Rozistark pills 10mg №70

Mechanism of action

Pharmacological action - hypolipidemic.

Pharmacodynamics

Mechanism of action. Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, which is a precursor of cholesterol. The main target of rosuvastatin is the liver, where cholesterol (Xc) is synthesized and LDL catabolism occurs.

Rosuvastatin increases the number of liver LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which leads to inhibition of the synthesis of VLDL, thereby reducing the total amount of LDL and VLDL.

Rosuvastatin reduces the increased content of Xc-LDL, total Xc and triglycerides (TG), increases the concentration of Xc-LPVP, and also reduces the concentration of apolipoprotein B (ApoB), Xc-non-LPVP, Xc-VLDLP, TG-VLDL and increases the concentration of apolipoprotein A (ApoA-I), reduces the ratio of Xc-LDL / Xc-HDL, total Xc / Xc-HDL and Xc-non-LPVP / Xc-HDL and the ratio ApoV / ApoA-I.

The therapeutic effect develops within one week after the start of therapy with the drug, after 2 weeks of treatment reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually achieved after 4 weeks of treatment and is maintained with further regular use of the drug.

Clinical efficacy. Rosuvastatin is effective in adult patients with hypercholesterolemia with or without symptoms of hypertriglyceridemia, regardless of their race, gender, or age, as well as in treating patients with diabetes and the hereditary form of familial hypercholesterolemia.

Rosuvastatin is effective in patients with hypercholesterolemia IIa and IIb type according to Fredrickson (the average initial concentration of LDL-C is about 4.8 mmol / l). In 80% of these patients who received 10 mg of rosuvastatin, the concentration reaches the target values ​​of Xc-LDL levels established by the European Community for the study of atherosclerosis - less than 3 mmol / l. Patients with heterozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 to 80 mg show a positive trend in lipid profile parameters.

As a result of titration of doses up to a daily dose of 40 mg (12 weeks of therapy), a decrease in the concentration of LDL-C is noted by 53%. In 33% of patients, the concentration of Xc-LDL is less than 3 mmol / l, which corresponds to the target standards of the European atherosclerosis research guidelines.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 and 40 mg, the average decrease in the concentration of LDL-C LDL is 22%. In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg / dL, who took rosuvastatin at a dose of 5 mg to 40 mg once a day for 6 weeks, the concentration of TG in the blood plasma significantly decreased.

The additive effect is observed in combination with fenofibrate in relation to the content of TG and with nicotinic acid (more than 1 g / day) in relation to the content of Xc-HDL. In patients with low risk of developing coronary heart disease (10-year risk on the Framingham scale - less than 10%), with an average concentration of Xc-LDL 4 mmol / l (154.5 mg / dL) and subclinical atherosclerosis, which was estimated by the thickness of the intima complex -media "carotid arteries (TCIM), rosuvastatin at a dose of 40 mg / day significantly slowed the rate of progression of the maximum TCIM for 12 segments of the carotid artery compared with placebo with a difference of -0,0145 mm / year (95% confidence interval (CI)): -0,0196 to -0,0093; p <0.001).

The study was conducted in patients with a low risk of coronary artery disease, for which a dose of 40 mg is not recommended. The dose of 40 mg should be prescribed only to patients with severe hypercholesterolemia and a high risk of cardiovascular diseases.

The results of a study on the use of statins for primary prophylaxis showed that rosuvastatin significantly reduced the risk of cardiovascular complications with a relative risk reduction of 44%.

The effectiveness of therapy was noted after 6 months of use of the drug. There was a statistically significant reduction of 48% of the combined criterion, including death from cardiovascular diseases, stroke and myocardial infarction, a 54% reduction in the occurrence of fatal or nonfatal myocardial infarction and 48% in fatal or nonfatal stroke.Total mortality decreased by 20% in the rosuvastatin group. The safety profile of patients taking rosuvastatin at a dose of 20 mg was similar to that of the placebo group.

Pharmacokinetics

Absorption and distribution

C_max Rosuvastatin in plasma is reached 5 hours after ingestion. Absolute bioavailability is approximately 20%.

Metabolism

Rosuvastatin is metabolized mainly by the liver, which is the main site of the synthesis of Xc and Xc-LDL metabolism. V_d Rosuvastatin is approximately 134 l. About 90% of rosuvastatin binds to plasma proteins, mainly albumin.

Subject to limited metabolism (approximately 10%). Rosuvastatin is a rather non-core substrate for metabolism by cytochrome P450 isoenzymes. CYP2C9 is the main isoenzyme involved in rosuvastatin metabolism, while CYP2C19, CYP3A4 and CYP2D6 isoenzymes are less involved in metabolism. The main identified metabolites of rosuvastatin are N-desmethylrozuvastatin, which is 50% less active than rosuvastatin, and lactone metabolites, which 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 metabolite.

Removal

Approximately 90% of the dose of rosuvastatin is excreted unchanged through the intestines (including absorbed and unabsorbed rosuvastatin), the rest is excreted by the kidneys. T_1/2 is about 19 hours, 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, the membrane capture Xc is involved in the process of hepatic uptake of rosuvastatin, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

Systemic exposure of rosuvastatin increases in proportion to the dose. Changes in pharmacokinetic parameters when taking the drug several times a day is not observed.

Special groups

Age and gender. They do not have a clinically significant effect on the pharmacokinetic parameters of rosuvastatin.

