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

Composition:

Active substance: atorvastatin;

One film-coated tablet contains 10 mg or 20 mg of atorvastatin calcium trihydrate, calculated as atorvastatin;

Excipients: microcrystalline cellulose, mannitol (E 421), sodium starch glycolate (type A), meglumine, poloxamer, hydroxypropylcellulose, magnesium stearate, Opadry White 03H18479 (titanium dioxide (E 171), hypromellose, propylene glycol, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, triangular, biconvex, film-coated tablets, embossed with "A" on one side and "10" or "20" on the other side.

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

Pharmacological properties.

Pharmacodynamics.

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

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme responsible for the rate-limiting step in the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a sterol precursor, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream in complex with lipoproteins. These complexes can be separated by ultracentrifugation into fractions: HDL (high-density lipoproteins), IDL (intermediate-density lipoproteins), LDL (low-density lipoproteins), and VLDL (very low-density lipoproteins). Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into blood plasma for transport to peripheral tissues. LDL particles are formed from VLDL and are catabolized via interaction with high-affinity LDL receptors. Clinical and pathological studies indicate that elevated levels of total cholesterol (TC), LDL cholesterol (LDL-C), and apolipoprotein B (apo B) in blood plasma promote the development of atherosclerosis in humans and are risk factors for cardiovascular diseases, whereas elevated levels of HDL cholesterol are associated with a reduced risk of cardiovascular disease.

In animal experimental models, atorvastatin reduces plasma cholesterol and lipoprotein levels by inhibiting hepatic HMG-CoA reductase and cholesterol synthesis, and by increasing the number of hepatic LDL receptors on cell surfaces, thereby enhancing the uptake and catabolism of LDL. Atorvastatin also reduces the production of LDL and the number of LDL particles. Atorvastatin reduces LDL cholesterol levels in some patients with homozygous familial hypercholesterolemia—individuals who rarely respond to treatment with other hypolipidemic agents.

Numerous clinical studies have shown that elevated levels of total cholesterol, LDL cholesterol, and apo B (the membrane complex for LDL cholesterol) promote the development of atherosclerosis. Similarly, low levels of HDL cholesterol (and its transport complex—apo A) are associated with the development of atherosclerosis. Epidemiological studies have established that cardiovascular disease and mortality increase directly with total cholesterol and LDL cholesterol levels and inversely with HDL cholesterol levels.

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

Like LDL, lipoproteins enriched with cholesterol and triglycerides—including VLDL, IDL, and remnants—may also contribute to the development of atherosclerosis. Elevated plasma triglyceride levels are often observed in a triad with low HDL cholesterol levels and small LDL particles, as well as in combination with non-lipid metabolic risk factors for ischemic heart disease. The total plasma triglyceride level per se has not been consistently proven to be an independent risk factor for ischemic heart disease. Furthermore, no independent effect of increasing HDL cholesterol or lowering triglycerides on the risk of coronary and cardiovascular morbidity and mortality has been established.

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

Pharmacokinetics.

Absorption. Atorvastatin is rapidly absorbed after oral administration, with peak plasma concentrations reached within 1–2 hours. The extent of absorption increases proportionally with the dose of atorvastatin. The absolute bioavailability of atorvastatin (parent drug) is approximately 14%, while the systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. The low systemic availability is attributed to pre-systemic clearance in the gastrointestinal mucosa and/or pre-systemic biotransformation in the liver. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as measured by Cmax and AUC, the reduction in LDL cholesterol is similar regardless of whether atorvastatin is taken with or without food. When atorvastatin is administered in the evening, plasma concentrations are lower (approximately 30% lower for Cmax and AUC) compared to morning administration. However, the reduction in LDL cholesterol is similar regardless of the time of administration (see section "Administration and dosage").

Distribution. The mean volume of distribution of atorvastatin is approximately 381 liters. Over 98% of the drug is bound to plasma proteins. The blood-to-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 human breast milk (see sections "Contraindications," "Use in pregnancy or lactation," and "Special precautions").

