INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATOVAKOR® (ATORVAKOR)

Composition:

Active substance: atorvastatin;

One tablet contains 10.82 mg or 21.64 mg or 43.28 mg or 86.56 mg of atorvastatin calcium, calculated as 100% substance (equivalent to atorvastatin) 10 mg or 20 mg or 40 mg or 80 mg;

Excipients: calcium carbonate; lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; polysorbate 80; hydroxypropylcellulose; magnesium stearate; Opadry II 85F18422 white (polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex film-coated tablets.

Pharmacotherapeutic group. Agents lowering serum cholesterol and triglycerides. HMG-CoA reductase inhibitors. ATC code C10AA05.

Pharmacological properties.

Pharmacodynamics.

Atorvакor® is a synthetic hypolipidemic medicinal product. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). This enzyme catalyzes the conversion of HMG-CoA to mevalonate—the initial and rate-limiting step in cholesterol biosynthesis.

Atorvакor® is a selective competitive inhibitor of HMG-CoA reductase—the enzyme responsible for the rate-limiting step in the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

In animal experimental models, atorvastatin reduces plasma cholesterol and lipoprotein levels by inhibiting hepatic HMG-CoA reductase and cholesterol synthesis, and by increasing the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, thereby enhancing the uptake and catabolism of LDL; atorvastatin also reduces the production of LDL and the number of LDL particles.

Atorvastatin, as well as some of its metabolites, is pharmacologically active in humans. The primary site of action of atorvastatin is the liver, which plays a central role in cholesterol synthesis and LDL clearance. The dose of the medicinal product correlates better with the reduction in LDL-C levels than the systemic concentration of the drug. Dose titration should be based on therapeutic response (see section "Dosage and administration").

Pharmacokinetics.

Absorption. Atorvastatin is rapidly absorbed after oral administration. Maximum plasma concentration (Cmax) is reached within 1–2 hours. The extent of absorption increases proportionally with dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14%, while the systemic bioavailability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability of the drug is attributed to pre-systemic clearance in the gastrointestinal mucosa and/or pre-systemic biotransformation in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, based on Cmax and AUC (area under the concentration-time curve), the reduction in LDL-C levels is similar regardless of whether atorvastatin is taken with food or separately. When atorvastatin is administered in the evening, its plasma concentration is lower (approximately 30% for both Cmax and AUC) compared to administration in the morning. However, the reduction in LDL-C levels is equivalent regardless of the time of administration (see section "Dosage and administration").

Distribution. The mean volume of distribution of atorvastatin is approximately 381 liters. Over 98% of the drug is bound to plasma proteins. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes. Based on animal studies, atorvastatin is expected to penetrate into human breast milk (see sections "Contraindications" and "Special precautions").

Metabolism. Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro studies show that the HMG-CoA reductase inhibition by ortho- and para-hydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating HMG-CoA reductase inhibitory activity is attributed to active metabolites. In vitro studies indicate that metabolism of atorvastatin by cytochrome P450 3A4 (CYP3A4) is significant, consistent with increased plasma concentrations of atorvastatin in humans when co-administered with erythromycin, a known inhibitor of this isoenzyme (see section "Interaction with other medicinal products and other forms of interaction").

Excretion. Atorvastatin and its metabolites are primarily eliminated via bile following hepatic and/or extrahepatic metabolism; however, this drug does not appear to undergo enterohepatic recirculation. The mean elimination half-life of atorvastatin in human plasma is approximately 14 hours, while the half-life of HMG-CoA reductase inhibitory activity ranges from 20 to 30 hours due to the contribution of active metabolites. Less than 2% of the dose is excreted in urine after oral administration.

Special patient populations

Elderly patients. Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly volunteers (aged 65 years and older) compared to younger adults. Clinical data indicate a greater degree of LDL reduction with any dose of the drug in elderly patients compared to younger patients (see section "Special precautions").

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

Gender. Plasma concentrations of atorvastatin in women differ from those in men (Cmax approximately 20% higher and AUC 10% lower). However, there is no clinically significant difference in LDL-C reduction between men and women when treated with atorvastatin.

Renal impairment. Renal disease does not affect plasma concentrations of atorvastatin or the reduction in LDL-C; therefore, dose adjustment in patients with renal impairment is not required (see sections "Special precautions" and "Dosage and administration").

Hemodialysis. Although studies in patients with end-stage renal disease have not been conducted, hemodialysis is not expected to significantly enhance the clearance of atorvastatin due to its extensive plasma protein binding.

Hepatic impairment. Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease. Cmax and AUC values are 4-fold higher in patients with Child-Pugh class A liver disease. In patients with Child-Pugh class B liver disease, Cmax and AUC values are increased approximately 16-fold and 11-fold, respectively (see section "Contraindications").

Drug interaction studies. Atorvastatin is a substrate of hepatic transporters OATP1B1 and OATP1B3. 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 intestinal absorption and biliary clearance of atorvastatin.

