IBANDRONOVA KISLOTA - FARMEKS

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ETSET (ATSAT)

Composition

active substance: atorvastatin; 1 tablet contains atorvastatin calcium equivalent to atorvastatin 10 mg, 20 mg, 40 mg or 80 mg; excipients: lactose monohydrate, microcrystalline cellulose, calcium carbonate, povidone K30, sodium croscarmellose, colloidal silicon dioxide anhydrous, magnesium stearate, Opadry 03F84827 pink*;

*Opadry 03F84827 pink: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red (E 172).

Pharmaceutical Form

Tablets, film-coated.

Main Physico-Chemical Properties

film-coated tablets 10 mg, 20 mg: round biconvex film-coated tablets of pink color with the inscription "10" or "20" on one side;

film-coated tablets 40 mg, 80 mg: round biconvex film-coated tablets of pink color, smooth on both sides.

Pharmacotherapeutic Group

Drugs that lower cholesterol and triglyceride levels in blood serum.

HMG-CoA reductase inhibitors. ATC code C10A A05.

Pharmacological Properties

Pharmacodynamics

Etset contains the active substance atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that determines the rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

In experimental animal models, atorvastatin lowers cholesterol and lipoprotein levels in plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of liver LDL receptors on the surface of cells to enhance LDL uptake and catabolism; atorvastatin also reduces LDL production and the number of these particles.

Atorvastatin, like some of its metabolites, is pharmacologically active in humans. The main site of action of atorvastatin is the liver, which plays a major role in cholesterol synthesis and LDL clearance. The dose of the drug, unlike the systemic concentration of the drug, is better correlated with the reduction in LDL cholesterol levels. Individual dose selection of the drug should be performed based on the therapeutic response (see "Method of administration and dosage").

Pharmacokinetics

Absorption.

Atorvastatin is rapidly absorbed after oral administration, and its maximum concentration in plasma is reached within 1-2 hours. The degree of absorption increases in proportion to the dose of atorvastatin. The absolute bioavailability of atorvastatin (original drug) is approximately 14%, and the systemic bioavailability of the inhibitory activity against HMG-CoA reductase is approximately 30%. The low systemic availability of the drug is associated with presystemic clearance in the gastrointestinal mucosa and/or presystemic biotransformation in the liver. Although food reduces the rate and extent of absorption of the drug by approximately 25% and 9%, respectively, in terms of Cmax and AUC (area under the concentration-time curve), the reduction in LDL cholesterol levels is similar when taking atorvastatin with food and separately. When atorvastatin was administered in the evening, its concentration in plasma was lower (approximately 30% for Cmax and AUC) than when taken in the morning. However, the reduction in LDL cholesterol levels is the same regardless of the time of administration of the drug (see "Method of administration and dosage").

Distribution.

The average volume of distribution of atorvastatin is approximately 381 liters. More than 98% of the drug is bound to plasma proteins. The concentration ratio of blood/plasma, which is approximately 0.25, indicates poor penetration of the drug into erythrocytes. It is believed that atorvastatin is able to penetrate breast milk (see "Contraindications" and "Special instructions").

Metabolism.

Atorvastatin is intensively metabolized to ortho- and para-hydroxylated derivatives and various products of beta-oxidation. In vitro inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to inhibition by atorvastatin. Approximately 70% of the circulating inhibitory activity against HMG-CoA reductase is associated with active metabolites. In vitro studies indicate the importance of atorvastatin metabolism by cytochrome P450 3A4 (CYP 3A4), which is consistent with increased concentrations of atorvastatin in human plasma after concomitant administration with erythromycin, a known inhibitor of this isoenzyme (see "Interaction with other medicinal products and other types of interactions").

Excretion.

Atorvastatin and its metabolites are excreted mainly with bile after hepatic and/or extrahepatic metabolism, but this drug apparently does not undergo enterohepatic recirculation. The average half-life of atorvastatin from human plasma is approximately 14 hours, but the half-life of the inhibitory activity against HMG-CoA reductase is from 20 to 30 hours due to the effect of active metabolites. After oral administration of the drug, less than 2% of the dose is excreted in the urine.

Special Patient Populations

Elderly patients.

The concentration of atorvastatin in plasma is higher (approximately 40% for Cmax and 30% for AUC) in healthy subjects of elderly age (65 years and older) than in young adult patients. Clinical data indicate a greater degree of LDL reduction when using any dose of the drug in elderly patients compared to young patients (see "Special instructions").

Children.

The apparent clearance of oral atorvastatin in children was found to be similar to the clearance in adult humans when scaled allometrically by body weight, as body weight was the only significant covariate in the population pharmacokinetic model of atorvastatin with data that included children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n = 29) in an open 8-week study.

