Torvacard^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Saneca Pharmaceuticals, a.s. (Slovakia)

Packaging and Quality Control Release

SANECA PHARMACEUTICALS, a.s. (Slovakia)

Or

ZiO-ZDOROVYE, JSC (Russia)

ATC Code

C10AA05 (Atorvastatin)

Active Substance

Atorvastatin (Rec.INN registered by WHO)

Dosage Forms

	Torvacard®	Film-coated tablets, 10 mg: 30, 60, or 90 pcs.
		Film-coated tablets, 20 mg: 30, 60, or 90 pcs.
		Film-coated tablets, 40 mg: 30, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from white to almost white, oval, biconvex.

Excipients: magnesium oxide, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate.

Film coating composition: hypromellose 2910/5, macrogol 6000, titanium dioxide, talc.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets from white to almost white, oval, biconvex.

Excipients: magnesium oxide, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate.

Film coating composition: hypromellose 2910/5, macrogol 6000, titanium dioxide, talc.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Film-coated tablets from white to almost white, oval, biconvex.

Excipients: magnesium oxide, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate.

Film coating composition: hypromellose 2910/5, macrogol 6000, titanium dioxide, talc.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

Hypolipidemic drug from the statin group. Selective competitive inhibitor of HMG-CoA reductase, the enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonic acid, which is a precursor of steroids, including cholesterol. In the liver, triglycerides and cholesterol are incorporated into VLDL, enter the blood plasma and are transported to peripheral tissues. LDL is formed from VLDL during interaction with LDL receptors. Atorvastatin reduces plasma levels of cholesterol and lipoproteins by inhibiting HMG-CoA reductase, cholesterol synthesis in the liver, and increasing the number of LDL receptors on the surface of liver cells, which leads to increased uptake and catabolism of LDL.

Atorvastatin reduces the formation of LDL and causes a pronounced and persistent increase in LDL receptor activity. Atorvastatin reduces LDL levels in patients with homozygous familial hypercholesterolemia, which is usually resistant to therapy with other hypolipidemic agents.

It reduces total cholesterol levels by 30-46%, LDL by 41-61%, apolipoprotein B by 34-50%, and triglycerides by 14-33%; it causes an increase in HDL cholesterol and apolipoprotein A concentrations. It dose-dependently reduces LDL levels in patients with homozygous hereditary hypercholesterolemia resistant to therapy with other hypolipidemic agents.

Pharmacokinetics

Absorption

Absorption is high. C_max is reached in 1-2 hours. C_max in women is 20% higher than normal, AUC is 10% lower than normal; C_max in patients with alcoholic liver cirrhosis is 16 times higher than normal, AUC is 11 times higher than normal. Food somewhat reduces the rate and duration of drug absorption (by 25% and 9%, respectively), but the reduction in LDL cholesterol is similar to that when atorvastatin is taken without food. The concentration of atorvastatin when taken in the evening is lower than in the morning (by approximately 30%). A linear relationship between the degree of absorption and the drug dose has been identified.

Bioavailability is 12%, systemic bioavailability of inhibitory activity against HMG-CoA reductase is 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and during first-pass through the liver.

Distribution

Mean V_d is 381 L. Plasma protein binding is 98%.

Metabolism

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 para-hydroxylated derivatives, beta-oxidation products). In vitro, ortho- and para-hydroxylated 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.

Excretion

It is excreted through the intestine with bile after hepatic and/or extrahepatic metabolism (does not undergo significant enterohepatic recirculation). T_1/2 is 14 hours. The inhibitory activity against HMG-CoA reductase persists for about 20-30 hours due to the presence of active metabolites. Less than 2% of the orally administered dose is detected in the urine. It is not excreted by hemodialysis.

