Rosucard tablets p/o 20mg №10×3

Name:
Rozucard tab. 20mg in bl. in pack. No. 10×3
Description:
Tablets 10 mg: light pink, oblong, biconvex film-coated tablets with a score line. Tablets 20 mg: pink, oblong, biconvex film-coated tablets. Tablets 40 mg: dark pink, oblong, biconvex film-coated tablets. The main active ingredient Rosuvastatin Release form Tablets Dosage 20 mg Special instructions Influence on the kidneys In patients receiving high doses of rosuvastatin (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria was not indicative of acute kidney disease or progression of kidney disease. In patients taking the drug at a dose of 40 mg, it is recommended to monitor indicators of kidney function during treatment. Effects on the musculoskeletal system With the use of rosuvastatin at all doses, and especially at doses greater than 20 mg, the following effects on the musculoskeletal system have been reported: myalgia, myopathy, in rare cases, rhabdomyolysis. Determination of CPK activity Determination of CPK activity should not be carried out after intense physical exertion or in the presence of other possible reasons for an increase in CPK activity, which may lead to incorrect interpretation of the results. If the initial activity of CPK is significantly increased (5 times higher than the upper limit of the norm), after 5-7 days a second measurement should be taken. You should not start therapy if a repeat test confirms the initial activity of CPK (more than 5 times the upper limit of the norm). Prior to initiation of therapy Caution should be exercised when using Rosucard®, as well as when using other HMG-CoA reductase inhibitors, in patients with existing risk factors for myopathy / rhabdomyolysis. The risk-benefit ratio should be assessed and, if therapy is necessary, clinical monitoring of the patient during treatment should be carried out. During therapy The patient should be informed about the need to immediately inform the doctor about cases of 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 ULN) or if muscle symptoms are pronounced and cause daily discomfort (even if CPK activity is increased less than 5 times compared to ULN). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing Rozucard® or other HMG-CoA reductase inhibitors at lower doses with careful monitoring of the patient. Routine monitoring of CPK activity in the absence of symptoms is impractical. There have been very rare cases of immune-mediated necrotizing myopathy with clinical manifestations in the form of persistent weakness of the proximal muscles and an increase in serum CK activity during treatment or upon discontinuation of statins, including rosuvastatin. Additional studies of the muscular and nervous system, serological studies, as well as immunosuppressive therapy may be required. There were no signs of increased exposure to skeletal muscle when taking rosuvastatin and concomitant therapy. However, an increase in the 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 in hypolipidemic doses (more than 1 g / day), azole antifungals, inhibitors HIV proteases and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when co-administered with certain HMG-CoA reductase inhibitors. Thus, the simultaneous use of Rozucard® and gemfibrozil is not recommended. The ratio of risk and possible benefit should be carefully weighed when using Rozucard® and fibrates or lipid-lowering doses of nicotinic acid together. It is contraindicated to take Rozucard® at a dose of 40 mg together with fibrates. 2-4 weeks after the start of treatment and / or with an increase in the dose of Rozucard®, monitoring of lipid metabolism parameters is necessary (if necessary, dose adjustment is required). Liver It is recommended to measure liver function tests prior to initiation of therapy and 3 months after initiation of therapy. Taking the drug Rozucard® should be discontinued or the dose of the drug should be reduced if the activity of hepatic transaminases in the blood plasma is 3 times higher than the upper limit of the norm. In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, treatment of underlying diseases should be carried out before starting treatment with Rosucard®. HIV protease inhibitors Co-administration of Rozucard® with HIV protease inhibitors is not recommended. Interstitial lung disease With the use of some statins, especially for a long time, isolated cases of interstitial lung disease have been reported. Symptoms of the disease may include shortness of breath, non-productive cough and deterioration in general well-being (weakness, weight loss and fever). If interstitial lung disease is suspected, Rosucard® therapy should be discontinued. Type 2 Diabetes The statin class of drugs can cause an increase in blood glucose levels. In some patients with a high risk of developing diabetes, such changes can lead to its manifestation, which is an indication for the appointment of hypoglycemic therapy. However, the reduction in the risk of vascular disease while taking statins exceeds the risk of developing diabetes, so this factor should not serve as a basis for discontinuing statin treatment. For patients at risk (fasting blood glucose concentration 5.6-6.9 mmol / l, BMI> 30 kg / m2, hypertriglyceridemia, history of arterial hypertension), medical supervision should be established and biochemical parameters should be monitored regularly. Lactose Rozucard should not be used in patients with lactase deficiency, galactose intolerance or glucose-galactose malabsorption. Ethnic groups In the course of pharmacokinetic studies among Chinese and Japanese patients, an increase in the systemic concentration of rosuvastatin was noted compared with the values obtained among Caucasian patients. Influence on the ability to drive vehicles and control mechanisms Care should be taken when driving vehicles and activities that require an increased concentration of attention and speed of psychomotor reactions (during therapy, dizziness may occur). Pharmacological action Lipid-lowering drug from the group of statins. Selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol (Xc). Increases the number of LDL receptors on the surface of hepatocytes, which leads to increased uptake and catabolism of LDL, inhibition of VLDL synthesis, reducing the total concentration of LDL and VLDL. Reduces the concentration of LDL-C, high-density non-lipoprotein cholesterol (Non-HDL-C), VLDL-C, total C, TG, VLDL-C, apolipoprotein B (ApoB), reduces the ratio of C-LDL/C-HDL, total C/C -HDL, Xc-non-HDL / Xc-HDL, ApoB / apolipoprotein A-1 (ApoA-1), increases the concentration of Xc-HDL and ApoA-1. The lipid-lowering effect is directly proportional to the amount of the prescribed dose. The therapeutic effect appears within 1 week after the start of therapy, after 2 weeks it reaches 90% of the maximum, by 4 weeks it reaches a maximum and after that remains constant. Clinical efficacy Effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, sex or age, incl. in patients with diabetes mellitus and familial hypercholesterolemia. In 80% of patients with type IIa and IIb hypercholesterolemia (according to the Fredrickson classification) with an average initial LDL-C concentration of about 4.8 mmol / l, while taking the drug at a dose of 10 mg, the LDL-C concentration reaches values less than 3 mmol / l. In patients with heterozygous familial hypercholesterolemia receiving rosuvastatin at a dose of 20-80 mg/day, there is a positive trend in lipid profile parameters. After titration to a daily dose of 40 mg (12 weeks of therapy), there was a decrease in the concentration of LDL-C by 53%. In 33% of patients, the concentration of LDL-C was less than 3 mmol/l. In patients with homozygous familial hypercholesterolemia receiving rosuvastatin at a dose of 20 mg and 40 mg, the average decrease in the concentration of LDL-C was 22%. In patients with hypertriglyceridemia with an initial concentration of TG from 273 mg / dl to 817 mg / dl, who received rosuvastatin at doses of 5 mg to 40 mg 1 time / day for 6 weeks, the concentration of TG in blood plasma was significantly reduced (see table 2 ). An additive effect is noted in combination with fenofibrate in relation to the concentration of TG and with nicotinic acid in lipid-lowering doses (more than 1 g / day) in relation to the concentration of HDL-C. In the METEOR trial, rosuvastatin therapy significantly slowed down the rate of progression of maximal intima-media thickness (IMMT) for 12 segments of the carotid artery compared to placebo. Compared to baseline, a 0.0014 mm/year decrease in peak IMT was observed in the rosuvastatin group compared with an increase of 0.0131 mm/year in the placebo group. To date, no direct relationship between a reduction in IMT and a reduction in the risk of cardiovascular events has been demonstrated. The results of the JUPITER study showed that rosuvastatin significantly reduced the risk of developing cardiovascular complications with a relative risk reduction of 44%. The effectiveness of therapy was noted after the first 6 months of using the drug. There was a statistically significant reduction of 48% in the combined criterion of death from cardiovascular causes, stroke and myocardial infarction, a 54% reduction in the occurrence of fatal or non-fatal myocardial infarction and a 48% reduction in fatal or non-fatal stroke. Overall mortality decreased by 20% in the rosuvastatin group. The safety profile in patients treated with rosuvastatin 20 mg was generally similar to that in the placebo group. PharmacokineticsAbsorption After oral administration, Cmax of rosuvastatin in plasma is reached after approximately 5 hours. Absolute bioavailability is approximately 20%. Distribution Plasma protein binding (mainly albumin) is approximately 90%. Vd – 134 l. Rosuvastatin is absorbed mainly by the liver, which is the main site for the synthesis of Xc and the metabolism of Xc-LDL. Penetrates through the placental barrier. Metabolism Biotransformed in the liver to a small extent (about 10%), being a non-core substrate for isoenzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is the CYP2C9 isoenzyme. Isoenzymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism. The main metabolites of rosuvastatin are N-dismethyl and lactone metabolites. N-dismethyl is approximately 50% less active than rosuvastatin; 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 its metabolites. As in the case of other HMG-CoA reductase inhibitors, a