Roxera pills 10mg, 90pcs

Composition

1 film-coated tablet contains:

Core:

Active ingredient:

Rosuvastatin calcium 10.42 mg, equivalent to rosuvastatin 10.00 mg.

Auxiliary substances:

Microcrystalline cellulose, lactose, crospovidone, colloidal silicon dioxide, magnesium stearate

Film shell:

Butylmethacrylate, dimethylaminoethylmethacrylate and methyl methacrylate copolymer [1: 2: 1], macrogol-6000, titanium dioxide, lactose monohydrate

Pharmacological action

Pharmacotherapy group: hypolipidemic agent-HMG-CoA reductase inhibitor ATX code: C 10 AA 07 Pharmacological properties

Mechanism of action

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

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

Rosuvastatin reduces elevated serum concentrations of cholesterol-low-density lipoprotein (cholesterol-LPNG 1), total cholesterol, triglycerides (TG), increases serum concentrations of cholesterol-high density lipoprotein (HDL-C) and reduced serum concentrations of apolipoprotein In (APO B), XC-delpup, cholesterol of very low density lipoproteins (cholesterol-VLDL), TG-VLDL and increases the concentration apolipoprotein A-I (APO A-I) (see tables 1 and 2) lowers cholesterol ratio LDL/HDL-C, total cholesterol/cholesterol-LH 1 VP and CH-nelepp/XR-LGTP and the ratio of APO b/APO A-I.

The therapeutic effect develops within one week after the start of rosuvastatin therapy, 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.

Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (type Na and HB according to Fredrickson) (average adjusted percentage change in io compared to baseline)

Dosage	Number	of LDL-C patients	Total		Cholesterol HDL-C TG	HDL-C Non-HDL	A to B	A by A-I
Placebo	13-7-5			3-3-7-3				0
5 mg	17-45-33			13-35-44-38				4
10 mg	17-52-36			14-10-48-42				4
20 mg	17-55-40			8-23-51-46				5
40 mg	18-63-46			10-28-60-54				0

Table 2. Dose-dependent effect in patients with hypertriglyceridemia (Fredrickson type lib and IV) (mean percentage change from baseline)

Dosage	Number	of patients with TG	-LDL-C	Total	Cholesterol HDL-C-Non-HDL	C-VLDL	TG-VLDL
Placebo	26	1	5	1-3		2	2	6
5 mg	25-21-28-24				3-29-25-24
10 mg	23-37-45-40				8-49-48-39
20 mg	27-37-31-34				22-43-49-40
40 mg	25-43-43-40				17-51-56-48

Clinical efficacy

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

In 80% of patients with hypercholesterolemia of Pa and PI type according to Fredrickson (the average initial serum concentration of LDL-C is about 4.8 mmol/l) against the background of taking the drug at a dose of 10 mg, the serum concentration of LDL-C reaches values of less than 3 mmol/l.

In patients with heterozygous familial hypercholesterolemia receiving rosuvastatin at a dose of 20-80 mg, there was a positive dynamics of lipid profile indicators (a study involving 435 patients). After adjusting the dose to a daily dose of 40 mg (12 weeks of therapy), the serum LDL-C concentration decreased by 53%. In 33% of patients, a serum LDL-C concentration of less than 3 mmol/l is achieved.

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

In patients with hypertriglyceridemia with an initial serum TG concentration of 273 to 817 mg / dl, receiving rosuvastatin at a dose of 5 mg to 40 mg once a day for 6 weeks, the concentration of TG in blood plasma significantly decreased (see table 2). An additive effect is observed in combination with fenofibrate in relation to the serum concentration of triglycerides and with nicotinic acid in lipid-lowering doses in relation to the serum concentration of HDL-C (see also the section “Special instructions”).

The METEOR study included 984 patients aged 45-70 years with a low risk of developing coronary heart disease (CHD) (10-year Framingham risk of less than 10%), an average serum 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 [IMT] of the carotid arteries) to study the effect of rosuvastatin on IMT. Patients received either rosuvastatin 40 mg / day or placebo for 2 years. Rosuvastatin therapy significantly slowed the rate of progression of maximal IMT for 12 carotid artery segments compared to placebo with a difference of -0.0145 mm / year [95% confidence interval (CI) -0.0196 to -0.0093, p Compared to baseline values, the rosuvastatin group showed a decrease in the maximum IMT value by 0.0014 mm / yr (0.12% / yr [unreliable difference]) compared to an increase in this indicator by 0.0131 mm / yr (1.12%/yr [p To date, no direct relationship has been demonstrated between a reduced IMT and a reduced risk of cardiovascular events.