Table 1

Effect of concomitantly administered medicinal products on the pharmacokinetics of atorvastatin

& Comparison by treatment methods (concomitant use of the medicinal product with atorvastatin compared to atorvastatin used alone).

For information on clinical relevance, see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use".

* Increased 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 L per day or more).

** Ratios based on single samples taken 8–16 hours after dose administration.

† Due to the dual interaction mechanism of rifampicin, concomitant administration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after rifampicin has been shown to result in a significant decrease in plasma concentrations of atorvastatin.

‡ The dose of the saquinavir + ritonavir combination used in this study is not the clinically recommended dose. The increase in atorvastatin exposure under clinical conditions is likely to be higher than that observed in this study. Therefore, the medicinal product should be used with caution at the lowest necessary dose.

Table 2

Effect of atorvastatin on the pharmacokinetics of concomitantly administered medicinal products

For clinical significance, see section "Interaction with other medicinal products and other forms of interaction".

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases in adults

For adult patients without clinically evident ischemic heart disease but with multiple risk factors for developing ischemic heart disease, such as age, tobacco smoking, arterial hypertension, low levels of high-density lipoprotein (HDL) or a family history of premature ischemic heart disease, Atorvакor® 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 evident ischemic heart disease, but with multiple risk factors for developing ischemic heart disease, such as retinopathy, albuminuria, smoking, or arterial hypertension, the medicinal product Atorvакor® is indicated for:

• reducing the risk of myocardial infarction;
• reducing the risk of stroke.

For adult patients with clinically evident ischemic heart disease, Atorvакor® 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, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglyceride levels, and to increase high-density lipoprotein cholesterol (HDL-C) levels in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification).
• As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (type IV according to Fredrickson classification).
• For the treatment of patients with primary dysbetalipoproteinemia (type III according to Fredrickson classification) when dietary management is insufficiently effective.
• To reduce total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering therapies (such as LDL apheresis) or when such therapies are unavailable.

In children

• As an adjunct to diet to reduce total cholesterol, LDL-C, and apolipoprotein B levels in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy the following criteria are met:

a) LDL-C remains ≥ 190 mg/dL (4.91 mmol/L), or

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

• a family history of premature cardiovascular disease, or
• two or more other cardiovascular risk factors are present

in the pediatric patient.

Contraindications.

• Active liver disease, which may include persistent elevations of serum transaminases of unknown etiology.
• Hypersensitivity to any component of this medicinal product.
• Pregnancy and breastfeeding.
• Concomitant use with the antiviral hepatitis C agents glecaprevir/pibrentasvir.

Interaction with other medicinal products and other forms of interaction.

The risk of developing myopathy during statin therapy is increased when co-administered with fibrates, lipid-modifying doses of niacin, cyclosporine, or potent inhibitors of cytochrome P450 3A4 (CYP3A4) (e.g., clarithromycin, HIV and hepatitis C virus protease inhibitors, and itraconazole) (see sections "Pharmacological properties" and "Special precautions for use").

Potent CYP3A4 inhibitors. Atorvакor® is metabolized by cytochrome P450 3A4. Concomitant use of Atorvакor® with potent CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see Table 1 and detailed information below). The extent of interaction and effect enhancement depends on the impact on CYP3A4. Concomitant use of atorvastatin with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for HCV treatment (e.g., elbasvir/grazoprevir), and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided if possible. If concomitant use with these medicinal products cannot be avoided, consideration should be given to using a lower initial and maximum dose of atorvastatin. Appropriate clinical monitoring of the patient is also recommended (see Table 1).

Moderate CYP3A4 inhibitors (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase atorvastatin plasma concentrations (see Table 1). Concomitant use of erythromycin and statins is associated with an increased risk of myopathy. Drug interaction studies assessing the effect of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil are known to inhibit CYP3A4 activity; therefore, concomitant use of these medicinal products with atorvastatin may lead to increased atorvastatin exposure. Thus, when atorvastatin is used concomitantly with these moderate CYP3A4 inhibitors, consideration should be given to using lower maximum doses of atorvastatin and clinical monitoring of the patient. Clinical monitoring is also recommended after initiating treatment with an inhibitor or adjusting its dose.

Grapefruit juice. Contains one or more components that inhibit CYP3A4 and may increase atorvastatin plasma concentration, especially with excessive consumption of grapefruit juice (more than 1.2 liters per day).

Clarithromycin. The AUC of atorvastatin was significantly increased when administered concomitantly at a dose of 80 mg with clarithromycin (500 mg twice daily) compared to atorvastatin alone (see section "Pharmacological properties"). Therefore, patients taking clarithromycin should use Atorvакor® with caution at doses exceeding 20 mg (see sections "Special precautions for use" and "Dosage and administration").

Combination of protease inhibitors. The AUC of atorvastatin was significantly increased when administered concomitantly with several combinations of protease inhibitors (see section "Pharmacological properties"). Patients taking tipranavir + ritonavir or glecaprevir + pibrentasvir should avoid concomitant use of Atorvакor®. Patients taking lopinavir + ritonavir or simeprevir should receive Atorvакor® at the lowest necessary dose. For patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, or elbasvir + grazoprevir, the dose of Atorvакor® should not exceed 20 mg. For patients taking nelfinavir, the dose of Atorvакor® should not exceed 40 mg, and careful clinical monitoring of patients is also recommended (see sections "Special precautions for use" and "Dosage and administration").

