Crestor tab. p pl.ob. 10mg N126
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Active ingredients
Composition
Each tablet contains the active substance: rosuvastatin 10, 20 or 40 mg in the form of rosuvastatin calcium. Excipients: lactose monohydrate 89.50 mg (for a dosage of 10 mg), 179.00 (for a dosage of 20 mg), 164.72 mg (for a dosage of 40 mg); microcrystalline cellulose 29.82 mg (for a dosage of 10 mg), 59.64 mg (for a dosage of 20 mg), 54.92 mg (for a dosage of 40 mg); calcium phosphate 10.90 mg (for a dosage of 10 mg), 21.80 mg (for a dosage of 20 mg), 20.00 mg (for a dosage of 40 mg); Crospovidone 7.50 mg (for a dosage of 10 mg), 15.00 mg (for a dosage of 20 mg), 15.00 mg (for a dosage of 40 mg); magnesium stearate 1.88 mg (for a dosage of 10 mg), 3.76 mg (for a dosage of 20 mg), 3.76 mg (for a dosage of 40 mg); tablet cover: lactose monohydrate 1.80 mg (for a dosage of 10 mg), 3.60 mg (for a dosage of 20 mg), 3.60 mg (for a dosage of 40 mg); hypromellose 1.26 mg (for a dosage of 10 mg), 2.52 mg (for a dosage of 20 mg), 2.52 mg (for a dosage of 40 mg), triacetin (glycerol triacetate) 0.36 mg (for a dosage of 10 mg), 0.72 mg (for a dosage of 20 mg), 0.72 mg (for a dosage of 40 mg); titanium dioxide 1.06 mg (for a dosage of 10 mg), 2.11 mg (for a dosage of 20 mg), 2.11 mg (for a dosage of 40 mg); iron dye red oxide 0.02 mg (for a dosage of 10 mg), 0.05 mg (for a dosage of 20 mg), 0.05 mg (for a dosage of 40 mg).
Pharmacological effect
The mechanism of action Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The main target of rosuvastatin action is the liver, where cholesterol (cholesterol) synthesis and low density lipoprotein catabolism (LDL) are performed. Rosuvastatin increases the number of “hepatic” 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 number of LDL and VLDL.
Крестор® reduces elevated concentrations of LDL cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density cholesterol or lipoprotein (HDL-C) , TG-VLDL and increases the concentration of apolipoprotein A-I (ApoA-I) (see Tables 1 and 2), reduces the ratio of X-LDL / X-HDL, total cholesterol / X-HDL and X-HDL and ApoB / ApoA-I ratio. The therapeutic effect develops within one week after the start of therapy with Crestor®, 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.
Clinical efficacy Crestor® is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, gender, or age, including patients with diabetes and familial hypercholesterolemia. In 80% of patients with hypercholesterolemia IIa and IIb type according to Fredrikson (the average initial concentration of LDL-C is about 4.8 mmol / l) while receiving the drug at a dose of 10 mg, the concentration of LDL-C makes up less than 3 mmol / l. Patients with heterozygous familial hypercholesterolemia receiving Crestor® at a dose of 20-80 mg show a positive trend in lipid profile parameters (a study involving 435 patients). 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. 33% of patients achieved a ChL-LDL concentration of less than 3 mmol / L. In patients with homozygous familial hypercholesterolemia, taking Crestor® 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 of 273 to 817 mg / dL who received Krestor® at a dose of 5 mg to 40 mg once a day for 6 weeks, the concentration of TG in plasma significantly decreased (see Table 2 ). An additive effect is observed in combination with fenofibrate in relation to the concentration of triglycerides and with nicotinic acid in lipid-lowering doses in relation to the concentration of HDL-C HDL (see also the section "Special Instructions"). In a METEOR study involving 984 patients aged 45–70 years with a low risk of developing coronary heart disease (CHD) (10-year Framingham risk less than 10%), an average concentration of LDL-C of 4.0 mmol / l (154.5 mg / dl) and subclinical atherosclerosis (which was estimated by the thickness of the intima-media complex of the carotid arteries - TCIM), the effect of rosuvastatin on the thickness of the intima-media complex was studied. Patients received rosuvastatin 40 mg / day or placebo for 2 years. Rosuvastatin therapy significantly slowed the rate of progression of maximal TCMI for 12 carotid artery segments compared with placebo, with a difference of –0,0145 mm / year [95% confidence interval from –0,0196 to –0.0093; p <0.001]. Compared to baseline values in the group of rosuvastatin, a decrease in the maximum value of TCIM by 0.0014 mm / year (0.12% / year (unreliable difference)) was observed compared with an increase in this indicator by 0.01131 mm / year (1.12 % / year (p <0.001)) in the placebo group.To date, no direct relationship has been shown between a decrease in TCIM and a decrease in the risk of cardiovascular events. The METEOR study was conducted