Sex.

The concentration of atorvastatin in plasma differs in women and men (approximately 20% higher for Cmax and 10% lower for AUC). However, there is no clinically significant difference in the reduction of LDL cholesterol levels when using atorvastatin in men and women.

Kidney function disorders.

Kidney disease does not affect the concentration of atorvastatin in plasma or the reduction of LDL cholesterol levels, and therefore, dose adjustment of the drug is not required for patients with kidney function disorders (see "Method of administration and dosage", "Special instructions").

Hemodialysis.

Although studies involving patients with end-stage renal disease have not been conducted, it is believed that hemodialysis does not significantly increase the clearance of atorvastatin, as it is intensively bound to plasma proteins.

Liver failure.

The concentrations of atorvastatin in plasma are significantly increased in patients with chronic alcoholic liver disease. The values of Cmax and AUC are 4 times higher in patients with liver disease class A according to the Child-Pugh scale. In patients with liver disease class B according to the Child-Pugh scale, the values of Cmax and AUC are increased approximately 16-fold and 11-fold, respectively (see "Contraindications").

Drug Interaction Studies

Atorvastatin is a substrate of liver transporters, OATP1B1 and OATP1B3 transporters. Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter breast cancer resistance protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin.

Table 1

Effect of concomitantly administered drugs on the pharmacokinetics of atorvastatin

& Ratio of treatments (concomitant administration of a drug with atorvastatin compared to administration of atorvastatin alone).

# For information on clinical significance, see "Special instructions" and "Interaction with other medicinal products and other types of interactions".

* Reports of greater increases in AUC (AUC ratio up to 2.5) and/or Cmax (Cmax ratio up to 1.71) have been reported with excessive consumption of grapefruit juice (750 mL - 1.2 liters per day or more).

** Ratio based on a single sample taken 8-16 hours after dosing.

† Due to the mechanism of dual interaction of rifampin, concomitant administration of atorvastatin with rifampin is recommended, as it has been shown that delayed administration of atorvastatin after rifampin administration is associated with a significant decrease in atorvastatin plasma concentration.

‡ The dose combination of saquinavir + ritonavir in this study is not a clinically used dose. The increase in atorvastatin exposure when used in clinical settings is likely to be higher than that observed in this study. Therefore, the drug should be used with caution and at the lowest necessary dose.

Clinical Characteristics

Indications

Prevention of cardiovascular diseases in adults

For adult patients without clinically manifest ischemic heart disease, but with several risk factors for the development of ischemic heart disease, such as age, smoking, arterial hypertension, low level of HDL cholesterol or a history of early ischemic heart disease in the family, Etset is indicated for:

- reducing the risk of myocardial infarction;

- reducing the risk of stroke;

- reducing the risk of revascularization procedures and angina.

For adult patients with type 2 diabetes mellitus and without clinically manifest ischemic heart disease, but with several risk factors for the development of ischemic heart disease, such as retinopathy, albuminuria, smoking or arterial hypertension, the drug Etset is indicated for:

- reducing the risk of myocardial infarction;

- reducing the risk of stroke.

For adult patients with clinically manifest ischemic heart disease, Etset is indicated for:

- reducing the risk of non-fatal myocardial infarction;

- reducing the risk of fatal and non-fatal stroke;

- reducing the risk of revascularization procedures;

- reducing the risk of hospitalization due to congestive heart failure;

- reducing the risk of angina.

Hyperlipidemia

In adult patients

- As an adjunct to diet to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B, and triglyceride levels, and to increase HDL cholesterol levels in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to the Fredrickson classification).

- As an adjunct to diet for the treatment of patients with elevated triglyceride levels in blood serum (type IV according to the Fredrickson classification).

- For the treatment of patients with primary dysbetalipoproteinemia (type III according to the Fredrickson classification) when dietary measures are insufficient.

- To reduce total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapeutic procedures (e.g., LDL apheresis) or when such procedures are not available.

In Children

- As an adjunct to diet to reduce levels of total cholesterol, LDL cholesterol, and apolipoprotein B in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy, the results of the analysis are such:

a) LDL cholesterol remains ≥ 190 mg/dL (4.91 mmol/L) or

b) LDL cholesterol ≥ 160 mg/dL (4.14 mmol/L) and:

• there is a family history of early cardiovascular disease or

• two or more other risk factors for cardiovascular disease are present in the child.

Contraindications

- Acute liver disease, which may include persistent elevation of liver transaminase levels of unknown etiology.

- Hypersensitivity to any component of this medicinal product.

- Pregnancy.

- Lactation.

