Flunol capsules 150mg №1×1

Name:
Flunol caps. 150mg in bl. in pack. No. 1×1 Main active ingredient Fluconazole Release form capsule Composition 1 capsule contains: fluconazole 50 mg, excipients: lactose monohydrate, colloidal anhydrous silicon dioxide (Aerosil 200), corn starch, magnesium stearate (E572), sodium lauryl sulfate (Texapon K 12 R) (E478) ; capsule body: titanium dioxide (E171), gelatin (E441); capsule cap: FD&C blue 2 indigo carmine (E132), titanium dioxide (E171), gelatin (E441).
Description:
Dark Blue Matte/White Matte #3 Hard Gelatin Capsules Dosage 150mg Indications Flunol 50mg is indicated for the treatment of the following conditions in adults: cryptococcal meningitis (see Precautions section); coccidioidomycosis (see section “Precautions”); invasive candidiasis; candidiasis of the mucous membranes, including oropharyngeal candidiasis, candidiasis of the esophagus, candiduria and chronic candidiasis of the skin and mucous membranes; chronic atrophic candidiasis of the oral cavity (associated with wearing dentures) with insufficient effectiveness of oral hygiene or local treatment; acute or recurrent vaginal candidiasis when topical therapy is not appropriate; candidal balanitis when topical therapy is not appropriate; dermatomycosis, including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and candidal infections of the skin, if systemic therapy is required; tinea ungium (onychomycosis) when other drugs are not acceptable. Flunol 50 mg is indicated for the prevention of the following diseases in adults: relapses of cryptococcal meningitis in patients at high risk of relapses; relapses of oropharyngeal candidiasis or esophageal candidiasis in HIV-infected patients with a high risk of relapses; to reduce the frequency of recurrence of vaginal candidiasis (4 or more episodes per year); for the prevention of candidal infections in patients with prolonged neutropenia (for example, in patients with hemoblastoses undergoing chemotherapy or patients who have undergone hematopoietic stem cell transplantation. The use of Flunol 50 mg for the treatment of full-term newborns, infants, toddlers and primary school children, as well as adolescents aged 0 to 17 years: The drug in the form of capsules can be used in this category of patients when children are able to swallow the capsule.Flunol 50 mg is not intended for use in children under 6 years of age due to the peculiarities of the dosage form.Flunol 50 mg is used to treat candidiasis mucosal (oropharyngeal and esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and prevention of candidal infections in immunocompromised patients.Flunol 50 mg can be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing recurrent cidivs (see section “Precautions”). Therapy can begin before the results of the culture method and other laboratory methods are known. However, after these results become known, an appropriate correction should be made to anti-infective therapy. Official guidelines for the appropriate use of antifungals should be taken into account. Contraindications to patients taking fluconazole, 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, is contraindicated; simultaneous use of terfenadine during repeated use of fluconazole at a dose of 400 mg / day or more; hypersensitivity to fluconazole, other components of the drug or azole substances with a structure similar to fluconazole. With caution, the drug is prescribed for violations of liver function indicators against the background of the use of fluconazole, with the appearance of a rash against the background of the use of fluconazole in patients with superficial fungal infection and invasive / systemic fungal infections, while using terfenadine and fluconazole at a dose of less than 400 mg / day, with potentially proarrhythmic conditions in patients with multiple risk factors (organic heart disease, electrolyte imbalance and concomitant therapy that contributes to the development of such disorders. Use during pregnancy and lactation Pregnancy The results of an observational study showed an increased risk of spontaneous abortions in women taking fluconazole during the first trimester of pregnancy. Cases of multiple malformations in newborns (including brachycephaly, auricular dysplasia, excessive enlargement of the anterior fontanel, hip curvature, humeroulnar synostosis) have been described, whose mothers for three and have taken high doses of fluconazole (400-800 mg daily) for the treatment of coccidioidomycosis for more than a month. The causal relationship of these cases with fluconazole is unclear. Animal studies have shown reproductive toxicity of the drug. Fluconazole at standard doses and for short-term treatment should not be used during pregnancy unless the expected benefit substantially outweighs the risk. Fluconazole at high doses and/or for long-term