Indications

• In combination with a diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides and to increase HDL cholesterol levels in patients with primary hypercholesterolemia, heterozygous familial and non-familial hypercholesterolemia, and combined (mixed) hyperlipidemia (Fredrickson types IIa and IIb);
• In combination with a diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson type IV) and patients with dysbetalipoproteinemia (Fredrickson type III) in whom diet therapy does not provide an adequate effect;
• To reduce total cholesterol and LDL cholesterol levels in patients with homozygous familial hypercholesterolemia when diet therapy and other non-pharmacological treatments are insufficiently effective (as an adjunct to hypolipidemic therapy, including autologous transfusion of LDL-apheresis);
• Cardiovascular diseases (in patients with increased risk factors for coronary artery disease – elderly age over 55 years, smoking, arterial hypertension, diabetes mellitus, peripheral vascular diseases, history of stroke, left ventricular hypertrophy, proteinuria/albuminuria, family history of coronary artery disease), including against the background of dyslipidemia – secondary prevention to reduce the overall risk of death, myocardial infarction, stroke, rehospitalization for angina, and the need for revascularization procedures.

ICD codes

Dosage Regimen

Before prescribing Torvacard^®, the patient should be recommended a standard hypolipidemic diet, which they must continue to follow throughout the entire therapy period.

The initial dose is on average 10 mg once a day. The dose varies from 10 to 80 mg once a day. The drug can be taken at any time of the day, regardless of meals. The dose is selected taking into account the initial LDL cholesterol levels, the therapy goal, and the individual effect. At the beginning of treatment and/or during dose increase of Torvacard^®, plasma lipid levels should be monitored every 2-4 weeks and the dose should be adjusted accordingly. The maximum daily dose is 80 mg in a single dose.

For primary hypercholesterolemia and mixed hyperlipidemia, in most cases, a dose of 10 mg of Torvacard^® once a day is sufficient. A significant therapeutic effect is observed after 2 weeks, and the maximum therapeutic effect is usually observed after 4 weeks. This effect is maintained during long-term treatment.

When determining the treatment goal, the following recommendations can be used.

A. Recommendations of the National Cholesterol Education Program (USA)

* Coronary artery disease or peripheral vascular atherosclerosis (including carotid artery disease accompanied by clinical symptoms).

** age (men ≥45 years, women ≥55 years or early menopause without estrogen replacement therapy), family history of early coronary artery disease, smoking, arterial hypertension, confirmed HDL cholesterol level <35 mg/dL (<0.91 mmol/L), and diabetes mellitus. One risk factor should be subtracted if the HDL cholesterol level is ≥60 mg/dL (≥1.6 mmol/L).

*** in patients with coronary artery disease with LDL cholesterol levels from 100 to 129 mg/dL, the decision on drug therapy is made by the doctor based on clinical experience.

B. Recommendations of the European Atherosclerosis Society (EAS) on the diagnosis and treatment of metabolic disorders

Goals of hypolipidemic therapy according to the European Atherosclerosis Society

In patients with a confirmed diagnosis of coronary artery disease and other patients at high risk of ischemic complications, the goal of treatment is to reduce LDL cholesterol levels to <115 mg/dL (<3 mmol/L) and total cholesterol to <190 mg/dL (<5 mmol/L).

C. National treatment recommendations

Homozygous familial hypercholesterolemia

In a study of adult patients with homozygous familial hypercholesterolemia, therapy with atorvastatin at a dose of 80 mg in most cases led to a reduction in LDL cholesterol levels by more than 15% (18-45%).

Use of the drug in patients with renal failure and kidney diseases does not affect the plasma level of atorvastatin or the degree of LDL cholesterol reduction during its use, therefore, no dose adjustment of the drug is required.

When using the drug in elderly patients, no differences in safety, efficacy, or achievement of hypolipidemic therapy goals were noted compared to the general population.

Adverse Reactions

The frequency of adverse reactions listed below was determined according to the following (WHO classification): very common (>1/10), common (from >1/100 to <1/10), uncommon (from >1/1000 to <1/100), rare (from >1/10,000 to <1/1000), very rare (from <1/10,000, including isolated reports).

From the central and peripheral nervous system: common – headache, asthenia; uncommon – dizziness, drowsiness, sleep disorders (including insomnia and nightmares), memory loss or impairment, depression, peripheral neuropathy, ataxia, hypoesthesia, paresthesia.

From the digestive system: common – nausea, vomiting, constipation or diarrhea, flatulence, stomach pain, abdominal pain; uncommon – anorexia or increased appetite, hepatitis, pancreatitis, cholestatic jaundice.

