Hypolipidemic drug – HMG-CoA reductase inhibitor.
Hypolipidemic drug, a selective competitive inhibitor of HMG-CoA reductase, which converts 3-hydroxy-3-methylglutarylCoA to mevalonate, a precursor of cholesterol.
The main target of action is the liver, where cholesterol synthesis and LDL catabolism take place. It inhibits HMG-CoA reductase activity (90% of the drug circulates in the blood).
increases the number of LDL receptors on the surface of hepatocytes, increasing the capture and catabolism of LDL, which leads to inhibition of LDL synthesis, reducing the total amount of LDL and LDL.
. Reduces concentrations of LDL-C, non-LDL cholesterol, LDL cholesterol, total cholesterol, TG, TG-LDL-C, apolipoprotein B (ApoB), LDL cholesterol/LDL cholesterol/LDL cholesterol ratio, total cholestrin/LDL cholesterol, non-LDL cholesterol/LDL cholesterol, apoB/apoA-I, increases the concentration of HDL cholesterol, apoA-I. Hypolipidemic effect is directly proportional to the value of the prescribed dose.
Therapeutic effect appears within 1 week after the start of therapy, after 2 weeks it reaches 90% of the maximum, the maximum effect is usually reached by 4 weeks and thereafter remains constant.
It is effective in adult patients with hypercholesterolemia with or without hypertriglyceridemia (regardless of race, sex or age), including patients with diabetes and familial hypercholesterolemia.
Additive effect is noted in combination with fenofibrate (with respect to reduction of TG concentration) and nicotinic acid (with respect to reduction of HDL cholesterol concentration).
The bioavailability is 20%. Food reduces the rate of absorption. Binding with plasma proteins (mainly with albumin) – 90%. TCmax is 3-5 hours. It penetrates through placental barrier. It is accumulated in the liver. Volume of distribution – 134 l.
It is metabolized in the liver in 10% of the administered dose. As in the case of other HMG-CoA reductase inhibitors, a specific membrane cholesterol transporter is involved in the hepatic uptake of the drug, which plays an important role in its hepatic elimination. Rosuvastatin has been shown to be a non-core substrate for metabolism by enzymes of cytochrome P450 system.
The main isoenzyme involved in metabolism of rosuvastatin is CYP2C9. CYP2C19, CYP3A4, CYP2D6 enzymes are less involved in metabolism. The main metabolite is N-desmethyl, which has 1/6-1/2 of the activity of rosuvastatin; lactone metabolites are pharmacologically inactive. T1/2 is 19 h (does not change with increasing drug dose). Mean geometric plasma clearance is 50 l/h.
Extracted mainly unchanged (90%) in the feces (including adsorbed and unadsorbed rosuvastatin); the remainder in the urine. It is not excreted by hemodialysis.
Gender and age have no clinically significant effect on the pharmacokinetics of rosuvastatin.
Pharmacokinetic parameters depend on race: AUC in Japanese and Chinese is 2 times higher than in Europe and North America.
In patients with mild to moderately severe renal impairment plasma concentrations of rosuvastatin or N-dismethyl do not change significantly. In patients with severe renal impairment (CK<30 ml/min) plasma concentrations of rosuvastatin are 3 times higher and N-dismethyl – 9 times higher than in healthy volunteers. Plasma concentrations of rosuvastatin in patients on hemodialysis are approximately 50% higher than in healthy volunteers.
In patients with various stages of hepatic failure with Child-Pugh score 7 and lower there was no increase of T1/2 of rosuvastatin; in 2 patients with Child-Pugh scores 8 and 9 it was observed prolongation of T1/2 by 2 times. There is no experience of using the drug in patients with more severe liver dysfunction.
Primary hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as an adjunct to diet when diet and other non-pharmacological treatments (exercise, weight loss) are insufficient.
Familial homozygous hypercholesterolemia as an adjunct to diet and other cholesterol-lowering therapy (LDL-apheresis) or when this therapy is not suitable for the patient.
Rosuvastatin 10 mg.
How to take, the dosage
Overly, the tablet should not be chewed or crushed, swallowed whole with water, can be taken at any time of the day regardless of meals. Recommended initial dose is 10 mg once daily; if necessary the dose may be increased up to 20 mg after 4 weeks; dose increase up to 40 mg is possible only under medical supervision in patients with severe homozygous familial hypercholesterolemia with high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia), in which the desired result of therapy in dose of 20 mg is not reached.