use should not be used during pregnancy except in cases of potentially life-threatening infections. Breastfeeding Fluconazole passes into breast milk, while its concentration in breast milk is lower than in blood plasma. You can continue breastfeeding after a single dose of fluconazole at a standard dose of 200 mg or less. It is not recommended to breastfeed with repeated use of fluconazole or when it is used in high doses. Dosage and administration Dosage The dose of fluconazole depends on the nature and severity of the fungal infection. For infections requiring repeat administration of the antifungal drug, treatment should be continued until clinical or laboratory signs of active fungal infection have disappeared. Insufficient duration of treatment can lead to a recurrence of a fungal infection. Adult patients Indications Dosing regimen Duration of treatment Cryptococcosis – Treatment of cryptococcal meningitis Loading dose: 400 mg on the 1st day. Maintenance dose: 200-400 mg per day Usually for at least 6-8 weeks. In cases of treatment of life-threatening infections, the daily dose can be increased to 800 mg. – Maintenance therapy for the prevention of recurrence of cryptococcal meningitis in patients with a high risk of relapse 200 mg per day For an unlimited period of time at a dose of 200 mg per day. Coccidioidomycosis 200-400 mg for 11-24 months or more, depending on the patient’s response. For the treatment of some forms of injection, especially in meningeal lesions, it may be appropriate to use the drug at a dose of 800 mg per day. Invasive candidiasis Loading dose: 800 mg on day 1. Maintenance dose: 400 mg per day In general, the recommended duration of therapy for candidemia is 2 weeks after the first negative blood culture and the disappearance of signs and symptoms of candidemia. Treatment of candidiasis of the mucous membranes – Oropharyngeal candidiasis Loading dose: 200-400 mg on the 1st day. Maintenance dose: 100-200 mg per day for 7-21 days (until remission of oropharyngeal candidiasis is achieved). In patients with severely impaired immune system function, longer treatment can be carried out – Esophageal candidiasis Loading dose: 200-400 mg on the 1st day. Maintenance dose: 100-200 mg per day for 14-30 days (until remission of esophageal candidiasis is achieved). In patients with severely impaired immune system function, longer treatment can be carried out – Candiduria 200-400 mg per day for 7-21 days. In patients with severely impaired immune system function, longer treatment can be carried out – Chronic atrophic candidiasis 50 mg per day for 14 days – Chronic candidiasis of the skin and mucous membranes 50-100 mg per day Up to 28 days, but the duration of treatment may be increased depending on the severity and the type of infection or if the immune system is impaired. Prevention of recurrence of mucosal candidiasis in HIV-infected patients with a high risk of relapse – Oropharyngeal candidiasis 100-200 mg per day or 200 mg 3 times a week For an unlimited period of time in patients with chronically reduced immunity. – Esophageal candidiasis 100-200 mg per day or 200 mg 3 times a week For an unlimited period of time in patients with chronic immunosuppression. Genital candidiasis – Acute vaginal candidiasis – Candida balanitis 150 mg Single dose – Treatment and prevention of recurrence of vaginal candidiasis (4 or more episodes per year) 150 mg once every three days – 3 doses in total (in the 1st, 4th and 7th day), followed by a maintenance dose of 150 mg once a week Maintenance dose: 6 months. Ringworm – tinea pedis, – tinea corporis, – tinea cruris, – candida infection 150 mg once a week or 50 mg once a day for 2-4 weeks, but treatment of tinea pedis may require therapy for up to 6 weeks. -tinea versicolor 300-400mg once a week for 1-3 weeks 50mg once a day for 2-4 weeks -tinea ungium (onychomycosis) 150mg once a week healthy nail). It usually takes 3 to 6 months and 6 to 12 months to regenerate fingernails and toenails, respectively. However, the rate of growth can vary greatly from person to person and depends on age. In some cases, after the successful completion of the treatment of a long chronic infection, the nail plates remain deformed. Prevention of candidal infections in patients with prolonged neutropenia 200-400 mg Treatment should begin a few days before the expected development of neutropenia and continue for 7 days after the number of neutrophils exceeds 1000 cells per mm3. Special categories of patients Elderly patients The dose of the drug should be adjusted based on the state of renal function (see subsection “Impaired renal function”). Impaired renal function With a single dose of the drug, dose adjustment is not required. In patients (including children) with impaired renal function, if repeated use of fluconazole is necessary, the initial dose