Itraconazole. The AUC of atorvastatin was significantly increased when atorvastatin 40 mg was administered concomitantly with itraconazole 200 mg (see section "Pharmacological properties"). Therefore, caution should be exercised in patients taking itraconazole if the atorvastatin dose exceeds 20 mg (see sections "Special precautions for use" and "Dosage and administration").

Cyclosporine. Atorvastatin is a substrate of hepatic transporters. Atorvastatin metabolites are substrates of the OATP1B1 transporter. Inhibitors of OATP1B1 (e.g., cyclosporine) may increase the bioavailability of atorvastatin. The AUC of atorvastatin was significantly increased when the medicinal product was administered at a dose of 10 mg with cyclosporine at 5.2 mg/kg/day compared to atorvastatin alone (see section "Pharmacological properties"). Concomitant use of Atorvакor® and cyclosporine should be avoided (see section "Special precautions for use").

Letermovir. Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased exposure to atorvastatin (AUC ratio: 3.29) (see section "Pharmacokinetics").

Letermovir is an inhibitor of efflux transporters P-gp, BCRP, MRP2, OAT2, and the hepatic transporter OATP1B1/1B3, thereby increasing atorvastatin exposure. The dose of Atorvакor® should not exceed 20 mg daily (see section "Dosage and administration").

The extent of CYP3A- and OATP1B1/1B3-mediated drug interactions may vary when letermovir is coadministered with cyclosporine. Use of Atorvакor® is not recommended in patients taking letermovir concomitantly with cyclosporine.

Glecaprevir and pibrentasvir, elbasvir and grazoprevir. Concomitant use of glecaprevir and pibrentasvir or elbasvir and grazoprevir may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy.

When glecaprevir and pibrentasvir are used concomitantly with atorvastatin, plasma concentrations of atorvastatin may increase up to 8.3-fold, partly due to inhibition of BCRP, OATP1B1/1B3, and CYP3A. Therefore, concomitant use of Atorvакor® is not recommended in patients receiving medicinal products containing glecaprevir and pibrentasvir.

When elbasvir and grazoprevir are used concomitantly with atorvastatin, plasma concentrations of atorvastatin may increase up to 1.9-fold, partly due to inhibition of BCRP, OATP1B1/1B3, and CYP3A. Therefore, the dose of Atorvакor® should not exceed 20 mg daily in patients receiving medicinal products containing elbasvir and grazoprevir (see sections "Pharmacokinetics", "Special precautions for use", and "Dosage and administration").

Medical recommendations for the use of interacting medicinal products are provided in Table 3 (see also sections "Pharmacological properties", "Special precautions for use", and "Dosage and administration").

Table 3

Drug interactions associated with an increased risk of myopathy/rhabdomyolysis

*Use the lowest necessary dose.

Gemfibrozil. Due to the increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are used concomitantly with gemfibrozil, combination therapy of Atorvachor® with gemfibrozil should be avoided (see section "Special precautions").

Other fibrates. Since it is known that the risk of developing myopathy during treatment with HMG-CoA reductase inhibitors increases when other fibrates are used concomitantly, Atorvachor® should be used with caution in combination with other fibrates (see section "Special precautions").

Niacin. The risk of adverse effects on skeletal muscles increases when the medicinal product Atorvachor® is used in combination with niacin; therefore, dose reduction of this medicinal product should be considered under such conditions (see section "Special precautions").

Rifampicin or other cytochrome P450 3A4 inducers. Concomitant use of the drug with inducers of cytochrome P450 3A4 (such as efavirenz, rifampicin) may lead to unstable reduction in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, simultaneous administration of Atorvachor® with rifampicin is recommended, as delayed administration of the drug after rifampicin intake has been shown to be associated with a significant decrease in plasma atorvastatin concentrations.

Diltiazem hydrochloride. Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) results in increased plasma concentrations of atorvastatin.

Cimetidine. No signs of interaction between atorvastatin and cimetidine were observed during studies.

Antacids. Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxide is associated with approximately a 35% reduction in atorvastatin plasma concentration. However, the hypolipidemic effect of atorvastatin was not altered.

Colestipol. Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when atorvastatin and colestipol were administered together. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded the effect achieved by administration of each of these drugs separately.

Azithromycin. Concomitant administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not associated with changes in atorvastatin plasma concentrations.

Transport inhibitors. Inhibitors of transport proteins (e.g., cyclosporine, letermovir) can increase systemic exposure to atorvastatin (see Table 1). The effect of inhibition of uptake transporters on atorvastatin concentrations in liver cells is unknown. If concomitant administration of these drugs cannot be avoided, dose reduction is recommended, along with clinical monitoring of atorvastatin efficacy (see Table 1).