specific membrane carrier, the organic anion transporting polypeptide (OATP) 1B1, is involved in the process of hepatic uptake of the drug, which plays an important role in its hepatic elimination. Withdrawal T1 / 2 – approximately 19 hours, does not change with increasing doses of the drug. The mean plasma clearance is approximately 50 l/h (coefficient of variation 21.7%). About 90% of the dose of rosuvastatin is excreted unchanged through the intestines, the rest – by the kidneys. Linearity The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake. Pharmacokinetics in special clinical situations In patients with mild to moderate renal insufficiency, the plasma concentration of rosuvastatin or N-dismethyl does not change significantly. In patients with severe renal insufficiency (CC less than 30 ml / min), the concentration of rosuvastatin in plasma is 3 times higher, and N-dismethyl – 9 times higher than in healthy volunteers. The plasma concentration of rosuvastatin in patients on hemodialysis is approximately 50% higher than in healthy volunteers. In patients with impaired liver function of 7 points and below on the Child-Pugh scale, an increase in T1 / 2 of rosuvastatin was not detected; in patients with impaired liver function 8 and 9 on the Child-Pugh scale, a 2-fold increase in T1 / 2 was noted. There is no experience of using the drug in patients with more severe hepatic impairment. Gender and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin. Pharmacokinetic parameters of rosuvastatin depend on race. AUC in representatives of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) is 2 times higher than in representatives of the Caucasian race. In Indians, the average value of AUC and Cmax increased by 1.3 times. Genetic polymorphism HMG-CoA reductase inhibitors, incl. rosuvastatin binds to transport proteins OATP1B1 (organic anion transport polypeptide involved in the uptake of statins by hepatocytes) and BCRP (efflux transporter). Carriers of the genotypes SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA showed an increase in exposure (AUC) to rosuvastatin by 1.6 and 2.4 times, respectively, compared with carriers of the genotypes SLCO1B1 c.521TT and ABCG2 c.421CC. Indications for use Treatment of hypercholesterolemia Primary hypercholesterolemia (type Ha, including heterozygous form of hereditary hypercholesterolemia) or mixed dyslipidemia (type IIb) as an adjunct to diet when dietary therapy and other non-pharmacological methods (for example, exercise and weight loss) have failed in adults, adolescents and children over 10 years old. Homozygous form of hereditary hypercholesterolemia as an adjunct to diet when diet therapy and other treatments aimed at lowering lipoprotein levels (for example, LDL apheresis) are ineffective or when such therapy is not possible. Prevention of cardiovascular disease In patients without clinical evidence of coronary heart disease, but with an increased risk of cardiovascular disease (age >50 years in men and >60 years in women, highly sensitive CRP > 2 mg/l, and the presence of at least at least one of the additional risk factors for cardiovascular disease, such as arterial hypertension, low HDL cholesterol, smoking, or a family history of premature coronary heart disease) rosuvastatin is indicated in order to: – reduce the risk of stroke; – reduce the risk of myocardial infarction; – to reduce the risk of arterial revascularization procedures Dosage and administration Prior to treatment, the patient should be transferred to a standard cholesterol-lowering diet and should adhere to this diet until the end of treatment. The dose is selected individually for each patient, depending on the purpose of treatment and the response to therapy. Rosuvastatin is taken at any time of the day, regardless of the intake of ping. Treatment of hypocholesteuinemia The recommended starting dose is 5 or 10 mg once daily for both statin-naive and HMG-CoA reductase inhibitor patients. The 5 mg dose can be taken by dividing the 10 mg tablet into two parts according to the score line. When choosing an initial dose, one should take into account the level of cholesterol and the risk of cardiovascular diseases, as well as the possible development of side effects (see sections on Special Instructions and Side Effects). If necessary, after 4 weeks, a change in the dosing regimen can be carried out. Patients with severe hypercholesterolemia with a high risk of complications of cardiovascular diseases (in particular, with familial hypercholesterolemia), in whom a dose of 20 mg did not give an adequate clinical effect, and for whom further medical supervision will be carried out (see section Special Instructions), the appointment the maximum dose of 40 mg should be administered after 4 weeks of treatment. Given the increase in the number of side effects when taking the drug at a dose of 40 mg, compared with lower dosages (see section Side effects), it is recommended to observe a specialist when increasing the dose of the drug to 40 mg. Prevention of cerebrovascular diseases The recommended dose of rosuvastatin is 20 mg per day. Use in children The use of rosuvastatin in children should only be carried out under the supervision of health care