The METEOR study was conducted in patients with a low risk of coronary heart disease, for whom a dose of rosuvastatin 40 mg is not recommended. The 40 mg dose should be given to patients with severe hypercholesterolemia and a high risk of cardiovascular disease (CVD).

The results of the JUPITER study (“Justification of statin use for primary prevention: an interventional study evaluating rosuvastatin”) in 17,802 patients showed that rosuvastatin significantly reduced the risk of developing cardiovascular complications (252 in the placebo group compared to 142 in the rosuvastatin group) (p The effectiveness of therapy was noted after the first 6 months of using the drug. There was a statistically significant 48% reduction in the combined criterion that included death from cardiovascular causes, stroke, and myocardial infarction (risk ratio: 0.52,95% CI,0.40-0.68, p Overall mortality was reduced by 20% in the rosuvastatin group (risk ratio: 0.80,95% CI 0.67-0.97, p = 0.02). The safety profile of patients taking rosuvastatin 20 mg was generally similar to that of the placebo group.

Pharmacokinetics

Absorption and distribution

The maximum concentration of rosuvastatin in blood plasma is reached approximately 5 hours after oral use. Absolute bioavailability is approximately 20%.

It is mainly metabolized by the liver, which is the main organ that synthesizes cholesterol and metabolizes LDL-C. The volume of distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin binds to plasma proteins, mainly albumin.

Metabolism

It undergoes a limited metabolism (about 10%). Rosuvastatin is a non-specific substrate of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9. Isoenzymes CYP2C19, CYP3A4, and CYP2D6 are involved in metabolism to a lesser extent. The main identified metabolites are N-desmethylrosuvastatin and lactone metabolites.

N-desmethylrosuvastatin is approximately 50% less active than rosuvastatin, and the lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting plasma HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.

Deduction

Approximately 90% of the rosuvastatin dose is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin). The remaining part is excreted by the kidneys. The half-life (Half-life) from the blood plasma is approximately 19 hours (does not change with increasing dose of the drug). The average geometric plasma clearance is 50 l / h (coefficient of variation-21.7%). As in the case of other HMG-CoA reductase inhibitors, the process of” hepatic “uptake of rosuvastatin involves a membrane transporter of cholesterol, which plays an important role in the” hepatic ” elimination of rosuvastatin.

Linearity

Systemic exposure to rosuvastatin increases in proportion to the dose.

Pharmacokinetic parameters do not change with daily use.

Pharmacokinetics in selected groups of patients

Age and gender

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

Ethnic group

Pharmacokinetic studies showed approximately a twofold increase in the median area under the curve “concentration-time” (AUC) and maximum concentration (Cmax) in plasma of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with patients of Caucasoid race, the Indians have shown an increase in median AUC and Cmax by 1.3 times. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among patients of Caucasian and black races.

Kidney failure

In patients with mild or moderate renal insufficiency, the plasma concentrations of rosuvastatin or N-desmethylrosuvastatin do not change significantly. In patients with severe renal insufficiency (creatinine clearance < 30 ml / min), the concentration of rosuvastatin in blood plasma is 3 times higher, and the concentration of N-desmethylrosuvastatin is 9 times higher than in healthy volunteers. The plasma concentration of rosuvastatin in patients undergoing hemodialysis is approximately 50% higher than in healthy volunteers.

Liver failure

No increase in systemic exposure to rosuvastatin was observed in patients with hepatic insufficiency of 7 points or lower on the Child-Pugh scale. Two patients with hepatic insufficiency of 8-9 points on the Child-Pugh scale showed an increase in systemic exposure by at least 2 times. There is no experience of using rosuvastatin in patients with hepatic insufficiency above 9 points on the Child-Pugh scale.

Genetic polymorphism

HMG-CoA reductase inhibitors, including rosuvastatin, bind to the transport proteins OATP 1 In 1 (an organic anion transport polypeptide involved in statin uptake by hepatocytes) and BCRP (efflux transporter). Carriers of the SLC01B1 (OATR 1V1) p. 521 CC and ABCG2 (BCRP) p. 421 AA genotypes showed a 1.6-and 2.4-fold increase in rosuvastatin systemic exposure (AUC), respectively, compared to carriers of the SLC01B1 p. 521 TT and ABCG2 p. 421 CC genotypes.

Indications

• Primary hypercholesterolemia according to the Fredrickson classification (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) – as an adjunct to diet, when diet and other non-drug treatments (for example, exercise, weight loss) are insufficient.
• Familial homozygous hypercholesterolemia – as an adjunct to diet and other lipid-lowering therapy (for example, LDL apheresis) or in cases where such therapy is not effective enough.
• Hypertriglyceridemia (type IV according to the Fredrickson classification) – as an adjunct to the diet.
• To slow the progression of atherosclerosis – as an adjunct to the diet in patients who are indicated for therapy to reduce the plasma 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 CHD, but with an increased risk of its development (age over 50 years for men and over 60 years for women, increased plasma 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 plasma concentration of HDL-C. smoking, family history of early-onset CHD).

