Torvacard tablets p / o 10mg, No. 90

• In combination with a diet to reduce elevated concentrations of total cholesterol, cholesterol / LDL, apolipoprotein B and triglycerides and increase HDL cholesterol concentrations in patients with primary hypercholesterolemia, heterozygous familial and non-familial hypercholesterolemia, and combined (mixed) hyperlipidemia II;

• In combination with a diet for the treatment of patients with elevated serum triglyceride concentrations (familial endogenous hypertriglyceridemia of type IV according to Frederickson) and patients with dysbetalipoproteinemia (type III according to Frederickson), in whom diet therapy does not give an adequate effect;

• To reduce the concentration of total cholesterol and cholesterol / LDL cholesterol in patients with homozygous familial hypercholesterolemia, when diet therapy and other non-pharmacological treatments are not effective enough (as an adjunct to lipid-lowering therapy, including autohemotransfusion of LDL-purified blood)

• Diseases of the cardiovascular system (in patients with increased risk factors for coronary artery disease - advanced age over 55 years, smoking, arterial hypertension, diabetes mellitus, peripheral vascular disease, stroke, left ventricular hypertrophy, protein / albuminuria, coronary artery disease in close relatives ), incl. against the background of dyslipidemia - secondary prevention in order to reduce the total risk of death, myocardial infarction, stroke, re-hospitalization for angina pectoris and the need for revascularization.

Before prescribing the drug TORVACARDЃ, the patient must be recommended a standard cholesterol-lowering diet, which he must continue to follow throughout the entire period of therapy.
The drug is taken orally at any time of the day, regardless of the time of the meal.
The initial dose is on average 10 mg 1 time / day. The dose varies from 10 to 80 mg 1 time / day. The dose is selected taking into account the initial concentrations of cholesterol / LDL, the goal of therapy and the individual effect. At the beginning of treatment and / or during an increase in the dose of TORVACARDЃ, it is necessary to monitor plasma lipid concentrations every 2-4 weeks and adjust the dose accordingly. The maximum daily dose is 80 mg in 1 dose.
Primary hypercholesterolemia and mixed hyperlipidemia
In most cases, it is sufficient to prescribe a dose of 10 mg of the drug TORVACARDЃ 1 time per day. A significant therapeutic effect is observed after 2 weeks, as a rule, and the maximum therapeutic effect is usually observed after 4 weeks. With long-term treatment, this effect persists.

Each film-coated tablet contains:
active substance:
atorvastatin 10 mg (in the form of atorvastatin calcium 10.34 mg),
excipients:
core: magnesium oxide, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, low-substituted hyprolose, colloidal silicon dioxide, magnesium stearate;
film shell: hypromellose 2910/5, macrogol 6000, titanium dioxide, talc.

• Hypersensitivity to the components of the drug;

• Active liver disease or increased serum activity of 'hepatic' transaminases (more than 3 times compared with the upper limit of normal) of unknown origin, liver failure (severity A and B on the Child-Pugh scale);

• Hereditary diseases such as lactose intolerance, lactase deficiency or glucose-galactose malabsorption (due to the presence of lactose in the composition);

• Pregnancy, lactation period;

• Women of reproductive age who do not use adequate contraceptive methods;

• Age up to 18 years (efficacy and safety have not been established).

With care:
alcohol abuse, a history of liver disease, severe disturbances in the water and electrolyte balance, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, major surgical interventions, injuries, diseases of skeletal muscles.

Trade name of the drug:
TORVACARDЃ

International non-proprietary name:
atorvastatin

Dosage form:

film-coated tablets

COMPOSITION
Each film-coated tablet contains:
active substance:
atorvastatin 10 mg (as atorvastatin calcium 10.34 mg),
atorvastatin 20 mg (as atorvastatin calcium 20.68 mg),
atorvastatin 40 mg (as atorvastatin calcium 41 , 36 mg);
excipients:
core: magnesium oxide, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, low-substituted hyprolose, colloidal silicon dioxide, magnesium stearate;
film shell: hypromellose 2910/5, macrogol 6000, titanium dioxide, talc.