should be from 50 mg to 400 mg, depending on the recommended daily dose for this indication. After that, the daily dose of the drug is determined (depending on the indications) in accordance with the following table: Creatinine clearance (ml / min) Percentage of the recommended dose >50 100% ?50 (without dialysis) 50% Regular dialysis 100% after each dialysis treatment Patients who are on regular dialysis, it is necessary to take the drug at 100% of the recommended dose after each session. On days free from dialysis, patients should take a lower dose of the drug, depending on the amount of creatinine clearance. Impaired liver function Since there is not enough information on the use of fluconazole in patients with impaired liver function, fluconazole should be used with caution in this category of patients (see sections “Precautions” and “Side Effects”). Children In pediatric patients, the maximum dose of 400 mg/day should not be exceeded. As in the case of the treatment of relevant infections in adults, the duration of treatment depends on the clinical effect and the results of microbiological studies. Flunol 50 mg is used daily once a day. For information on children with impaired renal function, see subsection “Impaired renal function”. Studies of the pharmacokinetics of fluconazole in children with renal insufficiency have not been conducted (for information on “term newborns”, in which immaturity of the kidneys is often detected, see below). Children 6 to 11 years of age Indication Dosing regimen Recommendations – Mucosal candidiasis Loading dose: 6 mg/kg Maintenance dose: 3 mg/kg per day A loading dose may be given on the first day to achieve steady state more quickly. – Invasive candidiasis – Cryptococcal meningitis Dose: 6-12 mg/kg per day Depending on the severity of the disease. – Maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of relapse Dose: 6 mg/kg per day Depending on the severity of the disease. – Prevention of candidal infections in immunocompromised patients Dose: 3-12 mg/kg per day Depending on the severity and duration of induced neutropenia (see dosing recommendations in the “Adults” section) Adolescents (aged 12 to 17 years) Depending on body weight and pubertal development, the doctor should evaluate which dose of the drug (for adults or for children) is the most optimal for the patient. Clinical data suggest that fluconazole clearance is higher in children than in adults. The use of doses of 100, 200 and 400 mg in adults and doses of 3, 6 and 12 mg/kg in children leads to comparable systemic exposure. The efficacy and safety of fluconazole for the treatment of genital candidiasis in children has not been established. Currently available data on the safety of the drug for other indications in children are given in the “Side Effects” section. If it is necessary to use the drug for the treatment of genital candidiasis in adolescents (aged 12 to 17 years), the dosage should be the same as for adults. Route of administration Fluconazole can be administered orally or intravenously, the route of administration depends on the clinical condition of the patient. When switching from intravenous to oral administration or vice versa, it is not required to change the daily dose of the drug. Capsules are taken orally, without opening or chewing, regardless of the meal. 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 fluconazole, 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). Organ system class Common Uncommon Rare Blood and lymphatic system disorders Anemia Agranulocytosis, leukopenia, neutropenia, thrombocytopenia. Immune system disorders Anaphylaxis Metabolic disorders Decreased appetite Hypertriglyceridem, hypercholesterolemia, hypokalemia Psychiatric disorders Drowsiness, insomnia Nervous system disorders Headache Convulsions, dizziness, paresthesia, taste disturbances Tremor Hearing and labyrinth disorders Vertigo sides of the heart Paroxysmal ventricular tachycardia of the torsades de pointes, prolongation of the QT interval Gastrointestinal disorders Abdominal pain, diarrhea, nausea, vomiting Constipation, dyspepsia, flatulence, dry mouth Liver and biliary tract disorders Elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase Cholestasis, jaundice, elevated bilirubin Hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage Skin and subcutaneous tissue disorders Rash Toxidermia*, urticaria, pruritus, increased sweating Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioedema, facial edema, alopecia Musculoskeletal and connective tissue disorders Myalgia General disorders and disorders at the injection site Fatigue, malaise, asthenia, fever. *Including stable dosage form. Children and adolescents The nature and frequency of adverse reactions, as well as deviations in the results of laboratory tests, recorded in children and adolescents during clinical studies, with the exception of genital candidiasis, were comparable to those in adult patients. Overdose Symptoms: hallucinations, paranoia. Treatment: symptomatic, gastric lavage, forced diuresis. Hemodialysis within 3 hours reduces the concentration of fluconazole in plasma by approximately 50%. Interaction with other drugs Co-administration of fluconazole and the following drugs is contraindicated: Cisapride: In patients taking fluconazole and cisapride at the same time, the development of reactions from the heart, incl. paroxysmal ventricular tachycardia of the pirouette type (torsade de pointes). 