Rosistarck, 10 mg 56 pcs.

Mechanism of action

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, which is a precursor of cholesterol. The main target of rosuvastatin action is the liver, where the synthesis of cholesterol (cholesterol) and catabolism of low-density lipoproteins (LDL) are performed.
Rosuvastatin increases the number of “hepatic” LDL receptors on the surface of cells, increasing the capture and catabolism of LDL, which leads to inhibition of synthesis of very low density lipoproteins (VLDL), thus reducing the total amount of LDL and LDL.

Pharmacodynamics

. Rosuvastatin reduces elevated LDL cholesterol (LDL-C), total cholesterol and 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-I (ApoA-I), decreases the ratio of HDL-C/HDL-C, total HC/LDL and non-LDL-C/HDL-C and the apoB/ApoA-I ratio.

Therapeutic effect is developed within 1 week after initiation of therapy with the drug and after 2 weeks of therapy reaches 90% of maximum possible effect.
Maximal therapeutic effect is usually reached after 4 weeks of therapy and is maintained with further regular use of the drug.

Clinical efficacy

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

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

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

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

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg/dL who took rosuvastatin in doses of 5 mg to 40 mg once daily for six weeks, plasma TG concentrations were significantly reduced.

Additive effect is noted in combination with fenofibrate for TG content and with nicotinic acid (more than 1 g per day) for HDL-C content. In patients with low risk of coronary heart disease (CHD) (10-year Framingham scale risk less than 10%), with a mean concentration of 4.0 mmol/L (154.5 mg/dL) of LDL-C and subclinical atherosclerosis, which was assessed by thickness of “intima-media” carotid artery complex – SCIM, Rosuvastatin at a dose of 40 mg/day significantly slowed the rate of progression of maximum SCIM for 12 carotid artery segments compared with placebo with a difference of -0.0145 mm/year (95% confidence interval (CI): -0.0196 to -0.0093; p The results of the study of statins for primary prevention showed that rosuvastatin significantly reduced the risk of cardiovascular complications with a relative risk reduction of 44%. Efficacy of therapy was noted after 6 months of using the drug.

There was a statistically significant 48% reduction in the combined criterion including cardiovascular death, stroke, and myocardial infarction, a 54% reduction in the occurrence of fatal or nonfatal myocardial infarction, and a 48% reduction in the occurrence of fatal or nonfatal stroke. Overall mortality decreased by 20% in the rosuvastatin group. The safety profile in patients taking rosuvastatin at a dose of 20 mg was similar to that of the placebo group.

Pharmacokinetics

Absorption and distribution
Maximum plasma concentration of rosuvastatin is reached 5 h after oral administration. Absolute bioavailability is approximately 20%.
Rosuvastatin is metabolized primarily by liver, which is the main site of cholesterol synthesis and metabolism of LDL-C. The volume of distribution of rosuvastatin is approximately 134 liters. About 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

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

The main identified metabolites of rosuvastatin are N-desmethylrosuvastatin, which is 50% less active than rosuvastatin, and lactone metabolites, which are pharmacologically inactive. More than 90% of the pharmacological activity for inhibition of circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

Elimation
Approximately 90% of the administered dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin), the remainder is excreted by the kidneys. The elimination half-life (T1/2) is approximately 19 h.

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

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

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

Ethnic groups
Comparative pharmacokinetic studies showed approximately two-fold increase in mean AUC (area under the curve “concentration-time”) and Cmax (time to reach maximum drug concentration in plasma) values in patients of Mongoloid race (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared to those of Caucasoid race. In Hindus, there was an increase in the mean AUC and Cmax of approximately 1.3-fold. Pharmacokinetic analysis showed no clinically significant differences in pharmacokinetics between Caucasoid and non-Hispanic races.

Renal failure
In patients with mild to moderate renal failure, plasma concentrations of rosuvastatin or N-dismethylrosuvastatin 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-dismethylrosuvastatin concentration is 9 times higher compared to healthy volunteers.
Plasma concentration of rosuvastatin in patients on hemodialysis was approximately 50% higher than in healthy volunteers.

