Atoris

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

Composition:

Active ingredient: atorvastatin;

1 tablet contains 30 mg, or 60 mg, or 80 mg of atorvastatin as atorvastatin calcium;

Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, sodium croscarmellose, crospovidone, polysorbate 80, sodium hydroxide, magnesium stearate;

coating: polyvinyl alcohol, talc, macrogol 3000, titanium dioxide (E 171).

Medicinal form. Film-coated tablets.

Main physicochemical properties:

30 mg: white or almost white, round, slightly convex, film-coated tablets with beveled edges;

60 mg: white or almost white, oval, biconvex, film-coated tablets;

80 mg: white or almost white, capsule-shaped, biconvex, film-coated tablets.

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

Pharmacological properties.

Pharmacodynamics.

Atoris® contains the active substance atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase — the enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very-low-density lipoproteins (VLDL), which enter the bloodstream and are transported to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is primarily catabolized via interaction with high-affinity LDL receptors (LDL receptors).

Atorvastatin reduces plasma cholesterol and serum lipoprotein concentrations by inhibiting HMG-CoA reductase and hepatic cholesterol biosynthesis, as well as by increasing the number of hepatic LDL receptors on cell surfaces, thereby enhancing the uptake and catabolism of LDL.

Atorvastatin reduces the formation of LDL and the number of LDL particles. It induces a pronounced and sustained increase in LDL receptor activity in combination with favorable changes in the quality of circulating LDL particles. Atorvastatin effectively lowers LDL cholesterol (LDL-C) levels in patients with homozygous familial hypercholesterolemia, a group that has not always responded to therapy with lipid-lowering agents.

In addition to its effects on plasma lipids, atorvastatin has other effects that enhance its antiatherosclerotic action. It inhibits the synthesis of isoprenoids — compounds that act as growth factors for vascular smooth muscle cell proliferation — reduces plasma viscosity and activity of certain coagulation factors, and promotes normalization of blood coagulation processes. Furthermore, HMG-CoA reductase inhibitors affect macrophage metabolism and thereby suppress their activation, reducing the risk of atherosclerotic plaque rupture.

It has been demonstrated that atorvastatin reduces total cholesterol (30–46%), LDL-C (41–61%), apolipoprotein B (34–50%), and triglycerides (14–33%), while causing variable increases in HDL-C and apolipoprotein A levels in dose-response studies. These results are consistent across patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus.

It has been proven that lowering levels of total cholesterol, LDL-C, and apolipoprotein B reduces the risk of cardiovascular complications and cardiovascular mortality.

Pharmacokinetics.

Absorption

Atorvastatin is rapidly absorbed after oral administration and reaches peak plasma concentration within 1–2 hours. The extent of absorption and plasma concentration of atorvastatin are dose-dependent. The bioavailability of atorvastatin in tablet form is 95% and 99% compared to solution, respectively. Absolute bioavailability of atorvastatin is approximately 12–14%, while systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is due to presystemic clearance in the gastrointestinal mucosa and biotransformation during first-pass metabolism in the liver.

Distribution

The mean volume of distribution of atorvastatin is approximately 381 L. Plasma protein binding is > 98%. The blood-to-plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes.

Metabolism

Atorvastatin is extensively metabolized, forming ortho- and parahydroxylated derivatives and various β-oxidation products. In vitro, ortho- and parahydroxylated metabolites exhibit HMG-CoA reductase inhibitory activity equivalent to that of atorvastatin. Circulating metabolites account for approximately 70% of the drug's inhibitory effect on HMG-CoA reductase.

Elimination

Atorvastatin and its metabolites are primarily excreted in bile following hepatic and/or extrahepatic biotransformation, but do not undergo enterohepatic recirculation. The mean elimination half-life of atorvastatin in humans is approximately 14 hours. The inhibitory effect on HMG-CoA reductase persists for 20–30 hours due to the presence 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 atorvastatin in healthy elderly volunteers (aged > 65 years) are higher than in younger individuals, although the lipid-lowering effects are comparable to those observed in younger patients.

Pediatric population

Apparent oral clearance of atorvastatin in children was found to be similar to that in adults when scaled allometrically by body weight, as body weight was the only significant covariate in the population pharmacokinetic model of atorvastatin using data that included children with heterozygous familial hypercholesterolemia (aged 6 to 17 years).

