Suvardio, 10 mg 90 pcs
€35.09 €29.24
Pharmacodynamics
Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase – the enzyme that converts 3-hydroxy-3-methylglutarylcoenzyme A to mevalonate, a precursor of cholesterol. Rosuvastatin acts on the liver, where cholesterol (cholesterol) synthesis and low-density lipoprotein (LDL) catabolism take place.
Rosuvastatin increases the number of LDL receptors on the surface of hepatocytes, which increase the capture and catabolism of LDL, and inhibits liver synthesis of very low density lipoproteins (VLDL), thereby reducing LDL and VLDL.
. Rosuvastatin reduces the concentration of low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides (TG), increases the concentration of high-density lipoprotein cholesterol (HDL-C) and decreases the concentration of apolipoprotein B (ApoB), non-HDL-C, HDL-C, TG-LDL-C and increases the concentration of apolipoprotein A-1 (ApoA-1) (see Table 1), decreases the ratio of LDL-C/HC-LDL, total CH/LC-LDL and non-LC-LDL/CC-LDL and the apoB/apoA-1 ratio.
After the start of therapy with rosuvastatin therapeutic effect appears within one week, after 2 weeks of treatment it reaches 90% of the maximum possible effect. Maximum therapeutic effect is usually reached by 4 weeks and is maintained with regular use of the drug.
Table 1. Dependence of treatment response on rosuvastatin dose in patients with primary hypercholesterolemia (Fredrickson types IIa and IIb)
(mean adjusted percentage change relative to baseline concentration)
/p>
Dose, mg | Number of patients | LDL cholesterol | Total cholesterol | HDL cholesterol | TG | CHC-not HDL | ApoB | ApoA1 | |
Placebo | 13 | -7 | -5 | 3 | -3 | -7 | -3 | 0 | |
5 | 17 | -45 | -33 | 13 | -35 | -44 | -38 | 4 | |
10 | 17 | -52 | -36 | 14 | -10 | -48 | -42 | 4 | |
20 | 17 | -55 | -40 | 8 | -23 | -51 | -46 | 5 | |
40 | 18 | -63 | -46 | 10 | -28 | -60 | -54 | 0 |
Clinical effectiveness
Rosuvastatin is effective in adult patients with hypercholesterolemia, with or without hypertriglyceridemia, regardless of their race, sex, or age, including patients with diabetes and familial hypercholesterolemia.
In 80% of patients with Fredrickson type IIa and IIb hypercholesterolemia (mean baseline LDL-C concentration of approximately 4.8 mmol/L), the LDL-C concentration reaches values less than 3 mmol/L when using rosuvastatin in a dose of 10 mg.
In patients with heterozygous familial hypercholesterolemia who received rosuvastatin in doses from 20 to 80 mg according to the scheme of forced dose titration, positive dynamics of lipid profile parameters were observed. After titration of daily dose up to 40 mg per day (12 weeks of therapy) LDL-C concentration decreased by 53%. In 33% of patients a decrease in LDL-C concentration of less than 3 mmol/l was achieved.
In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 and 40 mg, the average decrease in LDL-C concentration was 22%.
Additive effect was observed in combination with fenofibrate for TG concentration and with nicotinic acid (more than 1 g per day) for HDL-C concentration.
. Patients with low risk of coronary heart disease (CHD) (Framingham Scale risk less than 10% over 10 years), with a mean LDL-C concentration of 4.0 mmol/L (154.5 mg/dL) and subclinical atherosclerosis, which was assessed by carotid intima-media complex (CTIM) thickness, rosuvastatin at a dose of 40 mg/day significantly slowed the rate of progression of maximum CTIM for 12 carotid segments compared with placebo at a rate of – 0.0145 mm/year (95% confidence interval (CI): -0.0196 to – 0.0093, at p <0.0001). The dose of 40 mg should only be administered in patients with significant hypercholesterolemia and high risk of cardiovascular disease.
Pharmacokinetics
Absorption
The maximum concentration (Cmax) of rosuvastatin in plasma is reached approximately 5 h after oral administration. Absolute bioavailability is ≈20%.
Distribution
Rosuvastatin is metabolized primarily by the liver, which is the main site of cholesterol synthesis and metabolism of LDL-C. The volume of distribution of rosuvastatin is approximately 134 liters. About 90% of rosuvastatin is bound to plasma proteins, mainly to albumin.
Metabolism
A limited amount of rosuvastatin undergoes biotransformation (approximately 10%).
