Rosistarck, 10 mg 28 pcs.

Hypolipidemic drug from the group of statins. Selective competitive inhibitor of HMG-CoA reductase – an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, which is a precursor of cholesterol. The main target of rosuvastatin action is the liver, where cholesterol (Chs) synthesis and LDL catabolism take place.

Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, increasing the capture and catabolism of LDL, which leads to the inhibition of LDL synthesis, thereby reducing the total amount of LDL and LDL.

. Rosuvastatin reduces elevated levels of CHDL, total cholesterol and triglycerides (TG), increases the concentration of HDL, and decreases apolipoprotein B (ApoB) concentrations, Chs-non-LDL, Chs-LDL, TG-LDL and increases the concentration of apolipoprotein A-I (ApoA-I), decreases the ratio of Chs-LDL/Hs-LDL, total Chs/Hs-LDL and Chs-non-LDL/Hs-LDL and the apoB/ApoA-I ratio.

Therapeutic effect develops within 1 week after the start of therapy with the drug, after 2 weeks of treatment it reaches 90% of the maximum possible effect. Maximum therapeutic effect is usually reached 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, sex or age as well as in treatment of patients with diabetes mellitus and hereditary form of familial hypercholesterolemia.

The drug is effective in patients with Fredrickson type IIa and IIb hypercholesterolemia (mean baseline concentration of hs-LDL about 4.8 mmol/L). In 80% of these patients who received 10 mg of rosuvastatin, the concentration reaches the target values of CHDL levels set by the European Society for Atherosclerosis Research – less than 3 mmol/l. In patients with heterozygous familial hypercholesterolemia who took rosuvastatin in doses from 20 to 80 mg, positive dynamics of lipid profile parameters were observed.

As a result of titration of doses to a daily dose of 40 mg (12 weeks of therapy) there is a 53% decrease in concentration of LDL-C. In 33% of patients reached concentration of HDL-C less than 3 mmol/l, corresponding to the target standards of the European Community guidelines for atherosclerosis research.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 and 40 mg, the average decrease in concentration of hs-LDL is 22%. Patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg/dL who took rosuvastatin in doses of 5 mg to 40 mg once daily for 6 weeks had a significant decrease in plasma TG concentration.

Additive effect is noted in combination with fenofibrate for TG content and with nicotinic acid (more than 1 g/day) for HDL-C content. In patients with a low risk of CHD (10-year Framingham scale risk less than 10%), with a mean concentration of hs-LDL of 4 mmol/L (154.5 mg/dL) and subclinical atherosclerosis, as assessed by carotid intima-media complex (CTIM) thickness, rosuvastatin at a dose of 40 mg/day significantly slowed the rate of progression of maximum CTIM for 12 carotid segments compared with placebo with a difference of -0.0145 mm/yr (95% confidence interval (CI): -0.0196 to -0.0093; p < 0.001). The study was conducted in patients at low risk of CHD for whom the 40 mg dose is not recommended. The 40 mg dose should only be administered to patients with significant hypercholesterolemia and high risk of cardiovascular disease.

The results of a study on the use of statins for primary prevention 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 using the drug. There was a statistically significant 48% reduction in the combined criterion including cardiovascular death, stroke and myocardial infarction, a 54% reduction in the incidence of fatal or non-fatal myocardial infarction and a 48% reduction in the incidence of fatal or non-fatal stroke. Overall mortality was reduced by 20% in the rosuvastatin group. The safety profile in patients taking rosuvastatin at a dose of 20 mg was similar to that of the placebo group.

Pharmacokinetics

Intake and distribution

Cmax of rosuvastatin in plasma is reached 5 h after oral administration. Absolute bioavailability is approximately 20%.

The Vd of rosuvastatin is approximately 134 l. About 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Rosuvastatin is absorbed primarily by the liver, which is the main site of Xs synthesis and metabolism of Xs-LDL.

The systemic exposure of rosuvastatin increases in proportion to the dose. No changes in pharmacokinetic parameters are observed when taking the drug several times a day.

Metabolism

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

Pharmacokinetics in special clinical cases

In patients with mild to moderate renal failure, plasma concentrations of rosuvastatin or N-dismethyl-rosuvastatin do not change significantly. In patients with severe renal failure (CKR < 30 ml/min) plasma concentrations of rosuvastatin are 3 times higher and concentrations of N-dismethyl-rosuvastatin are 9 times higher compared to healthy volunteers. Plasma concentrations of rosuvastatin were approximately 50% higher in patients on hemodialysis than in healthy volunteers.

In patients with various stages of hepatic failure (7 points or lower on the Child-Pugh scale) no increase in T1/2 of rosuvastatin was found. However, in 2 patients (8 and 9 points by Child-Pugh score) there was observed increase of T1/2 approximately by 2 times. There is no experience of using rosuvastatin in patients with a Child-Pugh score of more than 9.