Interaction with Other Medicinal Products and Other Types of Interactions

Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp or BCRP). Atorvastatin plasma levels may be significantly increased when co-administered with CYP3A4 and transporter inhibitors. The following is a list of drugs that may increase atorvastatin exposure and the risk of myopathy and rhabdomyolysis when co-administered, as well as recommendations for their management and prevention (see "Special instructions" and "Pharmacological properties").

Table 3

Interactions with other medicinal products that may increase the risk of myopathy and rhabdomyolysis when using atorvastatin

Special Instructions

Myopathy and Rhabdomyolysis

Atorvastatin may cause myopathy (muscle pain, tenderness, or weakness in combination with elevated creatine kinase (CK) levels more than 10 times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure due to myoglobinuria). Rare, fatal cases of rhabdomyolysis have been reported with statin use, including atorvastatin.

Risk factors for myopathy

Risk factors for myopathy include age 65 years or older, uncontrolled hypothyroidism, renal impairment, concomitant use of certain other drugs, and increased doses of atorvastatin (see "Interaction with other medicinal products and other types of interactions").

Measures to reduce the risk of myopathy and rhabdomyolysis or prevent such risk

Atorvastatin exposure may increase due to interaction with other medicinal products through inhibition of the cytochrome P450 3A4 enzyme and/or transporters (e.g., breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP1B1/OATP1B3), and P-glycoprotein (P-gp)), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant administration of cyclosporine, gemfibrozil, tipranavir + ritonavir, or glecaprevir + pibrentasvir with atorvastatin is not recommended. Dose adjustments of atorvastatin are recommended for patients taking certain antiviral drugs, azole antifungal agents, or macrolide antibiotics (see "Method of administration and dosage"). Cases of myopathy/rhabdomyolysis have been reported when co-administering atorvastatin with lipid-modifying doses of niacin (> 1 g/day niacin), fibrates, colchicine, and the combination of ledipasvir + sofosbuvir. The benefit of concomitant administration of these drugs with atorvastatin should be evaluated (see "Interaction with other medicinal products and other types of interactions").

Concomitant administration of large quantities of grapefruit juice (more than 1.2 liters per day) should be avoided in patients taking atorvastatin (see "Interaction with other medicinal products and other types of interactions").

Atorvastatin should be discontinued if there is a significant increase in CK levels or if myopathy is diagnosed or suspected. Muscle symptoms and elevated CK levels resolve upon discontinuation of atorvastatin. Atorvastatin should be temporarily discontinued in patients with acute or severe conditions at high risk of developing renal failure due to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled epilepsy).

Patients should be informed of the risk of myopathy and rhabdomyolysis at the start of treatment or when the dose of atorvastatin is increased. Patients should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.

Immune-Mediated Necrotizing Myopathy

Rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use, have been received. IMNM is characterized by proximal muscle weakness and elevated serum CK levels, persisting despite discontinuation of statin treatment; positive anti-HMG-CoA reductase antibody; and muscle biopsy showing necrotizing myopathy. Additional neuromuscular and serological studies may be necessary. Immunosuppressive therapy may be required. The risk of IMNM should be carefully weighed before starting another statin. If statin therapy is initiated, monitoring for signs and symptoms of IMNM is necessary.

Liver Function

Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (more than 3 times the upper limit of normal, occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The frequency of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for doses of the drug of 10, 20, 40, and 80 mg, respectively.

During clinical trials of the drug, one patient developed jaundice. Elevated liver function tests in other patients were not associated with jaundice or other clinical symptoms. After reduction of the dose, interruption of treatment, or discontinuation of atorvastatin, liver enzyme levels returned to pre-treatment levels or approximately to those levels without adverse consequences. 18 of 30 patients with persistent elevations in liver function tests continued to receive atorvastatin at lower doses.

Prior to initiating atorvastatin therapy, liver function tests should be obtained. If liver function tests are abnormal, the patient should be monitored and atorvastatin therapy should be discontinued if liver function tests become markedly elevated.

Post-marketing reports of fatal and non-fatal hepatic failure have been received in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, prompt discontinuation of therapy should occur.

Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Atorvastatin is contraindicated in active liver disease or persistent elevations of liver transaminases of unknown cause (see "Contraindications").

Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with statin use, including atorvastatin.