In patients with risk factors for myopathy the initial dose of the drug should be 5 mg.
When administered with gemfibrzil the dose of rosuvastatin should not exceed 10 mg/day
In mild to moderate renal failure and in elderly adults no dose adjustment is required.
There is no experience of using the drug in patients with hepatic impairment greater than 9 on the Child-Pugh scale.
It does not affect the plasma concentration of cyclosporine. Cyclosporine enhances the effect of rosuvastatin (slows its excretion, increases AUC by 7 times, Cmax – by 11 times), vitamin K antagonists (including warfarin, may lead to prolongation of prothrombin time, its monitoring is recommended).
Gemfibrozil enhances the effect of rosuvastatin (increases its Cmax and AUC by 2-fold).
Antacids containing Al3+ and Mg2+ reduce plasma concentrations of rosuvastatin by approximately 50% (antacids should be used 2 h after taking rosuvastatin; the clinical significance of this interaction has not been studied).
Eritromycin increases gastrointestinal motility that leads to decreased effect of rosuvastatin (decreases its AUC by 20% and Cmax by 30%).
It increases effect of oral contraceptives (increases AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively, that should be considered while choosing a dose of oral contraceptives). There are no pharmacokinetic data on concomitant use of rosuvastatin and hormone replacement therapy; therefore, a similar effect cannot be excluded with this combination.
There are no expected clinically significant interactions of rosuvastatin with digoxin or fenofibrate.
Hemfibrozil, other fibrates and lipid-lowering doses of nicotinic acid (high doses or 1 g/day equivalent) increase the risk of myopathy when used concomitantly with other HMG-CoA reductase inhibitors, possibly due to the fact that they themselves may cause myopathy when used as monotherapy.
The results of in vivo and in vitro studies have shown that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 enzymes. In addition, rosuvastatin is a non-core substrate for these enzymes. No clinically significant interaction between rosuvastatin and fluconazole (CYP2C9 and CYP3A4 inhibitor) and ketoconazole (CYP2A6 and CYP3A4 inhibitor) was observed. Co-administration of rosuvastatin and itraconazole (CYP3A4 inhibitor) increases the AUC of rosuvastatin by 28% (clinically insignificant). Thus, no interaction related to metabolism through the cytochrome P450 system is expected.
Concomitant use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of reduction of endogenous steroid hormones.
Before the start of therapy and throughout the treatment period, a standard hypolipidemic diet should be followed. During treatment every 2-4 weeks the lipid profile should be monitored and according to it the dose of the drug should be adjusted if necessary.
The dose of 40 mg is contraindicated in patients with risk factors for rhabdomyolysis (moderate renal failure (CKG less than 60 ml/min), hypothyroidism, own or family history of muscle disease, myotoxicity while taking other drugs). HMG-CoA reductase inhibitors or fibrates, alcohol abuse; conditions accompanied by increased concentration of the drug in the systemic blood stream), concomitant use of fibrates, patients of Asian race).
In patients taking the drug at a dose of 40 mg it is recommended to monitor renal function parameters.
The determination of CPK activity should not be performed after vigorous physical activity or in the presence of other possible causes of CPK increase, which may lead to misinterpretation of the results. If the initial CPK increase is 5 times higher than the upper limit of normal in 5-7 days the measurement should be repeated. Therapy should not be initiated if the repeat test confirms an initial increase in CPK activity of more than 5 times the upper limit of normal.
In patients with existing risk factors for rhabdomyolysis, the ratio of risk to possible benefit of therapy should be considered and clinical monitoring should be performed throughout the course of treatment.
Patients should be informed to immediately inform their physician if they experience sudden onset of muscle pain, muscle weakness, or cramping, especially if combined with malaise and fever. In such patients, CPK activity should be monitored. Therapy should be stopped if CPK activity is more than 5 times higher than the upper limit of normal, or if muscle symptoms are severe and cause daily discomfort (even if CPK activity is 5 times lower than the upper limit of normal). If symptoms disappear and CPK activity returns to normal, re prescription of the drug or other HMG-CoA reductase inhibitors at lower doses should be considered with close monitoring of the patient. Routine monitoring of CPK activity in the absence of symptoms of rhabdomyolysis is not advisable.
