Rosuvastatin-SZ, 20 mg 60 pcs

Pharmacodynamics

Mechanism of action

. Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the enzyme that converts Z-hydroxy-Z-methylglugaryl coenzyme A to mevalonic acid, a precursor of cholchterol. The main target of rosuvastatin action is the liver, where cholesterol (cholesterol) synthesis and low-density lipoprotein (LDL) catabolism take place.

Rosuvastatin increases the number of “hepatic” LDL receptors on the surface of cells, increasing the capture and catabolism of LDL, which in turn leads to inhibition of synthesis of very low density lipoproteins (VLDL), thereby reducing the total amount of LDL and VLDL.

Pharmacodynamics

Rosuvastatin-CZ reduces elevated concentrations of LDL cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases concentrations of high-density lipoprotein cholesterol (HDL-C) and decreases concentrations of apolipoprotein B (ApoB), non-LDL-C, HDL-C, TG-LDL-C and increases the concentration of apolipoprotein A-1 (ApoA-1), reduces the ratio of HDL-C/HD-LDL, total HC/HDL and non-HDL-C/HD-LDL and the apoB/apoA-1 ratio.

Therapeutic effect is developed within 1 week after the start of therapy with Rosuvastatin-CS, after 2 weeks of treatment reaches 90% of the maximum possible effect. Maximum therapeutic effect is usually reached 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, sex or age, including patients with diabetes mellitus and familial hypercholesterolemia.

In 80% of patients with hypercholesterolemia of type HA and Hb according to Fredrickson (mean baseline concentration of LDL-C about 4.8 mmol/L) with the use of the drug in dose of 10 mg LDL-C concentration reaches values less than 3 mmol/L.

In patients with heterozygous familial hypercholesterolemia receiving Rosuvastatin-CS at a dose of 20-80 mg, positive dynamics of lipid profile parameters are observed. After titration to a daily dose of 40 mg (12 weeks of therapy), there is a decrease in LDL-C concentration by 53%. In 33% of patients the concentration of LDL-C is less than 3 mmol/l.

In patients with homozygous familial hypercholesterolemia receiving Rosuvastatin-CS in doses of 20 mg and 40 mg the mean decrease of LDL-C concentration is 22%.

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg/dp who received Rosuvastatin-SZ in doses of 5 mg to 40 mg once daily for 6 weeks, plasma TG concentrations were significantly reduced.

Additive effect is noted in combination with fenofibrate with regard to triglycerides and with nicotinic acid in lipid-lowering doses with regard to HDL-C (see also section “Special indications”).

Based on the results of clinical studies, patients with significant hypercholesterolemia and high risk of cardiovascular disease (CVD) should be prescribed the dose of Rosuvastatin-CZ 40 mg.

The results of a clinical study (Rationale for Statins in Primary Prevention: An Interventional Study to Evaluate Rosuvastatin) showed that Rosuvastatin significantly reduced the risk of cardiovascular complications. Pharmacokinetics Absorption and distribution

Maximum plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. 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 l. About 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by enzymes of cytochrome P450 system. The main isoenzyme involved in metabolism of rosuvastatin is CYP2C9 isoenzyme. CYP2C19, CYP3A4 and CYP2D6 isoenzymes are less involved in metabolism.

The main identified metabolites of rosuvastatin are N-desmethylrosuvastagin and lactone metabolites. N-desmethylrosuvastatin is about 50% less active than rosuvastatin, lactone metabolites 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.

The elimination half-life does not change with increasing drug dose. The geometric mean plasma clearance is approximately 50 L/hour (coefficient of variation 21.7%). As in the case of other HMG-CoA reductase inhibitors, the membrane cholesterol transporter, which plays an important role in hepatic elimination of rosuvastatin, is involved in the “hepatic” uptake of rosuvastatin.

Linearity

The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily administration.

Particular patient populations.

Age and sex

Percentage and age have no clinically significant effect on the pharmacokinetics of rosuvastatin. Ethnic groups

Pharmacokinetic studies have shown approximately two-fold increase in median AUC (area under the curve “concentration-time”) and Stakh (maximum concentration in blood plasma) of rosuvastatin in patients of Mongoloid race (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared to Caucasoid; in Hindus a median AUC and Stakh increase by 1.3 times was shown. Pharmacokinetic analysis showed no clinically significant differences in pharmacokinetics among Caucasians and non-Hispanics.

