Description
Packing
1 pc
Pharmacological action
Pharmacotherapeutic group of the drug: lipid-lowering agent – HMG-CoA reductase inhibitor
ATX code: [C10AA07]
Pharmacological properties of
Pharmacodynamics
Mechanism of action of
Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase 3 enzyme, 3 enzyme mevalonic acid, a precursor to cholesterol. The main target of the action of rosuvastatin is the liver, where the synthesis of cholesterol (cholesterol) and the catabolism of low density lipoproteins (LDL) are carried out. Rosuvastatin increases the number of liver LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of the synthesis of very low density lipoproteins (VLDL), thereby reducing the total amount of LDL and VLDL.
Pharmacodynamics
Rosuvastatin-SZ reduces elevated concentrations of LDL cholesterol (cholesterol-LDL), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-cholesterol), and also reduces the concentration of apolipoprotein B non-HDL, cholesterol-VLDL, TG-VLDLP and increases the concentration of apolipoprotein A-I (ApoA-I), reduces the ratio of cholesterol-LDL / cholesterol-HDL, total cholesterol-cholesterol-HDL and cholesterol-HDL / cholesterol-HDL and the ratio of apoV / ApoA-I. The therapeutic effect develops within one week after the start of therapy with the drug Rosuvastatin-SZ, after 2 weeks of treatment reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular use of the drug. Rosuvastatin-SZ is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, gender or age, including patients with diabetes mellitus and familial hypercholesterolemia. In 80% of patients with type IIa and IIb hypercholesterolemia according to Fredrickson (the average initial concentration of LDL-C is about 4.8 mmol / L) when taking the drug at a dose of 10 mg, the concentration of LDL-C reaches less than 3 mmol / L. In patients with heterozygous familial hypercholesterolemia, receiving Rosuvastatin-SZ at a dose of 20-80 mg, there is a positive dynamics in the lipid profile. After titration to a daily dose of 40 mg (12 weeks of therapy), a decrease in the concentration of LDL-C by 53% is noted. In 33% of patients, an LDL-C concentration of less than 3 mmol / L is achieved. In patients with homozygous familial hypercholesterolemia, taking Rosuvastatin-SZ at a dose of 20 mg and 40 mg, the average decrease in the concentration of LDL-C is 22%. In patients with hypertriglyceridemia with an initial TG concentration from 273 to 817 mg / dl, treated with Rosuvastatin-SZ at a dose of 5 mg to 40 mg once a day for 6 weeks, the concentration of TG in the blood plasma was significantly reduced. An additive effect is observed in combination with fenofibrate in relation to the content of triglycerides and with nicotinic acid in lipid lowering doses in relation to the content of HDL-C (see also the section Special Instructions ). According to the results of clinical studies, patients with severe hypercholesterolemia and a high risk of cardiovascular disease (CVD) should be prescribed a dose of 40 mg of Rosuvastatin-SZ. The results of a clinical study (The rationale for using statins for primary prevention: an interventional study evaluating rosuvastatin) showed that rosuvastatin significantly reduced the risk of developing cardiovascular complications.
Pharmacokinetics
Absorption and distribution of
The maximum concentration of rosuvastatin in blood plasma is reached approximately 5 hours after ingestion. Absolute bioavailability is approximately 20%. Rosuvastatin is metabolized mainly by the liver, which is the main site of cholesterol synthesis and metabolism of LDL-C. The volume of distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin binds to plasma proteins, mainly albumin.
Metabolism
Undergoes limited metabolism (about 10%).The main mechanism of action of the drug is due to the reversible binding of torasemide with a sodium / chlorine / potassium ion transporter located in the apical membrane of the thick segment of the ascending Henle loop, resulting in a decrease or inhibition of sodium ion reabsorption and the osmotic pressure of intracellular fluid and water reabsorption. Blocks aldosterone myocardial receptors reduces fibrosis and improves diastolic myocardial function. Torasemide to a lesser extent than furosemide causes hypokalemia, while it is more active and its effect is longer. The use of torasemide is the most reasonable choice for long-term therapy.
Pharmacokinetics
After oral administration, torasemide is rapidly and almost completely absorbed in the gastrointestinal tract. The half-life (T1 / 2) of torasemide and its metabolites is 3 to 4 hours and does not change in chronic renal failure. The total clearance of torasemide is 40 ml / min, renal clearance – 10 ml / min. On average, about 83% of the dose taken is excreted by the kidneys: unchanged (24%) and as predominantly inactive metabolites (M1 – 12%, M3 – 3%, M5 – 41%). With renal failure, T1 / 2 does not change, T1 / 2 of the metabolites M3 and M5 increases. Torasemide and its metabolites are slightly excreted by hemodialysis and hemofiltration. With liver failure, the concentration of torasemide in the blood plasma increases due to a decrease in the metabolism of the drug in the liver. In patients with heart or liver failure, T1 / 2 of torasemide and M5 metabolite is slightly increased, the cumulation of the drug is unlikely. which creates a need to increase the concentration of fluconazole in the intracellular fluid to suppress all enzyme molecules in the cell.