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

Excretion. Atorvastatin and its metabolites are primarily excreted in bile following hepatic and/or extrahepatic metabolism, although this drug does not appear to undergo enterohepatic recirculation. The mean elimination half-life of atorvastatin in human plasma is approximately 14 hours, while the half-life of HMG-CoA reduct enzyme 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 transporter 1B3 (OATP1B3). Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters 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. Atorvastatin plasma concentrations are higher (approximately 40% higher for Cmax and 30% higher for AUC) in healthy elderly patients (aged 65 years or older) compared to younger adults. Clinical data indicate a greater degree of LDL reduction with any dose of the drug in elderly patients compared to younger individuals (see section "Special precautions").

Children. Pharmacokinetic data in pediatric patients are not available.

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

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

Hemodialysis. Although studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance atorvastatin clearance due to the drug's extensive plasma protein binding. Hepatic impairment. Atorvastatin plasma concentrations 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").

Table 1.

Effect of concomitantly administered drugs on the pharmacokinetics of atorvastatin.

& Data presented as change in fold represent a simple ratio between co-administration cases and atorvastatin alone (i.e., 1-fold = no change). Data presented as % change represent % difference relative to values with atorvastatin administered alone (i.e., 0% = no change).

For information on clinical significance, see sections "Special Instructions" and "Interaction with Other Medicinal Products and Other Forms of Interaction".

* Greater increases in AUC (up to 2.5-fold) and/or Cmax (up to 71%) have been reported with excessive consumption of grapefruit juice (750 ml – 1.2 litres per day or more).

** Single sample taken 8–16 hours after dose administration.

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

‡ The dose of the combination of saquinavir + ritonavir used in this study is not a clinically applicable dose. The increase in atorvastatin exposure under clinical conditions is likely to be higher than that observed in this study. Therefore, the drug should be used with caution 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 the development of ischemic heart disease, such as age, smoking, arterial hypertension, low HDL cholesterol levels, or a family history of premature ischemic heart disease, Atocor is indicated for:

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

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

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

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

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

Hyperlipidemia.

In adult patients.

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

In children.

• As an adjunct to diet to reduce levels of total cholesterol, LDL cholesterol, and apolipoprotein B in boys and girls after the onset of menstruation, aged 10 to 17 years, with heterozygous familial hypercholesterolemia, if after appropriate dietary therapy the following laboratory results are present:

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

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

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

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Effect of concomitantly administered drugs on atorvastatin

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

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

Potent CYP3A4 inhibitors. Concomitant use of atorvastatin with potent CYP3A4 inhibitors may lead to increased plasma concentrations of atorvastatin (see Table 1 and detailed information below). The extent of interaction and effect enhancement depends on the variability of the effect on CYP3A4. Concomitant use with potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral agents for hepatitis C treatment (e.g., elbasvir/grazoprevir), HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. If concomitant use with these agents cannot be avoided, consideration should be given to using a lower initial and maximum dose of atorvastatin. Appropriate clinical monitoring of the patient is also recommended (see Table 1).

Moderate CYP3A4 inhibitors (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase atorvastatin plasma concentrations (see Table 1). Concomitant use of erythromycin and statins is associated with an increased risk of myopathy. Drug interaction studies to assess the effect of amiodarone or verapamil on atorvastatin have not been conducted. It is known that amiodarone and verapamil inhibit CYP3A4 activity; therefore, concomitant administration of these agents with atorvastatin may lead to increased atorvastatin exposure. Thus, when atorvastatin is used concomitantly with these moderate CYP3A4 inhibitors, consideration should be given to prescribing lower maximum doses of atorvastatin. Clinical monitoring of the patient is also recommended. After initiating treatment with an inhibitor or adjusting its dose, clinical monitoring of the patient is recommended.

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. AUC values of atorvastatin were significantly increased when atorvastatin 80 mg was administered concomitantly with clarithromycin (500 mg twice daily) compared to atorvastatin alone (see section "Pharmacological properties"). Therefore, in patients taking clarithromycin, atorvastatin doses above 20 mg should be used with caution (see sections "Special precautions for use" and "Dosage and administration").

