Rho-statin, capsules 5 mg 30 pcs

Mechanism of action

Rosuvastatin is a selective, competitive inhibitor of GM G-CoAg reductase, an enzyme that converts Z-hydroxy-Z-methylglutaryl coenzyme A into mevalonate, 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 the inhibition of synthesis of very low density lipoproteins (VLDL), thereby reducing the total amount of LDL and LDL.

Pharmacodynamics

Rosuvastatin reduces the increased concentration of LDL cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C) and decreases the concentration of apolipoprotein B (ApoB), non-LDL, HDL-C, TG-LDL and increases the level of apolipoprotein A-I (ApoA-1), reduces the ratio of HDL-C/HC-LDL, total HC/ HC-LDL and non-HC-LDL/ HC-LDL and the ratio of apoB/ApoA-1.

Therapeutic effect appears within 1 week after the start of therapy with Ro-Statin, after 2 weeks of treatment it reaches 90% of the maximum possible effect. The maximum therapeutic effect is usually reached by the 4th week and is maintained with regular use of the drug.

Clinical efficacy

Rosuvastatin 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 of B and lib type according to Fredrickson classification (mean baseline concentration of cholesterol-LDL is about 4.8 mmol/l) during the drug treatment in dose of 10 mg cholesterol-LDL concentration reaches the values less than 3 mmol/l.

In patients with heterozygous familial hypercholesterolemia receiving rosuvastatin at a dose of 20-80 mg, positive dynamics of lipid profile parameters are observed. After titration up to the daily dose of 40 mg (12 weeks of therapy), there is a 53% decrease of LDL-C concentration.

In patients with homozygous familial hypercholesterolemia receiving rosuvastatin in doses of 20 mg and 40 mg, the average decrease of LDL-C concentration is 22%. Additive effects are observed in combination with fenofibrate for triglyceride concentration and with nicotinic acid at lipid-lowering doses (more than 1 g/day) for HDL-C concentration.

Indications

• Primary hypercholesterolemia according to Fredrickson classification (type H, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type lib) 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 when such therapy is not sufficiently effective.

• Hypertriglyceridemia (type IV according to Fredrickson classification) as an adjunct to diet.

• To slow the progression of atherosclerosis, as an adjunct to the diet in patients who are indicated for therapy to reduce total cholesterol and LDL-C concentrations.

• Primary prevention of major cardiovascular complications (stroke, infarction, arterial revascularization) in adult patients without clinical signs of coronary heart disease (CHD), but with an increased risk of its development (age over 50 years for men and over 60 years for women, increased concentration of C-reactive protein (>2 mg/L) with at least one additional risk factor, such as hypertension, low HDL-C, smoking, family history of early onset of CHD).

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Active ingredient

Rosuvastatin

Composition

Active ingredient:

Rosuvastatin calcium – 5,210 mg in terms of rosuvastatin -5,000 mg.

Excipients:

lactose monohydrate (milk sugar) -144.824 mg;

microcrystalline cellulose – 25.344 mg;

Croscarmellose sodium – 9,311 mg;

Povidon-K25 -5,431 mg;

Colloidal silica -1,940 mg;

Magnesium stearate – 1,940 mg.

Capsule body composition: iron oxide black dye – 0,05%, titanium dioxide – 2%, gelatin to 100%.

Capsule cap composition: iron oxide black dye – 0,05%, titanium dioxide – 2%, gelatin to 100%.

How to take, the dosage

Orally, do not chew or open the capsule, swallow it whole with water. The drug may be administered at any time of the day regardless of meal time. Before starting therapy with Ro-Statin, the patient should begin a standard hypocholesterolemic diet and continue to comply with 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 to take the drug or for patients transferred from other HMG-CoA reductase inhibitors should be 5 or 10 mg of Ro-Statin once daily.

