Rosistarck, 20 mg 28 pcs.

Hypolipidemic drug from the group of statins, HMG-CoA reductase inhibitor. By the principle of competitive antagonism, statin molecule binds to the part of coenzyme A receptor, where this enzyme is attached. The other part of the statin molecule inhibits the conversion of hydroxymethylglutarate into 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 of intracellular cholesterol content and a compensatory increase of LDL-receptor activity and corresponding acceleration of LDL cholesterol (Xc) catabolism.

The hypolipidemic effect of statins is associated with a decrease in total Xc levels at the expense of LDL Xc. The decrease in LDL levels is dose-dependent and is exponential rather than linear.

The statins do not affect the activity of lipoprotein and hepatic lipases and have no significant effect on the synthesis and catabolism of free fatty acids, so their effect on TG levels is secondary and mediated through their main effects on reducing LDL-C levels. A moderate decrease in TG levels during treatment with statins appears to be due to the expression of remnant (apo E) receptors on the surface of hepatocytes involved in catabolism of LDL, which includes approximately 30% of TG.

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

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

Indications

– primary hypercholesterolemia (Fredrickson type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (Fredrickson type IIb) as an adjunct to diet when diet and other nonmedicamental therapies (eg, exercise, weight loss) are insufficient;

– a homozygous form of hereditary hypercholesterolemia as an adjunct to diet and other lipid-lowering therapy (such as LDL-apheresis) or when such therapy is not sufficiently effective;

– hypertriglyceridemia (Fredrickson type IV) as a dietary supplement;

– to slow the progression of atherosclerosis as a dietary supplement in patients who are indicated for therapy to reduce total CHs and LDL-C concentrations;

– Reducing the risk of major cardiovascular complications (cardiovascular death, stroke, heart attack, unstable angina, and arterial revascularization) in adult patients with a history of increased risk factors for cardiovascular complications of atherosclerosis (such as, elevated C-reactive protein concentration, age, arterial hypertension, low HDL-C concentration, smoking and a family history of early onset CHD);

. – primary prevention of major cardiovascular complications (stroke, heart attack, arterial revascularization) in adult patients without clinical signs of CHD but with an increased risk of developing it (age over 50 years for men and over 60 years for women, elevated concentration of C-reactive protein (>2 mg/L) in the presence of at least one additional risk factor, such as arterial hypertension, low concentration of HDL-C, smoking, family history of early CHD).

Active ingredient

Composition

1 tablet rosuvastatin calcium 20.8 mg, which corresponds to the content of rosuvastatin 20 mg

Excipients:

Lactose monohydrate – 179.28 mg,

microcrystalline cellulose – 85.37 mg,

crospovidone – 12 mg,

magnesium stearate – 2.55 mg.

Shell composition:

lactose monohydrate – 3.6 mg,

hypromellose – 2.52 mg,

titanium dioxide – 2.1555 mg,

triacetin – 0.72 mg,

quinoline yellow – 0.0045 mg.

How to take, the dosage

The drug is taken orally. The tablet should be swallowed whole with water, without chewing or crushing. The drug can be taken at any time of the day regardless of meals.

Before starting treatment, patients should begin a diet of low cholesterol foods, which should be continued for the duration of treatment.

The dose of the drug should be adjusted individually depending on the goals of therapy and response to treatment, taking into account current accepted recommendations for target lipid concentrations.

When a 5-mg dose is necessary, it is recommended that rosuvastatin be used in another dosage form or dosage form, such as 5-mg tablets or 10-mg tablets with a rice (the 10-mg tablet should be divided into two parts by rice).

The recommended starting dose of the drug is 5 mg or 10 mg once daily both for patients who have not previously taken statins and for patients switched to this drug after therapy with other HMG-CoA reductase inhibitors. When choosing the initial dose, the cholesterol level in each individual patient should be taken into account and the possible risk of cardiovascular complications should be taken into account, as well as the potential risk of side effects. If necessary, the dose may be increased after 4 weeks.