Renal failure

In patients with mild to moderately severe renal failure, plasma concentrations of rosuvastatin or N-desmethylrosuvastatin do not change significantly. In patients with severe renal insufficiency (creatinine clearance (CK) less than 30 ml/min) the plasma concentration of rosuvastatin is 3 times higher, and N-desmethylrosuvastatin concentration is 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin were approximately 50% higher in patients on hemodialysis than in healthy volunteers.

Hepatic failure

In patients with various stages of hepatic failure, there was no increase in the half-life of rosuvastatin in patients with a Child-Pugh score of 7 or lower. Two patients with Child-Pugh scores 8 and 9 showed at least 2-fold increase in half-life. There is no experience with rosuvastatin in patients with more than a Child-Pugh score of 9.

Genetic polymorphisms

HMG-CoA reductase inhibitors, including rosuvastatin, bind to the transport proteins OATP1B1 (organic anion transport polypeptide involved in statin capture by hepatocytes) and BCRP (efflux transporter), In carriers of SLC01B1 (OATP1B1) genotypes C.521CC and ABCG2 (BCRP) with 421AA had 1.6 and 2.4-fold increased exposure (AUC) to rosuvastatin, respectively, compared with carriers of SLC01B1 C.521T and ABCG2 C.421CC genotypes.

Indications

• Fredrickson primary hypercholesterolemia (type H, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type Hb) as an adjunct to diet when diet and other non-medicinal treatments (e.g., exercise, weight loss) are insufficient,

• familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy

• Familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (e.g., LDL-apheresis), or in cases where such therapy is not sufficiently effective,

• Hypertriglyceridemia (Fredrickson type IV) as an adjunct to diet.

• To slow the progression of atherosclerosis as an adjunct to diet in patients who are indicated for therapy to reduce total cholesterol and LDL-C concentrations.

• Primary prevention of major cardiovascular complications (stroke, infarction, arterial revascularization) in adult patients without clinical signs of CHD, but with an increased risk of its development (age over 50 years for men and over 60 years for women, increased concentration of C-reactive protein (more than 2 mg/L) in the presence of at least one additional risk factor, such as hypertension, low HDL-C, smoking, family history of early-onset CHD).

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Active ingredient

Rosuvastatin

Composition

Active substance:

calcium rosuvastatin converted to rosuvastatin – 20 mg.

Excipients:

core – lactose monohydrate (milk sugar) – 67.6 mg; calcium hydrophosphate dihydrate – 20.0 mg; povidone (polyvinylpyrrolidone medium molecular) – 9.0 mg; sodium crharmellose (lrimellose) – 6.6 mg; sodium stearyl fumarate – 2.0 mg; colloidal silica (aerosil) – 0.8 mg; microcrystalline cellulose – 74.0 mg;

coating – Oladray II (polyvinyl alcohol, partially hydrolyzed – 2.64 mg; Macrogol (polyethylene glycol) 3350 – 0.741 mg; talc -1.2 mg; titanium dioxide E 171 – 1.1502 mg; soy lecithin E 322 – 0.21 mg; aluminum varnish based on indigo carmine dye – 0.0036 mg; aluminum varnish based on azorubin dye – 0.0306 mg; aluminum varnish based on crimson dye [Ponso 4R] – 0.0246 mg).

How to take, the dosage

Orally, do not chew or crush the tablet, swallow it whole by pouring water on it. The drug can be taken at any time of the day regardless of meals.

People should start a standard hypocholesterolemic diet before starting therapy with Rosavastatin-SZ and continue this diet during 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 recommendations for target lilidyl concentrations.

The recommended starting dose for patients starting to take the drug or switching from other HMG-CoA reductase inhibitors should be 5 mg or 10 mg of Rosuvastatin-CZ once daily. When choosing the initial dose, individual cholesterol content should be guided and possible risk of cardiovascular complications should be taken into account, as well as the potential risk of side effects should be assessed.

If necessary, the dose may be increased to a higher dose after 4 weeks (see section “Pharmacodynamics”).

Because of the possible development of side effects when taking a dose of 40 mg, compared to lower doses of the drug (see section “Side Effects”). Due to possible development of side effects of 40 mg dose compared to lower doses of the drug (see section “Side effects”), dose increase to 40 mg, after additional dosing above the recommended initial dose during 4 weeks of therapy, may be conducted only in patients with severe hypercholesterolemia and with high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia), in whom the desired therapy result was not reached while taking 20 mg dose, and who will be under specialist supervision (see section “Special indications”). We recommend especially close monitoring of patients receiving the drug in a dose of 40 mg.

