PHARMA START #Atherosclerosis #HEALTH_CARE
Pharmacological properties
Pharmacodynamics. Rosuvastatin is a selective competitive inhibitor of hmg-coa reductase, an enzyme that converts hmg-coa into mevalonate, a precursor of chs. the main site of action of rosuvastatin is the liver, where the synthesis of xc and LDL catabolism is carried out.
Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, increasing the uptake and catabolism of LDL, which in turn leads to inhibition of VLDL synthesis, thereby decreasing the total amount of LDL and VLDL.
Rosuvastatin reduces the elevated content of LDL cholesterol, total cholesterol and triglycerides, increases the content of HDL cholesterol. It reduces the amount of apolipoprotein B (ApoB), non-HDL cholesterol, VLDL cholesterol, VLDL TG and increases the level of apolipoprotein A-I (ApoA-I), reduces the ratio of LDL cholesterol / HDL cholesterol, total cholesterol / HDL cholesterol and cholesterol / non-HDL cholesterol HDL and the ApoV / ApoA-I ratio.
The therapeutic effect appears within 1 week after the start of rosuvastatin therapy, after 2 weeks of treatment, the effect reaches 90% of the maximum possible. The maximum effect is usually achieved after 4 weeks and then continues continuously.
Clinical efficacy. Rosuvastatin is effective for adult patients with hypercholesterolemia with / without hypertriglyceridemia, regardless of race, gender or age, including those with diabetes mellitus and familial hypercholesterolemia.
In 80% of patients with hypercholesterolemia IIa and IIb types (the average baseline level of LDL cholesterol is about 4.8 mmol / L) while taking the preparation at a dose of 10 mg, the level of LDL cholesterol reaches 3 mmol / L.
An additive effect is observed in combination with fenofibrate in relation to the content of triglycerides and with nicotinic acid in relation to the content of HDL cholesterol.
Pharmacokinetics
Absorption and distribution. Cmax of rosuvastatin in blood plasma is achieved approximately 5 hours after oral administration. Bioavailability is ≈20%. Rosuvastatin accumulates in the liver. Its volume of distribution is ≈134 liters. About 90% of rosuvastatin binds to blood plasma proteins, mainly albumin.
Metabolism. Rosuvastatin undergoes limited metabolism (≈10%). In vitro metabolism studies using human hepatocytes indicate that rosuvastatin is a weak substrate for metabolism based on cytochrome P450 enzymes. The main isoenzyme involved is CYP 2C9, with 2C19, 3A4 and 2D6 playing a slightly lesser role. The main identified metabolites of rosuvastatin are N-desmethyl and lactone metabolites. N-desmethyl is ≈50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. Rosuvastatin accounts for more than 90% of the activity of a circulating inhibitor of HMG-CoA reductase.
Excretion. About 90% of the dose of rosuvastatin is excreted unchanged in the feces. The other part is excreted in the urine. T½ from blood plasma is ≈19 hours. T½ does not change with increasing dose. The average clearance is ≈50 l / h, the membrane transporter OATP-C is involved in the process of hepatic uptake of rosuvastatin, which plays an important role in the hepatic elimination of rosuvastatin.
Linearity. The systemic exposure of rosuvastatin increases in proportion to the dose. When taking several daily doses, the pharmacokinetic parameters do not change.
Special populations of patients
Age and gender. There is no clinically significant effect of age and gender on the pharmacokinetics of rosuvastatin in adults. The pharmacokinetics of rosuvastatin in children with heterozygous familial hypercholesterolemia was similar to that in adult volunteers.
Ethnic groups. It is known that pharmacokinetic studies have revealed that in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans), the median values of AUC and Cmax are approximately 2 times higher than in Europeans; in Indians, the median values of AUC and Cmax were increased by about 1.3 times. Pharmacokinetic analysis of different ethnic groups did not establish clinically significant differences in pharmacokinetics among representatives of the Caucasian and Negroid races.
