Crestor 5mg 28 tablets

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tableti saghech i

Dosage mg

5

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28

CRESTOR CRESTOR Trade name: CRESTOR International Nonproprietary Name: Rosuvastatin Dosage Form: Film-coated tablets Composition Each film-coated tablet contains: Active substance: Rosuvastatin calcium 5.20 mg (in terms of rosuvastatin - 5.00 mg). Excipients: Lactose monohydrate 93.08 mg, Microcrystalline cellulose (type: PH-200) 31.02 mg, Crospovidone 7.50 mg, Magnesium stearate 1.88 mg; Tablet coating contains: Lactose monohydrate 1.80 mg, Hypromellose 1.26 mg, Triacetin (glycerol triacetate) 0.36 mg, Titanium dioxide (E171) 0.90 mg, Iron oxide yellow dye (E172) 0.18 mg. Description of the medicinal product 5 mg tablet: Round, biconvex, yellow, film-coated tablets with unilateral engraving "ZD4522 5". Pharmacotherapeutic group: Hypolipidemic agent – HMG-CoA reductase inhibitor See blog: CRESTOR – A cholesterol-regulating medication ATC code: C10AA07 Pharmacological properties Mechanism of action Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to the cholesterol precursor mevalonic acid. The target organ of rosuvastatin action is the liver, where cholesterol synthesis and low-density lipoprotein catabolism occur. Rosuvastatin increases the number of low-density lipoprotein "hepatic" receptors on the cell membrane, thereby increasing the uptake and catabolism of low-density lipoproteins, which in turn leads to the inhibition of very low-density lipoprotein synthesis. As a result, the total amount of low and very low-density lipoproteins decreases. Pharmacodynamics The drug CRESTOR reduces cholesterol-low-density lipoproteins, total cholesterol, increases cholesterol-high-density lipoprotein content, and also reduces apolipoprotein B (Apo-B), cholesterol-non-high-density lipoproteins, cholesterol-very low-density lipoproteins, and increases apolipoprotein A-I levels (Apo-A-I) (see Tables 1, 2), reduces the ratio of cholesterol-low-density lipoproteins/cholesterol-high-density lipoproteins, total cholesterol/cholesterol-high-density lipoproteins, and cholesterol-non-high-density lipoproteins/cholesterol-high-density lipoproteins, and Apo-B/Apo-A-I. The therapeutic effect is observed within one week of taking CRESTOR, reaching 90% of the maximum effect after two weeks. The maximum therapeutic effect is achieved by the 4th week of taking the drug and is maintained with regular intake. Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (type IIa and IIb according to Fredrickson) (average adjusted percentage change from baseline). Dose Number of patients Cholesterol-low-density lipoproteins Total cholesterol Cholesterol-high-density lipoproteins Triglycerides Cholesterol-non-high-density lipoproteins Apo B Apo A-I Placebo 13 -7 -5 -33 3 -3 0 5 mg 17 -45 -33 13 -35 -44 -38 4 10 mg 17 -52 -36 14 -10 -48 -42 4 20 mg 17 -55 -40 8 -23 -51 -46 5 40 mg 18 -63 -46 10 -28 -60 -54 0 Table 2. Dose-dependent effect in patients with hypertriglyceridemia (type IIb and IV according to Fredrickson) (average adjusted percentage change from baseline). Dose Number of patients Triglycerides Cholesterol-low-density lipoproteins Total cholesterol Cholesterol-high-density lipoproteins Cholesterol-non-high-density lipoproteins Cholesterol-very low-density lipoproteins Triglycerides-very low-density lipoproteins Placebo 26 1 5 1 -3 2 2 6 5 mg 26 25 1 -21 5 -28 1 -24 -3 3 2 -29 2 -25 6 -24 10 mg 23 -37 -45 -40 8 -49 -48 -39 20 mg 27 -37 -31 -34 22 -43 -49 -40 40 mg 25 -43 -43 -40 17 -51 -56 -48 Clinical efficacy The drug CRESTOR is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia, regardless of race, sex, and age, including patients with diabetes mellitus and familial hypercholesterolemia. In 80% of patients with Fredrickson type IIa and IIb hypercholesterolemia (baseline average low-density lipoprotein cholesterol concentration approximately 4.8 mmol/L), the low-density lipoprotein cholesterol concentration reaches below 3 mmol/L with the drug at a dose of 10 mg. In patients with heterozygous familial hypercholesterolemia receiving CRESTOR at doses of 40-80 mg, a positive dynamic of lipid profile is observed (study of 435 patients). With titration to a daily dose of 40 mg (over 12 weeks), a 53% reduction in low-density lipoprotein cholesterol concentration is observed. In 33% of patients, a low-density lipoprotein cholesterol concentration below 3 mmol/L is achieved. In patients with homozygous familial hypercholesterolemia who received CRESTOR at doses of 20 mg and 40 mg, the average reduction in low-density lipoprotein cholesterol concentration was 22%. In patients with hypertriglyceridemia with baseline triglyceride levels from 273 to 817 mg/dL, who received CRESTOR at doses from 5 mg to 40 mg daily for 6 weeks, a significant decrease in blood triglyceride concentration was observed (see Table 2). An additive effect is observed in combination with fenofibrate for triglyceride content and with lipid-lowering doses of nicotinic