Hepatic failure
In patients with various stages of hepatic failure with a Child-Pugh score of 7 or lower no increase in the elimination half-life of rosuvastatin was found. However, in 2 patients with Child-Pugh scores 8 and 9 there was approximately 2-fold increase of 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 Rosistar®, bind to the transport proteins OATP1B1 (organic anion transport polypeptide involved in statin uptake 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 SLCO1B1 c.521TT and ABCG2 c.421CC genotypes carriers.

Indications

Fredrickson primary hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) 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, myocardial infarction, 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 (≥ 2 mg/l) in the presence of at least one of the additional risk factors, such as arterial hypertension, low concentration HDL-C, smoking, family history of early development of coronary artery disease).

Pharmacological effect

Mechanism of action

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, which is a precursor to cholesterol. The main target of action of rosuvastatin is the liver, where the synthesis of cholesterol (CH) and the catabolism of low-density lipoproteins (LDL) take place.
Rosuvastatin increases the number of “liver” LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which leads to inhibition of very low-density lipoprotein (VLDL) synthesis, thereby reducing the total amount of LDL and VLDL.

Pharmacodynamics

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

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

Clinical effectiveness

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

Rosuvatatin is effective in patients with Fredrickson type IIa and IIb hypercholesterolemia (average initial LDL-C concentration of about 4.8 mmol/l). In 80% of such patients receiving 10 mg of rosuvastatin, the concentration reaches the target LDL-C levels established by the European Society for Research on Atherosclerosis – less than 3 mmol/l. In patients with heterozygous familial hypercholesterolemia who took rosuvastatin in doses from 20 to 80 mg, positive dynamics of lipid profile parameters were noted.

As a result of dose titration to a daily dose of 40 mg (12 weeks of therapy), a decrease in LDL-C concentration by 53% was observed. In 33% of patients, an LDL-C concentration of less than 3 mmol/l was achieved, corresponding to the target standards of the European Atherosclerosis Community guidelines.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 and 40 mg, the average reduction in LDL-C concentrations was 22%.

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg/dL, taking rosuvastatin at a dose of 5 mg to 40 mg once daily for six weeks, the concentration of TG in the blood plasma was significantly reduced.

An additive effect is observed in combination with fenofibrate in terms of TG content and with nicotinic acid (more than 1 g per day) in terms of HDL-C content. In patients with a low risk of developing coronary heart disease (CHD) (10-year risk according to the Framingham scale less than 10%), with an average LDL-C concentration of 4.0 mmol/l (154.5 mg/dl) and subclinical atherosclerosis, which was assessed by the thickness of the intima-media complex of the carotid arteries – IMT, rosuvastatin at a dose of 40 mg/day significantly slowed the rate of progression of maximum IMT for 12 segments of the carotid artery compared with placebo with a difference of – 0.0145 mm/year (95% confidence interval (CI): -0.0196 to -0.0093; p The results of a study on the use of statins for primary prevention showed that rosuvastatin significantly reduced the risk of cardiovascular complications with a reduction in relative risk of 44%. The effectiveness of therapy was noted after 6 months of use drug.

There was a statistically significant reduction of 48% in the composite criterion including death from cardiovascular diseases, stroke and myocardial infarction, a 54% reduction in the occurrence of fatal or non-fatal myocardial infarction and a 48% reduction in fatal or non-fatal stroke. Overall mortality decreased by 20% in the rosuvastatin group. The safety profile in patients taking rosuvastatin 20 mg was similar to the safety profile in the placebo group.

Pharmacokinetics

Absorption and distribution
The maximum concentration of rosuvastatin in blood plasma is achieved 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. About 90% of rosuvastatin is bound to plasma proteins, mainly albumin.

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

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

Removal
Approximately 90% of the dose of rosuvastatin is excreted unchanged through the intestines (including absorbed and unabsorbed rosuvastatin), the remainder is excreted by the kidneys. The half-life (T1/2) 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. There are no changes in pharmacokinetic parameters when taking the drug several times a day.