Use during pregnancy and lactation

Roxera® is contraindicated during pregnancy and lactation.

Women of reproductive age should use adequate methods of contraception.

Since cholesterol and substances synthesized from cholesterol are important for fetal development, the potential risk of HMG-CoA reductase inhibition for the fetus exceeds the benefit of using the drug during pregnancy for the mother.

If pregnancy occurs during therapy, the use of the drug should be stopped immediately.

There are no data on the penetration of rosuvastatin into breast milk (it is known that other HMG-CoA reductase inhibitors can enter breast milk), so the use of the drug should be discontinued during breastfeeding.

Contraindications

• Hypersensitivity to rosuvastatin and/or any of the excipients in the composition of the drug;
• liver disease in the active phase (including a persistent increase in activity of “hepatic” transaminases and increased activity of “liver” transaminases in the serum of more than 3 times compared with the upper limit of normal);
• renal failure of moderate and severe (CC less than 60 ml/min);
• myopathy;
• the simultaneous use of cyclosporine;
• patients predisposed to the development myotoxicity complications;
• pregnancy, lactation;
• use in women with preserved reproductive potential who are not using adequate contraceptive methods;
• hypothyroidism;
• muscle disease in history (including family history);
• myotoxicity the use of other inhibitors of HMG-COA reductase inhibitors or fibrates in history;
• excessive alcohol consumption;
• status, which may lead to increased concentrations of rosuvastatin in plasma;
• the simultaneous use of fibrates;
• lactose intolerance, lactase deficiency, a syndrome of glucose-galactose malabsorption;
• patients of the Mongoloid race;
• the age of 18.

Side effects

AES observed with rosuvastatin are usually mild and resolve on their own. As with other HMG-CoA reductase inhibitors, the incidence of AE is mainly dose-dependent.

Classification of the incidence of AE recommended by the World Health Organization (WHO):

very often ≥ 1/10

often ≥ 1/100 to < 1/10

infrequently ≥ 1/1000 to < 1/100

rare ≥ 1/10000 to < 1/1000

very rare < 1/10000

frequency unknown cannot be estimated based on available data.

Disorders of the blood and lymphatic system

frequency unknown: thrombocytopenia.

Immune system disorders

rare: hypersensitivity reactions, including angioedema.

Endocrine disorders

are common: type 2 diabetes mellitus.

Nervous system disorders

common: headache, dizziness;

very rare: memory loss or loss;

frequency unknown: peripheral neuropathy.

Respiratory, thoracic and mediastinal

disorders frequency unknown: cough, shortness of breath.

Gastrointestinal disorders

common: constipation, nausea, abdominal pain;

rare: pancreatitis;

very rare: jaundice, hepatitis;

frequency unknown: diarrhea.

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

Skin and subcutaneous tissue disorders

uncommon: pruritus, skin rash, urticaria;

frequency unknown: Stevens-Johnson syndrome.

Musculoskeletal and connective tissue

disorders common: myalgia;

rare: myopathy (including myositis), rhabdomyolysis (with or without acute renal failure);

very rare: arthralgia;

frequency unknown: immune-mediated necrotizing myopathy.

A dose-dependent increase in plasma creatine phosphokinase (CPK) activity is observed in a small number of patients taking rosuvastatin. In most cases, it is minor, asymptomatic, and temporary. If the activity of CPK in blood plasma increases more than 5 times higher than the upper limit of normal, therapy should be suspended.

Renal and urinary tract

disorders very rare: hematuria.

Proteinuria may occur in patients receiving rosuvastatin therapy. A change in the amount of protein in the urine (from no or trace amounts to ++ or more) is observed in less than 1% of patients receiving 10-20 mg of rosuvastatin, and in approximately 3% of patients receiving 40 mg of rosuvastatin. A slight change in the amount of protein in the urine was observed when taking a dose of 20 mg. In most cases, proteinuria decreases or disappears during therapy and does not indicate the occurrence of acute or progressive existing kidney disease.

Genital and breast disorders

frequency unknown: gynecomastia.

General disorders and disorders at the injection site

often: asthenic syndrome;

frequency unknown: peripheral edema.

Laboratory and instrumental data

When using rosuvastatin, the following changes in laboratory parameters were also observed: hyperglycemia, increased bilirubin concentration in blood plasma, gamma-glutamyltranspeptidase activity, alkaline phosphatase in blood plasma, changes in the serum concentration of thyroid hormones.