professionals. Children and adolescents aged 10 to 17 years (boys with a Tanner score of 2 or more, girls who are at least 1 year old after the onset of menarche) The initial dose of rosuvastatin for children and adolescents with heterozygous hereditary hypercholesterolemia is 5 mg once a day. day. The dose range is 5-20 mg once a day. The dose is selected individually for each patient, depending on the response of the child to the therapy. Children and adolescents should be placed on a standard cholesterol-lowering diet, which should be followed until the end of treatment. The safety and efficacy of doses exceeding 20 mg per day have not been studied in this group of patients. The use of the drug at a dose of 40 mg is not recommended for this group of patients. Fly in vozuaste up to 10 years Experience with the drug in children under 10 years of age is limited to a small number of patients (aged 8 to 10 years) with homozygous hereditary Use in elderly patients For patients over 70 years of age, the recommended initial dose is 5 mg (see section Special instructions). Changes in the dosing regimen in this group of patients are not required. Application by patients with renal insufficiency For patients with mild and moderate renal insufficiency, dose changes are not required. The recommended starting dose is 5 mg for patients with moderate renal impairment (creatinine clearance <60 ml/min). The use of the drug at a dose of 40 mg in patients with moderate renal insufficiency is contraindicated. The use of rosuvastatin is contraindicated in patients with severe renal impairment (see section Contraindications). Use in patients with hepatic insufficiency No increase in systemic exposure to rosuvastatin was observed in patients with Child-Pugh values of 7 or below. However, an increase in systemic exposure to rosuvastatin was observed in individuals with Child-Pugh values of 8 and 9. In these patients, an assessment of renal function should be performed (see section Special Instructions). Data on individuals with Child-Pugh values above 9 are not available. Rosuvastatin is contraindicated in patients with any active liver disease (see section Contraindications). Race Increased systemic exposure was observed in individuals of the Mongoloid race (see section Special Instructions). The recommended initial dose for this group of patients is 5 mg, the appointment of a dose of 40 mg is contraindicated. Dosage in patients with a predisposition to the development of myopathy The recommended initial dose is 5 mg for patients with a predisposition to the development of myopathy (see section Special Instructions). The 40 mg dose is contraindicated in these patients (see section Contraindications). Use during pregnancy and lactation The use of rosuvastatin during pregnancy can lead to the formation of serious birth defects in infants. The use of rosuvastatin is prohibited during pregnancy and lactation (see section Contraindications). Women of childbearing age should use contraceptives while taking the drug. Since the level of cholesterol and other products of cholesterol biosynthesis have a significant impact on fetal development, the possible risk of inhibiting HMG-CoA reductase outweighs the benefit of treatment during pregnancy. Animal studies provide only limited data on reproductive toxicity. If pregnancy occurs in a woman taking rosuvastatin, the drug should be stopped immediately. Rosuvastatin has been found in the breast milk of rats. There are no data on the excretion of the drug along with human breast milk (see section Contraindications). Precautions Impaired kidney function Proteinuria, detected by a test strip and mainly tubular in origin, was observed in patients receiving higher doses of rosuvastatin, namely 40 mg. Proteinuria is not a harbinger of the development of acute or progressive renal failure (see section Side effects). The frequency of serious impairment of renal function identified in post-marketing studies was higher at a dose of 40 mg. Assessment of renal function should be performed during the routine examination of patients receiving a dose of 40 mg. Musculoskeletal disorders In patients treated with rosuvastatin at any dose, especially at doses greater than 20 mg, musculoskeletal side effects such as myalgia, myopathy and, less commonly, rhabdomyolysis were observed. Rare cases of rhabdomyolysis have been observed in patients receiving ezetimibe in combination with HMG-CoA reductase inhibitors. A pharmacodynamic interaction of these drugs cannot be ruled out (see section Interaction with other medicinal products) and their combined use should be treated with caution. As with other HMG-CoA reductase inhibitors, reports of cases of rhabdomyolysis with the use of rosuvastatin in non-Non-Ni-Mgmtavite percol were mainly associated with taking 40 mg of rosuvastatin. Creatine phosphokinase (CPK) measurement this may lead to incorrect results. If the initial level of CPK is significantly increased (> 5-fold excess of the upper limit of normal), a second analysis should be carried out within 5-7 days. If the repeated analysis confirms an excess of 5 times the normal level of CPK, treatment cannot be started. Before treatment The appointment of rosuvastatin, as