When selecting the initial dose, individual cholesterol concentrations should be guided by the possible risk of cardiovascular complications and the potential risk of side effects should be assessed. If necessary, the dose may be increased to a larger one in 4 weeks.

Due to the possible development of side effects when taking a dose of 40 mg, compared to lower doses of the drug, increasing the dose to 40 mg, after an additional dose above the recommended initial dose for 4 weeks of therapy may be conducted only in patients with severe hypercholesterolemia and with a 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 will be monitored by a specialist.

Especially close monitoring of patients receiving the drug at a dose of 40 mg is recommended. It is not recommended to prescribe the 40 mg dose to patients who have not previously seen a physician. After 2-4 weeks of therapy and/or when the dose of Ro-Statin is increased, monitoring of lipid metabolism parameters is required (if necessary, dose adjustment is required).

Elderly patients

The initial recommended dose in patients over the age of 70 is 5 mg, otherwise no dose adjustment is required depending on age.

Patients with renal insufficiency

In patients with renal insufficiency of mild to moderate severity dose adjustment is not required. The use of all doses of Ro-Statin is contraindicated in patients with severe renal insufficiency (CKR less than 30 ml/min). The drug administration in dosage 40 mg is contraindicated in patients with moderate renal impairment (CKR less than 60 ml/min).

Patients with moderate renal dysfunction (CKR less than 60 ml/min) should take the initial dose of the drug 5 mg.

Patients with hepatic impairment

The drug Ro-statin is contraindicated in patients with liver disease in the active phase. Special populations.

Ethnic groups

When studying pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, an increase in systemic concentration of rosuvastatin among Japanese and Chinese was noted. This fact should be considered when prescribing rosuvastatin to these groups of patients.

When prescribing doses of 10 and 20 mg the recommended starting dose for mongoloid patients is 5 mg.

The drug is contraindicated in a dose of 40 mg in patients of mongoloid race.

Patients predisposed to myopathy

The drug is contraindicated in a dose of 40 mg in patients with factors that may indicate predisposition to myopathy. At prescribing doses of 10 and 20 mg the recommended starting dose for this group of patients is 5 mg.

Genetic polymorphism

Carriers of SLC01B1 (OATP1B1) genotypes c.521CChABCG2(BCRP) c.421AA had increased exposure (AUC) to rosuvastatin compared with carriers of SLC01B1 genotypes c.521T and ABCG2 c.421CC. For patients-carriers of C.521CC or C.421AA genotypes it is recommended maximal dose of drug Rozuvastatin is 20 mg once per day.

Concomitant therapy

Rosuvastatin binds with various transport proteins (particularly with OATP1B1 and BCRP). When concomitant use of the drug Ro-statin with drugs (such as cyclosporine, some HIV protease inhibitors, including the combination of ritonavir with atazanavir, lopinavir and/or tipranavir) that increase the concentration of rosuvastatin in plasma due to interaction with transport proteins, the risk of myopathy (including rhabdomyolysis) may increase.

In such cases, the possibility to prescribe alternative therapy or temporary discontinuation of rosuvastatin should be assessed. If the use of the above drugs is necessary, the benefit-risk ratio of concomitant therapy with Ro-Statin should be assessed and the possibility of reducing its dose should be considered.

Interaction

Transport protein inhibitors

Rosuvastatin binds to several transport proteins, in particular to OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of transport proteins may be accompanied by increased plasma concentrations of rosuvastatin and an increased risk of myopathy.

Cyclosporine: When concomitant use of rosuvastatin and cyclosporine the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers. No effect on the plasma concentration of cyclosporine. The drug Ro-statin is contraindicated in patients taking cyclosporine.

Indirect anticoagulants: initiation of therapy with rosuvastatin or increase of the drug dose in patients receiving simultaneously vitamin K antagonists (e.g., warfarin) may lead to prolongation of prothrombin time (International Normalized Ratio – MHO). Cancellation of rosuvastatin or reduction of the drug dose may lead to a decrease in MHO. In such cases it is recommended to control MHO.