The metabolism of rosuvastatin is slightly associated with isoenzymes of cytochrome P450 system. CYP2C9 is the main isoenzyme involved in metabolism of rosuvastatin, while CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism.
The main identified metabolites of rosuvastatin are N-dismethylrosuvastatin and lactone metabolites.
N-dismethylrosuvastatin is approximately 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity for inhibition of circulating HMG-CoA reductase is provided by rosuvastatin, the rest by its metabolites.
Approximately 90% of the administered dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin), the remainder is excreted by the kidneys. About 5% of the administered drug dose is excreted unchanged by the kidneys. The elimination half-life (T1/2) is 19 h, it does not change when increasing the drug dose. Mean geometric plasma clearance is approximately 50 l/h (coefficient of variation 21.7%). As with other HMG-CoA reductase inhibitors, the membrane membrane-bound cholesterol transporter is involved in the “hepatic” uptake of rosuvastatin. This transporter plays a major role in the excretion of rosuvastatin by the liver.
Linearity
The systemic exposure of rosuvastatin increases in proportion to the dose. There are no changes in pharmacokinetic parameters after multiple daily doses of the drug.
Genetic polymorphism
HMK-CoA reductase inhibitors, including rosuvastatin, bind to transport proteins OATP1B1 (organic anion transport polypeptide involved in the capture of statins by hepatocytes) and BCRP (efflux transporter). Carriers of SLCO1B1 (OATP1B1) C.521CC and ABCG2 (BCRP) C.421AA genotypes had 1.6 and 2.4-fold increased exposure (AUC – area under the concentration-time curve) to rosuvastatin compared with SLCO1B1c.521TT and ABCG2 c.421AA genotypes, respectively.
Particular patient populations
Age and sex
Age and sex have no clinically significant effect on the pharmacokinetic parameters of rosuvastatin.
Ethnic groups
Pharmacologic studies have shown an approximately two-fold increase in median AUC and Cmax of rosuvastatin in patients of mongoloid race (Japanese, Chinese, Filipino, Vietnamese and Koreans) compared to those of Caucasian race; median AUC and Cmax increased approximately 1.3-fold in Hindu patients. At the same time, analysis of pharmacokinetic parameters for the whole studied population did not reveal clinically significant differences in pharmacokinetics of the drug among representatives of Caucasoid and non-Hispanic races.
Renal failure
In patients with mild to moderate renal failure, plasma concentrations of rosuvastatin or N-desmethylrosuvastatin do not change significantly. In patients with severe renal insufficiency (creatinine clearance (CK) less than 30 ml/min) the plasma concentration of rosuvastatin is 3 times higher, and N-desmethylrosuvastatin concentration is 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin in patients on hemodialysis are approximately 50% higher than in healthy volunteers.
Hepatic failure
Patients with varying degrees of hepatic failure with a Child-Pugh score of 7 or lower have not shown increased T1/2 of rosuvastatin. However, 2 patients with Child-Pugh scores 8 and 9 showed prolongation of T1/2, approximately 2 times more than patients with lower Child-Pugh scores. There is no experience with rosuvastatin in patients with a Child-Pugh score above 9.
Indications
Active ingredient
How to take, the dosage
Interaction
When using rosuvastatin and cyclosporine concomitantly, the AUC of rosuvastatin was on average 7 times higher than the value observed in healthy volunteers. Concomitant use of these drugs leads to an 11-fold increase in plasma concentrations of rosuvastatin, while the plasma concentration of cyclosporine does not change.
In the use of other statins there have been reports of cases of rhabdomyolysis with concomitant use of rosuvastatin and fusidic acid, monitoring of patients is required, if necessary, temporary discontinuation of rosuvastatin is possible.
As with other HMG-CoA reductase inhibitors, starting therapy with rosuvastatin or increasing the dose of the drug in patients receiving concomitant vitamin K antagonists (such as warfarin or other coumarin anticoagulants) may lead to an increase in international normalized ratio (MHO). Cancellation or reduction of the dose of rosuvastatin may cause a decrease in MHO. In such cases, MHO should be monitored.
The concomitant use of rosuvastatin and gemfibrozil and other lipid-lowering agents leads to a 2-fold increase in Cmax and AUC of rosuvastatin.
Table 2. Effect of concomitant therapy on rosuvastatin exposure
(AUC, data in descending order)
Based on specific interaction data, no pharmacokinetic interaction with fenofibrate is expected; pharmacodynamic interaction is possible.