in patients with a low risk of coronary artery disease for whom the dose of Crestor® 40 mg is not recommended. A dose of 40 mg should be used in patients with severe hypercholesterolemia and a high risk of cardiovascular disease (CVD). The results of the study JUPITER (Rationale for the use of statins for primary prophylaxis: an interventional study assessing rosuvastatin) in 17802 patients showed that rosuvastatin significantly reduced the risk of cardiovascular complications (252 in the placebo group compared to 142 in the rosuvastatin group) (p <0.001 ) with a relative risk reduction of 44%. The effectiveness of therapy was noted after 6 first months of use of the drug. A statistically significant decrease by 48% of the combined criterion was noted, including death from cardiovascular causes, stroke and myocardial infarction (risk ratio: 0.52, 95%, confidence interval 0.40-0.68, p <0.001), a decrease by 54% of the occurrence of a fatal or non-fatal myocardial infarction (hazard ratio: 0.46, 95%, confidence interval 0.30-0.70) and 48% of a fatal or non-fatal stroke. Total mortality decreased by 20% in the group of rosuvastatin (risk ratio: 0.80, 95%, confidence interval 0.67– 0.97, p = 0.02). The safety profile of patients taking rosuvastatin at a dose of 20 mg was, in general, similar to the safety profile in the placebo group.
Pharmacokinetics
Absorption and distribution The maximum concentration of rosuvastatin in the 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 Exposed to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by cytochrome P450 enzymes. The main isoenzyme involved in rosuvastatin metabolism is the isoenzyme CYP2C9.CYP2C19, CYP3A4 and CYP2D6 isoenzymes are less involved in metabolism. The main identified metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N-desmethyl is about 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity on inhibition of circulating HMG-CoA reductase is provided by rosuvastatin, the rest is provided by its metabolites. Withdrawal About 90% of the dose of rosuvastatin is excreted unchanged through the intestines (including absorbed and not absorbed rosuvastatin). The rest is excreted by the kidneys. The plasma half-life (T ½) is approximately 19 hours. The half-life does not change with increasing dose of the drug. The geometric mean plasma clearance is approximately 50 l / h (coefficient of variation 21.7%). As in the case of other HMG-CoA reductase inhibitors, membrane cholesterol transporter is involved in the process of hepatic capture of rosuvastatin, which plays an important role in the hepatic elimination of rosuvastatin. Linearity Systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake. Special populations of patients. Age and Sex Gender and age do not have a clinically significant effect on rosuvastatin pharmacokinetics. Ethnic groups Pharmacokinetic studies showed an approximately twofold increase in the AUC median (area under the concentration-time curve) and Cmax (maximum plasma concentration) of rosuvastatin in patients of Asian ethnicity (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with Europeans; Indian patients showed an increase in the median AUC and Cmax by a factor of 1.3. Pharmacokinetic analysis revealed no clinically significant differences in pharmacokinetics among Europeans and representatives of the Negroid race. Renal failure In patients with mild to moderate renal insufficiency, the plasma concentration of rosuvastatin or N-desmethyl does not change significantly. In patients with severe renal insufficiency (creatinine clearance (CC) less than 30 ml / min.), The concentration of rosuvastatin in plasma is 3 times higher, and the concentration of N-desmethyl is 9 times higher than in healthy volunteers.The plasma concentration of rosuvastatin in hemodialysis patients was about 50% higher than in healthy volunteers. Hepatic insufficiency In patients with various stages of liver failure, no increase in the half-life of rosuvastatin in patients with a score of 7 or lower on the Child-Pugh scale was found. Two patients with grades 8 and 9 on the Child-Pugh scale showed an increase in the half-life of at least 2 times. Experience with rosuvastatin in patients with a score above 9 on the Child-Pugh scale is absent. Genetic polymorphism HMG-CoA reductase inhibitors, including Crestor®, bind to the transport proteins OATP1B1 (a polypeptide of organic anion transport that participates in the capture of statins by hepatocytes) and BCRP (efflux transporter). In carriers of the SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes, there was an increase in exposure (AUC) to rosuvastatin 1.6 and 2.4 times, respectively, compared to the carriers of the SLCO1B1 genotypes c.521TT and ABCG2 c .421CC.
