ATORVASTATIN PILLS 40MG

Trade name of the drug: Atorvastatin-SZ

International non-proprietary name: Atorvastatin

Description
Tablets, film-coated pink, round, biconvex. In cross section, the core of the pill is white or almost white.

Pharmacotherapeutic group of the drug:
Lipid-lowering agent - HMG-CoA reductase inhibitor

Pharmacological properties
Pharmacodynamics
Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, the key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA into mevalonate, the precursor of steroids, including cholesterol; synthetic lipid-lowering agent.
In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and atorvastatin mixed dyslipidemia, atorvastatin decreases plasma cholesterol (cholesterol) concentration, low-density lipoprotein cholesterol (LDL) cholesterol and apolipoprotein, and there is no time, I’m I’m not using your time. very low density (cholesterol-VLDL) and triglycerides (TH), causes an unstable increase in the concentration of high-density lipoprotein cholesterol (cholesterol-HDL).
Atorvastatin reduces plasma cholesterol and lipoprotein concentrations by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of “hepatic” LDL receptors on the cell surface, which leads to increased capture and catabolism of LDL-C.
Atorvastatin reduces the production of LDL-C and the number of LDL particles, causes a pronounced and persistent increase in the activity of LDL-receptors in combination with favorable qualitative changes in LDL-particles, and also reduces the concentration of LDL-C in patients with homozygous familial familial hypercholesterolemia resistant to other hypolipids. means.
Atorvastatin in doses from 10 mg to 80 mg reduces the concentration of cholesterol by 30% - 46%, cholesterol-LDL - by 41% - 61%, apolipoprotein-B - by 34% - 50% and TG - by 14% - 33 % The results of therapy are similar in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed hyperlipidemia, including in patients with type 2 diabetes.
In patients with isolated hypertriglyceridemia, atorvastatin reduces the concentration of cholesterol, LDL-C, LDL-C, VLDL, apo-B and TG and increases the concentration of HDL-C. In patients with dysbetalipoproteinemia, atorvastatin reduces the concentration of intermediate density lipoprotein cholesterol.
In patients with type IIa and IIb hyperlipoproteinemia according to Fredrickson's classification, the mean value of the increase in the concentration of HDL cholesterol in the treatment with atorvastatin (10-80 mg) compared to the baseline is 5.1% - 8.7% and does not depend on the dose.There is a significant dose-dependent decrease in the ratio: total cholesterol / cholesterol-HDL and cholesterol-LDL / cholesterol-HDL by 29% - 44% and 37% - 55%, respectively.
The anti-sclerotic effect of atorvastatin is a consequence of its effect on the walls of blood vessels and blood components. Atorvastatin inhibits the synthesis of isoprenoids, which are growth factors for the cells of the inner lining of blood vessels. Under the action of atorvastatin, endothelium-dependent dilation of blood vessels is improved, the concentration of cholesterol-LDL, apolipoprotein B, and TG is reduced, and the concentration of cholesterol-HDL cholesterol and apolipoprotein A increases.
Atorvastatin reduces the viscosity of blood plasma and the activity of some coagulation factors and platelet aggregation. Due to this, it improves hemodynamics and normalizes the state of the coagulation system. HMG-CoA reductase inhibitors also have an effect on the metabolism of macrophages, block their activation and prevent the rupture of an atherosclerotic plaque.
Atorvastatin-SZ at a dose of 80 mg reliably reduces the risk of ischemic complications and mortality by 16% after a 16-week course, and the risk of repeated hospitalization for angina accompanied by signs of myocardial ischemia by 26%. In patients with different baseline concentrations of LDL-C, atorvastatin-SZ causes a reduction in the risk of ischemic complications and mortality (in patients with myocardial infarction without Q wave and unstable angina, as in men and women, and in patients younger than 65 years old).
The decrease in plasma concentration of cholesterol-LDL correlates better with the dose of the drug than with its concentration in the blood plasma.The dose is selected based on the therapeutic effect (see the section "Dosage and administration").
The therapeutic effect is achieved 2 weeks after the start of therapy, reaches a maximum after 4 weeks and lasts for the entire period of therapy.
Pharmacokinetics
Suction
Atorvastatin is rapidly absorbed after oral administration: the time to reach its maximum concentration (TCmax) in the blood plasma is 1-2 hours. In women, the maximum concentration (Cmax) of atorvastatin is 20% higher, and the area under the concentration-time curve (AUC) is 10% lower than that of men. The degree of absorption and concentration in the blood plasma increase in proportion to the dose.
Absolute bioavailability is about 14%, and systemic bioavailability of the inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is caused by presystemic metabolism in the mucous membrane of the gastrointestinal tract and / or during the "primary passage" through the liver. Eating reduces the rate and degree of absorption of the drug (by 25% and 9%, respectively), as evidenced by the results of Cmax and AUC, but the decrease in cholesterol-LDL is similar to that when taking atorvastatin on an empty stomach. Despite the fact that after taking atorvastatin in the evening, its plasma concentration is lower (Cmax and AUC, by about 30%) than after taking it in the morning, the decrease in the concentration of LDL-C is not dependent on the time of day at which they take a drug.
Distribution
The average distribution of atorvastatin is about 381 liters. Communication with proteins of a blood plasma not less than 98%. The ratio of the content in erythrocytes / blood plasma is about 0.25, i.e. atorvastatin does not penetrate into the erythrocytes poorly.
Metabolism
Atorvastatin is extensively metabolized to form ortho and parahydroxylated derivatives and various β-oxidation products. In vitroortho- and parahydroxylated metabolites have an inhibitory effect on HMG-CoA reductase comparable to that of atorvastatin. Approximately 70% reduction in the activity of HMG-CoA reductase occurs due to the action of active circulating metabolites. Research results invitrosuggest that the liver isoenzyme CYPZA4 plays an important role in the metabolism of atorvastatin. This is evidenced by an increase in the concentration of the drug in the blood plasma while taking Erythromycin , which is an inhibitor of this isoenzyme. Research invitroalso showed that atorvastatin is a weak inhibitor of the isoenzyme CYP3A4. Atorvastatin does not have a clinically significant effect on plasma concentration of terfenadine, which is metabolized mainly by the isoenzyme CYPA4, therefore its significant effect on the pharmacokinetics of other substrates of the isoenzyme CYPZ4 is unlikely (see the section "Interaction with other drugs").
Removal
Atorvastatin and its metabolites are excreted mainly with bile after hepatic and / or extrahepatic metabolism (atorvastatin is not subjected to severe enterohepatic recirculation). Atorvastatin's half-life (T1 / 2) is about 14 hours, while the inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites and lasts about 20 to 30 hours due to their presence. After ingestion in the urine is detected less than 2% of the dose of the drug.
Special patient groups
Elderly patients
Atorvastatin concentrations in the blood plasma of patients over 65 years old are higher (Cmax by about 40%, AUC by about 30%) than in adult patients of young age. Differences in the efficacy and safety of the drug, or the achievement of the goals of lipid-lowering therapy in elderly patients compared with the general population have not been identified.
Children
Studies of the pharmacokinetics of the drug in children were not conducted.
Kidney failure
Impaired renal function does not affect the concentration of atorvastatin in the blood plasma or its effect on lipid metabolism, therefore, the dose change in patients with impaired renal function is not required.
Atorvastatin is not excreted during hemodialysis due to intense binding to plasma proteins.
Atorvastatin has not been studied in patients with end-stage renal disease.
Liver failure
The concentration of the drug is significantly increased (Cmax about 16 times, AUC about 11 times) in patients with alcoholic cirrhosis of the liver (stage B on the Child-Pugh scale) (see the section "Contraindications").

