Description
Pharmacological action
Synthetic lipid-lowering agent. Atorvastatin is a selective competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase (HMG-CoA reductase), a key enzyme, converting 3-hydroxy-3-methylglutaryl-CoA to mevalonate – a precursor of sterols, including cholesterol.
In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin lowers the concentration of total cholesterol (cholesterol), low-density lipoprotein cholesterol (LDL-C) and Apolepop and Apolipop in Apolipop very low density (cholesterol-VLDL) and triglycerides (TG), causes an unstable increase in the concentration of high-density lipoprotein cholesterol (cholesterol-HDL).
Atorvastatin reduces the concentration of cholesterol and lipoproteins in blood plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of “liver” LDL receptors on the cell surface, leading to increased uptake and catabolism of LDL-C.
Atorvastatin reduces the formation of LDL cholesterol and the number of LDL particles, causes a pronounced and persistent increase in LDL receptor activity in combination with favorable qualitative changes in LDL particles, and also reduces the concentration of LDL cholesterol in patients with homozygous familial familial hypercholesterolemia resistant to therapy with other lipid-lowering drugs.
Atorvastatin in doses of 10 mg to 80 mg reduces the concentration of total cholesterol by 30-46%, LDL-C by 41-61%, Apo-B by 34-50% and TG by 14-33%.
The treatment results 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 lowers total cholesterol, cholesterol-LDL, cholesterol-VLDL, apo-B and TG and increases the concentration of HDL-cholesterol.
In patients with dysbetalipoproteinemia, atorvastatin lowers the concentration of intermediate-density lipoprotein cholesterol. In patients with type IIa and IIb hyperlipoproteinemia according to Fredrickson, the average value of increasing the concentration of HDL-C during treatment with atorvastatin (10-80 mg) compared with the initial value is 5.1-8.7% and is not dose-dependent. There is a significant dose-dependent decrease in the ratio: total cholesterol / HDL-C and HDL-C / HDL-cholesterol by 29-44% and 37-55%, respectively.
Atorvastatin in a dose of 80 mg significantly reduces the risk of ischemic complications and mortality by 16% after a 16-week course, and the risk of re-hospitalization for angina pectoris, accompanied by signs of myocardial ischemia, is 26%.
Atorvastatin causes a reduction in the risk of ischemic complications and mortality in patients with different initial LDL-C concentrations, (in patients with myocardial infarction without Q wave and unstable angina, as in men and women, and in patients under the age of 65). A decrease in plasma concentration of LDL-C correlates better with the dose of the drug than with its concentration in the blood plasma.
The dose is selected taking into account the therapeutic effect. The therapeutic effect is achieved 2 weeks after the start of therapy, reaches a maximum after 4 weeks and persists throughout the entire period of therapy.
Atorvastatin at a dose of 10 mg reduces the fatal and non-fatal outcomes of coronary heart disease (CHD) compared with placebo in patients with arterial hypertension with three or more risk factors.
Pharmacokinetics
Absorption
Atorvastatin is rapidly absorbed after oral administration: the time to reach its maximum concentration (TCmax) in blood plasma is 1-2 hours. In women, the maximum concentration of atorvastatin (Cmax) is 20% higher, and the area under the concentration-time curve “(AUC) – 10% lower than men.
The degree of absorption and concentration in blood plasma increase in proportion to the dose. The absolute bioavailability is about 14%, and the systemic bioavailability of the inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to a presystemic metabolism in the mucous membrane of the gastrointestinal tract and / or during the “primary passage” through the liver.
Eating slightly reduces the speed and degree of absorption of the drug (by 25% and 9%, respectively, as evidenced by the results of the determination of Cmax and AUC), but the decrease in LDL-C is similar to those when taking atorvastatin on an empty stomach. Despite the fact that after taking atorvastatin in the evening, its concentration in the blood plasma is lower (Cmax and AUC, approximately 30%) than after taking in the morning, the decrease in the concentration of LDL-C does not depend on the time of day at which a drug.
Distribution
The average volume of distribution of atorvastatin is about 381 liters. Communication with blood plasma proteins is not less than 98%. The ratio of the content in red blood cells / blood plasma is about 0.25, i.e. atorvastatin does not penetrate red blood cells well.