Gemfibrozil and other hypolipidemic agents: co-administration of rosuvastatin and gemfibrozil leads to a 2-fold increase in maximal plasma concentration of rosuvastatin and AUC of rosuvastatin. Based on specific interaction data, no pharmacokinetic interaction with fenofibrate is expected, pharmacodynamic interaction is possible.

Hemfibrozil, fenofibrate, other fibrates, and lipid-lowering doses of nicotinic acid (greater than 1 g/day) increased the risk of myopathy when used concurrently with HMG-CoA reductase inhibitors, possibly due to the fact that they can also cause myopathy when used in monotherapy.

When concomitant use of the drug with gemfibrozil, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day) patients are recommended a starting dose of the drug of 5 mg, taking a dose of 40 mg is contraindicated when concomitant administration with fibrates.

Ezetimibe: concomitant use of rosuvastatin in a dose of 10 mg ezetimibe was accompanied by increased AUC of rosuvastatin in patients with hypercholesterolemia. An increased risk of side effects due to pharmacodynamic interaction between Ro-statin and ezetimibe cannot be excluded.

HIV protease inhibitors (human immunodeficiency virus): although the exact mechanism of interaction is unknown, co-administration of HIV protease inhibitors may lead to a significant increase in rosuvastatin exposure.

The concomitant use of rosuvastatin and HIV protease inhibitors in treatment of patients with HIV is not recommended.

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

Eritromycin: Concomitant use of rosuvastatin and erythromycin decreases AUC of rosuvastatin by 20% and TAC of rosuvastatin by 30%. This interaction may occur due to increased intestinal motility caused by erythromycin.

Peroral contraceptives/hyurmone replacement therapy: Concomitant 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 taken into account when selecting a dose of oral contraceptives.

Pharmacokinetic data on concomitant use of Ro-statin and hormone replacement therapy are not available; therefore, a similar effect cannot be excluded with 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.

Cytochrome P450 isoenzymes: the results of in vivo and in vitro studies showed that rosuvastatin is neither inhibitor nor 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 between rosuvastatin and fluconazole (inhibitor of CYP2C9 and CYP3A4 isoenzymes) and ketoconazole (inhibitor of CYP2A6 CYP3A4 isoenzymes) was noted.

Drug interactions that require dose adjustment of rosuvastatin

The dose of the drug Ro-statin should be adjusted if it is necessary to use simultaneously with drugs that increase exposure to rosuvastatin. If exposure is expected to increase 2-fold or more, the starting dose of Ro-statin should be 5 mg once daily.

The maximum daily dose of Ro-statin 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.

For example, the maximum daily dose of Ro-statin when used concomitantly with gemfibrozil is 20 mg (1.9-fold increase in exposure) and with ritonavir/atazanavir is 10 mg (3.1-fold increase in exposure).

Special Instructions

Urinary system disorders

In patients receiving high doses of rosuvastatin (mainly 40 mg), there was tubular proteinuria, which in most cases was transient. Such proteinuria was not indicative of acute kidney disease or pro-trending renal disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor renal function parameters during treatment.

Musculoskeletal disorders

The following musculoskeletal effects have been reported with rosuvastatin at all doses and especially with doses greater than 20 mg: myalgia, myopathy, and in rare cases rhabdomyolysis.

Creatine phosphokinase activity determination

The determination of CPK activity should not be performed after intense physical activity or in the presence of other possible causes of increased CPK activity, which may lead to misinterpretation of the results. If the baseline CPK activity is significantly elevated (5 times higher than the upper limit of normal), a repeat measurement should be performed after 5-7 days.

The therapy should not be started if the repeat test confirms the baseline CPK activity (higher by more than 5 times the upper limit of normal).

Pending therapy

Patients with existing risk factors for myopathy/rhabdomyolysis should be cautious when prescribing Ro-Statin, as with other HMG-CoA reductase inhibitors, and should consider the risk/benefit ratio of therapy and perform clinical monitoring.