Gender and age have no clinically significant effect on the pharmacokinetic parameters of rosuvastatin.

Paramacokinetic comparative studies have shown approximately a two-fold increase in mean AUC and Tmax values in patients of mongoloid race (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared to those of Caucasoid race. In Hindus, there was an increase in mean AUC and Tmax of approximately 1.3-fold. Pharmacokinetic analysis showed no clinically significant differences in pharmacokinetics between Caucasoid and non-Hispanic races.

Indications

Active ingredient

Composition

1 tablet contains:

Active substance:

rosuvastatin 10 mg;

Associated substances:

lactose monohydrate;

MCC;

Crospovidone;

Magnesium stearate;

Capsule film:

lactose monohydrate;

hypromellose;

titanium dioxide;

triacetin;

quinoline yellow.

How to take, the dosage

To the mouth, do not chew or crush the tablet, swallow it whole with water. The drug can be used at any time of the day regardless of meals.

Before starting treatment, patients should begin a diet with low-cholesterol products, which should be continued for the duration of treatment. The dose of the drug should be adjusted 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 a dose of 5 mg is necessary, rosuvastatin may be used in another dosage form or dosage form, such as 5 mg tablets or 10 mg tablets with a rice (the 10 mg tablet should be divided into two parts by rice). The recommended starting dose of the drug is 5 or 10 mg once daily both for patients who have not taken statins before and for patients transferred to this drug after therapy with other HMG-CoA reductase inhibitors. When choosing the initial dose, the level of cholesterol in each individual patient should be considered and the possible risk of cardiovascular complications should be taken into account, as well as the potential risk of side effects. If necessary, the dose can be increased after 4 weeks.

With regard to the possible development of side effects when taking a dose of 40 mg (see “Side Effects”). “Side effects”), increasing the dose to 40 mg, after an additional dose above the recommended initial dose for 4 weeks of therapy, may only be done under medical supervision in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with hereditary hypercholesterolemia), in whom the desired result of therapy was not achieved when taking the 20 mg dose (see “Cautionary Note”). When prescribing a dose of 40 mg, close monitoring of the patient is recommended. It is not recommended to prescribe the 40 mg dose to patients who have not previously consulted a physician.

After 2-4 weeks of therapy and/or when increasing the dose of the drug, lipid metabolism parameters should be monitored; if necessary, the dose should be adjusted.

The dose of the drug should be adjusted if it is necessary to combine it with drugs that increase exposure to rosuvastatin. If an increase in exposure by 2-fold or more is expected, the starting dose of the drug should be 5 mg once daily. The maximum daily dose should also be adjusted so that the expected exposure to rosuvastatin does not exceed that of a 40 mg dose taken without concomitant administration of drugs that interact with rosuvastatin (see “Interactions”, Table 1).

Patient special groups

Elderly patients. No dose adjustment is required.

Patients with renal impairment. Patients with mild to moderate renal impairment do not require dosage adjustment. Patients with severe renal failure (creatinine Cl

Patients with hepatic failure. The drug is contraindicated in patients with liver disease in the active phase (see “Contraindications”).

Ethnic groups. Increased systemic concentration of rosuvastatin is possible in patients of mongoloid race. This fact should be considered when prescribing the drug in these groups of patients. In administration of 10 and 20 mg doses the recommended initial dose of this medicine for Mongoloid patients is 5 mg. The use of the drug in a dose of 40 mg is contraindicated in these patients (see “Contraindications”).

Genetic polymorphism. Carriers of SLCO1B1 (OATP1B1) p.521CC and ABCG2 (BCRP) p.421AA had increased exposure (AUC) to rosuvastatin compared to carriers of SLCO1B1 C.521TT and ABCG2 C.421CC genotypes. For patients who are carriers of c.521CC or c.421AA genotypes the recommended maximum dose of Rosistar® is 20 mg once daily (see “Pharmacokinetics”, “Special Precautions” and “Interactions”).

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

Companion therapy. Rosuvastatin binds to various transport proteins, particularly to OATP1B1 and BCRP. Co-administration of Rosistark® with drugs (such as cyclosporine, some HIV protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase the plasma concentration of rosuvastatin through interaction with transport proteins may increase the risk of myopathy, including rhabdomyolysis (see “Cautions” and “Interactions”). In such cases, the possibility of alternative therapy or temporary discontinuation of Rosistarco® should be assessed. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with Rosistarca® should be assessed and the possibility of reducing its dose should be considered (see “Interactions).

Interaction

The effect of the use of other drugs on rosuvastatin

Transport protein inhibitors: Rosuvastatin binds to some transport proteins, in particular to OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see Table 1, “Administration and Doses” and “Special Precautions”).