An increase in myositis and myopathy has been reported in patients taking other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives, including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when concomitantly prescribed with some HMG-CoA reductase inhibitors. Thus, concomitant administration of rosuvastatin and gemfibrozil is not recommended. The risk/benefit ratio of co-administration of rosuvastatin and fibrates or nicotinic acid should be carefully weighed.
Liver function tests are recommended before therapy and 3 months after the start of therapy. If serum “hepatic” transaminase activity exceeds 3 times the upper limit of normal, the drug dose should be reduced or discontinued.
In most cases, proteinuria decreases or disappears during therapy and does not indicate the onset of acute or progressive existing renal disease.
If hypercholesterolemia and hypothyroidism or nephrotic syndrome are combined, therapy for the underlying disease should be given before starting treatment with rosuvastatin.
Perhaps caution should be exercised when driving or working with high concentration and psychomotor reaction (dizziness may occur during therapy).
Women of reproductive age should use adequate methods of contraception. Because cholesterol and substances synthesized from cholesterol are important for fetal development, the potential risk of HMG-CoA reductase inhibition exceeds the benefits of using the drug during pregnancy.
In a study in rats (use in doses from 2-50 mg/kg/day) decreased fetal weight, delayed bone ossification in the fetus, and decreased survival of the offspring were found. If pregnancy occurs during therapy, the drug should be immediately discontinued. There are no data on excretion of rosuvastatin with the milk of women, therefore breastfeeding should be discontinued.
liver diseases in the active phase (including persistent increase in the activity of “hepatic” transaminases, as well as any increase in the activity of “hepatic” transaminases in blood serum more than 3 times the upper limit of normal),
significant renal dysfunction (CK<30 ml/min), myopathy, concomitant use of cyclosporine,
pregnancy, lactation; women of reproductive age who do not use adequate methods of contraception;
age under 18 years (effectiveness and safety not established).
With caution. Renal insufficiency,
hypothyroidism, personal or family history of hereditary muscle disease and prior history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates),
age over 65 years,
history of liver disease, sepsis, arterial hypotension,
extensive surgery, trauma,
severe metabolic, endocrine or electrolyte disorders, proteinuria, uncontrolled epilepsy,
Asians (Japanese and Chinese).
The incidence of side effects is dose-dependent: frequently (1-10%), less frequently (0.1-1%), rarely (0.01-0.1%).
Nervous system disorders: frequently – headache, dizziness, asthenic syndrome; less frequently – anxiety, depression, insomnia, neuralgia, paresthesias.
Gastrointestinal disorders: frequently – constipation, nausea, abdominal pain; frequency unknown – reversible transient dose-dependent increase in “liver” transaminase activity; less frequently – dyspepsia (including diarrhea, flatulence, vomiting), gastritis, gastroenteritis.
The respiratory system: often – pharyngitis; less frequently – rhinitis, sinusitis, bronchial asthma, bronchitis, cough, shortness of breath, pneumonia.
Periodic heart rate: less frequently – angina pectoris, increased BP, palpitations, vasodilation.
Musculoskeletal system: frequently – myalgia; less frequently – arthralgia, arthritis, muscle hypertonicity, back pain, pathological limb fracture (without injury); rarely – myopathy, rhabdomyolysis (concomitantly with impaired renal function, while taking the drug in a 40 mg dose).
Urinary system disorders: tubular proteinuria (in less than 1% of cases – for doses of 10 and 20 mg, 3% of cases – for 40 mg dose); less frequently – peripheral edema (hands, feet, ankles, shins), lower abdominal pain, urinary system infections.
Allergic reactions: less frequently – skin rash, itching; rarely – angioedema.
Laboratory parameters: transient dose-dependent increase of CPK activity (in case of CPK activity increase more than 5 times higher than the upper limit of normal, the therapy should be temporarily suspended).
Others: less frequently – accidental trauma, anemia, chest pain, diabetes mellitus, ecchymosis, flu-like syndrome, periodontal abscess.
Treatment: symptomatic, control of liver function and CPK activity is necessary; there is no specific antidote, hemodialysis is ineffective.
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