INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIVOSTOR (LIVOSTOR)

Composition:

Active substance: atorvastatin;

One tablet contains calcium atorvastatin trihydrate equivalent to 10 mg, or 20 mg, or 40 mg of atorvastatin;

Excipients: hydroxypropylcellulose, polysorbate 80, sodium lauryl sulfate, lactose monohydrate, calcium carbonate, microcrystalline cellulose, sodium croscarmellose, magnesium stearate;

Coating: film-coating mixture Opadry II White (hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide (E 171), triacetin).

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group. Drugs that reduce cholesterol and triglyceride levels in blood serum. HMG-CoA reductase inhibitors. ATC code C10AA05.

Pharmacological properties.

Pharmacodynamics.

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

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

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

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

Pharmacokinetics.

Absorption. Levostor is rapidly absorbed after oral administration, and peak plasma concentration is reached within 1–2 hours. The extent of absorption increases proportionally with the dose of Levostor. The absolute bioavailability of atorvastatin (parent drug) is approximately 14%, while the systemic bioavailability of HMG-CoA reductase inhibitory activity is about 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, based on Cmax and AUC (area under the concentration-time curve), the reduction in LDL cholesterol levels is similar when Levostor is taken with or without food. When atorvastatin is administered in the evening, plasma concentrations are lower (approximately 30% lower based on Cmax and AUC) than when administered in the morning. However, the reduction in LDL cholesterol levels is similar regardless of the time of administration (see section "Dosage and administration").

Distribution. The mean volume of distribution of Levostor 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, Levostor is considered capable of passing into breast milk (see sections "Contraindications" and "Special precautions").

Metabolism. Levostor is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro studies show that the HMG-CoA reductase inhibition by ortho- and parahydroxylated metabolites is equivalent to that of the parent drug Levostor. Approximately 70% of circulating HMG-CoA reductase inhibitory activity is attributed to active metabolites. In vitro studies indicate that metabolism of Levostor is mediated primarily by cytochrome P450 3A4 (CYP3A4), consistent with increased plasma concentrations of Levostor 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").

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

Special patient populations

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

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

Gender. Plasma concentrations of Levostor in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC).

However, there is no clinically significant difference in LDL cholesterol reduction between men and women when treated with Levostor.

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

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

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

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

Table 1

Effect of concomitantly administered drugs on the pharmacokinetics of atorvastatin

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

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

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

** Ratios based on a single sample 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 reduction 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 use 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	Concomitantly administered 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".

The use of the medicinal product Levostor did not clinically significantly affect prothrombin time in patients receiving long-term warfarin therapy.

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases in adults

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

• reducing the risk of myocardial infarction;
• reducing the risk of stroke;
• reducing the risk of revascularization procedures and angina.

For adult patients with type 2 diabetes mellitus and without clinically evident ischemic heart disease, but with multiple risk factors for developing ischemic heart disease, such as retinopathy, albuminuria, smoking, or arterial hypertension, the medicinal product Levostor is indicated for:

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

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

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

Hyperlipidemia.

In adults

• 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 insufficiently effective.
• 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 levels of total cholesterol, LDL-C, and apolipoprotein B in children aged 10 to 17 years with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy the following criteria are met:

a) LDL-C 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.

Interaction with other medicinal products and other forms of interaction.

The medicinal product Levostor is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Plasma levels of Levostor may be significantly increased when co-administered with inhibitors of CYP3A4 and transporters. Table 3 lists medicinal products that may increase exposure to Levostor and the risk of myopathy and rhabdomyolysis when used concomitantly, along with recommendations for managing and preventing such risks (see sections "Special precautions for use" and "Pharmacological properties").

Table 3

Interaction with other medicinal products that may increase the risk of myopathy and rhabdomyolysis during treatment with Levostor

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

Table 4

Interaction with medicinal products that may reduce exposure to the medicinal product Levostor

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

Table 5

Effect of the medicinal product Levostor on other medicinal products

Oral contraceptives
Clinical effect	Concomitant use of the medicinal product Levostor and oral contraceptives increased plasma concentrations of norethisterone and ethinylestradiol (see section "Pharmacological properties").
Management	This fact should be taken into account when selecting an oral contraceptive for patients taking Levostor.
Digoxin
Clinical effect	When multiple doses of the medicinal product Levostor and digoxin are used concomitantly, digoxin plasma trough concentrations are increased (see section "Pharmacological properties").
Management	Patients taking digoxin should be appropriately monitored.

Diltiazem hydrochloride.

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

Cimetidine.

Studies have not revealed 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 concentrations. However, the hypolipidemic effect of atorvastatin remains unchanged.

Cholestyramine.

Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when administered concomitantly with cholestyramine. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and cholestyramine exceeds the effect achieved by administration of each drug separately.

Azithromycin.

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

Transport inhibitors.

Inhibitors of transport proteins (e.g., cyclosporine, letermovir) may increase systemic exposure to atorvastatin (see Table 1). The impact of inhibition of uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant administration 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 events increases when ezetimibe is used concomitantly with atorvastatin. Appropriate clinical monitoring of these patients is recommended.