The following AES have been reported with some HMG-CoA reductase inhibitors (statins): depression, sleep disorders, including insomnia and “nightmarish” dreams, sexual dysfunction, and increased blood glycated hemoglobin concentrations. Isolated cases of interstitial lung disease have been reported, especially with prolonged use of medications (see section “Special instructions”).

Interaction

Effect of other medications on rosuvastatin

Transport protein inhibitors

Rosuvastatin is a substrate for some transport proteins, in particular, OATP1 In 1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in the concentration of rosuvastatin in blood plasma and an increased risk of developing myopathy (see the sections “Dosage and use”, “Special instructions” and Table 3).

Cyclosporine

With the simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin is on average 7 times higher than that observed in healthy volunteers (see Table 3). Concomitant use with rosuvastatin does not affect the concentration of cyclosporine in blood plasma. The use of rosuvastatin is contraindicated in patients taking cyclosporine (see section “Contraindications”).

HIV protease inhibitors

Concomitant use of HIV protease inhibitors may significantly increase rosuvastatin exposure (see table 3). Concomitant use of 20 mg rosuvastatin and a combination of two HIV protease inhibitors (400 mg lopinavir/100 mg ritonavir) is accompanied by an increase in steady-state AUC_{(0-24 h)} and_cmax of rosuvastatin by 2 and 5 times, respectively. Therefore, simultaneous use of rosuvastatin and HIV protease inhibitors is not recommended (see the section “Dosage and use” and Table 3).

Gemfibrozil and other lipid-lowering agents

Simultaneous use of rosuvastatin and gemfibrozil leads to_{a 2-fold increase in the cmax} and AUC of rosuvastatin in blood plasma (see the section “Special instructions”). Based on the specific interaction data, no pharmacokinetically significant interaction with fenofibrate is expected, and a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of nicotinic acid (greater than 1 g / day) increased the risk of myopathy when co-administered with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy when used in monotherapy (see section “Special instructions”). Concomitant use of fibrates and rosuvastatin in a daily dose of 30 mg is contraindicated. In such patients, therapy should begin with a dose of 5 mg / day (see the sections “Contraindications”, “Method of use and doses”, “Special instructions”).

Ezetimibe

Concomitant use of rosuvastatin 10 mg and ezetimibe 10 mg was associated with an increase in rosuvastatin AUC in patients with hypercholesterolemia (see table 3). A pharmacodynamic interaction between rosuvastatin and ezetimibe, which may increase the risk of adverse reactions, cannot be excluded.

Antacids

Concomitant use of rosuvastatin and antacids containing aluminum and / or magnesium hydroxide leads to a decrease in the plasma concentration of rosuvastatin by about 50%. This effect is less pronounced if antacids are applied 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in rosuvastatin AUC_(0-t) and a 30% decrease in rosuvastatin C max. This interaction may occur as a result of increased intestinal motility caused by the use of erythromycin.

Cytochrome P450 isoenzymes

The results of studies conducted in vivo and in vitro showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for this isoenzyme system. Therefore, rosuvastatin is not expected to interact with other drugs at the level of metabolism involving cytochrome P450 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).

Drug interactions that require dose adjustment of rosuvastatin (see table 3)

The dose of Roxera® should be adjusted if it is necessary to use it simultaneously with drugs that increase the exposure of rosuvastatin. If exposure is expected to increase by a factor of 2 or more, the initial dose of Roxera® should be 5 mg once a day.

The maximum daily dose of Roxera® should also be adjusted so that the expected exposure to rosuvastatin does not exceed that for a 40 mg dose taken without concomitant use of drugs that interact with rosuvastatin. For example, the maximum daily dose of Roxera® when used concomitantly 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 rosuvastatin exposure (AUC, data are given in descending order) – results of published clinical studies

