Rosuvastatin-SZ tablets coated. 20 mg, 90 pcs. (rosuvastatin)

Pharmacological action of

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to 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 lowers elevated concentrations of LDL cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C), and also reduces the concentrations of apolipoprotein B (ApoV), non-HDL cholesterol, cholesterol-VLDL, TG-VLDL and increases the concentration of apolipoprotein A-I (ApoA-I), reduces the ratio of cholesterol - LDL-C / HDL-C, total cholesterol / HDL-C and HDL-C / HDL-C and the ratio 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 in 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%). Rosuvastatin is a non-core substrate for metabolism by enzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin, is an isoenzyme of CYP2C9. The isoenzymes СYР2С19, СЫРЗА4, and CYP2D6 are less involved in metabolism. The main identified metabolites of rosuvastatin are N-desmethyltrosluvuvastatin and lactone metabolites. N-desmethylrozuvastatin is approximately 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity in inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest is metabolites.

Excretion of

About 90% of the dose of rosuvastatin is excreted unchanged through the intestines (including absorbed and unabsorbed rosuvastatin). The rest is excreted by the kidneys. The plasma half-life (T1 / 2) is approximately 19 hours. The half-life does not change with an increase in the 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 cholesterol membrane carrier 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 dose. Pharmacokinetic parameters do not change with daily use. Special patient populations.

Age and gender

Sex and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin.

Ethnic groups

Pharmacokinetic studies showed an approximately twofold increase in the median AUC (area under the concentration-time curve) and Cmax (maximum plasma concentration) of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with Caucasians in Indians showed an increase in the median AUC and Cmax by 1.3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among Caucasians and representatives of the Negroid race.

Renal failure

In patients with mild to moderate renal failure, the plasma concentration of rosuvastatin or N-desmethylrose-vastatin does not change significantly. In patients with severe renal failure (creatinine clearance (CC) less than 30 ml / min. ) the concentration of rosuvastatin in blood plasma is 3 times higher, and the concentration of N-desmethylrosuvastatin is 9 times higher than that of healthy volunteers. The plasma concentration of rosuvastatin in hemodialysis patients was approximately 50% higher than in healthy volunteers.

Hepatic insufficiency

Patients with various stages of liver failure did not show an increase in the half-life of rosuvastatin in patients with 7 points or lower on the Child-Pugh scale. Two patients with 8 and 9 points on the Child-Pugh scale showed an increase in half-life by at least 2 times. There is no experience with rosuvastatin in patients with more than 9 Child-Pugh scores.

Indications

- primary hypercholesterolemia according to the classification of Fredrickson (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as a supplement to the diet, when diet and other non-drug treatments (e.g. physical exercise, weight loss) are found to be insufficient

- familial homozygous hypercholesterolemia as an adjunct to diet and other therapy (for example, LDL apheresis), or in cases where such therapy is not effective enough

- hypertriglyceridemia (type IV according to Fredrickson) as an addition to the diet

- to slow the progression of atherosclerosis as a supplement to the diet in patients who are shown therapy to reduce the concentration of total Chs and LDL-Cs

- the primary prevention of major cardiovascular complications (stroke, heart attack, arterial revascularization) in adult patients without clinical signs of coronary artery disease, but with an increased risk of its development (age over 50 for men and over 60 for women, increased concentration of C-reactive protein (> 2 mg / l) in the presence of at least one of additional risk factors such as arterial hypertension, low concentration of HDL-C, smoking, family history of early onset of coronary heart disease).

Contraindications

- 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 compared with VGN)

- severe renal failure (CC less than 30 ml / min)

- increased CPK concentration in the blood by more than 5 times compared with VGN

- myopathy

- predisposition to the development of myotoxic complications

- concomitant use of cyclosporine

- combined use with HIV protease inhibitors

- pregnancy

- breastfeeding

- g women who do not use adequate methods of contraception

- children and adolescents under 18

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

- hypersensitivity to rosuvastatin or any of the components of the drug.

Special instructions

Renal effects of

In patients treated with high doses of rosuvastatin-C3 (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria did not indicate acute kidney disease or progression of kidney disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor renal function indicators during treatment.