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, with the use of fluconazole at a dose of 200 mg / day, prolongation of the QTc interval was not detected. 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. Co-administration of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section "Contraindications"). When using the drug 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 the drug fluconazole and astemizole is contraindicated (see section "Contraindications"). Pimozide: Although appropriate in vitro or in vivo studies have not 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, 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"). Amiodarone: The simultaneous use of fluconazole in combination with amiodarone may lead to inhibition of the metabolism of amiodarone. When using amiodarone, prolongation of the QT interval was detected. The simultaneous use of fluconazole with amiodarone 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 by inhibiting CYP3A4. The simultaneous use of fluconazole and halofantrine may increase the risk of developing cardiotoxicity (prolongation of the QT interval, 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. Hydrochlorothiazide: In a pharmacokinetic drug-drug interaction study, multiple doses of hydrochlorothiazide in fluconazole-treated healthy volunteers resulted in a 40% increase in fluconazole plasma concentrations. With this severity of exposure, there is no need to change the dosage of fluconazole in patients taking diuretics at the same time. Effect of Fluconazole on other medicinal products Fluconazole is a potent inhibitor of cytochrome P450 isoenzyme CYP2C9 and a moderate inhibitor of CYP3A4. In addition, fluconazole is an inhibitor of CYP2C19. 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"). Alfetanil: In healthy volunteers, the simultaneous use of fluconazole (at a dose of 400 mg) and alfentanil (at a dose of 20 mcg / kg intravenously) resulted in a two-fold increase in AUC10 (probably due to inhibition of CYP3A4). Dose adjustment of alfentanil may be required. Amitriptyline, nortriptyline: Fluconazole enhances the effect of amitriptyline and nortriptyline. It is recommended that 5-nortriptyline and/or S-amitriptyline concentrations be measured at the start 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 (hematoma formation, epistaxis, gastrointestinal bleeding, hematuria and melena) due to prolongation of the prothrombin time with the simultaneous use of fluconazole and warfarin. 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 or indancyon in conjunction with fluconazole, it is recommended to carefully monitor prothrombin time. If necessary, the dose of the anticoagulant should be adjusted. Short-acting benzodiazepines, eg midazolam, 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 elimination 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 trialozam were noted. If patients receiving fluconazole need to be treated concomitantly with benzodiazepines, 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: A fatal case of 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: The simultaneous use of fluconazole and 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 appropriate in vitro and in vivo studies have not been conducted, 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 angiothesin 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 can increase the serum concentration of methadone. 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 of S-(+)-ibuprofen increased by 15% and 82%, respectively, compared with those of racemic ibuprofen alone. 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 serum concentrations of rifabutin, resulting in 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 effects of rifabutin. Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir by approximately 50% and 55%, respectively, by inhibiting 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 the 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 sulfonylureas 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. At manifestation of signs of toxicity it is necessary to carry out the corresponding correction of therapy. 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 i