Gender

Plasma concentrations of atorvastatin differ between women and men (maximum plasma concentration [Cmax] is approximately 20% higher in women, while area under the curve [AUC] is 10% lower). However, these differences are not clinically significant, and the lipid-lowering effect of the drug is nearly identical in men and women.

Renal impairment

Renal disease does not affect plasma concentrations or lipid-lowering effects of atorvastatin and its active metabolites.

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

Hepatic impairment

Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease. Cmax and AUC values are 4-fold higher in patients with Child-Pugh class A liver disease.

In patients with Child-Pugh class B liver disease, Cmax and AUC values are increased approximately 16-fold and 11-fold, respectively (see section "Contraindications").

Clinical characteristics.

Indications.

Prevention of cardiovascular diseases

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

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

For adult patients with type 2 diabetes mellitus and without clinically evident ischemic heart disease, but with multiple risk factors for IHD 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 adult 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 the need for myocardial revascularization procedures;
• reducing the risk of hospitalization due to congestive heart failure;
• reducing the risk of angina pectoris.

Hyperlipidemia

In adult patients

• Primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification). As an adjunct to diet to reduce elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglycerides, as well as to increase high-density lipoprotein cholesterol (HDL-C) levels.
• Hypertriglyceridemia (type IV according to Fredrickson classification). As an adjunct to diet for the treatment of patients with elevated serum triglyceride levels.
• Primary dysbetalipoproteinemia (type III according to Fredrickson classification). For treatment of patients when dietary compliance is insufficiently effective.
• Homozygous familial hypercholesterolemia. To reduce TC and LDL-C as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when such therapies are unavailable.
• Heterozygous familial hypercholesterolemia in pediatric patients (aged 10–17 years). As an adjunct to diet to reduce levels of TC, LDL-C, and apolipoprotein B in adolescent boys and girls after menarche aged 10 to 17 years, if after appropriate dietary therapy laboratory results are as follows:

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

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

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

Contraindications.

• Hypersensitivity to any component of the medicinal product.
• Active liver disease or persistent elevations (of unknown origin) in serum transaminases by three times or more the upper limit of normal.
• The drug is contraindicated in pregnant women, breastfeeding women, and women of reproductive potential who are not using appropriate contraceptive methods (see section "Use in pregnancy or lactation").
• Concomitant use with the hepatitis C antiviral agents glecaprevir/pibrentasvir.

Interaction with other medicinal products and other forms of interaction.

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

Table 1

Interaction of Atoris® with other medicinal products that increases the risk of myopathy and rhabdomyolysis with Atoris®.

Table 2

Interaction with medicinal products that may reduce exposure to the medicinal product Aторis®

Table 3

Effect of the medicinal product Atoris® on other medicinal products

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 aluminium hydroxide results in approximately a 35 % reduction in atorvastatin plasma concentrations. However, the hypolipidemic effect of atorvastatin was not altered.

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 may increase systemic exposure to atorvastatin (see Table 1). Cyclosporine and letermovir are inhibitors of transporters involved in the disposition of atorvastatin, including OATP1B1/1B3, P-gp, and BCRP, leading to increased systemic exposure to atorvastatin (see Table 1). The effect of inhibition of uptake transporters on atorvastatin exposure in hepatocytes is unknown. If concomitant use cannot be avoided, a dose reduction of atorvastatin is recommended, along with clinical monitoring of therapeutic efficacy (see Table 1).

Atorvastatin is not recommended in patients receiving letermovir concomitantly with cyclosporine (see section "Special precautions for use").

Gemfibrozil/fibrates

The use of fibrates as monotherapy has been associated with muscle-related adverse effects, including rhabdomyolysis. The risk of such events may be increased when fibrates are used concomitantly with atorvastatin. If concomitant use cannot be avoided, the lowest dose of atorvastatin should be used to achieve the therapeutic goal, and patients should be appropriately monitored (see section "Special precautions for use").

Ezetimibe

The use of ezetimibe alone has been associated with muscle-related adverse effects, including rhabdomyolysis. Therefore, the risk of such events may be increased when ezetimibe is used concomitantly with atorvastatin. Appropriate clinical monitoring of such patients is recommended.

Colestipol

Plasma concentrations of atorvastatin and its active metabolites were lower (by approximately 25 %) when colestipol was administered concomitantly with atorvastatin. However, lipid-lowering effects were greater when atorvastatin and colestipol were administered together than when either drug was administered alone.