From the musculoskeletal system

The following effects on the musculoskeletal system: myalgia, myopathy, in rare cases, rhabdomyolysis were reported with the use of the drug rosuvastatin-SZ in all doses, and especially when taking the drug in doses exceeding 20 mg.

Determination of CPK

Determination of CPK activity should not be carried out after intense physical exertion or if there are other possible reasons for the increase in CPK activity, which may lead to an incorrect interpretation of the results. If the initial activity of CPK is significantly increased (5 times higher than VGN), after 5-7 days, a second measurement should be carried out. Therapy should not be started if a repeat test confirms the initial activity of KFK (more than 5 times higher compared with VGN).

Before initiating

therapy When prescribing Rosuvastatin-SZ, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy / rhabdomyolysis, it is necessary to consider the risk and potential benefits of therapy and conduct clinical observation.

During

therapy, the patient should be informed of the need to immediately inform the doctor of cases of sudden onset of muscle pain, muscle weakness or cramping, especially in combination with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if the activity of CPK is significantly increased (more than 5 times compared with VGN) or if symptoms from the muscles are pronounced and cause daily discomfort (even if the activity of CPK is 5 times less compared to VGN). If symptoms disappear, and CPK activity returns to normal, consideration should be given to re-prescribing the drug Rosuvastatin-SZ or other HMG-CoA reductase inhibitors in lower doses with careful monitoring of the patient. Routine monitoring of CPK activity in the absence of symptoms is impractical.

Very rare cases of immune-mediated necrotizing myopathy with clinical manifestations in the form of persistent weakness of the proximal muscles and an increase in the activity of CPK in the blood serum during treatment or when stopping statins, including rosuvastatin. Additional studies of the muscle and nervous system, serological studies, as well as immunosuppressive therapy may be required.

There were no signs of increased effects on skeletal muscle when taking Rosuvastatin-SZ and concomitant therapy. However, an increase in the incidence of myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, antifungals from the azole group, protease inhibitors and antibiotics from the macrolide group. Gemfibrozil increases the risk of myopathy when used together with certain HMG-CoA reductase inhibitors. Thus, the simultaneous use of the drug Rosuvastatin-SZ and gemfibrozil is not recommended. The ratio of risk and possible benefit should be carefully weighed when the combined use of the drug Rosuvastatin-SZ and fibrates or nicotinic acid in lipid-lowering doses. The use of the drug Rosuvastatin-SZ at a dose of 40 mg together with fibrates is contraindicated.

2-4 weeks after the start of treatment and / or with an increase in the dose of the drug Rosuvastatin-SZ, monitoring of lipid metabolism is necessary (dose adjustment is necessary if necessary).

Liver

It is recommended to determine the liver function indices before the start of therapy and 3 months after the start of therapy. Taking the drug Rosuvastatin-SZ should be discontinued or the dose of the drug should be reduced if the activity of transaminases in the blood serum is 3 times higher than VGN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy of the main diseases should be carried out before treatment with Rosuvastatin-SZ.

Ethnic groups

Pharmacokinetic studies among Chinese and Japanese patients showed an increase in systemic concentrations of rosuvastatin compared with those obtained among patients of the Caucasian race.

HIV protease inhibitors

The combined use of the drug with HIV protease inhibitors is not recommended.

Lactose

The drug should not be used in patients with lactase deficiency, galactose intolerance and glucose-galactose malabsorption.

Interstitial pulmonary disease

With the use of certain statins, especially for a long time, isolated cases of interstitial pulmonary disease have been reported. Manifestations of the disease can include shortness of breath, unproductive cough, and general well-being (weakness, weight loss, and fever). If interstitial pulmonary disease is suspected, statin therapy should be discontinued.

Type 2 diabetes mellitus

In patients with a glucose concentration of 5.6 to 6.9 mmol / L, therapy with Rosuvastatin-S3 was associated with an increased risk of type 2 diabetes.

