INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIMISTIN 20 LIMISTIN 40 (LIMISTIN 20 LIMISTIN 40)

Composition:

Active substance: atorvastatin;

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

Excipients: calcium carbonate; microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; polysorbate 80; hydroxypropylcellulose; magnesium stearate; hydroxypropylmethylcellulose; propylene glycol; polyethylene glycol-6000; talc; titanium dioxide (E 171) – for 20 mg tablets;

calcium carbonate; microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; polysorbate 80; hydroxypropylcellulose; magnesium stearate; crospovidone; sodium lauryl sulfate; hydroxypropylmethylcellulose; polyethylene glycol-6000; talc; titanium dioxide (E 171) – for 40 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

• white or almost white, capsule-shaped, film-coated tablets with a break line on one side (20 mg tablets);
• white or almost white, round, biconvex, film-coated tablets (40 mg tablets).

Pharmacotherapeutic group. Lipid-lowering agents, single component. HMG-CoA reductase inhibitors. ATC code C10AA05.

Pharmacological Properties

Pharmacodynamics

Atorvastatin is a synthetic hypolipidemic agent. 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.

Atorvastatin 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 animal experimental models, atorvastatin reduced 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; atorvastatin also reduced the production of LDL and the number of these particles.

Atorvastatin, as well as some of its metabolites, is pharmacologically active in humans. The primary site of action of atorvastatin is the liver, which plays a central role in cholesterol synthesis and LDL clearance. The dose of the drug, rather than systemic drug concentration, correlates better with the reduction in LDL cholesterol levels. Individual dose titration should be 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. The absolute bioavailability of atorvastatin (parent drug) is approximately 14%, while the systemic bioavailability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability of the drug is attributed to pre-systemic clearance in the gastrointestinal mucosa and/or pre-systemic metabolism in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, based on Cmax and AUC (area under the concentration-time curve), the reduction in LDL cholesterol levels is similar whether the drug is taken with or without food. When atorvastatin is administered in the evening, its plasma concentration is lower (approximately 30% lower in terms of Cmax and AUC) compared to morning administration. 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 the drug is approximately 381 liters. Over 98% of atorvastatin is bound to plasma proteins. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes. Based on observations in rats, atorvastatin is considered capable of passing into breast milk (see sections "Contraindications" and "Special Precautions").

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

Excretion. Atorvastatin and its metabolites are primarily eliminated via bile following hepatic and/or extrahepatic metabolism, although this drug apparently does not undergo enterohepatic recirculation. The mean elimination half-life of the drug 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 the dose is excreted in urine after oral administration.

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

Special Patient Populations

Elderly patients. Drug plasma concentrations are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly volunteers (aged 65 years and older) compared to younger adults. Clinical data indicate a greater degree of LDL reduction with any dose of the drug in elderly patients compared to younger patients (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 8-week study in children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n = 29).

Gender. Drug plasma concentrations 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 when the drug is administered.

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

Hemodialysis. Although studies have not been conducted in patients with end-stage renal disease, hemodialysis is not considered to significantly enhance atorvastatin clearance due to the drug's extensive binding to plasma proteins.

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

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

Table 1

Effect of concomitantly administered drugs on atorvastatin pharmacokinetics

& Ratio 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 (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive consumption of grapefruit juice (750 mL – 1.2 L per day or more).

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

*** Concomitant treatment with glecaprevir/pibrentasvir is contraindicated (see section "Contraindications").

† Due to the dual interaction mechanism of rifampicin, concomitant use 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 concentration.

‡ 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 will likely 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

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

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases in adults

For adult patients without clinically evident ischemic heart disease but with multiple risk factors for ischemic heart disease, such as age, smoking, arterial hypertension, low levels of high-density lipoprotein (HDL) or a family history of premature ischemic heart disease, the drug 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 II 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, the drug is indicated for:

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

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

In children

• As an adjunct to diet to reduce total cholesterol, LDL-C, and apolipoprotein B levels in 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 pediatric patients.

Contraindications.

Active liver disease, which may include persistent elevations of serum transaminases of unknown etiology.

Hypersensitivity to any component of this medicinal product.

Pregnancy.

Breastfeeding.

Concomitant use of the hepatitis C antiviral agents glecaprevir/pibrentasvir.

Interaction with other medicinal products and other forms of interaction.

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

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

Concomitant use of atorvastatin with strong CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see Table 3 and detailed information below). The extent of interaction and effect enhancement depends on the potential impact on CYP3A4. Concomitant use of the drug with strong CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain hepatitis C antivirals (e.g., elbasvir/grazoprevir), and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided whenever possible. If concomitant use cannot be avoided, consideration should be given to using a lower starting and maximum dose 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. No drug interaction studies have evaluated the effect of amiodarone or verapamil on atorvastatin. Amiodarone and verapamil are known to inhibit CYP3A4 activity; therefore, concomitant use with atorvastatin may lead to increased atorvastatin exposure. Thus, when atorvastatin is used concomitantly with these moderate CYP3A4 inhibitors, consideration should be given to using lower maximum doses of atorvastatin and clinical monitoring of the patient. Clinical monitoring is also recommended after initiating or adjusting the dose of the inhibitor.