Hemfibrozil, fenofibrate, other fibrates and nicotinic acid at lipid-lowering doses (1 g or more per day) when used concomitantly with HMG-CoA reductase inhibitors increased the risk of myopathy, possibly due to the fact that they can also cause myopathy when used in monotherapy. Concomitant use of 40 mg rosuvastatin and fibrates is contraindicated. When concomitant use of the drug with gemfibrozil and other lipid-lowering drugs the initial dose of rosuvastatin is 5 mg.
In concomitant use of rosuvastatin and ezetimibe there is no change in AUC or Cmax of both drugs. However, the possibility of pharmacodynamic interaction between rosuvastatin and ezetimibe cannot be excluded, which may cause adverse events.
While the exact mechanism of interaction is unknown, concomitant use of rosuvastatin with protease inhibitors may result in prolongation of T1/2 of rosuvastatin. In pharmacokinetic study in concurrent administration of 20 mg rosuvastatin and combined preparation containing two protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers it was determined that AUC(0-24) and 5 times Cm of rosuvastatin, respectively, increased 2-fold. Therefore, it is not recommended to simultaneously prescribe rosuvastatin and protease inhibitors during therapy of patients with human immunodeficiency virus (HIV).
The concomitant use of rosuvastatin and antacids in suspensions containing aluminum or magnesium hydroxide leads to a decrease in plasma concentration of rosuvastatin by approximately 50%. This effect is weaker if antacids are used 2 h after rosuvastatin administration. The clinical significance of this interaction has not been established.
The concomitant use of rosuvastatin and erythromycin decreases AUC(0-t)rosuvastatin by 20% and Cmax of rosuvastatin by 30%. This interaction may be due to increased intestinal motility caused by taking erythromycin.
The concomitant use of rosuvastatin and oral contraceptives increases AUC of ethinylestradiol and AUC of nogestrel by 26 % and 34 %, respectively. This increase in plasma concentrations should be considered when selecting a dose of oral contraceptives. There are no pharmacokinetic data on the simultaneous use of rosuvastatin and hormone replacement therapy, therefore, a similar effect cannot be excluded when using this combination. However, this combination was widely used by women during clinical trials and was well tolerated.
There are no expected clinically significant interactions with the concomitant use of rosuvastatin and digoxin.
The results of 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 for these isoenzymes. No clinically significant interaction between rosuvastatin and fluconazole (inhibitor of CYP2C9 and CYP3A4 isoenzymes) or ketoconazole (inhibitor of CYP2A6 and CYP3A4 isoenzymes) was observed. Co-administration of rosuvastatin and itraconazole (CYP3A4 isoenzyme inhibitor) increases the AUC of rosuvastatin by 28% (clinically not significant). Therefore, no drug interaction related to cytochrome P450 metabolism is expected.
Special Instructions
Proteinuria (determined using test strips), predominantly of tubular origin, has been observed in patients taking high doses of rosuvastatin, especially 40 mg, but in most cases was intermittent or transient. It has been shown that such proteinuria does not indicate the occurrence of acute or progression of existing renal disease. The incidence of severe renal function impairment is increased when taking 40 mg of rosuvastatin. It is recommended to monitor renal function parameters during rosuvastatin therapy.
Myalgia, myopathy and, in rare cases, rhabdomyolysis have been reported with all doses of Suvardio, and particularly with doses greater than 20 mg. Rhabdomyolysis was very rare when concomitant administration of ezetimibe and HMG-CoA reductase inhibitors occurred.
In this case, pharmacological interaction of the drugs cannot be ruled out, so Suvardio and ezetimibe should be used together with caution.
The incidence of rhabdomyolysis is increased when Suvardio is taken with 40 mg.
The determination of CPK activity should not be performed after vigorous physical activity or in the presence of other possible causes of increased CPK activity, which may lead to misinterpretation of the results obtained. If CPK activity is significantly elevated (5-fold higher than IGN) before the start of therapy, a repeat measurement should be performed after 5Ë7 days. Do not start therapy with Suvardio if the repeat test confirms the initial CPK activity (more than 5 times higher than the ULN).
Rosuvastatin, like other HMG-CoA reductase inhibitors, should be administered with extreme caution in patients with existing risk factors for myopathy/rhabdomyolysis. These factors include:
In such patients, the risk/benefit ratio of therapy should be evaluated and clinical monitoring should be performed throughout the course of therapy.
Patients should be advised to promptly inform their physician if muscle pain, muscle weakness, or cramping suddenly occurs, especially if it is associated with malaise or fever!