Fusidic acid.

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

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

Other medicinal products.

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

Special precautions for use.

Myopathy and rhabdomyolysis

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

Myopathy risk factors

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

Measures to reduce or prevent the risk of myopathy and rhabdomyolysis

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

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

Treatment with Livostor should be discontinued if markedly elevated CK levels are observed or if myopathy is diagnosed or suspected. Muscle symptoms and elevated CK levels resolve after discontinuation of Livostor. Livostor should be temporarily discontinued in patients with acute or serious conditions at high risk of renal failure due to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disturbances; uncontrolled epilepsy).

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

Immune-mediated necrotizing myopathy

Rare cases of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with statin use, have been reported. IMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy; positive antibodies to HMG-CoA reductase; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive therapy. Additional neuromuscular and serological investigations may be required. Immunosuppressive therapy may be needed. The risk of IMNM should be carefully considered before initiating another statin. If therapy with another statin is initiated, monitoring for signs and symptoms of IMNM is necessary.

Hepatic function

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

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

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

Livostor should be prescribed with caution in patients who consume alcohol excessively and/or have a history of liver disease. Livostor 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 Livostor.

Statins inhibit cholesterol synthesis and may theoretically impair adrenal and/or gonadal steroid hormone secretion. Clinical studies have shown that Livostor 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 on the hypothalamic-pituitary-gonadal system in premenopausal women. Caution should be exercised when co-administering statin-class drugs with medicinal products that may reduce levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Use in patients with recent stroke or transient ischemic attack

In a post-hoc analysis of the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, in which atorvastatin 80 mg was administered versus placebo 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 vs. 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 across treatment groups (17 and 18 in the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) compared to the placebo group (16, 0.7%). Certain baseline characteristics, including a history of hemorrhagic and lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group (see section "Adverse reactions").

Among 39,828 patients who received atorvastatin in clinical trials, 15,813 (40%) were aged 65 years or older, and 2,800 (7%) were aged 75 years or older. No overall differences in safety and efficacy were observed between these patients and younger patients, nor were there any differences in treatment response between elderly and younger patients according to other clinical experience; however, increased sensitivity of some elderly patients cannot be excluded. Since advanced age (over 65 years) is a risk factor for myopathy, Livostor should be prescribed with caution in elderly patients.

Hepatic impairment

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

Before starting treatment

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

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

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

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

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

Measurement of creatine kinase levels

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

During treatment

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

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

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

After resolution of symptoms and normalization of CK levels, 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 elevation of CK levels (exceeding ULN by more than 10 times) is observed or if rhabdomyolysis is diagnosed (or suspected).

Concomitant use with other medicinal products

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

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

Atorvastatin must not be co-administered with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom systemic fusidic acid is considered necessary, statin therapy should be suspended for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis (including fatal cases) have been reported in patients receiving fusidic acid and statins in combination (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 treatment is required (e.g., for treatment of severe infections), the need for concomitant use of Livostor and fusidic acid should be considered on an individual basis and under close physician supervision.

Interstitial lung disease

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

Excipients

The medicinal product contains lactose. This product should not be taken by patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Lipid-modifying drug therapy should be one component of comprehensive therapy for patients at significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when dietary restriction of saturated fat 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, treatment with Livostor may be initiated concurrently with dietary measures.

Limitations of use

The medicinal product has not been studied under conditions where the primary lipoprotein abnormality is elevated chylomicrons (Fredrickson types I and V).

Use during pregnancy or breastfeeding

Pregnancy

Risk assessment

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

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

Contraception

Livostor may harm the fetus when administered to a pregnant woman. Women of childbearing 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 calcium atorvastatin have not shown an increased risk of major congenital malformations or miscarriages.

Rare reports of congenital anomalies have been reported after 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 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 followed prospectively, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Breastfeeding

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

Ability to affect reaction speed when driving vehicles or operating machinery. Has a very minor influence on the ability to drive vehicles or operate machinery.

Dosage and Administration.

Hyperlipidemia and Mixed Dyslipidemia

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

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

The recommended starting dose of Livostor is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily. Doses of the medicinal product should be individually adjusted according to treatment goals. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous Familial Hypercholesterolemia

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

Concomitant Lipid-Lowering Therapy

Livostor may be used with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be administered 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 LDL-C reduction with Livostor; therefore, dose adjustment of the medicinal product 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 Livostor should be avoided in patients taking cyclosporine or the HIV protease inhibitor tipranavir + ritonavir, or the hepatitis C virus protease inhibitor glecaprevir + pibrentasvir, or letermovir when coadministered with cyclosporine. In HIV patients receiving lopinavir + ritonavir, Livostor should be administered at the lowest necessary dose. In patients taking clarithromycin, itraconazole, elbasvir + grazoprevir, or in HIV patients receiving combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, or letermovir, the therapeutic dose of Livostor should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose of Livostor. In patients taking the HIV protease inhibitor nelfinavir, treatment with Livostor should be limited to a dose of 40 mg (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Pediatric Use

Heterozygous Familial Hypercholesterolemia

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

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

o 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 atorvastatin is supported by evidence from:

• A placebo-controlled clinical trial of 6 months' duration 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 overall adverse reaction profiles similar to those of patients receiving placebo. In this limited controlled trial, no significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls was observed.
• An open-label, uncontrolled 3-year 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 the medicinal product in lowering LDL-C were generally consistent with those observed in adult patients, despite limitations inherent in the design of an uncontrolled study.