Grapefruit juice

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

Clarithromycin

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

Combination of protease inhibitors

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

Itraconazole

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

Cyclosporine

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

Letermovir. Concomitant use of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased atorvastatin exposure (AUC ratio: 3.29) (see section "Pharmacokinetics").

Letermovir is an inhibitor of efflux transporters P-gp, BCRP, MRP2, OAT2, and hepatic transporter OATP1B1/1B3, thus increasing atorvastatin exposure. The dose of the drug 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. The use of the drug is not recommended in patients taking letermovir concomitantly with cyclosporine.

Glecaprevir and pibrentasvir, elbasvir and grazoprevir. Concomitant use of glecaprevir and pibrentasvir or elbasvir and grazoprevir may increase atorvastatin plasma concentrations and increase the risk of myopathy.

When glecaprevir and pibrentasvir are coadministered with atorvastatin, plasma concentrations of atorvastatin increase up to 8.3-fold, partly due to inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, concomitant use of atorvastatin is not recommended in patients taking medications containing glecaprevir and pibrentasvir.

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

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

Table 3

Drug interactions associated with an increased risk of myopathy/rhabdomyolysis

*Use the lowest necessary dose.

Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are used concomitantly with gemfibrozil, combination therapy of Limistin 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, Limistin should be used with caution when coadministered 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 Limistin 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 variable decreases in atorvastatin plasma concentrations. 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 result in a significant reduction in atorvastatin plasma concentration.

Diltiazem hydrochloride

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

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

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

Azithromycin

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

Inhibitors of transport proteins

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 liver cells is unknown. If concomitant use of these drugs cannot be avoided, dose reduction and clinical monitoring of atorvastatin efficacy are recommended (see Table 1).

Ezetimibe

Ezetimibe monotherapy has been associated with muscle-related adverse effects, including rhabdomyolysis. Therefore, the risk of such events increases when ezetimibe is used concomitantly with atorvastatin. 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 cases) 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").

Digoxin

When multiple doses of atorvastatin and digoxin are administered concomitantly, steady-state digoxin plasma concentrations increase (see section "Pharmacokinetics"). Patients receiving digoxin should be appropriately monitored.

Oral contraceptives

When atorvastatin is used concomitantly with oral contraceptives, increased AUC values for norethisterone and ethinylestradiol have been observed (see section "Pharmacological properties"), which should be considered when selecting an oral contraceptive for women taking atorvastatin.

Warfarin

Atorvastatin had no clinically significant effect on prothrombin time in patients undergoing long-term warfarin therapy.

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine; therefore, atorvastatin should be prescribed with caution when used with colchicine.

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

Other medicinal products

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

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 of this class. A history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients require careful monitoring for skeletal muscle disorders.

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

Atorvastatin use may cause immune-mediated necrotizing myopathy (IMNM)—an autoimmune myopathy associated with statin use. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy; muscle biopsy reveals necrotizing myopathy without significant inflammation; and a positive response is observed with immunosuppressive therapy.

The possibility of developing myopathy should be considered in patients with diffuse myalgia, muscle tenderness or weakness, and/or significant elevation of CPK. Patients should be advised to immediately report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever, or if muscle signs and symptoms persist after discontinuation of atorvastatin. Treatment should be discontinued in the event of a marked increase in CPK levels, or if myopathy is diagnosed or suspected.

The risk of myopathy during treatment with drugs of this class increases with concomitant use of medicinal products listed in Table 3. Physicians considering combination therapy with atorvastatin and any of these drugs should carefully weigh the potential benefits and 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 medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). In such situations, periodic CPK monitoring may be considered, although there is no guarantee that such monitoring will prevent cases of severe myopathy.

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

In isolated cases, statins have been reported to induce de novo or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). In case of symptom exacerbation, atorvastatin should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Liver function

Statins, like some other lipid-lowering therapeutic agents, have been associated with abnormalities in liver function biochemical parameters. Persistent elevations (more than 3 times the ULN, occurring on two or more occasions) in serum transaminases were observed in 0.7% of patients receiving atorvastatin. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for atorvastatin doses of 10, 20, 40, and 80 mg, respectively.

There are data indicating that use of the drug led to jaundice in one patient. Elevated liver function test (LFT) values in other patients were not associated with jaundice or other clinical symptoms. After dose reduction, interruption, or discontinuation of the drug, transaminase levels returned to pre-treatment levels or approximately to this level without adverse consequences. Eighteen of 30 patients with persistent elevation of liver function tests continued atorvastatin treatment at lower doses.

Liver enzyme test results should be obtained before initiating therapy and repeated as clinically necessary. Rare post-marketing reports of fatal and non-fatal hepatic failure have been received in patients taking statin drugs, including atorvastatin. In the event of serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice during atorvastatin use, treatment should be immediately discontinued. If no alternative etiology is identified, reinitiation of the drug should not be attempted.