Protease inhibitor combinations. AUC values of atorvastatin were significantly increased when atorvastatin was administered concomitantly with several HIV protease inhibitor combinations, as well as with the hepatitis C virus protease inhibitor telaprevir, compared to atorvastatin alone (see section "Pharmacological properties"). Therefore, in patients taking the HIV protease inhibitor tipranavir + ritonavir or the hepatitis C virus protease inhibitor telaprevir, concomitant use with atorvastatin should be avoided. The drug should be prescribed with caution to patients taking the HIV protease inhibitor lopinavir + ritonavir, and the lowest necessary dose should be used. In patients taking HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, or elbasvir + grazoprevir, the atorvastatin dose should not exceed 20 mg and should be used with caution (see sections "Special precautions for use" and "Dosage and administration"). When administered to patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, the atorvastatin dose should not exceed 40 mg, and careful clinical monitoring of patients is recommended.

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

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

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

*Use with caution and at the lowest necessary dose.

Gemfibrozil. Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are administered concomitantly with gemfibrozil, the combined use of atorvastatin with gemfibrozil should be avoided (see section "Special precautions").

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

Niacin. The risk of adverse skeletal muscle effects may increase when the drug is used in combination with niacin; therefore, under such conditions, dose reduction of atorvastatin should be considered (see section "Special precautions").
Rifampicin or other cytochrome P450 3A4 inducers. Concomitant use of the drug with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampicin) may lead to 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 intake has been shown to result in a significant reduction in atorvastatin plasma concentrations.

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

Cimetidine. Clinical studies have shown no evidence of interaction between atorvastatin and cimetidine.

Antacids. Concomitant oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxide results in approximately a 35% reduction in atorvastatin plasma concentrations. However, the hypolipidemic effect of atorvastatin remains unchanged.

Cholestyramine. Atorvastatin plasma concentrations were lower (atorvastatin concentration ratio: 0.74) when atorvastatin was administered concomitantly with cholestyramine. Nevertheless, the hypolipidemic effect of the combination of atorvastatin and cholestyramine 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) 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. The use of ezetimibe as monotherapy has been associated with muscle-related adverse effects, including rhabdomyolysis. Thus, 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) remains unknown. Cases of rhabdomyolysis (including fatal cases) 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 administered concomitantly, steady-state digoxin plasma concentrations increase by approximately 20%. Patients receiving digoxin should be appropriately monitored.

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

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

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

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

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

Special precautions for use.

Muscle.

Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been reported with atorvastatin and other drugs in this class. A history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients require closer monitoring for signs of skeletal muscle disorders.

Atorvastatin, like other statins, 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 medications, such as cyclosporine and potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors, and hepatitis C virus protease inhibitors), increases the risk of myopathy/rhabdomyolysis.

Rare cases of immune-mediated necrotizing myopathy (IMNM)—an autoimmune myopathy associated with statin use—have been reported. IMNM is characterized by the following features: proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin therapy; muscle biopsy shows necrotizing myopathy without significant inflammation; positive response to immunosuppressive therapy. The possibility of myopathy should be considered in any patient presenting with diffuse myalgias, muscle tenderness or weakness, and/or markedly elevated CPK. Patients should be advised to report immediately any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if symptoms persist after discontinuation of atorvastatin. Treatment should be discontinued in cases of markedly elevated CPK levels, or if myopathy is diagnosed or suspected.

The risk of myopathy during treatment with statins increases with concomitant use of cyclosporine, fibrates, erythromycin, clarithromycin, the hepatitis C virus protease inhibitor telaprevir, combinations of HIV protease inhibitors (including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir, and fosamprenavir + ritonavir), as well as niacin or azole antifungals. Physicians considering combination therapy with atorvastatin and fibrates, erythromycin, clarithromycin, combinations of saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits against the risks and closely monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any dose escalation periods of either drug. Consideration should be given to using lower starting and maintenance doses of atorvastatin when coadministered with the above-mentioned drugs (see section "Interaction with other medicinal products and other forms of interaction"). In such situations, periodic CPK monitoring may be considered, although there is no guarantee that such monitoring will prevent cases of severe myopathy.

