Rosistarc tablets coated film 10 mg 28 pcs. (rosuvastatin)

Release form

tablets

Packing

28 pcs

Pharmacological action

Rosistark - lipid-lowering.

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 the action of rosuvastatin is the liver, where the synthesis of cholesterol (cholesterol) and LDL catabolism are carried out.

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

Rosuvastatin reduces the elevated levels of LDL cholesterol, total cholesterol and triglycerides (TG), increases the concentration of HDL cholesterol, and also reduces the concentration of apolipoprotein B (ApoV), non-HDL cholesterol, cholesterol-VLDL, TG-VLDL and increases the concentration of apol I (ApoA-I), reduces the ratio of LDL-C / HDL-C, the total cholesterol / HDL-C and HDL-C / HDL, and the ratio Apo / Apo-I.

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

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

Rosuvastatin is effective in patients with type IIa and IIb hypercholesterolemia according to Fredrickson (the average initial concentration of LDL-C is about 4.8 mmol / l). In 80% of these patients receiving 10 mg of rosuvastatin, the concentration reaches the target values ​​of the level of LDL-C established by the European Community for the Study of Atherosclerosis - less than 3 mmol / l. In patients with heterozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 to 80 mg, a positive dynamics of the lipid profile was observed.

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 by 53% is noted. In 33% of patients, an LDL-C concentration of less than 3 mmol / L is achieved that meets the target guidelines of the European Atherosclerosis Study Guide.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 and 40 mg, the average decrease in LDL-C concentration is 22%. In patients with hypertriglyceridemia with an initial concentration of TG from 273 to 817 mg / dl, taking rosuvastatin 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.

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 HDL-C. In patients with a low risk of developing CHD (a 10-year risk on the Framingham scale is less than 10%), with an average concentration of LDL-C 4 mmol / l (154.5 mg / dl) and subclinical atherosclerosis, which was assessed by the thickness of the intima complex -Media "of the carotid arteries (TCIM), rosuvastatin at a dose of 40 mg / day significantly slowed the progression rate of maximum TCIM for 12 segments of the carotid artery compared with placebo with a difference of 0.0145 mm / year (95% confidence interval (CI): from 0.0196 to 0.0093 r

The study was conducted in patients with a low risk of coronary heart disease, for whom dose of 40 mg is not recommended. The dose of 40 mg should be given only to patients with severe hypercholesterolemia and at high risk of cardiovascular disease.

results of studies on the use of statins for primary prophylaxis have shown that rosuvastatin significantly reduced the risk of developing cardiovascular complications with a relative risk reduction of 44%.

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

Pharmacokinetics

Absorption and distribution of

Cmax of rosuvastatin in blood plasma is achieved 5 hours after ingestion. Absolute bioavailability is approximately 20%.

Metabolism

Rosuvastatin is metabolized primarily by the liver, which is the main site of cholesterol synthesis and metabolism of LDL-C. Vd of rosuvastatin is approximately 134 liters. About 90% of rosuvastatin binds to plasma proteins, mainly with albumin.

Undergoes limited metabolism (approximately 10%). Rosuvastatin is a rather non-core substrate for metabolism by isoenzymes of the cytochrome P450 system. CYP2C9 is the main isoenzyme involved in the metabolism of rosuvastatin, while the isoenzymes CYP2C19, CYP3A4 and CYP2D6 are less involved in the metabolism. The main identified metabolites of rosuvastatin are N-desmethylrosuvastatin, which is 50% less active than rosuvastatin, and lactone metabolites, which are pharmacologically inactive. More than 90% of the pharmacological activity in inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolite.

Excretion

Approximately 90% of the administered dose of rosuvastatin is excreted unchanged through the intestines (including absorbed and unabsorbed rosuvastatin), the remainder is excreted by the kidneys. T1 / 2 is approximately 19 hours, does not change with increasing dose. The geometric mean plasma clearance is approximately 50 l / h (coefficient of variation - 21.7%). As with 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. Changes in pharmacokinetic parameters when taking the drug several times a day are not observed.

Special Groups

Age and Gender. Do not have a clinically significant effect on the pharmacokinetic parameters of rosuvastatin.

Ethnic groups. Comparative pharmacokinetic studies showed an approximately twofold increase in the mean plasma AUC and Tmax values ​​in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with those in the Caucasian race. Indians showed an increase in the average values ​​of AUC and Tmax by about 1.3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among representatives of the Caucasian and Negroid races.

