INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ESCOLAN–sanovel (ESCOLAN–sanovel)

Composition:

Active substance: atorvastatin;

One film-coated tablet contains 10.85 mg of atorvastatin calcium trihydrate, equivalent to 10 mg of atorvastatin;

One film-coated tablet contains 21.69 mg of atorvastatin calcium trihydrate, equivalent to 20 mg of atorvastatin;

One film-coated tablet contains 43.38 mg of atorvastatin calcium trihydrate, equivalent to 40 mg of atorvastatin;

Excipients: calcium carbonate, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, polysorbate 80, hydroxypropyl cellulose, magnesium stearate, Opadry White 02F28526 (hydroxypropyl methylcellulose, titanium dioxide (E 171), talc, polyethylene glycol 8000).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: elongated biconvex film-coated tablets of white color.

Pharmacotherapeutic group. Hypolipidemic agents, single-component. HMG-CoA reductase inhibitors. Atorvastatin. ATC code C10AA05.

Pharmacological Properties

Pharmacodynamics

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase), the key enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A into mevalonic acid, a precursor of sterols including cholesterol.

Atorvastatin reduces cholesterol and lipoprotein levels in plasma by inhibiting hepatic HMG-CoA reductase and increasing the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, thereby enhancing the uptake and catabolism of cholesterol/LDL. Atorvastatin reduces the production of cholesterol/LDL and the number of LDL particles. It induces a pronounced and sustained increase in LDL receptor activity and also positively affects the quality of circulating LDL. Atorvastatin effectively lowers cholesterol/LDL levels in patients with homozygous hypercholesterolemia, a condition typically unresponsive to other lipid-lowering agents.

In dose-response studies, atorvastatin (at doses of 10–80 mg) reduced total cholesterol levels (by 30–46%), LDL cholesterol (by 41–61%), apolipoprotein B (by 34–50%), and triglycerides (by 14–33%). Treatment outcomes were similar in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed hypercholesterolemia, including patients with non-insulin-dependent diabetes mellitus.

Pharmacokinetics

Absorption. Atorvastatin is rapidly absorbed after oral administration. Maximum plasma concentration (C_max) is reached within 1–2 hours. The extent of absorption and plasma concentrations increase proportionally with dose. Absolute bioavailability of atorvastatin is 14%, while 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 C_max 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 administered in the evening, plasma concentrations of atorvastatin are lower (by approximately 30% in terms of C_max and AUC) compared to morning administration. However, the reduction in LDL cholesterol levels is equivalent regardless of the time of administration (see section "Dosage and Administration").

Distribution. The extent of plasma protein binding of atorvastatin is ≥98%. The mean volume of distribution is 565 L. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes. Based on observations in rats, atorvastatin is considered capable of passing into breast milk (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Metabolism. Atorvastatin undergoes extensive metabolism, forming ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro, the inhibitory effects of ortho- and para-hydroxylated metabolites on HMG-CoA reductase are similar to those of atorvastatin. Approximately 70% of the 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 observed 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").

Elimination. Atorvastatin and its metabolites are primarily eliminated via bile following hepatic and/or extrahepatic metabolism. However, atorvastatin does not undergo enterohepatic recirculation. The elimination half-life is approximately 4 hours, while the half-life of HMG-CoA reductase inhibitory activity is 20–30 hours, which is attributed to the presence of active metabolites. Less than 2% of the administered dose is excreted in urine.

Atorvastatin is a substrate of hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and transporter 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of multiple drug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.

Pharmacokinetics in Special Clinical Situations

Plasma concentrations of atorvastatin are markedly increased (C_max and AUC increased approximately 16-fold and 11-fold, respectively) in patients with alcoholic cirrhosis (Child-Pugh class B).

Renal disease does not affect plasma concentrations of atorvastatin or its effect on lipid parameters.

Elderly Patients. Plasma concentrations of atorvastatin are higher (approximately 40% for C_max 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 atorvastatin at any dose in elderly patients compared to younger patients (see section "Special Warnings and Precautions for Use").

Pediatric Population. 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 10–17 years, n=29).

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

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

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

Concomitantly administered drugs and dosing regimen	Atorvastatin
	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	8.3	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	1.95	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 "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use".

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

‡ The dose of the saquinavir + ritonavir combination used 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 medicinal product and dosing regimen
	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".