well as other inhibitors of HMG-CoA reductase, is indicated with caution in patients with predisposing factors for the development of myopathy / rhabdomyolysis. These factors are: renal failure; hypothyroidism; muscle disorders in the patient’s history or family history; the provision of a toxic effect on the muscles earlier when taking another inhibitor of HMG-CoA reductase or fibrate; alcohol addiction; age over 70; situations in which an increase in plasma concentrations is possible; combined use with fibrates. In such patients, the risk of therapy should be weighed against the intended effect, and inpatient monitoring is recommended. If the initial level of CPK exceeds 5 times the normal level of CPK, treatment cannot be started. During treatment, patients are advised to immediately report unexplained muscle pain, lethargy or weakness, especially if accompanied by malaise or fever. In these patients, CPK levels should be measured. Treatment should be discontinued if the CPK level exceeds 5 times the normal CPK level or if the side effects from the muscular system are significant and cause everyday discomfort (even if the CPK levels exceed 5 times the normal CPK level). If symptoms resolve and CPK levels return to normal, rosuvastatin therapy may be restarted or another HMG-CoA reductase inhibitor at a lower dose may be given with careful monitoring of the patient. Routine monitoring of CPK levels in patients without these symptoms is not necessary. In clinical trials, there was no evidence of an increase in musculoskeletal side effects in a small group of patients who received rosuvastatin in combination with other drugs. However, there has been an increase in the incidence of myositis and myopathy in patients treated with other HMG-CoA reductase inhibitors along with fibrates, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolides. The use of gemfibrozil in combination with HMG-CoA reductase inhibitors increases the risk of myopathy. Therefore, the co-administration of rosuvastatin with gemfibrozil is not recommended. With the combined use of rosuvastatin with fibrates or niacin, there are possible risks of side effects that should be taken into account when prescribing such combinations. The use of rosuvastatin at a dose of 40 mg is contraindicated in case of compatibility with fibrates. (see sections Interaction with other medicinal products and Side effects). Rosuvastatin should not be administered to patients with acute conditions that contribute to the development of myopathy or with a predisposition to the development of renal failure due to rhabdomyolysis (for example, sepsis, hypotension, surgery, trauma, metabolic, endocrine and electrolyte disorders; or uncontrolled convulsions). Liver Adverse Effects As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume excessive amounts of alcohol or have a history of liver disease. It is recommended to conduct a study of liver function before starting treatment and during the first 3 months. In cases where the content of transaminases exceeds the upper limit of the norm by 3 times, the treatment is canceled. The likelihood of effects on the liver (mainly in the form of an increase in transaminase levels) is higher at a dose of 40 mg. In patients with secondary hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, treatment begins with compensation for the underlying disease (prior to the start of therapy with rosuvastatin). Race Pharmacokinetic studies have shown that the drug has a stronger effect on representatives of the Mongoloid race than on representatives of the Caucasian race (see section Dosage and method of application). Protease inhibitors Co-administration with protease inhibitors is not recommended (see section Interaction with other medicinal products). Chronic lung disease with connective tissue damage In exceptional cases, with the use of some statins, especially with long-term treatment, interstitial lung disease has been reported (see section Side effects). Difficulty breathing, a dry cough, and general deterioration in health (fatigue, weight loss, and fever) may also occur. If interstitial lung disease is suspected, statin therapy should be discontinued. Diabetes mellitus Some evidence suggests that statins can increase blood glucose levels and, in patients with a predisposition to diabetes mellitus, can lead to a level of hyperglycemia at which it is reasonable to prescribe diabetes mellitus treatment. However, the benefit of statin treatment outweighs this risk, and therefore discontinuation of statin therapy is not required. Patients at risk (fasting glucose level – 5.6 – 6.9 mmol / JI, BMI> 30 kg / m2, elevated triglycerides, hypertension) should be under careful clinical and biochemical monitoring in accordance with national requirements. In a clinical trial, the overall reported incidence of diabetes mellitus was 2.8% in the rosuvastatin group and 2.3% in the placebo group, mainly in patients with fasting glucose levels of 5.6 to 6.9 mmol/l. Children Assessment of linear height (height), weight, BMI (body mass index), and secondary characteristics of puberty according to the Tanner scale in children aged 10 to 17 years taking rosuvastatin is limited to a period of 1 year. After 52 