Contraindications
Hypersensitivity to any component of the drug.
Active liver disease or increased activity of liver transaminases in plasma of unknown origin is more than 3 times compared with the upper limit of normal.
Age up to 18 years (not enough clinical data on the efficacy and safety of the drug in this age group).
lactose intolerance , lactase deficiency, glucose-galactose malabsorption.
Hypersensitivity to soy and peanuts.
Pregnancy and breastfeeding period.
Use in women planning pregnancy and not using reliable methods of contraception.
Carefully
Alcohol abuse, liver disease in history, muscular system diseases (in history from the use of other members of the HMG-CoA reductase group of inhibitors), severe violations of water and electrolyte balance, endocrine (hyperthyroidism) and metabolic disorders, severe acute infections (sepsis), arterial hypotension, diabetes mellitus, uncontrolled epilepsy, extensive surgical intervention, trauma.
Use during pregnancy and lactation
The drug Atorvastatin-SZ is contraindicated in pregnancy.
Women of reproductive age during treatment should use adequate methods of contraception. Atorvastatin-SZ can be prescribed to women of reproductive age only if the probability of pregnancy is very low and the patient is informed about the possible risk of treatment for the fetus.
The drug Atorvastatin-SZ is contraindicated during lactation.It is not known whether atorvastatin is excreted in breast milk. If necessary, the appointment of the drug during lactation, breastfeeding should be stopped to avoid the risk of adverse events in infants.