In these patients, CPK activity should always be monitored. Treatment should be discontinued if CPK activity is more than 5 times VGN or if muscle symptoms are severe and cause daily discomfort throughout the day (even if CPK activity is 5 times less than VGN). If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing the drug or prescribing an alternative HMG-CoA reductase inhibitor at a lower dose with close monitoring of the patient. Regular monitoring of CPK activity in patients without symptoms of rhabdomyolysis is not advisable.
There is no evidence of increased skeletal muscle adverse events with Suvardio and concomitant therapy. However, increased incidence of myositis and myopathy has been found in patients taking other HMG-CoA reductase inhibitors together with fibrin acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g/day), azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with some HMG-CoA reductase inhibitors. Therefore, concomitant administration of rosuvastatin and gemfibrozil is not recommended. It is necessary to carefully assess the risk/benefit ratio when co-administering rosuvastatin with fibrates or nicotinic acid at lipid-lowering doses (more than 1 g/day). Concomitant use of rosuvastatin in a dose of 40 mg and fibrates is contraindicated.
The drug Suvardio should not be administered in patients with acute, severe illnesses, suspected myopathy or with the possible development of secondary renal failure (e.g., sepsis, arterial hypertension, surgery, trauma, metabolic syndrome, diabetes, seizures, endocrine disorders, water-electrolyte disorders).
After 2-4 weeks after the start of treatment and/or when increasing the dose of the drug it is necessary to monitor the parameters of lipid metabolism (if necessary, a dose adjustment is required).
As with other HMG-CoA reductase inhibitors, rosuvastatin should be administered with particular caution in patients who abuse alcohol or have a history of liver disease.
It is recommended that liver function tests be performed before and 3 months after the start of treatment. If the activity of “hepatic” transaminases in blood serum exceeds 3 times the upper limit of normal, the drug should be discontinued or the dose taken should be reduced. The incidence of marked liver function abnormalities (associated mainly with an increase in “hepatic” transaminases activity) is increased when taking 40 mg of the drug. In patients with secondary hypercholesterolemia due to hypothyroidism, nephrotic syndrome therapy of the underlying disease should be carried out prior to treatment with rosuvastatin.
Pharmacokinetic studies have shown increased systemic concentrations of rosuvastatin in patients of mongoloid race compared to data obtained in Caucasoid race.
The concomitant use of rosuvastatin with HIV protease inhibitors is not recommended.
Single cases of interstitial lung disease have been reported with some statins, especially over long periods of time. Manifestations of the disease may include dyspnea, non-productive cough, and deterioration in general well-being (weakness, weight loss, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.
In patients with glucose concentrations between 5.6 and 6.9 mmol/L, therapy with the drug has been associated with an increased risk of developing type 2 diabetes.
Contraindications
For daily doses of 5 mg, 10 mg and 20 mg:
for a daily dose of 40 mg:
– moderate renal insufficiency (CK – hypothyroidism;
– history of myopathies, including hereditary;
– history of myotoxicity with other HMG-CoA reductase inhibitors or fibrates;
– excessive alcohol consumption;
– conditions that may lead to increased plasma concentration of rosuvastatin;
– concomitant use of fibrates;
– use in mongoloid patients;
Cautions
For daily doses of 5 mg, 10 mg, and 20 mg: presence of risk of myopathy/rhabdomyolysis – renal failure, hypothyroidism; personal or family history of hereditary muscle disease and prior history of muscle toxicity with other HMG-CoA reductase inhibitors (statins) or fibrates; excessive alcohol consumption; conditions in which increased plasma concentration of rosuvastatin was noted; age over 65 years; high risk of diabetes mellitus development; liver diseases in anamnesis; sepsis; arterial hypotension; extensive surgical interventions; trauma; severe metabolic, endocrine or water-electrolyte disorders; uncontrolled epilepsy; race (mongoloid race); concomitant use of fibrates.
For daily dose of 40 mg: presence of risk of myopathy/rhabdomyolysis – mild renal insufficiency (CK more than 60 ml/min), age older than 65 years; high risk of diabetes mellitus; history of liver disease; sepsis; arterial hypotension; major surgical interventions; injuries; severe metabolic, endocrine or water-electrolyte disorders, uncontrolled epilepsy.
Side effects
Overdose
Pregnancy use
Similarities
Weight | 0.040 kg |
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Manufacturer | Lek d.d., Slovenia |
Medication form | pills |
Brand | Lek d.d. |
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