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

Ethnic groups
Comparative pharmacokinetic studies have shown an approximately twofold increase in the average value of AUC (area under the concentration-time curve) and Cmax (time to reach the maximum concentration of the drug in the blood plasma) in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with values ​​in representatives of the Caucasian race. In Indians, an increase in the average AUC and Cmax by approximately 1.3 times was noted. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between representatives of the Caucasian and Negroid races.

Kidney failure
In patients with mild to moderate renal failure, plasma concentrations of rosuvastatin or N-dismethylrosuvastatin do 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-dismethylrosuvastatin is 9 times higher compared to 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 with scores of 7 and below on the Child-Pugh scale, no increase in the half-life of rosuvastatin was detected. However, in 2 patients with 8 and 9 points on the Child-Pugh scale, an approximately 2-fold increase in the half-life 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 Rozystark®, bind to the transport proteins OATP1B1 (organic anion transport polypeptide involved in the uptake of statins by hepatocytes) and BCRP (efflux transporter). Carriers of the SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA genotypes showed an increase in exposure (AUC) to rosuvastatin by 1.6 and 2.4 times, respectively, compared with carriers of the SLCO1B1 c.521TT and ABCG2 c.421CC genotypes.

Special instructions

Impact on the ability to drive vehicles and machinery

Studies have not been conducted to study the effect of rosuvastatin on the ability to drive vehicles and machines. Based on the pharmacodynamic properties of the drug, it can be assumed that rosuvastatin should not have such an effect, however, it must be taken into account that dizziness may occur during treatment.

Active ingredient

Rosuvastatin

Composition

One film-coated tablet contains:

Active substance: rosuvastatin 10 mg, 20 mg or 40 mg in the form of rosuvastatin calcium 10.4000 mg, 20.8000 mg or 41.6000 mg, respectively.

Excipients: lactose monohydrate – 89.6400 / 179.2800 / 229.6450 mg, microcrystalline cellulose – 42.6850 / 85.3700 / 109.3550 mg, crospovidone – 6.0000 / 12.0000 / 16.0000 mg, magnesium stearate – 1.2750 / 2.5500 / 3.4000 mg;

tablet shell: lactose monohydrate – 1.8000 / 3.6000 / 4.8000 mg, hypromellose – 1.2600 / 2.5200 / 3.3600 mg, titanium dioxide – 1.0778 / 2.1555 / 2.8740 mg, triacetin – 0.3600 / 0.7200 / 0.9600 mg, quinoline yellow – 0.0022 / 0.0045 / 0.0060 mg.

Pregnancy

ROZISTARK® is contraindicated during pregnancy and breastfeeding.

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

Since cholesterol and other products of cholesterol biosynthesis are of great importance for fetal development, the potential risk of inhibiting HMG-CoA reductase outweighs the benefit of using the drug in pregnant women.
If pregnancy is diagnosed during therapy, the drug should be stopped immediately.
There is no data on the excretion of rosuvastatin in breast milk, so the drug should be discontinued during breastfeeding.

Contraindications

For tablets 10 and 20 mg

hypersensitivity to rosuvastatin or any of the components of the drug;
liver disease in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity more than 3 times the upper limit of normal;
severe renal failure (creatinine clearance less than 30 ml/min);
myopathy;
simultaneous use of cyclosporine;
in patients predisposed to the development of myotoxic complications;
pregnancy and breastfeeding;
in women of childbearing age who do not use reliable contraception;
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;
age under 18 years (efficacy and safety have not been established);
lactose intolerance, lactase deficiency or glucose-galactose malabsorption (since the drug contains lactose).
For tablets 40 mg
hypersensitivity to rosuvastatin or any of the components of the drug;
liver disease in the active phase, including a persistent increase in serum transaminase activity and any increase in serum transaminase activity more than 3 times the upper limit of normal;
moderate renal failure (creatinine clearance less than 60 ml/min);
myopathy;
simultaneous use of cyclosporine;
myotoxicity due to a history of taking other HMG-CoA reductase inhibitors or fibrates;
hypothyroidism;
personal or family history of muscle diseases;
excessive alcohol consumption;
conditions that can lead to increased concentrations of rosuvastatin in blood plasma;
simultaneous use of fibrates;
pregnancy and breastfeeding;
in women of childbearing age who do not use reliable contraception;
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;
a patient of the Mongoloid race;
age under 18 years (efficacy and safety have not been established);
lactose intolerance, lactase deficiency or glucose-galactose malabsorption (since the drug contains lactose).