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

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

Myasthenia gravis, ocular myasthenia.

Rare cases have been reported in which statins induce de novo myasthenia gravis or exacerbate pre-existing myasthenia gravis or ocular myasthenia (see section "Side effects"). If symptoms worsen, discontinuation of the medicinal product Atokor should be considered. Recurrences have been reported upon re-administration of the same or another statin.

Liver function.

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

During clinical trials, one patient developed jaundice. Elevated liver function test (LFT) results in other patients were not associated with jaundice or other clinical signs or symptoms. Transaminase levels returned to pre-treatment or near pre-treatment levels after dose reduction, interruption, or discontinuation of the drug, without residual effects. Eighteen of 30 patients with persistent elevations in liver function tests continued atorvastatin therapy at lower doses.

Prior to initiating atorvastatin therapy, baseline liver enzyme tests should be obtained and repeated as clinically indicated. Rare post-marketing reports of fatal and non-fatal hepatic failure have been reported in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during atorvastatin therapy, treatment should be discontinued immediately. If no alternative etiology is identified, re-initiation of the drug should not be considered.

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

Endocrine function.

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

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

Use in patients with recent stroke or transient ischemic attack.

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

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

Hepatic impairment.

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

Before starting treatment.

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

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

For elderly patients (aged 70 years or 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 or in special patient populations, including those with inherited disorders.

In such cases, a risk-benefit assessment of treatment should be performed, and clinical monitoring of patients should be conducted. If baseline CPK levels are markedly elevated (exceeding ULN by more than 5 times), treatment should not be initiated.

Measurement of creatine kinase levels.

Creatine kinase levels should not be measured following 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 levels (exceeding ULN by more than 5 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 report immediately the onset of muscle pain, cramps, or weakness, especially if accompanied by malaise or fever. If these symptoms occur during atorvastatin therapy, CPK levels should be measured. If CPK levels are markedly elevated (exceeding ULN by more than 5 times), treatment should be discontinued.

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

After resolution of symptoms and normalization of CK levels, re-initiation of atorvastatin therapy or initiation of an alternative statin may be considered, provided the lowest possible dose is used and the patient is closely monitored.

Atorvastatin therapy 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 drugs that may increase plasma concentrations of atorvastatin. Examples include potent inhibitors of CYP3A4 or transport proteins: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir. The risk of myopathy also increases with concomitant use of gemfibrozil and other fibrates, antiviral agents for hepatitis C (HCV) (boceprevir, telaprevir, elbasvir/grazoprevir), erythromycin, niacin, or ezetimibe. If possible, alternative drugs (that do not interact with atorvastatin) should be used instead of the above-mentioned agents.

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 the medicinal product Atokor should be considered in patients receiving daptomycin, unless the benefit outweighs the risk. If concomitant use cannot be avoided, CPK levels should be monitored 2–3 times per week, and patients should be closely observed for any signs or symptoms suggestive of myopathy.

If concomitant therapy with atorvastatin and the above-mentioned drugs is necessary, the benefits and risks should be carefully weighed. In patients receiving drugs 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 used concomitantly 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 concomitantly (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.

In exceptional circumstances requiring long-term systemic fusidic acid therapy, such as for the treatment of severe infections, concomitant use of atorvastatin and fusidic acid should only be considered on an individual basis and under strict medical supervision.

Interstitial lung disease.

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

Lipid-modifying therapy should be one component of a comprehensive treatment strategy 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 fat and cholesterol, and other non-pharmacological measures, have been insufficient. In patients with ischemic heart disease or multiple risk factors for ischemic heart disease, atorvastatin may be initiated concurrently with dietary changes.