DESCRIPTION
White to off-white oval film-coated biconvex tablets

PHARMACOTHERAPEUTIC GROUP
Lipid-lowering agent - HMG-CoA reductase inhibitor

PHARMACOLOGICAL PROPERTIES
Pharmacodynamics
Lipid-lowering agent from the statin group. Selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, which is a precursor of sterols, including cholesterol. Triglycerides (TG) and cholesterol in the liver are included in the composition of very low density lipoproteins (VLDL), enter the blood plasma and are transported to peripheral tissues. Low density lipoproteins (LDL) are formed from VLDL through interaction with LDL receptors. Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase, 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. Reduces the formation of LDL,causes a pronounced and persistent increase in the activity of LDL receptors. Reduces the concentration of LDL in patients with homozygous familial hypercholesterolemia, which usually does not respond to lipid-lowering therapy. Reduces the concentration of total cholesterol by 30-46%, LDL - by 41-61%, apolipoprotein B - by 34-50% and TG - by 14-33%; causes an increase in the concentration of HDL cholesterol (high density lipoproteins) and apolipoprotein A. Dose-dependently reduces the concentration of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.apolipoprotein B - by 34-50% and TG - by 14-33%; causes an increase in the concentration of HDL cholesterol (high density lipoproteins) and apolipoprotein A. Dose-dependently reduces the concentration of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.apolipoprotein B - by 34-50% and TG - by 14-33%; causes an increase in the concentration of HDL cholesterol (high density lipoproteins) and apolipoprotein A. Dose-dependently reduces the concentration of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.

Pharmacokinetics
Absorption - high. The maximum concentration (Cmax) in blood plasma is reached after 1-2 hours, Cmax in women is 20% higher, the area under the concentration-time curve (AUC) is 10% lower; Cmax in patients with alcoholic cirrhosis of the liver is 16 times, AUC is 11 times higher than normal. Food somewhat reduces the rate and duration of absorption of the drug (by 25% and 9%, respectively), however, the decrease in LDL cholesterol is similar to that when using atorvastatin without food. The concentration of atorvastatin when used in the evening is lower than in the morning (by about 30%). A linear relationship was found between the degree of absorption and the dose of the drug.
Bioavailability - 12%, systemic bioavailability of inhibitory activity against HMG-CoA reductase - 30%. Low systemic bioavailability is due to first pass metabolism in the gastrointestinal tract mucosa and during the 'first pass' through the liver.
The average volume of distribution is 381 liters, the connection with blood plasma proteins is 98%. It is metabolized mainly in the liver under the action of isoenzymes CYP3A4, CYP3A5 and CYP3A7 with the formation of pharmacologically active metabolites (ortho- and parahydroxylated derivatives, beta-oxidation products). In vitro, ortho- and parahydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin.
The inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites.
It is excreted through the intestines with bile after hepatic and / or extrahepatic metabolism (does not undergo pronounced intestinal-hepatic recirculation).
The half-life is 14 hours. The inhibitory activity against HMG-CoA reductase lasts about 20-30 hours due to the presence of active metabolites. Less than 2% of the oral dose of the drug is determined in the urine. Not excreted during hemodialysis.

INDICATIONS FOR USE

• In combination with a diet to reduce elevated concentrations of total cholesterol, cholesterol / LDL, apolipoprotein B and triglycerides and increase HDL cholesterol concentrations in patients with primary hypercholesterolemia, heterozygous familial and non-familial hypercholesterolemia, and combined (mixed) hyperlipidemia II;

• In combination with a diet for the treatment of patients with elevated serum triglyceride concentrations (familial endogenous hypertriglyceridemia of type IV according to Frederickson) and patients with dysbetalipoproteinemia (type III according to Frederickson), in whom diet therapy does not give an adequate effect;

• To reduce the concentration of total cholesterol and cholesterol / LDL cholesterol in patients with homozygous familial hypercholesterolemia, when diet therapy and other non-pharmacological treatments are not effective enough (as an adjunct to lipid-lowering therapy, including autohemotransfusion of LDL-purified blood)

• Diseases of the cardiovascular system (in patients with increased risk factors for coronary artery disease - advanced age over 55 years, smoking, arterial hypertension, diabetes mellitus, peripheral vascular disease, stroke, left ventricular hypertrophy, protein / albuminuria, coronary artery disease in close relatives ), incl. against the background of dyslipidemia - secondary prevention in order to reduce the total risk of death, myocardial infarction, stroke, re-hospitalization for angina pectoris and the need for revascularization.

CONTRAINDICATIONS

• Hypersensitivity to the components of the drug;

• Active liver disease or increased serum activity of 'hepatic' transaminases (more than 3 times compared with the upper limit of normal) of unknown origin, liver failure (severity A and B on the Child-Pugh scale);

• Hereditary diseases such as lactose intolerance, lactase deficiency or glucose-galactose malabsorption (due to the presence of lactose in the composition);

• Pregnancy, lactation period;

• Women of reproductive age who do not use adequate contraceptive methods;

• Age up to 18 years (efficacy and safety have not been established).

