Ultrox 40mg 28 tablets

ULTROX 40 mg film-coated tablets Composition: Each film-coated tablet contains calcium rosuvastatin as the active substance, equivalent to 40 mg rosuvastatin, and lactose monohydrate as excipients, and Kollicoat IR Sunset Yellow, Kollicoat IR White II, and Kollicoat IR Carmine as colorants. Pharmacological properties: Pharmacodynamic properties: Pharmacotherapeutic group: HMG-CoA reductase inhibitors Mechanism of action: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, which is the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for cholesterol reduction. Rosuvastatin increases the number of LDL "hepatic" receptors on the surface of liver cells, thereby increasing LDL uptake and catabolism, which leads to the inhibition of hepatic synthesis of very-low-density lipoproteins (VLDL). As a result, the total amount of low and very-low-density lipoproteins decreases. Pharmacodynamic effect: Rosuvastatin reduces elevated concentrations of LDL cholesterol, total cholesterol, and triglycerides, and increases the concentration of HDL cholesterol. Clinical efficacy and safety: Ultrox is effective in adults with hypercholesterolemia, with or without hypertriglyceridemia, regardless of race, sex, or age, and in special patient groups such as patients with diabetes and familial hypercholesterolemia. Pharmacokinetic properties: Absorption: Peak plasma concentration of rosuvastatin is reached approximately 5 hours after oral administration. Absolute bioavailability is approximately 20%. Distribution: Rosuvastatin is primarily metabolized in the liver, which is the main organ for cholesterol and low-density lipoprotein cholesterol synthesis. The volume of distribution of rosuvastatin is approximately 134 liters. Approximately 90% of rosuvastatin is bound to plasma proteins, mainly albumin. Metabolism: Rosuvastatin undergoes limited metabolism (approximately 10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate of the cytochrome P450 system. CYP2C9 is the main isoenzyme involved in its metabolism, with 2C19, 3A4, and 2D6 involved to a lesser extent. The main identified metabolites are N-desmethyl and lactone metabolites. The N-desmethyl metabolite is approximately 50% less active than rosuvastatin, and the lactone metabolites are clinically inactive. More than 90% of circulating HMG-CoA reductase inhibition is achieved by rosuvastatin. Excretion: Approximately 90% of the administered dose of rosuvastatin is excreted unchanged in feces (including absorbed and unabsorbed active substance), and the remaining part is excreted in urine. Approximately 5% is excreted unchanged in urine. The plasma half-life is approximately 19 hours. The half-life does not increase with high doses. The mean geometric plasma clearance is approximately 50 L/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the hepatic uptake of rosuvastatin involves the OATP-cholesterol membrane transporter, which plays a significant role in the hepatic elimination of rosuvastatin. Linearity: Systemic exposure to rosuvastatin increases proportionally to the dose. Pharmacokinetic parameters do not change with daily administration. Indications: Treatment of hypercholesterolemia in adults, adolescents, and children aged 6 years and older with primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type IIb) as an adjunct to diet, when diet and other non-pharmacological measures (e.g., exercise, weight reduction) are insufficient. In adults, adolescents, and children aged 6 years and older with homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering therapies (e.g., LDL apheresis) or when such therapies are not appropriate. Prevention of cardiovascular events: Prevention of major cardiovascular events in patients at high risk of primary cardiovascular complications (see Pharmacodynamic Properties section) as an adjunct to correction of other risk factors. Contraindications: Ultrox is contraindicated in: - Patients with hypersensitivity to rosuvastatin or any of the excipients. - Patients with active liver disease, including unexplained persistent increase in serum transaminase activity and any increase in serum transaminase activity more than 3 times the upper limit of normal (ULN). - Patients with severe hepatic insufficiency (creatinine clearance <30 mL/min). - Patients with myopathy. - Patients receiving concomitant therapy with cyclosporine. - During pregnancy and lactation, and in women of childbearing potential who are not using effective methods of contraception. The 40 mg dose is contraindicated in patients with risk factors for myopathy/rhabdomyolysis. These factors include: - Moderate renal impairment (creatinine clearance <60 mL/min) - Hypothyroidism - Personal or family history of hereditary muscle diseases - Myotoxicity from previous use of HMG-CoA reductase inhibitors or fibrates - Excessive alcohol consumption - Conditions that may lead to increased plasma concentration of rosuvastatin - Patients of