Fusidic acid

Drug interaction studies between atorvastatin and fusidic acid have not been conducted. As with other statins, muscle-related adverse effects, including rhabdomyolysis, have been observed during concomitant use of atorvastatin and fusidic acid. The mechanism of this interaction is unknown. Patients should be closely monitored, and temporary discontinuation of atorvastatin may be considered.

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin and colchicine. Therefore, atorvastatin should be used with caution when administered 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 for use").

Effect of atorvastatin on concomitantly administered medicinal products

Digoxin

When atorvastatin and digoxin are coadministered, steady-state digoxin plasma concentrations increase by approximately 20 %. Patients taking digoxin should be appropriately monitored.

Oral contraceptives

Concomitant administration of atorvastatin with oral contraceptives increases plasma concentrations of norethisterone and ethinylestradiol. These increases should be considered when selecting an oral contraceptive for women taking atorvastatin.

Warfarin

In a clinical study of patients on long-term warfarin therapy, concomitant administration of 80 mg atorvastatin daily with warfarin resulted in a small reduction (approximately 1.7 seconds) in prothrombin time during the first 4 days of therapy, but this parameter returned to baseline within the next 15 days of atorvastatin treatment. Although clinically significant anticoagulant interactions have been reported only very rarely, prothrombin time should be measured frequently after initiating atorvastatin therapy in patients receiving coumarin anticoagulants, to confirm the absence of a significant change. Once a stable prothrombin time has been established, monitoring can continue at intervals routinely recommended for patients on coumarin anticoagulants. This procedure should be repeated if atorvastatin therapy is discontinued or the dose changed. In patients not receiving anticoagulants, atorvastatin therapy was not associated with bleeding or changes in prothrombin time.

Special precautions for use.

Myopathy and rhabdomyolysis

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

Risk factors for development of myopathy

Risk factors for the development of myopathy include age 65 years or older, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and use of higher doses of Atoris® (see section "Interaction with other medicinal products and other forms of interaction").

Measures to avoid or reduce the risk of myopathy and rhabdomyolysis

Exposure to Atoris® may be increased due to interactions with other drugs via inhibition of the cytochrome P450 3A4 enzyme (CYP3A4) and/or transporters (e.g., breast cancer resistance protein [BCRP], organic anion transporting polypeptide [OATP1B1/OAT0B3], P-glycoprotein [P-gp]), increasing the risk of myopathy and rhabdomyolysis. Concomitant use of Atoris® with cyclosporine, gemfibrozil, the combination of tipranavir + ritonavir, or glecaprevir + pibrentasvir is not recommended. Dose modification of Atoris® is recommended for patients taking certain antiviral agents, azole antifungals, or macrolide antibiotics (see section "Dosage and administration"). Cases of myopathy/rhabdomyolysis have been reported with concomitant use of atorvastatin and lipid-modifying doses (>1 g/day) of niacin, fibrates, colchicine, or the combination of ledipasvir + sofosbuvir. The benefit-risk balance of using these drugs should be evaluated considering the increased risk of myopathy and rhabdomyolysis (see section "Interaction with other medicinal products and other forms of interaction").

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

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

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

Immune-mediated necrotizing myopathy (IMNM)

Rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after treatment with certain statins. Clinically, IMNM is characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels, which persist despite discontinuation of statin therapy; positive antibodies to HMG-CoA reductase; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive therapy. Additional neuromuscular and serological investigations may be required. Immunosuppressive therapy may be needed. The risk of developing IMNM should be carefully considered before initiating another statin. If another statin is initiated, monitoring for signs and symptoms of IMNM is necessary.

Liver effects

Liver enzyme tests should be obtained before starting therapy and periodically thereafter. Patients who develop symptoms suggestive of liver dysfunction should have liver function tests performed. Patients with elevated transaminase levels should have liver function monitored until abnormalities resolve. If persistent elevations of serum transaminases occur at 3 times or more above the upper limit of normal (ULN), discontinuation of the drug is recommended (see section "Adverse reactions").

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

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

Post hoc analysis of stroke subtypes in patients without ischemic heart disease (IHD) who had recently experienced a stroke or transient ischemic attack (TIA) showed a higher incidence of hemorrhagic stroke with atorvastatin 80 mg compared to placebo. The increased risk was particularly noted in patients with prior hemorrhagic stroke or lacunar infarction at study entry. For patients with prior hemorrhagic stroke or lacunar infarction, the risk-benefit balance of atorvastatin 80 mg is not established; therefore, the potential risk of hemorrhagic stroke should be carefully evaluated before initiating treatment.