Ezetimibe. Use of ezetimibe as monotherapy has been associated with muscle-related adverse effects, including rhabdomyolysis. Therefore, when ezetimibe is used concomitantly with atorvastatin, the risk of such effects increases. Appropriate clinical monitoring of these patients is recommended.

Fusidic acid. Concomitant systemic use of fusidic acid with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic, pharmacokinetic, or both) remains unknown. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination.

If systemic use of fusidic acid is necessary, atorvastatin should be discontinued for the entire duration of fusidic acid treatment (see section "Special precautions").

Digoxin. When multiple doses of Atorvachor® and digoxin are used concomitantly, steady-state digoxin plasma concentrations increase (see section "Pharmacokinetics"). Patients receiving digoxin should be appropriately monitored.

Oral contraceptives. Concomitant use of atorvastatin with oral contraceptives increases AUC values for norethisterone and ethinylestradiol (see section "Pharmacological properties"). This increase should be taken into account when selecting an oral contraceptive for women taking Atorvachor®.

Warfarin. Atorvachor® did not exert clinically significant effects on prothrombin time in patients receiving long-term warfarin therapy.

Colchicine. Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine; therefore, atorvastatin should be prescribed with caution together with colchicine.

Daptomycin. Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin. If concomitant use cannot be avoided, appropriate clinical monitoring is recommended (see section "Special precautions").

Other medicinal products. Clinical studies have shown that concomitant use of atorvastatin with antihypertensive agents and its use during estrogen replacement therapy are not associated with clinically significant adverse effects. Interactions with other medicinal products have not been studied.

Special precautions for use.

Muscle

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and other drugs in this class. A history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients require closer monitoring for skeletal muscle effects.

Atorvastatin, like other statin drugs, occasionally causes myopathy, defined as muscle pain or weakness accompanied by elevated creatine phosphokinase (CPK) levels more than 10 times the upper limit of normal. Concomitant use of higher doses of atorvastatin with certain medicinal products, such as cyclosporine and potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors, and hepatitis C virus protease inhibitors), increases the risk of myopathy/rhabdomyolysis.

Rare post-marketing reports of immune-mediated necrotizing myopathy (IMNM)—an autoimmune myopathy associated with statin use—have been reported. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy; muscle biopsy reveals necrotizing myopathy without significant inflammation; and a positive response to immunosuppressive therapy is observed.

The possibility of myopathy should be considered in any patient presenting with diffuse myalgia, muscle tenderness or weakness, and/or markedly elevated CPK. Patients should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever, or if muscle symptoms persist after discontinuation of AtorvAcor®. Treatment should be discontinued in cases of markedly elevated CPK levels, or if myopathy is diagnosed or suspected.

The risk of myopathy during treatment with statins increases with concomitant use of the medicinal products listed in Table 3. Physicians considering combination therapy with AtorvAcor® and any of these agents should carefully weigh the potential benefits and risks and closely monitor patients for any symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during dose titration periods. Consideration should be given to using lower starting and maintenance doses of atorvastatin when coadministered with the aforementioned medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). In such situations, periodic CPK monitoring may be considered, although there is no guarantee that such monitoring will prevent severe myopathy.

Treatment with AtorvAcor® should be temporarily suspended or permanently discontinued in any patient with an acute, serious condition indicating the development of myopathy, or in the presence of a risk factor for renal failure due to rhabdomyolysis (e.g., severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, or uncontrolled seizures).

Hepatic function

Statins, like some other lipid-lowering agents, have been associated with abnormalities in liver function tests. Persistent elevations (more than three times the upper limit of normal, occurring on two or more occasions) in serum transaminases were observed in 0.7% of patients receiving atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for doses of 10 mg, 20 mg, 40 mg, and 80 mg, respectively.

During clinical trials, one patient developed jaundice. Elevated liver function test (LFT) values in other patients were not associated with jaundice or other clinical symptoms. Transaminase levels returned to pre-treatment or near pre-treatment levels after dose reduction, interruption, or discontinuation of the drug, without adverse consequences. Eighteen of 30 patients with persistent elevations in LFTs continued atorvastatin at lower doses.

Prior to initiating AtorvAcor®, liver enzyme tests should be obtained and repeated as clinically indicated. Rare post-marketing reports of fatal and non-fatal hepatic failure have been reported in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with AtorvAcor®, treatment must be immediately discontinued. Reinitiation of therapy should not be considered unless an alternative etiology is identified.

AtorvAcor® should be prescribed with caution in patients who consume alcohol excessively and/or have a history of liver disease. The medicinal product is contraindicated in active liver disease or persistent elevations of hepatic transaminases of unknown etiology (see section "Contraindications").

Endocrine function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.