Patients with renal insufficiency. In patients with mild or moderate renal impairment, the level of concentration of rosuvastatin and N-desmethyl in blood plasma does not change significantly. In persons with severe renal failure (creatinine clearance 30 ml / min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration of N-desmethyl is 9 times higher than in healthy volunteers. The plasma concentration of rosuvastatin in hemodialysis patients was ≈50% higher than in healthy volunteers.
Patients with hepatic impairment. Individuals with various stages of liver failure with a score of ≤7 on the Child-Pugh scale did not show an increase in T½ of rosuvastatin. However, patients with scores 8 and 9 on the Child-Pugh scale showed an increase in T½ by at least 2 times compared to those with lower values on the Child-Pugh scale. There is no experience of using rosuvastatin in patients with a score of 9 on the Child-Pugh scale.
Genetic polymorphism. The distribution of HMG-CoA reductase inhibitors, including rosuvastatin, occurs with the participation of transport proteins OATP1B1 and BCRP. Patients with genetic polymorphisms SLCO1B1 (OATP1B1) and / or ABCG2 (BCRP) are at risk of increased exposure to rosuvastatin. In certain forms of polymorphism SLCO1B1 c.521СС and ABCG2 c.421АА, the exposure of rosuvastatin (AUC) is increased compared to genotypes SLCO1B1 c.521ТТ or ABCG2 c.421СС. Special genotyping in clinical practice is not provided, but patients with such polymorphism are recommended to use rosuvastatin in a low dose.
Children. Pharmacokinetic parameters in children with heterozygous familial hypercholesterolemia aged 10 to 17 years have not been fully determined. It is known that a small study of the pharmacokinetics of rosuvastatin (in the form of tablets) with the participation of pediatric patients showed that the exposure of the preparation in children is similar to that in adult patients. The results also indicate that significant dose-proportional deviations are not expected.
Indications
Treatment for hypercholesterolemia. adults and children over the age of 10. primary hypercholesterolemia (type iia, including heterozygous familial hypercholesterolemia) or mixed dyslipidemia (type iib) as an adjunct to diet when diet and other non-pharmacological means (such as exercise, weight loss) are insufficient.
Homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering treatments (eg LDL apheresis) or when such treatments are inappropriate.
Prevention of cardiovascular disorders. Prevention of significant cardiovascular disorders in patients estimated to be at high risk for a first cardiovascular event, in addition to correcting other risk factors.
Application
Before starting treatment, the patient should be prescribed a standard cholesterol-lowering diet, which must be adhered to throughout the treatment. the dose must be selected individually, depending on the goals of therapy and the effectiveness of treatment, taking into account the current recommendations.
Clivas can be taken at any time of the day, regardless of food intake. The tablet should not be chewed, but it can be divided. Drink with water.
Treatment of hypercholesterolemia. The recommended starting dose is 5 or 10 mg orally once a day for both patients who have not previously used statins and those who have previously used other HMG-CoA reductase inhibitors. When choosing an initial dose, one should take into account the individual level of cholesterol in patients and the possible cardiovascular risk, as well as the potential risk of adverse reactions (see below). If necessary, the dose can be increased after 4 weeks. Due to the fact that when using a dose of 40 mg, side reactions occur more often than at lower doses, titration of the dose to a maximum level of 40 mg should only be used in patients with severe hypercholesterolemia and high cardiovascular risk (in particular, people with familial hypercholesterolemia), in which failed to achieve the desired result at a dose of 20 mg and who should be monitored regularly. At the beginning of a dose of 40 mg, specialist supervision is recommended.
Prevention of cardiovascular disorders. In the study of reducing the risk of complications from the cardiovascular system, the daily dose of the preparation was 20 mg. Patients with hypercholesterolemia should undergo standard lipid testing and adhere to dosage recommendations for the treatment of hypercholesterolemia.
Use in elderly patients. The recommended starting dose for patients over the age of 70 is 5 mg. No other dose adjustment is required depending on age.