Concomitant therapy regimen	Rosuvastatin treatment regimen	Change in rosuvastatin AUC*
Cyclosporine 75-200 mg twice daily,6 months	10 mg once daily,10 days	7.1 x increase
Regorafenib 160 mg once daily,14 days	5 mg once	3.8 x increase
Atazanavir 300 mg / ritonavir 100 mg once daily,8 days	10 mg once	3.1 x increase
Simeprevir 150 mg once a day,7 days	10 mg once	2.8 x increase
Velpatasvir 100 mg once a day	10 mg once	2.7 x increase
Ombitasvir 25 mg / paritaprevir 150 mg / ritonavir 100 mg once daily / dasabuvir 400 mg twice daily,14 days	5 mg once	2.6 x increase
Grazoprevir 200 mg / elbasvir 50 mg once a day,11 days	10 mg once	2.3 x increase
Glecaprevir 400 mg / pibrentasvir 120 mg once daily,7 days	5 mg once daily,7 days	2.2 x increase
Lopinavir 400 mg / ritonavir 100 mg 2 times a day,17 days	20 mg 1 time a day,7 days	2.1 x increase
Clopidogrel 300 mg (loading dose), then 75 mg after 24 hours	20 mg once	2-fold increase in
Gemfibrozil 600 mg 2 times a day,7 days	80 mg once	1.9 x increase
Eltrombopag 75 mg once a day,5 days	10 mg once	1.6-fold increase
Darunavir 600 mg / ritonavir 100 mg 2 times a day,7 days	10 mg 1 time a day,7 days	1.5 x increase
Tipranavir 500 mg / ritonavir 200 mg 2 times a day,11 days	10 mg once	1.4-fold increase
Dronedarone 400 mg 2 times a day	No data available	1.4-fold increase
Itraconazole 200 mg once a day,5 days	10 mg once	**1.4-fold increase
Ezetimibe 10 mg once daily,14 days	10 mg once daily,14 days	**1.2 x increase
Fosamprenavir 700 mg / ritonavir 100 mg 2 times a day,8 days	10 mg once	No changes
Aleglitazar 0.3 mg,7 days	40 mg,7 days	No changes
Silymarin 140 mg 3 times a day,5 days	10 mg once	No changes
Fenofibrate 67 mg 3 times a day,7 days	10 mg,7 days	No changes
Rifampicin 450 mg once a day,7 days	20 mg once	No changes
Ketoconazole 200 mg 2 times a day,7 days	80 mg once	Unchanged
Fluconazole 200 mg once daily,11 days	80 mg single dose	No changes
Erythromycin 500 mg 4 times a day,7 days	80 mg once	20% reduction
Baikalin 50 mg 3 times a day,14 days	20 mg once	47% reduction

*The data presented as multiple changes represent a simple ratio between concomitant use and use of rosuvastatin alone. The data presented as changes in% represent the difference in% of concomitant use compared to the use of rosuvastatin alone.

**Several studies have been conducted to study the interaction of different doses of rosuvastatin, the table shows the most significant change.

Effect of rosuvastatin on other medications

Vitamin K Antagonists

As with other HMG-CoA reductase inhibitors, starting rosuvastatin therapy or increasing its dose in patients taking concomitant vitamin K antagonists (for example, warfarin) may lead to an increase in the international normalized ratio (MHO). Discontinuation of rosuvastatin or reduction of its dose may lead to a decrease in MHO. In such cases, MHO monitoring is recommended.

Oral contraceptives/Hormone replacement therapy (HRT)

Concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and norgestrel by 26% and 34%, respectively. Such an increase in blood plasma concentration should be taken into account when selecting the dose of hormonal contraceptives.

Pharmacokinetic data on the concomitant use of rosuvastatin and HRT are not available, therefore, it is impossible to exclude 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.

Fusidic acid

The risk of developing myopathy, including rhabdomyolysis, may be increased with simultaneous use of systemic fusidic acid and statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) is still unknown. There have been reports of rhabdomyolysis (including fatal outcomes in some cases) in patients receiving concomitant statins and fusidic acid.

If systemic fusidic acid is necessary, rosuvastatin therapy should be discontinued for the entire period of fusidic acid use.

How to take, course of use and dosage

Inside, the tablet should not be chewed or crushed, swallowed whole, washed down with water, it can be taken at any time of the day, regardless of the time of food intake.

Before starting therapy with Roxera®, the patient should begin to follow a standard hypocholesterolemic diet and continue to follow it during treatment. The dose of the drug should be selected individually, depending on the goals of therapy and the therapeutic response to treatment, taking into account national recommendations for target concentrations of lipids in blood plasma.

The recommended starting dose of Roxera® for patients starting to take the drug, or for patients transferred from taking other HMG-CoA reductase inhibitors, should be 5 or 10 mg 1 time per day.

When the drug is co-administered with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), patients are recommended an initial dose of 5 mg/day.

When choosing the initial dose, you should be guided by the individual concentration of cholesterol in the blood plasma and take into account the possible risk of developing cardiovascular complications, as well as the potential risk of adverse reactions (AES). If necessary, the dose can be increased after 4 weeks.

Due to the possible development of AES when using a dose of 40 mg/day compared to lower doses of the drug, increasing the dose to a maximum of 40 mg/day should only be considered in patients with severe hypercholesterolemia and at high risk of developing cardiovascular complications (especially in patients with familial hypercholesterolemia), who did not achieve the desired result of therapy with a dose of 20 mg/day, and who Especially careful monitoring of patients receiving the drug at a dose of 40 mg/day is recommended.