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

Endocrine function

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

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

Use in patients with recent stroke or transient ischemic attack

In patients without ischemic heart disease who had a history of stroke or transient ischemic attack within the previous 6 months, treatment with atorvastatin 80 mg was associated with a higher incidence of hemorrhagic stroke compared to placebo. The incidence of fatal hemorrhagic stroke was similar across all treatment groups. The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group compared to the placebo group. Some baseline characteristics, including the presence of hemorrhagic and lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.

In patients aged 65–75 years receiving atorvastatin, no overall differences in safety and efficacy of the drug were observed compared to younger patients, nor were there any differences in drug effects between elderly and younger patients; however, increased sensitivity in some elderly patients cannot be excluded. Since elderly patients (aged 65 years and older) are more prone to myopathy, atorvastatin should be prescribed with caution.

Liver impairment

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

Before starting treatment

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

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

For elderly patients (aged 70 years and older), 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 inherited 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 (more than 5 times ULN) before starting treatment, therapy should not be initiated.

Measurement of CK levels

CK levels should not be measured after intense 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 of the need to immediately 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. 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 five times 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 of the patient 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 developing rhabdomyolysis increases with concomitant use of atorvastatin and certain medicinal products that may increase atorvastatin plasma concentrations. Examples include potent CYP3A4 or transporter protein inhibitors: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibrates, antiviral agents for hepatitis C (telaprevir, elbasvir/grazoprevir), erythromycin, niacin, ezetimibe, telaprevir, or telaprevir/ritonavir combination. If possible, alternative medicinal products (not interacting with atorvastatin) should be used instead.

If concomitant therapy with atorvastatin and these drugs is necessary, the benefits 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 prescribed concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid. In patients for whom systemic fusidic acid is considered necessary, statin therapy should be suspended for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis, including fatal cases, have been reported in patients receiving fusidic acid and statins in combination (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness.

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

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

The risk of myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Consideration should be given to temporarily suspending atorvastatin in patients receiving daptomycin, unless the benefit outweighs the risk. If concomitant use cannot be avoided, CK levels should be monitored 2–3 times weekly, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.

Lung interstitial disease

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

Excipients

The Limestin formulation contains lactose. This medicine should not be used in 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. 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. In patients with ischemic heart disease or multiple risk factors for ischemic heart disease, Limestin may be initiated concurrently with dietary measures.

Limitations of use

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

Use during pregnancy or breastfeeding.

Pregnancy

Risk assessment

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

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

Contraception

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

Clinical data

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

Rare reports of congenital anomalies after intrauterine exposure to other HMG-CoA reductase inhibitors have been received. Prospective observation of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed that the frequency of fetal congenital anomalies, miscarriages, and intrauterine deaths/stillbirths did not exceed the frequency expected in the general population. The number of cases is sufficient to exclude a ≥3–4-fold increase in fetal developmental anomalies compared to the background rate. In 89% of the prospectively observed pregnancies, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Lactation

The drug 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 of 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 the drug should not breastfeed (see section "Contraindications").

Ability to affect reaction speed while driving or operating machinery.

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

Method of administration and dosage.

Hyperlipidemia and mixed dyslipidemia

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

Heterozygous familial hypercholesterolemia in pediatric patients (aged 10 to 17 years)

The recommended initial dose of atorvastatin is 10 mg daily. The usual dosage range is 10 to 20 mg orally once daily. Doses should be individually adjusted according to treatment goals. Dose adjustments should be made at intervals of 4 weeks or longer.

Homozygous familial hypercholesterolemia

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

Limistin may be used with bile acid sequestrants. 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 precautions for use").

Dosing in patients with renal impairment

Renal disease does not affect either the plasma concentration of the drug or the reduction in LDL-C levels during treatment; therefore, dose adjustment in patients with impaired renal function is not required (see sections "Pharmacokinetics" and "Special precautions for use").

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

The use of the drug should be avoided in patients taking cyclosporine or the HIV protease inhibitor tipranavir + ritonavir, or the hepatitis C virus protease inhibitor glecaprevir + pibrentasvir, or letermovir when coadministered with cyclosporine. For HIV patients taking lopinavir + ritonavir, atorvastatin should be administered at the lowest necessary dose. For patients taking clarithromycin, itraconazole, elbasvir + grazoprevir, or HIV patients taking combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, or letermovir, the therapeutic dose of the drug should be limited to 20 mg; appropriate clinical monitoring is also recommended to ensure the use of the lowest necessary atorvastatin dose.

In patients taking the hepatitis C virus protease inhibitor elbasvir/grazoprevir concomitantly with atorvastatin, the atorvastatin dose must not exceed 20 mg/day (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

For patients taking the HIV protease inhibitor nelfinavir, atorvastatin treatment should be limited to a dose of 40 mg. When atorvastatin is coadministered with other protease inhibitors, appropriate clinical monitoring is recommended to ensure the use of the lowest necessary dose of the drug (see sections "Interaction with other medicinal products and other forms of interaction" and "Special 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 the following criteria are met after an adequate trial of dietary therapy:

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

• A 6-month placebo-controlled clinical trial involving 187 boys and girls after onset of menstruation, aged 10 to 17 years. Patients receiving atorvastatin at doses of 10 mg or 20 mg daily had an overall adverse reaction profile similar to those receiving placebo. In this small, controlled study, no significant effect of atorvastatin on growth or sexual maturation in boys or on menstrual cycle length in girls was observed.
• A 3-year open-label, uncontrolled study involving 163 children aged 10 to 15 years with heterozygous familial hypercholesterolemia, in whom doses were titrated to achieve a target LDL-C level <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 the limitations of the uncontrolled study design.