Dosing for patients with impaired renal function. For patients with mild to moderate renal impairment, there is no need for dose adjustment. The recommended starting dose for patients with moderate renal impairment (creatinine clearance 60 ml / min) is 5 mg. The 40 mg dose is contraindicated in patients with moderate renal impairment. For persons with severe renal impairment, the use of Clivas is contraindicated in any dose.
Dosing for patients with impaired liver function. There was no increase in the systemic exposure of rosuvastatin in patients with hepatic insufficiency of 7 points on the Child-Pugh scale. However, an increase in systemic exposure was noted in individuals whose condition was estimated at 8 and 9 points on the Child-Pugh scale. In such patients, renal function should be assessed. There is no experience of using the preparation in patients with 9 points on the Child - Pugh scale. Clivas is contraindicated in persons with active liver disease.
Race. In patients of the Mongoloid race, an increase in the systemic exposure of rosuvastatin was noted. The recommended starting dose for these patients is 5 mg. The use of a dose of 40 mg is contraindicated. The maximum daily dose is 20 mg.
Dosing for patients with a tendency to develop myopathy. The recommended starting dose for patients with a predisposition to the development of myopathy is 5 mg. The 40 mg dose is contraindicated in some of these patients. The maximum daily dose is 20 mg.
Genetic polymorphism. Certain types of genetic polymorphisms can lead to increased exposure to rosuvastatin. Patients with a known presence of these types of polymorphism are advised to use the preparation at a low dose.
Simultaneous use. Rosuvastatin is a substrate for various transport proteins (eg OATP1B1 and BCRP). The risk of myopathy (including rhabdomyolysis) increases with the concomitant use of rosuvastatin with certain preparations that can increase the plasma concentration of rosuvastatin due to interactions with these transport proteins (for example, cyclosporine and certain protease inhibitors, including combinations of ritonavir with atazanavir, lopinavir and / or tipranavir (see sections SPECIAL INSTRUCTIONS, INTERACTIONS) .If possible, consider the use of alternative preparations and, if necessary, temporarily discontinue therapy with Clivas. If the concomitant use of these preparations with Clivas cannot be avoided, the benefit / risk ratio should be carefully weighed from concomitant use and adjust the dose of the preparation accordingly (see INTERACTIONS).
Contraindications
Hypersensitivity to rosuvastatin or any excipient; liver disease in the active phase, including a persistent increase in the level of transaminases in the blood plasma of unknown etiology and any increase in the level of transaminase by 3 times compared with the upper limit of normal (UHN); severe renal dysfunction (creatinine clearance 30 ml / min); myopathy; concomitant use of cyclosporine; During pregnancy and breastfeeding; women of reproductive age need to use adequate contraception.
The 40 mg dose is contraindicated in patients with factors contributing to the development of myopathy / rhabdomyolysis. These factors include: moderate renal dysfunction (creatinine clearance 60 ml / min); hypothyroidism; a personal or family history of hereditary muscle diseases; a history of myotoxicity caused by other inhibitors of HMG-CoA reductase or fibrates; alcohol abuse; situations that can lead to an increase in the level of the preparation in the blood plasma; belonging of patients to the Mongoloid race; concomitant use of fibrates.
Side effects
Adverse reactions observed with the use of Clivas are usually mild and transient. adverse reactions are presented below in accordance with the frequency of occurrence: often (1/100, 1/10); infrequently (1/1000, 1/100); rarely (1/10 000, 1/1000); very rare (1/10 000); the frequency is unknown (cannot be determined from the available data).
On the part of the blood and lymphatic system: rarely - thrombocytopenia.
From the immune system: rarely - hypersensitivity reactions, including angioedema.
Endocrine disorders: often - diabetes mellitus 1.
From the nervous system: often - headache, dizziness; very rarely - polyneuropathy, memory loss; frequency unknown - peripheral polyneuropathy, sleep disorders, including insomnia and nightmares.