Statins inhibit cholesterol synthesis and may theoretically reduce adrenal and/or gonadal steroid secretion. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effect of statins on sperm fertility has not been adequately studied. It is unknown whether the drug affects or has any effect on the hypothalamic-pituitary-gonadal axis in premenopausal women. Caution should be exercised when coadministering statins with medicinal products that may reduce the level 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 (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, in which 4731 patients without ischemic heart disease and with a history of stroke or transient ischemic attack within the previous 6 months received atorvastatin 80 mg versus placebo, a higher incidence of hemorrhagic stroke was observed in the atorvastatin group compared to the placebo group (55 cases, 2.3% in the atorvastatin group vs. 33 cases, 1.4% in the placebo group; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 and 18 in the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) compared to the placebo group (16, 0.7%). Certain baseline characteristics, including a history of hemorrhagic and lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group (see section "Adverse reactions").

Among 39,828 patients receiving atorvastatin in clinical trials, 15,813 (40%) were aged 65 years or older, and 2,800 (7%) were aged 75 years or older. No overall differences in safety and efficacy were observed between these patients and younger patients, nor were there differences in treatment response according to other clinical experience; however, increased sensitivity in some elderly patients cannot be ruled out. Since patients aged 65 years and older are more prone to myopathy, AtorvAcor® should be prescribed with caution in this population.

Hepatic impairment

AtorvAcor® is contraindicated in patients with active liver disease, including persistent elevations of hepatic transaminases of unknown etiology (see sections "Pharmacological properties" and "Contraindications").

Before starting treatment

Atorvastatin should be prescribed with caution in patients predisposed to rhabdomyolysis. Prior to initiating statin therapy in patients predisposed to rhabdomyolysis, creatine kinase (CK) levels should be measured in the following cases:

• renal impairment;
• hypothyroidism;
• personal or family history of hereditary muscle disorders;
• previous history of statin- or fibrate-induced myotoxicity;
• previous history of liver disease and/or alcohol abuse.

For elderly patients (aged 70 years or older), the need for these measures should be evaluated considering the presence of other risk factors for rhabdomyolysis.

Increased plasma levels of the drug may occur, particularly due to drug interactions (see section "Interaction with other medicinal products and other forms of interaction") and in specific patient populations, including those with hereditary disorders.

In such cases, the risk-benefit ratio of treatment should be carefully evaluated, and clinical monitoring of patients is recommended. If CK levels are markedly elevated (more than five times the upper limit of normal [ULN]) prior to treatment initiation, therapy should not be started.

Measurement of creatine kinase levels

CK levels should not be measured after strenuous physical exertion or in the presence of any other possible alternative causes of elevated CK, as this may complicate interpretation of results. If baseline CK levels are markedly elevated (exceeding ULN by more than five times), repeat measurement should be performed after 5–7 days to confirm the result.

During treatment

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

If these symptoms occur during atorvastatin therapy, CK levels should be measured. If CK levels are markedly elevated (exceeding ULN by more than five times), treatment should be discontinued.

Discontinuation of therapy should also be considered if CK elevation does not exceed five times ULN, but muscle symptoms are severe and cause daily discomfort.

After symptom resolution and normalization of CK levels, reinitiation of atorvastatin therapy or initiation of an alternative statin may be considered, using the lowest possible dose and with close patient monitoring.

Atorvastatin therapy must be discontinued if clinically significant elevation of CK (exceeding ULN by more than 10 times) is observed or if rhabdomyolysis is diagnosed or suspected.

Concomitant use with other medicinal products

The risk of rhabdomyolysis increases with concomitant use of atorvastatin and certain medicinal products that may increase atorvastatin plasma concentrations. Examples include potent CYP3A4 or transporter protein inhibitors: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibrates, boceprevir, erythromycin, niacin, ezetimibe, telaprevir, or the telaprevir/ritonavir combination. Where possible, alternative medicinal products (not interacting with atorvastatin) should be used instead of the above.

If concomitant therapy with atorvastatin and these agents is necessary, the benefits and risks of such treatment should be carefully weighed. If patients are taking medicinal products that increase atorvastatin plasma concentrations, it is recommended to reduce the atorvastatin dose to the minimum. Additionally, when using potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered. Appropriate clinical monitoring of these patients is also recommended.

Atorvastatin must not be coadministered with systemic fusidic acid or within 7 days of stopping fusidic acid treatment. In patients for whom systemic fusidic acid is considered necessary, statin therapy should be suspended for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis, including fatal cases, have been reported in patients receiving fusidic acid and statins concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness.

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

Under exceptional circumstances, when long-term systemic fusidic acid treatment is required (e.g., for severe infections), the need for concomitant use of AtorvAcor® and fusidic acid should be considered on an individual basis and under strict medical supervision.

Interstitial lung disease

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

Excipients

AtorvAcor® contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

AtorvAcor® contains less than 1 mmol sodium per dose, i.e., essentially "sodium-free."

Lipid-modifying therapy should be one component of comprehensive treatment for patients at significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Pharmacological therapy is recommended as an adjunct to diet when dietary restriction of saturated fats and cholesterol and other non-pharmacological measures have not been sufficient. In patients with ischemic heart disease or multiple risk factors for ischemic heart disease, AtorvAcor® may be initiated concurrently with dietary therapy.