acid for cholesterol-low-density lipoproteins (see also section "Special Instructions"). In the METEOR study involving 984 patients aged 45-70 years with a low risk of developing ischemic heart disease (10-year risk less than 10% according to the Framingham scale), with an average low-density lipoprotein cholesterol concentration of 4 mmol/L (154.5 mg/dL) and subclinical atherosclerosis (assessed by the thickness of the carotid artery intima-media complex), the effect of rosuvastatin on the thickness of the intima-media complex was studied. Patients received 40 mg of rosuvastatin daily or placebo for 2 years. Rosuvastatin therapy significantly reduced the maximum thickness of the intima-media complex in 12 segments of the carotid artery compared to placebo, with a difference of 0.0145 mm/year (95% confidence interval 0.0196-0.0093; p < 0.0001). In the rosuvastatin group, a maximum reduction in the intima-media complex of 0.0014 mm/year (0.12%/year (non-significant) compared to baseline was observed, while in the placebo group, the same indicator increased by 0.0131 mm/year (1.12%/year (p < 0.0001). A direct correlation between the thickness of the intima-media complex and the reduction in the risk of cardiovascular disease development has not yet been established. The METEOR study was conducted in patients with a low risk of ischemic heart disease, for whom 40 mg of rosuvastatin is not recommended. 40 mg of rosuvastatin should be prescribed to patients with severe hypercholesterolemia and a high risk of cardiovascular disease development. According to the results of the JUPITER study involving 17802 patients (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin), rosuvastatin significantly reduces the risk of cardiovascular complications (252 in the placebo group compared to 142 in the rosuvastatin group) (p < 0.001) with a 44% reduction in relative risk. The effectiveness of therapy was observed 6 months after the start of the drug. A statistically significant 48% reduction in the composite endpoint, including cardiovascular death, stroke, and myocardial infarction (hazard ratio: 0.52, 95% confidence interval 0.40-0.68, p < 0.001), a 54% reduction in fatal and non-fatal myocardial infarction (hazard ratio: 0.46, 95% confidence interval 0.30-0.70, p), and a 48% reduction in fatal and non-fatal stroke was observed. Overall mortality decreased by 20% in the rosuvastatin group (hazard ratio: 0.80, 95% confidence interval 0.67-0.97, p = 0.02). Safety profile In patients receiving 20 mg of rosuvastatin, the safety profile was generally similar to that of the placebo group. Pharmacokinetics Absorption and distribution Maximum plasma concentration of rosuvastatin is reached approximately 5 hours after administration. Absolute bioavailability is approximately 20%. Rosuvastatin is primarily metabolized in the liver, which is the main organ for cholesterol and cholesterol-low-density lipoprotein synthesis. The volume of distribution of rosuvastatin is approximately 134 L. Approximately 90% of the administered dose is bound to plasma proteins, mainly albumin. Metabolism undergoes limited metabolism (approximately 10%). Rosuvastatin is a non-specific substrate of the cytochrome P450 enzyme system. The main enzyme involved in its metabolism is the CYP2C9 isoenzyme. Isoenzymes CYP2C19, CYP3A4, and CYP2D6 are less involved in metabolism. The main identified metabolites of rosuvastatin are N-desmethylrosuvastatin and lactone metabolites. N-desmethylrosuvastatin is approximately 50% less active than rosuvastatin, and lactone metabolites are inactive. 90% of pharmacological activity is exerted by rosuvastatin in the form of inhibition of circulating HMG-CoA reductase, the remainder by its metabolites. Elimination 90% of the administered dose is excreted unchanged in the feces (including absorbed and unabsorbed rosuvastatin). The remaining portion is excreted by the kidneys. The plasma half-life (T ½) is approximately 19 hours. The half-life is not dose-dependent. The average geometric plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). Like other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves a cholesterol membrane transporter, which plays an important role in the hepatic elimination of rosuvastatin. Linearity Systemic exposure to rosuvastatin increases proportionally with dose. Pharmacokinetic parameters do not change with daily administration. Special populations of patients. Age and sex Sex and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin. Ethnic groups In patients of Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese, Koreans), pharmacological studies have shown a twofold increase in the median area under the curve (AUC) (concentration-time curve) and maximum plasma concentration (C max) of rosuvastatin compared to Caucasians; in Indians, the median AUC and C max are 1.3 times higher. No clinically significant difference was found between Caucasians and Negroids in pharmacokinetic analysis. Renal impairment In patients with mild and moderate renal