Mental disorders: frequency unknown - depression.
Respiratory, chest and mediastinal disorders: frequency unknown - cough, shortness of breath.
From the digestive system: often - constipation, nausea, abdominal pain; rarely - pancreatitis; frequency unknown - diarrhea.
On the part of the hepatobiliary system: rarely - an increase in the level of hepatic transaminases; very rarely - jaundice, hepatitis.
On the part of the skin and subcutaneous tissue: infrequently - itching, rash, urticaria; frequency unknown - Stevens-Johnson syndrome.
From the musculoskeletal system and connective tissue: often - myalgia; rarely, myopathy (including myositis) and rhabdomyolysis; very rarely - arthralgia; frequency unknown - tendon disorders, sometimes complicated by ruptures, immune-mediated necrotizing myopathy.
From the side of the kidneys: very rarely - hematuria.
From the reproductive system and mammary glands: very rarely - gynecomastia.
General condition: often - asthenia; frequency unknown - edema.
1Frequency depends on the presence of risk factors (fasting glucose ≥5.6 mmol / L, body mass index (BMI) 30 kg / m2, elevated TG, AH levels in history).
As with other HMG-CoA reductase inhibitors, the frequency of adverse reactions depends on the dose.
Effects on the kidneys. In patients using Cleivas, cases of proteinuria, mainly of tubular origin (determined by a test strip), have been noted. Changes in the amount of protein in the urine from no or trace amounts to (++) or more are noted after some time in 1% of patients using rosuvastatin at a dose of 10 and 20 mg, and in approximately 3% of patients using a dose of 40 mg. A slight increase in the number of cases of increased protein in the urine from absence or traces to (+) was observed with a dose of 20 mg. In most cases, the severity of proteinuria decreased or disappeared spontaneously with continued use of rosuvastatin. Revision of data from clinical trials and post-marketing observations has not currently made it possible to identify a causal relationship between proteinuria and acute or progressive kidney disease.
Hematuria has been reported in patients treated with rosuvastatin, and clinical data indicate a low incidence.
Effects on skeletal muscle. Skeletal muscle changes, such as myalgia, myopathy (including myositis), and rarely rhabdomyolysis, with or without acute renal failure, have been reported with rosuvastatin at any dose, and especially with 20 mg doses. In patients taking rosuvastatin, a dose-dependent increase in the CPK level was noted, which in most cases was mild, asymptomatic and temporary. If the CPK level is elevated (5 relative to VGN), treatment should be discontinued.
Effects on the liver. As in the case of the use of other inhibitors of HMG-CoA reductase, in a small number of patients taking rosuvastatin, a dose-dependent increase in the level of transaminases was noted; in most cases, the phenomenon was mild, asymptomatic and temporary. With the use of rosuvastatin, an increase in HbA1c levels is also noted.
With the use of some statins, such side effects have been reported: sexual dysfunction; isolated cases of interstitial lung disease, especially in the case of long-term therapy (see SPECIAL INSTRUCTIONS).
The incidence of rhabdomyolysis, serious kidney and liver disorders (mainly elevated transaminase levels) was higher with a dose of 40 mg.
In the course of the clinical use of rosuvastatin, such an undesirable reaction as lethal and non-lethal liver failure was identified. Since this reaction was reported spontaneously from a population of indeterminate number, it is impossible to reliably estimate its frequency or establish the presence of a causal relationship with the use of rosuvastatin.
Occasionally, in clinical use, cognitive impairments (eg, memory impairment, forgetfulness, amnesia, confusion) have been reported that are associated with statin use. Such cognitive problems have been reported for all statins. The reported events are usually mild and resolve after statin withdrawal and have different times before symptoms appear (1 day to years) and disappear (median 3 weeks).
Children. An increase in CPK levels 10 times higher than ULN and muscle symptoms after exercise or increased physical activity were observed more often in children than in adults (see SPECIAL INSTRUCTIONS). However, the safety profile of rosuvastatin in children is similar to that in adults.