Girls after onset of menstruation should be counseled regarding contraception, as 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 daily over 1 year was evaluated in an uncontrolled study involving 8 pediatric patients with homozygous familial hypercholesterolemia.

Overdose.

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

Adverse Reactions

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

According to clinical trial data on atorvastatin, among 16,066 patients treated for up to 53 weeks, the most common adverse reactions leading to discontinuation of atorvastatin and 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%).

The most common adverse reactions (≥ 2% compared to placebo), regardless of causal relationship, in patients receiving atorvastatin therapy (n=8,755), were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremities (6.0%), and urinary tract infections (5.7%).

Table 4 summarizes the incidence of clinical adverse reactions, regardless of causal relationship, reported in 2% or more of patients and at a higher frequency than in the placebo group, among patients receiving atorvastatin (n=8,755) in 17 placebo-controlled trials.

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

Table 4

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

Other adverse reactions reported during placebo-controlled studies include:

General disorders: malaise, pyrexia;

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

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

Metabolism and nutrition disorders: increased transaminases, liver function test abnormalities, increased blood alkaline phosphatase, increased creatine kinase (CK) activity, hyperglycemia;

Nervous system disorders: nightmares;

Respiratory system disorders: epistaxis;

Skin and subcutaneous tissue disorders: urticaria;

Eye disorders: blurred vision, visual disturbance;

Ear and labyrinth disorders: tinnitus;

Renal and urinary disorders: leukocyturia;

Reproductive system and breast disorders: gynecomastia.

The frequency of adverse reactions was defined as follows: common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000).

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

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

Musculoskeletal and connective tissue disorders: common – arthralgia, back pain; very 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 – hepatic failure.

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

Cardiovascular disorders: rare – vasculitis.

Respiratory, thoracic and mediastinal disorders: common – throat and laryngeal 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 – liver function test abnormalities, increased blood CK activity; uncommon – positive urine leukocyte test.

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

Elevated serum CK activity (more than three times the upper limit of normal) was observed in 2.5% of patients treated with atorvastatin. This is consistent with observations during clinical studies of other HMG-CoA reductase inhibitors. In 0.4% of patients receiving atorvastatin, levels exceeded ten times the upper limit of normal.

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

Pediatric population (10–17 years). Adverse events observed in patients treated with atorvastatin were similar to those in the placebo group. The most common adverse events observed in both groups, regardless of causality, were infections.

Post-marketing experience with atorvastatin.

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

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

Rare cases of immune-mediated necrotizing myopathy associated with statin use have been reported (see section "Special precautions").

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

With some statins, adverse events such as sexual dysfunction have been described; rare cases of interstitial lung disease, particularly with long-term treatment, have 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; myasthenia gravis (frequency unknown).

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Eye disorders: ocular myasthenia (frequency unknown).

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 CK activity.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. 10 tablets in blisters, 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Arthura Pharmaceuticals Pvt. Ltd.

Manufacturer's address and place of business.

1505 Portia Road, Sri City SEZ, Sedyavedu Mandal, Chittoor District – 517 588, Andhra Pradesh, India.

Marketing authorization holder.

Ananta Medikear Ltd.

Address of the marketing authorization holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

INSTRUCTION

for medical use of the medicinal product

LIMISTIN 20

LIMISTIN 40

(LIMISTIN 20

LIMISTIN 40)

Composition:

Active substance: atorvastatin;

1 tablet contains atorvastatin calcium equivalent to 20 mg or 40 mg of atorvastatin;

Excipients: calcium carbonate; microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; polysorbate 80; hydroxypropylcellulose; magnesium stearate; hydroxypropylmethylcellulose; propylene glycol; polyethylene glycol-6000; talc; titanium dioxide (E 171) – for 20 mg tablets;

calcium carbonate; microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; polysorbate 80; hydroxypropylcellulose; magnesium stearate; crospovidone; sodium lauryl sulfate; hydroxypropylmethylcellulose; polyethylene glycol-6000; talc; titanium dioxide (E 171) – for 40 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

• white or almost white, capsule-shaped film-coated tablets with a break line on one side (20 mg tablets);
• white or almost white, round, biconvex, film-coated tablets (40 mg tablets).

Pharmacotherapeutic group. Lipid-lowering agents, single component. HMG-CoA reductase inhibitors. ATC code C10A A05.

Pharmacological properties.

Pharmacodynamics.

