INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ETSETÒ (ATSATÒ)

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 anhydrous silicon dioxide, magnesium stearate, Opadry 03F84827 pink*;

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets 10 mg, 20 mg: round, biconvex, film-coated tablets of pink color, marked with «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.

Medicinal products that reduce serum cholesterol and triglyceride levels.

HMG-CoA reductase inhibitors. ATC code C10A A05.

Pharmacological Properties

Pharmacodynamics

Etsеt® contains the active substance atorvastatin. Atorvastatin 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 LDL receptor molecules on the cell surface to enhance uptake and catabolism of LDL; atorvastatin also reduces the production of LDL and the number of these 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 drug correlates better with the reduction in LDL cholesterol levels than does systemic drug concentration. Dose titration should be individualized based on therapeutic response (see section "Dosage and Administration").

Pharmacokinetics

Absorption.

Atorvastatin is rapidly absorbed after oral administration, and peak plasma concentrations are reached within 1–2 hours. The extent of absorption increases proportionally with the dose of atorvastatin. The absolute bioavailability of atorvastatin (parent drug) is approximately 14%, and 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 metabolism in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as measured by Cmax and AUC (area under the concentration-time curve), the reduction in LDL cholesterol levels is similar whether atorvastatin is taken with or without food. When atorvastatin is administered in the evening, plasma concentrations are lower (approximately 30% lower for Cmax and AUC) than with morning dosing. However, the reduction in LDL cholesterol levels is similar 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. Atorvastatin is considered capable of passing into breast milk (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Metabolism.

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro studies show that the HMG-CoA reductase inhibitory activity of ortho- and parahydroxylated 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 atorvastatin metabolism is mediated primarily by cytochrome P450 3A4 (CYP3A4), 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, although this drug apparently does not undergo enterohepatic recirculation. The mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, while the half-life for HMG-CoA reductase inhibitory activity is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of an orally administered dose is excreted in urine.

Special Patient Populations

Elderly Patients.

Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (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 Warnings and Precautions for Use").

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 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 (approximately 20% higher for Cmax and 10% lower for AUC). However, there is no clinically significant difference in LDL cholesterol reduction between men and women when atorvastatin is administered.

Renal Impairment.

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

Hemodialysis.

Although studies have not been conducted in patients with end-stage renal disease, 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. Metabolites of atorvastatin 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 drugs on the pharmacokinetics of atorvastatin

Concomitantly administered drugs and dosing regimen	Atorvastatin
Concomitantly administered drugs and dosing regimen	Dose (mg)	Ratio AUC&	Ratio Cmax&
#Cyclosporine 5.2 mg/kg/day, stable dose	10 mg once daily for 28 days	8.69	10.66
#Tipranavir 500 mg twice daily / ritonavir 200 mg twice daily, 7 days	10 mg single dose	9.36	8.58
#Glecaprevir 400 mg once daily / pibrentasvir 120 mg once daily, 7 days	10 mg once daily for 7 days	8.28	22.00
#Telaprevir 750 mg every 8 hours, 10 days	20 mg single dose	7.88	10.60
#, ‡Saquinavir 400 mg twice daily / ritonavir 400 mg twice daily, 15 days	40 mg once daily for 4 days	3.93	4.31
#Elbasvir 50 mg once daily / grazoprevir 200 mg once daily, 13 days	10 mg single dose	1.94	4.34
#Simeprevir 150 mg once daily, 10 days	40 mg single dose	2.12	1.70
#Clarithromycin 500 mg twice daily, 9 days	80 mg once daily for 8 days	4.54	5.38
#Darunavir 300 mg twice daily / ritonavir 100 mg twice daily, 9 days	10 mg once daily for 4 days	3.45	2.25
#Itraconazole 200 mg once daily, 4 days	40 mg single dose	3.32	1.20
Letermovir 480 mg once daily, 10 days	20 mg single dose	3.29	2.17
#Fosamprenavir 700 mg twice daily / ritonavir 100 mg twice daily, 14 days	10 mg once daily for 4 days	2.53	2.84
#Fosamprenavir 1400 mg twice daily, 14 days	10 mg once daily for 4 days	2.30	4.04
#Nelfinavir 1250 mg twice daily, 14 days	10 mg once daily for 28 days	1.74	2.22
#Grapefruit juice, 240 ml once daily*	40 mg once daily	1.37	1.16
Diltiazem 240 mg once daily, 28 days	40 mg once daily	1.51	1.00
Erythromycin 500 mg four times daily, 7 days	10 mg once daily	1.33	1.38
Amlodipine 10 mg, single dose	80 mg once daily	1.18	0.91
Cimetidine 300 mg four times daily, 2 weeks	10 mg once daily for 2 weeks	1.00	0.89
Colestipol 10 g twice daily, 24 weeks	40 mg once daily for 8 weeks	Not applicable	0.74**
Maalox TC® 30 ml four times daily, 17 days	10 mg once daily for 15 days	0.66	0.67
Efavirenz 600 mg once daily, 14 days	10 mg for 3 days	0.59	1.01
#Rifampicin 600 mg once daily, 7 days (co-administered) †	40 mg once daily	1.12	2.90
#Rifampicin 600 mg once daily, 5 days (separate dosing) †	40 mg once daily	0.20	0.60
#Gemfibrozil 600 mg twice daily, 7 days	40 mg once daily	1.35	1.00
#Fenofibrate 160 mg once daily, 7 days	40 mg once daily	1.03	1.02
#Boceprevir 800 mg three times daily, 7 days	40 mg once daily	2.32	2.66

