INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AСTIN® (ASTIN)

Composition:

Active substance: atorvastatin calcium trihydrate;

1 tablet contains atorvastatin calcium trihydrate equivalent to atorvastatin 10 mg or 20 mg or 40 mg or 80 mg;

Excipients: microcrystalline cellulose (Avicel PH 101); calcium carbonate; lactose monohydrate (Super tab 11 SD); sodium croscarmellose (Ac-Di-Sol); hydroxypropylcellulose (Klucel EXF); polysorbate 80 (Tween 80); magnesium stearate (VG-EP); film coating Opadry white (YS-1-7040): HPMC 2910/hypromellose, macrogol/PEG, titanium dioxide (E 171), talc.

Dosage form. Film-coated tablets.

Main physicochemical properties:

10 mg tablets: white or almost white, film-coated, oval-shaped tablets with engraving «I» on one side and «90» on the other, approximately 9.70 mm in length and 5.10 mm in width;

20 mg tablets: white or almost white, film-coated, oval-shaped tablets with engraving «I» on one side and «91» on the other, approximately 12.00 mm in length and 6.50 mm in width;

40 mg tablets: white or almost white, film-coated, oval-shaped tablets with engraving «I» on one side and «92» on the other, approximately 15.30 mm in length and 8.00 mm in width;

80 mg tablets: white or almost white, film-coated, oval-shaped tablets with engraving «I» on one side and «93» on the other, approximately 19.00 mm in length and 10.40 mm in width.

Pharmacotherapeutic group. Hypolipidemic agents. HMG-CoA reductase inhibitors. ATC code C10AA05.

Pharmacological Properties

Pharmacodynamics

Astin® is a synthetic hypolipidemic agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase – the enzyme catalyzing the conversion of HMG-CoA to mevalonate, the initial and rate-limiting step in cholesterol biosynthesis.

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

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

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

Pharmacokinetics

Absorption. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentration (Cmax) reached within 1–2 hours. The extent of absorption increases proportionally with the dose of Astin®. Absolute bioavailability of atorvastatin (parent drug) is approximately 14%, while systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. The low systemic availability 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 absorption by approximately 25% and 9%, respectively, as measured by Cmax and AUC (area under the concentration-time curve), the reduction in LDL cholesterol levels is similar whether Astin® is taken with or without food. When atorvastatin is administered in the evening, plasma concentrations are lower (by approximately 30% for both Cmax and AUC) compared to morning dosing. However, the reduction in LDL cholesterol levels is similar regardless of the time of administration (see section "Dosage and Administration").

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

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

Excretion. Atorvastatin and its metabolites are primarily eliminated via bile following hepatic and/or extrahepatic metabolism, but apparently do not undergo enterohepatic recirculation. The mean elimination half-life of atorvastatin in human plasma is approximately 14 hours, while the half-life for HMG-CoA reductase inhibitory activity is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of the orally administered dose is excreted in urine.

Special Patient Populations

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

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

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

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

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

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

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

Table 1

Effect of concomitantly administered drugs on the pharmacokinetics of atorvastatin

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

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

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

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

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

‡ The dose of the saquinavir + ritonavir combination 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 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 drug and dosing regimen
Atorvastatin	Drug/dose (mg)	Ratio AUC	Ratio Cmax
80 mg once daily for 15 days	Antipyrine 600 mg single dose	1.03	0.89
80 mg once daily for 10 days	#Digoxin 0.25 mg once daily, 20 days	1.15	1.20
40 mg once daily for 22 days	Oral contraceptives once daily, 2 months: norethisterone 1 mg; ethinylestradiol 35 mcg	1.28 1.19	1.23 1.30
10 mg once daily	Tipranavir 500 mg twice daily / ritonavir 200 mg twice daily, 7 days	1.08	0.96
10 mg once daily for 4 days	Fosamprenavir 1400 mg twice daily, 14 days	0.73	0.82
10 mg once daily for 4 days	Fosamprenavir 700 mg twice daily / ritonavir 100 mg twice daily, 14 days	0.99	0.94