The risk of myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Consideration should be given to temporarily suspending AtorvAcor® in patients receiving daptomycin, unless the benefit outweighs the risk. If concomitant use cannot be avoided, CK levels should be monitored 2–3 times per week, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.

Use limitations

AtorvAcor® has not been studied in conditions where the primary lipoprotein abnormality is elevated chylomicrons (Fredrickson types I and V).

In isolated cases, statins have been reported to induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, AtorvAcor® should be discontinued. Recurrences have been reported upon rechallenge with the same or another statin.

Use during pregnancy or breastfeeding.

Pregnancy

AtorvAcor® is contraindicated in pregnant women, as safety during pregnancy has not been established and there is no clear benefit of lipid-lowering agents during pregnancy. Since HMG-CoA reductase inhibitors reduce cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, AtorvAcor® may be harmful to the fetus. AtorvAcor® should be discontinued as soon as pregnancy is confirmed (see section "Contraindications").

The background risk of major congenital malformations and spontaneous abortions in the indicated population is unknown. In the general US population, the estimated background risk of major congenital malformations and spontaneous abortions in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Contraception

AtorvAcor® may harm the fetus if used during pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment with this medicinal product.

Clinical data

Limited published observational studies, meta-analyses, and case reports on the use of calcium atorvastatin do not indicate an increased risk of serious congenital malformations or spontaneous abortions.

Rare reports of congenital anomalies have been reported after in utero exposure to other HMG-CoA reductase inhibitors. Prospective follow-up of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed that the rates of fetal congenital anomalies, spontaneous abortions, and intrauterine deaths/stillbirths did not exceed those expected in the general population. The number of cases is sufficient to exclude a ≥3–4-fold increase in fetal congenital anomalies compared to the background rate. In 89% of the prospectively followed pregnancies, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Breastfeeding

AtorvAcor® is contraindicated during breastfeeding. There is no information on the effects of the drug on the breastfed infant or on lactation. It is not known whether atorvastatin is excreted in human milk, but another drug in this class has been shown to pass into breast milk; atorvastatin is present in rat milk. Because statins may potentially cause serious adverse reactions in breastfed infants, women requiring treatment with AtorvAcor® should not breastfeed (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has negligible influence on the ability to drive or use machines.

Method of Administration and Dosage

Hyperlipidemia and Mixed Dyslipidemia

The recommended starting dose of Atorvакor® is 10 mg or 20 mg once daily. For patients requiring a large reduction in LDL-C levels (more than 45%), therapy may be initiated with a dose of 40 mg once daily. The dosage range of Atorvакor® is 10 mg to 80 mg once daily. The drug can be administered as a single dose at any time of day, regardless of food intake. Initial and maintenance doses of Atorvакor® should be individualized according to treatment goals and patient response. After initiation of therapy and/or dose titration, lipid levels should be analyzed within 2 to 4 weeks and the dose adjusted accordingly.

Heterozygous Familial Hypercholesterolemia in Pediatric Patients (Aged 10–17 Years)

The recommended starting dose of Atorvакor® is 10 mg daily; the maximum recommended dose is 20 mg daily (doses exceeding 20 mg have not been studied in this patient group). Doses should be individualized according to treatment goals. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous Familial Hypercholesterolemia

The dose of Atorvакor® for patients with homozygous familial hypercholesterolemia ranges from 10 mg to 80 mg daily. Atorvакor® should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or when such treatments are unavailable.

Concomitant Lipid-Lowering Therapy

Atorvакor® may be coadministered with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").

Dosing in Patients with Renal Impairment

Renal disease does not affect plasma concentrations of Atorvакor® or the reduction in LDL-C levels; therefore, dose adjustment of this medicinal product in patients with renal impairment is not required (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Dosing in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors

Treatment with Atorvакor® should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitor glecaprevir + pibrentasvir, or letermovir when coadministered with cyclosporine. For HIV patients taking lopinavir + ritonavir, Atorvакor® should be used at the lowest necessary dose. For patients taking clarithromycin, itraconazole, elbasvir + grazoprevir, or HIV patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, or letermovir, the therapeutic dose of Atorvакor® should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose. For patients taking the HIV protease inhibitor nelfinavir, Atorvакor® therapy should be limited to a dose of 40 mg. When atorvastatin is coadministered with other protease inhibitors, appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose of Atorvакor® (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").

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 dietary trial the following are observed:

• LDL-C ≥ 190 mg/dL (4.91 mmol/L), or
• LDL-C ≥ 160 mg/dL (4.14 mmol/L) and

o family history of familial hypercholesterolemia or premature cardiovascular disease in first- or second-degree relatives, or

o presence of two or more other cardiovascular risk factors.

The indication for atorvastatin use is supported by the following studies:

• A 6-month placebo-controlled clinical trial involving 187 boys and girls after onset of menstruation, aged 10 to 17 years. Patients receiving atorvastatin at doses of 10 mg or 20 mg daily had a generally similar adverse reaction profile compared to those receiving placebo. This narrow, controlled study did not detect any significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls.
• A 3-year open-label, uncontrolled study involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia, in whom doses were titrated to achieve a target LDL-C level <130 mg/dL (3.36 mmol/L). The safety and efficacy of atorvastatin in lowering LDL-C generally corresponded to those observed in adult patients, despite limitations of the uncontrolled study design.

