described. When using this combination of drugs, it is necessary to take into account the symptoms of the toxic effect of rifabutin. Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir by approximately 50% and 55%, respectively, due to inhibition of hepatic metabolism of saquinavir by CYP3A4 and inhibition of P-glycoprotein. Interaction studies between fluconazole and saquinavir/ritonavir have not been conducted, so interactions may be even more pronounced. Dose adjustment of saquinavir may be required. Sulfonylureas: Studies in healthy volunteers have shown that concomitant use of fluconazole with oral sulfonylureas (eg, chlorpropamide, glibenclamide, glipizide, tolbutamide) resulted in a prolongation of their half-life. With simultaneous use with fluconazole, regular monitoring of blood glucose levels and, if necessary, a timely reduction in the dose of sulfonylurea drugs is necessary. Theophylline: In a placebo-controlled drug interaction study, fluconazole 200 mg for 14 days reduced the mean plasma clearance rate of theophylline by 18%. When prescribing fluconazole to patients using high doses of theophylline or at an increased risk of developing toxic manifestations of theophylline, it is necessary to monitor the appearance of symptoms of theophylline toxic effect. If signs of toxicity appear, an appropriate correction of therapy should be carried out. Vinca alkaloids: Despite the lack of targeted studies, it is believed that fluconazole is able to increase plasma concentrations of vinca alkaloids (for example, vincristine and vinblastine) and, thus, lead to the development of neurotoxicity, which may possibly be associated with inhibition of the CYP3A4 isoenzyme. Vitamin A: There is a report of one case of the development of adverse reactions from the side of the central nervous system in the form of a pseudotumor of the brain with the simultaneous use of all-trans retinoic acid (the acid form of vitamin A) and fluconazole, which resolved after fluconazole was discontinued. The use of this combination is possible, but one should be aware of the possibility of developing adverse reactions from the central nervous system. Voriconazole (an inhibitor of CYP2C9, CYP2C19 and CYP3A4 isoenzymes): Simultaneous oral administration of voriconazole (400 mg every 12 hours on the first day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on the first day , then 200 mg every 24 hours for 4 days) in 8 healthy male volunteers resulted in an increase in Cmax and AUC of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. It is not known whether reducing the dose and/or frequency of voriconazole or fluconazole will eliminate this effect. When using voriconazole together with fluconazole, it is recommended to monitor the condition of patients for the development of adverse events associated with the use of voriconazole. Zidovudine: When administered orally, fluconazole reduces the clearance of zidovudine by approximately 45% and increases the Cmax and AUC of zidovudine by 84% and 74%, respectively. In addition, with simultaneous use with fluconazole, an increase in the half-life of zidovudine by about 128% was noted. Patients receiving this combination of drugs should be monitored for adverse reactions associated with the use of zidovudine. If necessary, it is possible to reduce the dose of zidovudine. Azithromycin: To determine the effect of a single dose of azithromycin at a dose of 1200 mg on the pharmacokinetics of fluconazole at a single dose of 800 mg, as well as the effect of fluconazole on the pharmacokinetics of azithromycin, an open, randomized, tripartite crossover study was conducted in 18 healthy volunteers. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Oral contraceptives: Two pharmacokinetic studies have been conducted on the use of a combined oral contraceptive against the background of multiple doses of fluconazole. When using fluconazole at a dose of 50 mg, a significant effect on hormone levels was not established, while with daily intake of fluconazole at a dose of 200 mg, the AUC of ethinyl estradiol and levonorgestrel increased by 40% and 24%, respectively. Thus, repeated use of fluconazole at the indicated doses is unlikely to affect the effectiveness of combined oral contraceptives. Ivacaftor: Simultaneous use with ivacaftor, a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, increased the exposure of ivacaftor by 3 times, and hydroxymethyl-ivacaftor (Ml) by