From the musculoskeletal system: very common – myalgia, arthralgia; uncommon – myopathy; rare – myositis, rhabdomyolysis, back pain, calf muscle cramps.

Allergic reactions: common – skin itching, rash; uncommon – urticaria; very rare – angioedema, anaphylactic shock, bullous eruptions, multiforme exudative erythema, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

From laboratory parameters: uncommon – hyperglycemia, hypoglycemia, increased serum creatine phosphokinase activity, increased AST and ALT activity, increased glycosylated hemoglobin concentration.

Other: common – chest pain, peripheral edema; uncommon – impotence, alopecia, tinnitus, weight gain, malaise, weakness, thrombocytopenia, secondary renal failure.

The following adverse events have been reported with the use of some statins: sexual dysfunctions; depression; gynecomastia; cases of immune-mediated necrotizing myopathy; isolated cases of interstitial lung disease (especially with long-term use); diabetes mellitus, the frequency of which depends on the presence or absence of risk factors (fasting blood glucose 5.6-6.9 mmol/L, BMI >30 kg/m², hypertriglyceridemia, history of arterial hypertension).

Contraindications

• Active liver diseases or unexplained persistent elevation of serum transaminases (more than 3 times the upper limit of normal);
• Liver failure (Child-Pugh class A and B);
• 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 not using adequate methods of contraception;
• Children and adolescents under 18 years of age (efficacy and safety have not been established);
• Hypersensitivity to the components of the drug.

Use with caution in cases of alcohol abuse, history of liver disease, severe disorders of water and electrolyte balance, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, major surgical interventions, trauma, skeletal muscle diseases, diabetes mellitus.

Use in Pregnancy and Lactation

Atorvastatin is contraindicated for use during pregnancy and lactation (breastfeeding).

Since cholesterol and substances synthesized from cholesterol are important for fetal development, the potential risk of inhibiting HMG-CoA reductase outweighs the benefit of using the drug during pregnancy. When lovastatin (an HMG-CoA reductase inhibitor) was used with dextroamphetamine in the first trimester of pregnancy, cases of children born with bone deformities, tracheo-esophageal fistula, and anal atresia are known. If pregnancy is diagnosed during therapy with Torvacard^®, the drug should be discontinued immediately, and patients should be warned of the potential risk to the fetus.

If it is necessary to use the drug during lactation, considering the possibility of adverse events in infants, the issue of discontinuing breastfeeding should be decided.

Use in women of reproductive age is possible only if reliable methods of contraception are used. The patient should be informed about the possible risk of treatment for the fetus.

Use in Hepatic Impairment

The drug is contraindicated in active liver diseases or with unexplained persistent elevation of serum transaminases (more than 3 times the upper limit of normal).

Use in Renal Impairment

Use of the drug in patients with renal failure and kidney diseases does not affect the plasma level of atorvastatin or the degree of LDL cholesterol reduction during its use, therefore, no dose adjustment of the drug is required.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age (efficacy and safety have not been established).

Geriatric Use

When using the drug in elderly patients, no differences in safety, efficacy, or achievement of hypolipidemic therapy goals were noted compared to the general population.

Special Precautions

Before starting therapy with Torvacard^®, it is necessary to attempt to control hypercholesterolemia through adequate diet therapy, increased physical activity, weight loss in obese patients, and treatment of other conditions.

The use of HMG-CoA reductase inhibitors to lower blood lipid levels may lead to changes in biochemical parameters reflecting liver function. Liver function should be monitored before starting therapy, 6 weeks and 12 weeks after starting Torvacard^®, and after each dose increase, as well as periodically (for example, every 6 months). An increase in serum liver enzyme activity may be observed during therapy with Torvacard^® (usually in the first 3 months). Patients who have elevated transaminase levels should be monitored until the enzyme levels return to normal. If ALT or AST values exceed the upper limit of normal by more than 3 times, it is recommended to reduce the dose of Torvacard^® or discontinue treatment.