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

For information on clinical significance, see sections «Special precautions for use» and «Interaction with other medicinal products and other forms of interaction».

* 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 litres 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 be associated with a significant decrease in atorvastatin plasma concentrations.

‡ The dose of the combination of saquinavir + ritonavir in this study is not a clinically applicable 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 and at the lowest necessary dose.

Table 2

Effect of atorvastatin on the pharmacokinetics of concomitantly administered medicinal products

Atorvastatin	Concomitant Medication and Dosing Regimen
Atorvastatin	Drug/Dose (mg)	Ratio AUC	Ratio Cmax
80 mg once daily for 15 days	Antipyrine 600 mg single dose	1.03	0.89
80 mg once daily for 10 days	#Digoxin 0.25 mg once daily, 20 days	1.15	1.20
40 mg once daily for 22 days	Oral contraceptives once daily, 2 months norethisterone 1 mg ethinylestradiol 35 mcg	1.28 1.19	1.23 1.30
10 mg once daily	Tipranavir 500 mg twice daily/ritonavir 200 mg twice daily, 7 days	1.08	0.96
10 mg once daily for 4 days	Fosamprenavir 1400 mg twice daily, 14 days	0.73	0.82
10 mg once daily for 4 days	Fosamprenavir 700 mg twice daily/ritonavir 100 mg twice daily, 14 days	0.99	0.94

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

Administration of atorvastatin had no clinically significant effect on prothrombin time in patients receiving long-term warfarin therapy.

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases in adults

For adult patients without clinically evident ischemic heart disease but with multiple risk factors for ischemic heart disease, such as age, smoking, arterial hypertension, low HDL-C levels, or a family history of premature ischemic heart disease, Etset® is indicated for:

reduction of the risk of myocardial infarction;
reduction of the risk of stroke;
reduction of 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 ischemic heart disease, such as retinopathy, albuminuria, smoking, or arterial hypertension, Etset® is indicated for:

reduction of the risk of myocardial infarction;
reduction of the risk of stroke.

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

reduction of the risk of non-fatal myocardial infarction;
reduction of the risk of fatal and non-fatal stroke;
reduction of the risk of revascularization procedures;
reduction of the risk of hospitalization due to congestive heart failure;
reduction of the risk of angina.

Hyperlipidemia

In adults

As an adjunct to diet to reduce elevated total cholesterol, LDL-C cholesterol, apolipoprotein B, and triglyceride levels, as well as to increase HDL-C cholesterol 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 measures are insufficiently effective.
For reduction of total cholesterol and LDL-C cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such therapies are unavailable.

In children

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

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

b) LDL-C cholesterol ≥ 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.

Acute liver disease, which may include persistent elevations of hepatic transaminases 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). Plasma levels of atorvastatin may be significantly increased when co-administered with inhibitors of CYP3A4 and transporters. Table 3 lists medicinal products that may increase atorvastatin exposure and the risk of myopathy and rhabdomyolysis when used concomitantly, along with recommendations for managing and preventing such risks (see sections "Special precautions for use" and "Pharmacological properties").

