Rosuvastatin-SZ, 10 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 the synthesis of cholesterol (cholesterol) and catabolism of low-density lipoproteins (LDL) takes 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 Stah (maximum concentration in blood plasma) of rosuvastatin in patients of Mongoloid race (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared to Caucasians; in Indians median AUC and Stah increase 1.3-fold 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

Primary hypercholesterolemia according to the Fredrickson classification (type Ha, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type Hb) as an adjunct to diet when diet and other non-drug treatments (eg, exercise, weight loss) are insufficient,

Familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (eg, 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 the concentration of total cholesterol and LDL-C.

Primary prevention of major cardiovascular complications (stroke, heart attack, arterial revascularization) in adult patients without clinical signs of coronary artery disease, but with an increased risk of its development (age over 50 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 of the additional risk factors, such as arterial hypertension, low concentration of HDL-C, smoking, family history of early onset of IHD).

Pharmacological effect

Pharmacodynamics

Mechanism of action

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglugaryl coenzyme A into mevalonic acid, a precursor of cholchterol. The main target of action of rosuvastatin is the liver, where the synthesis of cholesterol (C) and the catabolism of low-density lipoproteins (LDL) take place.

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

Pharmacodynamics

Rosuvastatin-SZ reduces elevated concentrations of LDL-cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C), and also reduces the concentrations of apolipoprotein B (ApoB), non-HDL-C, VLDL-C, TG-VLDL and increases the concentration of apolipoprotein A-1 (ApoA-1), reduces LDL-C/HDL-C ratio, total cholesterol/HDL-C and non-HDL-C/HDL-C ratio and ApoB/ApoA-1 ratio.

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

Rosuvastatin-SZ is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, gender or age, including patients with diabetes mellitus and familial hypercholesterolemia.

In 80% of patients with Fredrickson type Ha and Hb hypercholesterolemia (the average initial LDL-C concentration is about 4.8 mmol/l), when taking the drug at a dose of 10 mg, the LDL-C concentration reaches values ​​of less than 3 mmol/L.

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

In patients with homozygous familial hypercholesterolemia taking Rosuvastatin-SZ at a dose of 20 mg and 40 mg, the average reduction in LDL-C concentration is 22%.

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg/dp, who received Rosuvastatin-SZ at a dose of 5 mg to 40 mg once a day for 6 weeks, the concentration of TG in the blood plasma significantly decreased.

An additive effect is observed in combination with fenofibrate in relation to the content of triglycerides and with nicotinic acid in lipid-lowering doses in relation to the content of HDL-C (see also section “Special instructions”).

Based on the results of clinical studies, patients with severe hypercholesterolemia and a high risk of cardiovascular diseases (CVD) should be prescribed a dose of Rosuvastatin-SZ 40 mg.

The results of a clinical study (Rationale for the use of statins for primary prevention: an intervention study to evaluate rosuvastatin) showed that rosuvastatin significantly reduced the risk of developing cardiovascular complications. Pharmacokinetics Absorption and distribution

The maximum concentration of rosuvastatin in blood plasma is achieved approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%. Rosuvastatin is metabolized primarily by the liver, which is the main site of cholesterol synthesis and LDL-C metabolism. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

Metabolism

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

The main identified metabolites of rosuvastatin are N-desmethyl rosuvastagin and lactone metabolites. N-desmethyl rosuvastatin is approximately 50% less active than rosuvastatin; the lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

Removal

About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin). The remaining part is excreted by the kidneys. The plasma half-life (Ti) is approximately 19 hours.

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

Linearity

Systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily use.

Special populations of patients.

Age and gender

Gender and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin. Ethnic groups

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

Kidney 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 (creatinine clearance (CC) less than 30 ml/min.), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration of N-desmethylrosuvastatin is 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin in hemodialysis patients were approximately 50% higher than in healthy volunteers.

Liver failure

In patients with various stages of liver failure, there was no increase in the half-life of rosuvastatin in patients with scores of 7 and below on the Child-Pugh scale. In two patients with Child-Pugh scores of 8 and 9, an increase in the half-life of at least 2 times was noted. There is no experience with the use of rosuvastatin in patients with a Child-Pugh score of more than 9.

Genetic polymorphism

HMG-CoA reductase inhibitors, including rosuvastatin, bind to the transport proteins OATP1B1 (organic anion transport polypeptide involved in the uptake of statins by hepatocytes) and BCRP (efflux transporter). In carriers of genotypes SLC01B1 (OATP1B1) C.521CC and ABCG2 (BCRP) with 421AA, there was an increase in exposure (AUC) to rosuvastatin by 1.6 and 2.4 times, respectively, compared with carriers of the SLC01B1 C.521TT and ABCG2 C.421CC genotypes.

Special instructions

Renal effects

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

From the musculoskeletal system

When using the drug Rosuvastatin-SZ in all doses and, in particular, when taking doses of the drug exceeding 20 mg, the following effects on the musculoskeletal system were reported: myalgia, myopathy, and in rare cases, rhabdomyolysis.

Determination of creatine phosphokinase

Determination of CPK activity should not be carried out after intense physical activity or in the presence of other possible reasons for increased CPK activity, which may lead to incorrect interpretation of the results obtained. If the initial CPK activity is significantly increased (5 times higher than the upper limit of normal), a repeat measurement should be taken after 5-7 days. Therapy should not be started if a repeat test confirms the initial CPK activity (more than 5 times the upper limit of normal).

Before starting therapy

When prescribing Rosuvastatin-SZ, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis (see section “With caution”), the balance of risk and possible benefit of therapy should be considered and clinical observation should be carried out.

During therapy

The patient should be informed to immediately report to the doctor the unexpected onset of muscle pain, muscle weakness or cramps, especially in combination with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued 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 less than the upper limit of normal). If symptoms disappear and CPK activity returns to normal, re-prescribing Rosuvastatin-SZ or other HMG-CoA reductase inhibitors in lower doses should be considered with careful monitoring of the patient.

Routine monitoring of CPK activity in the absence of symptoms is impractical.

Very rare cases of immune-mediated necrotizing myopathy have been reported with clinical manifestations of persistent proximal muscle weakness and increased serum CPK levels during treatment or upon discontinuation of statins, including rosuvastatin. Additional studies of the muscular and nervous system, serological studies, and therapy with immunosuppressive drugs may be required.

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

2-4 weeks after the start of treatment and/or when the dose of Rosuvastatin-SZ is increased, monitoring of lipid metabolism parameters is necessary (dose adjustment is required if necessary).

Liver

It is recommended to determine liver function indicators before starting therapy and 3 months after starting therapy. Taking Rosuvastatin-SZ should be stopped or the dose reduced if the activity of transaminases in the blood serum is 3 times higher than the upper limit of normal.

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

Special populations. Ethnic groups

During pharmacokinetic studies among Chinese and Japanese patients, an increase in the systemic concentration of rosuvastatin was noted compared with the values ​​​​obtained among Caucasian patients (see sections “Dosage and Administration” and “Pharmacokinetics”).

HIV protease inhibitors

Concomitant use of the drug with HIV protease inhibitors is not recommended (see sections “Interaction with other drugs” and “Contraindications”).

Lactose

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

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with some statins, especially over long periods of use. Manifestations of the disease may include shortness of breath, non-productive cough and deterioration in general health (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 from 5.6 to 6.9 mmol/l, therapy with Rosuvastatin-SZ was associated with an increased risk of developing type 2 diabetes mellitus.

Impact on the ability to drive vehicles and operate machinery

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

Active ingredient

Rosuvastatin

Composition

Active substance:

rosuvastatin calcium in terms of rosuvastatin – 10 mg.

Excipients:

core – lactose monohydrate (milk sugar) – 44.3 mg;

calcium hydrogen phosphate dihydrate – 10.0 mg;

povidone (medium molecular weight polyvinylpyrrolidone) – 6.0 mg;

sodium carmellose (lrimellose) – 4.0 mg;

sodium stearyl fumarate -1.2 mg;

colloidal silicon dioxide (Aerosil) – 0.5 mg;

microcrystalline cellulose – 44.0 mg;

shell – Opadry II (polyvinyl alcohol, partially hydrolyzed – 1.76 mg; macrogol (polyethylene glycol) 3350 – 0.494 mg; talc – 0.8 mg; titanium dioxide E 171 – 0.7668 mg; soy lecithin E 322 – 0.14 mg; aluminum varnish based on indigo carmine dye – 0.0024 mg; aluminum varnish based on azorubine dye – 0.0204 mg, aluminum varnish based on crimson dye [Ponceau 4R] – 0.0164 mg).

Pregnancy

Rosuvastatin-SZ is contraindicated during pregnancy and 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 inhibiting HMG-CoA reductase outweighs the benefit of using the drug in pregnant women.

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

There are no data regarding the excretion of rosuvastatin in breast milk, therefore, during breastfeeding, the drug should be discontinued (see section “Contraindications”).

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 of age

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

severe renal failure (creatinine clearance less than 30 ml/min.)

myopathy

concomitant use of cyclosporine

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

an increase in the concentration of creatine phosphokinase (CPK) in the blood by more than 5 times compared to the upper limit of normal

combined use with HIV protease inhibitors

patients predisposed to the development of myotoxic complications For the drug 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)

children under 18 years of age

concomitant use of cyclosporine

in women: pregnancy, breastfeeding, lack of adequate contraceptive methods

an increase in the concentration of creatine phosphokinase (CPK) in the blood by more than 5 times compared to the upper limit of normal

combined use with HIV protease inhibitors

moderate to severe renal failure (creatinine clearance less than 60 ml/min.)

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 the upper limit of normal) in patients with risk factors for the development of myopathy/rhabdomyolysis, namely:

hypothyroidism

history of myotoxicity due to other HMG-CoA reductase inhibitors or fibrates

excessive alcohol consumption

conditions that may lead to increased plasma concentrations of rosuvastatin

concomitant use of fibrates

myopathy

personal or family history of muscle diseases

patients of the Mongoloid race

WITH CAUTION

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

There is a risk of developing myopathy/rhabdomyolysis – renal failure, hypothyroidism, personal or family history of hereditary muscle diseases and a previous history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; age over 65 years; conditions in which an increase in plasma concentration of rosuvastatin is noted; race (Mongoloid race); simultaneous administration with fibrates (see section “Pharmacokinetics”); history of liver disease; sepsis; arterial hypotension; major surgery, trauma, severe metabolic, endocrine or electrolyte disturbances, or uncontrolled seizures.

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

For the drug Rosuvastatin-SZ at a daily dose of 40 mg:

Mild renal failure (creatinine clearance more than 60 ml/min); age over 65 years; history of liver disease; sepsis; arterial hypotension; major surgery, trauma, severe metabolic, endocrine or electrolyte disturbances, or uncontrolled seizures.

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

Patients with liver failure

There are no data or experience with the use of the drug in patients with more than 9 points on the Child-Pugh scale (see sections “Pharmacodynamics” and “Special Instructions”).

Side Effects

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

Immune system

Rarely: hypersensitivity reactions, including angioedema.

Endocrine system

Common: type 2 diabetes mellitus

From the central nervous system

Common: headache, dizziness

From the digestive tract

Common: constipation, nausea, abdominal pain Rare: pancreatitis

From the skin

Uncommon: pruritus, rash, urticaria

From the musculoskeletal system

Common: myalgia Rare: myopathy (including myositis), rhabdomyolysis

Others

Common: asthenic syndrome

From the urinary system

Proteinuria may be detected in patients treated with Rosuvastatin-SZ. Changes in the amount of protein in the urine (from none or trace amounts to ++ or more) are observed in less than 1% of patients receiving 10 – 20 mg of the drug and in approximately 3% of patients receiving 40 mg of the drug. A slight change in the amount of protein in the urine was noted when taking a dose of 20 mg. In most cases, proteinuria decreases or disappears during therapy and does not indicate the onset of acute or progression of existing kidney disease.

From the musculoskeletal system

The following effects on the musculoskeletal system have been reported with the use of Rosuvastatin-SZ at all doses and, in particular, when taking doses of the drug exceeding 20 mg: myalgia, myopathy (including myositis), in rare cases, rhabdomyolysis with or without acute renal failure. A dose-dependent increase in creatine phosphokinase (CPK) activity is observed in a small number of patients taking rosuvastatin. In most cases it was minor, asymptomatic and temporary. If CK activity increases (more than 5 times the upper limit of normal), therapy should be suspended (see section “Special Instructions”).

From the liver

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

Laboratory indicators

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

Post-marketing use

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

From the digestive tract

Very rare: jaundice, hepatitis Rare: increased activity of liver transaminases. Not known: diarrhea, fatal and non-fatal liver failure

From the musculoskeletal system

Very rare: arthralgia. Not known: immune-mediated necrotizing myopathy

From the central nervous system

Very rare: polyneuropathy, forgetfulness, amnesia, memory loss, confusion Respiratory system Frequency unknown: cough, shortness of breath

From the urinary system

Very rare: hematuria, microhematuria

From the skin and subcutaneous fat

Frequency unknown: Stevens-Johnson syndrome Reproductive system and breast Frequency unknown: gynecomastia

Others

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

Interaction

Effect of the use of other drugs on rosuvastatin

Transport protein inhibitors:

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

Cyclosporine: with simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers (see Table 1). Does not affect plasma concentrations of cyclosporine. Rosuvastatin-SZ is contraindicated in patients taking cyclosporine (see section “Contraindications”).

Human immunodeficiency virus (HIV) protease inhibitors: Although the exact mechanism of interaction is unknown, coadministration of HIV protease inhibitors may result in a significant increase in rosuvastatin exposure.

A pharmacokinetic study of co-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 an approximately two-fold and five-fold increase in rosuvastatin AUC^ and Cmax, respectively. Therefore, simultaneous use of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Dosage and Administration”, “Contraindications” and “Special Instructions”).

Gemfibrozil and other lipid-lowering drugs: the combined use of rosuvastatin and gemfibrozil leads to a 2-fold increase in the maximum concentration of rosuvastatin in blood plasma and the AUC of rosuvastatin (see section “Special Instructions”).

Based on specific interaction data, a pharmacokinetically significant interaction with fenofibrate is not expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of niacin increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section “Special Instructions”).

When taking the drug simultaneously with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day), an initial dose of the drug of 5 mg is recommended for patients; taking a dose of 40 mg is contraindicated when co-administered with fibrates (see sections “Contraindications”, “Method of administration and doses”, “Special instructions”),

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

Antacids: simultaneous use of rosuvastatin and antacid suspensions containing aluminum and magnesium hydroxide leads to a decrease in plasma concentrations of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are used 2 hours after taking rosuvastatin.

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

Cytochrome P450 isoenzymes: 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, interaction of rosuvastatin with other drugs at the metabolic level involving cytochrome P450 isoenzymes is not expected. There was no clinically significant interaction of rosuvastatin with fluconazole (an inhibitor of the CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of the CYP2A6 and CYP3A4 isoenzymes).

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

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

For example, the maximum daily dose of Rosuvastatin-SZ when used simultaneously with gemfibrozil is 20 mg (increased exposure by 1.9 times), with ritonavir/atazanavir – 10 mg (increased exposure by 3.1 times).

Effect of rosuvastatin on other drugs

Vitamin K antagonists: Initiating rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (eg, warfarin) may lead to an increase in the International Normalized Ratio (INR). Discontinuation of rosuvastatin or reduction of the drug dose may lead to a decrease in INR. In such cases, INR monitoring is recommended.

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

This increase in plasma concentration should be taken into account when selecting the dose of oral contraceptives. There are no pharmacokinetic data on the simultaneous use of Rosuvastatin-SZ 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 medicinal products: No clinically significant interaction between rosuvastatin and digoxin is expected.

Overdose

When taking several daily doses simultaneously, the pharmacokinetic parameters of rosuvastatin do not change. There is no specific treatment for rosuvastatin overdose.

In case of overdose, it is recommended to carry out symptomatic treatment and measures aimed at maintaining the functions of vital organs and systems.

Monitoring of liver function and CPK levels is necessary. It is unlikely that hemodialysis will be effective.

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 30°C.

Shelf life

3 years. Do not use after the expiration date stated on the package.

Manufacturer

North Star NAO, Russia