With care:
alcohol abuse, a history of liver disease, severe disturbances in the water and electrolyte balance, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, major surgical interventions, injuries, diseases of skeletal muscles.

Use during pregnancy and lactation
Use in women of reproductive age is possible only if reliable methods of contraception are used and the patient is informed about the possible risk of treatment for the fetus.
Since cholesterol and substances synthesized from cholesterol are important for fetal development, the potential risk of inhibition of HMG-CoA reductase outweighs the benefits of using the drug during pregnancy. When mothers use lovastatin (an inhibitor of HMG-CoA reductase) with dextroamphetamine in the first trimester of pregnancy, there are cases of birth of children with bone deformity, tracheo-esophageal fistula, and atresia of the anus. If pregnancy is diagnosed during therapy with TORVACARDЃ, the drug should be discontinued immediately, and the patient should be warned of the potential risk to the fetus.
If it is necessary to use the drug during lactation, given the possibility of adverse events in infants, the issue of stopping breastfeeding should be resolved.

DOSAGE AND METHOD OF APPLICATION Before prescribing the drug TORVACARDЃ, the patient should be advised a standard cholesterol-lowering diet, which he should continue to follow during the entire period of therapy.
The drug is taken orally at any time of the day, regardless of the time of the meal.
The initial dose is on average 10 mg 1 time / day. The dose varies from 10 to 80 mg 1 time / day. The dose is selected taking into account the initial concentrations of cholesterol / LDL, the goal of therapy and the individual effect. At the beginning of treatment and / or during an increase in the dose of TORVACARDЃ, it is necessary to monitor plasma lipid concentrations every 2-4 weeks and adjust the dose accordingly. The maximum daily dose is 80 mg in 1 dose.
Primary hypercholesterolemia and mixed hyperlipidemia
In most cases, it is sufficient to prescribe a dose of 10 mg of the drug TORVACARDЃ 1 time per day. A significant therapeutic effect is observed after 2 weeks, as a rule, and the maximum therapeutic effect is usually observed after 4 weeks. With long-term treatment, this effect persists.

SIDE EFFECTS
The frequency of adverse reactions listed below was determined according to the following (classification of the World Health Organization):
very often - more than 1/10,
often - from more than 1/100 to less than 1/10,
infrequently - from more than 1/1000 to less than 1 / 100,
rarely - from more than 1/10000 to less than 1/1000,
very rarely - from less than 1/10000, including individual messages.
From the side of the central nervous system:
often - headache, asthenia, insomnia;
infrequently - dizziness, drowsiness, nightmares, amnesia, depression, peripheral neuropathy, ataxia, hypesthesia, paresthesia.
From the digestive system:
often - nausea, vomiting, constipation or diarrhea, flatulence, gastralgia, abdominal pain;
infrequently - anorexia or increased appetite, hepatitis, pancreatitis, cholestatic jaundice.
From the side of the musculoskeletal system:
very often - myalgia; arthralgia;
infrequently - myopathy;
rarely - myositis, rhabdomyolysis, back pain, cramps of the calf muscles of the legs.
Allergic reactions:
often - itching, rash;
infrequently - urticaria;
very rarely - angioedema, anaphylactic shock, bullous rashes, polyform exudative erythema, incl. Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).
Laboratory indicators:
infrequently - hyperglycemia, hypoglycemia, increased activity of serum creatine phosphokinase (CPK), increased activity of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT).
Others:
often - chest pain, peripheral edema;
infrequently - impotence, alopecia, tinnitus, weight gain, malaise, weakness, thrombocytopenia, secondary renal failure.

OVERDOSE
Treatment: there is no specific antidote, symptomatic therapy is performed. Hemodialysis is ineffective.