impairment, plasma concentrations of rosuvastatin or N-desmethylrosuvastatin do not change. In patients with severe renal impairment (creatinine clearance (CrCl) < 30 mL/min), plasma concentrations of rosuvastatin are 3 times higher, and N-desmethylrosuvastatin are 9 times higher compared to healthy volunteers. In patients on hemodialysis, plasma concentrations of rosuvastatin are 50% higher compared to healthy volunteers. Hepatic impairment In studies involving patients with varying degrees of hepatic impairment according to the Child-Pugh scale with 7 or fewer points, no increase in the half-life of rosuvastatin was observed. In two patients with Child-Pugh scores of 8 and 9, the half-life increased twofold compared to patients with lower scores. There is no experience with the use of rosuvastatin in patients with a Child-Pugh score of 9 or higher. Genetic polymorphism HMG-CoA reductase inhibitors, including CRESTOR, bind to transport proteins OATP1B1 (organic anion transporting polypeptide involved in statin uptake by hepatocytes) and BCRP (efflux transporter). Carriers of genotypes SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA have an increase in AUC exposure of 1.6 and 2.4 times, respectively, compared to carriers of SLCO1B1 c.521TT and ABCG2 c.421CC. Indications · Primary hypercholesterolemia according to Fredrickson (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an adjunct to diet when diet and other non-drug measures (e.g., exercise, weight reduction) are insufficient. · Familial homozygous hypercholesterolemia as an adjunct to diet and other lipid-lowering therapies (e.g., low-density lipoprotein apheresis) or when these therapies are insufficiently effective. · Hypertriglyceridemia (type IV according to Fredrickson) as an adjunct to diet. · To reduce the progression of atherosclerosis as an adjunct to diet in patients for whom cholesterol-low-density lipoprotein lowering therapy is indicated. · Primary prevention of major cardiovascular complications (stroke, myocardial infarction, arterial revascularization) in adult patients without clinical signs of CAD but with an increased risk of its development (age over 50 years in men, over 60 years in women, high C-reactive protein concentration (≥ 2 mg/L), presence of at least one additional risk factor, such as arterial hypertension, low cholesterol-high-density lipoprotein concentration, smoking, family history of early CAD). Contraindications For daily doses of 5 mg, 10 mg, and 20 mg: · Hypersensitivity to rosuvastatin and any component of the drug · Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption (the drug contains lactose) · Age under 18 years · Liver diseases in the active phase, persistent increase in serum transaminase activity, and any increase in transaminase activity (more than 3 times the upper limit of normal) · Severe renal impairment (CrCl < 30 mL/min) · Myopathy · Concomitant use of cyclosporine · In women; pregnancy, lactation, absence of adequate contraception · Patients predisposed to myotoxic complications For daily dose of 40 mg: · Hypersensitivity to rosuvastatin and any component of the drug · Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption (the drug contains lactose) · Age under 18 years · Concomitant use of cyclosporine · In women; pregnancy, lactation, absence of adequate contraception · Liver diseases in the active phase, persistent increase in serum transaminase activity, and any increase in transaminase activity (more than 3 times the upper limit of normal) · Patients with risk factors for myopathy/rhabdomyolysis, specifically: moderate renal impairment (CrCl < 60 mL/min) · Hypothyroidism · Personal or family history of muscle disease · History of myotoxicity from other HMG-CoA reductase inhibitors or fibrates · Excessive alcohol consumption · Conditions that may lead to increased plasma concentrations of rosuvastatin · Concomitant use of fibrates · Patients of Mongoloid race Use with caution for daily doses of 5 mg, 10 mg, and 20 mg: Risk of developing myopathy/rhabdomyolysis – renal impairment, hypothyroidism, personal or family history of muscle disease, and history of muscle toxicity from other HMG-CoA reductase inhibitors or fibrates; excessive alcohol consumption; age over 65 years; conditions that may lead to increased plasma concentrations of rosuvastatin; Mongoloid race; concomitant administration with fibrates (see section "Pharmacokinetics"); history of liver disease, sepsis, arterial hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders, or uncontrolled seizures. For daily dose of 40 mg: Mild to moderate renal impairment (CrCl > 60 mL/min); age over 65 years; history of liver disease; sepsis; arterial hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders, or uncontrolled seizures. Patients with hepatic impairment There is no experience with the use of the drug in patients with hepatic impairment of severity greater than 9 according to the Child-Pugh scale (see sections "Pharmacodynamics" and "Special Instructions"). Pregnancy