In therapy

The patient should be informed of the need to immediately inform the physician if muscle pain, muscle weakness, or cramps occur unexpectedly, especially if combined with malaise and fever. In such patients, CPK activity should be determined.

The therapy should be stopped if CPK activity is significantly increased (more than 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is 5 times less than the upper limit of normal).

If symptoms disappear and CPK activity returns to normal, re-prescribing Rho-statin or other HMG-CoA reductase inhibitors at lower doses with close monitoring of the patient should be considered. Routine 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 elevated serum CPK activity during treatment or upon discontinuation of statins, including rosuvastatin.

Muscle and nervous system additional studies, serologic studies, and therapy with immunosuppressive agents may be necessary.

There have been no indications of increased skeletal muscle effects with Ro-statin and concomitant therapy. However, an increase in myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses (over 1 g/day), azole antifungals, HIV protease inhibitors and macrolide antibiotics.

Gemfibrozil increases the risk of myopathy when coadministered with certain HMG-CoA reductase inhibitors. Thus, concomitant use of Ro-statin and gemfibrozil is not recommended. The ratio of risk to possible benefit of concomitant use of Ro-Statin and fibrates or lipid-lowering doses of nicotinic acid (more than 1 g/day) should be carefully weighed.

The use of Ro-statin at a dose of 40 mg together with fibrates is contraindicated. Lipid metabolism should be monitored 2-4 weeks after the start of treatment and/or if the dose of Ro-Statin is increased (if necessary, a dose adjustment is required).

Impact on liver function

It is recommended that liver function tests be performed before therapy and 3 months after the start of therapy. Ro-Statin should be discontinued or the dose should be reduced if serum hepatic transaminase activity exceeds 3 times the upper limit of normal.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy for underlying diseases should be given before starting treatment with Ro-Statin.

Particular populations.

Ethnic groups

In pharmacokinetic studies among Chinese and Japanese patients, increased systemic concentrations of rosuvastatin have been observed compared to those obtained in European patients.

HIV protease inhibitors

The co-administration of the drug with HIV protease inhibitors is not recommended.

Lactose

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

Interstitial lung disease

Single cases of interstitial lung disease have been reported with some statins, especially over a long period of time. Manifestations of the disease may include dyspnea, non-productive cough, and worsening of general well-being (weakness, weight loss, and fever).

If interstitial lung disease is suspected, statin therapy should be discontinued.

Type 2 diabetes

In patients with glucose concentrations between 5.6 and 6.9 mmol/L, rosuvastatin therapy has been associated with an increased risk of developing type 2 diabetes. HMG-CoA reductase inhibitors, including Ro-statin, may increase blood glucose concentrations.

Impact on the ability to drive motor transport and other mechanisms

There have been no studies on the effect of rosuvastatin on the ability to drive vehicles and use mechanisms. Caution should be exercised when driving motor transport or working with high concentration and psychomotor reaction (dizziness may occur during therapy).

Contraindications

• high sensitivity to rosuvastatin or any of the drug components;

• severe renal impairment (CKR less than 30 ml/min.)

• myopathy;

• current use of cyclosporine;

• children and adolescents under 18 years of age;

• in women: pregnancy, breastfeeding period, lack of adequate methods of contraception;

• patients prone to the development of myotoxic complications; lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose).

With caution

• . Risk of myopathy/rhabdomyolysis – renal failure, hypothyroidism, personal or family history of hereditary muscle disease, and prior history of muscle toxicity with other HMG-CoA reductase inhibitors or fibrates;

• excessive alcohol consumption;

• Age over 65 years;

• states in which increased plasma concentration of rosuvastatin has been noted;

• race (mongoloid race);

• simultaneous administration with fibrates;

• history of liver disease;

• sepsis;

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• arterial hypotension;

• extensive surgical procedures, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled seizures.