Table 3

Interaction with other medicinal products that may increase the risk of myopathy and rhabdomyolysis during atorvastatin use

Cyclosporine or gemfibrozil
Clinical effect	Plasma levels of atorvastatin were significantly increased when used concomitantly with cyclosporine, an inhibitor of CYP3A4 and OATP1B1 (see section "Pharmacological properties"). Monotherapy with gemfibrozil may cause myopathy. There is an increased risk of developing myopathy and rhabdomyolysis when cyclosporine or gemfibrozil is used concomitantly with atorvastatin.
Precautions	Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended.
Antiviral agents
Clinical effect	Plasma levels of atorvastatin were significantly increased when used concomitantly with many antiviral agents that are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) (see section "Pharmacological properties"). Cases of myopathy and rhabdomyolysis have been reported with concomitant use of the combination ledipasvir + sofosbuvir with atorvastatin.
Precautions	Concomitant use of the combination tipranavir + ritonavir or glecaprevir + pibrentasvir with atorvastatin is not recommended. In patients receiving lopinavir + ritonavir or simeprevir, the benefit/risk of concomitant use with atorvastatin should be evaluated. In patients receiving saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, or letermovir, the atorvastatin dose should not exceed 20 mg. In patients receiving nelfinavir, the atorvastatin dose should not exceed 40 mg (see section "Dosage and administration"). The benefit/risk of concomitant use of the combination ledipasvir + sofosbuvir with atorvastatin should be evaluated. Signs and symptoms of myopathy should be monitored in all patients, especially at the start of treatment and during dose increases of any drug.
Examples	Tipranavir + ritonavir, glecaprevir + pibrentasvir, lopinavir + ritonavir, simeprevir, saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, letermovir, nelfinavir, and ledipasvir + sofosbuvir.
Specific azole antifungals or macrolide antibiotics
Clinical effect	Plasma levels of atorvastatin were significantly increased when used concomitantly with specific azole antifungals or macrolide antibiotics due to inhibition of CYP3A4 and/or transporters (see section "Pharmacological properties").
Precautions	In patients receiving clarithromycin or itraconazole, the atorvastatin dose should not exceed 20 mg (see section "Dosage and administration"). The benefit/risk of concomitant use of specific azole antifungals or macrolide antibiotics with atorvastatin should be evaluated. Signs and symptoms of myopathy should be monitored in all patients, especially at the start of therapy and during dose increases of any drug.
Examples	Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.
Niacin
Clinical effect	Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid-modifying doses of niacin (>1 g/day of niacin) with atorvastatin.
Precautions	Consider whether the benefit of concomitant use of lipid-modifying doses of niacin with atorvastatin outweighs the increased risk of developing myopathy and rhabdomyolysis. If a decision is made to use them concomitantly, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of either drug.
Fibrates (other than gemfibrozil)
Clinical effect	Use of fibrates as monotherapy may cause myopathy. The risk of developing myopathy and rhabdomyolysis increases with concomitant use of fibrates and atorvastatin.
Precautions	Consider whether the benefit of concomitant use of fibrates with atorvastatin outweighs the increased risk of developing myopathy and rhabdomyolysis. If a decision is made to use them concomitantly, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of either drug.
Colchicine
Clinical effect	Cases of myopathy and rhabdomyolysis have been observed during concomitant use of colchicine with atorvastatin.
Precautions	Consider the benefit/risk of concomitant use of colchicine with atorvastatin. If a decision is made to use them concomitantly, patients should be monitored for signs and symptoms of myopathy, especially at the beginning of therapy and during dose increases of either drug.
Daptomycin
Clinical effect	Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) with daptomycin.
Precautions	If concomitant use cannot be avoided, appropriate clinical monitoring is recommended (see section "Special precautions").
Grapefruit juice
Clinical effect	Consumption of grapefruit juice, especially in large quantities (more than 1.2 liters per day), may lead to increased plasma levels of atorvastatin and increase the risk of developing myopathy and rhabdomyolysis.
Precautions	Avoid consumption of large amounts of grapefruit juice (more than 1.2 liters per day) during atorvastatin therapy.

Table 4

Interaction with medicinal products that may reduce atorvastatin exposure.

Rifampicin
Clinical effect	Concomitant administration of atorvastatin with rifampicin, a cytochrome P450 3A4 inducer and OATP1B1 inhibitor, may lead to an unstable reduction in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, delayed administration of atorvastatin after rifampicin dosing has been associated with a significant reduction in atorvastatin plasma concentrations.
Management	Concomitant administration of atorvastatin and rifampicin is recommended.

