Rosulip, 10 mg 28 pcs.

Pharmacotherapeutic group:

hypolipidemic agent – HMG-CoA reductase inhibitor.

ATC code: C10AA07

Pharmacological properties

Mechanism of action

Rosuvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol (CH). The main target of rosuvastatin action is the liver, where it synthesizes cholesterol and catabolizes low-density lipoproteins (LDL).

Rosuvastatin increases the number of “hepatic” LDL receptors on the surface of liver cells, increasing 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 LDL.

Pharmacodynamics

. Rosuvastatin reduces elevated concentrations of LDL-C, total cholesterol and triglycerides (TG), increases concentrations of high-density lipoprotein cholesterol (HDL-C), and decreases concentrations of apolipoprotein B (Apo B), low-density lipoprotein cholesterol (Non-LDL), HDL-C, TG-LDL-C, and increases apolipoprotein A-I concentration (Apo A-I) (see Tables 1 and 2). Tables 1 and 2), decreases the ratio of LDL-C/HC-LDL, total CH/LDL and non-LDL-C/HC-LDL and the apo B/Apo A-I ratio.

Therapeutic effect develops within one week after the start of treatment. Within 2 weeks of therapy, efficacy reaches a level that is 90% of the maximum possible. Maximum therapeutic effect is usually reached by the 4th week of therapy and is maintained with regular use of the drug.

Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (type ΙΙa and ΙΙb according to Fredrickson classification) (mean adjusted percentage change from baseline).

Table 2. Dose-dependent effect in patients with hypertriglyceridemia (type ΙΙb and ΙV according to Fredrickson classification) (mean percentage change from baseline).

Clinical effectiveness

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

In 80% of patients with hypercholesterolemia of IIa and IIb types by Fredrickson classification (mean baseline concentration of LDL-C about 4.8 mmol/l) during the drug treatment in dose of 10 mg LDL-C concentration reaches values less than 3 mmol/l.

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

Patients with hypertriglyceridemia with initial TG concentrations of 273 to 817 mg/dL who received rosuvastatin in doses of 5 mg to 40 mg once daily for 6 weeks had significantly reduced plasma TG concentrations (see Table 2).

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

Pharmacokinetics

Absorption and distribution

Maximum plasma concentration of rosuvastatin (C_max) is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%.

Rosuvastatin is metabolized primarily by the liver, which is the main site of CH synthesis and metabolism of LDL-C. The volume of distribution (V_d) of rosuvastatin is approximately 134 L. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism

Subject to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by isoenzymes 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-desmethylrosuvastatin and lactone metabolites. N-desmethylrosuvastatin is approximately 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.

Excretion

About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin). The remainder is excreted by the kidneys. Plasma elimination half-life (T_1/2) is approximately 19 hours. T_1/2 does not change with increasing drug dose. Mean geometric plasma clearance is approximately 50 L/hour (coefficient of variation 21.7%). As in the case of other HMG-CoA reductase inhibitors, hepatic uptake of rosuvastatin involves membrane cholesterol transporter, which plays an important role in hepatic elimination of rosuvastatin.

Linearity

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

Special patient populations.

Age and sex

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

Ethnic groups

Pharmacokinetic studies have shown an approximately twofold increase in median area under the concentration-time curve (AUC) and C_max rosuvastatin in patients of Asian origin (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to Europeans; a 1.3-fold increase in median AUC and C_max was shown in Indian patients. Pharmacokinetic analysis showed no clinically significant differences in pharmacokinetics among Europeans and members of the Negro race.

Renal failure

In patients with mild to moderately severe renal failure the plasma concentration of rosuvastatin or N-desmethylrosuvastatin does not change significantly. In patients with severe renal insufficiency (creatinine clearance (CK) < 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.

Liver failure

No increase in T_1/2 rosuvastatin was detected in patients with various stages of liver failure (with a Child-Pugh score of 7 or lower). Two patients with Child-Pugh scores of 8 and 9 showed at least a 2-fold increase in T_1/2. There is no experience with rosuvastatin in patients with a Child-Pugh score above 9.

Genetic polymorphism

. HMG-CoA reductase inhibitors, including rosuvastatin , bind to the transport proteins OATP1B1 (organic anion transport polypeptide involved in the capture of statins by hepatocytes) and BCRP (efflux transporter). Carriers of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes had 1.6 and 2.4-fold increased exposure (AUC) to rosuvastatin, respectively, compared with carriers of SLCO1B1 c.521TT and ABCG2 c.421CC genotypes.

Indications

.