Statins may interfere with cholesterol synthesis and theoretically may blunt adrenal and/or gonadal steroid hormone production. Clinical studies have shown that atorvastatin does not lower basal cortisol plasma levels and does not impair adrenal reserve. The effects of statins on the fertility of human sperm have not been studied in adequate numbers of patients. It is not known whether atorvastatin has an effect on the hypothalamic-pituitary-gonadal axis in premenopausal women. Caution should be exercised when co-administering a statin with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Use in Patients with Recent Stroke or Transient Ischemic Attack

In a post-hoc analysis of the SPARCL study (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), in which atorvastatin 80 mg versus placebo was administered to 4,731 patients without ischemic heart disease who had a stroke or transient ischemic attack within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to the placebo group (55 versus 33 cases, 2.3% atorvastatin versus 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 atorvastatin versus 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly higher in the atorvastatin group (38 non-fatal, 1.6%) compared to the placebo group (16 non-fatal, 0.7%).

Certain initial characteristics, including the presence of hemorrhagic and lacunar strokes at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group (see "Adverse reactions").

Elderly Patients

Among 39,828 patients who received atorvastatin in clinical studies, 15,813 (40%) patients were ≥ 65 years, and 2,800 (7%) patients were ≥ 75 years. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Liver Failure

Atorvastatin is contraindicated in active liver disease or persistent elevations of liver transaminases of unknown cause (see "Contraindications" and "Pharmacological properties").

Prior to Initiation of Therapy

Atorvastatin should be used with caution in patients with a history of myopathy or conditions that may predispose to the development of myopathy, such as:

- renal impairment;

- hypothyroidism;

- family history of muscular disorders;

- previous history of myotoxicity with statins or fibrates;

- previous history of liver disease and/or alcohol abuse.

For elderly patients (over 70 years), the need for these measures should be assessed in the presence of other risk factors for myopathy.

An increase in atorvastatin plasma levels may occur, particularly in the case of interaction (see "Interaction with other medicinal products and other types of interactions") and administration to special populations of patients (see "Pharmacokinetics"), including patients with hereditary diseases.

In such cases, the ratio of risks and expected benefits from treatment should be evaluated, and clinical monitoring of the patient's condition should be performed. If the CK level is significantly elevated (more than 5 times the upper limit of normal) before treatment, treatment should not be initiated.

Measurement of Creatine Kinase

CK levels should not be determined after strenuous exercise or in the presence of any possible alternative causes of CK elevation, as this may complicate the interpretation of the results. If the initial level shows a significant elevation of CK (more than 5 times the upper limit of normal), a repeat determination should be performed within 5-7 days to confirm the results.

During Treatment

Patients should be informed of the need to promptly report the development of muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.

If these symptoms occur during treatment with atorvastatin, the CK level should be determined in the patient. If the CK level is significantly elevated (more than 5 times the upper limit of normal), treatment should be discontinued.

The need to discontinue treatment should also be considered if the CK level elevation does not reach 5 times the upper limit of normal but the muscle symptoms are severe and interfere with daily activities.

After the symptoms have resolved and the CK level has returned to normal, it may be possible to consider restarting treatment with atorvastatin or starting treatment with an alternative statin at the lowest possible dose and under close supervision.

Treatment with atorvastatin should be discontinued if there is a clinically significant elevation of CK levels (more than 10 times the upper limit of normal) or if rhabdomyolysis is diagnosed or suspected.

Concomitant Use with Other Medicinal Products

The risk of myopathy and/or rhabdomyolysis may be increased when HMG-CoA reductase inhibitors (e.g., atorvastatin) are co-administered with daptomycin (see "Interaction with other medicinal products and other types of interactions"). The possibility of temporarily suspending the use of the medicinal product Etset in patients who are using daptomycin should be considered, unless the benefit of concomitant administration outweighs the risk. If concomitant administration cannot be avoided, CK levels should be monitored 2-3 times a week, and patients should be closely monitored for signs and symptoms that may indicate myopathy.

The risk of rhabdomyolysis is increased when atorvastatin is co-administered with certain medicinal products that may increase atorvastatin plasma levels. Examples of such drugs include potent CYP 3A4 inhibitors or transport proteins: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, leteribine, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, and darunavir. When co-administered with gemfibrozil and other fibric acid derivatives, boceprevir, erythromycin, niacin, and ezetimibe, telaprevir, or the combination of telaprevir/ritonavir, the risk of myopathy also increases. If possible, other medicinal products that do not interact with atorvastatin should be used instead of the aforementioned drugs.

If it is necessary to perform concomitant treatment with atorvastatin and the mentioned drugs, the benefit and risk should be carefully weighed. If patients are taking medicinal products that increase atorvastatin plasma levels, the dose of atorvastatin should be reduced to the minimum. Additionally, when potent CYP 3A4 inhibitors are used, the possibility of using a lower initial dose of atorvastatin should be considered. It is also recommended to perform appropriate clinical monitoring of these patients.