. Because of possible development of side effects when using 40 mg dose, compared to lower doses of the drug, titration to a maximum dose of 40 mg during 4 weeks of therapy can be conducted only in patients with severe hypercholesterolemia and with high risk of cardiovascular complications (especially in patients with hereditary hypercholesterolemia) in whom the desired therapy effect was not achieved with 20 mg dose, and who will be under medical supervision.

When prescribing the drug in a dose of 40 mg, close patient monitoring is recommended. Administration of 40 mg is not recommended in patients who have not previously seen a physician.

After 2-4 weeks of therapy and/or if the drug dose is increased, lipid metabolism parameters should be monitored; if necessary, the dose should be adjusted.

The dose of the drug should be adjusted if it is necessary to combine it with drugs that increase exposure to rosuvastatin. If an increase in exposure of 2 or more times is expected, the initial dose of the drug should be 5 mg once daily. The maximum daily dose should also be adjusted so that the expected exposure to rosuvastatin does not exceed that of a 40 mg dose taken without concomitant administration of drugs that interact with rosuvastatin (see section “Interaction with other medicinal products” in Table 1).

Patients of advanced age do not require dose adjustment.

In patients with mild to moderate renal failure, no dose adjustment is required. In patients with severe renal failure (CKD)

The drug is contraindicated in patients with active liver disease.

In patients of mongoloid race there may be increased systemic concentration of rosuvastatin. This fact should be taken into account when prescribing the drug in these groups of patients. When administering the drug in doses of 10 mg and 20 mg the recommended initial dose of the drug for Mongoloid patients is 5 mg. The use of the drug in a dose of 40 mg is contraindicated in these patients.

When the drug is prescribed in doses of 10 mg and 20 mg, the recommended starting dose for patients with predisposition to myopathy is 5 mg. The use of the drug in a dose of 40 mg is contraindicated in such patients.

Interaction

Transport protein inhibitors: Rosuvastatin binds to some transport proteins, in particular to OATP1B1 and HSCP. 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 “Cautions”).

Cyclosporine: Concomitant use of rosuvastatin and cyclosporine has increased AUC of rosuvastatin by 7 times compared to values obtained in healthy volunteers. Concomitant use leads to an 11-fold increase in plasma concentrations of rosuvastatin. Concomitant use of the drugs does not affect the plasma concentration of cyclosporine.

Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, starting therapy with rosuvastatin or increasing the drug dose in patients receiving concomitant indirect anticoagulants (such as warfarin or other coumarin anticoagulants) may lead to an increase in prothrombin time and INR. Discontinuation of rosuvastatin or reduction of the dose may cause a decrease in INR. INR should be monitored in such cases.

Ezetimibe: There is no change in AUC or Cmax of both drugs when using rosuvastatin and ezetimibe concomitantly.

Gemfibrozil and other hypolipidemic agents: Concomitant use of rosuvastatin and gemfibrozil leads to a 2-fold increase in Cmax and AUC of rosuvastatin. Based on the data of specific interaction studies, no pharmacokinetic interaction with fenofibrate is expected, but pharmacodynamic interaction is possible. Hemfibrozil, fenofibrate, other fibrates and nicotinic acid at lipid-lowering doses (1 g or more per day) when concomitantly used with HMG-CoA reductase inhibitors increased the risk of myopathy, possibly due to the fact that they can also cause myopathy when used as monotherapy. Simultaneous use of 40 mg of rosuvastatin and fibrates is contraindicated. When concomitant use of the drug with gemfibrozil and other lipid-lowering agents at a dose greater than 1 g/day the starting dose of Rosistar® should not exceed 5 mg.

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

Antacids: Concomitant administration of rosuvastatin and suspensions of antacids containing aluminum or magnesium hydroxide may lead to a decrease in plasma concentrations of rosuvastatin by about 50%. This effect is weaker if antacids are used 2 h after taking rosuvastatin. The clinical significance of this interaction has not been studied.

