ࡱ> x{uvw_ bjbj"=bb,, )!!!!!"""$Of"""""!!é///"!!/"//fb!hjP#D٩0 |B&Bbb x""/"""""*""" """"""""""""",? k: APPROVED Order of the Ministry of Health of Ukraine No. 1389 dated 22.12.2016 Marketing Authorization No. UA/15677/01/01 UA/15677/01/02 UA/15677/01/03 UA/15677/01/04 INSTRUCTION for medical use of medicinal product ATORVAKOR Composition: Active substance: atorvastatin; 1 tablet contains 10.82 mg or 21.64 mg or 43.28 mg or 86.56 mg of atorvastatin calcium trihydrate as calculated on 100% substance (equivalent to atorvastatin) 10 mg or 20 mg or 40 mg or 80 mg; Excipients: calcium carbonate; lactose, monohydrate; microcrystalline cellulose; sodium croscarmellose; polysorbate 80, hydroxypropyl cellulose; magnesium stearate; Opadry II 85F18422 white (polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171)). Pharmaceutical form Film-coated tablets. Basic physical and chemical properties: round, biconvex, white to off white, film-coated tablets. Pharmacotherapeutic group Lipid modifying agents. HMG CoA reductase inhibitors. "! Code !10 05. Pharmacological properties Pharmacodynamics Atorvakor is a synthetic lipid-lowering drug. Atorvastatin is a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor. This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early rate-limiting stage of cholesterol biosynthesis. Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.Cholesterol andtriglyceridescirculate in the bloodstream as part oflipoproteincomplexes. With ultracentrifugation, these complexes separate intoHDL(high-density lipoprotein), IDL (intermediate-density lipoprotein),LDL(low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinityLDL receptor. Clinical andpathologicstudies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote humanatherosclerosisand are risk factors for developingcardiovascular disease, while increased levels of HDL-C are associated with a decreasedcardiovascularrisk. In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake andcatabolismof LDL; atorvastatin also reduces LDL production and the number of LDL particles. Atorvastatin reduces LDL in some patients withhomozygousfamilialhypercholesterolemia (FH), a population that rarely responds to otherlipid-lowering medications. A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C. Atorvastatin reduces total-C, LDL-C, and apo B in patients with homozygous andheterozygousFH, nonfamilial forms of hypercholesterolemia, and mixeddyslipidaemia. Atorvastatin also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia. Like LDL, cholesterol-enriched triglyceride-richlipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronaryheart disease. As such, total plasma TG has not consistently been shown to be an independentrisk factorforCHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response (see section Posology and method of administration). Pharmacokinetics Absorption. Atorvastatin is rapidly absorbed after oral administration. Maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to the drug dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance ingastrointestinalmucosaand/or presystemic hepatic biotransformation. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether Atorvakor is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration (see section Posology and method of administration). Distribution. Mean volume of distribution of atorvastatin is approximately 381 litres. Atorvastatin is > 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration intored blood cells. Based on observations in rats, Atorvakor is likely to be secreted in human milk (see sections Contraindications, Use during pregnancy and in nursing women and Special warnings and precautions for use). Metabolism. Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products.In vitroinhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.In vitrostudies suggest the importance of Atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of Atorvastatin in humans following co-administration witherythromycin, a known inhibitor of this isozyme (see section Interaction with other medicinal products and other forms of interaction). Excretion. Atorvastatin and its metabolites are eliminated primarily in HYPERLINK "http://www.rxlist.com/script/main/art.asp?articlekey=2459" bilefollowing hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of Atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of Atorvastatin is recovered in urine following oral administration. Special populations Elderly. Plasma concentrations of Atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age >65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults (see section Special warnings and precautions for use). Paediatric patients. Pharmacokinetic data in the paediatric population are not available. Gender. Plasma concentrations of Atorvastatin 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-C reduction with Atorvastatin between men and women. Renal impairment. Renal disease has no influence on the plasma concentrations or LDL-C reduction of Atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary (see sections Posology and method of administration, Special warnings and precautions for use). Haemodialysis. While studies have not been conducted in patients withend-stage renal disease, HYPERLINK "http://www.rxlist.com/script/main/art.asp?articlekey=11433" haemodialysisis not expected to significantly enhance clearance of Atorvakor since the drug is extensively bound to plasma proteins. Hepatic impairment. In patients with chronic alcoholic HYPERLINK "http://www.rxlist.com/script/main/art.asp?articlekey=53394" liver disease, plasma concentrations of Atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease (see section Contraindications). Table 1. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drugs and dosing regimenAtorvastatinDose (mg)Change in AUC&Change in Cmax&#Cyclosporine 5.2mg/kg/day, stable dose 10 mg once daily for 28 days. (8,7 fold (10,7 fold#Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days10mg SD (9,4 fold (8,6 fold#Telaprevir 750 mg q8h, 10 days20mg SD (7,88 fold (10,6 fold#,! Saquinavir 400 mg BID/ ritonavir 400mg BID, 15 days 40 mg once daily for 4 days(3.9fold (4.3fold#Clarithromycin 500 mg BID, 9 days 80 mg once daily for 8 days (4.4 fold (5.4fold#Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days10 mg once daily for 4 days (3.4 fold (2.25 fold#Itraconazole 200 mg once daily, 4 days 40mg SD (3.3fold (20%#Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days10 mg once daily for 4 days.