It is not recommended to use a dose of 40 mg / day in patients who have not previously consulted a doctor. After 2-4 weeks of therapy and/or with an increase in the dose of Roxera®, monitoring of lipid metabolism parameters is necessary (if necessary, dose adjustment is required).

Patients with renal insufficiency

In patients with mild or moderate renal insufficiency, no dose adjustment is required. In patients with severe renal insufficiency (creatinine clearance less than 30 ml/min), the use of Roxera® is contraindicated. The use of Roxera® at a dose of more than 30 mg / day in patients with moderate to severe renal insufficiency (creatinine clearance less than 60 ml / min) is contraindicated. In patients with moderate renal insufficiency, the recommended starting dose of Roxera® is 5 mg / day.

Patients with hepatic insufficiency

Roxera® is contraindicated in patients with active liver disease.

Use in elderly patients

No dose adjustment is required.

Ethnic groups

In patients of the Mongolian race, an increase in systemic exposure to rosuvastatin was noted. For patients of the Mongolian race, the recommended initial dose of Roxera® is 5 mg / day, the use of Roxera® at a dose of 40 mg / day is contraindicated.

Genetic polymorphism

Carriers of the SLCO1B1 (OATR 1V1) C. 521CC and ABCG2 (BCRP) C. 421AA genotypes showed an increase in rosuvastatin AUC compared to carriers of the SLCO1B1 C. 521TT and ABCG2 C. 421CC genotypes. For patients with C. 521CC or C. 421 AA genotypes, the recommended maximum dose of Roxera® is 20 mg once a day.

Patients predisposed to myotoxic complications

The use of Roxera® at a dose of 40 mg in patients predisposed to the development of myotoxic complications is contraindicated. If doses of 10-20 mg / day are required, the recommended starting dose for this group of patients is 5 mg / day.

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, OATP1 In 1 and BCRP). Concomitant use of Roxera with medicinal products (such as cyclosporine, certain human immunodeficiency virus (HIV) protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and / or tipranavir) that increase the concentration of rosuvastatin in blood plasma due to interaction with transport proteins may increase the risk of developing myopathy (including rhabdomyolysis). You should read the instructions for use of the above drugs before prescribing them simultaneously with Roxera®. In such cases, the possibility of alternative therapy or temporary discontinuation of Roxera should be evaluated. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with Roxera® should be evaluated and the possibility of reducing its dose should be considered.

Overdose

The clinical picture of overdose is not described. The pharmacokinetic parameters of rosuvastatin do not change with simultaneous use of several daily doses of the drug.

Treatment of overdose is symptomatic and requires monitoring of liver function and serum CPK activity. There is no specific antidote. Hemodialysis is ineffective.

Description

5 mg tablets:

Round, biconvex tablets covered with a white film coating, with a chamfer and an engraving ” 5 ” applied on one side.

View at the break: a white rough mass with a white film shell.

Tablets 10 mg:

Round, biconvex tablets covered with a white film coating, with a chamfer and an engraving ” 10 ” applied on one side.

View at the break: a white rough mass with a white film shell.

Tablets 15 mg:

Round, biconvex tablets covered with a white film coating, with a chamfer and an engraving ” 15 ” applied on one side.

View at the break: a white rough mass with a white film shell.

Tablets 20 mg:

Round, biconvex tablets, white film-coated tablets with a chamfer.

View at the break: a white rough mass with a white film shell.

Tablets 30 mg:

Oblong with rounded ends, biconvex tablets, covered with a film-coated white color, with a risk on both sides.

View at the break: a white rough mass with a white film shell.

Tablets 40 mg:

Oblong with rounded ends, biconvex tablets, covered with a film-coated white color.

View at the break: a white rough mass with a white film shell.

Special instructions

With a daily dose of up to 30 mg

Risk of developing myopathy/rhabdomyolysis – renal failure, hypothyroidism, hereditary muscle diseases in the anamnesis (including family history) and a previous history of muscle toxicity with the use of other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; age over 65 years; conditions in which there is an increase in plasma concentrations of rosuvastatin; race (Mongoloid race-Japanese and Chinese); concomitant use of rosuvastatin in the blood. patients with fibrates; a history of liver disease; sepsis; hypotension; extensive surgery; injuries; severe metabolic, endocrine or electrolyte disorders; uncontrolled seizures; concomitant use with ezetimibe.

With a daily dose of 30 mg or more

Mild renal insufficiency (creatinine clearance greater than 60 ml / min); age over 65 years; history of liver disease; sepsis; hypotension; extensive surgery; injuries; severe metabolic, endocrine or electrolyte disorders; uncontrolled seizures; concomitant use with ezetimibe.