Atorvastatin is a synthetic hypolipidemic medicinal 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 rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

In experimental animal models, atorvastatin reduced 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 cell surfaces to enhance uptake and catabolism of LDL; atorvastatin also reduced 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. The dose of the drug, rather than the systemic concentration, correlates better with the reduction in LDL cholesterol levels. 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. 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 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 whether the drug is taken with food or independently of meals. When atorvastatin is administered in the evening, plasma concentrations are lower (approximately 30% lower in Cmax and AUC) compared to morning dosing. However, the reduction in LDL cholesterol levels is equivalent regardless of the time of administration (see section "Dosage and administration").

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

Metabolism. The drug is extensively metabolized to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro studies show that the inhibitory effect of ortho- and para-hydroxylated metabolites on HMG-CoA reductase is equivalent to that of the parent drug. Approximately 70% of circulating HMG-CoA reductase inhibitory activity is attributed to active metabolites. In vitro studies indicate that cytochrome P450 3A4 plays a significant role in atorvastatin metabolism, consistent with increased plasma concentrations of atorvastatin in humans when co-administered with erythromycin, a known inhibitor of this isoenzyme (see section "Interactions with other medicinal products and other forms of interactions").

Excretion. Atorvastatin 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 the drug 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 the dose is excreted in urine after oral administration.

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

Special patient populations

Elderly patients. Plasma concentrations of the drug are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly volunteers (aged 65 years and older) compared to younger adults. Clinical data indicate a greater degree of LDL reduction with any dose of the drug in elderly patients compared to younger patients (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 8-week study in children with heterozygous familial hypercholesterolemia (aged 10 to 17 years, n = 29).

Gender. Plasma concentrations of the drug 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 when the drug is administered.

Renal impairment. Renal disease does not affect plasma concentrations of atorvastatin or reduction in low-density lipoprotein cholesterol (LDL-C), therefore dose adjustment in patients with renal impairment is not required (see sections "Special precautions" and "Dosage and administration").

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

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

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

Table 1

Effect of concomitantly administered drugs on the pharmacokinetics of atorvastatin

& Ratio 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 warnings and precautions for use".

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

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

*** Concomitant treatment with glecaprevir/pibrentasvir is contraindicated (see section "Contraindications").

† Due to the dual interaction mechanism of rifampicin, concomitant use 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 concentration.

‡ 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

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

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases in adults

For adult patients without clinically evident ischemic heart disease but with multiple risk factors for ischemic heart disease, such as age, tobacco smoking, arterial hypertension, low levels of high-density lipoprotein (HDL) or a family history of premature ischemic heart disease, the drug 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, microalbuminuria, tobacco smoking, or arterial hypertension, the drug is indicated for:

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

For patients with clinically evident ischemic heart disease, the drug 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, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglyceride levels, and to increase high-density lipoprotein cholesterol (HDL-C) 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 management is insufficient.
• To reduce total cholesterol and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or when such treatments are unavailable.

In children

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

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

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

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

Contraindications.

Active liver disease, which may include persistent elevations of serum transaminases of unknown etiology.

Hypersensitivity to any component of this medicinal product.

Pregnancy.

Breastfeeding.

Concomitant use of the antiviral agents glecaprevir/pibrentasvir for hepatitis C.

Interaction with other medicinal products and other forms of interaction.

The risk of myopathy during statin therapy increases when fibrates, lipid-modifying doses of niacin, cyclosporine, or potent CYP3A4 inhibitors (e.g., clarithromycin, HIV and hepatitis C virus protease inhibitors, and itraconazole) are used concomitantly (see sections “Pharmacological properties” and “Special instructions”).

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

Concomitant use of atorvastatin with potent CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see Table 3 and detailed information below). The extent of interaction and effect enhancement depends on the potential impact on CYP3A4. Concomitant use of the drug with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for hepatitis C (HCV) (e.g., elbasvir/grazoprevir), and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided if possible. If concomitant use with these agents cannot be avoided, consider 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. No drug interaction studies have evaluated the effect of amiodarone or verapamil on atorvastatin. It is known that amiodarone and verapamil 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, consider prescribing lower maximum doses of atorvastatin and perform clinical monitoring of the patient. Clinical monitoring is also recommended after initiating or adjusting the dose of the inhibitor.

Grapefruit juice

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

Clarithromycin

The AUC of atorvastatin significantly increased when atorvastatin 80 mg was coadministered with clarithromycin (500 mg twice daily) compared to atorvastatin alone. Therefore, patients taking clarithromycin should use atorvastatin cautiously at doses above 20 mg (see sections “Special instructions” and “Method of administration and dosage”).

Combination of protease inhibitors

The AUC of atorvastatin significantly increased when atorvastatin was coadministered with several combinations of protease inhibitors (see section “Pharmacological properties”). Patients taking tipranavir + ritonavir or glecaprevir + pibrentasvir should avoid concomitant use of atorvastatin. For patients taking lopinavir + ritonavir or simeprevir, the drug should be used at the lowest necessary dose. For patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, or elbasvir + grazoprevir, the dose of the drug should not exceed 20 mg. For patients taking nelfinavir, the dose should not exceed 40 mg, and careful clinical monitoring of patients is recommended (see sections “Special instructions” and “Method of administration and dosage”).