Skeletal muscles

Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare cases affect skeletal muscle and cause myalgia, myositis, and myopathy, which may progress to rhabdomyolysis—a potentially life-threatening condition characterized by markedly elevated creatine kinase (CK) levels (>10 times above normal), myoglobinemia, and myoglobinuria, which may lead to renal failure.

Before starting treatment

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

• Renal impairment;
• Hypothyroidism;
• Personal or family history of hereditary muscle disorders;
• Previous episodes of statin- or fibrate-induced myotoxicity;
• Previous liver disease and/or alcohol abuse.

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

Increased plasma concentrations of the drug may occur, particularly due to drug interactions (see section "Interaction with other medicinal products and other forms of interaction") and in specific patient groups, including those with inherited disorders (see section "Pharmacokinetics").

In such cases, the risk-benefit ratio of treatment should be evaluated, and clinical monitoring of patients is recommended.

If CK levels are significantly elevated before treatment initiation (more than 5 times above ULN), treatment should not be started.

Measurement of creatine kinase 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 5 times) are observed initially, repeat testing should be performed after 5–7 days to confirm the result.

During treatment

• Patients should be informed about the need to report immediately any 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 significantly elevated (more than 5 times above ULN), treatment should be discontinued.
• Discontinuation of treatment should also be considered if CK elevation does not exceed fivefold ULN but muscle symptoms are severe and cause daily discomfort.
• After symptoms resolve and CK levels normalize, reinitiation of atorvastatin therapy or initiation of an alternative statin at the lowest possible dose with close monitoring may be considered.
• Atorvastatin treatment must be discontinued if clinically significant elevation of CK levels (more than 10 times above ULN) occurs or if rhabdomyolysis is diagnosed or suspected.

Concomitant use with other medicinal products

The risk of rhabdomyolysis increases with concomitant use of atorvastatin and certain drugs that may increase atorvastatin plasma concentrations, such as strong inhibitors of CYP3A4 or transporter proteins (e.g., 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 may also be increased with concomitant use of gemfibrozil and other fibric acid derivatives, antiviral agents for hepatitis C (HCV) (e.g., boceprevir, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir), erythromycin, niacin, or ezetimibe. Where possible, alternative (non-interacting) therapies should be considered instead of these drugs.

If concomitant treatment with atorvastatin and these drugs is necessary, the benefit-risk balance should be carefully evaluated. If patients are taking drugs that increase atorvastatin plasma concentrations, the dose of atorvastatin should be reduced to the lowest possible. Additionally, when using strong CYP3A4 inhibitors, a lower initial dose of atorvastatin should be considered, and appropriate clinical monitoring of these patients is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Atorvastatin should not be used concomitantly with systemic fusidic acid or within 7 days after discontinuation of fusidic acid treatment. In patients for whom fusidic acid treatment is considered essential, statin therapy should be discontinued throughout the duration of fusidic acid treatment. Cases of rhabdomyolysis (including some fatal cases) have been reported in patients receiving fusidic acid and statins concomitantly (see section "Interaction with other medicinal products and other forms of interaction"). Patients should seek immediate medical attention if symptoms of muscle weakness, pain, or tenderness occur.

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

In exceptional cases where prolonged fusidic acid therapy is required, e.g., for treatment of severe infections, the possibility of concomitant use of atorvastatin and fusidic acid should be considered on a case-by-case basis and under continuous medical supervision.

The risk of developing 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 Atoris® should be considered in patients receiving daptomycin unless the benefit of concomitant use 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.

Interstitial lung disease

Rare cases of interstitial lung disease have been reported with some statins, particularly with long-term treatment (see section "Adverse reactions"). Clinical manifestations may include dyspnea, dry cough, and deterioration in general health (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin treatment should be discontinued.

Paediatric population

In a three-year study assessing overall development using the Tanner scale and measurements of height and body weight, no clinically significant effect on overall and sexual development was observed (see section "Adverse reactions").

Diabetes mellitus

Some data indicate that statins as a class may increase HbA1c and serum glucose levels and may induce hyperglycemia requiring treatment in some patients at high risk of developing diabetes. However, this risk is outweighed by the reduction in cardiovascular risk with statin use and therefore should not be a reason to discontinue statin therapy. According to national guidelines, clinical and biochemical monitoring of at-risk patients (fasting glucose 5.6–6.9 mmol/L, BMI >30 kg/m², elevated triglycerides, hypertension) is recommended.