Asian race - Concomitant use of fibrates. (See Warnings/Precautions, Drug Interactions, and Pharmacokinetic Properties sections) Warnings / Precautions: Renal effects: Proteinuria, detected by dipstick urinalysis and mainly of tubular origin, has been observed in patients treated with high doses of rosuvastatin, especially at the 40 mg dose, which in most cases was transient and temporary. Proteinuria was not indicative of acute or progressive renal disease (see Adverse Reactions/Undesirable Effects section). In post-marketing use, the incidence of serious renal complications is higher with the 40 mg dose. Renal function assessment is required during routine monitoring in patients treated with the 40 mg dose. Skeletal muscle effects: Effects on skeletal muscle, such as myalgia, myopathy, and rarely rhabdomyolysis, have been observed in patients treated with rosuvastatin at all doses, especially at doses >20 mg. Very rare cases of rhabdomyolysis have been reported with the combination of ezetimibe and HMG-CoA reductase inhibitors. Pharmacodynamic interactions cannot be excluded (see Drug Interactions section), and caution should be exercised when combining these drugs. As with other HMG-CoA reductase inhibitors, the incidence of rhabdomyolysis cases caused by rosuvastatin is higher with the 40 mg dose in post-marketing use. Creatine kinase determination: Creatine kinase levels should not be determined in the presence of intense exercise or other potential causes of elevated creatine kinase that could alter the results. If creatine kinase levels are significantly elevated compared to baseline (more than 5 times the upper limit of normal), a confirmatory test should be performed within 5-7 days. Treatment should not be initiated if a repeat test confirms an increase of more than 5 times the upper limit of normal compared to baseline. Before initiating treatment: As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients with risk factors for myopathy/rhabdomyolysis. These factors include: renal impairment, hypothyroidism, personal or family history of hereditary muscle diseases, myotoxicity from previous use of HMG-CoA reductase inhibitors or fibrates, excessive alcohol consumption, age over 70 years, conditions that may lead to increased plasma concentration of rosuvastatin (see Dosage and Administration, Drug Interactions, and Pharmacokinetic Properties sections). Concomitant use of fibrates. The risk-benefit of treatment should be carefully considered in these patients, and clinical monitoring is recommended. Treatment should not be initiated if creatine kinase levels are significantly elevated compared to baseline (more than 5 times the upper limit of normal). During therapy, patients should be advised to report any sudden onset of muscle pain, weakness, or cramps, especially with general malaise or fever. Creatine kinase activity should be monitored in such patients. Treatment should be discontinued if creatine kinase levels are significantly elevated (more than 5 times the upper limit of normal) or if muscle symptoms are severe and cause daily discomfort throughout the day (even if creatine kinase activity is less than or equal to 5 times the upper limit of normal). If symptoms resolve and creatine kinase activity returns to normal, consideration should be given to re-initiating rosuvastatin or initiating an alternative HMG-CoA reductase inhibitor at a lower dose, with careful patient monitoring. Regular monitoring of creatine kinase levels in patients without symptoms of rhabdomyolysis is not recommended. Very rare cases of immune-mediated necrotizing myopathy have been reported with statins, including rosuvastatin, during or after treatment. Immune-mediated necrotizing myopathy is clinically characterized by proximal muscle weakness and elevated serum creatine kinase activity, which persists after discontinuation of statin therapy. Clinical trials have not provided evidence of an increased incidence of skeletal muscle effects in patients receiving rosuvastatin in combination with concomitant therapies. However, an increase in the number of cases of myositis and myopathy has been observed in patients taking other HMG-CoA reductase inhibitors along with fibric acid derivatives, gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when taken with certain HMG-CoA reductase inhibitors. Therefore, the combination of rosuvastatin and gemfibrozil is not recommended. The benefit of lipid-lowering effects should be carefully weighed against the potential risks when combining rosuvastatin with fibrates or niacin. Concomitant use of the 40 mg dose and fibrates is contraindicated (see Drug Interactions and Adverse Reactions/Undesirable Effects sections). The combination of rosuvastatin and fusidic acid is not recommended. Cases of rhabdomyolysis (including some fatal) have been reported in patients taking this combination (see Drug Interactions section). Ultrox should not be administered in combination