Itraconazole

The AUC of atorvastatin significantly increased when atorvastatin 40 mg was coadministered with itraconazole 200 mg (see section “Pharmacological properties”). Therefore, patients taking itraconazole should be cautious if the atorvastatin dose exceeds 20 mg (see sections “Special instructions” and “Method of administration and dosage”).

Cyclosporine

Atorvastatin is a substrate of hepatic transporters. Atorvastatin metabolites are substrates of the OATP1B1 transporter. Inhibitors of OATP1B1 (e.g., cyclosporine) may increase the bioavailability of atorvastatin. The AUC of atorvastatin significantly increased when atorvastatin 10 mg was coadministered with cyclosporine 5.2 mg/kg/day compared to atorvastatin alone (see section “Pharmacological properties”). Concomitant use of the drug Limistin and cyclosporine should be avoided (see section “Special instructions”).

Letermovir. Concomitant use of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased atorvastatin exposure (AUC ratio: 3.29) (see section “Pharmacokinetics”).

Letermovir is an inhibitor of efflux transporters P-gp, BCRP, MRP2, OAT2, and the hepatic transporter OATP1B1/1B3, thereby increasing atorvastatin exposure. The dose of the drug should not exceed 20 mg daily (see section “Method of administration and dosage”).

The extent of CYP3A- and OATP1B1/1B3-mediated drug interactions with concomitant medications may vary when letermovir is used with cyclosporine. The use of the drug is not recommended in patients taking letermovir concomitantly with cyclosporine.

Glecaprevir and pibrentasvir, elbasvir and grazoprevir. Concomitant use of glecaprevir and pibrentasvir or elbasvir and grazoprevir may increase atorvastatin plasma concentrations and increase the risk of myopathy.

When glecaprevir and pibrentasvir are coadministered with atorvastatin, plasma concentrations of atorvastatin increase up to 8.3-fold, partly due to inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, concomitant use of atorvastatin is not recommended in patients taking medications containing glecaprevir and pibrentasvir.

When elbasvir and grazoprevir are coadministered with atorvastatin, plasma concentrations of atorvastatin increase up to 1.9-fold, partly due to inhibition of BCRP, OATP1B1/1B3, and CYP3A; therefore, the dose of the drug should not exceed 20 mg daily in patients taking medications containing elbasvir and grazoprevir (see sections “Pharmacokinetics”, “Special instructions”, and “Method of administration and dosage”).

Medical recommendations regarding the use of interacting drugs are summarized in Table 3 (see also sections “Pharmacological properties”, “Method of administration and dosage”, and “Special instructions”).

Table 3

Drug interactions associated with an increased risk of myopathy/rhabdomyolysis

*Use the lowest necessary dose.

Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are used concomitantly with gemfibrozil, co-administration of the drug Limistin 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, Limistin should be used with caution 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, consideration should be given to reducing the dose of Limistin (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 unstable decreases 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 plasma concentrations of atorvastatin.

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

Plasma concentrations of atorvastatin were lower (atorvastatin concentration ratio 0.74) when atorvastatin was co-administered with colestipol. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded the effect achieved by each drug used separately.

Azithromycin

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

Inhibitors of transport proteins

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

Ezetimibe

Ezetimibe monotherapy has been associated with muscle-related adverse effects, including rhabdomyolysis. Therefore, the risk of such events increases when ezetimibe is used concomitantly with atorvastatin. 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

When multiple doses of atorvastatin and digoxin are used concomitantly, steady-state plasma concentrations of digoxin increase (see section "Pharmacokinetics"). Patients receiving digoxin should be appropriately monitored.

Oral contraceptives

When atorvastatin is used concomitantly with oral contraceptives, increased AUC values for norethisterone and ethinylestradiol have been observed (see section "Pharmacological properties"), which should be taken into account when selecting an oral contraceptive for women taking atorvastatin.

Warfarin

Atorvastatin had no clinically significant effect on prothrombin time in patients undergoing long-term warfarin therapy.

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported when atorvastatin is used concomitantly with colchicine; therefore, atorvastatin should be prescribed with caution when used with colchicine.

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

Other medicinal products

Clinical studies have shown that concomitant use of atorvastatin with antihypertensive agents or during estrogen replacement therapy is not associated with clinically significant adverse effects. Interactions with other drugs have not been studied.

Special precautions for use.

Muscle

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and other drugs in this class. A history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients require careful monitoring for skeletal muscle-related adverse effects.

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

Atorvastatin may cause immune-mediated necrotizing myopathy (IMNM)—an autoimmune myopathy associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy; muscle biopsy showing necrotizing myopathy without significant inflammation; and a positive response to immunosuppressive therapy.

Myopathy should be considered in patients presenting 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 symptoms persist after discontinuation of atorvastatin. Treatment 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 medicinal products listed in Table 3. Physicians considering combination therapy with atorvastatin and any of these agents should carefully weigh the potential benefits and 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 starting and maintenance doses of atorvastatin when coadministered with the aforementioned medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). In such situations, periodic CPK monitoring may be considered, although there is no guarantee that such monitoring will prevent cases of severe myopathy.