Atorvastatin should not be administered concomitantly with fusidic acid, which is used systemically, or within 7 days after the end of fusidic acid treatment. Statin therapy should be discontinued during the period of systemic fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients who received fusidic acid and statins in combination. Patients should be advised to promptly seek medical attention if they experience any symptoms of weakness, pain, or muscle tenderness.

Statin therapy can be resumed 7 days after the last dose of fusidic acid.

Under exceptional circumstances, when long-term systemic fusidic acid treatment is necessary, for example, for the treatment of severe infections, the need for concomitant administration of atorvastatin and fusidic acid should be considered on an individual basis and under close medical supervision.

Interstitial Lung Disease

Rare cases of interstitial lung disease have been described during treatment with some statins, particularly during long-term treatment. Symptoms of interstitial lung disease include dyspnea, non-productive cough, and general deterioration (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin treatment should be discontinued.

Lipid-Modifying Therapy

Lipid-modifying therapy should be one component of a comprehensive treatment program for patients with significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to diet, restriction of saturated fat and cholesterol, and other non-pharmacological measures has been inadequate. Patients with ischemic heart disease or at high risk of ischemic heart disease can start atorvastatin simultaneously with dietary measures.

Limitations of Use

Atorvastatin has not been studied in conditions where the primary abnormality is an elevation of chylomicrons (types I and V hyperlipoproteinemia according to the Fredrickson classification).

Myasthenia Gravis/Ocular Myasthenia

There have been rare reports of myasthenia gravis and exacerbation of existing myasthenia gravis following treatment with statins, including atorvastatin (see "Adverse reactions"). Treatment with the medicinal product Etset should be discontinued in the event of exacerbation of myasthenia gravis symptoms. Recurrences of the disease have been reported with the use of the same or different statins.

Excipients

The drug contains lactose. If you have been diagnosed with an intolerance to some sugars, consult your doctor before taking this medicinal product.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is essentially sodium-free.

Use During Pregnancy or Breastfeeding

Pregnancy

Risk assessment

Atorvastatin is contraindicated in pregnant women, as its safety in pregnant women has not been established, and there is no clear benefit to the use of lipid-lowering drugs during pregnancy. Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may cause harm to the fetus. Atorvastatin therapy should be discontinued as soon as pregnancy is recognized (see "Contraindications").

Background risk

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Contraception

Atorvastatin may cause harm to the fetus when administered to a pregnant woman. Women of childbearing potential should be advised to use effective contraception during treatment with this drug.

Clinical data

Limited published data on observational studies, meta-analyses, and case series with regard to the use of atorvastatin calcium in pregnant women do not show an increased risk of major congenital anomalies or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other HMG-CoA reductase inhibitors. A prospective observational study of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed that the incidence of congenital anomalies, miscarriages, and fetal deaths/stillbirths did not exceed that expected in the general population. The number of cases is sufficient to exclude a ≥ 3-4-fold increase in congenital anomalies compared to the background incidence. In 89% of pregnancies, treatment with the drug was initiated before pregnancy and was stopped during the first trimester after the pregnancy was detected.

Breastfeeding

Atorvastatin is contraindicated during breastfeeding. There is no information on the effect of the drug on the breastfed child or on lactation. It is not known whether atorvastatin is excreted in human milk; however, another drug in this class has been shown to be present in human milk. Because statins have the potential to cause serious adverse reactions in nursing infants, women who require atorvastatin treatment should not breastfeed their infants (see "Contraindications").

Ability to Affect the Speed of Reaction When Driving or Operating Other Mechanisms

Has a very minor effect on the speed of reaction when driving or operating other mechanisms.

Method of Application and Dosage

Hyperlipidemia and mixed dyslipidemia

The recommended initial dose of atorvastatin is 10 or 20 mg once a day. For patients who require significant reduction in LDL-C levels (more than 45%), therapy can be started at a dose of 40 mg once a day. The dose range of atorvastatin is from 10 to 80 mg once a day. The drug can be taken as a single dose at any time of the day and regardless of food intake. The initial and maintenance doses of atorvastatin should be selected individually, depending on the treatment goal and response. After starting treatment and/or after titrating the dose of atorvastatin, lipid levels should be analyzed within a period of 2 to 4 weeks and the dose adjusted accordingly.

Heterozygous familial hypercholesterolemia in pediatric patients (aged 10 to 17 years)

The recommended initial dose of atorvastatin is 10 mg/day, with a usual dose range of 10 to 20 mg orally once a day. The dose of the drug should be selected individually, according to the treatment goal. Dose adjustment should be done at intervals of 4 weeks or more.

Homogeneous familial hypercholesterolemia

The dose of atorvastatin for patients with homogeneous familial hypercholesterolemia is from 10 to 80 mg per day. Atorvastatin should be used as an adjunct to other hypolipidemic treatments (e.g., LDL apheresis) or if hypolipidemic treatments are not available.