Active ingredient

Rosuvastatin

Composition

Active ingredient:

Each tablet contains 5 mg, 10 mg, 20 mg, or 40 mg

rosuvastatin (in the form of, respectively: 5.34 / 10.68 / 21.36 / 42.72 mg rosuvastatin zinc).

Auxiliary substances:

ludipress 65.16 / 130.32 / 260.64 / 521.28 mg [(lactose monohydrate (93%), povidone (3.5%), crospovidone (3.5%)],

crospovidone 3.75/ 7.50/ 15.00/ 30.00 mg,

magnesium stearate 0.75/ 1.50/ 3.00/ 6.00 mg;

coating:

Opadray II White 85F 18422 1.90 / 3.80 / 7.50 / 15.00 mg [polyvinyl alcohol (40%), titanium dioxide (25%), macrogol 3350 (20.2%), talc (14.8%)].

How to take, the dosage

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

People should start a standard hypocholesterolemic diet prior to initiating therapy with the drug Rosulip® and continue this diet during therapy. 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 lipid concentrations.

The recommended starting dose for patients starting the drug or switching from other HMG-CoA reductase inhibitors should be 5 or 10 mg of Rosulip® once daily. When choosing the initial dose, the individual concentration of cholesterol should be guided and the 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 can be increased to a larger one in 4 weeks (see section “Pharmacodynamics”).

With regard to the possible development of side effects at a dose of 40 mg compared to lower doses of the drug (see section “Side effects”).

See side effects) dose increase to 40 mg after an additional dose above the recommended initial dose for 4 weeks of therapy may only be undertaken in patients with severe hypercholesterolemia and with a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia), in whom the desired therapy result was not achieved with the 20 mg dose and who will be under specialist supervision (see section “Special indications”). We recommend especially close monitoring of patients receiving the drug at 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 the dose of Rosulip® is increased, lipid metabolism parameters should be monitored (dose adjustment is required if necessary).

Elderly patients

Dose adjustment is not required.

Patients with renal impairment

Dose adjustment is not required in patients with mild to moderate renal impairment. In patients with severe renal insufficiency (CKD < 30 ml/min) the use of Rosulip® is contraindicated. The use of the drug in dose 40 mg is contraindicated in patients with moderate renal impairment (CKD < 30-60 ml/min) (see section “Cautionary Note” and “Pharmacodynamics”). In patients with moderate renal dysfunction, a starting dose of 5 mg is recommended.

Patients with hepatic impairment

Rosulip® is contraindicated in patients with active liver disease (see “Contraindications” sections).

Particular populations

Ethnic groups

In studying the 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 Rosulip® to these groups of patients. When prescribing doses of 10 and 20 mg, the recommended starting dose for mongoloid patients is 5 mg. A dose of 40 mg is contraindicated in mongoloid patients (see Contraindications).

Genetic polymorphisms

Carriers of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes showed increased exposure (AUC) to rosuvastatin compared to carriers of SLCO1B1 c.521TT and ABCG2 c.421CC genotypes. For c.521CC or c.421AA genotype carriers the recommended maximum dose of Rosulip® 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 and 20 mg, the recommended starting dose for this group of patients is 5 mg (see Contraindications).

Companion therapy

Rosuvastatin binds to various transport proteins (in particular to OATP1B1 and BCRP). When co-administration of Rosulip® with drugs (such as cyclosporine, certain human immunodeficiency virus (HIV) protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase plasma concentrations of rosuvastatin through interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may be increased (see sect. See sections “Cautions” and “Interaction with other medicinal products”). You should read the instructions for use for these drugs before prescribing them with Rosulip® , assess the possibility of alternative therapy or temporary discontinuation of Rosulip®. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with Rosulip® should be assessed and the possibility of reducing its dose should be considered (see section “Interaction with other medicinal products”).

Interaction

Influence 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 increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see Table 3 and sections “Administration and Doses” and “Precautions”).

Cyclosporine: When concomitant use of rosuvastatin and cyclosporine the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers (see Table 3). No effect on the plasma concentration of cyclosporine. Rosulip^® is contraindicated in patients taking cyclosporine (see section “Contraindications”).

HIV protease inhibitors: although the exact mechanism of interaction is unknown, co-administration of HIV protease inhibitors may result in a significant increase in exposure to rosuvastatin (see Table 3). 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_(0-24) and C_max rosuvastatin, respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Dosage and administration”, “Special indications”, Table 3).

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

Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when concomitantly used with HMG-CoA reductase inhibitors, possibly due to the fact that they may cause myopathy when used in monotherapy (see section “Special Indications”). In 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 in concomitant administration with fibrates (see sections “Contraindications”, “Dosage and administration”, “Cautions”).

