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Active substance

Rosuvastatin

Composition

Active ingredient: Rosuvastatin zinc;

Auxiliary substances: ludipress; Povidone; crospovidone; crospovidone; Magnesium stearate;

Shell film: Opadry II white 85F 18422; titanium dioxide; macrogol 3350; talc

pharmachologic effect

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase - an enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, which is a precursor of cholesterol (Xc). Rosuvastatin increases the number of LDL receptors on the surface of liver cells, thereby enhancing the absorption and catabolism of LDL, and also suppresses the synthesis of VLDLP in the liver. As a result, the total number of VLDL and LDL particles is reduced.

It lowers the elevated concentration of low-density lipoprotein cholesterol (Xc-LDL), total cholesterol and triglycerides, and also increases the concentration of high-density lipoprotein cholesterol (Xc-HDL). In addition, rosuvastatin reduces the concentration of apolipoprotein B (ApoB), non-HDL cholesterol (Xc-non-LPVP), very low-density lipoprotein cholesterol (Xc-VLDL), very low-density lipoprotein triglycerides (TG-VLDL), and increases the content of apolipoprotein-low-density lipoprotein (TG-VLVP) and increases the content of apolipoprotein-very low density lipoprotein (TG-VLDL) and increases the content of apolipoprotein, low density lipoprotein, and low-density lipoprotein cholesterol and increases the content of apolipoprotein and low-density lipoprotein cholesterol; ).

Rosuvastatin also reduces the ratio of Xc-LDL / Xc-HDL, total cholesterol / Xc-HDL, Xc-non LPP / Xc-HDL and ApoV / ApoA-I.

The therapeutic effect of the drug is manifested within one week after the start of treatment. After 2 weeks of therapy, the effectiveness reaches a level that is 90% of the maximum possible. The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with regular intake.

The safety and effectiveness of rosuvastatin in the pediatric population has not been proven. For this category of patients, the experience of using the drug is limited to a small number of patients (aged 8 years and older) with homozygous hereditary hypercholesterolemia.

Pharmacokinetics

Suction

Cmax of rosuvastatin in plasma is reached approximately 5 hours after ingestion. The absolute bioavailability of the drug is about 20%.

Distribution

Rosuvastatin is intensively absorbed by the liver, where the main synthesis of cholesterol and the elimination of Xc-LDL occurs. Vd Rosuvastatin reaches 134 l.

Approximately 90% of rosuvastatin binds to plasma proteins, primarily albumin.

Metabolism

Rosuvastatin undergoes limited metabolism (about 10%) in the liver. It is a non-core substrate for cytochrome P450 isoenzymes. CYP2C9 is the main isoenzyme involved in rosuvastatin metabolism. 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.

Removal

Approximately 90% of the dose of rosuvastatin is excreted unchanged through the intestines.

Approximately 5% of the dose is excreted by the kidneys unchanged. T1 / 2 drug from blood plasma is approximately 19 hours and does not change with increasing dose of the drug. Rosuvastatin plasma clearance reaches an average of 50 l / h (coefficient of variation - 21.7%).

As in the case of other HMG-CoA reductase inhibitors, a membrane cholesterol transporter is involved in the process of hepatic uptake of rosuvastatin, which plays an important role in the hepatic elimination of rosuvastatin.

The systemic bioavailability of rosuvastatin increases in proportion to the dose. When using the drug several times a day, pharmacokinetic parameters do not change.

Pharmacokinetics in special clinical situations

Gender and age do not have a clinically significant effect on rosuvastatin pharmacokinetics.

Pharmacokinetic studies have shown approximately a twofold increase in plasma AUC and Cmax of rosuvastatin in the blood plasma of patients of the Mongoloid race (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.The analysis revealed no clinically significant differences in pharmacokinetics among Caucasians and Negroids.

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 failure (CC less than 30 ml / min), plasma concentration of rosuvastatin is 3 times higher, and N-desmethyl 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.