The 40 mg dose is not recommended for patients who have not previously seen a physician. After 2-4 weeks of therapy and/or when increasing the dose of Rosuvastatin-SZ, lipid metabolism should be monitored (if necessary, a dose adjustment is required). Older patients No dose adjustment is required.

Patients with renal impairment

In patients with mild to moderate renal impairment, no dose adjustment is required. In patients with severe renal failure (CKD less than 30 ml/min) the use of Rosuvastatin-SZ is contraindicated. The use of the drug in dose of 40 mg is contraindicated in patients with moderate renal impairment (CK 30-60 ml/min) (see sections “Special indications” and “Pharmacodynamics”).

Patients with moderate renal dysfunction should receive a starting dose of 5 mg

Patients with hepatic impairment

Rosuvastatin-CS is contraindicated in patients with active hepatic disease (see “Contraindications. Contraindications),

Particular populations. Ethnic groups

When studying pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increased systemic concentration of rosuvastatin was noted among Japanese and Chinese (see section “Special indications”).

This fact should be considered when prescribing Rosuvastatin-SZ for these groups of patients When prescribing doses of 10 mg and 20 mg the recommended starting dose for patients of mongoloid race is 5 mg. A dose of 40 mg is contraindicated in patients of Mongoloid race (see “Contraindications”),

Hydetic polymorphism

In carriers of SLCOIBI (OATP1B1) genotype C.521CC and ABCG2 (BCRP) C.421AA had increased exposure (AUC) to rosuvastatin compared with SLCOIBI C.521TT and ABCG2 C.421CC genotypes carriers. For C.521CC or C.421AA genotype carriers the recommended maximum dose of Rosuvastatin-CZ is 20 mg once daily (see sections “Pharmacokinetics”, “Precautions” and “Interaction with other medicinal products”).

Patients with predisposition to myopathy

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

Companion therapy

Rosuvastatin binds to various transport proteins (in particular to OATP1B1 and BCRP). When co-administration of Rosuvastatin-CZ 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, the risk of myopathy (including rhabdomyolysis) may increase (see sections “Precautions” and “Interaction with other medicinal products”).

In such cases, alternative therapy or temporary discontinuation of Rosuvastatin-CZ should be evaluated. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with Rosuvastatin-SZ should be assessed and the possibility of reducing its dose should be considered (see section “Interaction with other medicinal products”).

Interaction

Effect of other drugs on rosuvastatin

Inhibitors of transport proteins:

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.

Cyclosporine: concomitant use of rosuvastatin and cyclosporine resulted in an average AUC of 7 times higher than that observed in healthy volunteers (see Table 1). No effect on the plasma concentration of cyclosporine. Rosuvastatin-CS is contraindicated in patients taking cyclosporine (see section “Contraindications”).

Human immunodeficiency virus (HIV) protease inhibitors: despite the fact that the exact mechanism of interaction is unknown, co-administration of HIV protease inhibitors may lead to a significant increase in rosuvastatin exposure.

A pharmacokinetic study of concomitant administration of 20 mg rosuvastatin with a combination drug containing two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers resulted in approximately twofold and fivefold increases in AUC^, and Stach of rosuvastatin, respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Dosage and administration”, “Contraindications” and “Cautions”).

Gemfibrozil and other hypolipidemic agents: co-administration of rosuvastatin and gemfibrozil leads to a 2-fold increase in maximum plasma concentration of rosuvastatin and AUC of rosuvastatin (see section “Special Precautions”).

Based on specific interaction data, no pharmacokinetic interaction with fenofibrate is expected, pharmacodynamic interaction is possible. Hemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they may cause myopathy when used in monotherapy (see section “Special Indications”).

When concomitant use of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day) patients are recommended the initial dose of the drug is 5 mg, taking a dose of 40 mg is contraindicated when combined with fibrates (see sect.

Ezetimibe: concomitant administration of the drug Rosuvastatin-SZ in dose 10 mg and ezetimibe in dose 10 mg was accompanied by increased AUC of rosuvastatin in patients with hypercholesterolemia (see Table 1). An increased risk of side effects due to pharmacodynamic interaction between the drug Rosuvastatin-SZ and ezetimibe cannot be excluded.