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, smoking, arterial hypertension, low levels of high-density lipoprotein (HDL) cholesterol, or a family history of premature ischemic heart disease:

• reduction in the risk of myocardial infarction;
• reduction in the risk of stroke;
• reduction in 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:

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

For adult patients with clinically evident ischemic heart disease:

• reduction in the risk of non-fatal myocardial infarction;
• reduction in the risk of fatal and non-fatal stroke;
• reduction in the risk of revascularization procedures;
• reduction in the risk of hospitalization due to congestive heart failure;
• reduction in 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 HDL cholesterol levels in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb).
• As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson type IV).
• For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson type III) when dietary measures are insufficient.
• To reduce total cholesterol and LDL-C 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 total cholesterol, LDL-C, and apolipoprotein B levels in boys and in girls after menarche, aged 10 to 17 years, with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy laboratory results are as follows:

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

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

• there is 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.
• Lactation.
• Treatment with the hepatitis C antiviral agents glecaprevir/pibrentasvir.

Interaction with other medicinal products and other forms of interaction.

Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin (see section "Pharmacological properties").

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

Concomitant use of atorvastatin with potent CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see Table 3 and detailed information below). The extent of interaction and effect enhancement depends on the variability of 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 whenever possible. If concomitant use cannot be avoided, consideration should be given to using lower initial and maximum doses of atorvastatin. Appropriate clinical monitoring of the patient is also recommended (see Table 3). 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. However, amiodarone and verapamil are known to inhibit CYP3A4 activity; therefore, concomitant use of these drugs 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. Clinical monitoring of the patient is also recommended. After initiating treatment with an inhibitor or adjusting its dose, clinical monitoring of the patient is recommended.

Grapefruit juice

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

Clarithromycin

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

Combination of protease inhibitors

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

Itraconazole

AUC values of atorvastatin were significantly increased when atorvastatin 40 mg was administered concomitantly with itraconazole 200 mg (see section "Pharmacological properties"). Therefore, patients taking itraconazole should be cautious if atorvastatin doses exceed 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. AUC values of atorvastatin were significantly increased when atorvastatin 10 mg was administered concomitantly with cyclosporine 5.2 mg/kg/day compared to atorvastatin alone (see section "Pharmacological properties"). Concomitant use of atorvastatin 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 atorvastatin exposure (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, thus increasing atorvastatin exposure. The atorvastatin dose 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 co-administered with cyclosporine. Atorvastatin use 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 increase atorvastatin plasma concentrations and increase the risk of myopathy.

When glecaprevir and pibrentasvir are administered concomitantly with atorvastatin, atorvastatin plasma concentrations increase up to 8.3-fold, partly due to inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, concomitant use of atorvastatin in patients receiving medicinal products containing glecaprevir and pibrentasvir is contraindicated.

When elbasvir and grazoprevir are administered concomitantly with atorvastatin, atorvastatin plasma concentrations increase up to 1.95-fold, partly due to inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, the atorvastatin dose 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 summarized 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

Drugs that interact	Medical recommendations for use
Cyclosporine, tipranavir + ritonavir, glecaprevir 400 mg + pibrentasvir 120 mg (for 7 days), ledipasvir when used concomitantly with cyclosporine	Avoid use of atorvastatin
Glecaprevir 50 mg + pibrentasvir 200 mg (for 13 days)	Do not exceed 20 mg of atorvastatin per day
Clarithromycin, itraconazole, saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, ledipasvir	Do not exceed 20 mg of atorvastatin per day
Nelfinavir	Do not exceed 40 mg of atorvastatin per day
Lopinavir + ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine	Use with caution and at the lowest necessary dose

*Use the lowest necessary dose.

Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are administered concomitantly with gemfibrozil, the combination of atorvastatin and 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, atorvastatin should be used with caution when co-administered with other fibrates (see section "Special precautions").

Niacin

The risk of skeletal muscle-related adverse effects may increase when the drug is used in combination with niacin; therefore, dose reduction of atorvastatin should be considered (see section "Special precautions").

Rifampicin or other cytochrome P450 3A4 inducers

Concomitant administration of the drug with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampicin) may lead to an inconsistent reduction in atorvastatin plasma concentrations. Because of the dual interaction mechanism of rifampicin, concomitant administration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after rifampicin dosing has been shown to result in a significant reduction in atorvastatin plasma concentrations.

Diltiazem hydrochloride

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

Cimetidine

No signs of interaction between atorvastatin and cimetidine were observed in clinical studies.

Antacids

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

Cholestyramine

Plasma concentrations of atorvastatin were lower (by approximately 25%) when atorvastatin was administered concomitantly with cholestyramine. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and cholestyramine exceeded the effect achieved by each drug administered 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.