The second significant resistance mechanism is the active removal of fluconazole from the intracellular space by activating two types of transporters involved in the active removal (efflux) of drugs from the fungal cell. Such transporters include the main mediator encoded by the MDR (multidrug resistance) genes and the superfamily of the ATP-binding transporter cassette encoded by the CDR genes (Candida fungal resistance genes to azole antimycotics).
Overexpression of the MDR gene leads to resistance to fluconazole, while overexpression of the CDR genes can lead to resistance to various azoles. The concentration in the blood plasma is proportional to the dose and reaches a maximum (Cmax) after 0.5-1.5 hours after taking fluconazole on an empty stomach, and the half-life is about 30 hours. 90% of the equilibrium concentration is reached by the 4-5th day after the start of therapy ( with multiple doses of the drug once a day). The maximum concentration of fluconazole in saliva when taking the capsule is reached after 4 hours.
The administration of a loading dose (on day 1), twice the usual daily dose, makes it possible to achieve 90% equilibrium concentration by day 2. The volume of distribution approaches the total water content in the body. Plasma protein binding is low (11-12%).
Fluconazole penetrates well into all body fluids. Fluconazole concentrations in saliva and sputum are similar to its plasma concentrations. Fluconazole at a dose of 200-400 mg / day does not have a clinically significant effect on endogenous steroid levels and their response to stimulation of adrenocorticotropic hormone (ACTH) in healthy male volunteers.
Mechanisms for the development of fluconazole resistance
Fluconazole resistance may develop in the following cases: a qualitative or quantitative change in the enzyme that is the target for fluconazole (lanosteril 14 – demethylase), decreased access to the target fluconazole, or a combination of these mechanisms.
Point mutations in the target enzyme ERG11 gene modify the target and decrease the affinity for azoles. Increased expression of the ERG11 gene leads to the production of high concentrations of the target enzyme,whether the concentration of steroids in women of childbearing age. Fluconazole at a dose of 200-400 mg / day does not have a clinically significant effect on endogenous steroid levels and their response to stimulation of adrenocorticotropic hormone (ACTH) in healthy male volunteers.
Mechanisms for the development of fluconazole resistance
Fluconazole resistance may develop in the following cases: a qualitative or quantitative change in the enzyme that is the target for fluconazole (lanosteril 14 – demethylase), decreased access to the target fluconazole, or a combination of these mechanisms.
Point mutations in the target enzyme ERG11 gene modify the target and decrease the affinity for azoles. Increased expression of the ERG11 gene leads to the production of high concentrations of the target enzyme, which creates a need to increase the concentration of fluconazole in the intracellular fluid to suppress all enzyme molecules in the cell.
The second significant resistance mechanism is the active removal of fluconazole from the intracellular space by activating two types of transporters involved in the active removal (efflux) of drugs from the fungal cell. Such transporters include the main mediator encoded by the MDR (multidrug resistance) genes and the superfamily of the ATP-binding transporter cassette encoded by the CDR genes (Candida fungal resistance genes to azole antimycotics).
Overexpression of the MDR gene leads to resistance to fluconazole, while overexpression of the CDR genes can lead to resistance to various azoles.
Candida glabrata resistance is usually mediated by overexpression of the CDR gene, resulting in resistance to many azoles. For those strains in which the minimum inhibitory concentration (MIC) is defined as intermediate (16-32 μg / ml), it is recommended to use the maximum dose of fluconazole.
Candida krusei should be considered resistant to fluconazole. The resistance mechanism is associated with a reduced sensitivity of the target enzyme to the inhibitory effect of fluconazole.
Pharmacokinetics
Pharmacokinetics of fluconazole is similar with intravenous and oral administration. After oral administration, fluconazole is well absorbed, its plasma concentrations (and total bioavailability) exceed 90% of those with intravenous administration. Simultaneous eating does not affect the absorption of fluconazole. The concentration in the blood plasma is proportional to the dose and reaches a maximum (Cmax) after 0.5-1.5 hours after taking fluconazole on an empty stomach, and the half-life is about 30 hours. 90% of the equilibrium concentration is reached by the 4-5th day after the start of therapy ( with multiple doses of the drug once a day). The maximum concentration of fluconazole in saliva when taking the capsule is reached after 4 hours.
The administration of a loading dose (on day 1), twice the usual daily dose, makes it possible to achieve 90% equilibrium concentration by day 2. The volume of distribution approaches the total water content in the body. Plasma protein binding is low (11-12%).
Fluconazole penetrates well into all body fluids. Fluconazole concentrations in saliva and sputum are similar to its plasma concentrations. In patients with fungal meningitis, fluconazole concentrations in the cerebrospinal fluid are about 80% of its plasma concentrations.
In the stratum corneum, epidermis, dermis and sweat, high concentrations are reached that exceed serum. Fluconazole accumulates in the stratum corneum. When taken at a dose of 50 mg once a day, the concentration of fluconazole after 12 days is 73 μg / g, and 7 days after discontinuation of treatment, only 5.8 μg / g. When applied at a dose of 150 mg once a week, the concentration of fluconazole in the stratum corneum on the 7th day is 23.4 μg / g, and 7 days after the second dose – 7.1 μg / g.
The concentration of fluconazole in nails after 4-month use at a dose of 150 mg once a week is 4.05 μg / g in healthy and 1, 8 μg / g in affected nails 6 months after completion of therapy, fluconazole is still determined in the nails.
The drug is excreted mainly by the kidneys. About 80% of the administered dose is found in the urine unchanged. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites were found.
The long half-life from blood plasma allows you to take fluconazole once with vaginal candidiasis and once a day or once a week for other indications.
Indications
Vaginal candidiasis, acute or relapsing when topical therapy is not applicable to reduce the recurrence rate of vaginal candidiasis (4 or more episodes per year). Candidiasis balanitis when topical therapy is not applicable.
Use during pregnancy and lactation
Fluconazole should be avoided during pregnancy, except in cases of severe and potentially life-threatening fungal infections, when the expected benefits of the treatment outweigh the potential risk to the fetus.
Fluconazole is found in breast milk at the same concentrations as in the blood, therefore, Diflucan is not recommended for use during lactation (breastfeeding).
Composition of
Each capsule contains:
active substance: fluconazole 150 mg
excipients: lactose 149.123 mg, corn starch 49.5 mg, silicon dioxide colloidal 0.352 mg, magnesium stearate 3.173 mg, sodium lauryl sulfate 0.352 mg capsule sulfate (E171) 1.47%, patent blue dye (E 131) 0.03%, gelatin up to 100%.
Ink for marking capsules 50 mg, 100 mg and 150 mg: shellac glaze 63%, black iron oxide (E172) 25%, N-butyl alcohol 8.995%, industrial methylated alcohol 74 OR 2%, soya lecithin 1%, anti-foam component DC 1510 0.005%.
Dosage and administration
Inside. In acute vaginal candidiasis, candidiasis balanitis, the drug is used once inside at a dose of 150 mg. To reduce the recurrence rate of vaginal candidiasis, the drug can be used in a dose of 150 mg every three days – only 3 doses (on the 1st, 4th and 7th day), then a maintenance dose of 150 mg once a week. A maintenance dose can be used up to 6 months.
Side effects
Frequent: headache, abdominal pain, diarrhea, nausea, vomiting, increased serum activity of aminotransferases (AST, ALT) and alkaline phosphatase, rash.
Drug Interaction
Anticoagulants. Like other antifungal agents – azole derivatives, fluconazole, with simultaneous use with warfarin, increases PV (by 12%), in connection with which the development of bleeding (hematoma, bleeding from the nose and gastrointestinal tract, hematuria, melena) is possible. Patients receiving coumarin anticoagulants should be monitored continuously for PV.
Azithromycin. When co-administered with fluconazole at a single dose of 800 mg with azithromycin at a single dose of 1200 mg expressed pharmacokinetic interaction between both drugs has not been established.
Benzodiazepines (short acting). After ingestion of midazolam, fluconazole significantly increases midazolam concentration and psychomotor effects, with this effect being more pronounced after fluconazole ingestion than when administered intravenously. If concomitant benzodiazepine therapy is required, patients receiving fluconazole should be monitored for the appropriate dose reduction of benzodiazepine.
Cisapride. With the concomitant use of fluconazole and cisapride, adverse reactions from the heart are possible, including: fluttering / fluttering of the ventricles (torsade de point s). The use of fluconazole at a dose of 200 mg once daily and cisapride at a dose of 20 mg 4 times a day leads to a marked increase in plasma concentrations of cisapride and an increase in the QT interval on the ECG. Co-administration of cisapride and fluconazole is contraindicated.
Cyclosporine. In patients with transplanted kidney, the use of fluconazole at a dose of 200 mg / day leads to a slow increase in the concentration of cyclosporine. However, with repeated administration of fluconazole at a dose of 100 mg / day, no change in the concentration of cyclosporine in bone marrow recipients was observed. With the use of fluconazole and cyclosporine, it is recommended to monitor the concentration of cyclosporine in the blood.
Hydrochlorothiazide. Repeated administration of hydrochlorothiazide with fluconazole leads to an increase in plasma fluconazole concentration by 40%. The effect of this degree of severity does not require a change in the dosage regimen of fluconazole in patients receiving diuretics at the same time, but the doctor should take this into account.
Oral contraceptives. Concomitant use of combined oral contraceptive with fluconazole at a dose of 50 mg has no significant effect on the level of hormones, while the daily intake of 200 mg of fluconazole AUC of ethinylestradiol and levonorgestrel increase by 40 and 24%, respectively, and when receiving 300 mg of fluconazole The AUC of ethinyl estradiol and norethindrone increased by 24 and 13%, respectively. Thus, repeated use of fluconazole at these doses is unlikely to have an effect on the effectiveness of combination oral contraceptives.
Phenytoin. Concomitant administration of fluconazole and phenytoin may be accompanied by a clinically significant increase in phenytoin concentration. If both drugs are to be used concomitantly, phenytoin concentration should be monitored and dose adjusted accordingly to ensure serum therapeutic concentration.
Rifabutin. Concomitant use of fluconazole and rifabutin may increase serum concentrations of the latter. When fluconazole and rifabutin are used concomitantly, cases of uveitis have been reported. Patients receiving rifabutin and fluconazole should be closely monitored.
Rifampicin. Concomitant administration of fluconazole and rifampicin results in a 25% reduction in AUC and a fluconazole duration of T1 / 2 by 20%. Patients taking rifampicin at the same time should consider the feasibility of increasing the dose of fluconazole.
Sulfonylureas. Fluconazole, co-administered, leads to an increase in T1 / 2 oral preparations of sulfonylurea (chlorpropamide, glibenclamide, glipizide and tolbutamide). Patients with diabetes can be prescribed the combined use of fluconazole and oral preparations of sulfonylurea, but the possibility of developing hypoglycemia should be considered.
Tacrolimus. Concomitant use of fluconazole and tacrolimus leads to an increase in serum concentrations of the latter. Cases of nephrotoxicity are described. Patients receiving both tacrolimus and fluconazole should be closely monitored.
Terfenadine. With the use of azole antifungal agents and terfenadine, serious arrhythmias may occur as a result of increasing the QT interval. No increase in QT interval was observed with fluconazole 200 mg / day, however, the use of fluconazole at doses of 400 mg / day and above causes a significant increase in the plasma concentrations of terfenadine. Concomitant administration of fluconazole at doses of 400 mg / day or more with terfenadine is contraindicated (see Contraindications section). Fluconazole treatment at doses less than 400 mg / day in combination with terfenadine should be closely monitored.
Theophylline. When co-administered with fluconazole at a dose of 200 mg for 14 days, the average plasma clearance rate of theophylline is reduced by 18%. When fluconazole is given to patients receiving theophylline at high doses or to patients at increased risk of theophylline toxicity, the symptoms of theophylline overdose should be monitored and, if necessary, adjusted.
Zidovudine. When co-administered with fluconazole, there is an increase in concentrations of zidovudine, which is probably due to a decrease in the metabolism of the latter to its major metabolite. A significant increase in zidovudine AUC (20%) was found before and after treatment with fluconazole at a dose of 200 mg / day for 15 days in patients with AIDS and ARC (AIDS-related complex).
When administered to HIV-infected patients, zidovudine at a dose of 200 mg every 8 h for 7 days in combination with or without fluconazole at a dose of 400 mg / day showed a significant increase in zidovudine AUC (74%) between the two regimens. when co-administered with fluconazole. Patients receiving this combination should be observed to identify side effects of zidovudine.
Concomitant use of fluconazole with astemizole or other drugs metabolised by the cytochrome P450 system may be accompanied by increased serum concentrations of these agents. Caution should be exercised when fluconazole is administered concomitantly in the absence of reliable information. Patients should be carefully observed.
Studies on the interaction of oral forms of fluconazole with its concomitant administration with food, cimetidine, antacids, as well as after total body irradiation to prepare for bone marrow transplantation have shown that these factors do not have a clinically relevant effect on the absorption of fluconazole.
These interactions have been established with repeated use of fluconazole to interact with drugs as a result of single administration of fluconazole.
Doctors should note that interaction with other drugs has not been specifically studied, but it is possible.
overdose
Symptoms: fluconazole overdose has been reported, and in one case, a 42-year-old HIV-infected patient had hallucinations and paranoid behavior after taking 8200 mg of the drug. The patient was hospitalized and his condition normalized within 48 hours.
Treatment: symptomatic treatment (including supportive measures and gastric lavage).
Fluconazole is excreted mainly in the urine, so forced diuresis can probably accelerate the excretion of the drug. A 3-hour hemodialysis session reduces plasma fluconazole levels by about 50%.
Storage conditions
The drug should be stored at a temperature not exceeding 30 ° C, out of the reach of children.
Expiration
3 Year
Deystvuyuschee substances
Fluconazole
Terms of pharmacy leave
Over-the-counter
dosage form
dosage form
capsules
Pfizer, United States