Contraindicated in persons under 18 years of age.

Patients with renal insufficiency

In patients with mild or moderate renal insufficiency, no dose adjustment is required. In patients with severe renal insufficiency (creatinine clearance less than 30 ml/min), the use of Roxera® is contraindicated. The use of Roxera® at a dose of more than 30 mg / day in patients with moderate to severe renal insufficiency (creatinine clearance less than 60 ml / min) is contraindicated. In patients with moderate renal insufficiency, the recommended starting dose of Roxera® is 5 mg / day.

Patients with hepatic insufficiency

Roxera® is contraindicated in patients with active liver disease.

Use in elderly patients

No dose adjustment is required.

Impaired renal function

In patients receiving high doses of rosuvastatin (in particular,40 mg/day), tubular proteinuria was observed, which was detected using test strips and in most cases was periodic or short-term. Such proteinuria does not indicate an acute disease or progression of concomitant kidney disease. The incidence of serious renal impairment observed in the post-marketing study of rosuvastatin is higher with a dose of 40 mg / day. In patients taking Roxera® at a dose of 30 or 40 mg/day, it is recommended to monitor renal function indicators during treatment (at least once every 3 months).

Impact on the musculoskeletal system

The following effects on the musculoskeletal system have been reported with rosuvastatin at all doses, but especially at doses exceeding 20 mg / day: myalgia, myopathy, and in rare cases rhabdomyolysis. Very rare cases of rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors and ezetimibe. This combination should be used with caution, as pharmacodynamic interactions cannot be excluded.

As with other HMG-CoA reductase inhibitors, the incidence of rhabdomyolysis with post-marketing use of rosuvastatin is higher with a dose of 40 mg / day.

Determination of serum CPK activity

The serum activity of CPK cannot be determined after intense physical exertion and in the presence of other possible reasons for increasing its activity, this may lead to incorrect interpretation of the results obtained. If the initial serum CPK activity is significantly exceeded (5 times higher than the upper limit of normal), a second analysis should be performed after 5-7 days. You should not start therapy if the results of repeated analysis confirm the initial high serum activity of CKK (more than 5 times the upper limit of normal).

Before starting therapy

Depending on the daily dose, Roxera should be used with caution in patients with existing risk factors for myopathy/rhabdomyolysis.

These factors include:

• impaired renal function,
• hypothyroidism,
• a history of muscle diseases (including a family history),
• myotoxic events when taking other HMG-CoA reductase inhibitors or fibrates in the anamnesis,
• excessive alcohol consumption,
• age over 65 years,
• conditions in which the concentration of rosuvastatin in blood plasma may increase,
• simultaneous use of fibrates.

In such patients, it is necessary to assess the risk and possible benefit of therapy. Clinical monitoring is also recommended. If the initial serum CPK activity is more than 5 times higher than the upper limit of normal, therapy with Roxera® should not be initiated.

During drug therapy

The patient should be informed of the need for immediate notification to the doctor in case of unexpected occurrence of muscle pain, muscle weakness or spasms, especially in combination with malaise and fever. In such patients, the serum activity of CPK should be determined. Therapy should be discontinued if the serum activity of CPK is significantly increased (more than 5 times the upper limit of normal), or if muscle symptoms are severe and cause daily discomfort (even if the serum activity of CPK is no more than 5 times the upper limit of normal). If symptoms disappear and serum CPK activity returns to normal, consideration should be given to resuming the use of Roxera® or other HMG-CoA reductase inhibitors in lower doses, with careful medical supervision. Monitoring of serum CPK activity in the absence of symptoms is impractical.

Very rare cases of immuno-mediated necrotizing myopathy with clinical manifestations in the form of persistent weakness of the proximal muscles and increased activity of CPK in the blood serum were noted during therapy or upon discontinuation of HMG-CoA reductase inhibitors, including rosuvastatin. Additional studies of the muscular and nervous system, serological studies, and immunosuppressive therapy may be required.

There were no signs of increased effects on skeletal muscle with rosuvastatin and concomitant therapy. However, an increase in myositis and myopathy has been reported in patients treated with other HMG-CoA reductase inhibitors in combination with fibroic acid derivatives (e. g. gemfibrozil), cyclosporine, nicotinic acid in lipid – lowering doses (more than 1 g/day), antifungal agents such as azole derivatives, HIV protease inhibitors, and macrolide antibiotics.

When used concomitantly with certain HMG-CoA reductase inhibitors, gemfibrozil increases the risk of developing myopathy. Therefore, concomitant use of Roxera and gemfibrozil is not recommended. The benefits of further changes in plasma lipid concentrations when Roxera is combined with fibrates or nicotinic acid in lipid-lowering doses should be carefully weighed against the possible risk. The drug Roxera® at a dose of 30 mg / day is contraindicated for combination therapy with fibrates.