Ezetimibe: concomitant administration of 10 mg rosuvastatin and 10 mg ezetimibe was accompanied by increased AUC of rosuvastatin in patients with hypercholesterolemia (see Table 3). An increased risk of side effects due to pharmacodynamic interaction between Rosulip^® and ezetimibe cannot be excluded.

Antacids: concomitant use of rosuvastatin and suspensions of antacids containing magnesium and aluminum hydroxide leads to decrease of plasma concentration of rosuvastatin by approximately 50%. This effect is weaker if antacids are used 2 hours after rosuvastatin administration. The clinical significance of this interaction has not been studied.

Erythromycin: Concomitant use of rosuvastatin and erythromycin decreases AUC of rosuvastatin by 20% and C_max of rosuvastatin by 30%. This interaction may occur as a result of increased intestinal motility caused by taking erythromycin.

Cytochrome P450 isoenzymes: 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 isoenzymes inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzymes inhibitor) was observed.

Fusidic acid: There have been no studies on interaction between rosuvastatin and fusidic acid. As with other statins, there have been post-marketing reports of cases of rhabdomyolysis when co-administering rosuvastatin and fusidic acid. Patients should be closely monitored. If necessary, temporary discontinuation of rosuvastatin is possible.

Drug interactions that require rosuvastatin dose adjustment (see Table 3)

The dose of Rosulip^® should be adjusted if it is necessary to combine it with drugs that increase exposure to rosuvastatin. Read the instructions for use of these drugs before prescribing them together with rosuvastatin. If an increase in exposure by 2-fold or more is expected, the initial dose of Rosulip^® should be 5 mg once daily. The maximum daily dose of Rosulip^® should also 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, maximum daily dose of Rosulip^® in concomitant use with gemfibrozil is 20 mg (1.9-fold increase in exposure), with ritonavir/atazanavir – 10 mg (3.1-fold increase in exposure).

Table 3. Effect of concomitant therapy on exposure to rosuvastatin (AUC, data are given in descending order) – results of published clinical trials

Effect of rosuvastatin use on other drugs

Vitamin K antagonists: Starting therapy with rosuvastatin or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (e.g., warfarin) may increase the 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 control 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. Pharmacokinetic data on concomitant use of Rosulip^® and hormone replacement therapy are not available, therefore, one cannot rule out a similar effect 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 of rosuvastatin with digoxin is expected.

Special Instructions

Renal effects

In patients receiving high doses of rosuvastatin (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such 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 at all doses and especially with doses higher than 20 mg: myalgia, myopathy and, rarely, rhabdomyolysis.

The determination of CPK activity

The determination of CPK activity should not be performed after vigorous physical activity or in the presence of other possible reasons for the increase of CPK activity, which may lead to misinterpretation of the results. If the baseline CPK activity is significantly elevated (>5x VGN), a repeat measurement should be performed after 5-7 days. Do not initiate therapy if the repeat test confirms baseline CPK activity (>5x BHN).

Pending therapy

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

At the time of therapy

The patient should be informed of the need to immediately inform the physician if muscle pain, muscle weakness, or cramps occur unexpectedly, especially in conjunction with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (>5x VGN) or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is increased not >5x VGN). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing Rosulip® 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 activity 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 with rosuvastatin 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 in lipid-lowering doses (over 1 g/day), azole antifungals, HIV protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when concomitantly prescribed with some HMG-CoA reductase inhibitors. Thus, concomitant administration of Rosulip® and gemfibrozil is not recommended. It should be carefully weighed the ratio of risk to possible benefit when concomitant use of Rosulip® and fibrates or lipid-lowering doses of nicotinic acid. Rosulip® at a dose of 40 mg together with fibrates is contraindicated (see sections “Interaction with other medicinal products” and “Contraindications”).

Lipid metabolic parameters should be monitored 2-4 weeks after the start of treatment and/or when increasing the dose of Rosulip® (if necessary, a dose adjustment is required).

The liver

Liver function tests are recommended before the start of therapy and 3 months after the start of therapy. Rosulip® should be discontinued or the dose of the drug should be reduced if serum hepatic transaminase activity > 3x VGN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy for the underlying disease should be given before starting treatment with Rosulip®.

Particular populations. Ethnic groups

Pharmacokinetic studies in Chinese and Japanese patients have shown increased systemic rosuvastatin concentrations compared to those in European 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 section “Interaction with other medicinal products”).

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 worsening of 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, rosuvastatin therapy has been associated with an increased risk of developing type 2 diabetes mellitus.