With caution

For tablets 10 and 20 mg

There is a risk of developing myopathy/rhabdomyolysis – renal failure, hypothyroidism; personal or family history of hereditary muscle diseases and previous history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; conditions in which an increase in plasma concentration of rosuvastatin is noted; age over 70 years; history of liver disease; sepsis; arterial hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine or water-electrolyte disorders; uncontrolled epilepsy; race (Mongoloid race); simultaneous use of fibrates; simultaneous use with colchicine and ezetimibe.

For tablets 40 mg

Moderate renal failure (creatinine clearance more than 60 ml/min); age over 70 years; history of liver disease; sepsis; arterial hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine or water-electrolyte disorders; uncontrolled epilepsy; simultaneous use with colchicine and ezetimibe.

Patients with liver failure
There are no data on the use of the drug in patients with more than 9 points on the Child-Pugh scale.

Side Effects

Side effects associated with taking Rozistark® are usually moderate and go away on their own. The incidence of side effects is mainly dose-dependent, as with the use of other HMG-CoA reductase inhibitors.
The following classification is used to indicate the frequency of side effects: often (? 1/100 and ? 1/10), infrequently (? 1/1000 and ? 1/100), rarely (? 1/10000 and ? 1/1000), very rarely (? 1/10000), unspecified frequency (cannot be calculated from the available data).

From the skin:
uncommon: skin itching, rash, urticaria;
unspecified frequency: Stevens-Johnson syndrome.

From the digestive tract:
often: constipation, nausea, abdominal pain;
rarely: pancreatitis;
very rare: jaundice, hepatitis;
unspecified frequency: diarrhea.

From the central nervous system:
often: headache, dizziness;
very rare: polyneuropathy, memory loss.

From the immune system:
rarely: hypersensitivity, including angioedema.

From the endocrine system:
often: type 2 diabetes mellitus.

Other:
often: asthenic syndrome;
unspecified frequency: peripheral edema.

From the musculoskeletal system:
often: myalgia;
rare: myopathy (including myositis), rhabdomyolysis;
very rarely: arthralgia;
unspecified frequency: immune-mediated necrotizing myopathy.
Effects on skeletal muscle causing myalgia, myopathy (including myositis) and in rare cases rhabdomyolysis with or without acute renal failure have been observed in patients taking any dose of rosuvastatin, particularly when taking doses exceeding 20 mg. A dose-dependent increase in creatine phosphokinase (CPK) activity was detected in patients taking rosuvastatin, but in most cases these manifestations were minor, asymptomatic and temporary. If CPK activity increases by more than 5 times compared to the upper limit of normal, therapy should be suspended (see section “Special Instructions”).

From the urinary system
Proteinuria may occur when taking rosuvastatin. Changes in urinary protein (from absent or trace amounts to ++ or higher) are observed in less than 1% of patients taking rosuvastatin 10 mg and 20 mg, and in approximately 3% of patients taking the drug at a dose of 40 mg. A slight change in the amount of protein in the urine, expressed as a change from a zero level or the presence of traces to a + level, was observed when taking the drug at a dose of 20 mg. In most cases, proteinuria decreased and resolved spontaneously during treatment. Analysis of clinical trial data did not reveal a causal relationship between proteinuria and acute or progressive kidney disease.
Very rare: hematuria, microhematuria.

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, this increase is minor, asymptomatic and temporary.

Laboratory indicators
When using rosuvastatin, the following changes in laboratory parameters were observed: increased concentrations of glucose, bilirubin, gamma-glutamyl transpeptidase activity, alkaline phosphatase, thyroid dysfunction.

From the hematopoietic system:
unspecified frequency: thrombocytopenia.

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

From the reproductive system and mammary gland:
unspecified frequency: gynecomastia.

The following side effects have been reported with some statins: depression, sleep disturbances including insomnia and nightmares, and sexual dysfunction.

Isolated cases of interstitial lung disease have been reported with long-term use of rosuvastatin.