Antacids: concomitant use of rosuvastatin and antacid suspensions containing aluminum and magnesium hydroxide leads to a decrease in plasma concentration of rosuvastatin by about 50%. This effect is weaker if antacids are used 2 hours after taking rosuvastatin.

The clinical significance of this interaction has not been studied. Erythromycin: concomitant use of rosuvastatin and erythromycin leads to a decrease in AUC of rosuvastatin by 20% and rosuvastatin by 30%. This interaction may result from increased intestinal motility caused by erythromycin.

Cytochrome P450 isoenzymes: the results of in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes.

Therefore, no interaction of rosuvastatin with other drugs at the level of metabolism involving cytochrome P450 isoenzymes is expected. No clinically significant interaction of rosuvastatin with fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor) was noted.

The dose of Rosuvastatin-SZ should be adjusted if it is necessary to use it together with drugs that increase exposure to rosuvastatin. If it is expected to increase exposure by 2 times or more, the initial dose of Rosuvastatin-SZ should be 5 mg once daily.

Also, the maximum daily dose of Rosuvastatin-SZ should be adjusted so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without concomitant administration of drugs that interact with rosuvastatin.

For example, the maximum daily dose of rosuvastatin-CS when concomitantly administered with gemfibrozil is 20 mg (1.9-fold increase in exposure), with ritonavir/atazanavir is 10 mg (3.1-fold increase in exposure).

Influence of rosuvastatin administration on other drugs

Vitamin K antagonists: Initiation of therapy with rosuvastatin or increase of drug dose in patients receiving simultaneously vitamin K antagonists (for example, warfarin) may lead to increase of International Normalized Ratio (INR). Discontinuation of rosuvastatin or reduction of the drug dose may lead to a decrease in INR. In such cases, it is recommended to monitor INR.

Oral contraceptives/hormone replacement therapy: Concomitant use of rosuvastatin and oral contraceptives increases AUC of ethinylestradiol and AUC of nogestrel by 26 % and 34 %, respectively.

This increase in plasma concentration should be considered when selecting a dose of oral contraceptives. There are no pharmacokinetic data on concomitant use of Rosuvastatin-CZ and hormone replacement therapy, 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.

Special Instructions

Renal effects

In patients receiving high doses of Rosuvastatin-CZ (mainly 40 mg), there was tubular proteinuria, which in most cases was transient. This proteinuria was not indicative of acute kidney disease or progression of renal disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor renal function parameters during treatment.

Musculoskeletal disorders

The following musculoskeletal effects have been reported with Rosuvastatin-CZ at all doses and especially with doses greater than 20 mg: myalgia, myopathy, and in rare cases rhabdomyolysis.

Creatine phosphokinase determination

The determination of CPK activity should not be performed after intense physical activity or in the presence of other possible reasons for the increase in CPK activity, which may lead to misinterpretation of the results obtained. If the initial CPK activity is significantly elevated (5 times higher than the upper limit of normal) the measurement should be repeated in 5-7 days. The therapy should not be started if the repeated test confirms the initial CPK activity (more than 5 times higher than the upper limit of normal).

Pending therapy

When prescribing Rosuvastatin-CZ, as with other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis (see section “Caution”), the risk/benefit ratio of therapy should be considered and clinical monitoring should be performed.

In therapy

The patient should be informed of the need to immediately inform the physician if muscle pain, muscle weakness, or spasms occur unexpectedly, especially in conjunction with malaise and fever. In such patients, CPK activity should be determined. Therapy should be stopped if CPK activity is significantly elevated (more than 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is 5 times lower than the upper limit of normal). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing Rosuvastatin-CZ or other HMG-CoA reductase inhibitors at lower doses with close monitoring of the patient.

Routine 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 of 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 required.

There have been no indications of increased skeletal muscle effects when taking Rosuvastatin-SZ and concomitant therapy. However, an increase in myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when coadministered with some HMG-CoA reductase inhibitors. Thus, concomitant use of Rosuvastatin-CZ and gemfibrozil is not recommended. It should be carefully weighed the ratio of risk to possible benefit when concomitant use of Rosuvastatin-CZ and fibrates or lipid-lowering doses of nicotinic acid. Rosuvastatin-CZ at a dose of 40 mg in combination with fibrates is contraindicated (see sections “Interaction with other medicinal products” and “Contraindications”).