Eritromycin: Concomitant administration of rosuvastatin and erythromycin may decrease AUC(0-t) of rosuvastatin by 20% and Cmax of rosuvastatin by 30%. Such interaction may be due to increased intestinal motility caused by taking erythromycin.

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

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 rather weak substrate for these isoenzymes. No clinically significant interaction between rosuvastatin and fluconazole (inhibitor of CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (inhibitor of CYP2A6 and CYP3A4 isoenzymes) was found. Current use of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases the AUC of rosuvastatin by 28% (clinically significant). Therefore, no drug interaction related to cytochrome P450 metabolism is expected.

Other medicinal products: No clinically significant interaction is expected in concomitant use of rosuvastatin and digoxin.

Interactions with drugs that require dose adjustment of rosuvastatin

Table 1. Effect of concomitant therapy on rosuvastatin exposure

Regime of concomitant therapyRosuvastatin regimenChange in AUC of rosuvastatinCyclosporine 75-200 mg 2 times/day, 6 months10 mg once/day, 10 daysExtension in 7.1xAtazanavir 300 mg/ritonavir 100 mg once daily, 8 days10 mg once Increase by 3.1 timesLopinavir 400 mg/ritonavir 100 mg twice daily, 17 days20 mg once daily, 7 days Increase by 2.1xGemfibrozil 600 mg 2 times/day, 7 days80 mg onceEltrombopag 75 mg 1 time/day, 10 days10 mg once Increase 1.6 timesDarunavir 600 mg/ritonavir 100 mg 2 times/day, 7 days10 mg 1 time/day, 7 days Increase 1.5 timesTipranavir 500 mg/ritonavir 200 mg 2 times/day, 11 days10 mg once Increase 1.4 timesDronedarone 400 mg 2 times/dayNo data Increase 1.Itraconazole 200 mg once daily, 5 days10 mg or 80 mg once Increase 1.4xEzetimibe 10 mg once daily, 14 days10 mg once daily, 14 days Increase 1.2xFosamprenavir 700 mg/ritonavir 100 mg 2 times daily, 8 days10 mg onceNo changeAleglitazar 0.3 mg, 7 days40 mg, 7 daysNo changeSilimarin 140 mg 3 times/day, 5 days10 mg onceNo changeFenofibrate 67 mg 3 times/day, 7 days10 mg, 7 daysNo changeRifampin 450 mg 1 time/day, 7 days20 mg onceNo changeKetoconazole 200 mg 2 times/day No changeFluconazole 200 mg once daily, 11 days80 mg onceNo changeEritromycin 500 mg 4 times daily, 7 days80 mg onceDecrease by 28%Baicalin 50 mg 3 times daily, 14 days20 mg onceDecrease by 47%br>

Special Instructions

Kidney

Proteinuria, predominantly of tubular origin, has been observed in patients taking rosuvastatin at high doses, particularly 40 mg, which in most cases has been intermittent or transient. Such proteinuria does not indicate the occurrence of acute or progressive renal disease. The incidence of serious renal dysfunction is increased when taking 40 mg of rosuvastatin. In these patients, it is recommended to monitor renal function parameters during treatment with Rosistarco®.

Musculoskeletal system

Myalgia, myopathy and, rarely, rhabdomyolysis have been observed with Rosistarca® at all doses, and particularly with doses greater than 20 mg. In very rare cases rhabdomyolysis occurred when concomitant administration of ezetimibe and HMG-CoA reductase inhibitors. In this case, pharmacological effects of the drugs cannot be excluded, therefore concomitant use of these drugs should be treated with caution. The incidence of rhabdomyolysis increases with the use of Rosistarca® at a dose of 40 mg.

Precipitation of CPK activity

Precipitation of CPK activity should not be performed after vigorous exercise or if there are other possible causes of increased CPK activity, which may lead to misinterpretation of results. If the baseline CPK level is significantly elevated (more than 5 times the IGN), the measurement should be repeated after 5-7 days. Therapy should not be initiated if the repeat measurement confirms the baseline CPK level (5 times higher than VGN).