with systemic fusidic acid or within 7 days of completing fusidic acid therapy. If systemic fusidic acid is necessary, statin therapy should be discontinued during fusidic acid treatment. Cases of rhabdomyolysis (including some fatal) have been reported in patients taking a combination of fusidic acid and statins (see section 4.5). Patients should be informed to seek immediate medical attention for any symptoms of muscle weakness, pain, or tenderness. Statins may be resumed seven days after the last dose of fusidic acid. In exceptional cases where prolonged systemic fusidic acid is necessary, such as for severe infections, the combination of Ultrox and fusidic acid should be used only under individual medical supervision. Ultrox should not be administered to patients with acute, severe illness that may predispose to myopathy or the development of secondary renal failure due to rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine, and electrolyte disturbances; or uncontrolled seizures). Hepatic effects: As with other HMG-CoA reductase inhibitors, Ultrox should be used with caution in patients with excessive alcohol consumption or a history of liver disease. Liver function tests should be performed before initiating treatment and 3 months after initiation. If serum transaminase levels exceed 3 times the upper limit of normal, rosuvastatin intake should be discontinued or the dose reduced. In the post-marketing period, the incidence of serious liver dysfunction (primarily related to elevated liver transaminases) increases with doses of rosuvastatin above 40 mg. In patients with secondary hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the underlying condition should be treated before initiating rosuvastatin therapy. Race: Pharmacokinetic studies have shown increased rosuvastatin exposure in patients of Asian race compared to Caucasians (see Dosage and Administration, Contraindications, and Pharmacokinetic Properties sections). Protease inhibitors: Concomitant use of rosuvastatin with various protease inhibitors and ritonavir has been associated with increased systemic exposure to rosuvastatin. The benefits of lipid-lowering with rosuvastatin in HIV patients taking protease inhibitors should be carefully assessed, taking into account the potential increase in plasma rosuvastatin concentrations at the start of treatment and during dose titration in patients taking protease inhibitors. Concomitant use with certain protease inhibitors is not recommended without dose adjustment of rosuvastatin (see Dosage and Administration and Drug Interactions sections). This product is not intended for patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. Ultrox contains Sunset Yellow (E110) colorant. May cause allergic reactions. One dose of Ultrox contains less than 0.01 mg of sodium. However, this amount of sodium is usually not problematic. Interstitial lung disease: With some statins, particularly with long-term therapy, isolated cases of interstitial lung disease have been reported (see Adverse Reactions/Undesirable Effects section). Symptoms may include dyspnea, non-productive cough, and deterioration of general condition (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued. Diabetes mellitus: There is evidence that statins, as a class of drugs, increase blood glucose levels and may, in some patients at high risk of developing diabetes, provoke hyperglycemia to a degree that requires standard diabetes treatment. However, this risk is outweighed by the reduction in vascular risk with statins, so there is no reason to discontinue statin therapy. In patients at risk (fasting glucose 5.6-6.9 mmol/L, BMI >30 kg/m2, elevated triglycerides, hypertension), clinical and biochemical parameters should be monitored according to national recommendations. In the JUPITER study, the overall 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 between 5.6 and 6.9 mmol/L. Use in pediatrics: In pediatric patients aged 6-17 years, studies evaluating the linearity of rosuvastatin's effects on growth (height), weight, body mass index, and Tanner stages of sexual maturity are limited to a treatment period of up to 2 years. After 2 years, no effects on growth, weight, body mass index, or sexual maturity were observed (see Pharmacodynamic Properties section). In clinical studies in children and adolescents receiving rosuvastatin for 52 weeks, increases in creatine kinase more than 10 times the upper limit of normal and muscle symptoms after exercise and increased physical activity were observed more frequently than in adult clinical studies (see Adverse Reactions/Undesirable Effects section). Fertility, pregnancy, and lactation: Ultrox is contraindicated during pregnancy and lactation. Women of childbearing potential should use effective methods of contraception. Since cholesterol and other products of cholesterol biosynthesis are important for fetal development, the potential risk of HMG-CoA reductase inhibitors