Inhibitors of transport proteins

Inhibitors of transport proteins (e.g., cyclosporine, letermovir) may increase systemic exposure to atorvastatin. The effect of inhibition of uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant use of these drugs cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended (see Table 1).

Ezetimibe

Ezetimibe monotherapy has been associated with muscle-related adverse effects, including rhabdomyolysis. Therefore, the risk of such effects increases when ezetimibe is used concomitantly with atorvastatin. Appropriate clinical monitoring of such 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 not fully understood. Cases of rhabdomyolysis (including fatal outcomes) have been reported in patients receiving this combination.

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

Digoxin

Concomitant administration of multiple doses of atorvastatin and digoxin increases steady-state digoxin plasma concentrations by approximately 20% (see section "Pharmacokinetics"). Patients taking digoxin should be appropriately monitored.

Oral contraceptives

Concomitant administration of atorvastatin with oral contraceptives increases the AUC for norethisterone and ethinylestradiol (see section "Pharmacological properties"). These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.

Warfarin

Atorvastatin had no clinically significant effect 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 when used with colchicine.

Other medicinal products

Concomitant administration of atorvastatin with antihypertensive agents and its use during estrogen replacement therapy were not associated with clinically significant adverse effects. Drug interaction studies with other agents have not been conducted.

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").

Special precautions.

Musculoskeletal system

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 more careful monitoring for skeletal muscle disorders.

Atorvastatin, like other statin drugs, occasionally causes myopathy, defined as muscle pain or weakness in combination with elevated creatine phosphokinase (CPK) levels more than 10 times the upper limit of normal (ULN). 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 cases of immune-mediated necrotizing myopathy (IMNM)—an autoimmune myopathy associated with statin use—have been reported. IMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase (CK) levels that persist despite discontinuation of statin therapy; muscle biopsy reveals necrotizing myopathy without significant inflammation; positive response to immunosuppressive therapy.

The possibility of myopathy should be considered in any patient 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 the drug. Treatment with the drug should be discontinued in the event of markedly elevated CPK levels, diagnosis of, or suspicion of myopathy.

The risk of myopathy during treatment with drugs in this class increases with concomitant use of medicinal products listed in Table 3. Physicians considering combination therapy with atorvastatin and any of the drugs listed in Table 3 should carefully weigh the potential benefits and risks and closely monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any dose-titration periods. Consideration should be given to using lower initial 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 cases of severe myopathy.

Atorvastatin therapy should be temporarily 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, and electrolyte disorders, and uncontrolled seizures).

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, Escolan-Sanovel should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Hepatic function

Statins, like some other hypolipidemic therapeutic agents, have been associated with abnormalities in hepatic biochemical parameters. Persistent elevations (more than three 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 doses of 10, 20, 40, 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. After dose reduction, interruption, or discontinuation of the drug, transaminase levels returned to pre-treatment levels or approximately to these levels without adverse consequences. Eighteen of 30 patients with persistent elevations in liver function tests continued atorvastatin treatment at lower doses.

Liver enzyme test results should be obtained before initiating atorvastatin therapy and repeated as clinically indicated. In the event of serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice during atorvastatin use, treatment should be immediately discontinued. If no alternative etiology is identified, reinitiation of the drug should not be attempted.

Atorvastatin should be prescribed with caution to patients who abuse alcohol 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").

Cases of fatal and non-fatal hepatic failure have been reported in patients taking statin drugs, including atorvastatin.

Endocrine function

Elevations in HbA1c and fasting plasma glucose concentrations have been reported with HMG-CoA reductase inhibitors. The effect of statins on sperm fertility has not been studied in a sufficient number of patients.

Atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. Statins inhibit cholesterol synthesis and may theoretically reduce adrenal and/or gonadal steroid secretion. It is unknown how the drug affects or whether it affects at all the hypothalamic-pituitary-gonadal axis in premenopausal women. Caution should be exercised when coadministering statin-class drugs 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

Since advanced age (over 65 years) is a predisposing factor for myopathy, the drug should be prescribed with caution in elderly patients. In a study of atorvastatin for stroke prevention, the frequency of non-fatal hemorrhagic stroke was significantly higher in the group receiving atorvastatin compared to the placebo group. Certain baseline characteristics, including a history of hemorrhagic and lacunar stroke at study entry, were associated with a higher frequency of hemorrhagic stroke in the atorvastatin group (see section "Adverse reactions").