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

Clinical characteristics

Indications

Prevention of cardiovascular disease in adults

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

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

For adult patients with clinically evident ischemic heart disease, Asten® 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 cholesterol, apolipoprotein B, and triglyceride levels, and to increase HDL cholesterol levels in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification);
as an adjunct to diet for the treatment of patients with elevated serum triglyceride levels (type IV according to Fredrickson classification);
for the treatment of patients with primary dysbetalipoproteinemia (type III according to Fredrickson classification) when dietary measures are insufficient;
to reduce total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such therapies are unavailable.

In children:

as an adjunct to diet to reduce total cholesterol, LDL cholesterol, 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 cholesterol remains ≥ 190 mg/dL (4.91 mmol/L), or

b) LDL cholesterol ≥ 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, including persistent elevations of hepatic transaminases of unknown etiology.
Hypersensitivity to any component of the drug.
Pregnancy.
Breastfeeding period.

Interaction with other medicinal products and other types of interactions

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

Potent CYP3A4 inhibitors. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant use of Asten® with potent CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see Table 1 and detailed information below). The extent of interaction and effect enhancement depends on the variability of the impact on CYP3A4. Concomitant use with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for HCV treatment (e.g., elbasvir/grazoprevir), and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided if possible. If concomitant use with 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. Amiodarone and verapamil are known to inhibit CYP3A4 activity; therefore, concomitant use of these drugs with atorvastatin may lead to increased atorvastatin exposure. Thus, when atorvastatin is used concomitantly with these moderate CYP3A4 inhibitors, consideration should be given to prescribing lower maximum doses of atorvastatin and conducting clinical monitoring of the patient. Clinical monitoring is also recommended after initiating treatment with an inhibitor or adjusting its dose.

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

Clarithromycin. AUC values of atorvastatin were 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 Asten® cautiously at doses exceeding 20 mg (see sections "Special precautions for use" and "Dosage and administration").

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

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

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

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

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

The extent of CYP3A- and OATP1B1/1B3-mediated drug interactions with concomitant medications may vary when letermovir is used with cyclosporine. Use of Asten® 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 co-administered with atorvastatin, plasma concentrations of atorvastatin increase up to 8.3-fold due to partial inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, concomitant use of Asten® is not recommended in patients taking medications containing glecaprevir and pibrentasvir.

When co-administered with atorvastatin, plasma concentrations of atorvastatin increase up to 1.9-fold due to partial inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, the dose of Asten® should not exceed 20 mg daily when administered to patients taking medications containing elbasvir and grazoprevir (see sections "Pharmacokinetics", "Special precautions for use", "Dosage and administration").

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

Table 3

Drug interactions associated with an increased risk of myopathy/rhabdomyolysis

Drugs that interact	Medical recommendations for use
Cyclosporine, tipranavir + ritonavir, glecaprevir + pibrentasvir, ledipasvir when used concomitantly with cyclosporine	Avoid use of atorvastatin
Clarithromycin, itraconazole, saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, elbasvir + grazoprevir, ledipasvir	Do not exceed 20 mg of atorvastatin per day
Nelfinavir	Do not exceed 40 mg of atorvastatin per day
Lopinavir + ritonavir, simeprevir, fibrinic acid derivatives, erythromycin, azole antifungal agents, 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 used concomitantly with gemfibrozil, the co-administration 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 cautiously when co-administered with other fibrates (see section "Special precautions").

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

Rifampicin or other cytochrome P450 3A4 inducers. Concomitant use of the drug with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampicin) may lead to an inconsistent decrease in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampicin, simultaneous administration of Atorvastatin® with rifampicin is recommended, as delayed administration of atorvastatin after rifampicin intake has been shown to result in a significant reduction in atorvastatin plasma concentration.