Dosage and administration
Inside Take at any time of the day, regardless of the meal.
Before starting treatment with atorvastatin-SZ, one should try to achieve control of hypercholesterolemia through diet, exercise and weight loss in patients with obesity, as well as therapy of the underlying disease.
When prescribing the drug, the patient should be advised to recommend a standard cholesterol-lowering diet, which he should follow during the entire period of therapy.
The dose of the drug varies from 10 mg to 80 mg 1 time per day and is titrated based on the initial concentration of LDL-C, the goal of therapy and the individual effect on the therapy being administered.
The maximum daily dose for a single dose is 80 mg.
At the beginning of treatment and / or during the dose increase of the drug Atorvastatin-SZ, it is necessary every 2 to 4 weeks to control the concentration of lipids in the blood plasma and adjust the dose of the drug accordingly.
Primary hypercholesterolemia and combined (mixed) hyperlipidemia
For most patients, 10 mg 1 time per day; therapeutic effect occurs within 2 weeks and usually reaches a maximum within 4 weeks. With long-term treatment, the effect is preserved.
Homozygous familial hypercholesterolemia
The initial dose is selected individually depending on the severity of the disease. In most cases, the optimal effect is observed when using the drug at a dose of 80 mg 1 time per day (a decrease in the concentration of LDL-C by 18 - 45%).
Liver failure
In case of insufficiency of the liver function, caution is necessary (in connection with slowing down the elimination of the drug from the body). Clinical and laboratory findings should be closely monitored (regular monitoring of the activity of liver transaminases: aspartate aminotransferase (AST) and alanine aminotransferase (ALT)). With a significant increase in liver transaminases, the dose of atorvastatin-SZ should be reduced or treatment should be discontinued.
Kidney failure
Impaired renal function does not affect the concentration of atorvastatin in the blood plasma or the degree of decrease in the concentration of LDL-cholesterol during therapy with Atorvastatin-SZ, therefore, dose adjustment of the drug is not required.
Elderly patients
No differences in efficacy, safety or therapeutic effect of atorvastatin-SZ have been found in elderly patients compared with the general population and dose adjustment is not required (see the Pharmacokinetics section).
Use in combination with other drugs.
If necessary, concurrent use with cyclosporine, telaprevir, or a tipranavir / ritonavir combination, the dose of atorvastatin-SZ should not exceed 10 mg / day.Care must be taken to apply the lowest effective dose of atorvastatin while being used with HIV protease inhibitors, hepatitis C inhibitors, Clarithromycin and itraconazole. (see section “Special Instructions”).

Overdose
In case of overdose, the following general measures are necessary: ​​monitoring and maintaining the vital functions of the body, as well as preventing further absorption of the drug (gastric lavage, taking Activated carbon or laxatives).
With the development of myopathy with subsequent rhabdomyolysis and acute renal failure (a rare but severe side effect), the drug should be immediately canceled and the infusion of diuretic and sodium bicarbonate should be started. If necessary, hemodialysis should be carried out. Rhabdomyolysis can lead to hyperkalemia, which requires the elimination of intravenous calcium chloride solution or Calcium gluconate solution, infusion of 5% dextrose (glucose) with insulin , the use of potassium exchange resins. Since the drug is actively associated with plasma proteins, hemodialysis is ineffective.

Interaction with other drugs
The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased by the simultaneous use of cyclosporin, fibrates, antibiotics (erythromycin, clarithromycin, quinupristin / dalfopristin), nefazodone, HIV protease inhibitors (indinavir, ritonavir), colchicine, antifungals - azole derivatives - and nicotinic acid in lipid-lowering doses (more than 1 g / day) (see the section "Special Instructions").
Inhibitors of the isoenzyme CYPZA4
Since atorvastatin is metabolized by the isoenzyme CYPZA4, the combined use of atorvastatin with the inhibitors of the isoenzyme CYPZA4 can lead to an increase in the concentration of atorvastatin in the blood plasma.The degree of interaction and the effect of potentiation are determined by the variability of exposure to the isoenzyme СYРЗА4.
Inhibitors of the transport protein OATP1B1
Atorvastatin and its metabolites are substrates of the transport protein OATP1B1. OATP1B1 inhibitors (for example, cyclosporine) may increase the bioavailability of atorvastatin. Thus, the combined use of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg / kg / day leads to an increase in the concentration of atorvastatin in the blood plasma by 7.7 times. If necessary, the simultaneous use of cyclosporine dose of atorvastatin-SZ should not exceed 10 mg / day (see the section "Dosage and administration").
Erythromycin / clarithromycin
With simultaneous use of atorvastatin and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg 2 times a day), which inhibit the CYPA4 isoenzyme, an increase in the concentration of atorvastatin in the blood plasma was observed (see the section "Special Instructions"). Care should be taken to apply the lowest effective dose of atorvastatin while using clarithromycin.
Protease inhibitors
The simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the isoenzyme CYPZA4, is accompanied by an increase in the concentration of atorvastatin in the blood plasma (while using atorvastatin with erythromycin Cmax increases by 40%).
The combination of protease inhibitors
Patients taking HIV protease inhibitors and hepatitis C inhibitors should use caution and use the lowest effective dose of atorvastatin.In patients taking telaprevir or a tipranavir / ritonavir combination, the dose of atorvastatin-SZ should not exceed 10 mg / day.
Patients receiving HIV protease inhibitor tipranavir plus ritonavir or hepatitis C protease inhibitor telaprevir should avoid taking Atorvastatin-NZ at the same time. Patients taking HIV protease inhibitors lopinavir plus ritonavir should be careful when prescribing Atorvastatin-SZ and the lowest required dose should be prescribed. In patients taking HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir or fosamprenavir plus ritonavir, the dose of atorvastatin-SZ should not exceed 20 mg and the drug should be used with caution. In patients taking HIV protease inhibitor nelfinavir or hepatitis C protease inhibitor boceprevir, the dose of atorvastatin-SZ should not exceed 40 mg and careful clinical monitoring is recommended.
Diltiazem
The combined use of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in plasma atorvastatin concentration.
Ketoconazole , spironolactone and cimetidine
Caution should be exercised with the simultaneous use of atorvastatin with drugs that reduce the concentration of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.
Itraconazole
The simultaneous use of atorvastatin in doses from 20 mg to 40 mg and itraconazole at a dose of 200 mg resulted in an increase in the AUC value of atorvastatin. Caution should be exercised and apply the lowest effective dose of atorvastatin while using itraconazole.
Grapefruit juice
Since grapefruit juice contains one or more components that inhibit the isoenzyme CYPA4, its excessive consumption (more than 1.2 liters per day) may cause an increase in plasma atorvastatin concentration.
Inductors of the isoenzyme SYRZA4
The combined use of atorvastatin with inducers of the isoenzyme CYPZA4 (for example, efavirenz, phenytoin or rifampicin) can lead to a decrease in plasma atorvastatin concentrations. Due to the dual mechanism of interaction with rifampicin (inducer of the CYPA4 isoenzyme and hepatocyte transport protein inhibitor OATP1B1), simultaneous use of atorvastatin and rifampicin is recommended, since delayed atorvastatin intake after taking rifampicin leads to a significant decrease in atorvastatin plasma levels.
Antacids
Simultaneous ingestion of a suspension containing Magnesium hydroxide and aluminum hydroxide, reduced the concentration of atorvastatin in the blood plasma by about 35%, however, the degree of reduction in the concentration of LDL-C did not change.
Phenazone
Atorvastatin does not affect the pharmacokinetics of phenazone, therefore, interaction with other drugs metabolized by the same cytochrome isoenzymes is not expected.
Colestipol
With simultaneous use of colestipol, the concentration of atorvastatin in the blood plasma decreased by approximately 25%; however, the lipid-lowering effect of the combination of atorvastatin and colestipol was superior to that of each drug separately.
Digoxin
When repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentration of digoxin in the blood plasma did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg / day. digoxin concentration increased by about 20%. Patients receiving digoxin in combination with atorvastatin require appropriate monitoring.
Azithromycin
With simultaneous use of atorvastatin at a dose of 10 mg 1 time per day and azithromycin at a dose of 500 mg 1 time per day, the concentration of atorvastatin in the blood plasma did not change.
Oral contraceptives
With simultaneous use of atorvastatin and oral contraceptive containing norethisterone and ethinyl estradiol, there was a significant increase in the AUC of norethisterone and ethinyl estradiol by about 30% and 20%, respectively. This effect should be considered when choosing an oral contraceptive for a woman taking atorvastatin.
Terfenadine
With simultaneous use of atorvastatin and terfenadine, there were no clinically significant changes in the pharmacokinetics of terfenadine.
Warfarin
The simultaneous use of atorvastatin with warfarin may in the first days increase the effect of warfarin on blood coagulation rates (decrease in prothrombin time). This effect disappears after 15 days of simultaneous use of these drugs.
Amlodipine
With simultaneous use of atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg, the pharmacokinetics of atorvastatin in an equilibrium state did not change.
Other concomitant therapy
In clinical studies, atorvastatin was used in combination with antihypertensives and estrogens as part of replacement therapy; signs of clinically significant undesirable interactions were noted; Research on the interaction with specific drugs was not conducted.