INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATORVASTEROL (ATORVASTEROL®)

Composition:

Active substance: atorvastatin;

One film-coated tablet contains 10.36 or 20.72 or 41.44 mg of atorvastatin calcium, equivalent to 10 or 20 or 40 mg of atorvastatin, respectively;

Excipients: mannitol (E 421), microcrystalline cellulose, calcium carbonate, povidone, sodium croscarmellose, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, titanium dioxide (E 171), macrogol 6000, talc.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

10 mg: film-coated tablets, white, round, biconvex, 7 mm in diameter;

20 mg: film-coated tablets, white, round, biconvex, 9 mm in diameter;

40 mg: film-coated tablets, white, oval, biconvex, 8.2×17 mm in size.

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

Pharmacological Properties.

Pharmacodynamics.

Atorvastatin is a synthetic hypolipidemic medicinal agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early step in cholesterol biosynthesis that limits the rate of its formation.

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. Cholesterol and triglycerides circulate in the bloodstream in complexes with lipoproteins. These complexes are separated by ultracentrifugation into fractions of HDL (high-density lipoproteins), IDL (intermediate-density lipoproteins), LDL (low-density lipoproteins), and VLDL (very low-density lipoproteins). Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into plasma for transport to peripheral tissues. LDL is formed from VLDL and is catabolized via interaction with high-affinity LDL receptors. Clinical and pathological studies indicate that elevated levels of total cholesterol (TC), LDL cholesterol (LDL-C), and apolipoprotein B (apo B) in plasma contribute to the development of atherosclerosis in humans and are risk factors for cardiovascular disease, whereas elevated HDL cholesterol levels are associated with a reduced risk of cardiovascular disease.

Elevated levels of total cholesterol, LDL cholesterol, and apo B (the membrane complex for LDL cholesterol) promote the development of atherosclerosis. Similarly, reduced levels of HDL cholesterol (and its transport complex, apo A) are associated with the development of atherosclerosis.

Epidemiological studies have established that cardiovascular disease and mortality are directly proportional to the levels of total cholesterol and LDL cholesterol and inversely proportional to the level of HDL cholesterol.

Atorvastatin reduces levels of total cholesterol, LDL cholesterol, and apo B in patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin also reduces levels of VLDL cholesterol and triglycerides and causes a transient increase in HDL cholesterol and apolipoprotein A-1 levels. Atorvastatin reduces total cholesterol, LDL cholesterol, VLDL cholesterol, apo B, triglycerides, and non-HDL cholesterol, and increases HDL cholesterol levels in patients with isolated hypertriglyceridemia. Atorvastatin reduces IDL cholesterol in patients with dysbetalipoproteinemia.

Similar to LDL, lipoproteins enriched with cholesterol and triglycerides, including VLDL, IDL, and remnants, may also contribute to the development of atherosclerosis. Elevated plasma triglyceride levels are often found in a triad with low HDL cholesterol levels and small LDL particles, as well as in combination with non-lipid metabolic risk factors for ischemic heart disease. It has not been consistently demonstrated that total plasma triglyceride levels per se are an independent risk factor for ischemic heart disease. Furthermore, an independent effect of increasing HDL cholesterol levels or decreasing triglyceride levels on the risk of coronary and cardiovascular disease and mortality has not been established.

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, rather than systemic drug concentration, correlates better with the reduction in LDL cholesterol levels. Individual dose adjustment should be based on the therapeutic response (see section "Dosage and Administration").

Pharmacokinetics.

Absorption. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentrations reached within 1–2 hours. The extent of absorption increases proportionally with the dose of the drug. 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 intestinal mucosa and/or pre-systemic biotransformation in the liver. Although food reduces the rate and extent of drug absorption by approximately 25% and 9%, respectively, based on Cmax and AUC values, the reduction in LDL cholesterol levels is similar regardless of whether atorvastatin is taken with food or separately. When atorvastatin is administered in the evening, its plasma concentration is lower (approximately 30% for Cmax and AUC) compared to morning administration. However, the reduction in LDL cholesterol levels is the same regardless of the time of administration (see section "Dosage and Administration").