In patients with different stages of liver failure, no increase in Rosuvastatin T1 / 2 was detected (patients with a score of 7 or lower on the Childe-Pugh scale). In 2 patients with points 8 and 9 on the Childe-Pugh scale, an increase in T1 / 2 was noted at least 2 times. Experience with rosuvastatin in patients with a score above 9 on the Childe Pugh scale is absent.

Indications

  • homozygous hereditary hypercholesterolemia, as a supplement to the diet and other methods of treatment aimed at reducing the level of lipids in the blood (such as LDL apheresis), as well as in cases when these methods are not sufficiently effective;
  • to slow the progression of atherosclerosis, as a supplement to the diet in patients, including which shows therapy to reduce the level of total Xc and Xc-LDL;
  • primary hypercholesterolemia (type IIa according to Fredrickson) 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;
  • hypertriglyceridemia (type IV by Fredrickson), as a supplement to the diet;
  • prevention of major cardiovascular complications (stroke, myocardial infarction, 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 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, a family history of early onset ischemic pain heart ailments.

Contraindications

  • 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 as compared with VGN);
  • severe renal dysfunction (CC less than 30 ml / min);
  • myopathy;
  • simultaneous administration of cyclosporine;
  • pregnancy;
  • lactation period;
  • the lack of adequate methods of contraception in women with intact reproductive function;
  • predisposition to the development of myotoxic complications;
  • children and adolescents under 18 years of age (due to the lack of sufficient clinical data, efficacy and safety have not been established);
  • lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the product contains lactose);
  • hypersensitivity to rosuvastatin and other components of the drug.

Side effects

On the part of the immune system: rarely - hypersensitivity reactions, including angioedema.

On the part of the nervous system: often - headache, dizziness; very rarely - polyneuropathy, loss of memory.

On the part of the digestive system: often - constipation, nausea, abdominal pain; infrequently, a slight, asymptomatic, transient increase in liver transaminase activity; rarely - pancreatitis; unspecified frequency - diarrhea; very rarely - jaundice, hepatitis.

On the part of the skin and subcutaneous structures: infrequently - pruritus, rash, and urticaria; unspecified frequency - Stevens-Johnson syndrome.

From the musculoskeletal system: often - myalgia; rarely, myopathy (including myositis) and rhabdomyolysis with or without acute renal failure . A dose-dependent increase in CPK concentration is observed in a small number of patients taking rosuvastatin. In most cases, it was minor, asymptomatic and temporary. In the case of increasing the concentration of CK more than 5 times higher than VGN therapy should be suspended. Very rarely - arthralgia.

On the part of the urinary system: proteinuria (less than 1% of patients receiving a dose of 10-20 mg, and about 3% of patients receiving a dose of 40 mg). In most cases, proteinuria diminishes or disappears during therapy and does not mean the onset or the progression of an existing kidney disease. Very rarely - hematuria.

On the part of the respiratory system: the frequency is unknown - cough, shortness of breath.

From the laboratory indicators: an increase in the concentration of glucose, bilirubin, activity of GGTP, alkaline phosphatase.

Other: often - asthenic syndrome; possible dysfunction of the thyroid gland.

Interaction

Cyclosporine. With the simultaneous use of rosuvastatin and cyclosporine, AUCrozuvastatin is on average 7 times higher than the value observed in healthy volunteers. The combined use leads to an increase in the concentration of rosuvastatin in the blood plasma by 11 times, while the plasma concentration of cyclosporin does not change.

Vitamin K antagonists. Starting therapy with rosuvastatin or increasing the dose of a drug in patients receiving vitamin K antagonists at the same time (for example, warfarin) may lead to an increase in PV and MHO. Canceling rosuvastatin or reducing its dose may lead to a decrease in MHO. In such cases, control of MHO is recommended.

Gemfibrozil and hypolipidemic agents. The combined use of rosuvastatin and gemfibrozil leads to an increase of 2 times Cmax in blood plasma and rosuvastatin AUC. Perhaps pharmacodynamic interaction. Gemfibrozil, other fibrates and nicotinic acid in lipid-lowering doses (more than 1 g / day) increased the risk of myopathy while being used with other HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy and when used as monotherapy.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. Rosuvastatin therapy at a dose of 40 mg is contraindicated with the concomitant use of fibrates.