Influence on the ability to drive vehicles and control mechanisms

No studies have been conducted to study the effect of the drug Rosuvastatin-SZ on the ability to drive a vehicle and use mechanisms. Caution should be exercised when driving a car or working that requires an increased concentration of attention and speed of psychomotor reactions (dizziness may occur during therapy).

Composition

1 tab. rosuvastatin (in the form of calcium salt) 20 mg

Excipients: lactose monohydrate (milk sugar) - 67.6 mg, calcium hydrogen phosphate dihydrate - 20 mg, povidone (low molecular weight polyvinyl pyrrolidone) - 9 mg, croscarmellose sodium (primrose sodium) - 6.6 mg - 2 mg, colloidal silicon dioxide (Aerosil) - 0.8 mg, microcrystalline cellulose - 74 mg.

Shell composition: Opadry II (polyvinyl alcohol, partially hydrolyzed - 2.64 mg, macrogol (polyethylene glycol) 3350 - 0.741 mg, talc - 1.2 mg, titanium dioxide (E171) - 1.1502 mg, soy lecithin (E322) - 0.21 mg, aluminum varnish based on dye indigo carmine - 0.0036 mg, aluminum varnish based on dye azorubine - 0.0306 mg, aluminum varnish based on dye crimson [Ponceau 4R] - 0.0246 mg).

Dosage and Administration

Inside, do not chew or grind the tablet, swallow whole, washed down with water. The drug can be prescribed at any time of the day, regardless of food intake. Before starting therapy with Rosuvastatin-S3, the patient should begin to follow a standard hypocholesterolemic diet and continue to follow it during treatment. The dose of the drug should be selected individually depending on the goals of therapy and the therapeutic response to treatment, taking into account current recommendations on target lipid concentrations. The recommended starting dose for patients starting to take the drug, or for patients transferred from taking other HMG-CoA reductase inhibitors, should be 5 mg or 10 mg of the drug Rosuvastatin-SZ 1 time per day. When choosing an initial dose, one should be guided by the individual cholesterol content and take into account the possible risk of cardiovascular complications, and it is also necessary to assess the potential risk of side effects. If necessary, the dose can be increased to a larger after 4 weeks (see section "Pharmacodynamics"). Due to the possible development of side effects when taking a dose of 40 mg, compared with lower doses of the drug (see section “Side effects”), increasing the dose to 40 mg after an additional dose is higher than the recommended initial dose for 4 weeks therapy can be carried out only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia), who have not achieved the desired result of therapy when taking a dose of 20 mg, and which will be under the supervision of a specialist (see section "Special instructions"). Particularly careful monitoring of patients receiving the drug at a dose of 40 mg is recommended. A dosage of 40 mg is not recommended for patients who have not previously consulted a doctor. After 2-4 weeks of therapy and / or with an increase in the dose of the drug Rosuvastatin-SZ, monitoring of lipid metabolism is necessary (dose adjustment is necessary if necessary).

Homozygous hereditary hypercholesterolemia

Recommended starting dose is 20 mg once daily.

Elderly patients

Patients over the age of 65 are advised to start using the drug with a dose of 5 mg once a day.

Patients with renal failure

Dose adjustment is not required in patients with mild or moderate renal failure.

In patients with severe renal failure (CC less than 30 ml / min.), the use of the drug Rosuvastatin-SZ is contraindicated. The use of the drug in a dose of 40 mg is contraindicated in patients with moderate impaired renal function (CC 30-60 ml / min.) (See sections "Special Instructions" and "Pharmacodynamics"). For patients with moderate impaired renal function, an initial dose of 5 mg is recommended.

Patients with liver failure

Rosuvastatin-S3 is contraindicated in patients with active liver disease (see section "Contraindications").

Special Populations.

Ethnic groups In the study of 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 noted (see the section "Special Instructions"). This fact should be taken into account when prescribing Rosuvastatin-SZ to these patient groups. When prescribing doses of 10 mg and 20 mg, the recommended initial dose for patients of the Mongoloid race is 5 mg. The administration of the drug in a dose of 40 mg is contraindicated for patients of the Mongoloid race (see section "Contraindications").