Concomitant hypolipidemic therapy

Atorvastatin can be administered with bile acid sequestrants. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections "Special Instructions" and "Interactions with Other Medicinal Products and Other Forms of Interaction").

Dosing for patients with renal impairment

Kidney disease does not affect either plasma concentrations or LDL-C reduction when using atorvastatin; therefore, dose adjustment for patients with renal impairment is not required (see sections "Special Instructions" and "Pharmacokinetics").

Dosing for patients taking cyclosporine, clarithromycin, itraconazole, letermovir, or certain protease inhibitors

Treatment with atorvastatin should be avoided in patients taking cyclosporine or HIV protease inhibitor tipranavir/ritonavir, or hepatitis C protease inhibitor glecaprevir/pibrentasvir, or letermovir when co-administered with cyclosporine. Patients with HIV taking lopinavir/ritonavir should take atorvastatin at the lowest necessary dose. Patients taking clarithromycin, itraconazole, elbasvir/grazoprevir, or patients with HIV taking combinations of saquinavir/ritonavir, darunavir/ritonavir, or fosamprenavir, fosamprenavir/ritonavir, or letermovir, the therapeutic dose of atorvastatin should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure the use of the lowest necessary dose of atorvastatin. Patients taking HIV protease inhibitor nelfinavir should limit atorvastatin treatment to a dose of 40 mg (see sections "Special Instructions" and "Interactions with Other Medicinal Products and Other Forms of Interaction").

Children

Heterozygous familial hypercholesterolemia

The safety and efficacy of atorvastatin have been established in children aged 10 to 17 years with heterozygous familial hypercholesterolemia as an adjunct to diet to reduce total cholesterol, LDL-C, and apolipoprotein B levels when, after an adequate trial of diet therapy, the following are present:

• LDL-C ≥ 190 mg/dL (4.91 mmol/L) or
• LDL-C ≥ 160 mg/dL (4.14 mmol/L) and
• a family history of premature cardiovascular disease or
• two or more other risk factors for cardiovascular disease.

The indication for atorvastatin is supported by evidence from:

• A 6-month placebo-controlled clinical trial involving 187 boys and postmenarchal girls aged 10 to 17 years. Patients who received atorvastatin at a dose of 10 mg or 20 mg daily had an adverse reaction profile similar to that of patients who received placebo. In this limited controlled trial, no significant effect on growth or sexual maturation in boys or on the duration of the menstrual cycle in girls was observed.
• A 3-year open-label uncontrolled trial involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia, for whom the dose was titrated to achieve an LDL-C level < 130 mg/dL (3.36 mmol/L). The safety and efficacy of atorvastatin in lowering LDL-C were generally consistent with those observed in adult patients, despite the limitations of an open-label uncontrolled design.

Girls should be advised on contraception if appropriate for the patient.

The long-term efficacy of atorvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

The safety and efficacy of atorvastatin have not been established in children under 10 years of age with heterozygous familial hypercholesterolemia.

Homogeneous familial hypercholesterolemia

The clinical efficacy of the drug at doses up to 80 mg/day for 1 year was evaluated in an uncontrolled study in patients with homogeneous familial hypercholesterolemia, which included 8 children.

Overdose

There is no specific treatment for atorvastatin overdose. In the event of an overdose, the patient should be treated symptomatically and, if necessary, supportive measures should be applied. Due to the high degree of binding of the drug to plasma proteins, it is not expected that the clearance of atorvastatin will be significantly enhanced by hemodialysis.

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

According to data from clinical trials of atorvastatin, among 16,066 patients (8,755 received atorvastatin and 7,311 received placebo; age range 10-93 years, 39% women, 91% Caucasian, 3% African American, 2% Asian, and 4% other), with a median treatment duration of 53 weeks, 9.7% of patients who received atorvastatin and 9.5% of patients who received placebo discontinued treatment due to adverse reactions, regardless of causality.

The five most common adverse reactions in patients who received atorvastatin that led to discontinuation of atorvastatin and occurred at a frequency greater than placebo were myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), elevated alanine transaminase (ALT) (0.4%), and elevated liver enzymes (0.4%).

In patients who received atorvastatin in placebo-controlled trials (n = 8,755), the most common adverse reactions (incidence ≥ 2% and greater than placebo), regardless of causality, were:

In Table 6, the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% of patients and at a greater frequency than placebo, in patients who received atorvastatin (n = 8,755), from 17 placebo-controlled trials.