Table 5

Effect of atorvastatin on other medicinal products.

Oral contraceptives
Clinical effect	Concomitant administration of atorvastatin and oral contraceptives increases plasma concentrations of norethisterone and ethinylestradiol (see section "Pharmacological properties").
Precautions	This fact should be taken into account when selecting an oral contraceptive for patients taking atorvastatin.
Digoxin
Clinical effect	Concomitant administration of multiple doses of atorvastatin and digoxin increases steady-state digoxin plasma concentrations (see section "Pharmacological properties").
Precautions	Patients taking digoxin should be appropriately monitored.

Diltiazem hydrochloride.

Concomitant administration of atorvastatin (40 mg) and diltiazem (240 mg) is associated with increased plasma concentrations of atorvastatin.

Cimetidine.

No evidence of interaction between atorvastatin and cimetidine has been observed in clinical studies.

Antacids.

Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminium hydroxide results in approximately a 35% reduction in atorvastatin plasma concentration. However, the hypolipidemic effect of atorvastatin remains unchanged.

Colestipol.

Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when atorvastatin was administered concomitantly with colestipol. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded the effect achieved with either agent administered alone.

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) may increase systemic exposure to atorvastatin (see Table 1). The impact of inhibition of uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant administration of these agents cannot be avoided, dose reduction of atorvastatin and clinical monitoring of efficacy are recommended (see Table 1).

Ezetimibe.

Ezetimibe monotherapy has been associated with muscle-related adverse events, including rhabdomyolysis. Therefore, concomitant use of ezetimibe and atorvastatin may increase the risk of such events. Appropriate clinical monitoring of these patients is recommended.

Fusidic acid.

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

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

Other medicinal products.

Clinical studies have shown that concomitant administration of atorvastatin with antihypertensive agents or during estrogen replacement therapy is not associated with clinically significant adverse effects. Studies on interactions with other drugs have not been conducted.

Special precautions for use.

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 statins, including atorvastatin.

Myopathy risk factors

Risk factors for developing myopathy include age 65 years and older, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other medications, and higher atorvastatin doses (see section "Interaction with other medicinal products and other forms of interaction").

Measures to reduce or prevent the risk of myopathy and rhabdomyolysis

Exposure to atorvastatin may increase due to interactions with other medicinal products through inhibition of cytochrome P450 3A4 enzyme (CYP3A4) and/or transporters (e.g., breast cancer resistance protein [BCRP], organic anion transporting polypeptide [OATP1B1/OATP1B3], and P-glycoprotein [P-gp]), leading to an increased risk of myopathy and rhabdomyolysis. Concomitant use with cyclosporine, gemfibrozil, the combination of tipranavir + ritonavir, or glecaprevir + pibrentasvir is not recommended. Dose modifications of atorvastatin are recommended for patients taking certain antiviral agents, azole antifungals, or macrolide antibiotics (see section "Method of administration and dosage"). Cases of myopathy/rhabdomyolysis have been reported with concomitant use of atorvastatin and lipid-modifying doses (>1 g/day) of niacin, fibrates, colchicine, and the combination of ledipasvir + sofosbuvir. The benefit of using these agents should be weighed against the increased risk of myopathy and rhabdomyolysis (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant consumption of large quantities of grapefruit juice (more than 1.2 liters per day) is not recommended in patients taking atorvastatin (see section "Interaction with other medicinal products and other forms of interaction").

Atorvastatin should be discontinued if markedly elevated CK levels are observed or if myopathy is diagnosed or suspected. Muscle symptoms and elevated CK levels resolve after discontinuation of atorvastatin. Atorvastatin should be temporarily discontinued in patients with acute or serious 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 disturbances; uncontrolled epilepsy).

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

Immune-mediated necrotizing myopathy

Rare cases 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; positive antibodies to HMG-CoA reductase; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive therapy. Additional neuromuscular and serological investigations may be required. Immunosuppressive therapy may be needed. The risk of IMNM should be carefully considered before initiating another statin. If another statin is initiated, monitoring for signs and symptoms of IMNM is necessary.

Hepatic function

Statins, like some other lipid-lowering therapeutic agents, have been associated with abnormalities in liver function tests. Persistent elevations (more than 3 times the upper limit of normal range, occurring on two or more occasions) of 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 10, 20, 40, and 80 mg doses of the drug, respectively.