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

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

Liver function

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

There are data indicating that jaundice developed in one patient during treatment with the drug. 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 out of 30 patients with persistent elevations in liver function tests continued atorvastatin treatment at lower doses.

Prior to initiating therapy, it is recommended to obtain baseline liver enzyme test results and repeat testing as clinically indicated. Rare post-marketing reports of fatal and non-fatal hepatic failure have been received in patients treated with statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during atorvastatin therapy, treatment should be immediately discontinued. Reinitiation of treatment with the drug should not be considered unless an alternative etiology is identified.

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

Endocrine function

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

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

Use in patients with recent stroke or transient ischemic attack

In patients without ischemic heart disease who had a history of stroke or transient ischemic attack within the previous 6 months, treatment with atorvastatin 80 mg was associated with a higher incidence of hemorrhagic stroke compared to placebo. The incidence of fatal hemorrhagic stroke was similar across treatment groups. The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group compared to placebo. Certain baseline characteristics, including a history of hemorrhagic or lacunar stroke at study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.

Among patients aged 65–75 years receiving atorvastatin, no overall differences in safety and efficacy of the drug were observed compared to younger patients, nor were there differences in drug effects between elderly and younger patients. However, increased sensitivity in some elderly patients cannot be ruled out. Since elderly patients (aged 65 years and older) are more susceptible to myopathy, atorvastatin should be prescribed with caution.

Liver failure

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

Before starting treatment

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

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

For elderly patients (aged 70 years and older), 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 drug interactions (see section "Interaction with other medicinal products and other forms of interaction") and in special patient populations (see section "Pharmacokinetics"), including patients with hereditary disorders.

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

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 levels (exceeding ULN by more than five times) are 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 onset of muscle pain, cramps, or weakness, especially if accompanied by malaise or fever.

If these symptoms occur during treatment with atorvastatin, CK levels should be measured. If CK levels are markedly elevated (exceeding ULN 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 ULN but muscle symptoms are severe, intolerable, or persist daily.

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.

Treatment with atorvastatin 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 plasma concentrations of atorvastatin. Examples include potent CYP3A4 or transporter protein inhibitors: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, and others. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibrates, antiviral agents for hepatitis C (telaprevir, elbasvir/grazoprevir), erythromycin, niacin, ezetimibe, telaprevir, or telaprevir/ritonavir combination. If possible, alternative medicinal products (not interacting with atorvastatin) should be used instead of the above-mentioned agents.

If concomitant therapy with atorvastatin and these agents is necessary, the benefits and risks should be carefully weighed. If patients are taking medicinal products that increase plasma concentrations of atorvastatin, 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 coadministered with systemic fusidic acid or within 7 days after discontinuation of fusidic acid. In patients requiring systemic fusidic acid, statin therapy should be suspended for the entire duration of fusidic acid treatment. Cases of rhabdomyolysis, including fatal cases, have been reported in patients receiving fusidic acid and statins in combination (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be advised to seek immediate medical attention if they experience any symptoms of muscle weakness, pain, or tenderness.

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

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

The risk of myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., atorvastatin) and daptomycin (see section "Interaction with other medicinal products and other forms of interaction"). Temporary discontinuation of atorvastatin should be considered in patients receiving daptomycin, unless the benefit outweighs the risk. If concomitant use cannot be avoided, CK levels should be monitored 2–3 times per week, and patients should be closely monitored for any signs or symptoms suggestive of myopathy.

Lung interstitial disease

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

Excipients

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

Lipid-modifying therapy should be one component of comprehensive management in 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 fats and cholesterol and other non-pharmacological interventions have not provided adequate response. Limistin 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 was elevated chylomicrons (Fredrickson types I and V).

Use during pregnancy or breastfeeding

Pregnancy

Risk assessment

The drug is contraindicated in pregnant women, as its safety in pregnancy has not been established and there is no clear benefit of lipid-lowering drugs during pregnancy. Since HMG-CoA reductase inhibitors reduce cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin may have harmful effects on the fetus. Drug administration 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 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 case reports on the use of atorvastatin calcium do not indicate an increased risk of major congenital malformations or spontaneous abortions.

Rare reports of congenital anomalies have been received following in utero exposure to other HMG-CoA reductase inhibitors. Prospective monitoring of approximately 100 pregnancies in women treated with simvastatin or lovastatin showed that the rates of fetal congenital anomalies, spontaneous abortions, and intrauterine deaths/stillbirths did not exceed those expected in the general population. The number of cases is sufficient to exclude a ≥3–4-fold increase in fetal developmental anomalies compared to the background rate. In 89% of the prospectively monitored pregnancies, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Breastfeeding

The drug is contraindicated during breastfeeding. There is no information on the effect of the drug on the breastfed infant or on lactation. It is not known 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 this drug should not breastfeed (see section "Contraindications").

Ability to affect reaction speed when driving or operating machinery

The drug has negligible influence on the ability to drive or operate machinery.