INTERACTION WITH OTHER DRUGS
During treatment with drugs of the class of lipid-lowering drugs and the simultaneous use of cyclosporine, fibrates, erythromycin, clarithromycin, immunosuppressive and antifungal drugs (related to azoles), nicotinic acid and nicotinamide, drugs that inhibit metabolism, mediated by cytochrome P450ZA4 isoenzymes, and atorvastatin in blood plasma (and the risk of myopathy) increases. Prescribing these drugs, one should carefully weigh the expected benefits and risks of treatment, regularly observe patients in order to identify pain or weakness in the muscles, especially during the first months of treatment and during the period of increasing the dose of any drug, periodically determine the activity of CPK, although such monitoring does not allow to prevent the development of severe myopathy.Therapy with TORVACARDЃ should be discontinued in case of a pronounced increase in CPK activity or in the presence of confirmed or suspected myopathy.
Atorvastatin did not have a clinically significant effect on the concentration of terfenadine in blood plasma, which is metabolized mainly by cytochrome P45oZA4 isoenzymes; in this regard, it seems unlikely that atorvastatin is able to significantly affect the pharmacokinetic parameters of other substrates of cytochrome P-5o3A4 isoenzymes. With the simultaneous use of atorvastatin (10 mg once a day) and azithromycin (500 mg once a day), the concentration of atovastatin in the blood plasma does not change.
With the simultaneous administration of atorvastatin and preparations containing magnesium and aluminum hydroxide, the concentration of atorvastatin in the blood plasma decreased by about 35%, but the degree of decrease in cholesterol / LDL levels did not change.
With the simultaneous use of colestipol, the concentration of atorvastatin in the blood plasma decreased by about 25%. However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug separately.
With the simultaneous use of atorvastatin does not affect the pharmacokinetics of phenazone, therefore, interaction with other drugs metabolized by the same cytochrome P450ZA4 isoenzymes is not expected.
When studying the interaction of atorvastatin with warfarin, cimetidine, phenazone, no signs of a clinically significant interaction were found.
Simultaneous use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of lowering endogenous steroid hormones (caution should be exercised).
There was no clinically significant undesirable interaction of atorvastatin and antihypertensive drugs, as well as with estrogens.
With the simultaneous use of atorvastatin at a dose of 80 mg / day and oral contraceptives containing norethindrone and ethinyl estradiol, there was a significant increase in the concentration of norethindrone and ethinyl estradiol by about 30% and 20%, respectively. This effect should be taken into account when choosing an oral contraceptive for women receiving TORVACARDЃ.
With the simultaneous use of atorvastatin 80 mg and amlodipine 10 mg, the pharmacokinetics of atorvastatin in the equilibrium state did not change.
With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in blood plasma did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg / day, the concentration of digoxin increased by about 20%.
Patients receiving digoxin in combination with atorvastatin should be monitored.
Interaction studies with other drugs have not been conducted.

SPECIAL INSTRUCTIONS
Before starting therapy with TORVACARDЃ, it is necessary to try to control hypercholesterolemia by adequate diet therapy, increasing physical activity, reducing body weight in obese patients and treating other conditions. The use of HMG-CoA reductase inhibitors to lower blood lipids can lead to changes in the biochemical parameters of liver function, which should be monitored before starting therapy, 6 and 12 weeks after starting TORVACARDЃ and after each dose increase, as well as periodically, for example every 6 months. An increase in the activity of 'hepatic' transaminases in the blood serum can be observed during therapy with TORVACARDЃ (usually in the first three months). Patients who have an increase in the level of activity of 'hepatic' transaminases,should be monitored until enzyme levels return to normal. In the event that the ACT or ALT values ??are more than 3 times higher than the norm, it is recommended to reduce the dose of TORVACARD or stop treatment.
Treatment with TORVACARDЃ can cause myopathy (pain and weakness in the muscles in combination with an increase in CPK activity more than 10 times compared to the upper limit of the norm). TORVACARDЃ can cause an increase in serum CPK, which should be taken into account in the differential diagnosis of chest pain. Patients should be warned to see a doctor immediately if they develop unexplained muscle pain or weakness, especially if accompanied by malaise or fever. Therapy with TORVACARDЃ should be temporarily discontinued or completely canceled if signs of possible myopathy or a risk factor for the development of renal failure associated with rhabdomyolysis appear (for example, severe acute infection, arterial hypotension, major surgery, trauma,severe metabolic, endocrine and electrolyte disturbances and uncontrolled convulsions).

Influence on the ability to drive vehicles and engaging in other activities that require concentration of attention and speed of psychomotor reactions
About the adverse effect of the drug TORVACARDЃ, film-coated tablets on the ability to drive vehicles and other activities that require concentration of attention and speed of psychomotor reactions reported.

FORM OF RELEASE
Film-coated tablets 10 mg, 20 mg and 40 mg.
There are 10 tablets in a blister of A1 / A1. 3 or 9 blisters are placed in a cardboard box along with instructions for use.

STORAGE CONDITIONS
Does not require special storage conditions. Keep out of the reach of children!

SHELF LIFE
2 years.
The drug should not be used after the expiration date indicated on the package.

TERMS OF RELEASE FROM PHARMACIES
By prescription.