Metabolism
Atorvastatin is extensively metabolized to form ortho- and para-hydroxylated derivatives and various -oxidation products. In vitro, ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin.
An approximately 70% decrease in HMG-CoA reductase activity occurs due to the action of active circulating metabolites. In vitro studies suggest that the liver CYP3A4 isoenzyme plays an important role in the metabolism of atorvastatin. This fact is supported by an increase in the concentration of atorvastatin in 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 the CYPZA4 isoenzyme. Atorvastatin does not have a clinically significant effect on the concentration in the blood plasma of terfenadine, which is metabolized mainly by the CYP3A4 isoenzyme, therefore, its significant effect on the pharmacokinetics of other substrates of the CYP3A4 isoenzyme is unlikely.
Excretion of
Atorvastatin and its metabolites are excreted mainly through the intestines with bile after hepatic and / or extrahepatic metabolism (atorvastatin does not undergo severe enterohepatic recirculation). The half-life (T1 / 2) is about 14 hours, Moreover, the inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites and lasts about 20-30 hours due to their presence. After oral administration, less than 2% of the accepted dose of the drug is found in the urine.
Special patient groups
Elderly patients
Atorvastatin plasma concentrations of patients older than 65 years are higher (Cmax by about 40%, AUC by about 30%) than in adult patients of a young age.
There were no differences in the efficacy and safety of the drug, or achievement of the goals of lipid-lowering therapy in elderly patients compared with the general population.
Children
Studies of the pharmacokinetics of the drug in children have not been conducted.
Insufficiency of renal function
Impaired renal function does not affect plasma atorvastatin concentration or lipid metabolism, therefore dose adjustment is not required in patients with impaired renal function. Atorvastatin is not excreted during hemodialysis due to intense binding to plasma proteins blood.
Lack of liver function
Atorvastatin concentration increases significantly (Cmax about 16 times, AUC about 11 times) in patients with alcoholic cirrhosis (class B according to the Child-Pugh classification).
Indications
primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia (type IIa according to the Fredrickson classification)
combined (mixed) hyperlipidemia (type IIa and IIb according to the Fredrickson classification) srdlkröpolephenium dysbenet )
familial endogenous hypertriglyceridemia (type IV according to the Fredrickson classification), resistant to a cholesterol diet
homozygous familial hypercholesterolemia with under the effective effectiveness of diet therapy and other non-pharmacological treatments for
primary prevention of cardiovascular complications in patients without clinical signs of coronary heart disease, but with several risk factors for its development: age over 55 years, nicotine addiction, arterial hypertension, diabetes mellitus, low plasma concentrations of HDL-C, HDL, genetic predisposition, including against the background of
dyslipidemia, secondary prevention of cardiovascular complications in patients with coronary heart disease in order to reduce the total mortality rate, myocardial infarction, stroke, re-hospitalization for angina pectoris and the need for revascularization procedures.
Contraindications
Hypersensitivity to any component of the drug.
An active liver disease or an increase in the activity of “liver” transaminases in blood plasma of unclear origin more than 3 times in comparison with the upper limit of normal (VGN).
Age up to 18 years (insufficient clinical data on the efficacy and safety of the drug in this age group).
Use in women of reproductive age who do not use adequate methods of contraception.
Pregnancy, the period of breastfeeding.
Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
With caution: alcohol abuse, a history of liver disease, severe disturbances in water-electrolyte balance, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, extensive surgery, injuries, skeletal muscle diseases, diabetes mellitus.
Special instructions
Before starting therapy with Novostat, the patient must be prescribed a standard hypocholesterol diet, which he must follow during the entire treatment period.
The use of HMG-CoA reductase inhibitors to lower blood lipids can lead to a change in biochemical parameters that reflect liver function. Liver function should be monitored before starting therapy, 6 weeks, 12 weeks after the start of taking Novostat and after each dose increase, and also periodically, for example, every 6 months.
An increase in the activity of “liver” enzymes in the blood serum can be observed during Novostat therapy.
Patients with increased enzyme activity should be monitored until the enzyme activity returns to normal. In the case of a persistent increase in ALT or ACT activity to a level exceeding more than 3 times VGN, it is recommended to reduce the dose of Novostat or stop treatment.