During clinical trials, jaundice developed in one patient. Elevated liver function test (LFT) results in other patients were not associated with jaundice or other clinical symptoms. After dose reduction, interruption, or discontinuation of atorvastatin, transaminase levels returned to pretreatment levels or approximately to these levels without adverse consequences. Eighteen of 30 patients with persistent elevation of liver function tests continued atorvastatin treatment at lower doses.

Liver enzyme tests should be obtained before initiating atorvastatin therapy 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 atorvastatin use, treatment should be discontinued immediately. The drug should not be restarted unless an alternative etiology is identified.

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

Endocrine function

Elevations in HbA1c and fasting plasma glucose concentrations 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 data have shown that atorvastatin does not reduce baseline plasma cortisol concentration or impair adrenal reserve. The effect of statins on sperm fertility has not been adequately studied in a sufficient number of patients. It is unknown whether atorvastatin affects or has any effect on the hypothalamic-pituitary-gonadal axis in premenopausal women. Caution should be exercised when co-administering statin-class drugs with medicinal products that may reduce 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 (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, 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 80 mg 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%). Some baseline characteristics, including the presence 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 who received 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 of the drug were observed between these patients and younger patients, nor were there any differences in treatment response between elderly and younger patients according to other clinical experience; however, increased sensitivity in some elderly patients cannot be excluded. Since advanced age (over 65 years) is a predisposing factor for myopathy, atorvastatin should be used with caution in elderly patients.

Hepatic impairment

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

Before starting treatment

Atorvastatin should be prescribed with caution in patients predisposed to rhabdomyolysis. Before initiating statin therapy in patients predisposed to rhabdomyolysis, CK levels should be measured in the following conditions:

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

For elderly patients (over 70 years), the need for these measures should be evaluated considering the presence of other predisposing factors for rhabdomyolysis.

Increased plasma drug levels are possible, particularly due to interactions (see section "Interaction with other medicinal products and other forms of interaction") and use in special patient populations (see section "Pharmacokinetics"), including patients with inherited disorders.

In such cases, the risk-benefit ratio of treatment should be carefully evaluated and clinical monitoring of patients should be performed. If baseline CK levels are markedly elevated (exceeding ULN by more than 5 times), treatment should not be initiated.

Measurement of creatine kinase levels

Creatine kinase levels should not be measured after intense physical exertion or in the presence of any possible alternative causes of elevated CK levels, as this may complicate interpretation of results. If marked elevation of CK (exceeding ULN by more than 5 times) is observed at baseline, repeat measurement should be performed after 5–7 days to confirm the result.

During treatment

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

If these symptoms occur during atorvastatin treatment, CK levels should be measured in the patient. If CK levels are markedly elevated (exceeding ULN by more than 5 times), treatment should be discontinued.

Discontinuation of treatment should also be considered if CK elevation does not exceed fivefold ULN but muscle symptoms are severe and cause daily discomfort.

After resolution of symptoms and normalization of CK levels, resumption of atorvastatin therapy or initiation of an alternative statin may be considered, provided the lowest possible dose is used and the patient is closely monitored.

Atorvastatin treatment should be discontinued if clinically significant elevation of CK levels (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 myopathy and/or rhabdomyolysis may be increased when HMG-CoA reductase inhibitors (e.g., atorvastatin) are used concomitantly with daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Consideration should be given to temporarily suspending Etset® in patients receiving daptomycin unless the benefit of concomitant use 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.

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

If concomitant treatment with atorvastatin and the mentioned drugs is necessary, the benefit-risk ratio 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, consideration should be given to using a lower initial dose of atorvastatin. Appropriate clinical monitoring of these patients is also recommended.

Atorvastatin must not be co-administered with systemic fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where systemic fusidic acid is considered necessary, statin treatment should be suspended for the entire duration of fusidic acid therapy. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins in combination (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.

In exceptional circumstances where long-term systemic fusidic acid therapy is required, e.g., for treatment of severe infections, concomitant use of atorvastatin and fusidic acid should be considered only on an individual basis and under close physician supervision.

Interstitial lung disease

Rare cases of interstitial lung disease have been reported with some statins (particularly during long-term treatment). Manifestations of this disease 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.

Lipid-modifying drug therapy should be one component of comprehensive therapy 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 fat and cholesterol intake and other non-pharmacological measures have been insufficient. In patients with ischemic heart disease or multiple risk factors for ischemic heart disease, atorvastatin may be initiated concurrently with dietary therapy.

Limitations of use

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

Myasthenia gravis/ocular myasthenia

Several cases of de novo occurrence or exacerbation of existing myasthenia gravis or ocular myasthenia have been reported with statin use (see section "Adverse reactions"). Etset® should be discontinued if symptoms of the disease worsen. Recurrences of the disease have been reported upon re-administration of the same or another statin.

Excipients

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

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

Use during pregnancy or breastfeeding

Pregnancy

Assessment of risk

Atorvastatin is contraindicated in pregnant women, as its safety in 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, atorvastatin may have harmful effects on the fetus. Atorvastatin should be discontinued as soon as pregnancy is confirmed (see section "Contraindications").

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

Contraception

Atorvastatin may harm the fetus when administered to a pregnant woman. Women of reproductive potential should be informed of the need for effective contraception during treatment with this drug.

Clinical data

Limited published data from observational studies, meta-analyses, and case reports on the use of calcium atorvastatin have not shown an increased risk of major congenital malformations or miscarriages.

Rare reports of congenital anomalies have been received after intrauterine 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, miscarriages, 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 developmental 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 period

Atorvastatin is contraindicated during breastfeeding. There is no information on the effect of the drug on the breastfed child or on lactation. It is unknown whether atorvastatin passes into human breast milk, but it has been shown that another drug in this class is excreted in breast milk; atorvastatin is present in rat milk. Since statins have the potential to cause serious adverse reactions in breastfed infants, women requiring atorvastatin therapy should not breastfeed (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery.

Has a very minor influence on the ability to drive or operate machinery.

Method of Administration and Dosage

Hyperlipidemia and Mixed Dyslipidemia

The recommended initial dose of atorvastatin is 10 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 atorvastatin dosage range is from 10 to 80 mg once daily. The drug can be administered as a single dose at any time of day and is not dependent on food intake. Initial and maintenance doses of atorvastatin should be individually adjusted based on treatment goals and patient response. After initiation of treatment 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 (Ages 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 daily. Doses should be individually adjusted according to treatment goals. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous Familial Hypercholesterolemia

The atorvastatin dose for patients with homozygous familial hypercholesterolemia ranges from 10 to 80 mg daily. Atorvastatin 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

Atorvastatin may be administered with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections "Special Warnings", "Interaction with Other Medicinal Products and Other Forms of Interaction").

Dosing in Patients with Renal Impairment

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

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

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

Pediatric Use

Heterozygous Familial Hypercholesterolemia

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 the following conditions are present after an adequate trial of dietary therapy:

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

o a 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.

Indications for atorvastatin use are supported by clinical 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 an overall adverse reaction profile similar to those receiving placebo. In this limited controlled study, no significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls was observed.
A 3-year open-label, uncontrolled study involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia, in whom dose titration was performed to achieve a target LDL-C level < 130 mg/dL (3.36 mmol/L). Safety and efficacy of atorvastatin in lowering LDL-C were generally consistent with those observed in adult patients, despite limitations of the uncontrolled study design.

Girls after onset of menstruation should be counseled regarding contraception if appropriate for the patient.

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

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 atorvastatin at doses up to 80 mg/day over 1 year was evaluated in an uncontrolled study involving 8 pediatric patients with homozygous familial hypercholesterolemia.

Overdose.

There is no specific antidote for atorvastatin overdose. In case of overdose, the patient should be treated symptomatically and supportive measures should be instituted as needed. Due to the high degree of plasma protein binding of atorvastatin, enhanced clearance by hemodialysis is not expected to be significant.

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 of another drug and may not reflect the rates observed in clinical practice.

According to data from atorvastatin clinical trials 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 common adverse reactions in patients treated with atorvastatin that led to discontinuation of the drug and occurred at a higher frequency 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%).

In patients treated with atorvastatin in placebo-controlled trials (n=8,755), the most commonly observed 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%), pain in extremities (6.0%), and urinary tract infection (5.7%).

Table 6 summarizes the incidence of clinical adverse reactions, regardless of causal relationship, reported in ≥2% of patients treated with atorvastatin (n=8,755) and at a higher frequency than in the placebo group, based on data from 17 placebo-controlled trials.

Table 6.