Distribution. The mean volume of distribution of the drug is approximately 381 liters. Over 98% of the drug is bound to plasma proteins. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes. Based on observations in rats, atorvastatin is considered capable of passing into breast milk (see sections "Contraindications," "Pregnancy and Breastfeeding," and "Special Warnings").

Metabolism. Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro studies show that the inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of the circulating HMG-CoA reductase inhibitory activity is attributed to active metabolites. In vitro studies indicate the importance of atorvastatin metabolism by cytochrome P450 3A4 (CYP3A4), consistent with increased atorvastatin plasma concentrations in humans after co-administration 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 excreted in bile after hepatic and/or extrahepatic metabolism, although this drug apparently does not undergo enterohepatic recirculation. The mean elimination half-life of the drug in human plasma is approximately 14 hours, but the half-life of HMG-CoA reductase inhibitory activity is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of the dose is excreted in urine after oral administration.

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 multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.

Elderly patients. Atorvastatin plasma concentrations are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly patients (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 individuals (see section "Special Warnings").

Children. Pharmacokinetic data in pediatric patients are lacking.

Gender. Atorvastatin plasma concentrations 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 the reduction of LDL cholesterol levels when atorvastatin is administered to men and women.

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

Hemodialysis. Although studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance drug clearance, as the drug is extensively bound to plasma proteins.

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

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

Effect of concomitantly administered drugs on atorvastatin pharmacokinetics

Table 1

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	3.23	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
#Rifampin 600 mg once daily, 7 days (co-administered) †	40 mg once daily	1.12	2.90
#Rifampin 600 mg once daily, 5 days (separate doses) †	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 versus atorvastatin used alone).

For information on clinical relevance, see sections "Special warnings and 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 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 combination of saquinavir + ritonavir used in this study is not a clinically applicable dose. The increase in atorvastatin exposure under clinical use 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.

Effect of atorvastatin on the pharmacokinetics of concomitantly administered medicinal products

Table 2

Atorvastatin	Concomitantly administered drug 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 ischemic heart disease, such as age, tobacco smoking, arterial hypertension, low HDL-C levels, or a family history of premature ischemic heart disease, Atorvasterol 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, microalbuminuria, tobacco smoking, or arterial hypertension, Atorvasterol 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, Atorvasterol 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 adult patients

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

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

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

• To reduce total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or when such treatments are unavailable.

In children

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

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

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

• a family history of premature cardiovascular disease, or
• two or more other cardiovascular risk factors are present in the pediatric patient.

Contraindications.

• Active liver disease, which may include persistent elevations of hepatic transaminases of unknown etiology.
• Hypersensitivity to any component of this medicinal product.
• Treatment of hepatitis C with antiviral agents – glecaprevir/pibrentasvir.
• Pregnancy.
• Breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Effect of concomitantly administered drugs on atorvastatin

Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate of hepatic transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin (see section "Pharmacokinetics"). The risk of developing myopathy during statin therapy increases with concomitant use of 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 "Special warnings and precautions for use" and "Pharmacological properties").

Potent CYP3A4 inhibitors.

Concomitant use of the medicinal product with potent CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see detailed information below). The extent of interaction and effect enhancement depends on the variability of the effect on CYP3A4. Concomitant use with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for hepatitis C treatment (e.g., elbasvir/grazoprevir), and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided if possible. If concomitant use with atorvastatin 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. It is known that amiodarone and verapamil inhibit CYP3A4 activity; therefore, concomitant administration 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 prescribing 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. Such monitoring is also recommended after initiating treatment with an inhibitor or adjusting its dose.

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

Clarithromycin. The AUC of atorvastatin significantly increased when atorvastatin 80 mg was co-administered with clarithromycin (500 mg twice daily) compared to atorvastatin alone (see section "Pharmacological properties"). Therefore, patients taking clarithromycin should use atorvastatin cautiously at doses above 20 mg (see sections "Special warnings and precautions for use" and "Dosage and administration").