Limitations of use.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Atorvastatin is contraindicated in pregnant women and in women who may become pregnant. Statins may cause fetal harm when administered to pregnant women. Atorvastatin may be used in women of reproductive potential only if pregnancy is highly unlikely and patients have been informed of the potential risks. If a woman becomes pregnant while receiving atorvastatin, the drug should be discontinued immediately, and the patient should be re-counseled regarding potential fetal risks and the lack of known clinical benefit from continuing therapy during pregnancy.

During normal pregnancy, serum cholesterol and triglyceride levels increase. The use of lipid-lowering agents during pregnancy will not provide benefit, as cholesterol and its derivatives are essential for normal fetal development. Atherosclerosis is a chronic process; therefore, interruption of lipid-lowering therapy during pregnancy is not expected to significantly affect the long-term outcomes of primary hypercholesterolemia treatment.

Adequate and well-controlled studies of atorvastatin use during pregnancy have not been conducted. Rare reports of congenital anomalies following in utero exposure to statins have been received. In a prospective observational study of approximately 100 pregnancies in women treated with other statins, the rates of congenital anomalies, miscarriages, and intrauterine fetal deaths/stillbirths did not exceed those expected in the general population. However, this study could only exclude a 3- to 4-fold increase in the risk of congenital malformations compared to the background rate. In 89% of these cases, treatment was initiated before pregnancy and discontinued during the first trimester after pregnancy was detected.

Contraception.

Atokor may cause fetal harm when administered to a pregnant woman. Women of reproductive potential should be advised to use effective contraception during treatment with this drug.

Lactation.

It is unknown whether atorvastatin is excreted in human milk, although it is known that a small amount of another drug in this class is excreted in breast milk. Because statins may potentially cause serious adverse reactions in breastfed infants, women requiring atorvastatin therapy should not breastfeed their infants (see section "Contraindications").

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

Dosage and Administration

Hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb).

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 40 mg once daily. The atorvastatin dosage range is 10 to 80 mg once daily. The drug can be administered as a single dose at any time of day, regardless of food intake. Initial and maintenance doses of atorvastatin should be individualized according to treatment goals and patient response. Lipid levels should be analyzed within 2 to 4 weeks after initiating therapy and/or adjusting the atorvastatin dose, and the dose should be adjusted accordingly.

Heterozygous familial hypercholesterolemia in pediatric patients (aged 10–17 years).
The recommended starting dose of atorvastatin is 10 mg/day; the maximum recommended dose is 20 mg/day (doses exceeding 20 mg have not been studied in this patient group). Doses should be individually titrated according to the recommended treatment goals. Dose adjustments should be made at intervals of at least 4 weeks.

Homozygous familial hypercholesterolemia.

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

Concomitant lipid-lowering therapy.

Atorvastatin may be used with bile acid sequestrants. Combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see sections "Special Warnings", "Drug Interactions").

Dosing in patients with renal impairment.

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

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

Atorvastatin therapy should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir), or hepatitis C virus protease inhibitors (telaprevir). Atorvastatin should be used with caution in HIV-infected patients taking lopinavir + ritonavir and should be administered at the lowest necessary dose. In patients taking clarithromycin, itraconazole, elbasvir + grazoprevir, or HIV-infected patients receiving combination therapy with saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the therapeutic dose of atorvastatin should be limited to 20 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C virus protease inhibitor boceprevir, atorvastatin therapy should be limited to a maximum dose of 40 mg, and appropriate clinical monitoring is recommended to ensure use of the lowest necessary dose (see sections "Special Warnings" and "Drug Interactions").

Pediatric use.

The safety and efficacy of atorvastatin in patients aged 10–17 years with heterozygous familial hypercholesterolemia were evaluated in a 6-month controlled clinical trial in adolescent boys and girls after menarche. Patients receiving atorvastatin had an adverse reaction profile generally similar to those receiving placebo. Infections were the most commonly observed adverse events in both groups, regardless of causal assessment. Doses higher than 20 mg have not been studied in this patient group. In this limited controlled study, no significant effect of the drug on growth or sexual maturation in boys or on menstrual cycle length in girls was observed (see sections "Adverse Reactions", "Dosage and Administration"). Adolescent girls should be advised about appropriate contraceptive methods during atorvastatin therapy (see sections "Use in Pregnancy or Lactation" and "Use in Specific Patient Populations").