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

Adverse reaction*	Any dose N=8755	10 mg N=3908	20 mg N=188	40 mg N=604	80 mg N=4055	Placebo N=7311
Nasopharyngitis	8.3	12.9	5.3	7	4.2	8.2
Arthralgia	6.9	8.9	11.7	10.6	4.3	6.5
Diarrhea	6.8	7.3	6.4	14.1	5.2	6.3
Limb pain	6	8.5	3.7	9.3	3.1	5.9
Urinary tract infection	5.7	6.9	6.4	8	4.1	5.6
Dyspepsia	4.7	5.9	3.2	6	3.3	4.3
Nausea	4	3.7	3.7	7.1	3.8	3.5
Musculoskeletal pain	3.8	5.2	3.2	5.1	2.3	3.6
Muscle spasms	3.6	4.6	4.8	5.1	2.4	3
Myalgia	3.5	3.6	5.9	8.4	2.7	3.1
Insomnia	3	2.8	1.1	5.3	2.8	2.9
Pharyngolaryngeal pain	2.3	3.9	1.6	2.8	0.7	2.1

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

Other adverse reactions reported during studies include:

General disorders: malaise, pyrexia.

Gastrointestinal system: gastrointestinal discomfort, eructation, flatulence, hepatitis, cholestasis.

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

Metabolism and nutrition: increased transaminases, abnormal liver function tests, increased blood alkaline phosphatase, increased creatine phosphokinase activity, hyperglycemia.

Nervous system: nightmares.

Respiratory system: epistaxis.

Skin and appendages: urticaria.

Eye disorders: blurred vision, visual disturbance.

Ear and labyrinth disorders: tinnitus.

Renal and urinary system: leukocyturia.

Reproductive system and breast: gynecomastia.

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

Nervous system: common – headache; uncommon – dizziness, paraesthesia, hypoaesthesia, dysgeusia, amnesia; rare – peripheral neuropathy.

Gastrointestinal tract: common – constipation; uncommon – pancreatitis, vomiting.

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

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

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

Liver and biliary system: very rare – hepatic failure.

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

Respiratory, thoracic and mediastinal 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.

Eye disorders: uncommon – blurred vision.

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

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

An increase in serum creatine kinase activity exceeding the upper limit of normal by more than 3 times was observed in 2.5% of patients receiving atorvastatin. This is consistent with observations during clinical trials of other HMG-CoA reductase inhibitors. Levels exceeding the upper limit of normal by more than 10 times were observed in 0.4% of patients receiving atorvastatin.

Adverse reactions observed during clinical trials: urinary tract infection, diabetes mellitus, stroke.

In the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), which included 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 the CARDS (Collaborative Atorvastatin Diabetes Study), which included 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 receiving atorvastatin 10 mg daily (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. No cases of rhabdomyolysis were reported.

In the TNT (Treating to New Targets Study), which included 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 coronary 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 upper limit of normal, 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 upper limit of normal) were generally low but higher in the high-dose group (13, 0.3%) compared to the low-dose group (6, 0.1%).

In the IDEAL (Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study), which included 8,888 patients (age range 26–80 years, 19% women; 99.3% Caucasian, 0.4% Asian, 0.3% Black, and 0.04% other) receiving 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) study, which included 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 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 incidence of persistent elevations in liver transaminases (≥3 times upper limit of normal on two occasions 4–10 days apart) was observed in the atorvastatin group (0.9%) compared to placebo (0.1%). Cases of creatine kinase elevation (≥10 times upper limit of normal) were rare but more frequent 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").

A post-hoc analysis demonstrated 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 who entered the study with a history of hemorrhagic stroke had an increased risk of recurrent hemorrhagic stroke (7 (16%) atorvastatin vs. 2 (4%) placebo).

No significant differences in all-cause mortality were observed between treatment groups: 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 during clinical trials of atorvastatin in children

In a 26-week controlled trial in boys and girls after onset of menstruation with heterozygous familial hypercholesterolemia (aged 10 to 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 cholesterol, 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 eruptions (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").

Rare post-marketing reports of cognitive disorders (such as 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, were reversible upon discontinuation of statin therapy, had variable onset times (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 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, hypoaesthesia, dysgeusia, myasthenia gravis.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Eye disorders: ocular 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: increased alanine aminotransferase activity, increased blood creatine phosphokinase activity.

Reporting of adverse reactions.

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System 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 reach of children.

Packaging.

14 tablets in blisters; 2, 4, or 6 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's location and address of business activity.

40020, Ukraine, Sumy region, Sumy city, Skryabina St., 54.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's location and address of business activity.

40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhoriia St., 54.