Roxera should not be used concomitantly or for 7 days after discontinuation of systemic fusidic acid therapy. In patients in whom the use of fusidic acid is considered necessary, statin therapy should be discontinued for the entire period of fusidic acid therapy. There have been reports of rhabdomyolysis (including fatal outcomes in some cases) in patients receiving fusidic acid concomitantly with statins. The patient should seek immediate medical attention if any symptoms of muscle weakness, pain, or soreness occur.

Therapy with Roxera® can be resumed 7 days after the last dose of fusidic acid.

In exceptional cases where long-term use of systemic fusidic acid is required, for example, in the treatment of severe infections, the need for simultaneous use of Roxera® and fusidic acid should be considered individually and subject to careful medical supervision.

Due to the increased risk of rhabdomyolysis, Roxera® should not be used in patients with acute conditions that may lead to myopathy or conditions predisposing to the development of renal failure (for example, sepsis, hypotension, extensive surgery, trauma, severe metabolic, endocrine or electrolyte disorders, uncontrolled seizures).

In 2-4 weeks after the start of treatment and/or when increasing the dose of Roxera®, monitoring of lipid metabolism parameters is necessary (if necessary, dose adjustment is required).

The liver

Depending on the daily dose, Roxera® should be used with caution in patients with excessive alcohol consumption and/or in patients with a history of liver disease, or its use is contraindicated.sections “Contraindications” and “With caution”).

It is recommended to determine liver function tests before the start of therapy and 3 months after its start. The use of Roxera® should be discontinued or the dose of the drug should be reduced if the activity of “hepatic” 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 of the underlying diseases should be performed before starting treatment with Roxera®.

Ethnic features

In the course of pharmacokinetic studies, an increase in the plasma concentration of rosuvastatin was observed in representatives of the Mongolian race compared with representatives of the Caucasian race.

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with the use of certain HMG-CoA reductase inhibitors, especially for a long time. Symptoms of the disease may include shortness of breath, an unproductive cough, and poor overall health (weakness, weight loss, and fever).

If interstitial lung disease is suspected, HMG-CoA reductase inhibitors should be discontinued.

Type 2 diabetes mellitus

In patients with a glucose concentration of 5.6 to 6.9 mmol / L, rosuvastatin therapy was associated with an increased risk of developing type 2 diabetes.

HIV protease inhibitors

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

Special information on excipients

Roxera ® contains lactose, so it is contraindicated in patients with lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Studies on the effect of rosuvastatin on the ability to drive vehicles and work with mechanisms have not been conducted. However, taking into account the possibility of developing dizziness and other AES, care should be taken when driving vehicles and other mechanisms that require increased concentration of attention and speed of psychomotor reactions.

Form of production

Film-coated tablets,5 mg,10 mg,15 mg,20 mg,30 mg,40 mg.

During production at JSC “KRKA, D. D., Novo Mesto”, Slovenia:

Film-coated tablets, 5 mg,10 mg,15 mg and 20 mg:

10 or 14 tablets in a blister of combined OPA / Al material/PVC-aluminum foil.

1,2,3,6 or 9 blisters (10 tablets each), or 1,2,4 or 6 blisters (14 tablets each) together with the instructions for use are placed in a cardboard pack.

Film-coated tablets,30 mg and 40 mg:

7 or 10 tablets in a blister of combined OPA / Al material/PVC-aluminum foil.

2,4,8 or 12 blisters (7 tablets each), or 1,2,3,6 or 9 blisters (10 tablets each) together with the instructions for use are placed in a cardboard pack.

During production at KRKA-RUS LLC, Russia:

Film-coated tablets,5 mg,10 mg,15 mg and 20 mg:

10 or 14 tablets in a contour cell package made of a combined material OPA / Al / PVC-aluminum foil.

1,2,3,6 or 9 contour cell packages (10 tablets each), or 1,2,4 or 6 contour cell packages (14 tablets each) together with the instructions for use are placed in a cardboard pack.

Film-coated tablets,30 mg and 40 mg:

7 or 10 tablets in a contour cell package made of combined OPA/Al material/PVC-aluminum foil.

2,4,8 or 12 contour cell packages (7 tablets each), or 1,2,3,6 or 9 contour cell packages (10 tablets each) together with the instructions for use are placed in a cardboard pack.

Storage conditions

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging.

Keep out of reach of children.

Shelf

life is 3 years.

Do not use the drug after the expiration date.

Active ingredient

Rosuvastatin

Conditions of release from pharmacies

By prescription

Dosage form

Tablets