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

Cimetidine. Clinical 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 remains unchanged.

Colestipol. Atorvastatin plasma concentration was lower (atorvastatin concentration ratio 0.74) when atorvastatin and colestipol were administered concomitantly. However, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded the effect achieved by each drug administered separately.

Azithromycin. Concomitant administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) did not result in changes in atorvastatin plasma concentration.

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

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

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

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

Digoxin. Concomitant administration of multiple doses of atorvastatin and digoxin increases the steady-state plasma concentrations of digoxin (see section "Pharmacokinetics"). Patients receiving digoxin should be appropriately monitored.

Oral contraceptives. Concomitant use of atorvastatin with oral contraceptives increases the AUC of norethisterone and ethinylestradiol (see section "Pharmacological properties"). These increases should be taken into account when selecting an oral contraceptive for a woman taking Atorvastatin®.

Warfarin. Atorvastatin did not clinically significantly affect 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 (including atorvastatin) and daptomycin. If concomitant use cannot be avoided, appropriate clinical monitoring is recommended (see section "Special precautions").

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

Special precautions for use

Skeletal muscles

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 may be a risk factor for the development of rhabdomyolysis. Such patients require closer monitoring for skeletal muscle effects.

Atorvastatin, like other statin drugs, occasionally causes myopathy, defined as muscle pain or weakness in combination with elevated creatine phosphokinase (CPK) levels more than 10 times the upper limit of normal. Concomitant use of higher doses of atorvastatin with certain drugs, such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors, and hepatitis C virus 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 necrotizing myopathy without significant inflammation; a positive response is observed with immunosuppressive agents.

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

The risk of myopathy during treatment with drugs in this class increases with concomitant use of the medications listed in Table 3. Physicians considering combined therapy with Astin® and any of these drugs should carefully weigh potential benefits against risks and closely monitor patients for any signs of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any dose-titration periods. Consideration should be given to using lower initial and maintenance doses of atorvastatin when coadministered with the aforementioned drugs (see section "Interaction with other medicinal products and other types of interactions"). In such cases, 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 with colchicine should be prescribed with caution (see section "Interaction with other medicinal products and other types of interactions").

The risk of myopathy and/or rhabdomyolysis may increase with concomitant use of HMG-CoA reductase inhibitors (including atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other types of interactions"). Consider temporary discontinuation of Astin® in patients receiving daptomycin, unless the benefit of concomitant use outweighs the risk. If concomitant use cannot be avoided, creatine kinase levels should be monitored 2–3 times per week, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.

Astin® therapy should be temporarily or permanently discontinued in patients with an acute, serious condition indicating the development of myopathy or in the presence of risk factors for renal failure due to rhabdomyolysis (e.g., severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, and uncontrolled seizures).

Hepatic function

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

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

Prior to initiating Astin® therapy, liver enzyme test results 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 statin drugs, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Astin®, the drug should be discontinued immediately. Reinitiation of therapy with the drug should not be attempted unless an alternative etiology is identified.

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

Endocrine function

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

Statins inhibit cholesterol synthesis and theoretically may reduce adrenal and/or gonadal steroid secretion. Clinical studies have shown that atorvastatin does not reduce baseline plasma cortisol concentration or impair adrenal reserve. The effect of statins on sperm fertility has not been adequately studied in a sufficient number of patients. It is unknown whether the drug affects, or has any effect at all, on the "gonadal-pituitary-hypothalamus" system in premenopausal women. Caution should be exercised when coadministering 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 (TIA)

In a post-hoc analysis of the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study, in which 4731 patients without ischemic heart disease and with a history of stroke or TIA within the previous 6 months received atorvastatin 80 mg versus placebo, a higher incidence of hemorrhagic stroke was observed in the atorvastatin 80 mg group compared to the placebo group (55 cases, 2.3%, in the atorvastatin group versus 33 cases, 1.4%, in the placebo group; HR: 1.68, 95% CI: 1.09, 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar in both treatment groups (17 and 18 in the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) compared to the placebo group (16, 0.7%). Certain baseline characteristics, including a history of hemorrhagic and lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group (see section "Adverse reactions").