Lipid metabolism should be monitored 2-4 weeks after the start of therapy and/or if the dose of Rosuvastatin-SZ is increased (if necessary, a dose adjustment is required).

The liver

It is recommended that liver function parameters be determined before therapy and 3 months after the start of therapy. Rosuvastatin-SZ should be discontinued or the dose should be reduced if serum transaminase activity exceeds 3 times the upper limit of normal.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy for underlying diseases should be performed before starting treatment with Rosuvastatin-SZ.

Particular populations. Ethnic groups

Pharmacokinetic studies in Chinese and Japanese patients have shown increased systemic rosuvastatin concentrations compared to those in Caucasian patients (see sections “Administration and Doses” and “Pharmacokinetics”).

HIV protease inhibitors

The co-administration of the drug with HIV protease inhibitors is not recommended (see sections “Interaction with other medicinal products” and “Contraindications”).

Lactose

The drug should not be used 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, non-productive cough, and deterioration in general well-being (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Type 2 diabetes mellitus

In patients with glucose concentrations between 5.6 and 6.9 mmol/L, therapy with Rosuvastatin-CS has been associated with an increased risk of developing type 2 diabetes mellitus.

Influence on driving and operating machinery

There have been no studies to study the effect of the drug Rosuvastatin-SZ on the ability to drive vehicles and use mechanisms. Caution should be exercised when driving motor vehicles or performing work requiring increased concentration and rapid psychomotor reactions (dizziness may occur during therapy).

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Contraindications

For the drug Rosuvastatin-SZ in a daily dose of 5 mg. 10 mg and 20 mg:

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

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

• children under 18 years

active phase liver disease, including persistent elevation of serum transaminase activity and any increase in serum transaminase activity (more than 3 times the upper limit of normal)

• severe renal failure (CK less than 30 ml/min.)

• myopathy

• concomitant administration of cyclosporine

• in women: pregnancy; period of breastfeeding, lack of adequate methods of contraception

• increased concentration of creatine phosphokinase (CPK) in blood more than 5 times the upper limit of normal

• co-use with HIV protease inhibitors

• Patients who are prone to developing myotoxic complications For Rosuvastatin-SZ at a daily dose of 40 mg:

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

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

Lactose intolerance, lactase deficiency or glucose-galactose malabsorption

• childhood under 18 years

• concurrent administration of cyclosporine

• in women: pregnancy, breastfeeding period, lack of adequate methods of contraception

• increased blood creatine phosphokinase (CPK) concentrations more than 5 times the upper limit of normal

• co-administration with HIV protease inhibitors

• moderate to severe renal failure (CKD less than 60 ml/min.)

• Hepatic disease in the active phase, including persistent elevation of serum transaminase activity and any increase in serum transaminase activity (more than 3 times the upper limit of normal) in patients with risk factors for myopathy/rhabdomyolysis, namely:

• hypothyroidism

• myotoxicity with a history of taking other HMG-CoA reductase inhibitors or fibrates

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• excessive alcohol consumption

• conditions that may lead to increased plasma concentrations of rosuvastatin

• concomitant administration of fibrates

• myopathy

• personal or family history of muscle disease

• Mongoloid patients

WARNING

For Rosuvastatin-SZ in daily doses of 5 mg 10 mg and 20 mg:

Presence of risk of myopathy/rhabdomyolysis – renal failure, hypothyroidism, personal or family history of hereditary muscle disease, and prior history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; age over 65 years; conditions with increased plasma concentrations of rosuvastatin; race (Mongoloid race); concomitant administration with fibrates (see section “Pharmacokinetics”); history of liver disease; sepsis; arterial hypotension; major surgical interventions, trauma, severe metabolic, endocrine or electrolyte disorders or uncontrolled seizures.

Simultaneous use with colchicine and with ezetimibe (see section “Interaction with other medicinal products”).

For the drug Rosuvastatin-CZ in a daily dose of 40 mg:

Mild renal impairment (CK greater than 60 mL/min); age over 65 years; history of liver disease; sepsis; arterial hypotension; extensive surgery, trauma, severe metabolic, endocrine or electrolyte disorders or uncontrolled seizures.

Simultaneous use with colchicine and with ezetimibe (see section “Interaction with other medicinal products”).