Combination of protease inhibitors. The AUC of atorvastatin significantly increased when the medicinal product was co-administered with several combinations of HIV protease inhibitors, as well as with the hepatitis C virus protease inhibitor telaprevir, compared to atorvastatin alone (see section "Pharmacological properties"). Patients taking HIV protease inhibitors tipranavir + ritonavir or glecaprevir + pibrentasvir should avoid concomitant use with atorvastatin. The medicinal product should be prescribed cautiously to patients taking HIV protease inhibitors lopinavir + ritonavir and used at the lowest necessary dose. For patients taking HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, or elbasvir + grazoprevir, the atorvastatin dose should not exceed 20 mg, and these drugs should be used cautiously. When administered to patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, the atorvastatin dose should not exceed 40 mg, and careful clinical monitoring of patients is also recommended (see sections "Special warnings and precautions for use" and "Dosage and administration").

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

Cyclosporine. Atorvastatin is a substrate of hepatic transporters. Atorvastatin metabolites are substrates of the OATP1B1 transporter. Inhibitors of OATP1B1 (e.g., cyclosporine) may increase the bioavailability of atorvastatin. The AUC of atorvastatin significantly increased when the medicinal product 10 mg was co-administered 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 warnings and precautions for use").

Medical recommendations for the use of interacting medicinal products are summarized in Table 1 (see also sections "Dosage and administration", "Special warnings and precautions for use").

Letermovir. Concomitant use 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 CYP3A4- and OATP1B1/1B3-mediated drug interactions with concomitant medications may vary when letermovir is used 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 lead to increased atorvastatin plasma concentrations and an increased risk of myopathy.

When glecaprevir and pibrentasvir are co-administered with atorvastatin, atorvastatin plasma concentration increases up to 8.3-fold, partially due to inhibition of BCRP, OATP1B1/1B3, and CYP3A4; therefore, concomitant use of Atorvasterol with medicinal products containing glecaprevir and pibrentasvir is not recommended.

When elbasvir and grazoprevir are co-administered with atorvastatin, atorvastatin plasma concentration increases up to 1.9-fold, partially due to inhibition of BCRP, OATP1B1/1B3, and CYP3A4; therefore, the atorvastatin dose should not exceed 20 mg daily when administered to patients concomitantly taking medicinal products containing elbasvir and grazoprevir (see sections "Dosage and administration", "Special warnings and precautions for use", and "Pharmacokinetics").

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

Drug interactions associated with an increased risk of myopathy/rhabdomyolysis

Table 3

Interacting drugs	Medical recommendations for use
Cyclosporine, tipranavir + ritonavir, letermovir when used concomitantly with cyclosporine	Avoid use of atorvastatin
Glecaprevir + pibrentasvir	Concomitant use with medicinal products containing glecaprevir or pibrentasvir is contraindicated (see section "Contraindications")
Clarithromycin, itraconazole, saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, letermovir	Do not exceed 20 mg of atorvastatin per day
Nelfinavir	Do not exceed 40 mg of atorvastatin per day
Lopinavir + ritonavir, simeprevir, fibrinic 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 combined use of atorvastatin with gemfibrozil should be avoided (see section "Special precautions").

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

Niacin. The risk of adverse skeletal muscle effects increases when the drug is used in combination with niacin; therefore, under such conditions, consideration should be given to reducing the dose of atorvastatin (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 has been shown to be associated with a significant reduction in atorvastatin plasma concentrations.

Diltiazem hydrochloride

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

Cimetidine

Studies have shown no evidence of interaction between atorvastatin and cimetidine.

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 was not altered.

Colestipol

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

Transport protein inhibitors

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

Ezetimibe

The use of ezetimibe as monotherapy has been associated with adverse effects on the muscular system, including rhabdomyolysis. Thus, when ezetimibe and atorvastatin are used concomitantly, the risk of these effects increases. Appropriate clinical monitoring of such patients is recommended.

