Rozistark^® (Tablets) Instructions for Use

ATC Code

C10AA07 (Rosuvastatin)

Active Substance

Rosuvastatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

A hypolipidemic agent from the group of statins, an HMG-CoA reductase inhibitor. Through the principle of competitive antagonism, the statin molecule binds to the part of the coenzyme A receptor where this enzyme attaches. Another part of the statin molecule inhibits the process of converting hydroxymethylglutaryl-CoA to mevalonate, an intermediate product in the synthesis of the cholesterol molecule. Inhibition of HMG-CoA reductase activity leads to a series of sequential reactions, resulting in a decrease in intracellular cholesterol content and a compensatory increase in LDL receptor activity and, accordingly, an acceleration of LDL cholesterol (LDL-C) catabolism.

The hypolipidemic effect of statins is associated with a decrease in total cholesterol levels due to LDL-C. The reduction in LDL levels is dose-dependent and is not linear but exponential in nature.

Statins do not affect the activity of lipoprotein and hepatic lipases and do not have a significant effect on the synthesis and catabolism of free fatty acids; therefore, their effect on TG levels is secondary and mediated through their primary effects of lowering LDL-C levels. The moderate reduction in TG levels during statin treatment is likely associated with the expression of remnant (apo E) receptors on the surface of hepatocytes, which are involved in the catabolism of IDL, which contains approximately 30% TG.

In addition to their hypolipidemic effect, statins have a positive effect on endothelial dysfunction (a preclinical sign of early atherosclerosis), the vascular wall, the state of atheroma, improve the rheological properties of blood, and possess antioxidant and antiproliferative properties.

The therapeutic effect appears within 1 week after the start of therapy and reaches 90% of the maximum possible effect after 2 weeks of treatment, which is usually achieved by the 4th week and thereafter remains constant.

Pharmacokinetics

After oral administration, the C_max of rosuvastatin in plasma is reached in approximately 5 hours. Bioavailability is approximately 20%.

Rosuvastatin accumulates in the liver. The V_d is approximately 134 L. Binding to plasma proteins (mainly albumin) is approximately 90%.

It is biotransformed to a small extent (about 10%), being a non-profile substrate for the cytochrome P450 system isoenzymes. The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9. Isoenzymes CYP2C19, CYP3A4, and CYP2D6 are involved in the metabolism to a lesser extent.

The main identified metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N-desmethyl is approximately 50% less active than rosuvastatin; lactone metabolites are pharmacologically inactive.

About 90% of the rosuvastatin dose is excreted unchanged in the feces. The remainder is excreted in the urine. The plasma T_1/2 is approximately 19 hours. The T_1/2 does not change with increasing dose. The mean plasma clearance is approximately 50 L/h (coefficient of variation 21.7%).

As with other HMG-CoA reductase inhibitors, the membrane cholesterol transporter, which plays an important role in the hepatic elimination of rosuvastatin, is involved in the process of hepatic uptake of rosuvastatin.

The systemic exposure of rosuvastatin increases proportionally to the dose.

In patients with severe renal impairment (CrCl<30 mL/min), the plasma concentration of rosuvastatin is 3 times higher, and the concentration of N-desmethyl is 9 times higher than in healthy volunteers. The plasma concentration of rosuvastatin in patients on hemodialysis was approximately 50% higher than in healthy volunteers.

In patients with hepatic impairment classified as Child-Pugh scores 8 and 9, an increase in T_1/2 of at least 2 times was noted.

Indications

Hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an adjunct to diet, when diet and other non-pharmacological treatments (e.g., exercise, weight loss) are insufficient.

Familial homozygous hypercholesterolemia as an adjunct to diet and other cholesterol-lowering therapy or in cases where such therapy is not suitable for the patient.

ICD codes

Dosage Regimen

Tablets

Take orally. The recommended starting dose is 10 mg once daily. If necessary, the dose can be increased to 20 mg after 4 weeks. Increasing the dose to 40 mg is possible only in patients with severe hypercholesterolemia and high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) with insufficient efficacy at a dose of 20 mg and under medical supervision.

Adverse Reactions

From the nervous system: common – headache, dizziness, asthenic syndrome; possible – anxiety, depression, insomnia, neuralgia, paresthesia.

From the digestive system: common – constipation, nausea, abdominal pain; possible – reversible transient dose-dependent increase in liver transaminase activity, dyspepsia (including diarrhea, flatulence, vomiting), gastritis, gastroenteritis.

From the respiratory system: common – pharyngitis; possible – rhinitis, sinusitis, bronchial asthma, bronchitis, cough, dyspnea, pneumonia.

From the cardiovascular system: possible – angina pectoris, increased blood pressure, palpitations, vasodilation.