Atorvastatin has not been studied in controlled clinical trials involving prepubertal patients or those under 10 years of age.

The clinical efficacy of atorvastatin at doses up to 80 mg/day over 1 year was evaluated in an uncontrolled study in pediatric patients (n=8) with homozygous familial hypercholesterolemia (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. Due to the high degree of plasma protein binding, significant enhancement of drug clearance by hemodialysis is not expected.

Adverse Reactions

The five most common adverse reactions in patients treated with atorvastatin that led to discontinuation of the drug and occurred at a higher frequency than in the placebo group were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), increased alanine aminotransferase (ALT) levels (0.4%), and increased liver enzymes (0.4%). In patients treated with atorvastatin in placebo-controlled studies (n=8755), the most frequently observed adverse reactions (incidence of 2% or higher and greater than placebo), regardless of causal relationship, were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), limb pain (6.0%), and urinary tract infection (5.7%).

Table 4 summarizes the incidence of clinical adverse reactions, regardless of causal relationship, reported in 2% or more patients and at a higher frequency than in placebo groups, among patients treated with atorvastatin (n=8755) from 17 placebo-controlled studies.

Other adverse reactions reported during placebo-controlled studies include:

General disorders: malaise, pyrexia;

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

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

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

Nervous system disorders: nightmares;

Respiratory system disorders: epistaxis;

Skin and subcutaneous tissue disorders: urticaria;

Eye disorders: blurred vision, visual disturbances;

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 neuropathies; frequency not known: myasthenia gravis.

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

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

General disorders: uncommon: asthenia, chest pain, peripheral edema, fatigue. Metabolism and nutrition disorders: uncommon: hypoglycemia, weight gain, anorexia.

Hepatobiliary disorders: very rare: hepatic failure.

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

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

Blood and lymphatic system disorders: rare: thrombocytopenia.

Vascular disorders: rare: vasculitis.

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

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

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

As with other HMG-CoA reductase inhibitors, elevated serum transaminase activity has been observed in patients taking atorvastatin. These changes were usually mild, transient, and did not require intervention or discontinuation of treatment. Clinically significant elevations in serum transaminase activity (more than 3 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. In 2.5% of patients receiving atorvastatin, creatine kinase serum activity increased to more than 3 times the upper limit of normal. This is consistent with observations during clinical trials with other HMG-CoA reductase inhibitors. In 0.4% of patients receiving atorvastatin, levels exceeding the upper limit of normal by more than 10 times were observed.

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

Children (aged 10–17 years).

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

Post-marketing experience.

During post-marketing use of atorvastatin, the following adverse reactions have been reported. Since these reactions were reported voluntarily from an unknown number of patients, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions associated with atorvastatin treatment, regardless of causal assessment, include: anaphylaxis, angioneurotic edema, bullous skin eruptions (including exudative erythema multiforme, 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 (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use have also been received. These cognitive disorders were reported with all statins. Reports were generally not classified as serious adverse reactions, and symptoms were reversible after discontinuation of statins, with variable time to onset (from 1 day to several years) and resolution (median duration of 3 weeks).

Adverse events described with some statins include sexual dysfunction; 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: hypoaesthesia, dysgeusia, headache.

Gastrointestinal disorders: abdominal pain.

Ear and labyrinth disorders: tinnitus.

Skin and subcutaneous tissue disorders: urticaria.

Musculoskeletal and connective tissue disorders: arthralgia, back pain.

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

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

**Shelf life. **2 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 25 °C.

Packaging. 10 tablets per blister, 1 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Dr. Reddy’s Laboratories Ltd (Production Unit – VI)

Manufacturer’s address and site of operations.

Village Khol, Nalagarh Road, Baddi, Solan District, Himachal Pradesh, India

Adverse reactions or lack of efficacy with this medicinal product can be reported via phone:

+380 44 207 51 97 or +380 50 414 39 39; or by email: [email protected] (available 24/7).