Ro-Statin, 20 mg capsules 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 to mevalonate, a precursor of cholesterol. 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 HA and LY type according to Fredrickson classification (mean baseline concentration of cholesterol-LDL is about 4.8 mmol/l) during the drug therapy 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 effect is observed in combination with fenofibrate with regard to triglyceride concentration and with nicotinic acid in lipid-lowering doses (more than 1 g/day) with regard to HDL-C concentration.

Indications

Active ingredient

Composition

Active ingredient:

calcium rosuvastatin – 20.830 mg, in terms of rosuvastatin – 20,000 mg.

Auxiliary substances:

Lactose monohydrate (milk sugar) – 132.329 mg;

Microcrystalline cellulose – 23.157 mg;

croscarmellose sodium – 8.842 mg;

povidone-K25 – 4.962 mg;

colloidal silica – 1.940 mg;

magnesium stearate – 1.940 mg.

Capsule contents: iron oxide black dye – 0.05%, titanium dioxide – 2%, gelatin to 100%

Capsule cap composition: iron oxide yellow dye – 0.1763%, titanium dioxide – 0.9744%, gelatin to 100%.

How to take, the dosage

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 in conjunction 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 of 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

Side effects

Overdose

Similarities