Special instructions
Effects on the kidneys. in patients receiving high doses of rosuvastatin, especially 40 mg, there were cases of proteinuria (determined by a test strip), mainly of tubular origin and in most cases temporary or short-lived. proteinuria was not indicative of acute or progressive kidney disease. adverse events from the kidneys were noted more often with a dose of 40 mg. in patients using the preparation at a dose of 40 mg, renal function should be monitored regularly.
Effects on skeletal muscle. Skeletal muscle lesions, such as myalgia, myopathy, and rarely rhabdomyolysis, have been reported in patients using rosuvastatin at any dose, and especially at a dose of 20 mg. When ezetimibe is used in combination with HMG-CoA reductase inhibitors, cases of rhabdomyolysis have been reported very rarely. The possibility of a pharmacodynamic interaction cannot be ruled out, and therefore this combination should be used with caution.
As with the use of other HMG-CoA reductase inhibitors, rhabdomyolysis associated with the use of rosuvastatin developed more often when used at a dose of 40 mg.
Determination of the CPK level. The CPK level should not be measured after significant physical exertion or in the presence of other alternative reasons for an increase in the CPK level, which may interfere with the interpretation of the results. If the initial CPK level is significantly increased (5 VGN), an additional confirmatory analysis should be performed within 5-7 days. If the reanalysis result confirms the baseline level of 5 VGN, treatment should not be started.
Before treatment. Cleivas, like other HMG-CoA reductase inhibitors, should be used with caution in patients with factors that contribute to the development of myopathy / rhabdomyolysis. These factors include: impaired renal function; hypothyroidism; a personal or family history of hereditary muscle diseases; a history of myotoxicity caused by other inhibitors of HMG-CoA reductase or fibrates; alcohol abuse; age 70; situations that can lead to an increase in the level of the preparation in the blood plasma; simultaneous use of fibrates. In such patients, it is necessary to assess the risk / benefit ratio when using the preparation; clinical monitoring is also recommended. You should not start treatment in the case of a significantly increased initial CPK level (5 VGN).
During the treatment period. Patients should be warned about the need to immediately report muscle pain of unknown origin, muscle weakness or cramps, especially if they are accompanied by malaise or fever. In such patients, it is required to determine the level of CPK. It is necessary to discontinue treatment if the CPK level is significantly increased (5 VGN) or if muscle symptoms are severe and lead to discomfort in everyday life (even if the CPK level is ≤5 VGN). If the symptoms disappear and the CPK level returns to normal, Clivas or an alternative inhibitor of HMG-CoA reductase can be tried again, but in minimal doses and under close supervision. Regular monitoring of the CPK level in patients without the above symptoms is not needed.
Very rarely, cases of immune-mediated necrotizing myopathy (IONM) have been reported during or after treatment with statins, including rosuvastatin. The clinical manifestations of IONM are the weakness of the proximal muscles and an increase in the level of CPK in the blood plasma, which persists even after the discontinuation of statins.
In clinical studies, in a small number of patients using rosuvastatin and concomitant preparations, there was no increased effect on skeletal muscle. However, an increased incidence of myositis and myopathy has been observed in patients using other inhibitors of HMG-CoA reductase with fibric acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors, and macrolide antibiotics. Clivas is not recommended for use in combination with gemfibrozil. The beneficial effect of subsequent changes in lipid levels while using Clewas with fibrates or niacin should be compared with the potential risk when using this combination. The simultaneous use of the preparation Clivas at a dose of 40 mg and fibrates is contraindicated (see INTERACTIONS and CONTRAINDICATIONS).
Clivas should not be used in patients with acute, serious conditions that contribute to the development of myopathy or increase the risk of renal failure associated with rhabdomyolysis (such as sepsis, arterial hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disturbances; uncontrolled convulsions) ...