Myasthenia gravis

Rare cases of statins inducing de novo myasthenia gravis or exacerbating existing myasthenia gravis or ocular myasthenia have been reported (see section "Adverse reactions"). If symptoms worsen, atorvastatin should be discontinued. Recurrences have been reported upon re-exposure to the same or another statin.

Excipients

The product contains lactose; therefore, it should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Women of childbearing potential should use appropriate contraceptive methods during treatment (see section "Contraindications"). If a patient intends to become pregnant during atorvastatin treatment, she should discontinue the drug no later than one month before planned conception.

Pregnancy

Atoris® is contraindicated during pregnancy, as safety has not been established and there are no controlled studies on the use of atorvastatin in pregnant women. Rare reports of congenital anomalies following in utero exposure to HMG-CoA reductase inhibitors have been received. Animal studies have shown toxic effects on reproductive function.

Atorvastatin treatment may reduce intrauterine mevalonate levels, which are necessary for cholesterol biosynthesis. Atherosclerosis is a chronic process; therefore, interruption of lipid-lowering therapy during pregnancy is not expected to have a significant impact on the long-term outcomes of primary hypercholesterolemia treatment.

Therefore, atorvastatin should not be used in pregnant women or in women who are planning or suspect they may be pregnant. Treatment with Atoris® should be discontinued during pregnancy or if pregnancy is suspected (see section "Contraindications").

Breastfeeding period

It is not known whether atorvastatin and its metabolites are excreted in human breast milk; however, it is known that small amounts of atorvastatin or its metabolites pass into rat milk. Due to the potential risk of serious adverse effects, women taking atorvastatin should discontinue breastfeeding (see section "Contraindications").

Atorvastatin is contraindicated during breastfeeding (see section "Contraindications").

Fertility

In animal studies, atorvastatin had no effect on fertility in males or females.

Ability to influence reaction speed when driving or operating machinery.

There are no reports of Atoris® affecting the ability to drive or operate machinery. However, during treatment, some patients may experience dizziness or muscle cramps. Therefore, caution should be exercised when driving or operating machinery during treatment.

Method of Administration and Dosage.

Dosage

Before initiating treatment with Atoris®, the degree of hypercholesterolemia should be determined and adherence to an appropriate diet, physical activity, weight reduction in obese patients, and management of other underlying medical conditions should be ensured. During treatment with Atoris®, the patient should follow a standard cholesterol-lowering diet.

Hyperlipidemia and mixed dyslipidemia

The recommended initial dose of atorvastatin is 10 mg or 20 mg once daily. For patients requiring a large reduction in LDL-C levels (more than 45%), therapy may be initiated with a dose of 40 mg once daily.

The dosage range of the medicinal product is from 10 mg to 80 mg once daily. The drug can be administered as a single dose at any time of day, independent of food intake. Initial and maintenance doses should be individually adjusted based on LDL-C levels, treatment goals, and response. Lipid levels should be monitored 2–4 weeks after initiation of therapy and/or dose adjustment, and the dose should be appropriately modified.

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

The recommended initial dose of atorvastatin is 10 mg/day, with a usual dosage range of 10 mg to 20 mg orally once daily. Doses should be individually adjusted according to treatment goals. Therapeutic response occurs within

2–4 weeks and is maintained during long-term therapy. 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 mg to 80 mg daily (see section "Pharmacodynamics"). Atorvastatin should be used as an adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or when other lipid-lowering therapies are unavailable.

Combination lipid-lowering therapy

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

Prevention of cardiovascular disease

The recommended initial dose is 10 mg/day. Higher doses may be required to achieve target LDL-C levels according to current guidelines.

Renal impairment

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

Hepatic insufficiency

Atoris® should be used with caution in patients with hepatic impairment (see sections "Special Warnings and Precautions for Use", "Pharmacokinetics"). Atoris® is contraindicated in patients with active liver disease (see section "Contraindications").

Use in combination with other medicinal products

Treatment with the drug should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitors (telaprevir). Use with caution in HIV patients receiving lopinavir + ritonavir, and administer at the lowest necessary dose. For patients taking clarithromycin, itraconazole, or HIV patients receiving combinations of saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the therapeutic dose of the drug should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest effective dose. For patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, treatment with the drug should be limited to a dose of 40 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest effective dose (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Elderly patients

For patients aged 70 years and older, the efficacy and safety of atorvastatin at recommended doses should be evaluated considering the presence of other risk factors for the development of rhabdomyolysis.

