Composition
Active ingredient:
atorvastatin (in the form of calcium salt) 10 mg;
Auxiliary substances:
calcium carbonate;
MCC;
lactose monohydrate;
croscarmellose sodium;
polysorbate 80;
hydroxypropylcellulose;
magnesium stearate;
Opadry White YS-1-7040 (contains hypromellose, polyethylene glycol, titanium dioxide, talc); simethicone emulsion (contains simethicone, stearic emulsifier, sorbic acid, water); candelil wax
Pharmacological action
Liprimar – hypolipidemic, hypocholesterolemic.
Pharmacodynamics
Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, a key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA to mevalonate, a precursor to steroids, including cholesterol, and a synthetic lipid-lowering agent.
In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed dyslipidemia, atorvastatin reduces the plasma levels of total cholesterol (Ch), LDL-C, and apolipoprotein B (apo-B), as well as VLDL-C and triglycerides (TG), and causes an unstable increase in HDL-C.
Atorvastatin reduces the concentration of cholesterol and lipoproteins in blood plasma, 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 uptake and catabolism of LDL-C.
Atorvastatin reduces the formation 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 level of LDL-C in patients with homozygous hereditary familial hypercholesterolemia resistant to therapy with other lipid-lowering agents.
Atorvastatin in doses from 10 to 80 mg reduces the content of total cholesterol by 30-46%, LDL-C — 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 patients with non-insulin-dependent diabetes mellitus.
In patients with isolated hypertriglyceridemia, atorvastatin reduces total cholesterol, LDL-C, VLDL-C, apo-B and TG and increases HDL-C levels.
In patients with dysbetalipoproteinemia, atorvastatin reduces the content of intermediate-density lipoprotein cholesterol.
In patients with hyperlipoproteinemia of type IIA and IIb according to Frederikson, the average increase in HDL-C content during treatment with atorvastatin (10-80 mg) compared to the initial indicator is 5.1-8.7% and does not depend on the dose. There is a significant dose-dependent decrease in the total cholesterol/HDL-C and LDL-C/HDL-C ratios by 29-44% and 37-55%, respectively.
Liprimar ® at 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 by 26%. In patients with different baseline LDL-C concentrations, Liprimar ® reduces the risk of ischemic complications and mortality (in patients with non-Q-wave myocardial infarction and unstable angina, regardless of the patient’s gender or age).
A decrease in the level of LDL-C in the blood plasma 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 (see the section “Dosage and use”).
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.
Prevention of cardiovascular complications
In the Anglo-Scandinavian study of cardiovascular complications (ASCOT-LLA) of the effect of atorvastatin on fatal and non-fatal outcomes of CHD, it was found that the effect of atorvastatin therapy at a dose of 10 mg significantly exceeded the effect of placebo, and therefore it was decided to terminate the study prematurely after 3.3 years instead of the expected 5 years.
Diabetes mellitus
In a combined study of the effect of atorvastatin on fatal and non-fatal outcomes of cardiovascular diseases in type 2 diabetes mellitus (CARDS), it was shown that atorvastatin therapy reduced the risk of developing the following cardiovascular complications regardless of the patient’s gender, age, or baseline LDL-C level.
Atherosclerosis
In a study of the reverse development of coronary atherosclerosis with intensive lipid-lowering therapy (REVERSE) with atorvastatin at a dose of 80 mg in patients with IHD, it was found that the average decrease in total atheroma volume (the primary criterion for effectiveness) from the beginning of the study was 0.4%.
Recurrent stroke
The Intensive Cholesterol Reduction Program (SPARCL) found that atorvastatin 80 mg / day reduced the risk of recurrent fatal or non-fatal stroke in patients who had had a stroke or transient ischemic attack (TIA) without a history of CHD by 15% compared to placebo. At the same time, the risk of major cardiovascular complications and revascularization procedures was significantly reduced. A reduction in the risk of cardiovascular disorders with atorvastatin therapy was observed in all groups except those with primary or recurrent hemorrhagic stroke (7 in the atorvastatin group versus 2 in the placebo group).