Effects on the liver. Like other inhibitors of HMG-CoA reductase, Clivas should be used with caution in patients with alcohol abuse and / or a history of liver disease. Biochemical indicators of liver function are recommended to be monitored before starting the use of the preparation and after 3 months of treatment. If the level of transaminases in blood plasma is 3 times higher than VGN, the use of Clivas should be discontinued or the dose should be reduced. Serious violations of liver function (mainly an increase in the level of hepatic transaminases) in the post-marketing period were reported more often with a dose of 40 mg.
In patients with secondary hypercholesterolemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated first, and then Clivas should be used.
In clinical practice, fatal or non-fatal cases of liver failure have rarely been reported in patients taking statins, including rosuvastatin. If, during treatment with rosuvastatin, serious liver damage with clinical symptoms and / or hyperbilirubinemia or jaundice develops, the preparation must be stopped immediately. If no other causes are identified, preparation treatment should not be resumed.
Race. In the course of pharmacokinetic studies, an increase in systemic exposure in patients of the Mongoloid race compared with Europeans was observed approximately 2 times. For such patients, a dose adjustment of the preparation Clivas is necessary (see APPLICATION, CONTRAINDICATIONS). For patients of the Mongoloid race, the initial dose of Clivas should be 5 mg. An increased concentration of rosuvastatin in blood plasma was noted in patients of the Mongoloid race (see Pharmacokinetics). An increased systemic exposure should be taken into account when treating patients of the Mongoloid race in whom hypercholesterolemia is not adequately controlled with doses up to 20 mg.
Protease inhibitors. Increased systemic exposure of rosuvastatin was observed in individuals taking rosuvastatin simultaneously with various protease inhibitors in combination with ritonavir. Consideration should be given to both the benefits of lowering lipid levels with the help of the Clevis preparation in patients with HIV who receive protease inhibitors, and the possibility of increasing the plasma concentrations of rosuvastatin at the beginning of therapy and with increasing the dose of Clevis in patients receiving protease inhibitors. Concomitant use of the preparation with protease inhibitors is not recommended if the dose of Clivas is not adjusted (see APPLICATION, INTERACTIONS).
Interstitial lung disease. With the use of some statins, especially with long-term treatment, cases of interstitial lung disease have been reported (see SIDE EFFECTS). If a patient is suspected of having developed interstitial lung disease (dyspnea, unproductive cough, and worsening general condition (fatigue, weight loss, and fever)), statins should be discontinued.
Diabetes. Some evidence suggests that statins increase blood glucose levels and, in selected patients at high risk of developing diabetes mellitus in the future, can cause hyperglycemia at a level that requires proper diabetes treatment. This threat, however, outweighs the reduction in the risk of vascular disorders with statin use, and therefore should not warrant discontinuation of statin therapy. In patients at risk (fasting glucose 5.6–6.0 mmol / L, BMI 30 kg / m2, elevated TG, AH levels), both clinical and biochemical control should be established in accordance with national guidelines.
As in the case of the use of other inhibitors of HMG-CoA reductase, with the use of rosuvastatin, an increase in HbA1c and plasma glucose levels was observed.
In some cases, these indicators may exceed the limit value for the diagnosis of diabetes mellitus, especially in patients with a high risk of developing diabetes mellitus.
It is known that monotherapy with rosuvastatin does not cause a decrease in the base concentration of cortisol in the blood plasma and does not affect the adrenal reserve. Caution is needed with the simultaneous use of the preparation Clivas and other preparations that can reduce the level or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.
Use during pregnancy and lactation. Clevis is contraindicated during pregnancy and lactation. Women of reproductive age should use adequate contraception while taking Clivas .
Since cholesterol and other products of cholesterol biosynthesis are important for the development of the fetus, the potential risk of inhibition of HMG-CoA reductase outweighs the possible benefit from using the preparation during pregnancy. If pregnancy occurs while using the preparation, treatment should be discontinued immediately.
Since another preparation of this class passes into breast milk and given that HMG-CoA reductase inhibitors can cause serious adverse reactions in infants, women who need treatment with Clivas should be advised to refrain from breastfeeding. There is no data on the penetration of the preparation into breast milk.