outweighs the benefit of treatment in pregnant women. Animal studies have provided limited data regarding reproductive toxicity. If a patient becomes pregnant during treatment, therapy should be discontinued immediately. Rosuvastatin is excreted in rat milk. There are no reports of drug excretion in human breast milk (see Contraindications section). Effects on ability to drive and use machines: Studies on the effect on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, rosuvastatin is unlikely to affect these abilities. When driving and operating machinery, it should be noted that dizziness may occur during treatment. Adverse Reactions / Undesirable Effects: Side effects of rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of patients treated with rosuvastatin were withdrawn due to adverse reactions. Table of side effects: The table below presents the side effect profile of rosuvastatin obtained from clinical trials and post-marketing use. Side effects in the table are classified by frequency and organ system class. The incidence of adverse reactions is presented as follows: Common (>1/100, <1/10); Uncommon (>1/1000, <1/100); Rare (>1/10000, <1/1000); Very Rare (<1/10000); Frequency unknown (frequency cannot be estimated from available data). Table 2. Adverse reactions obtained from clinical trials and post-marketing use Organ system class | Common | Uncommon | Rare | Very Rare | Frequency unknown -------------------|--------|----------|------|-----------|----------------- 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 | | Peripheral neuropathy, Memory loss, Sleep disorders (including insomnia and nightmares) | Polyneuropathy Respiratory, thoracic and mediastinal disorders | | | | Cough, Dyspnea | Gastrointestinal disorders | Constipation | Nausea, Abdominal pain | | Pancreatitis | Diarrhea Hepatobiliary disorders | | | Increased hepatic transaminase activity | Jaundice, Hepatitis | Skin and subcutaneous tissue disorders | | Pruritus, Rash, Urticaria | | Stevens-Johnson syndrome | Skeletal muscle and connective tissue disorders | Myalgia | | Myopathy (including myositis), Arthralgia | Rhabdomyolysis, Tendon disorders, sometimes complicated by tendon rupture, Immune-mediated necrotizing myopathy | Renal and urinary disorders | | | | Hematuria | Reproductive system and breast disorders | | | | Gynecomastia | General disorders and administration site conditions | Asthenia | | | Edema | 1. Incidence depends on the presence or absence of risk factors (fasting glucose concentration >5.6 mmol/L, BMI >30 kg/m2, elevated triglycerides, history of hypertension). As with other HMG-CoA reductase inhibitors, the incidence of side effects is mainly dose-dependent. Renal effects: Proteinuria, detected by dipstick urinalysis and mainly of tubular origin, has been observed in patients treated with rosuvastatin. Changes in urinary protein levels from trace to ++ or more occur in less than 1% of patients taking 10-20 mg, and in approximately 3% of patients taking 40 mg. A slight increase in urinary protein from trace to +- is observed with the 20 mg dose. In most cases, proteinuria decreases or resolves spontaneously during therapy. A review of clinical trial data and current post-marketing experience has not established a causal relationship between proteinuria and acute or progressive renal disease. Hematuria has been observed in patients treated with rosuvastatin. Clinical trial data show that its incidence is low. Skeletal muscle effects: Effects on the musculoskeletal system, such as myalgia, myopathy (including myositis), and in rare cases, rhabdomyolysis with or without acute renal failure, have been observed with rosuvastatin at all doses, especially at doses >20 mg. Dose-dependent increases in creatine kinase activity have been observed in patients taking rosuvastatin; these were mostly mild, asymptomatic, and transient. If creatine kinase activity is elevated (more than 5 times the upper limit of normal), therapy should be discontinued (see Warnings/Precautions section). Hepatic effects: As with other HMG-CoA reductase inhibitors, dose-dependent increases in transaminase activity occur in a small number of patients with rosuvastatin; these are mostly mild, asymptomatic, and transient. The following side effects have been reported with some statins: sexual dysfunction. Isolated cases of interstitial lung disease, especially with long-term therapy (see Warnings/Precautions section). The incidence of rhabdomyolysis, severe renal impairment, and severe hepatic impairment (primarily elevated liver transaminases) is higher with the 40 mg dose. Pediatric population: In a 52-week clinical study in children and adolescents, increases in creatine kinase more than 10 times the upper limit of normal and muscle symptoms after exercise and increased physical activity were observed more frequently than in adult clinical studies (see Warnings/Precautions section). Otherwise, the safety profile of rosuvastatin