Release form, composition and packing
Film-coated tablets almost white, round, biconvex, with Valium on one side allowed light roughness.
1 tab. atorvastatin (in the form of atorvastatin calcium trihydrate) 10 mg - - 20 mg.
Excipients: calcium carbonate, light, lactose, starch, sodium croscarmellose, povidone (K-30), magnesium stearate, colloidal silicon dioxide, anhydrous, crospovidone, primelloza 1915 CPS, purified talc, titanium dioxide, triacetin.
Clinico-pharmacological group: preparation, correcting lipid metabolism.
Lipid-lowering drug. Atorvastatin - a selective competitive inhibitor of HMG-CoA reductase - a key enzyme that converts 3-hydroxy-3-metilglyutarilkoenzim And mevalonic acid - a precursor of steroids, including cholesterol.
The liver TG and cholesterol (CH) are included in the VLDL, enter the blood plasma and transported to peripheral tissues. Formed from VLDL cholesterol, which kataboliziruyutsya interaction with high-affinity receptors of LDL. Atorvastatin lowers levels of cholesterol and lipoproteins in blood plasma by inhibiting HMG-CoA reductase in the liver and increasing the number of LDL receptors on the surface of liver cells, which leads to increased capture and catabolism of LDL-C. Atorvastatin reduces the formation of LDL-C and LDL particle number. It causes marked and persistent increase in the activity of LDL receptors and also has a beneficial effect on the quality of circulating LDL. Atorvastatin effectively lowers LDL-C in patients with homozygous hypercholesterolemia, which is usually not amenable to treatment by other lipid-lowering drugs.
When studying the dose-dependent effect of atorvastatin was shown that the drug (at a dose of 10-80 mg) reduced total cholesterol (by 30-46%), LDL-C (at 41-61%), apolipoprotein B (in the 34-50%) and triglycerides (by 14-33%). The results of treatment were similar in patients with heterozygous familial hypercholesterolemia, non-family forms of hypercholesterolemia and mixed hyperlipidemia, including in patients with insulin-dependent diabetes mellitus.
Atorvastatin reduces total cholesterol, LDL-C, CS-VLDL, apolipoprotein B, triglyceride and cholesterol are not included in the composition of HDL, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin reduces intermediate density lipoprotein cholesterol in patients with disbetalipoproteinemiey. Like cholesterol, lipoproteins containing triglyceride (including VLDL), intermediate density lipoproteins and remnants, and accelerate the development of atherosclerosis.
Increased triglycerides in the blood plasma is often found in combination with reduced levels of HDL-C and the presence of LDL particles are small, as well as in combination with nonlipid metabolic risk factors for CHD. While not proven, that the increase in total triglycerides in the blood plasma is an independent risk factor for CHD.
Also no evidence that raising HDL-C or lowering triglycerides by itself affects the risk of coronary and other cardiovascular complications and mortality of patients.
The primary target organ of atorvastatin is the liver, where the synthesis of cholesterol and LDL clearance. Dynamics of the level of LDL-C is better correlated with the dose of the drug than with its concentration in blood plasma. Dose of atorvastatin should be taken into account when the therapeutic effect.
Atorvastatin is rapidly absorbed after oral administration. Cmax plasma levels reached after 1-2 h. The degree of absorption and concentration of atorvastatin in plasma increased in proportion to dose. The bioavailability of tablets of atorvastatin compared with a solution of 95-99%. Absolute bioavailability is about 14% and systemic bioavailability, which determines inhibitory activity against HMG-CoA reductase inhibitors - about 30%. Low systemic bioavailability explain presystemic clearance in gastrointestinal mucosa and / or metabolism in the "first pass" through the liver.
Although food decreases the rate and extent of absorption by about 25% and 9% respectively (as shown by the definition of Cmax and AUC), but the cholesterol / LDL with atorvastatin on an empty stomach and during the meal down to the same extent. After dosing in the evening level of atorvastatin in plasma below (Cmax and AUC by approximately 30%) than after administration in the morning. However, the degree of lowering cholesterol / LDL is independent of time taking the medication during the day.
Mean Vd is approximately 381 liters. Plasma protein binding - 98%. The ratio of atorvastatin in erythrocytes / plasma is about 0.25, indicating that the low penetration of atorvastatin in red blood cells.
Atorvastatin is actively metabolized to form the ortho - and paragidroksilirovannyh derivatives and various beta-oxidation products. In vitro inhibitory effect of ortho - and paragidroksilirovannyh metabolites with respect to HMG-CoA reductase, comparable with that of atorvastatin.