Children. Estimation of linear growth (height), body weight, BMI and secondary characteristics of puberty according to Tanner at the age of 10 to 17 years in children using rosuvastatin is limited to a period of 1 year. No effect on height, body weight, BMI, or puberty was observed over the indicated period of study treatment. Experience in clinical trials of the preparation in children is limited, and the long-term effects of rosuvastatin (1 year) on puberty are unknown.
In children taking rosuvastatin, an increase in CPK levels 10 times higher than ULN, muscle symptoms after exercise or increased physical activity were observed more often compared with those in adults (see SIDE EFFECTS).
The use of the preparation in children should be carried out only by a specialist. It is used in children aged 10 to 17 years (boys at developmental stage II and higher according to Tanner and girls whose menstruation began less than a year ago).
The initial daily dose for children with heterozygous familial hypercholesterolemia is 5 mg. The preparation is usually taken orally at a dose of 5 to 20 mg once a day. It is necessary to increase the dose in accordance with the child's individual response to treatment and the tolerability of the preparation, following the recommendations for the treatment of children. Before starting rosuvastatin therapy, children should be prescribed a standard cholesterol-lowering diet, which patients should also follow during treatment. The safety and efficacy of the preparation in doses greater than 20 mg in this population have not been studied.
Children under the age of 10. Experience in treating children under 10 years of age is limited. Therefore, rosuvastatin is not recommended for use in children under 10 years of age.
The ability to influence the reaction rate when driving or working with other mechanisms. Studies of the effect of rosuvastatin on the ability to drive vehicles and work with other mechanisms have not been carried out. However, given its pharmacodynamic properties, it is unlikely that rosuvastatin will interfere with this ability. When driving or working with other mechanisms, you should take into account the possibility of dizziness during the period of treatment with Clivas.
Interactions
Effect of concomitant medications on rosuvastatin
Transport protein inhibitors. Rosuvastatin is a substrate for several transport proteins, including the hepatic OATP1B1 uptake transporter and the BCRP efflux transporter. The simultaneous use of the preparation Clivas with preparations that inhibit these transport proteins can lead to an increase in the concentration of rosuvastatin in the blood plasma and an increase in the risk of myopathy (see APPLICATION, SPECIAL INSTRUCTIONS).
Cyclosporine. With the simultaneous use of rosuvastatin and cyclosporin, the AUC value of rosuvastatin was, on average, 7 times higher than that of healthy volunteers. Clivas is contraindicated in patients concomitantly using cyclosporine (see CONTRAINDICATIONS).
Concomitant use did not affect the plasma concentration of cyclosporine.
Gemfibrozil and other lipid-lowering preparations. The simultaneous use of rosuvastatin and gemfibrozil led to a 2-fold increase in Cmax and AUC of rosuvastatin. Based on the data of special interaction studies, a significant pharmacokinetic interaction with fenofibrate is not expected, however, a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and niacin (nicotinic acid) in hypolipidemic doses (≥1 g / day) increase the risk of myopathy when combined with HMG-CoA reductase inhibitors, possibly due to the fact that they can cause myopathy and when used alone. A 40 mg dose of Clivas is contraindicated with the simultaneous use of fibrates. Treatment with Clivas in such cases should also be started with a dose of 5 mg.
Ezetimibe. The simultaneous use of rosuvastatin and ezetimibe in patients with hypercholesterolemia led to an increase in the AUC of rosuvastatin by 1.2 times. Pharmacodynamic interactions between Clivas and ezetimibe, which can lead to side effects, cannot be ruled out.
Protease inhibitors. Despite the fact that the exact mechanism of interaction is unknown, the combined use of protease inhibitors can lead to a significant increase in the exposure of rosuvastatin. It is known that in the course of a pharmacological study, the simultaneous use of rosuvastatin and a combined preparation containing two protease inhibitors (lopinavir 400 mg / ritonavir 100 mg) in healthy volunteers was associated with an approximately twofold and fivefold increase in the equilibrium AUC0-24 and Cmax values for rosuvastatin, respectively.