Girls after onset of menstruation should be counseled regarding contraception, if appropriate.

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

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

Homozygous Familial Hypercholesterolemia

Clinical efficacy of the drug at doses up to 80 mg daily over 1 year was evaluated in an uncontrolled study in patients with homozygous familial hypercholesterolemia, which included 8 children.

Overdose.

There is no specific antidote for overdose with Atorvакor®. In case of overdose, the patient should be treated symptomatically and supportive measures should be employed as needed. Due to the high degree of plasma protein binding of the drug, significant increase in clearance of Atorvакor® by hemodialysis is not expected.

Adverse Reactions

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

In the database of placebo-controlled clinical studies of atorvastatin involving 16,066 patients (8,755 receiving atorvastatin and 7,311 receiving placebo; age range 10–93 years, 39% women; 91% Caucasian, 3% Black, 2% Asian, 4% other races), with a median treatment duration of 53 weeks, 9.7% of patients receiving atorvastatin and 9.5% of those receiving placebo discontinued treatment due to adverse reactions, regardless of causal relationship to the drug. The five most commonly reported adverse reactions leading to discontinuation in patients treated with atorvastatin, occurring at higher rates than in the placebo group, were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), increased alanine aminotransferase (ALT) levels (0.4%), and increased liver enzymes (0.4%).

Among patients treated with atorvastatin in placebo-controlled studies (n=8,755), the most frequently reported adverse reactions (incidence >2% and higher than in the placebo group), regardless of causal relationship, were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), limb pain (6.0%), and urinary tract infections (5.7%).

Table 4 summarizes the incidence of clinical adverse reactions, regardless of causal relationship, reported in >2% of patients and at higher rates than in the placebo group, among patients treated with atorvastatin (n=8,755) from 17 placebo-controlled studies.

Table 4

Clinical adverse reactions occurring in >2% of patients treated with atorvastatin at any dose and at higher rates than in the placebo group, regardless of causal relationship (% of patients).

* In > 2% of patients treated with atorvastatin at any dose, the incidence of adverse reactions was higher than in the placebo group.

Other adverse reactions reported during placebo-controlled studies include:

General disorders: malaise, pyrexia.

Gastrointestinal disorders: gastrointestinal discomfort, belching, flatulence, hepatitis, cholestasis.

Musculoskeletal system disorders: musculoskeletal pain, increased muscle fatigue, neck pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture).

Metabolism and nutrition disorders: elevated transaminases, abnormal liver function tests, increased alkaline phosphatase levels in blood, increased creatine kinase (CK) activity, hyperglycemia.

Nervous system disorders: nightmares.

Respiratory system disorders: epistaxis.

Skin and appendages disorders: urticaria.

Eye disorders: blurred vision, visual disturbance.

Ear and labyrinth disorders: tinnitus.

Renal and urinary system disorders: leukocyturia.

Reproductive system and breast disorders: gynecomastia.

The frequency of adverse reactions was defined as follows: common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000), frequency not known (cannot be estimated from available data).

Nervous system disorders: common: headache; uncommon: dizziness, paraesthesia, hypaesthesia, dysgeusia, amnesia; rare: peripheral neuropathy; frequency not known: myasthenia gravis.

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

Musculoskeletal and connective tissue disorders: common: arthralgia, back pain; rare: myopathy, myositis, rhabdomyolysis, muscle rupture; very rare: lupus-like syndrome.

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

Metabolism and nutrition disorders: uncommon: hypoglycemia, weight gain, anorexia.

Hepatobiliary disorders: very rare: hepatic failure.

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

Respiratory, thoracic and mediastinal disorders: common: throat and laryngeal pain.

Blood and lymphatic system disorders: rare: thrombocytopenia.

Vascular disorders: rare: vasculitis.

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

Eye disorders: uncommon: blurred vision; frequency not known: ocular myasthenia.

Laboratory test abnormalities: common: abnormal liver function tests, increased blood CK activity; uncommon: positive test for leukocytes in urine.

As with other HMG-CoA reductase inhibitors, increases in serum transaminase activity have been observed in patients taking atorvastatin. These changes were generally mild, transient, and did not require intervention or discontinuation of treatment. Clinically significant increases in serum transaminase activity (exceeding the upper limit of normal [ULN] by more than 3 times) were observed in 0.8% of patients treated with atorvastatin. This increase was dose-dependent and reversible in all patients.

An increase in serum CK activity exceeding the ULN by more than 3 times was observed in 2.5% of patients treated with atorvastatin. This is consistent with observations from clinical trials of other HMG-CoA reductase inhibitors. In 0.4% of patients receiving atorvastatin, CK levels exceeded the ULN by more than 10 times.