Patients with hepatic impairment

There is no data or experience with the drug in patients with more than a Child-Pugh score of 9 (see sections “Pharmacodynamics” and “Special Precautions”).

Side effects

Side effects observed when taking Rosuvastatin-CZ 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 incidence of adverse effects is as follows: frequently (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, < 1/1000); very rarely (< 1/10000), unspecified frequency (cannot be calculated from the available data).

Immune system

Rare: hypersensitivity reactions, including angioedema.

Endocrine system

Often: type 2 diabetes mellitus

Central nervous system disorders

Often: headache, dizziness

Digestive tract side

Often: constipation, nausea, abdominal pain

Rarely: pancreatitis

Skin disorders

Infrequently: skin itching, rash, urticaria

Musculoskeletal disorders

Often: myalgia

Rarely: myopathy (including myositis), rhabdomyolysis Other

Often: Asthenic syndrome Urinary system side

Patients receiving Rosuvastatin-CZ may show proteinuria. Changes in the amount of protein in the urine (from no or trace amounts to ++ or greater) are seen 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.

Significant changes in the amount of protein in the urine have been observed with the 20 mg dose. In most cases, proteinuria decreases or disappears during therapy and does not indicate the onset of acute or progressive existing renal disease.

Musculoskeletal disorders

The following musculoskeletal effects have been reported with Rosuvastatin-CZ at all doses and, in particular, with doses greater than 20 mg: Myalgia, myopathy (including myositis), in rare cases, rhabdomyolysis with or without acute renal failure.

Dose-dependent increase in creatine phosphokinase (CPK) activity has been observed in a small number of patients taking rosuvastatin. In most cases it was insignificant, asymptomatic and temporary. In case of an increase in CPK activity (more than 5 times the upper limit of normal), therapy should be suspended (see section “Special Precautions”)

Hepatic disorders

When using rosuvastatin a dose-dependent increase in hepatic transaminases has been observed in a small number of patients. In most cases it is mild, asymptomatic and temporary.

Laboratory indices

When using Rosuvastatin-SZ the following changes in laboratory indices were also observed: increase in glucose concentration, bilirubin, activity of gamma-glutamyl transpeptidase, alkaline phosphatase, thyroid function disorders. Post-marketing use

The following side effects have been reported in the post-marketing use of Rosuvastatin-SZ:

Hematopoietic system side effects

Unspecified frequency: thrombocytopenia

Gastrointestinal tract side effects

Very rare: jaundice, hepatitis

Rarely: increased activity of “liver” transaminases

Unspecified frequency: Diarrhea

Musculoskeletal disorders

Very rare: arthralgia

Unspecified frequency: Immune-mediated necrotizing myopathy

Central nervous system disorders

Very rare: polyneuropathy, memory loss

Respiratory system disorders

Unspecified frequency: cough, shortness of breath

Urinary system disorders

Very rare: Hematuria

Skin and subcutaneous fat disorders Unspecified frequency: Stevens-Johnson syndrome Reproductive system and breast disorders Unspecified frequency: gynecomastia Other

Unspecified frequency: peripheral edema.

The following side effects have been reported with some statins: depression, sleep disturbances, including insomnia and “nightmares,” sexual dysfunction. Single cases of interstitial lung disease have been reported, especially with long-term use of the drugs (see section “Indications”).

Overdose

The pharmacokinetic parameters of rosuvastatin do not change when several daily doses are taken simultaneously.

There is no specific treatment for rosuvastatin overdose.

In case of overdose it is recommended to perform symptomatic treatment and measures aimed at maintenance of functions of vital organs and systems.

Liver function and CPK levels should be monitored.

Hemodialysis is unlikely to be effective.

Pregnancy use

Rosuvastatin-SZ is contraindicated in pregnancy and during breastfeeding. Women of reproductive age should use adequate methods of contraception. Since cholesterol and other products of cholesterol biosynthesis are important for fetal development, the potential risk of HMG-CoA reductase inhibition exceeds the benefit of using the drug in pregnant women.

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

There are no data on excretion of rosuvastatin with the breast milk, therefore during breast-feeding the drug should be discontinued (see section “Contraindications”).

Similarities

Mertenil, Crestor, Rosulip, Rosucard, Rosart, Rosuvastatin, Rosistarque, Roxera, Suvardio, Rosuvastatin NW, Cardiolip