Renal failure. In patients with mild to moderate renal failure, the plasma concentration of rosuvastatin or N-desmethylrosuvastatin does not change significantly. In patients with severe renal failure (Cl creatinine

Hepatic insufficiency. In patients with various stages of liver failure with 7 points and lower on the Child Pugh scale, no increase in T1 / 2 of rosuvastatin was detected. However, in 2 patients with 8 and 9 points on the Child scale -Pyu showed a 2-fold increase in T1 / 2. There is no experience with rosuvastatin in patients with more than 9 Child-Pugh scores

Genetic polymorphism. HMG-CoA reductase inhibitors, including Rosistark®, bind with transport proteins Oh ATP1B1 (a transport polypeptide of organic anions involved in the capture of statins by hepatocytes) and BCRP (efflux transporter). Carriers of genotypes SLCO1B1 (OATP1B1) s.521CC and ABCG2 (BCRP) s.421AA showed an increase in exposure (AUC) to rosuvastatin 1.6 and 2.4 times, respectively, compared with carriers of genotypes SLCO1B1 c.521TT and ABCG2 c.421CC .

Indications

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 the diet and other medication are not enough (for example, physical therapy is not enough)

familial homozygous hypercholesterolemia as a supplement to diet and other lipid lowering therapy (e.g. LDL apheresis) or in cases when such therapy is not effective enough

hypertriglyceridemia (Fredrickson type IV) as an adjunct to the

diet to slow the progression of atherosclerosis as an adjunct to diet in patients who are shown therapy to reduce the concentration of total cholesterol and LDL cholesterol

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 older than 50 years For men and over 60 years of age for women, an increased concentration of C-reactive protein ( 2 mg / L) in the presence of at least one of the additional risk factors, such as arterial hypertension, low concentration of HDL-C, smoking, a family history of early development coronary heart disease).

Contraindications

hypersensitivity to rosuvastatin or any of the components of the drug

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 (Cl

myopathy

co-administration of cyclosporine

predisposition to the development of myotoxic complications

pregnancy

breastfeeding

detor projectile loader age in women not using reliable contraception

increase blood concentrations of CK more than 5 times compared with FHG

combined use with HIV protease inhibitors

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

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

Use during pregnancy and lactation

RosistarkВ® is contraindicated in pregnancy and during breastfeeding.

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

Since cholesterol and other cholesterol biosynthesis products are of great importance for the development of the fetus, the potential risk of inhibiting HMG-CoA reductase exceeds the benefits of using the drug in pregnant women.

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

There are no data on the excretion of rosuvastatin with breast milk, so you should stop taking the drug during breastfeeding.

Composition

1 tablet contains:

Active ingredient:

rosuvastatin 10 mg

Excipients:

lactose monohydrate

MCC

crospovidone

magnesium stearate

film sheath:

lactose monohydrate

hypromellose

titanium dioxide

triacetin

x.

Dosage and administration

Inside, do not chew or grind the tablet, swallow whole, washed down with water. The drug can be used at any time of the day, regardless of food intake.

Before starting treatment, the patient should start a diet with low cholesterol products, which must be continued during the entire treatment period. 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 generally accepted recommendations for target lipid concentrations.

If you need to take the drug in a dose of 5 mg, you can use the drug rosuvastatin in another dosage form or dosage, for example, 5 mg tablets or 10 mg tablets with risk (10 mg tablet should be divided into two at risk). The recommended initial dose of the drug is 5 or 10 mg once a day, both for patients who have not previously taken statins, and for patients transferred to receive this drug after treatment with other HMG-CoA reductase inhibitors. When choosing an initial dose, the level of cholesterol in each individual patient should be taken into account and the possible risk of cardiovascular complications should be taken into account, as well as the potential risk of side effects. If necessary, after 4 weeks the dose may be increased.

Due to the possible development of side effects when taking a dose of 40 mg (see "Side effects"), increasing the dose to 40 mg, after an additional dose is higher than the recommended initial dose for 4 weeks of therapy, can only be carried out under the supervision of a doctor in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with hereditary hypercholesterolemia), in which, when taking a dose of 20 mg, the desired result of therapy was not achieved (see. "Special instructions"). When assigning a dose of 40 mg, careful monitoring of the patient 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, monitoring of lipid metabolism is necessary, if necessary, the dose should be adjusted.

The dose of the drug should be adjusted if necessary, its combined use with drugs that increase the exposure of rosuvastatin. If an increase in exposure of 2 times or more is expected, the initial dose of the drug should be 5 mg 1 time per day. You should also adjust the maximum daily dose of the drug so that the expected exposure of rosuvastatin does not exceed that for a dose of 40 mg taken without the simultaneous administration of drugs that interact with rosuvastatin (see “Interaction”, table 1).