Treatment with Torvacard^® may cause myopathy (muscle pain and weakness combined with an increase in CPK activity of more than 10 times the ULN). Torvacard^® may cause an increase in serum CPK levels, which should be taken into account in the differential diagnosis of chest pain. Patients should be warned that they should immediately consult a doctor if unexplained muscle pain or weakness appears, especially if it is accompanied by malaise or fever.

Therapy with Torvacard^® should be temporarily discontinued or completely withdrawn if signs of possible myopathy appear or if there is a risk factor for the development of renal failure against the background of rhabdomyolysis (for example, severe acute infection, arterial hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances, and uncontrolled seizures).

Drugs of the statin class can cause an increase in blood glucose concentration. In some patients at high risk of developing diabetes mellitus, such changes may lead to its manifestation, which is an indication for the prescription of antidiabetic therapy.

However, the reduction in the risk of vascular diseases while using statins outweighs the risk of developing diabetes mellitus, so this factor should not be a reason for discontinuing statin treatment. Patients at risk (fasting blood glucose 5.6-6.9 mmol/l, BMI>30 kg/m², hypertriglyceridemia, history of arterial hypertension) should be placed under medical supervision and regular monitoring of biochemical parameters should be carried out.

Effect on the ability to drive vehicles and operate machinery

No adverse effects of Torvacard^® on the ability to drive vehicles and engage in other activities requiring concentration and speed of psychomotor reactions have been reported.

Overdose

Treatment symptomatic therapy should be performed. There is no specific antidote. Hemodialysis is not effective.

Drug Interactions

With the simultaneous use of cyclosporine, fibrates, erythromycin, clarithromycin, immunosuppressive and antifungal drugs of the azole group, nicotinic acid and nicotinamide, drugs that inhibit metabolism mediated by the CYP450 3A4 isoenzyme and/or drug transport, the plasma concentration of atorvastatin (and the risk of myopathy) increases.

When prescribing these drugs, the expected benefit and risk of treatment should be carefully weighed, patients should be regularly monitored to detect muscle pain or weakness, especially during the first months of treatment and during the period of dose increase of any drug, periodic determination of CPK activity should be carried out, although such monitoring does not prevent the development of severe myopathy.

Therapy with Torvacard^® should be discontinued in case of a significant increase in CPK activity or in the presence of confirmed or suspected myopathy.

Atorvastatin did not have a clinically significant effect on the plasma concentration of terfenadine, which is metabolized mainly by the CYP3A4 isoenzyme; therefore, it seems unlikely that Atorvastatin can significantly affect the pharmacokinetic parameters of other substrates of the CYP3A4 isoenzyme.

With the simultaneous use of atorvastatin (10 mg once/day) and azithromycin (500 mg once/day), the plasma concentration of atorvastatin does not change.

With simultaneous oral administration of atorvastatin and drugs containing magnesium and aluminum hydroxides, the plasma concentration of atorvastatin decreased by approximately 35%, but the degree of reduction in LDL-C levels did not change.

With simultaneous use of colestipol, plasma concentrations of atorvastatin decreased by approximately 25%. However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug separately.

With simultaneous use, Atorvastatin does not affect the pharmacokinetics of phenazone, therefore interaction with other drugs metabolized by the same CYP450 isoenzymes is not expected.

In studies of the interaction of atorvastatin with warfarin, cimetidine, and phenazone, no signs of 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 reducing endogenous steroid hormones (caution should be exercised).

No clinically significant adverse interaction of atorvastatin with antihypertensive agents, as well as with estrogens, was noted.

With the simultaneous use of atorvastatin at a dose of 80 mg/day and oral contraceptives containing norethindrone and ethinyl estradiol, a significant increase in the concentration of norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively, was observed. This effect should be taken into account when choosing an oral contraceptive for women receiving Torvacard^®.

With the simultaneous use of atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg, the steady-state pharmacokinetics of atorvastatin did not change.

With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the steady-state plasma concentrations of digoxin did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg/day, the concentration of digoxin increased by approximately 20%. Patients receiving digoxin in combination with atorvastatin require monitoring.

Interaction studies with other drugs have not been conducted.

Storage Conditions

The drug should be stored out of the reach of children.

Shelf Life

Shelf life is 4 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.