Indications
Fredrickson primary hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as a supplement to the diet when diet and other non-drug therapies (such as exercise, weight loss) are insufficient.
Familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (for example, LDL-apheresis), or in cases when such therapy is not effective enough.
Hypertriglyceridemia (type IV according to Fredrickson) as a supplement to the diet.
To slow the progression of atherosclerosis as a supplement to the diet in patients who have been shown therapy to reduce the concentration of total cholesterol and LDL-C.
Primary prevention of major cardiovascular complications (stroke, heart attack, arterial revascularization) in adult patients without clinical signs of coronary heart disease, but with an increased risk of its development (age over 50 years for men and over 60 years for women, increased concentration of C-reactive protein (≥ 2 mg / l) in the presence of at least one of the additional risk factors such as hypertension, low concentration of HDL-C, smoking, family history of early onset of CHD).
Contraindications
For pills 10 mg and 20 mg: hypersensitivity to rosuvastatin or any of the components of the preparation liver disease in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity (more than 3 times as compared with the upper limit norms) pronounced renal dysfunction (CC less than 30 ml / min) myopathy simultaneous cyclosporine intake in women: pregnancy, lactation period, lack of adequate contraceptive methods patients, predisposition Affected by the development of myotoxic complications lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose) For 40 mg pills: hypersensitivity to rosuvastatin or any of the components of the drug simultaneous administration of cyclosporine in women: pregnancy, lactation, no adequate contraceptive methods liver diseases in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity ( more than 3 times compared with the upper limit of normal) in patients with risk factors for the development of myopathy / rhabdomyolysis, namely: moderate renal insufficiency (CC less than 60 ml / min) hypothyroidism personal or family history of muscular diseases mytoxicity history of other HMG-CoA reductase inhibitors or a history of fibrates; excessive alcohol intake; conditions that can lead to an increase in plasma concentration of rosuvastatin; simultaneous administration of fibrates; to patients of the Asian race; lactose intolerance, lactase deficiency or glucose-galactose malabsorption (product contains lactose) CAUTION For 10 mg and 20 mg pills: Risk of myopathy / rhabdomiolysis renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and previous history of hereditary muscle diseases and previous history of hemorrhoids, and hypothyroidism, personal or family history of hereditary muscle diseases and previous history of hereditary muscle diseases and previous history of hereditary muscular diseases and previous history of hereditary muscle diseases using other HMG-CoA reductase inhibitors or fibrates; excessive drinking; age over 65; conditions in which there is an increase in the plasma concentration of rosuvastatin; race (Asian race); simultaneous appointment with fibrates (seesection "Pharmacokinetics"); history of liver disease; sepsis; hypotension; extensive surgical intervention, trauma, severe metabolic, endocrine or electrolyte disturbances, or uncontrolled convulsive seizures. For pills 40 mg: Renal failure, mild severity (CC more than 60 ml / min); age over 65; history of liver disease; sepsis; hypotension; extensive surgical intervention, trauma, severe metabolic, endocrine or electrolyte disturbances, or uncontrolled convulsive seizures. Application in pediatric practice The efficacy and safety of the drug in children under 18 years of age has not been established. The experience of using the drug in pediatric practice is limited to a small number of children (8 years old and older) with familial homozygous hypercholesterolemia. Currently, it is not recommended to use Crestor® in children under 18 years of age. Patients with liver failure Data or experience with the use of the drug in patients with a score above 9 on the Child-Pugh scale is missing (see the sections "Pharmacodynamics" and "Special Instructions").