Adverse reactions observed during clinical trials:

urinary tract infections, diabetes mellitus, stroke.

In a study involving 10,305 participants (age range 40–80 years, 19% women; 94.6% Caucasian, 2.6% Black, 1.5% South Asian, and 1.3% mixed/other), who received atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of atorvastatin was comparable to that of placebo over a median follow-up period of 3.3 years.

In a 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 mellitus, who received atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall incidence of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 3.9 years. No cases of rhabdomyolysis were reported.

In a study involving 10,001 patients (age range 29–78 years, 19% women; 94.1% Caucasian, 2.9% Black, 1.0% Asian, and 2.0% other) with clinically evident ischemic heart disease, who received atorvastatin 10 mg daily (n=5,006) or atorvastatin 80 mg daily (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 group (69, 1.4%; 404, 8.1%, respectively) over a median follow-up period of 4.9 years. Persistent transaminase elevations (≥3 times ULN, confirmed on two occasions 4–10 days apart) occurred in 62 (1.3%) patients receiving atorvastatin 80 mg and in 9 (0.2%) patients receiving atorvastatin 10 mg. CK elevations (≥10 times ULN) were generally low but higher in the high-dose group (13, 0.3%) compared to the low-dose group (6, 0.1%).

In a study involving 8,888 patients (age range 26–80 years, 19% women; 99.3% Caucasian, 0.4% Asian, 0.3% Black, and 0.04% other), who received atorvastatin 80 mg daily (n=4,439) or simvastatin 20–40 mg daily (n=4,449), there was no difference in the overall incidence of adverse reactions or serious adverse reactions between treatment groups over a median follow-up period of 4.8 years.

In a study involving 4,731 patients (age range 21–92 years, 40% women; 93.3% Caucasian, 3.0% Black, 0.6% Asian, and 3.1% other) without clinically evident ischemic 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 incidence of persistent elevations in hepatic transaminases (≥3 times ULN on two occasions 4–10 days apart) was observed in the atorvastatin group (0.9%) compared to the placebo group (0.1%). Cases of creatine kinase elevation (≥10 times ULN) were rare but occurred more frequently in the atorvastatin group (0.1%) than in the placebo group (0.0%). 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 precautions for use").

Post-hoc analysis showed that atorvastatin 80 mg reduced the incidence of ischemic stroke (218 of 2,365, 9.2% vs. 274 of 2,366, 11.6%) but increased the incidence of hemorrhagic stroke (55 of 2,365, 2.3% vs. 33 of 2,366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 cases in the atorvastatin group vs. 18 in the placebo group). The incidence 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 entering the study with a history of hemorrhagic stroke had an increased risk of hemorrhagic stroke (7 (16%) in the atorvastatin group vs. 2 (4%) in the placebo group).

No significant differences between treatment groups in all-cause mortality 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 lower in the atorvastatin 80 mg group (3.3%) than in the placebo group (4.1%). The proportion of patients who died from non-cardiovascular causes was numerically higher in the atorvastatin 80 mg group (5.0%) than in the placebo group (4.0%).

Adverse reactions observed during clinical trials of atorvastatin in children:

In a 26-week controlled study in boys and girls after onset of menstruation with heterozygous familial hypercholesterolemia (aged 10–17 years) (n=140, 31% female; 92% Caucasian, 1.6% Black, 1.6% Asian, and 4.8% other ethnic groups), the safety and tolerability profile of atorvastatin 10–20 mg daily as an adjunct to diet for lowering 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 identified. Because these reactions are reported voluntarily from a population of unknown 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 after marketing authorization, regardless of causal assessment, include: anaphylaxis, angioedema, bullous rashes (including exudative multiform erythema, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, increased fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis, and interstitial lung disease.

Rare cases of immune-mediated necrotizing myopathy associated with statin use have been reported (see section "Special precautions for use").

Rare post-marketing reports of cognitive disorders (memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive disorders were reported with all statins. Generally, they were not considered serious adverse reactions and were reversible upon discontinuation of statin therapy, with variable onset time (from 1 day to several years) and resolution (median duration of 3 weeks).

With some statins, adverse events such as sexual dysfunction have been described; rare cases of interstitial lung disease, particularly with long-term treatment, have also been reported.

Adverse reactions reported during post-marketing surveillance:

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, hypaesthesia, dysgeusia.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain; rare: muscle rupture; very rare: lupus-like syndrome.

General disorders: chest pain, peripheral edema, malaise, fatigue.

Laboratory test abnormalities: increased ALT activity, increased blood CK activity.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicine after the expiry date stated on the packaging.

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

Keep out of the reach and sight of children.

Packaging.

Tablets 10 mg: № 30 (10x3), № 60 (10x6) in blisters, packed in a carton.

Tablets 20 mg: № 30 (10x3), № 40 (10x4) in blisters, packed in a carton.

Tablets 40 mg: № 30 (10x3) in blisters, packed in a carton.

Tablets 80 mg: № 30 (6x5) in blisters, packed in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.

74 Kyrylivska St., Kyiv, 04080, Ukraine.