and lactation The drug CRESTOR is contraindicated during pregnancy and lactation. Women of reproductive age should use adequate methods of contraception. Since cholesterol and other products of cholesterol biosynthesis are necessary for fetal development, the potential risk of HMG-CoA reductase inhibitors outweighs the benefits of drug use in pregnant women. If pregnancy occurs during therapy with the drug, its intake should be discontinued. There is no data on the excretion of rosuvastatin in breast milk, therefore, its use during breastfeeding should be discontinued (see section "Contraindications"). Method of administration and dosage Take orally with water, do not chew or crush, swallow whole. Administer at any time of day, independent of food intake. Before starting therapy with CRESTOR, the patient should follow a standard hypocholesterolemic diet and continue it during treatment. The dose is selected individually based on the therapeutic goal and effect, taking into account the recommended target concentrations of lipids. Recommended starting dose For initiation or switching from other HMG-CoA reductase inhibitors to rosuvastatin therapy, the dose should be 5 mg or 10 mg once daily. When selecting the starting dose, the individual cholesterol concentration and the possible risk of cardiovascular complications should be considered, as well as the risk of developing side effects. If necessary, the dose can be increased after 4 weeks (see section "Pharmacodynamics"). Due to the risk of side effects with a 40 mg dose compared to lower doses (see section "Side Effects"), increasing the dose up to 40 mg after 4 weeks of treatment with a higher than recommended starting dose is only possible in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially with familial hypercholesterolemia), in whom the desired result was not achieved with a 20 mg dose, and who will be under specialist supervision (see section "Special Instructions"). Close monitoring of patients receiving the drug at a dose of 40 mg is recommended. Administration of 40 mg is not recommended in patients who have not previously consulted a specialist. Lipid metabolism indicators must be monitored 2-4 weeks after starting CRESTOR therapy and/or dose increase (dose adjustment if necessary). Elderly patients Dose adjustment is not required in elderly patients. Patients with renal impairment Dose adjustment is not required in patients with mild and moderate renal impairment. Administration of CRESTOR is contraindicated in patients with severe renal impairment (CrCl < 30 mL/min). Administration of 40 mg is contraindicated in patients with moderate renal impairment (CrCl < 30-60 mL/min) (see sections "Pharmacodynamics" and "Special Instructions" and "Pharmacodynamics"). In patients with moderate renal impairment, a starting dose of 5 mg is recommended. Patients with hepatic impairment Liver diseases in the active phase are a contraindication for taking CRESTOR® (see section "Contraindications"). Special populations. Ethnic groups Studies of rosuvastatin pharmacokinetic parameters in different ethnic groups have revealed an increase in its systemic concentration in Japanese and Chinese (see section "Special Instructions"). This fact should be considered when prescribing CRESTOR to these ethnic groups. For those requiring 10 and 20 mg, the recommended starting dose for individuals of Mongoloid race is 5 mg. Administration of 40 mg of the drug is contraindicated in representatives of this race (see section "Contraindications"). Genetic polymorphism In carriers of genotypes SLCO1B1 (OATP1B1) c.521CC and ABCG2 (BCRP) c.421AA, an increase in AUC exposure was observed compared to carriers of SLCO1B1 c.521TT and ABCG2 c.421CC. For patients with genes c.521CC and c.421AA, the maximum recommended dose of CRESTOR is 20 mg (see sections "Pharmacokinetics", "Drug Interactions", and "Special Instructions"). Patients predisposed to myopathy Administration of 40 mg of the drug is contraindicated in patients with factors indicating a predisposition to myopathy (see section "Contraindications"). For those requiring 10 mg and 20 mg, the recommended starting dose for such patients is 5 mg (see section "Contraindications"). Concomitant therapy Rosuvastatin binds to various types of transport proteins (specifically, OATP1B1 and BCRP). When CRESTOR is co-administered with drugs (such as cyclosporine, some HIV protease inhibitors, including ritonavir and atazanavir, lopinavir and/or tipranavir combinations) that increase plasma concentrations of rosuvastatin due to binding to transporter proteins, the risk of myopathy (including rhabdomyolysis) may increase (see sections "Drug Interactions" and "Special Instructions"). The instructions for use of such drugs should be consulted before co-administration with CRESTOR. In such cases, the benefit of alternative therapy should be assessed or temporary discontinuation of CRESTOR intake should be considered. If the above-mentioned agents are necessary, the risk-benefit of concomitant therapy