Method of administration and dosage.

Hyperlipidemia and mixed dyslipidemia

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

Heterozygous familial hypercholesterolemia in pediatric patients (aged 10 to 17 years)

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

Homozygous familial hypercholesterolemia

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

Concomitant lipid-lowering therapy

Limistin may be used with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should be administered with caution (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").

Dosage in patients with renal impairment

Renal disease does not affect drug plasma concentration or LDL-C reduction during treatment; therefore, dose adjustment in patients with renal impairment is not required (see sections "Pharmacokinetics" and "Special precautions for use").

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

The use of the drug should be avoided in patients taking cyclosporine or the HIV protease inhibitor tipranavir + ritonavir, or the hepatitis C virus protease inhibitor glecaprevir + pibrentasvir, or letermovir when coadministered with cyclosporine. For HIV patients taking lopinavir + ritonavir, atorvastatin should be administered at the lowest necessary dose. For patients taking clarithromycin, itraconazole, elbasvir + grazoprevir, or HIV patients taking combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, or letermovir, the therapeutic dose of the drug should be limited to 20 mg; appropriate clinical monitoring is also recommended to ensure the use of the lowest necessary atorvastatin dose.

In patients taking the hepatitis C virus protease inhibitor elbasvir/grazoprevir concomitantly with atorvastatin, the atorvastatin dose should not exceed 20 mg/day (see sections "Special precautions for use" and "Interaction with other medicinal products and other types of interactions").

For patients taking the HIV protease inhibitor nelfinavir, atorvastatin treatment should be limited to a dose of 40 mg. When atorvastatin is coadministered with other protease inhibitors, appropriate clinical monitoring is recommended to ensure the use of the lowest necessary dose (see sections "Interaction with other medicinal products and other types of interactions" and "Special 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 dietary therapy trial the following are present:

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

The indication for atorvastatin use is supported by the following studies:

• A 6-month placebo-controlled clinical trial involving 187 boys and girls after onset of menstruation, aged 10 to 17 years. Patients receiving atorvastatin at doses of 10 mg or 20 mg daily had an overall adverse reaction profile similar to that of patients receiving placebo. In this small, controlled study, no significant effect of atorvastatin 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 <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 the limitations of the uncontrolled study design.

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

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

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

Homozygous familial hypercholesterolemia

The clinical efficacy of atorvastatin at doses up to 80 mg daily over 1 year was evaluated in an uncontrolled study in patients with homozygous familial hypercholesterolemia, which included 8 children.

Overdose.

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

Adverse Reactions

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

According to data from clinical trials of atorvastatin involving 16,066 patients over 53 weeks, the most common adverse reactions leading to discontinuation of atorvastatin treatment, 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%).

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

Table 4 summarizes the frequency of clinical adverse reactions, regardless of causal relationship, reported in 2% or more of patients and at a higher frequency than in the placebo group, among patients receiving atorvastatin treatment (n=8755), based on data from 17 placebo-controlled studies.

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

Table 4

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

Other adverse reactions reported during placebo-controlled studies include:

General disorders: malaise, pyrexia;

Gastrointestinal disorders: gastrointestinal discomfort, 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 levels, increased CK activity, hyperglycemia;

Nervous system disorders: disturbing dreams;

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 (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000).

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

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

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

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

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

Liver and biliary system disorders: very rare – liver failure.

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

Cardiovascular system disorders: rare – vasculitis.

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 CK activity; uncommon – positive test for leukocytes in urine.

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

Elevated serum CK activity (more than 3 times above ULN) was observed in 2.5% of patients receiving atorvastatin. This is consistent with observations during clinical trials of other HMG-CoA reductase inhibitors. In 0.4% of patients receiving atorvastatin, levels exceeding ULN by more than 10 times were observed.

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

Children (10–17 years). Adverse events observed in patients receiving atorvastatin were similar to those in the placebo group. The most common adverse events observed in both groups, regardless of causal relationship, were infections.

Post-marketing experience with atorvastatin.

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

Adverse reactions associated with atorvastatin treatment reported after marketing authorization, regardless of causal assessment, include: anaphylaxis, angioedema, bullous eruptions (including exudative erythema multiforme, 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 instructions").

Rare post-marketing reports of cognitive disorders (memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive disorders were reported with all statins. Overall, 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 of 3 weeks).

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

The following adverse reactions have been reported during post-marketing surveillance.

Blood and lymphatic system disorders: thrombocytopenia.

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

Metabolism and nutrition disorders: weight gain.

Nervous system disorders: headache, hypoesthesia, dysgeusia; myasthenia gravis (frequency unknown).

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Eye disorders: ocular myasthenia (frequency unknown).

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain.

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

Laboratory abnormalities: increased alanine aminotransferase activity, increased blood CK activity.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk profile of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. 10 tablets per blister, 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Marcsans Pharma Ltd.

Manufacturer's location and address of its business premises.

Plot No. L-82, L-83, Verna Industrial Estate, Verna Goa, IN – 403 722, India.

Marketing Authorization Holder.

Ananta Medikare Ltd.

Address of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.