Ethnic groups. Comparative pharmacokinetic studies have shown approximately a twofold increase in the mean AUC and C values._max drug in the blood plasma of patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with those of the Caucasians. Indians had an increase in the mean AUC and C_max about 1.3 times. Pharmacokinetic analysis revealed no clinically significant differences in pharmacokinetics among the Caucasians and Negroids.

Renal failure. In patients with mild to moderate renal insufficiency, the plasma concentration of rosuvastatin or N-desmethylrosuvastatin does not change significantly. In patients with severe renal insufficiency (Cl creatinine <30 ml / min), plasma plasma concentration of rosuvastatin is 3 times higher, and N-desmethylrozouvastatin concentration is 9 times higher than in healthy volunteers.The plasma concentration of rosuvastatin in hemodialysis patients was about 50% higher than in healthy volunteers.

Liver failure. In patients with various stages of liver failure with a score of 7 or less on the Child-Pugh scale, no increase in T was found._1/2 Rosuvastatin. However, an increase in T was noted in 2 patients with 8 and 9 points on the Child-Pugh scale._1/2 about 2 times. Experience with rosuvastatin in patients with more than 9 points on the Child-Pugh scale is absent.

Genetic polymorphism. HMG-CoA reductase inhibitors, incl. Rozistark^®, bind to the transport proteins OATP1B1 (a polypeptide transporting organic anions that are involved in the capture of statins by hepatocytes) and BCRP (efflux transporter). In carriers of the SLCO1B1 (OATP1B1) p.521CC and ABCG2 (BCRP) p.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 for Rozistark^®

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 C-reactive protein concentration (≥2 mg / l) in the presence of at least one of additional risk factors, such as hypertension, low concentration of HD-C, HDL, smoking, family history of early development of coronary heart disease);

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 Xc and Xc-LDL;

primary hypercholesterolemia (type IIa according to Fredrickson, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb according to Fredrickson) as a supplement to the diet, when diet and other non-drug therapies (eg exercise, weight loss) are insufficient;

hypertriglyceridemia (type IV by Fredrickson) as a supplement to the diet;

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 sufficiently effective.

Contraindications

For tablets 10 and 20 mg

hypersensitivity to rosuvastatin or any of the components of the drug;

liver diseases in the active phase, including a persistent increase in the activity of serum transaminases and any increase in the activity of transaminases in the serum by more than 3 times as compared with VGN;

severe renal impairment (Cl creatinine <30 ml / min);

myopathy;

simultaneous administration of cyclosporine;

predisposition to the development of myotoxic complications;

pregnancy and breastfeeding;

childbearing age in women who do not use reliable contraception;

increasing the concentration of CK in the blood of more than 5 times compared with VGN;

concomitant use with HIV protease inhibitors;

lactose intolerance, lactase deficiency or glucose-galactose malabsorption (because the drug contains lactose);

age up to 18 years (efficacy and safety have not been established).

For 40 mg tablets

hypersensitivity to rosuvastatin or any of the components of the drug;

liver diseases in the active phase, including a persistent increase in the activity of serum transaminases and any increase in the activity of transaminases in the serum by more than 3 times as compared with VGN;

moderate renal insufficiency (Cl creatinine <60 ml / min);

myopathy;

simultaneous administration of cyclosporine;

myotoxicity in the presence of other inhibitors of HMG-CoA reductase inhibitors or fibrates in history;

hypothyroidism;

personal or family history of muscular disease;

excessive drinking;

conditions that can lead to increased plasma concentrations of rosuvastatin;

simultaneous reception of fibrates;

pregnancy and breastfeeding;

women of childbearing age who do not use reliable contraception;

increasing the concentration of CK in the blood of more than 5 times compared with VGN;

concomitant use with HIV protease inhibitors;

Mongoloid patients;

lactose intolerance, lactase deficiency or glucose-galactose malabsorption (because the drug contains lactose);

age up to 18 years (efficacy and safety have not been established).

With care: for tablets of 10 and 20 mg - the risk of developing myopathy / rhabdomyolysis - renal failure, hypothyroidism; a personal or family history of hereditary muscular diseases and a previous history of muscular toxicity with the use of other HMG-CoA reductase inhibitors or fibrates; excessive drinking; conditions in which there is an increase in the plasma concentration of rosuvastatin; age over 70 years; history of liver disease; sepsis; hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine, or water-electrolyte disorders; uncontrolled epilepsy; race (mongoloid race); simultaneous reception of fibrates; simultaneous use with colchicine and ezetimibe;

for tablets 40 mg - renal failure of moderate severity (Cl creatinine> 60 ml / min); age over 70 years; history of liver disease; sepsis; hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine, or water-electrolyte disorders; uncontrolled epilepsy; simultaneous use with colchicine and ezetimibe.

Patients with liver failure. Data on the use of the drug in patients with more than 9 points on the Child-Pugh scale are not available.

Use during pregnancy and lactation

Rosistark^® contraindicated in pregnancy and during breastfeeding.

Women of reproductive age should use reliable and adequate methods of contraception.

Since cholesterol and other products of cholesterol biosynthesis are important for the development of the fetus, the potential risk of inhibition of HMG-CoA reductase exceeds the use of the drug in pregnant women.

If pregnancy is diagnosed during therapy, the drug should be immediately discontinued.

There are no data on the release of rosuvastatin with breast milk, therefore, during breastfeeding, the use of the drug should be discontinued.

Side effects

Side effects