with CRESTOR should be assessed and dose reduction considered. (See section "Drug Interactions"). Side effects Side effects observed during CRESTOR intake are insignificant and resolve on their own. In controlled clinical trials, less than 4% of patients treated with CRESTOR discontinued participation due to early adverse reactions. Table 3 lists the side effect profile according to clinical trials and extensive post-marketing use; side effects are grouped by frequency category and organ system class. The frequency of adverse events is presented as follows: often (> 1/100, < 1/10); infrequently (> 1/1000, < 1/100); rarely (> 1/10000, < 1/1000); very rarely (< 1/10000), unspecified frequency (cannot be calculated from available data). Table 3. Adverse reactions according to clinical trials and post-marketing use Organ system class Often Infrequently Rarely Very rarely Unspecified frequency Blood and lymphatic system disorders Thrombocytopenia Immune system disorders Hypersensitivity reactions, including angioedema Endocrine system disorders Diabetes mellitus 1 Psychiatric disorders Depression Nervous system disorders Headache, dizziness Polyneuropathy, memory loss Peripheral neuropathy, sleep disorders (including insomnia and nightmares) Respiratory, thoracic, and mediastinal disorders Cough, shortness of breath Gastrointestinal disorders Constipation, nausea, abdominal pain Pancreatitis Diarrhea Hepatic and biliary disorders Increased activity of "liver" transaminases Jaundice, hepatitis Skin and subcutaneous tissue disorders Pruritus, skin rash, urticaria Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) Skeletal, muscular, and connective tissue disorders Myalgia Myopathy (including myositis), rhabdomyolysis, lupus-like syndrome, muscle damage Arthralgia Tendinopathy, sometimes complicated by tendon rupture, immune-mediated necrotizing myopathy Renal and urinary tract disorders Hematuria Reproductive system and breast disorders Gynecomastia General disorders and administration site conditions Asthenia Edema 1 Frequency depends on the presence or absence of risk factors (fasting blood glucose concentration ≥ 5.6 mmol/L, body mass index (BMI) > 30 kg/m², elevated triglyceride concentration, history of arterial hypertension). As with other HMG-CoA reductase inhibitors, the frequency of drug side effects is generally dose-dependent. Renal disorders In patients treated with CRESTOR®, urine analysis using a test strip revealed the presence of proteinuria, mainly of tubular type. Changes in urine protein levels (ranging from absence or trace amounts to ++ or more) were observed in less than 1% of patients receiving the drug at doses of 10-20 mg and in approximately 3% of patients receiving the drug at a dose of 40 mg during treatment. At a dose of 20 mg, a slight increase in the frequency of changes in urine protein levels (ranging from absence or trace amounts to +) was observed. In most cases, proteinuria decreases or disappears spontaneously with continued therapy. Review of clinical trial results and post-marketing experience to date has not revealed a causal relationship between proteinuria and acute or progressive kidney disease. Hematuria was observed in patients taking CRESTOR®, and clinical trial results show that this phenomenon is rare. Skeletal muscle disorders With CRESTOR intake (at all doses), especially at doses above 20 mg, skeletal muscle effects were observed: myalgia, myopathy (including myositis), in rare cases – rhabdomyolysis with or without acute renal failure. Dose-dependent increase in creatine phosphokinase activity was observed in patients taking rosuvastatin. In most cases, this was insignificant, asymptomatic, and transient. If creatine phosphokinase activity increases (more than 5 times the upper limit of normal), rosuvastatin therapy should be discontinued (see section "Special Instructions"). Liver damage Like other HMG-CoA reductase inhibitors, a dose-dependent increase in transaminase activity was observed in a small number of patients using rosuvastatin, mostly insignificant, asymptomatic, and short-lived. The following side effects have been reported with the use of some statins: sexual dysfunction. Very rare cases of interstitial lung disease have been reported, mostly with long-term use of the drug (see section "Special Instructions"). The frequency of reports of rhabdomyolysis, severe renal and hepatic disorders (mainly associated with increased "liver" transaminase activity) was higher at a dose of 40 mg. Overdose Simultaneous intake of several daily doses does not change the pharmacokinetic parameters of rosuvastatin. There is no specific treatment for rosuvastatin overdose. In such cases, symptomatic therapy and measures aimed at maintaining vital organ and system functions are recommended. Liver function and creatine phosphokinase activity should be monitored. Hemodialysis is unlikely to be effective. Drug interactions Effect of concomitant use of other drugs on rosuvastatin Inhibitors of transport proteins: Rosuvastatin is a substrate of certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Co-administration of inhibitors of these transporter proteins with rosuvastatin may increase the plasma concentration of the latter and increase the risk of myopathy (see Table 4, sections "Method of administration and dosage" and "Special Instructions"). Cyclosporine: Co-administration of cyclosporine and rosuvastatin resulted in a 7-fold increase in rosuvastatin AUC in adult volunteers (see Table 4). CRESTOR® is contraindicated in patients concomitantly using cyclosporine (see section "Contraindications"). Concomitant use of these drugs does not affect cyclosporine concentrations in blood plasma. Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant use with protease inhibitors may lead to a significant increase in rosuvastatin exposure (see Table 4). For example, in a pharmacokinetic study, concomitant use of rosuvastatin 10 mg and a combination drug containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers resulted in approximately a threefold and sevenfold increase in rosuvastatin AUC and Cmax, respectively. Concomitant use of CRESTOR® and some combinations of protease inhibitors may be possible after thorough assessment of the possibility of CRESTOR dose adjustment, based on the expected increase in rosuvastatin exposure (see sections "Method of administration and dosage", "Special Instructions", and Table 4). Gemfibrozil and other hypolipidemic agents: Concomitant use of rosuvastatin and gemfibrozil resulted in a twofold increase in maximum plasma concentration and AUC of rosuvastatin (see section "Special Instructions"). Based on data from specific interaction studies, no significant pharmacokinetic interaction with fenofibrate is expected; 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 with HMG-CoA reductase inhibitors, likely because they can cause myopathy with monotherapy. Intake of CRESTOR® at a dose of 40 mg is contraindicated when used with fibrates (see sections "Contraindications" and "Special Instructions"). Such patients should start therapy at a dose of 5 mg. Ezetimibe: Co-administration of CRESTOR® 10 mg and ezetimibe 10 mg was associated with a 1.2-fold increase in rosuvastatin AUC in patients with hypercholesterolemia (see Table 4). A pharmacodynamic interaction between CRESTOR® and ezetimibe regarding adverse reactions cannot be ruled out (see section "Special Instructions"). Antacids: Concomitant use of CRESTOR and an antacid in the form of a suspension containing magnesium and aluminum hydroxide resulted in a decrease in rosuvastatin plasma concentration by approximately 50%. This effect is less pronounced if the antacid is used 2 hours after taking CRESTOR. The clinical significance of this interaction has not been studied. Erythromycin: Concomitant use of erythromycin and rosuvastatin resulted in a 20% decrease in rosuvastatin AUC and a 30% decrease in Cmax. This interaction may be due to increased intestinal motility by erythromycin. Cytochrome P450 isoenzymes: In vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these enzymes. Therefore, no interaction of rosuvastatin with other agents is expected at the level of metabolism involving cytochrome P450 isoenzymes. No clinically significant interaction of rosuvastatin with fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) and ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor) was observed. Interactions with drugs that cause rosuvastatin dose adjustment (see Table 4) CRESTOR dose adjustment is necessary when used with agents that cause rosuvastatin exposure. If exposure is expected to be more than 2 times, the starting dose of CRESTOR is 5 mg. Also, the maximum daily dose should be adjusted so that the expected exposure does not exceed the same value for 40 mg without concomitant medication. For example, the maximum daily dose of CRESTOR with gemfibrozil is 20 mg (exposure increase 1.9 times), with ritonavir/atazanavir – 10 mg (exposure increase 3.1 times). Dose adjustment of the starting dose of CRESTOR is not required if the exposure increase is expected to be less than 2 times, however, caution should be exercised when increasing the CRESTOR dose above 20 mg. Table 4. Effect of concomitant therapy on rosuvastatin exposure (AUC, data shown in descending order) – published clinical trial results Rosuvastatin AUC increase ≥ 2 times Treatment regimen with interacting drugs Rosuvastatin regimen Change in rosuvastatin AUC Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + voxilaprevir 100 mg once daily, 15 days 10 mg once daily Increase 7.4 times Cyclosporine 75-200 mg twice daily, 6 months 10 mg once daily, 10 days Increase 7.1 times Darolutamide 600 mg twice daily, 5 days 5 mg once daily Increase 5.2 times Regorafenib 160 mg once daily, 14 days 5 mg once daily Increase 3.8 times Atazanavir 300 mg/ritonavir 100 mg once daily, 8 days 10 mg once daily Increase 3.1 times Velpatasvir 100 mg once daily 10 mg once daily Increase 2.7 times Ombitasvir 25 mg/paritaprevir 150 mg/ritonavir 100 mg/dasabuvir 