Rosuvastatin-SZ, 5 mg 90 pcs

Pharmacotherapeutic drug group:

Hypolipidemic drug – HMG-CoA reductase inhibitor

ATX code: [C10AA07]

Pharmacological Properties

.Pharmacodynamics

Mechanism of action

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

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

Pharmacodynamics

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

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

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

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

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

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

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

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

According to the results of clinical studies, patients with significant hypercholesterolemia and high risk of cardiovascular disease (CVD) should be prescribed a dose of Rosuvastatin-SZ 40 mg.

The results of a clinical trial (Rationale for Statins in Primary Prevention: The Rosuvastatin Interventional Evaluation Study) showed that rosuvastatin significantly reduced the risk of cardiovascular complications.

Pharmacokinetics

Absorption and distribution

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

Rosuvastatin is metabolized primarily by the liver, which is the main site of cholesterol synthesis and metabolism of LDL-C. The volume of distribution of rosuvastatin is

approximately 134 liters. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by enzymes of cytochrome P450 system. The main isoenzyme involved in metabolism of rosuvastatin is CYP2C9 isoenzyme. CYP2C19, CYPZA4 and CYP2D6 isoenzymes are less involved in metabolism.

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

Elimation

About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin). The remaining part is excreted by the kidneys. Plasma elimination half-life (T_1/2) is approximately 19 hours. The elimination half-life 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, the membrane cholesterol transporter, which plays an important role in hepatic elimination of rosuvastatin, is involved in the “hepatic” uptake of rosuvastatin.

Linearity

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

Particular patient populations. Age and sex

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

Ethnic groups

. Pharmacokinetic studies have shown an approximately two-fold increase in median AUC (area under the concentration-time curve) and Cmax (maximum plasma concentration) of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipino, Vietnamese, and Korean) compared with Caucasians; Hindus showed a 1.3-fold increase in median AU and Cmax. Pharmacokinetic analysis showed no clinically significant differences in pharmacokinetics among Caucasians and non-Hispanics.

Renal failure

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

Hepatic failure

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

Genetic polymorphism

. HMG-CoA reductase inhibitors, including rosuvastatin, bind to the transport proteins OATP1B1 (an 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.421AAA genotypes had 1.6 and 2.4-fold increased exposure (AUC) to rosuvastatin compared with SLCO1B1 c.521TT and ABCG2 c.421CC genotypes, respectively.

Indications

Primary Fredrickson hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an adjunct to diet when diet and other nonmedicamental treatments (e.g. exercise, weight loss) are not sufficient.

• Family homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (e.g., LDL-apheresis), or in cases where such therapy is not sufficiently effective.
• Hypertriglyceridemia (type IV according to Fredrickson classification) as adjunct to diet.
• To slow the progression of atherosclerosis, as adjunct to diet in patients who are indicated for therapy to reduce total and LDL-C concentrations.
• .Primary prevention of major cardiovascular complications (stroke, infarction, arterial revascularization) in adult patients without clinical signs of CHD, but with an increased risk of its development (age over 50 years for men and over 60 years for women, elevated C-reactive protein concentration (more than 2 mg/L) with at least one additional risk factor, such as hypertension, low HDL-C, smoking, family history of early-onset CHD).

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Active ingredient

Rosuvastatin

Composition

Dosage 5 mg
Active ingredient: calcium rosuvastatin in terms of rosuvastatin – 5 mg.
Excipients:
core – lactose monohydrate (milk sugar) – 32.9 mg; calcium hydrophosphate dihydrate – 5.0 mg; povidone (polyvinylpyrrolidone medium molecular) – 3.0 mg; Croscarmellose sodium (primellose) – 3.0 mg; sodium stearyl fumarate – 0.8 mg; colloidal silica (aerosil) – 0.3 mg; microcrystalline cellulose – 30.0 mg;

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 before starting therapy with Rosuvastatin-SZ and continue it during treatment. The dose of the drug should be adjusted individually depending on the goals of therapy and the therapeutic response to treatment, taking into account current recommendations for target lipid concentrations.

The recommended starting dose for patients starting therapy or switching from other HMG-CoA reductase inhibitors should be 5 mg or 10 mg of Rosuvastatin-CZ once daily. When choosing the initial dose, the individual cholesterol content 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 may be

increased to a higher dose after 4 weeks (see section “Pharmacodynamics”).

Because of the possible development of side effects when taking a dose of 40 mg, compared to lower doses of the drug (see section “Side Effects”).

Particularly in patients with severe hypercholesterolemia and 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 monitored by a specialist (see section “Special considerations”), an increase in dose to 40 mg, after additional dosing above the recommended initial dose for 4 weeks of therapy, may only be undertaken.) 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 increasing the dose of Rosuvastatin-SZ, monitoring of lipid metabolism is necessary (if necessary, a dose adjustment is required).