Hemorrhagic stroke
Patients treated with atorvastatin 80 mg had a lower incidence of hemorrhagic or ischemic stroke (265 vs. 311) or CHD (123 vs. 204) than the control group.
Secondary prevention of cardiovascular complications
In a new targeted study (TNT), we compared the effect of atorvastatin at doses of 80 and 10 mg/day on the risk of cardiovascular complications in patients with clinically confirmed coronary heart disease. Atorvastatin 80 mg significantly reduced the development of the following complications.
Pharmacokinetics
Suction. Atorvastatin is rapidly absorbed after oral use:  Tmax in blood plasma — after 1-2 hours. In women, Cmax is 20% higher and AUC is 10% lower than in men. The degree of absorption and plasma concentration increase in proportion to the dose. The absolute bioavailability is about 14%, and the systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and/or at the first passage through the liver. Food slightly reduces the rate and degree of absorption of the drug (by 25 and 9%, respectively, as evidenced by the results of determining Cmax and AUC, but the decrease in low-density lipoprotein cholesterol (LDL-C) 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, approximately 30%) than after taking it in the morning, the decrease in LDL-C levels does not depend on the time of day at which the drug is taken.
Distribution. The average Vd of atorvastatin is about 381 liters. Binding to 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 well into red blood cells.
Metabolism. Atorvastatin is largely metabolized to form ortho – and para-hydroxylated derivatives and various beta-oxidation products. In vitro, ortho-and parahydroxylated metabolites have an inhibitory effect on HMG-CoA reductase comparable to that of atorvastatin. Approximately 70% of the decrease in HMG-CoA reductase activity occurs due to the action of active circulating metabolites. The results of in vitro studies suggest that the liver cytochrome CYP3A4 isoenzyme plays an important role in the metabolism of atorvastatin. This fact is supported by an increase in the concentration of the drug in blood plasma with simultaneous use of erythromycin, which is an inhibitor of this isoenzyme. In vitro studies have also shown that atorvastatin is a weak inhibitor of the cytochrome CYP3A4 isoenzyme. Atorvastatin does not have a clinically significant effect on the plasma concentration of terfenadine, which is mainly metabolized with the participation of the cytochrome CYP3A4 isoenzyme, so its significant effect on the pharmacokinetics of other substrates of the cytochrome CYP3A4 isoenzyme is unlikely (see the section “Interaction”).
Output. Atorvastatin and its metabolites are mainly excreted in the bile after hepatic and / or extrahepatic metabolism (atorvastatin does not undergo pronounced enterohepatic recirculation). T1 / 2 of the drug is about 14 hours, while the inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites and persists for about 20-30 hours due to their presence. After oral use, less than 2% of the drug dose is detected in the urine.
Special patient groups
Elderly patients. Plasma concentrations of atorvastatin in patients over 65 years of age are higher (Cmax-approximately 40%, AUC-approximately 30%) than in young adult patients. There were no differences in the efficacy and safety of the drug or in achieving the goals of lipid-lowering therapy in elderly patients compared to the general population.
Children. Pharmacokinetic studies of the drug in children have not been conducted.
Insufficient renal function. Impaired renal function does not affect the concentration of atorvastatin in blood plasma or its effect on lipid metabolism, and therefore a dose change in patients with impaired renal function is not required (see “Method of use and doses”).
Atorvastatin is not eliminated during hemodialysis due to intensive binding to plasma proteins.
Insufficient liver function. The concentration of the drug is significantly increased (Cmax-approximately 16 times, AUC-approximately 11 times) in patients with alcoholic cirrhosis of the liver (stage B according to the Child-Pugh classification).
Indications
- primary hypercholesterolemia (heterozygous familial and non-family hypercholesterolemia (type IIa on Frederickson);
- combined (mixed) hyperlipidemia (IIa and IIb types for Frederickson) ;
- dysbetalipoproteinemia (type III according to Frederickson) (as a Supplement to the diet);
- family of endogenous hypertriglyceridemia (type IV according to Frederickson) that are resistant to diet;
- homozygous familial hypercholesterolemia with the ineffectiveness of diet therapy and other non-pharmacological methods of treatment;
- primary prevention of cardiovascular events in patients without clinical signs of coronary heart disease, but with multiple risk factors for its development over 55 years of age, nicotine dependence, hypertension, diabetes, low concentrations of HDL-C in plasma, genetic predisposition, including on the background of dyslipidemia;
- secondary prevention of cardiovascular events in patients with coronary artery disease to reduce total mortality, myocardial infarction, stroke, re-hospitalization for about angina and the need for revascularization.