Interaction

The 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 increased 7 times compared to the values ​​obtained in healthy volunteers (see section “Contraindications”). Combined use leads to an 11-fold increase in the concentration of rosuvastatin in blood plasma. The simultaneous use of drugs does not affect the concentration of cyclosporine in the blood plasma.

Ezetimibe: When rosuvastatin and ezetimibe were co-administered, there was no change in the AUC or Cmax of both drugs. However, the risk of side effects due to the pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded.

Gemfibrozil and other lipid-lowering drugs: simultaneous use of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax and AUC of rosuvastatin (see section “Special instructions”). Based on data from specific interaction studies, a pharmacokinetically significant interaction with fenofibrate is not expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and niacin at lipid-lowering doses (1 g or more per day) when used concomitantly with HMG-CoA reductase inhibitors increased the risk of myopathy, possibly due to the fact that they can cause myopathy when used as monotherapy. Concomitant use of 40 mg of rosuvastatin and fibrates is contraindicated (see section “Special instructions” and “Contraindications”). When taking the drug simultaneously with gemfibrozil and other lipid-lowering drugs at a dose of more than 1 g/day, the initial dose of Rozistark should not exceed 5 mg.

HIV protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant use of rosuvastatin with HIV protease inhibitors may result in a significant increase in rosuvastatin exposure. In a pharmacokinetic study with simultaneous administration of 20 mg of rosuvastatin and a combination drug containing two HIV protease inhibitors (400 mg of lopinavir / 100 mg of ritonavir) in healthy volunteers, a 2-fold increase in AUC (0-24) and a 5-fold increase in Cmax of rosuvastatin was detected. Therefore, simultaneous use of rosuvastatin and HIV protease inhibitors when treating patients with HIV is not recommended.

Antacids: simultaneous administration of rosuvastatin and antacid suspensions containing aluminum or magnesium hydroxide can lead to a decrease in the concentration of rosuvastatin in the blood plasma 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: Concomitant use of rosuvastatin and erythromycin can lead to a decrease in AUC(0-t) of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may be due to increased intestinal motility caused by erythromycin.

Cytochrome P450 isoenzymes: the results of in vitro and in vivo studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a fairly weak substrate for these isoenzymes. There was no clinically significant interaction between rosuvastatin and fluconazole (an inhibitor of the CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (an inhibitor of the CYP2A6 and CYP3A4 isoenzymes). Modern use of rosuvastatin and itraconazole (inhibitor of the CYP3A4 isoenzyme) increases the AUC of rosuvastatin by 28% (clinically significant). Therefore, any drug interactions related to cytochrome P450 metabolism are not expected.

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

The effect of rosuvastatin on other drugs

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, initiating rosuvastatin therapy or increasing the dose of the drug in patients receiving concomitant indirect anticoagulants (for example, warfarin or other coumarin anticoagulants) may lead to an increase in prothrombin time (international normalized ratio – INR). Discontinuation of rosuvastatin or dose reduction may cause a decrease in INR. In such cases, INR monitoring should be performed.

Oral contraceptives/hormone replacement therapy:
Concomitant use of rosuvastatin and oral contraceptives may increase the AUC of ethinyl estradiol and norgestrel by 26% and 34%, respectively. This increase in plasma concentration should be taken into account when choosing the dose of oral contraceptives. There are no pharmacokinetic data on the simultaneous use of rosuvastatin and hormone replacement therapy, therefore, a similar effect cannot be excluded when using this combination. However, this combination of drugs was widely used in clinical trials and was well tolerated by patients.

Other medicinal products: No clinically significant interaction is expected with the simultaneous use of rosuvastatin and digoxin.

Overdose

There is no specific treatment for rosuvastatin overdose. In case of overdose, it is recommended to carry out symptomatic treatment and support the functions of vital organs and systems. Liver function and CPK activity should be monitored. Hemodialysis in this case is probably ineffective.

Storage conditions

Store at a temperature not exceeding 25 °C.
Keep out of the reach of children!

Shelf life

3 years.
Do not use after expiration date.

Manufacturer

Belupo, medicines and cosmetics d.d., Croatia