Novostat should be used with caution in patients who abuse alcohol and / or have liver disease. Active liver disease or a persistent increase in the activity of aminotransferases of unknown origin are a contraindication to the appointment of Novostat.
Treatment with Novostat, like other inhibitors of HMG-CoA reductase, can cause myopathy. The diagnosis of myopathy (muscle pain and weakness, combined with an increase in CPK activity of more than 10 times compared with VGN) should be discussed in patients with common myalgia, muscle soreness or weakness and / or a marked increase in CPK activity.
Patients should be warned that they should immediately inform the doctor about the appearance of unexplained pain or weakness in the muscles if they are accompanied by malaise or fever. Novostat therapy should be discontinued if there is a marked increase in KFK activity or in the presence of confirmed or suspected myopathy.
The risk of myopathy in the treatment of other drugs of this class increased with the simultaneous use of cyclosporine, fibrates, erythromycin, nicotinic acid in lipid lowering doses (more than 1 g / day) or azole antifungal agents. Many of these drugs inhibit the metabolism mediated by cytochrome P4503A4 and / or drug transport. Atorvastatin is biotransformed under the action of the CYP3A4 isoenzyme.
When prescribing Novostat in combination with fibrates, erythromycin, immunosuppressive drugs, azole antifungal agents or nicotinic acid in lipid lowering doses (more than 1 g / day), the expected benefit and risk of treatment should be carefully weighed and patients should be regularly monitored to detect muscle pain or weakness , especially during the first months of treatment and during the period of increasing the dose of any drug. In such situations, periodic determination of CPK activity can be recommended, although such control does not prevent the development of severe myopathy.
When using Novostat, as well as other drugs of this class, cases of rhabdomyolysis with acute renal failure due to myoglobinuria are described. Novostat therapy should be temporarily discontinued or completely discontinued if there are signs of possible myopathy or a risk factor for the development of renal failure due to rhabdomyolysis (for example, severe acute infection, arterial hypotension, serious surgery, trauma, severe metabolic, endocrine and water-electrolyte disturbances and uncontrolled seizures )
Before starting therapy with Novostat, it is necessary to try to achieve control of hypercholesterolemia by adequate diet therapy, increased physical activity, weight loss in patients with obesity and treatment of other conditions. Patients should be warned that they should immediately consult a doctor if unexplained pain or muscle weakness occurs, especially if they are accompanied by malaise or fever.
When using HMG-CoA reductase inhibitors (statins), including atorvastatin, there have been cases of increased glycosylated hemoglobin and fasting plasma glucose concentrations. However, the risk of hyperglycemia is lower than the degree of reduction in the risk of vascular complications with statins.
Influence on the ability to drive vehicles and work with mechanisms
The adverse effects of atorvastatin on the ability to drive vehicles and engage in potential hazardous activities requiring increased concentration and speed of psychomotor reactions were not reported. However, given the possibility of developing dizziness, caution should be exercised when performing the above activities.
Composition
Active ingredient:
atorvastatin calcium trihydrate (crystalline) – 21.69 mg, in terms of atorvastatin – 20.0 mg.
Excipients:
lactose monohydrate (milk sugar) – 87.41 mg,
microcrystalline cellulose – 30.0 mg,
sodium lauryl sulfate – 1.0 mg,
povidone-K17 – 5.0 mg,
calcium carbonate – 35 , 0 mg,
sodium carboxymethyl starch – 8.0 mg,
magnesium stearate – 1.9 mg.
Capsule composition:
Shell: iron dye oxide yellow – 0.1%, titanium dioxide – 2.0%, gelatin – up to 100%.
Cap: dye iron oxide yellow – 0.1%, titanium dioxide – 2.0%, gelatin – up to 100%.
Dosage and Administration
Inside.
Take at any time of the day, regardless of food intake. Before starting treatment with the drug,
should try to achieve control of hypercholesterolemia through diet, exercise and weight loss in patients with obesity, as well as therapy for the underlying disease.
When prescribing the drug, the patient should recommend a standard hypocholesterolemic diet, which he must adhere to during the entire period of therapy.
The dose of the drug varies from 10 mg to 80 mg once a day and is titrated taking into account the initial content of LDL-C, the purpose of the therapy and the individual effect on the therapy.
The maximum daily dose for a single dose is 80 mg.