Contraindications
- hypersensitivity to any component of the drug;
- active liver disease or increased activity of hepatic transaminases in blood plasma of unknown origin by more than 3 times compared to ULN;
- age under 18 years (insufficient clinical data on the effectiveness and safety of the drug in this age group).
With caution:Â alcohol abuse; a history of liver disease.
Side effects
From the central nervous system:Â insomnia, headache, asthenic syndrome.
From the digestive tract:Â nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.
Musculoskeletal and connective tissue disorders:Â myalgia.
From the central nervous system and peripheral nervous system:Â malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypesthesia.
From the digestive tract:Â vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.
Musculoskeletal and connective tissue disorders:Â back pain, muscle cramps, myositis, myopathy, arthralgia, rhabdomyolysis.
Allergic reactions:Â urticaria, pruritus, rash, anaphylactic reactions, bullous rash, polymorphic exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).
From the side of metabolism:Â hypoglycemia, hyperglycemia, increased serum creatine phosphokinase (CPK).
From the side of hematopoietic organs:Â thrombocytopenia.
Other services:Â impotence, peripheral edema, weight gain, chest pain, secondary renal failure, alopecia, tinnitus, increased fatigue.
Interaction
Inhibitors of the cytochrome CYP3A4 isoenzyme. Since atorvastatin is metabolized by the cytochrome CYP3A4 isoenzyme, the combined use of atorvastatin with inhibitors of the cytochrome CYP3A4 isoenzyme may lead to an increase in the concentration of atorvastatin in blood plasma. The degree of interaction and the potentiation effect are determined by the variability of the effect on the cytochrome CYP3A4 isoenzyme.
Inhibitors of the transport protein OATP1B1. Atorvastatin and its metabolites are substrates of the transport protein OATP1B1. OATP1B1 inhibitors (e. g. 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 blood plasma by 7.7 times (see “Method of use and doses”).
Erythromycin/clarithromycin. Concomitant use of atorvastatin and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg 2 times a day), which inhibit the cytochrome CYP3A4 isoenzyme, increased the concentration of atorvastatin in blood plasma (see “Special instructions”).
Protease inhibitors. Concomitant use of atorvastatin with protease inhibitors, known as cytochrome CYP3A4 isoenzyme inhibitors, is accompanied by an increase in the concentration of atorvastatin in blood plasma (when used simultaneously with erythromycin, the max of atorvastatin increases by 40%).
Diltiazem. Concomitant use of atorvastatin 40 mg with diltiazem 240 mg leads to an increase in the concentration of atorvastatin in blood plasma.
Cimetidine. There was no clinically significant interaction between atorvastatin and cimetidine.
Itraconazole. Concomitant use of atorvastatin in doses from 20 to 40 mg and itraconazole in a dose of 200 mg resulted in an increase in the AUC of atorvastatin.
Grapefruit juice. Since grapefruit juice contains one or more components that inhibit the cytochrome CYP3A4 isoenzyme, excessive consumption (more than 1.2 liters per day) can cause an increase in the concentration of atorvastatin in blood plasma.
Inducers of the cytochrome CYP3A4 isoenzyme. Co-use of atorvastatin with inducers of the cytochrome CYP3A4 isoenzyme (for example, efavirenz or rifampicin) may lead to a decrease in the concentration of atorvastatin in blood plasma. Due to the dual mechanism of interaction with rifampicin (an inducer of the cytochrome CYP3A4 isoenzyme and an inhibitor of the hepatocyte transport protein OATP1B1), simultaneous use of atorvastatin and rifampicin is recommended, since delayed use of atorvastatin after taking rifampicin leads to a significant decrease in the concentration of atorvastatin in blood plasma.