Pending therapy

Rosystark®, like other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with existing risk factors for myopathy/rhabdomyolysis. These factors include:

– renal impairment;

– hypothyroidism (for 40 mg dose);

– indication in personal or family history of muscle disease (for 40 mg dose);

A history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates (for 40 mg dose);

– alcohol abuse (for 40 mg dose);

– age over 70 years;

– conditions accompanied by increased blood plasma concentrations of the drug (for a dose of 40 mg);

– concomitant administration of fibrates (for a dose of 40 mg).

In such patients the risk/benefit ratio of therapy should be evaluated and clinical monitoring should be performed throughout the course of treatment.

In therapy

Patients should be advised to promptly inform their physician if muscle pain, muscle weakness, or cramps occur unexpectedly, especially if associated with malaise or fever. In such patients, monitoring of CPK activity should always be performed. Treatment should be discontinued if CPK activity is more than 5 times the ULN or if 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 prescription of Rosistarco® or other HMG-CoA reductase inhibitors at lower doses should be considered with close monitoring of the patient. Regular monitoring of CPK activity in the absence of symptoms is unnecessary.

There have been very rare cases of immune-mediated necrotizing myopathy with clinical manifestations as persistent proximal muscle weakness and increased serum CPK activity during treatment or upon discontinuation of statins, including rosuvastatin. Additional muscular and nervous system studies, serologic studies, and therapy with immunosuppressive agents may be necessary.

There have been no indications of increased skeletal muscle effects with rosuvastatin and concomitant therapy. However, an increase in myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors together with fibric acid derivatives (including gemfibrozil), cyclosporine, nicotinic acid, antifungal drugs, protease inhibitors and antibiotics from macrolide group. Gemfibrozil increases the risk of myopathy when co-administered with some HMG-CoA reductase inhibitors. Therefore, concomitant administration of rosuvastatin and gemfibrozil is not recommended. It is necessary to carefully assess the risk/benefit ratio when co-administering rosuvastatin with fibrates or nicotinic acid in lipid-lowering doses (more than 1 g/day). Concomitant administration of 40 mg rosuvastatin and fibrates is contraindicated. Lipid metabolism parameters should be controlled 2-4 weeks after the treatment start and/or in case of Rosistarck® dose increase; if necessary the dose adjustment is required.

The drug should not be administered in patients with acute, severe diseases suggestive of myopathy or with possible development of secondary renal failure (e.g., sepsis, arterial hypertension, surgery, trauma, metabolic syndrome, seizures, endocrine disorders, water and electrolyte disorders).

Liver

Like other HMG-CoA reductase inhibitors, Rosistar® should be prescribed with special caution in patients who abuse alcohol or have a history of liver disease. It is recommended that liver function tests be performed before therapy and 3 months after the start of therapy. If serum hepatic transaminase activity is 3 times higher than BHN, Rosistarco® should be discontinued or the drug dose should be decreased. The incidence of liver function abnormalities, mainly associated with increased hepatic transaminase activity, is increased when taking 40 mg of the drug.

In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy of the underlying disease should be performed before starting treatment with rosuvastatin.

Ethnic groups

Pharmacokinetic studies have shown increased systemic rosuvastatin concentrations in patients of Chinese and Japanese origin compared to those in patients of Caucasian race.

HIV protease inhibitors

The concomitant use of rosuvastatin with HIV protease inhibitors is not recommended.

Lactose

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

Interstitial lung disease

Single cases of interstitial lung disease have been reported with some statins, especially for long periods of time. Manifestations of the disease may include dyspnea, dry cough, and worsening of general well-being (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes mellitus

For patients with glucose concentrations between 5.6 and 6.9 mmol/L, use of rosuvastatin leads to an increased risk of developing type 2 diabetes mellitus.

Influence on driving and operating machinery

There have been no studies on the effect of rosuvastatin on driving and operating machinery. Based on the pharmacodynamic properties of the drug it can be assumed that rosuvastatin should have no such effect, however, it should be taken into account that dizziness may occur during treatment.