Ezetimibe. The simultaneous use of the drug Rosulip and ezetimiba was not accompanied by a change in AUC and Cmax both drugs. However, between rosuvastatin and ezetimibe pharmacodynamic interaction with the development of side effects cannot be excluded.

Protease inhibitors. Although the exact mechanism of interaction is unknown, co-administration of protease inhibitors can lead to a significant increase in the exposure of rosuvastatin. A pharmacokinetic study on the simultaneous use of 20 mg of rosuvastatin with a combination preparation containing two 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 rosuvastatin respectively. Therefore, simultaneous administration of rosuvastatin and protease inhibitors in the treatment of patients with HIV is not recommended.

Antacids. The simultaneous use of rosuvastatin and suspensions of antacids containing aluminum and magnesium hydroxide, reduces the plasma concentration of rosuvastatin by about 50%. This effect is less pronounced if the antacid suspension is 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 AUC of rosuvastatin by 20% and Cmax rosuvastatin by 30%, probably as a result of increased intestinal motility caused by taking erythromycin.

Oral contraceptives / hormone replacement therapy. The simultaneous use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and AUCnorgestrel by 26 and 34%, respectively. Such an increase in plasma concentration should be taken into account when selecting the dose of oral contraceptives against the background of Rosulip. Pharmacokinetic data on the simultaneous use of Rosulip and hormone replacement therapy are absent, therefore, a similar effect cannot be excluded when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Other drugs. No clinically significant interaction of rosuvastatin with Digoxin is expected.

Isoenzymes of cytochrome P450. The results of in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of isoenzymes of the cytochrome P450 system. In addition, rosuvastatin is a weak substrate for these isoenzymes. There was no clinically significant interaction between rosuvastatin and Fluconazole (an inhibitor of CYP2C9 and CYP3A4 isoenzymes) and Ketoconazole (an inhibitor of CYP2A6 and CYP3A4 isoenzymes).The combined use of rosuvastatin and itraconazole (an isoenzyme inhibitor CYP3A4) increases the AUC of rosuvastatin by 28% (clinically insignificant). Thus, interactions associated with the cytochrome P450 system are not expected.

How to take, the course of administration and dosage

Inside, do not chew or crush the pill, swallow whole, washed down with water. Rosulip can be taken at any time of the day, regardless of the meal.

Before starting treatment with Rosulip, the patient should be prescribed a standard diet low in cholesterol. The patient must follow a diet during the entire course of therapy. The dose of the drug should be selected individually depending on the indications and therapeutic response to treatment, taking into account the current recommendations on target lipid levels.

The recommended initial dose of Rosulip for patients starting the drug or transferred from receiving other HMG-CoA reductase inhibitors is 5 or 10 mg once a day. When choosing the initial dose, one should be guided by the patient’s cholesterol content and take into account the risk of cardiovascular complications, and the potential risk of side effects should be assessed. If necessary, after 4 weeks the dose may be increased.

After taking a dose for 4 weeks that exceeds the recommended initial dose, its subsequent increase to 40 mg can be performed 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 treatment when taken in a dose of 20 mg and which will be under the supervision of a specialist. Especially careful monitoring of patients receiving the drug at a dose of 40 mg is recommended.

For treatment of patients over 65, the recommended starting dose is 5 mg. There is no need for other changes in the dose of the drug related to the age of the patients.

Patients with renal insufficiency of mild or moderate severity dose adjustment is not required. Patients with moderate renal impairment (creatinine Cl less than 60 ml / min) are recommended an initial dose of 5 mg. A dose of 40 mg is contraindicated in patients with moderate renal impairment. In severe renal failure, Rosulip is contraindicated in any dose (see "Contraindications").

When prescribing doses of 10 and 20 mg, the recommended starting dose for patients of the Asian race is 5 mg. The drug is prescribed in a dose of 40 mg for patients of the Asian race (see "Contraindications").

When prescribing doses of 10 and 20 mg, the recommended initial dose for patients predisposed to myopathy is 5 mg. The prescription 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