400 mg twice daily 10 mg once daily Increase 2.6 times Teriflunomide No data Increase 2.5 times Grazoprevir 200 mg/elbasvir 50 mg once daily, 11 days 10 mg once daily Increase 2.3 times Glecaprevir 400 mg/pibrentasvir 120 mg once daily, 7 days 5 mg once daily Increase 2.2 times Lopinavir 400 mg/ritonavir 100 mg twice daily, 17 days 20 mg once daily, 7 days Increase 2.1 times Capmatinib 400 mg twice daily 10 mg once daily Increase 2.1 times Clopidogrel 300 mg (loading dose), then 75 mg every 24 hours 20 mg once daily Increase 2 times Fosamprenavir 100 mg twice daily 20 mg once daily Increase 2 times Febuxostat 120 mg once daily 10 mg once daily Increase 1.9 times Gemfibrozil 600 mg twice daily, 7 days 80 mg once daily Increase 1.9 times Rosuvastatin AUC increase < 2 times Treatment regimen with interacting drugs Rosuvastatin regimen Change in rosuvastatin AUC Eltrombopag 75 mg once daily, 10 days 10 mg once daily Increase 1.6 times Darunavir 600 mg/ritonavir 100 mg twice daily, 7 days 10 mg once daily, 7 days Increase 1.5 times Tipranavir 500 mg/ritonavir 200 mg twice daily, 11 days 10 mg once daily Increase 1.4 times Dronedarone 400 mg twice daily No data Increase 1.4 times Itraconazole 200 mg once daily, 5 days 10 mg once daily Increase 1.4 times Ezetimibe 10 mg once daily, 14 days 10 mg once daily, 14 days Increase 1.2 times Fosamprenavir 700 mg/ritonavir 100 mg twice daily, 8 days 10 mg once daily No change Rosuvastatin AUC decrease Treatment regimen with interacting drugs Rosuvastatin regimen Change in rosuvastatin AUC Erythromycin 500 mg 4 times daily, 7 days 80 mg once daily Decrease 28% Baicalin 50 mg 3 times daily, 14 days 20 mg once daily Decrease 47% 1 Data are presented as a fold change in AUC, which is the ratio of the AUC value with concomitant therapy to the value with rosuvastatin monotherapy. Data presented as % represent the % difference in AUC between concomitant therapy and rosuvastatin monotherapy. 2 Several interaction studies of CRESTOR® were conducted using different doses, and the table shows the most significant ratios. The following drugs and their combinations did not have a clinically significant effect on rosuvastatin exposure when used concomitantly: Alogliptin 0.3 mg, 7 days; Fenofibrate 67 mg 3 times daily, 7 days; Fluconazole 200 mg once daily, 11 days; Fosamprenavir 700 mg/ritonavir 100 mg twice daily for 8 days; Ketoconazole 200 mg twice daily, 7 days; Rifampicin 450 mg once daily, 7 days; Silymarin 140 mg 3 times daily for 5 days. Effect of rosuvastatin on other concomitantly used drugs Vitamin K antagonists: Like other HMG-CoA reductase inhibitors, initiating treatment or increasing the dose of CRESTOR in patients concomitantly taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) may lead to an increase in the international normalized ratio (INR). Discontinuation of CRESTOR or dose reduction may lead to a decrease in INR. In such cases, INR monitoring is recommended. Oral contraceptives/hormone replacement therapy: Concomitant use of rosuvastatin with oral contraceptives increased the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. Such an increase in plasma concentration should be considered when selecting the dose of the oral contraceptive. Pharmacokinetic data on the concomitant use of CRESTOR and hormone replacement therapy are not available, therefore, the development of a similar effect during their concomitant use cannot be ruled out. However, such a combination was widely used in clinical trials in women and was well tolerated by patients. Other medicinal products: Digoxin: Based on data from specific drug interaction studies, no clinically significant interaction of rosuvastatin with digoxin is expected. Fusidic acid: Interaction studies of rosuvastatin and fusidic acid have not been conducted. Concomitant systemic therapy with fusidic acid and statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic or pharmacokinetic, or both) has not yet been studied. Rhabdomyolysis (including fatal outcome) has been reported in patients treated with this combination. If systemic therapy with fusidic acid is necessary, CRESTOR treatment should be discontinued during the period of fusidic acid intake (see section "Special Instructions ~"). Special instructions Renal effects In patients receiving high doses of CRESTOR (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria did not indicate the development of acute kidney disease or progression of existing disease. For patients receiving the drug at a dose of 40 mg, monitoring of kidney function during treatment is recommended. Skeletal muscle disorders With CRESTOR intake (at all doses), especially at doses above 20 mg, the following skeletal muscle effects were observed: myalgia, myopathy, in rare cases rhabdomyolysis. Determination of creatine phosphokinase activity Creatine phosphokinase activity should not be determined in the presence of intense physical exertion or other causes of its increase to avoid misinterpretation of the obtained results. If the baseline creatine