Fusidic acid

Studies on the interaction between atorvastatin and fusidic acid have not been conducted. As with other statins, during the post-marketing period, adverse effects on the muscular system (including rhabdomyolysis) have been observed with concomitant use of atorvastatin and fusidic acid. The mechanism of this interaction remains unknown. Patients require close monitoring, and temporary discontinuation of atorvastatin therapy may be necessary.

Digoxin. Concomitant administration of multiple doses of atorvastatin and digoxin increases steady-state digoxin plasma concentrations by approximately 20%. Patients receiving 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 undergoing 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.

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

Other medicinal products

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

Special precautions for use.

Musculoskeletal system

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

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

Rare 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 levels that persist despite discontinuation of statin therapy; muscle biopsy reveals necrotic myopathy without significant inflammation; a positive response to immunosuppressive therapy is observed.

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

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

Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine; therefore, atorvastatin should be prescribed with caution when used concomitantly with colchicine (see section "Interaction with other medicinal products and other forms of interaction").

Atorvastatin therapy should be temporarily or permanently discontinued in any patient with an acute serious condition suggestive of developing myopathy or in the presence of risk factors for renal failure due to rhabdomyolysis (e.g., severe acute infection, arterial hypotension, surgery, trauma, severe metabolic, endocrine, or electrolyte disturbances, and uncontrolled seizures).

Cases of de novo occurrence or exacerbation of pre-existing myasthenia gravis or ocular myasthenia have been reported following statin use (see section "Adverse reactions"). The use of atorvastatin should be discontinued if symptoms worsen. Recurrences have been reported upon re-exposure to the same or another statin.

Hepatic function

Statins, like some other hypolipidemic agents, have been associated with abnormalities in liver function tests. Persistent increases in serum transaminases (more than 3 times above the upper limit of normal, occurring on two or more occasions) have been observed in patients receiving atorvastatin in clinical trials.

One case of jaundice has been reported. Elevated liver function test (LFT) values in other patients were not associated with jaundice or other clinical symptoms. Transaminase levels returned to pre-treatment or near pre-treatment levels after dose reduction, temporary interruption, or discontinuation of the drug, without residual effects. More than half of patients with persistent elevations in liver function tests continued atorvastatin therapy 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. Treatment should be immediately discontinued in cases of serious liver injury with clinical symptoms of hyperbilirubinemia or jaundice during atorvastatin therapy. Reinitiation of treatment should not be considered unless an alternative etiology is identified.

Atorvastatin should be prescribed with caution in patients who consume large amounts of 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").

Endocrine function

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

Statins inhibit cholesterol synthesis and may theoretically impair adrenal and/or gonadal steroid hormone secretion. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effect of statins on sperm fertility has not been adequately studied in a sufficient number of patients. It is unknown whether the drug affects, or has any effect at all, on the hypothalamic-pituitary-gonadal axis in premenopausal women. Caution should be exercised when coadministering statins with medicinal products that may reduce levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Use in patients after recent stroke or transient ischemic attack

In a clinical trial where atorvastatin 80 mg was administered to 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. The incidence of fatal hemorrhagic stroke was similar across all treatment groups. The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group compared to the placebo group. Certain baseline characteristics, including a history of hemorrhagic and lacunar stroke at enrollment, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group (see section "Adverse reactions").

No differences in safety and efficacy of the drug were observed between patients aged 65 to 75 years and those aged 75 years or older, nor were there any differences in treatment response between elderly and younger patients; however, increased sensitivity in some elderly patients cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, atorvastatin should be prescribed with caution in elderly patients.

Hepatic impairment

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

Before starting treatment

Atorvastatin should be prescribed with caution in patients predisposed to rhabdomyolysis. Prior to initiating statin therapy in patients predisposed to rhabdomyolysis, CPK levels should be measured in the following cases:

-impaired renal function;

-hypothyroidism;

-personal or family history of inherited muscle disorders;

-prior history of statin- or fibrate-induced myotoxicity;

-prior history of liver disease and/or heavy alcohol consumption.

For elderly patients (≥70 years), the necessity of these measures should be evaluated considering the presence of other risk factors for rhabdomyolysis.