* Adverse reaction > 2% in any dose, more than placebo

Other adverse reactions reported during clinical trials include:

• General disorders: malaise, pyrexia.
• Gastrointestinal disorders: gastrointestinal discomfort, eructation, flatulence, hepatitis, cholestasis.
• Musculoskeletal and connective tissue disorders: musculoskeletal pain, muscle fatigue, neck pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture).
• Metabolism and nutrition disorders: elevated transaminases, abnormal liver function tests, elevated alkaline phosphatase, elevated creatine phosphokinase, hyperglycemia.
• Nervous system disorders: nightmares.
• Respiratory, thoracic, and mediastinal disorders: epistaxis.
• Skin and subcutaneous tissue disorders: urticaria.
• Eyes: blurred vision, visual disturbance.
• Ears and labyrinth: tinnitus.
• Urinary system: leukocyturia.
• Reproductive system and breast disorders: gynecomastia.

All adverse reactions are classified by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Nervous system disorders: common - headache; uncommon - dizziness, paresthesia, hypesthesia, dysgeusia, amnesia; rare - peripheral neuropathy.

Gastrointestinal disorders: common - constipation; uncommon - pancreatitis, vomiting.

Musculoskeletal and connective tissue disorders: common - joint pain, back pain; rare - myopathy, myositis, rhabdomyolysis.

General disorders: uncommon - asthenia, chest pain, peripheral edema, fatigue.

Metabolic and nutritional disorders: uncommon - hypoglycemia, weight gain, anorexia.

Hepatobiliary disorders: very rare - liver failure.

Skin and subcutaneous tissue disorders: uncommon - skin rash, pruritus, alopecia; rare - angioedema, bullous dermatitis (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), lichenoid drug reaction.

Respiratory system disorders: common - throat and larynx pain.

Blood and lymphatic system disorders: rare - thrombocytopenia.

Vascular disorders: rare - vasculitis.

Immune system disorders: common - allergic reactions; very rare - anaphylaxis.

Eyes: uncommon - blurred vision.

Laboratory findings: common - abnormal liver function tests, elevated creatine phosphokinase; uncommon - positive urine test for leukocytes.

As with other HMG-CoA reductase inhibitors, elevations in serum transaminases have been reported with atorvastatin. These changes were usually mild, transient, and did not require interruption or discontinuation of treatment. Clinically significant elevations in serum transaminases (> 3 times the upper limit of normal) were observed in 0.8% of patients who received atorvastatin. This elevation was dose-dependent and reversible in all patients.

In 2.5% of patients who received atorvastatin, elevations in serum creatine kinase (CK) > 3 times the upper limit of normal were observed. This is consistent with observations with other HMG-CoA reductase inhibitors in clinical trials. In 0.4% of patients who received atorvastatin, CK levels > 10 times the upper limit of normal were observed.

Adverse reactions reported during post-marketing experience with atorvastatin include: urinary tract infection, diabetes mellitus.

In the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) involving 10,305 participants (age range 40-80 years, 19% women; 94.6% Caucasian, 2.6% African American, 2.6% South Asian, and 1.3% other), who received atorvastatin 10 mg/day (n = 5,168) or placebo (n = 5,137), the safety profile and tolerability of atorvastatin in patients who received atorvastatin were comparable to those in the placebo group over a median follow-up period of 3.3 years.

In the CARDS (Collaborative Atorvastatin Diabetes Study) involving 2,838 patients (age range 39-77 years, 32% women; 94.3% Caucasian, 2.4% South Asian, 2.3% Afro-Caribbean, and 1% other) with type 2 diabetes, who received atorvastatin 10 mg/day (n = 1,428) or placebo (n = 1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 3.9 years.

In the TNT (Treating to New Targets Study) involving 10,001 patients (age range 29-78 years, 19% women; 94.1% Caucasian, 2.9% African American, 1% Asian, and 2% other) with clinically evident coronary heart disease, who received atorvastatin 10 mg/day (n = 5,006) or atorvastatin 80 mg/day (n = 4,995), more serious adverse reactions and discontinuations due to adverse reactions were observed in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) compared to the low-dose atorvastatin group (69, 1.4%; 404, 8.1%, respectively) over a median follow-up period of 4.9 years. Persistent elevations in liver transaminases (> 3 times the upper limit of normal on two consecutive occasions 4-10 days apart) were observed in 62 (1.3%) patients who received atorvastatin 80 mg and in 9 (0.2%) patients who received atorvastatin 10 mg. Elevations in CK (> 10 times the upper limit of normal) were rare but were more frequent in the high-dose atorvastatin group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).

In the IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study) involving 8,888 patients (age range 26-80 years, 19% women; 99.3% Caucasian, 0.4% Asian, 0.3% African American, and 0.04% other), who received atorvastatin 80 mg/day (n = 4,439) or simvastatin 20-40 mg/day (n = 4,449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 4.8 years.