Concomitant use with other medicinal products

In patients who are taking the hepatitis C antiviral agents elbasvir/grazoprevir or letermovir for cytomegalovirus infection prophylaxis concomitantly with atorvastatin, the atorvastatin dose should not exceed 20 mg/day (see sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction").

The use of atorvastatin is not recommended in patients taking letermovir concomitantly with cyclosporine (see sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children.

Heterozygous familial hypercholesterolemia

For patients aged 10 years and older with heterozygous familial hypercholesterolemia, the recommended initial dose of atorvastatin is 10 mg daily (see section "Pharmacodynamics"). The dose may be increased up to 80 mg daily according to response and tolerability. Doses should be individually adjusted according to therapeutic goals. Dose adjustments should be made at intervals of 4 weeks or longer. Titration to 80 mg daily is supported by data from studies in adults and limited clinical data in children with heterozygous familial hypercholesterolemia (see sections "Adverse Reactions" and "Pharmacodynamics").

Safety and efficacy data in children aged 6 to 10 years with heterozygous familial hypercholesterolemia were obtained from open-label studies. Atorvastatin should not be used for treatment in patients under 10 years of age (see sections "Adverse Reactions", "Pharmacodynamics", and "Pharmacokinetics").

Another pharmaceutical form/dosage may be more appropriate for this patient group.

Clinical efficacy studies of atorvastatin at doses up to 80 mg/day for 1 year in patients with homozygous familial hypercholesterolemia included 8 pediatric patients (see section "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. Liver function tests should be performed and serum creatine kinase levels monitored. Due to the high degree of plasma protein binding of atorvastatin, a significant increase in atorvastatin clearance is not expected with hemodialysis.

Adverse Reactions

Since clinical trials are conducted under widely varying conditions, the incidence rates of adverse reactions observed in the clinical trials of a drug cannot be directly compared with those of another drug, and may not reflect the rates observed in clinical practice.

According to clinical trial data, the most commonly reported adverse reactions leading to discontinuation of atorvastatin treatment and occurring at a higher frequency (> 2%) than in the placebo group were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), increased alanine aminotransferase (ALT) levels (0.4%), and elevated liver enzymes (0.4%).

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

Other adverse reactions reported during placebo-controlled trials include:

General disorders: malaise, pyrexia.

Gastrointestinal disorders: gastrointestinal discomfort, belching, 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, abnormal liver function tests, elevated alkaline phosphatase in blood, increased creatine phosphokinase activity, hyperglycemia.

Nervous system disorders: nightmares.

Respiratory system disorders: epistaxis.

Skin and subcutaneous tissue disorders: urticaria.

Eye disorders: blurred vision, visual disturbances.

Ear and labyrinth disorders: tinnitus.

Vascular disorders: vasculitis.

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 (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000).

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

Eye disorders: frequency not known: ocular myasthenia.

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

Musculoskeletal and connective tissue disorders: common: joint pain, back pain; rare: myopathy, myositis, rhabdomyolysis, and red-brown discoloration of urine.

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: skin rashes, pruritus, alopecia; rare: angioedema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced lichenoid reaction.

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

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

Elevated creatine kinase serum activity, exceeding three times the upper limit of normal, was observed in 2.5% of patients receiving atorvastatin. This is consistent with observations from clinical trials 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 infection, diabetes mellitus, stroke, increased serum transaminase activity (dose-dependent and reversible in all patients), increased serum creatine kinase activity, diabetes mellitus.

Post-marketing experience

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 and 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, and pancreatitis.

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 (e.g., partial memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have been received. These cognitive disorders have been reported with all statins. Overall, these reactions were not considered serious adverse reactions and were reversible upon discontinuation of statin therapy, with variable time to onset (from 1 day to several years) and resolution (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.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

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

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

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

Pediatric population

Pediatric patients aged 10 to 17 years receiving atorvastatin had an adverse reaction profile generally similar to that of placebo-treated patients. In a three-year study assessing overall development using the Tanner scale and measurements of height and body weight, no clinically significant effects on overall or sexual development were observed. The safety and tolerability profile in pediatric patients was similar to the known safety profile of atorvastatin in adult patients.

The clinical safety database includes safety data from 520 pediatric patients who received atorvastatin, including 7 patients under 6 years of age, 121 patients aged 6 to 9 years, and 392 patients aged 10 to 17 years. Based on available data, the frequency, type, and severity of adverse reactions in children are similar to those in adults.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging.

10 tablets per blister; 3, 6, or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.