In a post-hoc analysis of the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, in which atorvastatin 80 mg versus placebo was administered to 4731 patients without ischemic heart disease who had a history of stroke or transient ischemic attack within the previous 6 months, 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 versus 33 cases, 1.4% in the placebo group; RR: 1.68; 95% CI: 1.09; 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar in both 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 frequency 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. There were no overall differences in safety and efficacy 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 ruled out. Since advanced age (over 65 years) is a predisposing factor for myopathy, atorvastatin should be prescribed with caution in elderly patients.

Hepatic insufficiency

Atorvastatin 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 to patients predisposed to developing rhabdomyolysis. Before initiating statin therapy in patients predisposed to rhabdomyolysis, CPK levels should be measured in the following cases:

• renal dysfunction;
• hypothyroidism;
• familial or personal history of hereditary muscle disorders;
• previous history of statin or fibrate myotoxicity;
• previous history of liver disease and/or excessive alcohol consumption.

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

Increased plasma levels of the drug are possible, particularly due to interactions and use in special patient populations, including patients with hereditary diseases.

In such cases, it is recommended to evaluate the risk-benefit ratio of treatment and perform clinical monitoring of patients. If baseline CPK levels are markedly elevated (exceeding ULN by more than five times), treatment should not be initiated.

Measurement of CPK levels

CPK levels should not be measured after intense physical exertion or in the presence of any possible alternative causes of elevated CPK, as this may complicate interpretation of results. If baseline CPK is 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 development of muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.

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

The need for discontinuation should also be considered if CPK elevation does not reach fivefold ULN but muscle symptoms are severe and cause daily discomfort.

After symptom resolution and normalization of CPK levels, reinitiation of atorvastatin therapy or initiation of an alternative statin may be considered, provided the lowest possible dose is used and close patient monitoring is maintained.

Atorvastatin therapy must be discontinued if clinically significant elevation of CPK 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 rhabdomyolysis increases with concomitant use of atorvastatin and certain medicinal products that may increase atorvastatin plasma concentration. 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, and darunavir. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibric acid derivatives, erythromycin, niacin, and ezetimibe. If possible, alternative medicinal products that do not interact with atorvastatin should be used instead of the above-mentioned drugs.

If concomitant therapy with atorvastatin and the mentioned drugs is necessary, the benefits and risks of concomitant therapy should be carefully weighed. If patients are taking medicinal products that increase atorvastatin plasma concentration, 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.

Concomitant administration of atorvastatin and fusidic acid is not recommended; therefore, temporary discontinuation of atorvastatin during fusidic acid treatment or for 7 days after discontinuation of fusidic acid should be considered. 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 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.

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

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 Escolan-Sanovel in patients receiving daptomycin unless the benefit outweighs the risk. If concomitant use cannot be avoided, creatine kinase levels should be monitored 2–3 times per week, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.

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, and fever). If interstitial lung disease is suspected, statin therapy should be discontinued.

Excipients

The drug contains lactose. This drug should not be administered to patients with rare hereditary conditions associated with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. Lipid-modifying 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 results from dietary restriction of saturated fats and cholesterol and other non-pharmacological measures are insufficient. Patients with ischemic heart disease or multiple risk factors for ischemic heart disease may initiate drug therapy concurrently with dietary measures. The medicinal product contains less than 1 mmol sodium (23 mg)/tablet. In this case, the drug should be used with caution in patients on a sodium-restricted diet.

Limitations of use

Atorvastatin has not been studied under conditions where the primary lipoprotein abnormality was elevated chylomicrons (Fredrickson types I and V).

Use during pregnancy or breastfeeding.

Pregnancy

Atorvastatin is contraindicated in pregnant women and women who may become pregnant, as the safety of its use during pregnancy has not been established and there is no clear benefit from lipid-lowering drugs during pregnancy. Statins may harm the fetus when administered to pregnant women, as HMG-CoA reductase inhibitors reduce cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol. Atorvastatin may be used in women of reproductive potential only if pregnancy is highly unlikely and patients have been informed of the potential risk factors. If a woman becomes pregnant during atorvastatin therapy, the drug should be immediately discontinued and the patient should be re-counseled regarding potential risks to the fetus and the lack of known clinical benefit from continuing the drug during pregnancy.