Antacids. Simultaneous oral use of a suspension containing magnesium hydroxide and aluminum hydroxide reduced the concentration of atorvastatin in blood plasma by about 35%, but the degree of reduction in LDL-C content did not change.
Phenazone. Atorvastatin does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same cytochrome isoenzymes is not expected.
Kolestipol. With simultaneous use of colestipol, the concentration of atorvastatin in blood plasma decreased by about 25%; however, the lipid-lowering effect of the combination of atorvastatin and colestipol exceeded that of each drug separately.
Digoxin. With repeated use of digoxin and atorvastatin at a dose of 10 mg, the Css of digoxin in blood plasma did not change. However, when digoxin was used in combination with atorvastatin at a dose of 80 mg/day, the digoxin concentration increased by about 20%. Patients receiving digoxin in combination with atorvastatin should be monitored accordingly.
Azithromycin. Concomitant use of atorvastatin at a dose of 10 mg once a day and azithromycin at a dose of 500 mg once a day did not change the concentration of atorvastatin in blood plasma.
Oral contraceptives. When atorvastatin was co-administered with an oral contraceptive containing norethisterone and ethinylestradiol, a significant increase in the AUC of norethisterone and ethinylestradiol by approximately 30 and 20%, respectively, was observed. This effect should be considered when choosing an oral contraceptive for a woman taking atorvastatin.
Terfenadine. There were no clinically significant changes in the pharmacokinetics of terfenadine when atorvastatin and terfenadine were co-administered.
Warfarin. There were no signs of a clinically significant interaction between atorvastatin and warfarin.
Amlodipine. Concomitant use of atorvastatin 80 mg and amlodipine 10 mg did not alter the pharmacokinetics of atorvastatin at steady state.
Other concomitant therapy. In clinical studies, atorvastatin was used in combination with antihypertensive agents and estrogens as part of replacement therapy; no clinically significant undesirable interactions were observed; interaction studies with other specific drugs were not conducted.
How to take it, course of use and dosage
Inside, at any time of the day, regardless of food intake.
Before starting treatment with Liprimar®, an attempt should be made to control hypercholesterolemia through diet, exercise, and weight loss in obese patients, as well as therapy for the underlying disease.
When prescribing the drug, the patient should be recommended a standard hypocholesterolemic diet, which he should adhere to throughout the entire period of therapy.
The dose of the drug varies from 10 to 80 mg once a day and is titrated taking into account the initial content of LDL-C, the purpose of therapy and the individual effect on the therapy.
The maximum daily dose of the drug for a single dose is 80 mg.
At the beginning of treatment and/or during an increase in the dose of Liprimar®, it is necessary to monitor the level of lipids in blood plasma every 2-4 weeks and adjust the dose accordingly.
Primary hypercholesterolemia and combined (mixed) hyperlipidemia. For most patients-10 mg once a day; the therapeutic effect is manifested within 2 weeks and usually reaches a maximum within 4 weeks. With long-term treatment, the effect persists.
Homozygous familial hypercholesterolemia. In most cases,80 mg is prescribed once a day (a decrease in LDL-C content by 18-45%).
Insufficient liver function. In patients with hepatic insufficiency, the dose of Liprimar®should be reduced, with constant monitoring of the activity of hepatic transaminases AST and ALT.
Insufficient renal function. Impaired renal function does not affect the concentration of atorvastatin in blood plasma or the degree of decrease in LDL-C levels during therapy with Liprimar®, so no dose adjustment is required.
Elderly patients. There were no differences in the efficacy, safety or therapeutic effect of Liprimar® in elderly patients compared to the general population and no dose adjustment is required (see “Pharmacokinetics”).
Use in combination with other drugs. If necessary, the combined use with cyclosporine dose of Liprimar® it should not exceed 10 mg (see “Special instructions”).
Overdose
Treatment: There is no specific antidote for the treatment of overdose with Liprimar®.
In case of overdose, symptomatic treatment should be carried out as needed. Since the drug actively binds to plasma proteins, hemodialysis is ineffective.