Side effects

Side effects observed when taking rosuvastatin are usually insignificant and go away on their own. As with other HMG-CoA reductase inhibitors, the incidence of side effects is dose-dependent.

The incidence of adverse effects is as follows, according to the WHO classification:

Frequent (>1/100, <1/10); Infrequent (>1/1000, <1/100); Rare (>1/10,000, <1/1000); Very rare ( <1/10000), including individual reports; Frequency not established (cannot be calculated from available data).

Immune system

Rare: hypersensitivity reactions, including angioedema

Endocrine system

Frequent: type 2 diabetes.

On the central nervous system

Often: headache, dizziness

On the digestive tract

Often: constipation, nausea, abdominal pain

Rarely: pancreatitis

Skin side

Infrequently: skin itching, rash, urticaria br> Musculoskeletal disorders

Frequently: myalgia

Rarely: myopathy (including myositis), rhabdomyolysis

Other

Frequently: Asthenic syndrome

Urinary system disorders

Progesinuria may be detected in patients receiving rosuvastatin. Changes of protein amount in urine (from absence or trace amounts to ++ or more) are observed in less than 1% of patients receiving 10 – 20 mg of the drug and in approximately 3% of patients receiving 40 mg of the drug.
Little change in urine protein has been noted with the 20 mg dose. In most cases progesinuria decreases or disappears during therapy and does not indicate the occurrence of acute or progression of existing renal disease.

Musculoskeletal disorders

The following musculoskeletal effects have been reported with rosuvastatin at all doses and, in particular, with doses greater than 20 mg: Myalgia, myopathy (including myositis), rarely rhabdomyolysis with or without acute renal failure.

A dose-dependent increase in creatine phosphokinase (CPK) activity was observed in a small number of patients taking rosuvastatin. In most cases it was insignificant, asymptomatic and temporary. In case of increased CPK activity (more than 5 times the upper limit of normal) therapy should be suspended.

Liver

On administration of rosuvastatin a dose-dependent increase in “liver” transaminases has been observed in a small number of patients. In most cases it is insignificant, asymptomatic and temporary.

Laboratory parameters

Increase in glucose concentration, bilirubin, gamma-glutamyl transpeptidase activity, alkaline phosphatase, thyroid function disorders.

Postmarketing use

The following side effects have been reported in the postmarketing use of rosuvastatin:

On the hematopoietic system:

Rarely: thrombocytopenia.

Gastrointestinal tract

Very rare: jaundice, hepatitis

Rare: increased activity of “liver” transaminases

Frequency is not determined: Diarrhea

Musculoskeletal side

Very rare: arthralgia

Frequency not established: immune-mediated necrotizing myopathy.

Central nervous system

Very rare: polyneuropathy, memory loss

Respiratory system

Frequency not established: cough, shortness of breath.

Urinary system side

Very rare: hematuria.

Skin and subcutaneous fat

Frequency not identified: Stevens-Johnson syndrome

Reproductive system

Frequency not identified: gynecomastia.

Other

Frequency not established: peripheral edema.

The following side effects have been reported with some statins: depression, sleep disturbances including insomnia and “nightmares” dreams, sexual dysfunction. Single cases of interstitial lung disease have been reported, especially with long-term use of the drugs.

Overdose

Symptoms: in case of simultaneous administration of several daily doses, pharmacokinetic parameters of rosuvastatin do not change.

Treatment: there is no specific treatment for rosuvastatin overdose. In case of overdose it is recommended to perform symptomatic treatment and measures aimed at maintenance of functions of vital organs and systems. Control of liver function and CPK level is necessary. Hemodialysis is unlikely to be effective.

Similarities

Mertenil, Crestor, Rosulip, Rosucard, Rosart, Rosuvastatin, Rosistarque, Roxera, Suvardio, Rosuvastatin NW, Cardiolip