Special patient groups

Elderly patients. No dose adjustment required.

Patients with renal failure. For patients with mild or moderate renal failure, dose adjustment is not required. Patients with severe renal failure (Cl creatinine

Patients with liver failure. The drug is contraindicated in patients with active liver disease (see "Contraindications").

Ethnic groups. Patients of the Mongoloid race may increase the systemic concentration of rosuvastatin. This fact should be considered when prescribing the drug to these groups of patients.When prescribing doses of 10 and 20 mg, the recommended initial dose of the drug for patients of the Mongoloid race is 5 mg. 40 mg is contraindicated in such patients (see "Contraindications").

Genetic polymorphism. In carriers of the SLCO1B1 (OATP1B1) p.521CC and ABCG2 (BCRP) p.421AA genotypes, an increase in exposure (AUC) to rosuvastatin was noted compared with the genotype carriers SLCO1B1 C.521TT and ABCG2 C.421CC. For patients carriers of s.521SS or s.421AA genotypes, the recommended maximum dose of Rosistark® is 20 mg once a day (see “Pharmacokinetics”, “Special Instructions” and “Interaction”).

Patients predisposed to myopathy. When prescribing doses of 10 and 20 mg, the recommended initial dose of the drug for patients with a predisposition to myopathy is 5 mg. The use of the drug in a dose of 40 mg in such patients is contraindicated.

Concomitant therapy. Rosuvastatin binds to various transport proteins, in particular OATP1B1 and BCRP. With the combined use of the drug Rosistark® with drugs (such as cyclosporine, some HIV protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and / or tipranavir), increasing the concentration of rosuvastatin in plasma due to interaction with transport proteins, the risk of myopathy, including rhabdomyolysis, may increase (see "Special Instructions" and "Interaction"). In such cases, the possibility of prescribing alternative therapy or temporarily discontinuing the drug Rosistark® should be assessed. If the use of the above drugs is necessary, you should evaluate the ratio of the benefit and risk of concomitant therapy with Rosistark® and consider the possibility of reducing its dose (see “Interaction”).

Side effects

From the skin: infrequently - itching, rash, urticaria.

From the digestive tract: often - constipation, nausea, abdominal pain rarely - pancreatitis.

From the side of the central nervous system: often - headache, dizziness very rarely - polyneuropathy, memory loss.

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

From the endocrine system: often type 2 diabetes mellitus.

Other: often - asthenic syndrome of unspecified frequency - peripheral edema.

From the side of the musculoskeletal system: often - myalgia rarely - myopathy (including myositis), rhabdomyolysis of unspecified frequency - immuno-mediated necrotizing myopathy.

From the urinary system: when taking rosuvastatin, proteinuria may be observed. Changes in the protein content in the urine (from the absence or presence of trace amounts to the level of ++ and above) are observed in less than 1% of patients taking rosuvastatin at a dose of 10 and 20 mg, and in about 3% of patients taking the drug at a dose of 40 mg.

From the liver: with the use of rosuvastatin, a dose-dependent increase in the activity of hepatic transaminases is observed in a small number of patients. In most cases, this increase is insignificant, asymptomatic and temporary.

Laboratory indicators: when using rosuvastatin, the following changes in laboratory parameters were observed: an increase in the concentration of glucose, bilirubin, the activity of GGT, alkaline phosphatase, dysfunction of the thyroid gland.

From the hemopoietic system: unspecified frequency - thrombocytopenia.

From the respiratory system: unspecified frequency - cough, shortness of breath.

From the reproductive system and breast: unspecified frequency - gynecomastia.

Drug interaction

Effect of other drugs on rosuvastatin

Transport protein inhibitors: rosuvastatin binds to some transport proteins, in particular OATP1B1 and BCRP. The concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in the plasma concentration of rosuvastatin and an increased risk of myopathy (see Table 1, Methods and Doses and Special Instructions).

Cyclosporine: with the concomitant use of rosuvastatin and cyclosporine, the AUC of rosuvastatin increased 7-fold compared with values ​​obtained from healthy volunteers (see “Contraindications”). Co-administration results in an 11-fold increase in the concentration of rosuvastatin in blood plasma. Concomitant use of drugs does not affect the concentration of cyclosporine in blood plasma.

Ezetimibe: no changes in the AUC or Cmax of both drugs were observed with rosuvastatin and ezetimibe. However, the risk of side effects due to the pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be ruled out.