phosphokinase activity is significantly elevated (more than 5 times the upper limit of normal), a repeat test should be performed in 5-7 days. If the repeat test shows the same result (more than 5 times the upper limit of normal), starting treatment is not recommended. When prescribing CRESTOR before starting therapy, as with other HMG-CoA reductase inhibitors, caution should be exercised in patients at risk of myopathy/rhabdomyolysis (see section "Use with caution"), and the risk-benefit ratio should be compared and the patient clinically monitored. During therapy, the patient should be informed to immediately notify the doctor of muscle pain, weakness, and spasms, especially if accompanied by general malaise and fever. In such patients, determination of creatine phosphokinase activity is necessary. Therapy should be discontinued if significant increase in its activity (more than 5 times the upper limit of normal) is detected or if muscle symptoms are severely pronounced with discomfort (regardless of whether creatine phosphokinase activity is elevated above 5 times the upper limit of normal). If symptoms resolve and creatine phosphokinase activity returns to normal, it is recommended to prescribe CRESTOR and/or another HMG-CoA reductase inhibitor at a lower dose and monitor the patient closely. Routine monitoring of creatine phosphokinase in the absence of symptoms is not recommended. Very rare cases of immune-mediated necrotizing myopathy have been reported, with clinical manifestations of persistent proximal muscle weakness and elevated plasma creatine phosphokinase activity after statin treatment (including rosuvastatin) or discontinuation of their intake. Additional investigations of the muscular and nervous systems, as well as therapy with immunosuppressive agents, may be necessary. No skeletal muscle symptoms were observed with concomitant therapy during CRESTOR intake. However, there are reports of myositis and myopathy development when other HMG-CoA reductase inhibitors are used concomitantly with fibrinic acid (including gemfibrozil), cyclosporine, lipid-lowering doses of nicotinic acid (≥ 1 g/day), azole antifungal agents, HIV protease inhibitors, and macrolides. Gemfibrozil increases the risk of myopathy with concomitant administration of certain HMG-CoA reductase inhibitors. Therefore, concomitant intake of CRESTOR with gemfibrozil is not recommended. When co-administering CRESTOR with fibrates or lipid-lowering doses of nicotinic acid, the risk-benefit should be carefully assessed. 40 mg of CRESTOR is contraindicated for use with fibrates (see sections "Contraindications" and "Drug Interactions"). Patients taking CRESTOR should start therapy at a dose of 5 mg. Lipid metabolism indicators must be monitored 2-4 weeks after starting CRESTOR therapy and/or dose increase (dose adjustment if necessary). Liver Liver function should be monitored before starting therapy and 3 months after starting. CRESTOR intake should be discontinued or the dose reduced if the activity of "liver" transaminases in blood plasma exceeds the upper limit of normal by 3 times. In hypercholesterolemia developed against the background of hypothyroidism and nephrotic syndrome, the underlying disease should be treated before taking CRESTOR. Special populations. Ethnic groups Studies of rosuvastatin pharmacokinetic parameters in different ethnic groups have revealed an increase in its systemic concentration in Japanese and Chinese compared to Caucasians (see sections "Pharmacokinetics" and "Method of administration and dosage"). HIV protease inhibitors Concomitant use of the drug with HIV protease inhibitors is not recommended (see section "Drug Interactions"). Lactose The drug is not prescribed for patients with lactose deficiency, galactose intolerance, and glucose-galactose malabsorption. Interstitial lung disease With the use of some statins (especially with long-term intake), very rare cases of interstitial lung disease have been reported. Signs of disease development include shortness of breath, non-productive cough, and general deterioration of condition (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued. Diabetes mellitus Type II In patients with glucose concentration of 5.6-6.9 mmol/L, CRESTOR therapy was associated with an increased risk of developing type II diabetes mellitus. Effect on ability to drive and operate machinery Studies on the effect of CRESTOR on the ability to drive vehicles and operate machinery have not been conducted. When driving or operating machinery that requires concentration, caution should be exercised (dizziness may occur during therapy). Dosage form 5 mg, film-coated tablets 14 tablets in a PVC/aluminum blister, 2 blisters with instructions for use in a cardboard box with a first-opening control. Storage conditions Store at a temperature not exceeding 30°C, out of reach of children. Shelf life 3 years. Do not use after the expiry date indicated on the packaging. Dispensing conditions: Pharmaceutical product group II, dispensed by prescription N3