Special instructions
Effect on the liver. As with other lipid-lowering agents of this class, after treatment with Liprimar®, there was a moderate (more than 3 times higher than sVGN) increase in the activity of hepatic transaminases AST and ALT. A persistent increase in the serum content of hepatic transaminases (more than 3 times compared to ULN) was observed in 0.7% of patients receiving Liprimar®. The frequency of such changes when using the drug in doses of 10,20,40 and 80 mg was 0.2,0.2,0.6 and 2.3%, respectively. Increased activity of hepatic transaminases was usually not accompanied by jaundice or other clinical manifestations. When reducing the dose, temporarily or completely discontinuing the drug Liprimar® the activity of hepatic transaminases returned to the initial level. Most patients continued to take Liprimar® at a reduced dose without any clinical consequences.
Before starting therapy,6 and 12 weeks after starting Liprimar® or after increasing its dose, as well as during the entire course of treatment, it is necessary to monitor liver function indicators. Liver function should also be investigated if there are clinical signs of liver damage. If the level of hepatic transaminases increases, their activity should be monitored until it returns to normal. If the increase in the activity of AST or ALT by more than 3 times compared to ULN persists, it is recommended to reduce the dose or cancel the drug Liprimar® (see “Side effect”).
Liprimar® should be used with caution in patients who consume significant amounts of alcohol and/or have a history of liver disease. Active liver disease or permanently elevated levels of hepatic plasma transaminases of unknown origin are contraindications to the use of Liprimar® (see the section “Contraindications”).
Effect on skeletal muscles. Myalgia has been reported in patients treated with Liprimar® (see “Side effects”). The diagnosis of myopathy (muscle pain or muscle weakness combined with an increase in CPK activity by more than 10 times compared to ULN) should be assumed in patients with diffuse myalgia, muscle soreness or weakness, and/or a pronounced increase in CPK activity. Therapy with Liprimar® should be discontinued in the event of a marked increase in CK activity, in the presence of confirmed or suspected myopathy. The risk of myopathy during treatment with other drugs of this class increased with the simultaneous use of cyclosporine, fibrates, erythromycin, nicotinic acid in lipid-lowering doses (more than 1 g) or azole antifungal agents. Many of these drugs inhibit cytochrome CYP3A4-mediated metabolism and / or drug transport. It is known that the cytochrome CYP3A4 isoenzyme is the main liver isoenzyme involved in the biotransformation of atorvastatin. When prescribing Liprimar® in combination with fibrates, erythromycin, immunosuppressants, azole antifungal agents or lipid-lowering doses of nicotinic acid, the doctor should carefully weigh the expected benefit of treatment and the possible risk. Patients should be regularly monitored for muscle pain or weakness, especially during the first months of therapy and during the period of increasing the dose of any of these drugs. If combination therapy is necessary, the possibility of using lower initial and maintenance doses of the above drugs should be considered. In such situations, periodic monitoring of CPK activity can be recommended, although such monitoring does not prevent the development of severe myopathy (see “Interaction”).
Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been reported when Liprimar® is used, as with other statins. If there are symptoms of possible myopathy or a risk factor for developing renal failure associated with rhabdomyolysis (for example, severe acute infection, hypotension, extensive surgery, trauma, metabolic, endocrine and electrolyte disorders, and uncontrolled seizures), Liprimar®therapy should be temporarily discontinued or completely discontinued.
Patients should be warned to seek immediate medical attention if they experience unexplained pain or muscle weakness, especially if they are accompanied by malaise or fever.
Influence on the ability to drive a car or perform work that requires an increased rate of physical and mental reactions. There are no data on the effect of atorvastatin on the ability to drive a car and engage in potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.
Form of production
Tablets
Storage conditions
At a temperature not exceeding 25 °C
Shelf life
3 years
Active ingredient
Atorvastatin
Conditions of release from pharmacies
By prescription
Dosage form
Tablets
Purpose
For adults as directed by your doctor
Indications
Heart Attack Prevention, Atherosclerosis, Stroke Prevention
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Side effects of Liprimar, pills 10mg, 100pcs.
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