At the beginning of treatment and / or during an increase in the dose of the drug, it is necessary to monitor the concentration of lipids in the blood plasma every 2-4 weeks and adjust the dose of the drug accordingly.
Primary hypercholesterolemia and combined (mixed) hyperlipidemia
For most patients – 10 mg once a day, the therapeutic effect is manifested within 2 weeks of therapy and usually reaches a maximum within 4 weeks. With prolonged treatment, the effect persists.
Homozygous familial hypercholesterolemia
In most cases, 80 mg is prescribed once a day (decrease in the concentration of LDL-C by 18-45%).
Lack of liver function
If liver function is insufficient, the dose should be reduced, with regular monitoring of the activity of “liver” transaminases: aspartate aminotransferase (ACT) and alanine aminotransferase (ALT).
Insufficiency of renal function
Impaired renal function does not affect the concentration of atorvastatin in the blood plasma or the degree of decrease in the concentration of LDL-C during treatment with the drug, therefore, dose adjustment of the drug is not required.
Elderly patients
No differences were found in the efficacy, safety, or therapeutic effect of the drug in elderly patients compared with the general population, and dose adjustment is not required.
Use in combination with other medicines
If necessary, simultaneous use with cyclosporine should not exceed 10 mg per day.
Caution should be exercised and the lowest effective dose of atorvastatin should be used while used with HIV protease inhibitors, hepatitis C inhibitors, clarithromycin and itraconazole.
Side effects
The incidence of side effects is classified according to the recommendations of the World Health Organization: very often – at least 10% often – at least 1%, but less than 10% infrequently – at least 0.1%, but less than 1% rarely – not less than 0.01%, but less than 0.1% very rarely (including individual messages) – less than 0.01%, frequency unknown – cannot be calculated from the available data.
From the blood and lymphatic system: rarely – thrombocytopenia.
On the part of the immune system: often – allergic reactions are very rare – angioedema edema anaphylactic shock.
From the nervous system: often – headache infrequently – dizziness, paresthesia, hypesthesia, amnesia, taste disturbance, insomnia, “nightmare” dreams rarely – peripheral neuropathy frequency is unknown – depression.
From the side of the organ of vision: infrequently – decreased clarity of vision rarely – impaired visual perception.
On the part of the organ of hearing and labyrinth disorders: infrequently – “noise” in the ears, very rarely – hearing loss.
From the respiratory system, chest and mediastinal organs: often – nasopharyngitis, nosebleeds, pain in the pharyngeal-laryngeal region, frequency is unknown – interstitial lung disease.
From the digestive tract: often – nausea, flatulence, constipation, dyspepsia, diarrhea infrequently – belching, vomiting, abdominal pain, pancreatitis.
From the liver and bile ducts: infrequently – hepatitis rarely – cholestasis very rarely – liver failure, cholestatic jaundice.
On the part of the skin and subcutaneous tissues: infrequently – alopecia, skin rash, itching, urticaria rarely – bullous dermatitis, erythema multiforme very rarely – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).
From the side of the musculoskeletal system and connective tissue: often – myalgia, arthralgia, pain in the extremities, muscle spasm, back pain, swelling of the joints infrequently – neck pain, muscle weakness is rare – myopathy, myositis, rhabdomyolysis, tendinopathy, complicated by tendon rupture, frequency is unknown – immuno-mediated necrotizing myopathy.
From the reproductive system: very rarely – gynecomastia frequency is unknown – impotence.
General disorders: infrequently – asthenia, weakness, chest pain, peripheral edema, fever, fatigue, weight gain, anorexia.
Laboratory indicators: often – hyperglycemia, increased serum creatine phosphokinase activity infrequently – leukocyturia, hypoglycemia, increased activity of “liver” transaminases.
When using HMG-CoA reductase inhibitors (statins), including atorvastatin, there have been cases of increased glycosylated hemoglobin.
Overdose
There is no specific antidote for the treatment of drug overdose. In case of an overdose, symptomatic treatment should be carried out as necessary. It is necessary to control liver function and the activity of creatine phosphokinase (CPK) in serum. Since the drug actively binds to plasma proteins, hemodialysis is ineffective.
Active ingredient
Atorvastatin
lekarstvennaja form
tablets