Gemfibrozil and other hypolipidemic agents: the concomitant use of rosuvastatin and gemfibrozil results in a 2-fold increase in the Cmax and AUC of rosuvastatin (see “Special Instructions”). Based on specific interaction studies, no pharmacokinetically significant interaction with fenofibrate is expected, but pharmacodynamic interaction is possible.

Gemfibrozil, fenofibrate, other fibrates and nicotinic acid in lipid-lowering doses (1 g / day or more) with concomitant use with HMG-CoA reductase inhibitors increased the risk of myopathy, possibly due to the fact that they can cause myopathy even when used as monotherapy. Concomitant administration of 40 mg of rosuvastatin and fibrates is contraindicated (see “Special instructions” and “Contraindications”). When co-administered with gemfibrozil and other lipid-lowering agents at a dose of more than 1 g / day, the initial dose of Rosistark® should not exceed 5 mg.

HIV protease inhibitors: Although the exact mechanism of interaction is unknown, co-administration of rosuvastatin with HIV protease inhibitors can lead to a significant increase in rosuvastatin exposure.

In a pharmacokinetic study, 20 mg rosuvastatin and combination drug were co-administered, containing two HIV protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers increased 2-fold AUC0-24 and 5-fold Cmax of rosuvastatin. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors in the treatment of HIV patients is not recommended.

Antacids: Co-administration of rosuvastatin and suspensions of antacids containing aluminum or magnesium hydroxide can reduce the plasma concentration of rosuvastatin by about 50%. This action is less pronounced if antacids are administered 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin: Co-administration of rosuvastatin and erythromycin may result in a 20% decrease in AUC0-trozuvastatin and 30% reduction of rosuvastatin Cmax. This interaction can be caused by increased intestinal motility due to the intake of erythromycin.

Cytochrome P450 isoenzymes: results from in vitro and in vivo studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak enough substrate for these isoenzymes. No clinically relevant interaction was detected between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor). Co-administration of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases rosuvastatin AUC by 28% (clinically relevant).

Colchicine: cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of ing conditioned by the administration of erythromycin.

Cytochrome P450 isoenzymes: results from in vitro and in vivo studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak enough substrate for these isoenzymes. No clinically relevant interaction was detected between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor). Co-administration of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases rosuvastatin AUC by 28% (clinically relevant).

Colchicine: cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of ing conditioned by the administration of erythromycin.

Cytochrome P450 isoenzymes: results from in vitro and in vivo studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak enough substrate for these isoenzymes. No clinically relevant interaction was detected between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor). Co-administration of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases rosuvastatin AUC by 28% (clinically relevant).

Colchicine: cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of ing that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak enough substrate for these isoenzymes. No clinically relevant interaction was detected between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor). Co-administration of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases rosuvastatin AUC by 28% (clinically relevant).

Colchicine: cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of ing that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak enough substrate for these isoenzymes. No clinically relevant interaction was detected between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor). Co-administration of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases rosuvastatin AUC by 28% (clinically relevant).

Colchicine: cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of ing No clinically relevant interaction was detected between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor). Co-administration of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases rosuvastatin AUC by 28% (clinically relevant).

Colchicine: cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of ing No clinically relevant interaction was detected between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor). Co-administration of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases rosuvastatin AUC by 28% (clinically relevant).

Colchicine: cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of ingHMG-CoA reductase inhibitors, including rosuvastatin, and colchicine.

Effects of rosuvastatin on other drugs (INR). Cancellation of rosuvastatin or dose reduction may cause a decrease in INR. In such cases, the MNO should be monitored.

Oral contraceptives / hormone replacement therapy: co-administration of rosuvastatin and oral contraceptives may increase the AUC of ethinyl estradiol and norgestrel by 26 and 34%, respectively. This increase in plasma concentration should be considered when choosing a dose of oral contraceptives. There are no pharmacokinetic data on the concomitant use of rosuvastatin and hormone replacement therapy, so a similar effect on this combination cannot be ruled out. However, such a combination of drugs was widely used in clinical trials and was well tolerated by patients.

Other drugs: no clinically relevant interaction is expected when rosuvastatin and digoxin are co-administered.

Storage conditions

At room temperature not exceeding 25 ° C.

shelf life

3 years

Active ingredient

Rosuvastatin

dosage form

tablets

Possible product names

rosistark tablets 10 mg 28 pcs.

Belupo, medicines and cosmetics d.d, Croatia



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