Increased plasma drug levels may occur, particularly due to drug interactions or in specific patient populations, including those with inherited disorders.

In such cases, a risk-benefit assessment of treatment is recommended, along with clinical monitoring of patients. If baseline CPK levels are markedly elevated (more than 5 times above the upper limit of normal), treatment should not be initiated.

Measurement of creatine kinase levels

CPK levels should not be measured following 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 significantly elevated (exceeding the upper limit of normal by more than 5 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 any onset 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. If CPK levels are markedly elevated (exceeding the upper limit of normal by more than 5 times), treatment should be discontinued.

Discontinuation of treatment should also be considered if CPK elevation does not exceed 5 times the upper limit of normal but muscle symptoms are severe, intolerable, and persist daily.

After resolution of symptoms 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 monitoring is maintained.

Atorvastatin treatment must be discontinued if clinically significant CPK elevation (exceeding the upper limit of normal by more than 10 times) occurs or if rhabdomyolysis is diagnosed (or suspected).

Concomitant use with other medicinal products

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 discontinuing atorvastatin in patients receiving daptomycin unless the benefit outweighs the risk. If concomitant use cannot be avoided, CPK 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 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, darunavir, and tipranavir/ritonavir. Concomitant use with gemfibrozil and other fibric acid derivatives, antiviral agents for hepatitis C treatment (e.g., boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, niacin, or ezetimibe also increases the risk of myopathy. Where possible, alternative medicinal products (not interacting with atorvastatin) should be used instead of the above-mentioned agents.

If concomitant therapy with atorvastatin and these agents is necessary, the benefits and risks 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 lowest level. Additionally, when using potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered. Appropriate clinical monitoring of these patients is also recommended.

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

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

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

Pulmonary interstitial disease

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

Lipid-modifying therapy should be one component of comprehensive management in patients at significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Pharmacological therapy is recommended as an adjunct to diet when dietary restriction of saturated fats and cholesterol, along with other non-pharmacological measures, has been insufficient. In patients with ischemic heart disease or multiple risk factors for ischemic heart disease, atorvastatin may be initiated concurrently with dietary changes.

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).

Use during pregnancy or breastfeeding

Pregnancy

Atorvastatin is contraindicated in pregnant women and women who may become pregnant, as safety during pregnancy has not been established and there is no clear benefit of lipid-lowering drugs 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. Treatment with atorvastatin should be discontinued as soon as pregnancy is confirmed (see section "Contraindications").

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

Contraception

Atorvastatin may harm the fetus if used during pregnancy. Women of childbearing potential must 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 atorvastatin calcium do not indicate an increased risk of serious congenital malformations or spontaneous abortions.

Rare reports of congenital anomalies have been received following in utero exposure to other HMG-CoA reductase inhibitors. Prospective observation of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed that the rates of fetal congenital anomalies, spontaneous abortions, and intrauterine deaths/stillbirths did not exceed those expected in the general population. The number of cases is sufficient to exclude a ≥3–4-fold increase in fetal 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.

Lactation

Atorvastatin is contraindicated during breastfeeding. There is no information on the effect of the drug on the breastfed infant or on lactation. It is unknown whether atorvastatin passes into human breast milk; however, small amounts of another drug in this class have been shown to pass into breast milk, and atorvastatin has been detected in rat milk. Since statins may potentially 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

The effect on reaction speed during driving or operating machinery is negligible.

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 marked reduction in LDL-cholesterol levels (more than 45%), therapy may be initiated with a dose of 40 mg once daily. The dosage range of the drug is from 10 to 80 mg once daily. The drug can be taken as a single daily dose at any time, regardless of food intake. Initial and maintenance doses should be individually adjusted depending on the treatment goal and patient response. After initiation of treatment and dose titration of atorvastatin, lipid levels should be analyzed within 2 to 4 weeks and the dose adjusted accordingly.

Heterozygous familial hypercholesterolemia in pediatric patients (10–17 years of age)

The recommended initial dose is 10 mg/day; the maximum recommended dose is 20 mg/day (doses exceeding 20 mg have not been studied in this patient group). Doses should be individually adjusted according to the recommended treatment goals. 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 as primary therapy if lipid-lowering treatments are unavailable.