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

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

The safety and efficacy of the medicinal product 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 overdose with Livostor. In case of overdose, the patient should be treated symptomatically and supportive measures should be employed as needed. Due to the high degree of plasma protein binding of the drug, enhanced clearance of Livostor by hemodialysis is not expected to be significant.

Adverse Reactions

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

In the database of placebo-controlled clinical trials of atorvastatin, involving 16,066 patients (8,755 receiving atorvastatin and 7,311 receiving placebo; age range 10–93 years, 39% women, 91% Caucasian, 3% Black, 2% Asian, 4% other), with a median treatment duration of 53 weeks, 9.7% of patients receiving atorvastatin and 9.5% of those receiving placebo discontinued treatment due to adverse reactions, regardless of causal relationship to the drug. The five most common adverse reactions leading to discontinuation in patients treated with atorvastatin, 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%), limb pain (6.0%), and urinary tract infection (5.7%).

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

Table 6

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

Adverse reaction*	Any dose N=8755	10 mg N=3908	20 mg N=188	40 mg N=604	80 mg N=4055	Placebo N=7311
Nasopharyngitis	8.3	12.9	5.3	7	4.2	8.2
Arthralgia	6.9	8.9	11.7	10.6	4.3	6.5
Diarrhea	6.8	7.3	6.4	14.1	5.2	6.3
Limb pain	6	8.5	3.7	9.3	3.1	5.9
Urinary tract infection	5.7	6.9	6.4	8	4.1	5.6
Dyspepsia	4.7	5.9	3.2	6	3.3	4.3
Nausea	4	3.7	3.7	7.1	3.8	3.5
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 higher than in the placebo group

Other adverse reactions reported during placebo-controlled studies include:

General disorders: malaise, pyrexia;

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

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

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

Nervous system disorders: nightmares;

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, hypoaesthesia, dysgeusia, amnesia; rare: peripheral neuropathies.

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

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

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

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

Hepatobiliary disorders: very rare: liver failure.

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

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

Blood and lymphatic system disorders: rare: thrombocytopenia.

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

Eye disorders: uncommon: blurred vision.

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

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

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

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

In the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), which included 10,305 participants (age range 40–80 years, 19% women; 94.6% Caucasian, 2.6% Black, 1.5% South Asian, and 1.3% mixed/other), 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 the placebo group 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 mellitus receiving atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410), no differences in overall frequency of adverse reactions or serious adverse reactions were observed 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 discontinuations due to adverse reactions were observed in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) over a median follow-up period of 4.9 years. Persistent elevations of transaminases (≥3 times the upper limit of normal, confirmed on two occasions 4–10 days apart) occurred in 62 (1.3%) patients receiving atorvastatin 80 mg and in 9 (0.2%) patients receiving atorvastatin 10 mg. Elevations of 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 in overall frequency of adverse reactions or serious adverse reactions were observed between treatment groups over a median follow-up period of 4.8 years.

In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, which included 4,731 patients (age range 21–92 years, 40% women; 93.3% Caucasian, 3.0% Black, 0.6% Asian, and 3.1% other) without clinically evident coronary heart disease but with a history of stroke or transient ischemic attack (TIA) within the previous 6 months, receiving atorvastatin 80 mg (n=2,365) or placebo (n=2,366), 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%) over a median follow-up period of 4.9 years. Cases of creatine kinase 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").

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

No significant differences 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 observed during clinical studies of atorvastatin in children

According to published data, in a 26-week controlled study in boys and girls after onset of menstruation with heterozygous familial hypercholesterolemia (aged 10 to 17 years) (n = 140, 31% female; 92% Caucasian, 1.6% Black, 1.6% Asian, and 4.8% other ethnic groups), the safety and tolerability profile of atorvastatin 10–20 mg daily as an adjunct to diet for lowering total cholesterol, LDL-cholesterol, and apolipoprotein B levels was generally similar to that of placebo.

Post-marketing experience

During post-marketing use of the medicinal product Livostor, 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 Livostor treatment reported after marketing authorization, regardless of causal relationship 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 associated with statin use have been reported (see section "Special warnings and precautions for use").

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

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

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, hypoaesthesia, dysgeusia.

Rare reports of new onset or worsening of myasthenia gravis, including ocular myasthenia, and reports of recurrence upon use of the same or another statin have been received.

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 edema, malaise, fatigue.

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

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 mg tablets: 10 tablets in a blister; 3 or 7 blisters per pack.

20 mg tablets: 10 tablets in a blister; 3 or 7 blisters per pack.

40 mg tablets: 10 tablets in a blister; 3 blisters per pack.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of operations.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua.