Rosuvastatin-SZ, 60 pcs., 20 mg, film-coated tablets

Rosuvastatin-SZ, 60 pcs., 20 mg, film-coated tablets

Renal effects

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

From the musculoskeletal system

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

Determination of CPK

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

Before starting therapy

When prescribing Rosuvastatin-SZ, as well as when prescribing other HMG-CoA reductase inhibitors, caution should be exercised in patients with existing risk factors for myopathy/rhabdomyolysis (see Caution

), it is necessary to consider the balance of risk and possible benefit of therapy and conduct clinical observation.

During therapy

The patient should be informed to immediately notify the doctor if there is a sudden onset of muscle pain, muscle weakness or spasms, especially in combination with malaise and fever. In such patients, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (more than 5 times compared to ULN) or muscle symptoms are severe and cause daily discomfort (even if CPK activity is 5 times less than ULN). If symptoms disappear and CPK activity returns to normal, re-prescribing Rosuvastatin-SZ or other HMG-CoA reductase inhibitors in lower doses should be considered with careful monitoring of the patient.

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

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

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

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

Liver

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

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

Ethnic groups

In pharmacokinetic studies, an increase in systemic concentrations of rosuvastatin was noted in Chinese and Japanese patients compared to Caucasian patients (see “Pharmacokinetics” and “Dosage and Administration”).

HIV protease inhibitors

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

Lactose

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

Interstitial lung disease

Isolated cases of interstitial lung disease have been reported with some statins, especially over long periods of use. Manifestations of the disease may include shortness of breath, non-productive cough and deterioration in general health (weakness, weight loss and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus type 2

In patients with glucose concentrations between 5.6 and 6.9 mmol/L, treatment with Rosuvastatin-SZ was associated with an increased risk of developing type 2 diabetes mellitus.

Impact on the ability to drive vehicles and operate machinery.

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

Nosological classification (ICD-10)

• E78.0 Pure hypercholesterolemia
• E78.1 Pure hyperglyceridemia
• E78.2 Mixed hyperlipidemia
• E78.5 Hyperlipidemia, unspecified
• I10 Essential (primary) hypertension
• I15 Secondary hypertension
• I21 Acute myocardial infarction
• I25.9 Chronic ischemic heart disease, unspecified
• I64 Stroke not specified as hemorrhage or infarction
• I70 Atherosclerosis
• Z72.0 Tobacco use
• Z82.4 Family history of coronary heart disease and other diseases of the cardiovascular system

Compound

Pharmacokinetics

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

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

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

Excretion. 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 T1/2 is approximately 19 hours. T1/2 does not change with increasing doses of the drug. The geometric mean plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the process of hepatic uptake of rosuvastatin involves a membrane cholesterol transporter, which plays an important role in the hepatic elimination of rosuvastatin.

Linearity

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

Special patient groups

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

Ethnic groups. Pharmacokinetic studies have shown an approximately twofold increase in the median AUC and Cmax of rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared to Caucasians; Indians showed a 1.3-fold increase in median AUC and Cmax. Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasians and representatives of the Negroid race.

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

Liver dysfunction. In patients with various stages of liver failure (7 points and below on the Child-Pugh scale), an increase in T1/2 of rosuvastatin was not detected. In two patients with 8 and 9 points on the Child-Pugh scale, an increase in T1/2 was noted by at least 2 times. 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, incl. rosuvastatin 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 had an increase in rosuvastatin exposure (AUC) by 1.6 and 2.4 times, respectively, compared with carriers of the SLCO1B1 c.521TT and ABCG2 c.421CC genotypes.

Use during pregnancy and breastfeeding

Rosuvastatin-SZ is contraindicated during pregnancy and breastfeeding.

Women of reproductive age should use adequate methods of contraception.

Since cholesterol and cholesterol biosynthesis products are important for fetal development, the potential risk of inhibiting HMG-CoA reductase outweighs the benefit of using the drug in pregnant women.

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

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