Concomitant lipid-lowering therapy

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

Dosing in patients with renal impairment

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

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

Treatment with atorvastatin should be avoided in patients taking cyclosporine, HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitors (telaprevir). Atorvastatin should be administered with caution to HIV patients receiving lopinavir + ritonavir and should be used at the lowest necessary dose. For patients taking clarithromycin or itraconazole, and for HIV patients receiving saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the therapeutic dose of atorvastatin should be limited to 20 mg, and appropriate clinical monitoring is recommended to determine the lowest necessary dose of atorvastatin. For patients receiving the hepatitis C virus protease inhibitors elbasvir/grazoprevir concomitantly with atorvastatin, the atorvastatin dose should not exceed 20 mg/day (see section "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction"). For patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, atorvastatin treatment should be limited to a dose of 40 mg, and appropriate clinical monitoring is recommended to determine the lowest necessary dose of atorvastatin (see section "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children.

Heterozygous familial hypercholesterolemia

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

• LDL-cholesterol ≥ 190 mg/dL (4.91 mmol/L), or
• LDL-cholesterol ≥ 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.

The indication for use of Atorvasterol is supported by evidence from:

• a 6-month placebo-controlled clinical study involving 187 boys and girls after onset of menstruation, aged 10 to 17 years. Patients receiving Atorvasterol at doses of 10 mg or 20 mg daily had generally similar adverse reaction profiles 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 doses were titrated to achieve a target LDL-cholesterol level < 130 mg/dL (3.36 mmol/L). The safety and efficacy of Atorvasterol in reducing LDL-cholesterol were generally consistent with those observed in adult patients, despite the limitations of the uncontrolled study design.

Counseling on contraception should be provided to girls after onset of menstruation, as appropriate for the patient.

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

The safety and efficacy of Atorvasterol 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/day over 1 year was evaluated in an uncontrolled study in patients with homozygous familial hypercholesterolemia, which included 8 children.

Overdose.

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

Adverse Reactions

The most commonly reported adverse reactions in patients receiving atorvastatin therapy that led to discontinuation of the drug and occurred more frequently than in the placebo group were: myalgia, diarrhea, nausea, increased alanine aminotransferase (ALT) levels, and elevated liver enzymes.

The most frequently observed adverse reactions in patients treated with atorvastatin (regardless of causal relationship) were: nasopharyngitis, arthralgia, diarrhea, limb pain, and urinary tract infection.

Other adverse reactions include:

General disorders: malaise, pyrexia;

Gastrointestinal disorders: gastrointestinal discomfort, belching, flatulence, hepatitis, cholestasis, dyspepsia;

Musculoskeletal system disorders: musculoskeletal pain, increased muscle fatigue, neck pain, joint swelling, muscle rupture, tendinopathy (sometimes complicated by tendon rupture), muscle spasms, lupus-like syndrome; frequency unknown – myasthenia gravis.

Metabolism and nutrition disorders: elevated transaminases, abnormal liver function tests, increased alkaline phosphatase in blood, increased creatine phosphokinase activity, hyperglycemia;

Nervous system disorders: nightmares, insomnia;

Respiratory system disorders: epistaxis;

Skin and appendages disorders: urticaria;

Eye disorders: blurred vision, visual disturbances;

Ear and labyrinth disorders: tinnitus;

Renal and urinary system disorders: leukocyturia;

Reproductive system and breast disorders: gynecomastia.

The frequency of adverse reactions was defined as follows: common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000).

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

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

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

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

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

Hepatobiliary disorders: very rare: hepatic failure.

Skin and connective tissue disorders: skin rash, 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: common: throat and larynx pain.

Vascular disorders: rare: vasculitis.

Blood and lymphatic system disorders: rare: thrombocytopenia.

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

Eye disorders: uncommon: blurred vision; frequency unknown – ocular myasthenia.

Laboratory test abnormalities: common: abnormal liver function tests, increased blood creatine phosphokinase activity; uncommon: positive urine leukocyte test.