in children and adolescents was similar to that in adults. Consult your doctor if you notice any side effects. Drug Interactions: Effect of concomitant use of other drugs on rosuvastatin: Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin and medicinal products that are inhibitors of these transporter proteins may be associated with increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see Dosage and Administration, Warnings/Precautions, and Drug Interactions sections, Table 3). Cyclosporine: Co-administration of rosuvastatin and cyclosporine resulted in mean AUC values of rosuvastatin being approximately 7 times higher than those in healthy volunteers (see Table 3). Ultrox is contraindicated in patients receiving cyclosporine (see Contraindications section). Co-administration of the drugs does not affect cyclosporine plasma concentrations. Protease inhibitors: Although the exact mechanism of interaction is unknown, co-administration of rosuvastatin with protease inhibitors may lead to increased exposure to rosuvastatin (see Table 3). For example, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin with a combination drug containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with approximately a 3-fold increase in rosuvastatin AUC and a 7-fold increase in Cmax. Concomitant use of certain combinations of Ultrox and protease inhibitors may be possible with careful selection of the Ultrox dose, based on the expected increase in rosuvastatin exposure (see Dosage and Administration, Warnings/Precautions, and Drug Interactions sections, Table 3). Gemfibrozil and other lipid-lowering agents: Concomitant use of rosuvastatin and gemfibrozil leads to a 2-fold increase in rosuvastatin Cmax and AUC (see Warnings/Precautions section). Based on specific interaction study data, no pharmacokinetic interaction is expected with fenofibrate, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates, and niacin (nicotinic acid) at lipid-lowering doses (1 g or more per day) when used with HMG-CoA reductase inhibitors increase the risk of myopathy, as they can cause myopathy even when used as monotherapy. Concomitant use of 40 mg rosuvastatin and fibrates is contraindicated (see Contraindications and Warnings/Precautions sections). The initial dose of the drug in this patient group should be 5 mg. Ezetimibe: Co-administration of 10 mg rosuvastatin and 10 mg ezetimibe resulted in a 1.2-fold increase in rosuvastatin AUC in patients with hypercholesterolemia (Table 3). The risk of adverse events cannot be excluded due to potential pharmacodynamic interaction between Ultrox and ezetimibe (see Warnings/Precautions section). Antacids: Co-administration of rosuvastatin with an antacid suspension containing aluminum or magnesium hydroxide reduces plasma rosuvastatin concentrations by approximately 50%. This effect is less pronounced if the antacid is taken 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied. Erythromycin: Concomitant use of rosuvastatin and erythromycin leads to a 20% decrease in rosuvastatin AUC and a 30% decrease in Cmax. This interaction may be due to increased intestinal motility caused by erythromycin. Cytochrome P450 enzymes: In vitro and in vivo studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Furthermore, rosuvastatin is a weak substrate for these isoenzymes. Therefore, no drug interactions related to cytochrome P450 metabolism are expected. No clinically significant interactions have been identified between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 isoenzyme inhibitor) or ketoconazole (CYP2A6 and CYP3A4 isoenzyme inhibitor). Interactions with drugs requiring rosuvastatin dose adjustment (see also Table 3): Dose adjustment of Ultrox is required when used concomitantly with medicinal products that increase rosuvastatin exposure. If an increase in exposure (AUC) of 2-fold or more is expected, the initial dose of Ultrox should be 5 mg once daily. The maximum daily dose of Ultrox should be adjusted so that the expected exposure to rosuvastatin does not exceed the equivalent of the Ultrox 40 mg daily dose obtained without interacting medicinal products, e.g., Ultrox 20 mg with gemfibrozil (exposure increase 1.9-fold), and Ultrox 10 mg with ritonavir/atazanavir (exposure increase 3.1-fold). Table 3. Effect of concomitant therapy on rosuvastatin exposure (AUC data are listed in descending order) – results of published clinical studies. Concomitant therapy regimen | Rosuvastatin regimen | Rosuvastatin AUC change* | Cyclosporine 75-200 mg BID, 6 months | 10 mg OD, 10 days | 7.1-fold ↑ | Atazanavir 300 mg/Ritonavir 100 mg OD, 8 days | 10 mg OD | 3.1-fold ↑ | Simeprevir 150 mg OD, 7 days | 10 mg OD | 2.8-fold ↑ | Lopinavir 400 mg/Ritonavir 100 mg BID, 17 days | 20 mg OD, 7 days | 2.1-fold ↑ | Clopidogrel 300 mg loading dose, then 75 mg q24h | 20 mg OD | 2-fold ↑ | Gemfibrozil 600 mg BID, 7 days | 80 mg OD | 1.9-fold ↑ | Eltrombopag 75 mg OD, 10 days | 10 mg OD | 1.6-fold ↑ | Darunavir 600 mg/Ritonavir 100 mg BID, 7 days | 10 mg OD, 7 days | 1.5-fold ↑ | Tipranavir 500 mg/Ritonavir 200 mg BID, 11 days | 10 mg OD | 1.4-fold ↑ | Dronedarone 400 mg BID | No data | 1.4-fold ↑ | Itraconazole 200 mg OD, 5 days | 10 mg OD | **1.4-fold ↑ | Ezetimibe 10 mg OD, 14 days | 10 mg OD, 14 days | **1.2-fold ↑ | Fosamprenavir 700 mg/Ritonavir 100 mg BID, 8 days | 10 mg OD | ↔ | Aleglitazar 0.3 mg 7 days | 40 mg, 7 days | ↔ | Silymarin 140 mg TID, 5 days | 10 mg OD | ↔ | Fenofibrate 67 mg TID, 7 days | 10 mg, 7 days | ↔ | Rifampicin 450 mg OD, 7 days | 20 mg OD | ↔ | Ketoconazole 200 mg BID, 7 days | 80 mg OD | ↔ | Fluconazole 200 mg OD, 11 days | 80 mg OD | ↔ | Erythromycin 500 mg QID, 7 days | 80 mg OD | 28% ↓ | Baikalin 50 mg TID, 14 days | 20 mg OD | 47% ↓ | *Data are presented as a short-term change, showing the ratio of the parameter during co-administration to the same parameter during rosuvastatin monotherapy. Data are presented as % change, reflecting the change (%) relative to rosuvastatin monotherapy. Increase is shown by "↑", no change by "↔", and decrease by "↓". **Several drug interaction studies were performed with different doses of rosuvastatin; the table presents the most significant parameters. OD = once daily; BID = twice daily; TID = three times daily; QID = four times daily. Effect of rosuvastatin use on other drugs: Vitamin K antagonists: As with other HMG-CoA reductase inhibitors, initiating therapy with Ultrox or increasing the dose of the drug in patients taking vitamin K antagonists (e.g., warfarin or other coumarin anticoagulants) concomitantly may lead to an increase in the International Normalized Ratio (INR). Discontinuation or dose reduction of Ultrox may lead to a decrease in INR. In such cases, appropriate INR monitoring is necessary. Oral contraceptives/Hormone replacement therapy: Concomitant use of rosuvastatin and oral contraceptives resulted in an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. When selecting the dose of oral contraceptives, this increase in plasma concentration should be taken into account. Pharmacokinetic data on the use of Ultrox and hormone replacement therapy medications are not available, so a similar effect cannot be excluded during such combinations. However, these combinations were widely used and well-tolerated in women during clinical trials. Other medicinal products: Digoxin: Based on specific interaction study data, no clinically significant interaction is expected with concomitant use of digoxin. Fusidic acid: Interaction studies between rosuvastatin and fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased with concomitant use of systemic fusidic acid and statins. The mechanism of this interaction (pharmacodynamic or pharmacokinetic, or both) is currently unknown. Cases of rhabdomyolysis (including some fatal) have been reported in patients taking this combination. If systemic fusidic acid is necessary, Ultrox treatment should be discontinued during fusidic acid treatment. See also section 4.4. Use in children: Interaction studies have only been conducted in adults. The intensity of interactions in children is unknown. Dosage and administration: Before initiating treatment, the patient should follow a standard low-cholesterol diet, which should be continued throughout the course of treatment. The dose of the drug should be selected individually, based on the treatment goal and the patient's therapeutic response, taking into account current recognized recommendations. Ultrox should be taken at any time of day, regardless of food intake. Treatment of hypercholesterolemia: The recommended starting dose of the drug is 5 mg or 10 mg orally once daily in patients who have not previously taken statins, as well as in patients who are switching from therapy with other HMG-CoA reductase inhibitors. When selecting the initial dose, the cholesterol level, as well as the risk of cardiovascular complications and adverse reactions, should be considered for each individual patient (see below). If necessary, the dose can be adjusted after 4 weeks (see Pharmacodynamic Properties section). Since adverse reactions occur more frequently with the 40 mg dose than with lower doses (see Adverse Reactions/Undesirable Effects section), final dose titration up to the maximum of 40 mg is only necessary in patients with severe hypercholesterolemia at high cardiovascular risk (particularly those with familial hypercholesterolemia) who have not achieved the desired outcome with the 20 mg dose and who will be under specialist supervision (see Warnings/Precautions section). Specialist supervision is recommended when initiating treatment with the 40 mg dose. Prevention of cardiovascular events: In the study to reduce the risk of cardiovascular events, rosuvastatin was used at a dose of 20 mg per day (see Pharmacodynamic Properties section). Use in children: Use of the drug in children should only be carried out by a specialist physician. Children