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 failure (CKD less than 30 ml/min) the use of Rosuvastatin-SZ is contraindicated. The use of the drug in dose of 40 mg is contraindicated in patients with moderate renal impairment (CK 30-60 ml/min) (see sections “Special Indications” and “Pharmacodynamics”).

In patients with moderate renal dysfunction, a starting dose of 5 mg is recommended.

Patients with hepatic impairment

Rosuvastatin-CS is contraindicated in patients with active liver disease (see section “Contraindications”).

Special populations. Ethnic groups

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

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

Genetic polymorphisms

Carriers of SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRR) c.421AA had increased exposure (AUC) to rosuvastatin compared with SLCO1B1 c.521TT and ABCG2 c.421CC genotype carriers. For c.521CC or c.421AA genotype carriers, the recommended maximum dose of Rosuvastatin-CZ is 20 mg once daily (see sections “Pharmacokinetics” and “Precautions” and “Interaction with Other Medicinal Products”).

Patients susceptible 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 doses of 10 mg and 20 mg are prescribed, 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 VSRP). When co-administration of Rosuvastatin-CZ with drugs (such as cyclosporine, some HIV protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase the plasma concentration of rosuvastatin due to interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may increase (see sections “Cautions” and “Interaction with other medicinal products”). In such cases, the possibility of prescribing alternative therapy or temporary discontinuation of Rosuvastatin-CZ should be assessed. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with Rosuvastatin-SZ should be assessed and the possibility of reducing its dose should be considered (see section “Interaction with other medicinal products”).

Interaction

Influence of other drugs on rosuvastatin

Inhibitors of transport proteins:

Rosuvastatin binds to some transport proteins, particularly 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 1 and sections “Administration and Doses” and “Cautionary Note”).

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

Human immunodeficiency virus (HIV) protease inhibitors:

While the exact mechanism of interaction is unknown, co-administration of HIV protease inhibitors may result in a significant increase in rosuvastatin exposure (see Table 1). 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 Cmax of rosuvastatin, respectively. Therefore, concomitant administration of rosuvastatin and HIV protease inhibitors is not recommended (see sections “Dosage and administration”, “Contraindications” and “Special indications”, Table 1).

Hemfibrozil and other hypolipidemic agents: The co-administration of rosuvastatin and gemfibrozil results in a 2-fold increase in the maximum plasma concentration of rosuvastatin and the AUC of rosuvastatin (see “Special Indications”). Based on the data on specific interactions, no pharmacokinetic interaction with fenofibrate is expected, pharmacodynamic interaction is possible.

Hemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of nicotinic acid increased the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly due to the fact that they may cause myopathy when used in monotherapy (see section “Special Instructions”). In concomitant use of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day) patients are recommended to take an initial dose of the drug of 5 mg, taking a dose of 40 mg is contraindicated in concomitant administration with fibrates (see sections “Contraindications”, “Dosage and administration”, “Special indications”).

Ezetimibe: Concomitant administration of Rosuvastatin-SZ at dose 10 mg and ezetimibe at dose 10 mg was associated with increased AUC of rosuvastatin in patients with hypercholesterolemia (see Table 1). An increased risk of adverse events due to pharmacodynamic interaction between rosuvastatin-CZ and ezetimibe cannot be excluded.

Antacids: Simultaneous use of rosuvastatin and suspensions of antacids containing aluminum and magnesium hydroxide leads to a decrease in 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.

Eritromycin: Simultaneous 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: The results of in vivo and in vitro studies showed 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 (inhibitor of CYP2C9 and CYPCA4 isoenzymes) and ketoconazole (inhibitor of CYP2A6 and CYPCA4 isoenzymes) was observed.

Drug interactions that require dose adjustment of rosuvastatin (see. Table 1)

The dose of Rosuvastatin-SZ should be adjusted if it is necessary to combine it with drugs that increase exposure to rosuvastatin. If an increase in exposure is expected by a factor of 2 or more, the initial dose of Rosuvastatin-SZ should be 5 mg once daily. The maximum daily dose of Rosuvastatin-SZ should also be adjusted so that the expected exposure to rosuvastatin does not exceed that of the 40 mg dose taken without concomitant administration of drugs that interact with rosuvastatin. For example, maximal daily dose of drug Rosuvastatin-SZ in concomitant use with gemfibrozil is 20 mg (1.9-fold increase of exposure), with ritonavir/atazanavir – 10 mg (3.1-fold increase of exposure).

Table 1.

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

Influence of rosuvastatin use on other drugs

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

In combination use of oral contraceptives/hormone replacement therapy: The simultaneous use of rosuvastatin and oral contraceptives increases AUC of ethinylestradiol and AUC of nogestrel by 26% and 34%, respectively. This increase in plasma concentration should be considered when selecting a dose of oral contraceptives. There are no pharmacokinetic data on concomitant use of Rosuvastatin-CZ and hormone replacement therapy, therefore, a similar effect cannot be excluded when using this combination. However, this combination was widely used during clinical trials and was well tolerated by patients.

Other drugs: No clinically significant interaction of rosuvastatin with digoxin is expected.