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 increases in serum transaminase activity (more than three times the upper limit of normal) were observed in patients treated with atorvastatin. This increase was dose-dependent and reversible in all patients.

In some patients taking atorvastatin, creatine kinase serum activity increased to more than three times above the upper limit of normal. This phenomenon has also been observed with other HMG-CoA reductase inhibitors. In other patients receiving atorvastatin, levels exceeding the upper limit of normal by more than tenfold were observed.

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

In the ASCOT study, patients received atorvastatin 10 mg daily or placebo; the safety and tolerability profile in the atorvastatin group was comparable to that in the placebo group.

In the CARDS study, patients received atorvastatin 10 mg daily or placebo – no differences were observed in the overall frequency of adverse reactions or serious adverse reactions between the groups. No cases of rhabdomyolysis were reported.

In the TNT study, in patients with clinically evident coronary heart disease receiving either atorvastatin 10 mg daily or atorvastatin 80 mg daily, more severe adverse reactions and higher rates of drug discontinuation due to adverse reactions were observed in the high-dose atorvastatin group compared to the low-dose group. Persistent elevations in transaminase levels (≥3 times the upper limit of normal range, confirmed twice within 4–10 days) were observed in both the 80 mg and 10 mg atorvastatin groups. Elevations in creatine kinase (≥10 times the upper limit of normal range) were generally low but were higher in the high-dose atorvastatin group compared to the low-dose group.

In the IDEAL study, no differences were observed in the overall frequency of adverse reactions or serious adverse reactions between the groups.

In the SPARCL study involving patients 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 or placebo, a higher incidence of persistent elevation in liver transaminases (≥3 times the upper limit of normal range, confirmed twice within 4–10 days) was observed in the atorvastatin group compared to placebo. Cases of creatine kinase elevation (≥10 times the upper limit of normal) were rare but occurred more frequently in the atorvastatin group than in the placebo group. Diabetes mellitus was reported as an adverse reaction in both the atorvastatin and placebo groups (see section "Special warnings and precautions for use").

A retrospective analysis showed that atorvastatin 80 mg reduced the incidence of ischemic stroke but increased the incidence of hemorrhagic stroke compared to placebo.

No significant differences between treatment groups in all-cause mortality were observed. A numerically higher number of non-cardiovascular deaths occurred in the atorvastatin 80 mg group compared to the placebo group.

Post-marketing experience

During post-marketing use of atorvastatin, the following adverse reactions have been reported. Since these reactions were reported voluntarily and the patient population size is unknown, 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 include: anaphylaxis, angioedema, bullous skin eruptions (including exudative multiform erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis), rhabdomyolysis, increased fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis, and interstitial lung disease.

Rare post-marketing reports of immune-mediated necrotizing myopathy associated with statin use have been received (see section "Special warnings and precautions for use").

Rare post-marketing reports of cognitive disorders (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been reported. These cognitive disorders have been observed with all statins. The adverse reactions were generally not serious and were reversible after discontinuation of statins, with variable time to onset of symptoms (from 1 day to several years) and symptom resolution (median duration 3 weeks).

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

Adverse reactions reported during post-marketing surveillance include:

Blood and lymphatic system disorders: thrombocytopenia.

Immune system disorders: allergic reactions, anaphylaxis (including anaphylactic shock).

Metabolism and nutrition disorders: weight gain.

Nervous system disorders: headache, hypesthesia, dysgeusia.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

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

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

Laboratory test abnormalities: increased alanine aminotransferase activity, increased blood creatine phosphokinase activity.

Pediatric population (ages 10–17 years)

In a 26-week controlled study in boys and girls after onset of menstruation, the safety and tolerability profile of atorvastatin at doses of 10–20 mg daily was generally similar to that of placebo (see sections "Dosage and administration", "Pediatric population").

Shelf life. 2 years.

Do not use the medication after the expiry date.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister. 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pharmaceutical Works "Polpharma" S.A., Poland.

Manufacturer's address and place of business.

19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.