During normal pregnancy, serum cholesterol and triglyceride levels increase. The use of hypolipidemic drugs during pregnancy will not have a beneficial effect, as cholesterol and its derivatives are necessary for normal fetal development. Atherosclerosis is a chronic process; therefore, interruption of hypolipidemic drug therapy during pregnancy should not significantly impact the long-term outcomes of primary hypercholesterolemia treatment.

The background risk of major congenital malformations and miscarriages for 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 clinical cases on the use of atorvastatin calcium did not show an increased risk of major congenital malformations or miscarriages.

Rare reports of congenital anomalies after in utero exposure to other HMG-CoA reductase inhibitors have been received. Prospective observation of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed that the frequency of fetal congenital anomalies, miscarriages, and intrauterine deaths/stillbirths did not exceed the frequency 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 pregnant women under prospective observation, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Lactation

The drug is contraindicated during breastfeeding. It is unknown whether atorvastatin passes into human breast milk, but it is known that a small amount of another drug in this class passes into breast milk; atorvastatin is present in rat milk. Since statins may potentially cause serious adverse reactions in breastfed infants, women requiring atorvastatin therapy should not breastfeed their infants.

Ability to influence reaction speed when driving or operating machinery.

The medicinal product has a negligible effect on reaction speed when driving or operating machinery.

Method of Administration and Dosage.

Hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification)

The recommended initial dose of atorvastatin is 10 or 20 mg once daily. For patients requiring a substantial reduction in LDL-C levels (more than 45%), therapy may be initiated with a dose of 40 mg once daily. The dosage range of atorvastatin is 10 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 atorvastatin should be individually adjusted based on 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 initial dose 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 individually adjusted according to the recommended treatment goal. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous familial hypercholesterolemia

The dosage of the drug 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 used with bile acid sequestrants. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should be used with caution (see sections "Interaction with other medicinal products and other types of interactions" and "Special warnings and precautions for use").

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 impaired renal function 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

Concomitant use of atorvastatin should be avoided in patients taking cyclosporine or HIV protease inhibitors (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 used 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 the 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. When atorvastatin is coadministered with other protease inhibitors, appropriate clinical monitoring is recommended to ensure the use of the lowest necessary dose of the drug (see sections "Interaction with other medicinal products and other types of interactions" and "Special warnings and precautions for use").

Dosing in patients taking the hepatitis C antiviral elbasvir/grazoprevir

The dose of atorvastatin should not exceed 20 mg/day (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other types of interactions").

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
• family history of familial hypercholesterolemia or premature cardiovascular disease in first- or second-degree relatives, or
• presence of two or more other cardiovascular risk factors.

Indications for atorvastatin use have been confirmed based on 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 similar overall adverse reaction profile compared 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). The safety and efficacy of atorvastatin in lowering LDL-C generally corresponded to those observed in adult patients, despite the limitations of the uncontrolled study design.

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

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 8 pediatric patients with homozygous familial hypercholesterolemia.

Overdose.

In case of overdose, arterial hypotension may occur. Symptomatic therapy should be administered if necessary. Due to the high plasma protein binding of atorvastatin, hemodialysis is not effective. There is no specific antidote.

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed during 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 trials of atorvastatin, among 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), with a median treatment duration of 53 weeks, 9.7% of patients receiving atorvastatin and 9.5% of patients 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 leading to discontinuation of the drug, occurring 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 4 summarizes the frequency of clinical adverse reactions, regardless of causal relationship, reported in 2% or more of patients treated with atorvastatin (n=8,755) and at a higher frequency than in the placebo group, from 17 placebo-controlled trials.

Table 4
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
Peripheral 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
Back 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 placebo-controlled studies include:

General disorders: malaise, pyrexia;

Gastrointestinal disorders: gastrointestinal discomfort, flatulence, meteorism, hepatitis, cholestasis;

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

Metabolism and nutrition disorders: increased transaminases, abnormal liver function tests, increased blood alkaline phosphatase, increased CK activity, hyperglycaemia;

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 disorders: leucocyturia;

Reproductive system and breast disorders: gynaecomastia.

Atorvastatin is generally well tolerated. Adverse effects are usually mild and transient.

Frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Nervous system disorders: common – headache; uncommon – dizziness, paraesthesia, hypaesthesia, dysgeusia, amnesia; rare – peripheral neuropathy, insomnia, depression, nightmares, cognitive disorders (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion); frequency not known – myasthenia gravis.

Gastrointestinal disorders: common – constipation, flatulence, dyspepsia, diarrhoea, nausea; uncommon – pancreatitis, vomiting, abdominal pain, flatulence.