Use during pregnancy and lactation
Крестор® is contraindicated during pregnancy and lactation. Women of reproductive age should use adequate methods of contraception. Since cholesterol and other cholesterol biosynthesis products are important for fetal development, the potential risk of inhibition of HMG-CoA reductase exceeds the benefits of using the drug in pregnant women. In the event of pregnancy during therapy, the drug should be discontinued immediately. Data regarding the allocation of rosuvastatin with breast milk are not available, therefore, during breastfeeding, the drug should be stopped (see section "Contraindications").
Inside, do not chew or crush the pill, swallow whole, washed down with water. The drug can be administered at any time of the day, regardless of the meal. Before starting treatment with Crestor®, the patient should begin to follow the standard cholesterol-lowering diet and continue to follow it during treatment. The dose of the drug should be chosen individually depending on the goals of therapy and the therapeutic response to treatment.taking into account current recommendations on target lipid concentration. The recommended initial dose for patients starting to take the drug, or for patients transferred from taking other HMG-CoA reductase inhibitors, should be 5 or 10 mg of Crestor® 1 time per day. When choosing the initial dose, one should be guided by the individual cholesterol concentration and take into account the possible risk of cardiovascular complications, and also the potential risk of side effects should be assessed. If necessary, the dose can be increased to a maximum after 4 weeks (see the Pharmacodynamics section). Due to the possible development of side effects when taking a dose of 40 mg, compared with lower doses of the drug (see the section “Side Effects”), increasing the dose to 40 mg after an additional dose of the drug is higher than the recommended initial dose within 4 weeks treatment can only be carried out in patients with severe hypercholesterolemia and at high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) who have not achieved the desired result of therapy with a dose of 20 mg and who will be under the supervision of a specialist (see. "Special Instructions" section). Especially careful monitoring of patients receiving the drug at a dose of 40 mg is recommended. It is not recommended to prescribe a dose of 40 mg to patients who have not previously visited a doctor. After 2-4 weeks of therapy and / or with an increase in the dose of Crestor®, control of lipid metabolism indices is necessary (dose adjustment is necessary if necessary). Elderly patients No dose adjustment required. Patients with renal failure In patients with mild to moderate severity, dose adjustment is not required. In patients with severe renal insufficiency (CK less than 30 ml / min.), The use of Crestor® is contraindicated. Use of the drug in a dose of 40 mg is contraindicated in patients with moderately impaired renal function (CC less than 30-60 ml / min.) (See the section "Special Instructions" and "Pharmacodynamics"). Patients with moderate renal impairment are recommended an initial dose of 5 mg. Patients with liver failure Crestor® is contraindicated in patients with liver disease in the active phase (seesection "Contraindications"). Special populations. Ethnic groups When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increase in the systemic concentration of rosuvastatin among Japanese and Chinese was observed (see the section "Specific Instructions"). This fact should be taken into account when administering Crestor® to these groups of patients. When prescribing doses of 10 and 20 mg, the recommended initial dose for patients of the Mongoloid race is 5 mg. The prescription of the drug in a dose of 40 mg to patients of the Mongoloid race is contraindicated (see section “Contraindications”). Genetic polymorphism In carriers of the SLCO1B1 genotypes (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA, there was an increase in exposure (AUC) to rosuvastatin compared to the carriers of the SLCO1B1 genotypes c.521TT and ABCG2 c.421CC. For patients carrying genotypes p.521CC or c.421AA, the recommended maximum dose of Crestor® is 20 mg once a day (see the sections Pharmacokinetics, Special Instructions, and Interactions with Other Drugs and Other Drug Interactions). Patients predisposed to myopathy Contraindicated administration of the drug in a dose of 40 mg in patients with factors that may indicate a predisposition to the development of myopathy (see the section "Contraindications"). When prescribing doses of 10 and 20 mg, the recommended initial dose for this group of patients is 5 mg. (See section "Contraindications") Concomitant therapy Rosuvastatin binds to various transport proteins (in particular, OATP1B1 and BCRP). Combined use of Crestor® with drugs (such as cyclosporine, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir and / or tipranavir), increases the plasma concentration of rosuvastatin due to interaction with transport proteins, may increase the risk of myopathy (including rhabdomyolysis) (see sections “Special Instructions” and “Interaction with other medicinal products and other types of drug interactions”). You should read the instructions for use of these drugs before their appointment in conjunction with the drug Crestor®. In such cases, you should evaluate the possibility of prescribing alternative therapy or the temporary cessation of taking the drug Crestor®. If the use of the above preparations is necessary, the ratio of benefit and risk of concomitant therapy with Crestor® should be evaluated and the possibility of reducing its dose should be considered (seesection "Interaction with other drugs and other types of drug interactions").