In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) involving 4,731 patients (age range 21-92 years, 40% women; 93.3% Caucasian, 3% African American, 0.6% Asian, and 3.1% other) without clinically evident coronary heart disease but with a history of stroke or transient ischemic attack (TIA) within the previous 6 months, who received atorvastatin 80 mg (n = 2,365) or placebo (n = 2,366), over a median follow-up period of 4.9 years, a higher frequency of persistent elevations in liver transaminases (> 3 times the upper limit of normal on two consecutive occasions 4-10 days apart) was observed in the atorvastatin group (0.9%) compared to the placebo group (0.1%). Elevations in CK (> 10 times the upper limit of normal) were rare but were more frequent in the atorvastatin group (0.1%) compared to the placebo group (0%). Diabetes mellitus was reported as an adverse reaction in 144 patients (6.1%) in the atorvastatin group and in 89 patients (3.8%) in the placebo group (see section "Special Instructions").

In a post-hoc analysis, atorvastatin 80 mg reduced the frequency of ischemic stroke (218 of 2,365, 9.2%, vs 274 of 2,366, 11.6%) and increased the frequency of hemorrhagic stroke (55 of 2,365, 2.3%, vs 33 of 2,366, 1.4%) compared to placebo. The frequency of fatal hemorrhagic stroke was similar between groups (17 in the atorvastatin group vs 18 in the placebo group). The frequency of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38 non-fatal hemorrhagic strokes) compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the study with a hemorrhagic stroke in their medical history had an increased risk of hemorrhagic stroke (7 [16%] atorvastatin vs 2 [4%] placebo).

No significant differences between treatment groups in mortality from all causes were observed: 216 (9.1%) in the atorvastatin 80 mg/day group vs 211 (8.9%) in the placebo group. The proportion of patients who died from cardiovascular causes was numerically smaller in the atorvastatin 80 mg/day group (3.3%) compared to the placebo group (4.1%). The proportion of patients who died from non-cardiovascular causes was numerically higher in the atorvastatin 80 mg/day group (5.0%) compared to the placebo group (4.0%).

Adverse reactions during clinical trials of atorvastatin in children

In a 26-week controlled trial in boys and postmenarchal girls with heterozygous familial hypercholesterolemia (aged 10 to 17 years) (n = 140, 31% female; 92% Caucasian, 1.6% African American, 1.6% Asian, and 4.8% other), the safety and tolerability profile of atorvastatin at doses of 10 to 20 mg/day as an adjunct to diet to reduce total cholesterol, LDL-C, and apolipoprotein B levels was generally similar to that of placebo.

Post-Marketing Experience

During post-marketing use of atorvastatin, the following adverse reactions have been reported. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions associated with atorvastatin treatment, reported voluntarily during post-marketing experience, regardless of causality assessment, include: anaphylaxis, angioedema, bullous dermatitis (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myopathy, muscle fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis, and interstitial lung disease.

Rare reports of immune-mediated necrotizing myopathy associated with statin use have been received (see section "Special Instructions").

Rare post-marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive adverse reactions were generally not serious and were reversible upon statin discontinuation, with variable times to symptom onset (range from 1 day to years) and symptom resolution (median time to resolution 3 weeks).

Other adverse reactions reported during post-marketing surveillance include:

• Blood and lymphatic system disorders: thrombocytopenia.
• Immune system disorders: allergic reactions, anaphylaxis (including anaphylactic shock).
• Metabolism and nutrition disorders: weight gain.
• Nervous system disorders: headache, hypesthesia, dysgeusia, myasthenia gravis.
• Gastrointestinal disorders: abdominal pain.
• Ears and labyrinth disorders: tinnitus.
• Eyes: eye myasthenia.
• Skin and subcutaneous tissue disorders: urticaria.
• Musculoskeletal and connective tissue disorders: arthralgia, back pain.
• General disorders: chest pain, peripheral edema, malaise, fatigue.
• Laboratory findings: elevated alanine transaminase, elevated creatine phosphokinase.

Reporting of Adverse Reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals, patients, or their representatives should report any suspected adverse reactions via the automated information system for pharmacovigilance at https://aisf.dec.gov.ua.

Shelf Life

3 years.

Storage Conditions

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of the reach of children.

Packaging

14 tablets in blisters; 2, 4, or 6 blisters in a carton.

Prescription Status

Prescription only.

Manufacturer

TOV "KUSUM PHARM".

Manufacturer's Address

40020, Ukraine, Sumy region, Sumy, Skryabina street, 54.