Cyclosporine: Concomitant use of rosuvastatin and cyclosporine increased AUC of rosuvastatin 7-fold compared to values obtained in healthy volunteers (see “Contraindications”). Concomitant use leads to an 11-fold increase in plasma concentrations of rosuvastatin. Concomitant use of the drugs has no effect on the plasma concentration of cyclosporine.

Ezetimibe: in concomitant use of rosuvastatin and ezetimibe no changes in AUC orCmax of both drugs are observed. However, the risk of side effects due to pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded.

Gemfibrozil and other hypolipidemic agents: concomitant use of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax and AUC of rosuvastatin (see “Special Precautions”). Based on specific interaction studies, no pharmacokinetic interaction with fenofibrate is expected; however, pharmacodynamic interaction is possible.

Hemfibrozil, fenofibrate, other fibrates and nicotinic acid at lipid-lowering doses (1 g/day or more) when used concomitantly with HMG-CoA reductase inhibitors increased the risk of myopathy, possibly due to the fact that they can also cause myopathy when used as monotherapy. Simultaneous use of 40 mg of rosuvastatin and fibrates is contraindicated (see “Special Precautions” and “Contraindications”). When concomitant use of the drug with gemfibrozil and other lipid-lowering drugs at a dose of more than 1 g/day the initial dose of Rosistar® should not exceed 5 mg.

HIV protease inhibitors: although the exact mechanism of interaction is unknown, concomitant administration of rosuvastatin with HIV protease inhibitors may result in a significant increase in rosuvastatin exposure. In a pharmacokinetic study, concomitant administration of 20 mg of rosuvastatin and a combination drug containing two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers showed a 2-fold increase in AUC0-24 and 5-fold increase in Cmax of rosuvastatin. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors in patients with HIV is not recommended.

Antacids: Concomitant administration of rosuvastatin and suspensions of antacids containing aluminum or magnesium hydroxide may lead to a decrease in plasma concentrations of rosuvastatin by about 50%. This effect is weaker if antacids are used 2 h after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Eritromycin: Concomitant administration of rosuvastatin and erythromycin may decrease AUC0-trosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may be due to increased intestinal motility caused by taking erythromycin.

Cytochrome P450 isoenzymes: the results of 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 rather weak substrate for these isoenzymes. No clinically significant interaction between rosuvastatin and fluconazole (inhibitor of CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (inhibitor of CYP2A6 and CYP3A4 isoenzymes) was found. Concomitant use of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases AUC of rosuvastatin by 28% (clinically significant).

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

The effect of rosuvastatin on other drugs

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, starting therapy with rosuvastatin or increasing the dose of the drug in patients receiving indirect anticoagulants (such as warfarin or other coumarin anticoagulants) at the same time may lead to an increase in the INR. Discontinuation of rosuvastatin or reduction of the dose may cause a decrease in INR. INR should be monitored in such cases.

Peroral contraceptives/ hormone replacement therapy: Concomitant administration of rosuvastatin and oral contraceptives may increase AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. This increase in plasma concentration should be considered when choosing a dose of oral contraceptives. Pharmacokinetic data on concomitant use of rosuvastatin and hormone replacement therapy are not available, so a similar effect when using this combination cannot be excluded. However, this combination of drugs has been widely used in clinical trials and is well tolerated by patients.

Other drugs: No clinically significant interaction is expected with concomitant use of rosuvastatin and digoxin.

Special Instructions

Renal effects. Proteinuria, predominantly of tubular origin, has been observed in patients taking high doses of rosuvastatin, especially 40 mg, which in most cases was intermittent or transient. Such proteinuria does not indicate the occurrence of acute or progressive renal disease. The incidence of serious renal dysfunction is increased when taking 40 mg rosuvastatin. In these patients it is recommended to monitor renal function parameters during treatment with Rosistarcoe®.

Motor system disorders. Myalgia, myopathy and, in rare cases, rhabdomyolysis have been observed with Rosistarq® at all doses, and particularly with doses greater than 20 mg.

Determination of CPK activity. The study should not be performed after intense physical activity or if there are other possible causes of increased CPK activity, which may lead to misinterpretation of the results. If the baseline CPK level is significantly elevated (more than 5 times the IGN), repeat the measurement after 5-7 days. Therapy should not be initiated if a repeat measurement confirms the baseline CPK level (5-fold higher than IGN).

Pre-therapy. Rosistarca®, like other HMG-CoA reductase inhibitors, should be administered with caution in patients with existing risk factors for myopathy/rhabdomyolysis.

In these patients the risk/benefit ratio of therapy should be evaluated and clinical monitoring should be performed throughout the course of treatment.