Musculoskeletal and connective tissue disorders: common – arthralgia, back pain, limb pain, joint pain, muscle spasms, joint swelling; rare – myopathy, myositis, neck pain, rhabdomyolysis, myalgia, necrotizing myopathy, vasculopathy that may lead to tendon rupture; frequency not known – immune-mediated necrotizing myopathy.

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

Metabolism and nutrition disorders: common – hypoglycaemia; uncommon – weight gain, anorexia, diabetes mellitus.

Hepatobiliary disorders: uncommon – hepatitis; rare – cholestasis; very rare – liver failure.

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

Respiratory, thoracic and mediastinal disorders: throat and laryngeal pain, nasopharyngitis, rare cases of interstitial lung disease.

Blood and lymphatic system disorders: rare – thrombocytopenia, epistaxis, stroke, including haemorrhagic stroke.

Vascular disorders: rare – vasculitis.

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

Eye disorders: rare – visual disturbance, blurred vision, clouding of vision; frequency not known – ocular myasthenia.

Renal and urinary disorders: urinary tract infections.

Reproductive system and breast disorders: very rare – gynaecomastia, sexual dysfunction.

Laboratory test abnormalities: common – abnormal liver function tests, increased blood CK activity; uncommon – positive leucocyte urine test, elevated transaminases, elevated blood alkaline phosphatase, hyperglycaemia.

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

Elevated serum CK activity more than 3 times the upper limit of normal was observed in 2.5% of patients receiving atorvastatin. This is consistent with observations during clinical trials with other HMG-CoA reductase inhibitors. In 0.4% of patients receiving atorvastatin, levels exceeded the upper limit of normal by more than 10 times.

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), receiving 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), no differences were observed 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 receiving atorvastatin 10 mg daily (n=5,006) or atorvastatin 80 mg daily (n=4,995), more serious adverse reactions and higher rates of drug discontinuation 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 elevations in transaminase levels (≥3 times the upper limit of normal on two occasions 4–10 days apart) were observed in 62 (1.3%) patients receiving atorvastatin 80 mg and in 9 (0.2%) patients receiving atorvastatin 10 mg. Elevations in CK levels (≥10 times the upper limit of normal) were generally low but higher in the high-dose atorvastatin 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 daily (n=4,439) or simvastatin 20–40 mg daily (n=4,449), no differences were observed 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 ischaemic attack (TIA) within the previous 6 months, receiving 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 the upper limit of normal on two occasions 4–10 days apart) was observed in the atorvastatin group (0.9%) compared to the placebo group (0.1%). Cases of CK elevation (≥10 times the 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 warnings and precautions for use").

A post-hoc analysis showed that atorvastatin 80 mg reduced the frequency of ischaemic stroke (218 of 2,365; 9.2% vs. 274 of 2,366; 11.6%) but increased the frequency of haemorrhagic stroke (55 of 2,365; 2.3% vs. 33 of 2,366; 1.4%) compared to placebo. The frequency of fatal haemorrhagic stroke was similar between groups (17 cases in the atorvastatin group vs. 18 in the placebo group). The frequency of non-fatal haemorrhagic stroke was significantly higher in the atorvastatin group (38 non-fatal haemorrhagic strokes) compared to the placebo group (16 non-fatal haemorrhagic strokes). Patients who entered the study with a history of haemorrhagic stroke had an increased risk of haemorrhagic stroke (7 (16%) in the atorvastatin group vs. 2 (4%) in the placebo group).

No significant differences in all-cause mortality were observed between treatment groups: 216 (9.1%) in the atorvastatin 80 mg daily 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 studies of atorvastatin in children

In a 26-week controlled study in boys and girls after onset of menstruation with heterozygous familial hypercholesterolaemia (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 liver failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease.

Rare cases of immune-mediated necrotizing myopathy (IMNM) associated with statin use have been reported (see section "Special warnings and 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 serious adverse reactions and were reversible upon discontinuation of statin therapy, with variable onset time (from one day to several years) and resolution time (median duration 3 weeks).

Undesirable effects reported with some statins include sexual dysfunction; rare cases of interstitial lung disease, particularly with long-term treatment.

The following adverse reactions have been 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.

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

Laboratory test abnormalities: elevated alanine aminotransferase activity, elevated blood CK activity.

Shelf life. 5 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging. 10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Sanovel Ilac Sanayi ve Ticaret A.S.

Manufacturer's address and place of business.

Balaban Quarter, Cihangir Street No. 10, Silivri, Istanbul, 34580, Turkey.