The simultaneous use of 10 mg rosuvastatin and a combination preparation containing two protease inhibitors atazanavir / ritonavir (300 mg atazanavir / 100 mg ritonavir) was accompanied by an increase in the AUC and Cmax of rosuvastatin approximately 3 and 7 times, respectively. The simultaneous use of the preparation Clivas and some combinations of protease inhibitors is possible after careful consideration of adjusting the dose of the preparation Clivas, based on the expected increase in the exposure of rosuvastatin (see APPLICATION, SPECIAL INSTRUCTIONS).
Antacids. The simultaneous use of rosuvastatin and antacids containing aluminum or magnesium hydroxide leads to a decrease in the concentration of rosuvastatin by ≈50%. This effect is less pronounced if an antacid is taken 2 hours after taking rosuvastatin. The clinical significance of this interaction has not been studied.
Erythromycin. The simultaneous use of Clivas and erythromycin leads to a decrease in AUC0-t rosuvastatin by 20%, and Cmax - by 30%. Such an interaction can occur due to increased intestinal motility as a result of the action of erythromycin.
Cytochrome P450 enzymes. The results of in vitro and in vivo studies indicate that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak inhibitor of these enzymes. Therefore, interactions between preparations associated with metabolism mediated by cytochrome P450 are not expected. There were no clinically significant interactions between rosuvastatin and fluconazole (an inhibitor of CYP 2C9 and 3A4) or ketoconazole (an inhibitor of CYP 2A6 and 3A4).
Interactions requiring dose adjustment of rosuvastatin. If it is necessary to use the preparation Clivas with other preparations that can increase the exposure of rosuvastatin, the dose of the preparation Clivas needs to be adjusted. If the exposure of the preparation (AUC) is expected to increase by approximately ≥2 times, the use of Clivas should be started with a dose of 5 mg 1 time per day. The maximum daily dose of the preparation Clivas should be adjusted so that the expected exposure of rosuvastatin does not exceed the exposure that is observed when taking a dose of 40 mg / day without the use of preparations interacting with the preparation; for example, when used with gemfibrozil, the dose of Clewas will be 20 mg (increase in exposure by 1.9 times), when used with a combination of ritonavir / atazanavir - 10 mg (increase by 3.1 times). With simultaneous use with cyclosporine - 5 mg (an increase of 7.1 times).
Effect of concomitant medications on rosuvastatin exposure (AUC; in decreasing order of magnitude)
* Data, presented as a change in x times, represent the ratio between the use of rosuvastatin in combination and separately. The data, presented as a percentage change, represent the percentage difference in relation to indicators when using rosuvastatin alone.
Increase is indicated by ↑, no change - ↔, decrease - ↓.
** Several interaction studies have been conducted at various doses of rosuvastatin, the table shows the most significant ratio.
Effect of rosuvastatin on concomitant medications
Vitamin K antagonists As with other HMG-CoA reductase inhibitors, starting or gradually increasing the dose in patients taking vitamin K antagonists (such as warfarin or other indirect anticoagulants) can lead to an increase in the international normalized ratio ( INR). After discontinuation of Clivas or lowering the dose, the INR may decrease. In such cases, it is advisable to appropriately monitor the INR.
Oral contraceptives / hormone replacement therapy (HRT). The simultaneous use of rosuvastatin and oral contraceptives led to an increase in the AUC of ethinyl estradiol and norgestrel by 26 and 34%, respectively. Such an increase in plasma levels should be taken into account when selecting the dose of oral contraceptives. There are no data on the pharmacokinetics of preparations in patients simultaneously using rosuvastatin and HRT, so the possibility of an interaction cannot be ruled out. However, this combination was widely used in women in clinical trials and was well tolerated.
Other medicines. Given the data from s
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