and adolescents aged 6 to 17 years (Tanner stage <II-V): The standard starting dose in children and adolescents with heterozygous familial hypercholesterolemia is 5 mg per day. - In children aged 6-9 years with heterozygous familial hypercholesterolemia, the standard dose is 5-10 mg orally once daily. The safety and efficacy of doses greater than 10 mg have not been studied in this age group. - In children aged 10-17 years with heterozygous familial hypercholesterolemia, the standard dose is 5-20 mg orally once daily. The safety and efficacy of doses greater than 20 mg have not been studied in this age group. Dose titration should be based on the patient's individual response and tolerance to therapy, according to recommendations for treatment in children and adolescents (see Warnings/Precautions section). Before initiating rosuvastatin treatment, the patient should follow a standard low-cholesterol diet, which should be continued throughout the course of rosuvastatin treatment. Experience in children with homozygous familial hypercholesterolemia is limited to a small group of children aged 8 to 17 years. 40 mg tablets are not suitable for pediatric patients. Children under 6 years of age: The safety and efficacy of the drug in children under 6 years of age have not been studied. Therefore, the use of Ultrox in children under 6 years of age is not recommended. Use in the elderly: For patients over 70 years of age, the recommended starting dose of the drug is 5 mg (see Warnings/Precautions section). Dose adjustment based on age is not necessary. Dosage in patients with renal impairment: Dose adjustment is not necessary in patients with mild or moderate renal impairment. The recommended starting dose of the drug is 5 mg for patients with moderate renal impairment (creatinine clearance less than 60 mL/min). The 40 mg dose is contraindicated in moderate renal impairment. Use of any dose of Ultrox is contraindicated in patients with severe renal impairment (see Contraindications and Pharmacokinetic Properties sections). Dosage in patients with hepatic impairment: In patients with Child-Pugh scores of 7 or less, no increase in systemic exposure to rosuvastatin has been observed. However, an increase in systemic exposure to the drug has been observed in patients with Child-Pugh scores of 8 and 9 (see Contraindications section). In these patients, renal function should be monitored during therapy (see Warnings/Precautions section). Data on the use of the drug in patients with Child-Pugh scores of 9 or higher are not available. Ultrox is contraindicated in patients with active liver disease (see Contraindications section). Race: Increased systemic exposure has been observed in patients of Asian race (see Contraindications, Warnings/Precautions, and Pharmacokinetic Properties sections). The recommended starting dose of the drug in patients of Asian race is 5 mg. The 40 mg dose is contraindicated in this patient group. Genetic polymorphism: Certain types of genetic polymorphism are known to increase rosuvastatin exposure (see Pharmacokinetic Properties section). For patients known to have such polymorphism, relatively lower doses of Ultrox are recommended. Dosage in patients prone to myopathy: In patients prone to myopathy, the recommended starting dose of the drug is 5 mg (see Warnings/Precautions section). The 40 mg dose is contraindicated in some cases in this patient group (see Contraindications section). Concomitant therapy: Rosuvastatin is a substrate for various transporter proteins (e.g., OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases when rosuvastatin is used with medicinal products that increase plasma rosuvastatin concentrations through interaction with transporter proteins (such as cyclosporine and certain protease inhibitors, including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir; see Warnings/Precautions and Drug Interactions sections). In such cases, the possibility of initiating alternative therapy or temporarily discontinuing rosuvastatin intake should be assessed. If the use of the above-mentioned drugs and rosuvastatin is necessary, the benefit and risk of concomitant therapy should be assessed, and the possibility of reducing the rosuvastatin dose should be considered (see Drug Interactions section). Overdose: There is no specific treatment for overdose. In case of overdose, symptomatic treatment and supportive measures are recommended. Liver function and creatine kinase activity should be monitored. Hemodialysis is unlikely to be effective in this case. Storage conditions: Store below 25°C in the original packaging. Keep out of reach of children. Dispensing conditions: Pharmaceutical product group - II, dispensed by prescription form №3. Dosage form: Ultrox 40 mg film-coated tablets are packaged in Al-Al blister packs containing 14 or 28 film-coated tablets as primary packaging, and in cardboard boxes as secondary packaging. See also: Ultrox 20 mg 28 tablets