Contraindications

– liver disease in the active phase, including a persistent increase in hepatic transaminase activity and any increase in serum transaminase activity by more than 3 times that of IGN;

– Severe renal impairment (CKD)

– myopathy;

– concomitant administration of cyclosporine;

Patients prone to developing myotoxic complications;

– Women of reproductive age who are not using reliable contraception;

– pregnancy;

– lactation (breastfeeding) period;

– age less than 18 years (efficacy and safety not established);

– lactose intolerance, lactase deficiency or glucose-galactose malabsorption (because the drug contains lactose);

– hypersensitivity to rosuvastatin or any of the ingredients of the drug.

With caution:

Presence of risk of myopathy/rhabdomyolysis – renal failure, hypothyroidism; indication in personal or family history of hereditary muscle disease, indication in history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates; excessive alcohol intake; conditions with increased plasma concentration of rosuvastatin; age over 70 years; history of liver disease; sepsis; arterial hypotension; extensive surgical interventions; trauma; severe metabolic, endocrine or water-electrolyte disorders; uncontrolled epilepsy; race (mongoloid race); concomitant use of fibrates.

Side effects

Side effects associated with the use of Rosistarca® are usually moderate and go away on their own. The incidence of side effects is mostly dose-dependent, as with other HMG-CoA reductase inhibitors.

The following classification is used to indicate the frequency of side effects: often (>1/100 and1/1000 and1/10,000 and

Immune system disorders: rare – hypersensitivity, including angioedema.

CNS disorders: often – headache, dizziness; very rare – polyneuropathy, memory loss.

Hematopoietic system: unspecified frequency – thrombocytopenia.

The digestive system: often – constipation, nausea, abdominal pain; rarely – pancreatitis.

Hepatic disorders: when using rosuvastatin a dose-dependent increase in liver transaminase activity is observed in a small number of patients. In most cases this increase is insignificant, asymptomatic and temporary.

Endocrine system disorders: often – type 2 diabetes mellitus, thyroid dysfunction.

Muscular system: frequent – myalgia; rare – myopathy (including myositis), rhabdomyolysis; unspecified frequency – immune-mediated necrotizing myopathy.

Skeletal muscle effects causing myalgia, myopathy (including myositis) and, rarely, rhabdomyolysis with or without acute renal failure have been observed in patients taking any dose of rosuvastatin, especially when taking doses greater than 20 mg. A dose-dependent increase in CPK activity was detected in patients taking rosuvastatin, but in most cases these manifestations were insignificant, asymptomatic and transient. In case of an increase of CPK activity more than 5-fold of IGN, therapy should be suspended.

Urinary system disorders: proteinuria may occur while taking rosuvastatin. Changes in protein content in urine (from the absence or presence of trace amounts to levels ++ and higher) are observed in less than 1% of patients taking rosuvastatin in doses of 10 mg and 20 mg and in approximately 3% of patients taking the drug in dose of 40 mg. A slight change in the amount of protein in the urine, expressed as a change from zero or trace levels to a + level, was observed when taking the drug at a dose of 20 mg. In most cases, proteinuria decreased and passed on its own during treatment. When analyzing data from clinical studies, no causal relationship between proteinuria and acute or progressive kidney disease was found.

Skin disorders: infrequent – skin itching, rash, urticaria.

Reproductive system and mammary glands: unspecified frequency – gynecomastia.

Laboratory findings: increased concentration of glucose, bilirubin, GGT activity, ALP.

Others: frequent – asthenic syndrome; unspecified frequency – peripheral edema.

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

In long-term use of rosuvastatin, single cases of interstitial lung disease have been reported.

Overdose

there is no specific therapy for rosuvastatin overdose.

In case of overdose, symptomatic treatment and supportive measures of vital organs and systems are recommended.

Hepatic function and CPK activity should be monitored. Hemodialysis is probably ineffective in this case.

Similarities