At the time of therapy. Patients should be advised to promptly inform the physician about the unexpected onset of muscle pain, muscle weakness, or cramps, especially if associated with malaise or fever. In such patients, monitoring of CPK activity should always be performed. Treatment should be discontinued if CPK activity is more than 5 times the ULN or muscle symptoms are severe and cause daily discomfort, even if CPK activity is 5 times less than ULN. If symptoms disappear and CPK activity returns to normal, re-prescription of Rosistarco® or other HMG-CoA reductase inhibitors at lower doses should be considered with close monitoring of the patient. Regular monitoring of CPK activity in the absence of symptoms is unnecessary.

There have been very rare cases of immune-mediated necrotizing myopathy with clinical manifestations as persistent proximal muscle weakness and elevated serum CPK levels during treatment or upon discontinuation of statins, including rosuvastatin. Additional muscular and nervous system studies, serologic studies, and therapy with immunosuppressive agents may be necessary.

There have been no indications of increased skeletal muscle effects with rosuvastatin and concomitant therapy. However, an increase in myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors together with fibrin acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, antifungal drugs, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when co-administered with some HMG-CoA reductase inhibitors. Therefore, concomitant administration of rosuvastatin and gemfibrozil is not recommended. The risk/benefit ratio of co-administration of rosuvastatin with fibrates or nicotinic acid in lipid-lowering doses (more than 1 g/day) should be carefully evaluated.

The concomitant use of 40 mg rosuvastatin and fibrates is contraindicated (see “Interactions” and “Adverse effects”). Lipid metabolism parameters should be controlled 2-4 weeks after the treatment start and/or in case of Rosistar® dose increase; if necessary the dose adjustment is required.

The drug should not be administered in patients with acute, severe diseases suggestive of myopathy or possible development of secondary renal failure (e.g. sepsis, arterial hypertension, surgery, trauma, metabolic syndrome, seizures, endocrine disorders, water and electrolyte disorders) (see “Contraindications”, “With caution”).

The liver. Like other HMG-CoA reductase inhibitors, Rosistar® should be prescribed with special caution in patients who abuse alcohol or have a history of liver disease. It is recommended to determine liver function parameters before the start of therapy and 3 months after the start of therapy. If serum hepatic transaminase activity is 3 times higher than BHN, discontinue Rosistar® or decrease the drug dose (see “Dosage and administration”).

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome therapy of the underlying disease should be performed before starting treatment with rosuvastatin.

Ethnic groups. Pharmacokinetic studies have shown increased systemic concentrations of rosuvastatin in patients of Chinese and Japanese origin compared to those in patients of Caucasian race (see Administration and Doses and Pharmacokinetics).

HIV protease inhibitors. Concomitant use of rosuvastatin with HIV protease inhibitors is not recommended (see “Interaction”).

Lactose. Do not use the drug in patients with lactase deficiency, galactose intolerance and glucose-galactose malabsorption.

Interstitial lung disease. Single cases of interstitial lung disease have been reported with some statins, especially for long periods of time. Manifestations of the disease may include dyspnea, dry cough, and worsening of general well-being (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus type 2. In patients with glucose concentrations between 5.6 and 6.9 mmol/L, use of rosuvastatin leads to an increased risk of developing type 2 diabetes mellitus.

Impact on the ability to operate vehicles and mechanisms. Studies on the effect of rosuvastatin on the ability to drive vehicles and mechanisms have not been conducted. On the basis of pharmacodynamic properties of the drug it can be assumed that rosuvastatin should have no such effect, however it should be taken into account that dizziness may occur during treatment.

Contraindications

Side effects

Skin disorders: infrequent – skin itching, rash, urticaria.

Gastrointestinal tract: often – constipation, nausea, abdominal pain; rarely – pancreatitis.

CNS disorders: often – headache, dizziness; very rare – polyneuropathy, memory loss.

The immune system: rare – hypersensitivity, including angioedema.

Endocrine system: often – diabetes mellitus type 2.

Others: frequent – asthenic syndrome; unspecified frequency – peripheral edema.

Musculoskeletal system: common – myalgia; rare – myopathy (including myositis), rhabdomyolysis; unspecified frequency – immune-mediated necrotizing myopathy.

Urinary system disorders: proteinuria may be observed when taking rosuvastatin. Changes in protein content in urine (from the absence or presence of trace amounts to levels ++ and higher) are observed in less than 1% of patients taking rosuvastatin in doses of 10 and 20 mg and in about 3% of patients taking the drug in dose 40 mg.

Hepatic disorders: when using rosuvastatin, a dose-dependent increase in hepatic transaminase activity has been observed in a small number of patients. In most cases this increase is insignificant, asymptomatic and temporary.

Laboratory parameters: the following changes in laboratory parameters have been observed with rosuvastatin: increased concentration of glucose, bilirubin, GGT activity, ALF, thyroid dysfunction.

Hematopoietic system: unspecified frequency – thrombocytopenia.

Respiratory system: unspecified frequency – cough, shortness of breath.

Reproductive system and breast: unspecified frequency – gynecomastia.

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