Patients predisposed to myopathy

Administration of the drug in a dose of 40 mg is contraindicated in patients with factors that may indicate a predisposition to the development of myopathy (see section "Contraindications"). When prescribing doses of 10 mg and 20 mg, the recommended initial dose for this group of patients is 5 mg (see section "Contraindications").

Use with concomitant therapy

With the simultaneous use of the drug with gemfibrozil, fibrates, nicotinic acid in a dose of more than 1 g / day, an initial dose of 5 mg is recommended for patients. The dose of the drug Rosuvastatin-SZ should not exceed 10 mg once a day.

Side effects

Side effects observed when taking Rosuvastatin-SZ are usually mild and go away on their own. As with other HMG-CoA reductase inhibitors, the incidence of side effects is mainly dose-dependent. The frequency of occurrence of undesirable effects is presented as follows: often (> 1 / 100.1 / 1000.1 / 10000, <1/1000) is very rare (<1/10000), the frequency is unknown (according to the available data, it is not possible to establish the frequency of occurrence) including individual messages.



immune system Rarely: hypersensitivity reactions, including angioedema.

Endocrine system

Often: type 2 diabetes mellitus

From the central nervous system

Often: headache, dizziness

From the digestive tract

Often: constipation, nausea, abdominal pain Rarely: pancreatitis

From the side : pruritus, rash, urticaria

From the musculoskeletal system

Often: myalgia Rarely: myopathy (including myositis), rhabdomyolysis

Other

Often: asthenic

syndrome From the urinary system

Proteinuria may be detected in patients treated with rosuvastatin-SZ. 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 to 20 mg of the drug, and in approximately 3% of patients receiving 40 mg of the drug. A slight change in the amount of protein in the urine was observed when taking a dose of 20 mg. In most cases, proteinuria decreases or disappears during therapy and does not mean the occurrence of acute or progression of an existing kidney disease.

From the musculoskeletal system

When using the drug Rosuvastatin-SZ in all doses, 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 a small number of patients taking rosuvastatin. In most cases, it was mild, asymptomatic and temporary. In case of increased activity of CPK (more than 5 times compared with the upper limit of normal), therapy should be suspended (see section "Special instructions").

On the part of the liver

When using rosuvastatin, a dose-dependent increase in the activity of “liver” transaminases is observed in a small number of patients. In most cases, it is insignificant, asymptomatic and temporary.

Laboratory indicators

When using the drug Rosuvastatin-SZ, the following changes in laboratory parameters were also observed: an increase in the concentration of glucose, bilirubin, the activity of gamma-glutamyl transpeptidase, alkaline phosphatase, and dysfunction of the thyroid gland.

Post-marketing use of

The following side effects have been reported in the post-marketing use of rosuvastatin-C3:

From the digestive tract

Very rare: jaundice, hepatitis Rarely: increased activity of hepatic transaminases. Frequency unknown: diarrhea, fatal and non-fatal liver failure

From the musculoskeletal system

Very rare: arthralgia. Frequency unknown: Immuno-mediated necrotizing myopathy

From the central nervous system

Very rarely: polyneuropathy, forgetfulness, amnesia, memory loss, confusion From the respiratory system Frequency unknown: cough, shortness of breath

From the urinary system

Very rare: hematuria, microhematuria

From the skin and subcutaneous fat

Frequency unknown: Johnson's Reproductive System and Breast Frequency unknown: gynecomastia

Other

frequency unknown: peripheral edema thrombocytopenia interstitial lung disease. The following side effects have been reported with some statins: depression, sleep disturbances, including insomnia and nightmares, sexual dysfunction.

Overdose of

With the simultaneous administration of several daily doses, the pharmacokinetic parameters of rosuvastatin do not change.

Treatment: There is no specific treatment for an overdose of rosuvastatin. It is recommended to carry out symptomatic treatment and activities aimed at maintaining the functions of vital organs and systems. It is necessary to control liver function and CPK activity. Hemodialysis is unlikely to be effective.

Active ingredient

rosuvastatin

Pharmacy leave

Po

lekarstvennaja form

tablets

Northern Star, Russia



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