weeks of study, no effect of rosuvastatin treatment on height, weight, body mass index, or sexuality was found. Experience with the drug in children and adolescents is limited, and the long-term effect of rosuvastatin (> 1 year) on puberty is unknown. In clinical trials in children and adolescents taking rosuvastatin for 52 weeks, CPK levels were elevated (> 10-fold higher than the upper limit of normal), muscle symptoms after exercise or after increased physical activity were observed more often compared with observations during clinical trials in adults (see section Side effects). The drug contains lactose monohydrate, therefore taking rosuvastatin is contraindicated in patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome. Interactions with other drugs Be sure to inform your doctor about all the medicines you are taking, even if this happens occasionally. Cyclosporine: During co-therapy with rosuvastatin and cyclosporine, mean urinary concentrations of rosuvastatin were on average 7 times higher than in healthy volunteers (see section Contraindications). With the joint use of the concentration of cyclosporine in plasma did not change. Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, the initiation of treatment or an increase in the dosage of rosuvastatin in patients also receiving vitamin K antagonists (for example, warfarin or other coumarin anticoagulant) may lead to an increase in the international normalized ratio (INR). Discontinuation or dose reduction may lead to a decrease in INR. In such cases, appropriate INR monitoring is desirable. Gemfibrozil and other lipid-lowering drugs: Co-administration of rosuvastatin and gemifibrozil leads to a 2-fold increase in Cmax and AUC of rosuvastatin (see section Special Instructions). Based on data from specific interaction studies, a pharmacokinetic interaction with fenofibrates is not expected, however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and niacin (nicotinic acid) at lipid-lowering doses (> 1 g/day) increase the risk of myopathy when used concomitantly with HMG-CoA reductase inhibitors, possibly because they alone can cause myopathy. The appointment of a dose of 40 mg is contraindicated when sharing fibrates (see sections Contraindications and Special Instructions). Such patients are prescribed treatment with an initial dose of 5 mg. Ezetimibe: Co-administration of rosuvastatin and ezetimibe did not result in changes in the AUC or Cmax of both drugs. However, pharmacodynamic interactions between rosuvastatin and ezetimibe cannot be excluded (see section Special Instructions). Protease inhibitors: Although the exact mechanism of interaction is not known, the combined use of protease inhibitors with rosuvastatin can lead to a significant increase in the effect of rosuvastatin. In a pharmacokinetic study, co-administration of 20 mg rosuvastatin and a combination of two protease inhibitors (400 mg lopinavir/100 mg ritonavir) to healthy volunteers resulted in a twofold and fivefold increase in AUC(0-24) and Cmax, respectively. Thus, the combined use of rosuvastatin in HIV-infected patients is not recommended (see also the Special Instructions section). Antacids: Co-administration of rosuvastatin with a suspension containing aluminum and magnesium hydroxides resulted in a decrease in the plasma concentration of rosuvastatin by approximately 50%. This effect was reduced by the administration of antacids 2 hours after the administration of rosuvastatin. The clinical significance of this interaction has not been studied. Erythromycin: The combined use of rosuvastatin and erythromycin resulted in a 20% reduction in AUQ(ot) and a 30% reduction in Cmax of rosuvastatin. This may be due to increased peristalsis due to erythromycin. The use of oral contraceptives / hormone replacement therapy (HRT): Taking rosuvastatin together with oral contraceptives resulted in an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. These effects should be taken into account when selecting the dosage of oral contraceptives. There are no pharmacokinetic data available for women taking rosuvastatin concomitantly with HRT and thus a similar effect cannot be ruled out. However, this combination of drugs is widely used in clinical trials and is well tolerated by women. Other medicinal products: Based on data from special studies, clinically significant interactions with digoxin are not expected. Enzymes of the cytochrome P450 group: The results of in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of the action of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate for these isoenzymes. There was no significant interaction between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketonazole (an inhibitor of CYP2A6 and CYP3A4). Co-administration of itraconazole (a CYP3A4 inhibitor) and rosuvastatin resulted in a 28% increase in rosuvastatin AUC. This small increase is not clinically significant. Thus, drug interactions due to cytochrome P450-mediated metabolism are not expected. Contraindications hypersensitivity to rosuvastatin or other components of the drug; liver disease in the active phase, including persistent rises in serum transaminase levels of unknown etiology and any increase in serum transaminases ex