Among 39,828 patients receiving atorvastatin in clinical trials, 15,813 (40%) were aged 65 years or older, and 2,800 (7%) were aged 75 years or older. No overall differences in safety and efficacy of the drug were observed between elderly and younger patients, nor were there differences in treatment response between elderly and younger patients according to other clinical experience; however, increased sensitivity in some older individuals cannot be excluded. Since elderly patients (aged ≥65 years) are predisposed to myopathy, atorvastatin should be prescribed with caution.

Hepatic insufficiency

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

Before initiating treatment

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

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

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

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

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

Measurement of CK levels

CK 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 the upper limit of normal by more than five times) is observed at baseline, repeat measurement should be performed after 5–7 days to confirm the result.

During treatment

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

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

Discontinuation of treatment should also be considered if CK elevation does not exceed five times the upper limit of normal, but muscle symptoms are severe and cause daily discomfort.

After symptom resolution and normalization of CK levels, reinitiation of atorvastatin therapy or initiation of an alternative statin may be considered, 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 the upper limit of normal 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 drugs that may increase atorvastatin plasma concentrations. Examples include strong CYP3A4 or transporter protein inhibitors: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, and darunavir. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibric acid derivatives, boceprevir, erythromycin, niacin, ezetimibe, telaprevir, or telaprevir/ritonavir combination. If possible, alternative drugs (that do not interact with atorvastatin) should be used instead of the aforementioned agents.

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

Atorvastatin must not be prescribed concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. For 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 in combination (see section "Interaction with other medicinal products and other types of interactions"). 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 use is required (e.g., for treatment of severe infections), the need for concomitant use of Astin® and fusidic acid should be considered on an individual basis and under strict medical supervision.

Interstitial lung disease (ILD)

Rare cases of interstitial lung disease (ILD) 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, and fever). If ILD is suspected, statin therapy should be discontinued.

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

Limitations of use

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

In isolated cases, statins have been reported to induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reaction"). If symptoms worsen, the drug should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Excipients

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

Use during pregnancy or breastfeeding

Pregnancy

Risk assessment

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

The background risk of major congenital malformations and spontaneous abortions in the specified 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 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 spontaneous abortions.

Rare reports of congenital anomalies have been reported after intrauterine 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, spontaneous abortions, 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 period

Astin® 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, although another drug in this class has been shown to pass into breast milk; atorvastatin is present in rat milk. Since statins have the potential to cause serious adverse reactions in breastfed infants, women requiring treatment with Astin® should not breastfeed (see section "Contraindications").

Ability to influence reaction speed when driving or operating machinery

The drug has a negligible effect on reaction speed during driving or operating machinery.

Dosage and Administration

Hyperlipidemia and Mixed Dyslipidemia

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

Heterozygous Familial Hypercholesterolemia in Children Aged 10 to 17 Years

The recommended starting dose of Astin® is 10 mg/day, with a usual dose range of 10 to 20 mg orally once daily. Doses should be individually adjusted according to the treatment goal. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous Familial Hypercholesterolemia

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

Concomitant Lipid-Lowering Therapy

Astin® may be administered with bile acid sequestrants. In general, combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should be administered with caution (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").

Dosing in Patients with Renal Impairment

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

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

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

Children

Heterozygous Familial Hypercholesterolemia

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

LDL-C ≥ 190 mg/dL (4.91 mmol/L), or
LDL-C ≥ 160 mg/dL (4.14 mmol/L) and
- a family history of familial hypercholesterolemia or premature cardiovascular disease in first- or second-degree relatives, or
- presence of two or more other cardiovascular risk factors.