Side effects
The side effects observed when taking the drug Crestor® are usually not very pronounced and go away on their own. As with the use of other HMG-CoA reductase inhibitors, the frequency of side effects is mostly dose-dependent. The frequency of adverse effects is as follows: often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000), unspecified frequency (cannot be calculated from the available data). Immune system Rarely: hypersensitivity reactions, including angioedema. Endocrine system Often: diabetes mellitus type 2 Central nervous system Often: headache, dizziness Of the digestive tract Often: constipation, nausea, abdominal pain Rarely: pancreatitis Of the side skin Infrequently: pruritus, rash, urticaria On the part of the musculoskeletal system Often: myalgia Rarely: myopathy (including myositis), rhabdomyolysis Others Often: asthenic syndrome On the part of the urinary system emy Patients treated Krestor® can be detected proteinuria. Changes in the amount of protein in the urine (from the absence or trace amounts to ++ or more) are observed in less than 1% of patients receiving 10–20 mg of the drug, and in about 3% of patients receiving 40 mg of the drug. A slight change in the amount of protein in the urine was noted when taking a dose of 20 mg. In most cases, proteinuria diminishes or disappears during therapy and does not mean the onset or the progression of an existing kidney disease. On the part of the musculoskeletal system When using the Crestor® drug in all dosages, and especially when taking doses of the drug in excess of 20 mg, the following effects on the musculoskeletal system were reported: myalgia, myopathy (including myositis), in rare cases - rhabdomyolysis with acute renal failure or without it. A dose-dependent increase in the activity of creatine phosphokinase (CPK) is observed in an insignificant number of patients taking rosuvastatin. In most cases, it was minor, asymptomatic and temporary.In the case of increased activity of CPK (more than 5 times compared with the upper limit of the norm), therapy should be suspended (see the section "Special Instructions"). On the part of the liver When rosuvastatin is used, a dose-dependent increase in the activity of “liver” transaminases is observed in an insignificant number of patients. In most cases, it is insignificant, asymptomatic and temporary. Laboratory indicators At use of the drug Krestor® the following changes of laboratory indicators were also observed: increase in concentration of glucose, bilirubin, activity of gamma-glutamyltranspeptidase, alkaline phosphatase, dysfunction of a thyroid gland. Post-marketing use The following side effects have been reported in the post-marketing use of Crestor®: From the hematopoietic system Unspecified frequency: thrombocytopenia From the alimentary tract Very rarely: jaundice, hepatitis Rarely: increased activity of “hepatic” transaminase Unspecified frequency: diarrhea From the musculoskeletal system Very rarely: arthralgia Unspecified frequency: immune-mediated necrotizing myopathy From the central nervous system Very rarely: loss of silt and memory loss Unspecified frequency: peripheral neuropathy On the part of the respiratory system Unspecified frequency: cough, shortness of breath On the part of the urinary system Very rarely: hematuria On the part of the skin and subcutaneous fatty tissue Unspecified frequency: Stevens-Johnson syndrome On the part of the reproductive system and the mammary gland Unspecified frequencies: gynecomastia Other Unspecified frequencies: peripheral edema. When using certain statins, the following side effects were reported: depression, sleep disorders, on frustrating insomnia and nightmares, sexual dysfunction, hyperglycemia, increased glycated hemoglobin concentration. It was reported on isolated cases of interstitial lung disease, especially with prolonged use of drugs (see section "Special instructions").
Overdose
When several daily doses are taken simultaneously, the pharmacokinetic parameters of rosuvastatin do not change. There is no specific treatment for an overdose of rosuvastatin.In case of overdose, it is recommended to carry out symptomatic treatment and measures aimed at maintaining the functions of vital organs and systems. The control of liver function and the level of CPK is necessary. It is unlikely that hemodialysis will be effective.
Interaction with other drugs
Effect of the use of other drugs on rosuvastatin Transport protein inhibitors: Rosuvastatin binds to certain transport proteins, in particular, to OATP1B1 and BCRP. The concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in plasma concentration of rosuvastatin and an increased risk of myopathy (see Table 3 and the sections "Dosage and administration" and "Special instructions"). Cyclosporine: with simultaneous use of rosuvastatin and cyclosporine, AUC of rosuvastatin was on average 7 times higher than that observed in healthy volunteers (see table 3). It does not affect the plasma concentration of cyclosporine. Крестор® is contraindicated in patients taking cyclosporine (see section "Contraindications"). Human Immunodeficiency Virus Protease Inhibitors (HIV): Although the exact mechanism of interaction is unknown, co-administration of HIV protease inhibitors can lead to a significant increase in exposure to rosuvastatin (see Table 3). A pharmacokinetic study on the simultaneous use of 20 mg of rosuvastatin with a combination preparation containing two HIV protease inhibitors (400 mg of lopinavir / 100 mg of ritonavir) in healthy volunteers resulted in an approximately twofold and fivefold increase in AUC (0-24) and Cmax of rosuvastatin, respectively. Therefore, the concomitant use of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Dosage and administration”, “Special instructions”, table 3). Gemfibrozil and other lipid-lowering drugs: the combined use of rosuvastatin and gemfibrozil results in a 2-fold increase in the maximum concentration of rosuvastatin in the blood plasma and AUC of rosuvastatin (see the section "Special Instructions"). Based on data on specific interactions, pharmacokinetically significant interactions with fenofibrate are not expected; pharmacodynamic interactions are possible.Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy while being used with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see the Special Instructions section) . At the same time taking the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), an initial dose of 5 mg is recommended for patients, 40 mg is contraindicated when administered together with fibrates (see sections "Contraindications", " Dosage and administration "," Special instructions "). Ezetimibe: simultaneous use of the drug Crestor® at a dose of 10 mg and ezetimibe at a dose of 10 mg was accompanied by an increase in the AUC of rosuvastatin in patients with hypercholesterolemia (see table 3). An increase in the risk of side effects due to the pharmacodynamic interaction between Crestor® and ezetimib cannot be ruled out. Antacids: the simultaneous use of rosuvastatin and suspensions of antacids containing magnesium and aluminum hydroxide, reduces the plasma concentration of rosuvastatin by about 50%. This effect is less pronounced if antacids are applied 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied. Erythromycin: the simultaneous use of rosuvastatin and erythromycin leads to a decrease in the AUC of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. Such an interaction may occur as a result of increased intestinal motility caused by taking erythromycin. Cytochrome P450 isoenzymes: the results of in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. Therefore, the interaction of rosuvastatin with other drugs at the metabolic level with the participation of cytochrome P450 isoenzymes is not expected. No clinically significant interaction of rosuvastatin with fluconazole (an inhibitor of isoenzymes CYP2C9 and CYP3A4) and ketoconazole (an inhibitor of isoenzymes CYP2A6 and CYP3A4) was noted. Fuzidovaya acid: studies on the interaction of rosuvastatin and fusidic acid was not conducted.As with other statins, post-marketing reports of cases of rhabdomyolysis with rosuvastatin and fusidic acid were received. It is necessary to closely monitor patients. If necessary, it is possible to temporarily stop taking rosuvastatin. Drug interactions that require dose adjustment of rosuvastatin (see table 3) The dose of Crestor® should be adjusted if necessary to be used together with drugs that increase the exposure to rosuvastatin. You should read the instructions for use of these drugs before their appointment in conjunction with the drug Crestor®. If exposure is expected to increase by 2 times or more, the initial dose of Crestor® should be 5 mg once a day. You should also adjust the maximum daily dose of Crestor® so that the expected exposure to rosuvastatin