Inhibitory activity against HMG-CoA reductase inhibitors in blood plasma by approximately 70% due to active metabolites. In vitro studies indicate the importance of metabolism of atorvastatin under the influence of CYP3A4 in the liver is confirmed by increasing concentrations of atorvastatin in human blood plasma, while taking erythromycin, which is an inhibitor of this isoenzyme. In vitro studies have also shown that atorvastatin is a weak inhibitor of CYP3A4. In animals, the ortho-gidroksimetabolit undergoing further glyukuronirovaniyu.
Atorvastatin and its metabolites are mainly in the bile after liver and / or extrahepatic metabolism, but atorvastatin, apparently, is not subject to enterohepatic recycling. T1 / 2 is about 14 hours, but the half-life of inhibitory activity against HMG-CoA reductase is 20-30 hours, which is explained by the presence of active metabolites. After oral administration in the urine detected less than 2% of the dose of the drug.
Pharmacokinetics in special clinical situations
The concentration of atorvastatin in plasma in the elderly (aged over 65 years) is higher (Cmax by approximately 40%, AUC by approximately 30%) than in adult patients of young age.
However, differences in safety or effectiveness of achieving lipid-lowering therapy in the elderly compared with the general population were found. Pharmacokinetic studies of the drug in children has not been conducted. Concentrations of atorvastatin in plasma in women differ (Cmax by approximately 20% higher and the AUC 10% lower) from those of men. However, clinically significant differences in the influence of the drug on lipid metabolism in men and women were found.
Kidney disease does not affect the concentration of atorvastatin in plasma and its effect on lipid metabolism. In connection with this change in dose for patients with impaired renal function is not required. Although studies in patients with end-stage renal disease were not conducted, however, dialysis is unlikely to significantly enhance clearance of atorvastatin, as he is actively bound to plasma proteins. Concentrations of atorvastatin significantly increased (Cmax and AUC of approximately 16 and 11 times respectively) in patients with alcoholic liver cirrhosis (class B of Child-Pugh).
in combination with diet to reduce elevated levels of total cholesterol, LDL-C, apolipoprotein B and triglycerides and raising HDL-C in patients with primary hypercholesterolemia, heterozygous familial hypercholesterolemia and non-family, and combined (mixed) hyperlipidemia (Types IIa and IIb of Fredrickson) ;
in combination with diet to treat patients with elevated serum TG levels (Fredrickson Type IV on) and patients with disbetalipoproteinemiey (type III according to Fredrickson), whose nutritional treatment did not provide an adequate effect;
to reduce the levels of total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia when diet therapy and other non-pharmacological treatments are not effective enough.
Before the appointment Atomaxa patient must recommend a standard hypolipidemic diet, which he must continue to comply during the whole period of therapy. The initial dose is an average of 10 mg 1 time per day. The dose varies from 10 to 80 mg 1 time per day.
The drug can be taken any time of the day with food or regardless of mealtime. Dose is selected taking into account the initial LDL-C levels, the goals of therapy and individual effects. At the beginning of the treatment and / or during dose increase Atomaxa necessary every 2-4 weeks to control lipid levels in blood plasma and appropriately corrected dose. With primary hypercholesterolemia and mixed hyperlipidemia in most cases, a destination Atomaxa 10 mg 1 time per day.
Significant therapeutic effect is observed after 2 weeks, as a rule, the maximum therapeutic effect usually occurs within 4 weeks. Long-term treatment, this effect persists.
Use of the drug in patients with renal insufficiency and kidney disease has no effect on the level of atorvastatin in plasma or the degree of lowering the LDL-C in its application, so changing the dose is not required. Using the drug in elderly patients differences in safety or effectiveness of achieving lipid-lowering therapy in comparison with the general population have been noted.
CNS and peripheral nervous system: headache, dizziness, asthenic syndrome, insomnia or drowsiness, nightmares, amnesia, paresthesia, peripheral neuropathy, emotional lability, ataxia, hyperkinesis, depression, hypesthesia.
From the senses: amblyopia, tinnitus, dryness of the conjunctiva, disturbance of accommodation, eye hemorrhage, deafness, increased intraocular pressure, parosmiya, taste perversion, loss of taste sensation.
Cardio-vascular system: chest pain, palpitation, vasodilatation, postural hypotension, phlebitis, arrhythmia.
From the hematopoietic system: anemia, lymphadenopathy, thrombocytopenia.
With the respiratory system: bronchitis, rhinitis, dyspnea, asthma, epistaxis.
From the digestive system: nausea, heartburn, constipation or diarrhea, flatulence, stomachodynia, abdominal pain, anorexia or increased appetite, dry mouth, eructation, dysphagia, vomiting, stomatitis, esophagitis, glossitis, gastroenteritis, hepatitis, hepatic colic, Haley , duodenal ulcer, pancreatitis, cholestatic jaundice, elevated liver enzymes (AST, ALT), rectal bleeding, melena, bleeding gums, tenesmus.