From the musculoskeletal system: common – myalgia; possible – arthralgia, arthritis, muscle hypertonia, back pain, pathological fracture of a limb (without injury); rare – myopathy, rhabdomyolysis (concomitant with renal impairment, while taking rosuvastatin at a dose of 40 mg); frequency unknown – occurrence or exacerbation of myasthenia.

From the urinary system: tubular proteinuria (in less than 1% of cases – for doses of 10 and 20 mg, 3% of cases – for a dose of 40 mg); possible – peripheral edema (hands, feet, ankles, shins), lower abdominal pain, urinary tract infections.

From the organ of vision: frequency unknown – ocular myasthenia.

Allergic reactions: possible – skin rash, skin itching; rare – angioedema.

From laboratory parameters: transient dose-dependent increase in CPK activity (if CPK activity increases more than 5 times compared to the ULN, therapy should be temporarily discontinued).

Other: common – asthenic syndrome; possible – accidental injury, anemia, chest pain, diabetes mellitus, ecchymosis, flu-like syndrome, periodontal abscess.

Contraindications

Active liver disease (including persistent elevation of liver transaminases or any elevation of transaminases more than 3 times the ULN), severe renal impairment (CrCl<30 mL/min), myopathy, concurrent use of cyclosporine, pregnancy, lactation (breastfeeding), women of reproductive potential not using adequate contraception, children and adolescents under 18 years of age, hypersensitivity to rosuvastatin.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Do not use in women of reproductive potential not using reliable methods of contraception.

Use in Hepatic Impairment

Contraindicated in active liver disease (including persistent elevation of liver transaminases or any elevation of transaminases more than 3 times the ULN).

Use in Renal Impairment

Contraindicated in severe renal impairment (CrCl<30 mL/min).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age (since efficacy and safety have not been established).

Special Precautions

Use with caution in the presence of risk factors for rhabdomyolysis (including renal failure, hypothyroidism, personal or family history of hereditary muscle disorders, and previous history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates), in chronic alcoholism, in patients over 65 years of age, with a history of liver disease, sepsis, arterial hypotension, during major surgical procedures, trauma, severe metabolic, endocrine, or electrolyte disturbances, in uncontrolled epilepsy, in persons of Asian origin (Chinese, Japanese).

Therapy should be discontinued if the CPK level is significantly increased (more than 5 times the ULN) or if muscle symptoms are severe and cause daily discomfort (even if the CPK level is less than 5 times the ULN).

When using rosuvastatin at a dose of 40 mg, it is recommended to monitor renal function parameters.

In most cases, proteinuria decreases or disappears during therapy and does not indicate the occurrence of acute or progression of existing kidney disease.

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, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when co-administered with some HMG-CoA reductase inhibitors. Therefore, the simultaneous administration of rosuvastatin and gemfibrozil is not recommended. The risk-benefit ratio should be carefully weighed when using rosuvastatin concomitantly with fibrates or niacin.

It is recommended to determine liver function parameters before starting therapy and 3 months after starting therapy. The use of rosuvastatin should be discontinued or the dose reduced if the serum transaminase activity level exceeds 3 times the ULN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy for the underlying diseases should be carried out before starting treatment with rosuvastatin.

Effect on ability to drive vehicles and operate machinery

When engaging in potentially hazardous activities, patients should consider that dizziness may occur during therapy.

Drug Interactions

With simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers, while the plasma concentration of cyclosporine did not change.

Initiating rosuvastatin therapy or increasing the dose of the drug in patients simultaneously receiving vitamin K antagonists (e.g., warfarin) may lead to an increase in prothrombin time and INR, and discontinuation of rosuvastatin or dose reduction may lead to a decrease in INR (in such cases, monitoring of INR is recommended).

Concomitant use of rosuvastatin and gemfibrozil leads to a 2-fold increase in C_max in plasma and AUC of rosuvastatin.

Simultaneous use of rosuvastatin and antacids containing aluminum and magnesium hydroxide leads to a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect is less pronounced if antacids are taken 2 hours after taking rosuvastatin (clinical significance unknown).

Simultaneous use of rosuvastatin and erythromycin leads to a decrease in the AUC of rosuvastatin by 20% and C_max of rosuvastatin by 30% (probably as a result of increased intestinal motility caused by taking erythromycin).

Simultaneous use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and the AUC of norgestrel by 26% and 34%, respectively. Such interaction cannot be excluded with simultaneous use of rosuvastatin and hormone replacement therapy.

Gemfibrozil, other fibrates, and hypolipidemic doses of nicotinic acid (≥1 g/day) increased the risk of myopathy when used concomitantly with other HMG-CoA reductase inhibitors, possibly because they can cause myopathy when used as monotherapy.

Concomitant use of rosuvastatin and itraconazole (a CYP3A4 inhibitor) increases the AUC of rosuvastatin by 28% (clinically insignificant).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.