The indication for atorvastatin use is supported by studies:

A 6-month placebo-controlled clinical trial involving 187 boys and girls after onset of menstruation, aged 10 to 17 years. Patients receiving atorvastatin 10 mg or 20 mg daily had an overall adverse reaction profile similar to those receiving placebo. In this limited controlled study, no significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls was observed.
A 3-year open-label uncontrolled study involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia, in whom dose was titrated to achieve a target LDL-C level of < 130 mg/dL (3.36 mmol/L). The safety and efficacy of atorvastatin in lowering LDL-C were generally consistent with those observed in adult patients, despite limitations of the controlled study design.

For girls after onset of menstruation, contraception counseling should be provided if appropriate for the patient.

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

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

Homozygous Familial Hypercholesterolemia

The clinical efficacy of atorvastatin 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 Astin®. In case of overdose, the patient should be treated symptomatically and supportive measures should be applied as needed. Due to the high degree of protein binding of the drug in plasma, significant enhancement of Astin® clearance by hemodialysis is not expected.

Adverse Reactions

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

According to data from clinical trials, the most common adverse reactions leading to discontinuation of the drug in patients treated with atorvastatin, occurring at higher rates (9.7% and 9.5% of patients, respectively) compared to 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%).

The most frequently reported adverse reactions (≥2% compared to placebo), regardless of causality, in patients receiving placebo in the studies (N = 8755), were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), limb pain (6.0%), and urinary tract infections (5.7%).

Table 4

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

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

Other adverse reactions reported during placebo-controlled studies include:

General disorders: malaise, pyrexia;

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

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

Metabolism and nutrition disorders: 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 occurrence of adverse reactions was defined as follows: common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000).

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

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

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

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

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

Blood and vascular system disorders: rare – thrombocytopenia, vasculitis.

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

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

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

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 dose adjustment or discontinuation. Clinically significant elevations in serum transaminase activity (more than 3 times the upper limit of normal) were observed in 0.8% of patients treated with atorvastatin. This elevation was dose-dependent and reversible in all patients.

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

Adverse reactions reported during clinical trials include: urinary tract infections, diabetes mellitus, stroke.

Adverse reactions observed during clinical studies of atorvastatin in children

In a 26-week controlled study in boys and girls after onset of menstruation with heterozygous familial hypercholesterolemia (aged 10 to 17 years), the safety and tolerability profile of atorvastatin at doses of 10 to 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 with atorvastatin

The following adverse reactions have been identified during post-marketing use of atorvastatin. Because these reactions are reported voluntarily, it is often not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions associated with atorvastatin treatment reported after marketing authorization, regardless of causal assessment, include: anaphylaxis, angioedema, bullous eruptions (including exudative multiform erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis), rhabdomyolysis, myositis, increased fatigue, tendon rupture, fatal and non-fatal liver failure, dizziness, depression, peripheral neuropathy, pancreatitis, and interstitial lung disease.

Rare cases of immune-mediated necrotizing myopathy associated with statin use have been reported (see section "Special precautions"); cognitive disorders (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have also been reported. These cognitive disorders have been reported with all statins. Reports were generally not classified as serious adverse reactions, symptoms were reversible upon discontinuation of statin therapy, with variable time to onset (from first day to several years) and resolution (median duration of 3 weeks).

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

Adverse reactions reported during post-marketing surveillance

Blood and lymphatic system disorders: thrombocytopenia.

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

Metabolism and nutrition disorders: weight gain.

Nervous system disorders: headache, hyposthesia, dysgeusia.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain.

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

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

Reporting of suspected adverse reactions after medicine authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life: 2 years.

Storage conditions

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging: 10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription status: prescription only.

Manufacturer: Micro Labs Limited

Manufacturer's address and location of business activity

Plot No. S.155 - S.159 and N1, Verna Industrial Estate, Phase III and Phase IV, Verna Salcete, In-403 722, India