Pediatric use

The efficacy and safety of Rosulip® in children under 18 years of age has not yet been established; therefore, the use of this drug is contraindicated in patients in this age group.

The effect of rosuvastatin on the ability to drive vehicles and operate machinery

There have been no studies on the effect of rosuvastatin on the ability to drive vehicles and operate machinery. However, based on the pharmacodynamic properties, rosuvastatin should have no such effect. Caution should be exercised when driving motor transport or working with high concentration and psychomotor reactions (dizziness may occur during therapy).

Synopsis

Round biconvex film-coated tablets, white or almost white in color, engraved E on one side of the tablet and number 592 on the other side of the tablet, odorless or almost odorless.

Contraindications

• high sensitivity to rosuvastatin and any of the excipients of the drug;
• liver disease in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity (>3 x upper limit of normal (ULN);
• severe renal dysfunction (CK <30 ml/min);
• myopathy;
• concurrent use of cyclosporine;
• in women: pregnancy, breastfeeding period, and lack of adequate contraceptive methods in women with preserved reproductive function;
• patients predisposed to develop myotoxic complications;
• children under 18 years of age (due to lack of sufficient clinical data, effectiveness and safety are not established, see
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose).

With caution
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 (Asian race); concomitant use with fibrates (see Pharmacokinetics” section); liver diseases in anamnesis, sepsis; arterial hypotension; extensive surgical interventions, injuries, severe metabolic, endocrine or electrolyte disorders or uncontrolled convulsive seizures.

Side effects

Side effects observed when taking Rosulip® are usually mild and go away on their own. As with other HMG-CoA reductase inhibitors, the incidence of side effects is mostly dose-dependent.

The incidence of adverse effects is as follows:

Frequent (> 1/100, < 1/10); infrequent (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000), unspecified frequency (cannot be calculated from available data).

Immune system

Rare: hypersensitivity reactions, including angioedema

Endocrine system

Often: Diabetes mellitus type 2

Central nervous system (CNS) disorders

Often: headache, dizziness

Digestive tract disorders

Often: constipation, nausea, abdominal pain

Rarely: pancreatitis

Skin side

Infrequently: skin itching, skin rash, urticaria

Musculoskeletal disorders

Often: myalgia

Rarely: Myopathy (including myositis), rhabdomyolysis

Other

Often: asthenic syndrome

Urinary system disorders

In patients receiving rosuvastatin, proteinuria may be detected. 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. Slight changes in urine protein have been observed with the 20 mg dose. In most cases, proteinuria decreases or disappears during therapy and does not indicate the occurrence of acute or progression of existing renal disease.

Musculoskeletal disorders

The following musculoskeletal effects have been reported with rosuvastatin at all doses and especially 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 increased CPK activity (>5x VGN), therapy should be suspended (see section “Special Precautions”).

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 it is mild, asymptomatic and temporary.

Laboratory parameters

The following changes in laboratory parameters have also been observed with rosuvastatin: increase in glucose concentration, bilirubin, gamma-glutamyl transpeptidase activity, alkaline phosphatase, thyroid function disorders.

Postmarketing use

The following side effects have been reported in the postmarketing use of rosuvastatin:

Hematopoietic system disorders

The frequency is unknown: Thrombocytopenia

Digestive tract disorders

Very rare: jaundice, hepatitis

Rare: increased activity of “hepatic” transaminases

Frequency unknown: diarrhea

Musculoskeletal side

Very rare: arthralgia

Frequency unknown: Immune-mediated necrotizing myopathy

CNS side

Very rare: loss or impairment of memory

Prevalence unknown: peripheral neuropathy

Respiratory system disorders:

Prevalence unknown: cough, shortness of breath

Urinary system disorders

Very rare: Hematuria

Skin and subcutaneous fatty tissue disorders

Frequency unknown: Stevens-Johnson syndrome

Reproductive and mammary system disorders

Prevalence unknown: Gynecomastia

Other

Prevalence unknown: 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 “Special Precautions”).

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 carry out symptomatic and supportive therapy, measures aimed at maintenance of functions of vital organs and systems. Control of liver function and CPK activity is necessary. Hemodialysis is unlikely to be effective.

Pregnancy use

Rosulip is contraindicated in pregnancy and during lactation (breastfeeding). If pregnancy is diagnosed during therapy, the drug should be discontinued immediately.

Women of reproductive age should use adequate methods of contraception. Because chs and products of its biosynthesis are important for fetal development, the potential risk of HMG-CoA reductase inhibition exceeds the benefits of the drug.

There are no data on excretion of rosuvastatin with breast milk, therefore breastfeeding should be discontinued if it is necessary to use the drug during lactation.

Similarities

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