( 2.53 fold (2.84 fold#Fosamprenavir 1400 mg BID, 14 days10 mg once daily for 4 days (2.3 fold (4.04 fold#Nelfinavir 1250 mg BID, 14 days10 mg once daily for 28 days (74 % (2.2 fold#Grapefruit Juice, 240 mL once daily*40 mg once daily (37% (16%Diltiazem 240 mg once daily for 28 days 40 mg once daily (51%No changeErythromycin 500 mg QID, 7 days 10 mg once daily (33% (38%Amlodipine 10 mg, single dose 80 mg once daily (15% 12%Cimetidine 300 mg QID, 2 weeks 10 mg once daily for 2 weeks Less than 1 % 11%Colestipol 10 mg BID, 28 weeks 40 mg once daily for 28 weeksNot determined 26%**Maalox TC 30 mL once daily, 17 days 10 mg once daily for 15 days. 33% 34%Efavirenz 600 mg once daily for 14 days 10 mg for 3 days 41% 1%#Rifampin 600 mg once daily, 7 days (coadministered) 40 mg once daily (30% (2.7fold#Rifampin 600 mg once daily, 5 days (doses separated) 40 mg once daily 80% 40%#Gemfibrozil 600mg BID, 7 days40 mg once daily (35% Less than 1 %#Fenofibrate 160mg once daily, 7 days40 mg once daily (3% (2%#Boceprevir 800 mg TID, 7 days40 mg once daily( 2.3fold(2.66fold & Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change). # See Sections Special warnings and precautions for use and Interactions with other medicinal products and other forms of interaction for clinical significance. * Greater increases in AUC (up to 2.5 fold) and/or Cmax (up to 71%) have been reported with excessive grapefruit consumption (e"750 mL - 1.2 litres per day). ** Single sample taken 8 - 16 h post dose. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. Table 2. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drugs and dosing regimenDrug/dose (mg)Change in AUCChange in Cmax80 mg once daily for 15 days Antipyrine, 600 mg once daily (3%! 11%80 mg once daily for 14 days#Digoxin 0.25 mg once daily, 20 days (15% (20%40 mg once daily for 22 days Oral contraceptive once daily, 2 months  norethisterone 1mg  ethinyl estradiol35g  (28 %  (19%  (23%  (30%10 mg once dailyTipranavir 500 mg BID/ritonavir 200 mg BID, 7 daysNo changeNo change10 mg once daily for 4 daysFosamprenavir 1400 mg BID, 14 days 27 % 18 %10 mg once daily for 4 daysFosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 daysNo changeNo change# See Sections  Interactions with other medicinal products and other forms of interaction for clinical significance. Clinical particulars Indications Prevention of cardiovascular disease In adult patients without clinically evident coronaryheart disease, but with multiple risk factors for coronary heart disease such as age, smoking, HYPERLINK "http://www.rxlist.com/script/main/art.asp?articlekey=3846" hypertension, lowHDL-C, or a family history of early coronary heart disease, Atorvakor is indicated to: - reduce the risk ofmyocardial infarction; - reduce the risk ofstroke; - reduce the risk for revascularization procedures andangina. In patients withtype 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such asretinopathy,albuminuria, smoking, or hypertension, Atorvakor is indicated to: reduce the risk ofmyocardial infarction; reduce the risk ofstroke. In patients with clinically evident coronary heart disease, Atorvakor is indicated to: reduce the risk of non-fatal myocardial infarction; reduce the risk of fatal and non-fatal stroke; reduce the risk for revascularization procedures; reduce the risk of hospitalization for CHF; reduce the risk of angina. Hyperlipidaemia As an adjunct to diet to reduce elevated total-C,LDL-C, apo B, and TG levels and to increase HDLC in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidaemia (FredricksonTypes IIa and IIb). As an adjunct to diet for the treatment of patients with elevated serum TG levels (FredricksonType IV). For the treatment of patients with primary dysbetalipoproteinemia (FredricksonType III) who do not respond adequately to diet. To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDLapheresis) or if such treatments are unavailable. As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C remains (190 mg/dL or LDL-C remains (160 mg/dL and: there is a positive family history of prematurecardiovascular diseaseor two or more other CVD risk factors are present in the paediatric patient. Contraindications Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. Hypersensitivity to any of the drug excipients. Pregnancy and lactation. Women of child-bearing potential not using appropriate contraceptive measures. Interactions with other medicinal products and other forms of interaction The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives,lipid-modifying doses ofniacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) (see Special warnings and precautions for use and Pharmacological properties). Potent CYP 3A4 inhibitors.Atorvakor is metabolized by cytochrome P450 3A4. Concomitant administration of Atorvakor with potent CYP 3A4 inhibitors can lead to increase in plasma concentrations of atorvastatin (see Table 1 and detailed information below). The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4. Co-administration of potent CYP3A4 inhibitors (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided if possible. In cases where co-administration of these medicinal products with atorvastatin cannot be avoided lower starting and maximum doses of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended (see Table 1). Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 3). An increased risk of myopathy has been observed with the use of erythromycin in combination with statins. Interaction studies evaluating the effects of amiodarone or verapamil on atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit CYP3A4 activity and co-administration with atorvastatin may result in increased exposure to atorvastatin. Therefore, a lower maximum dose of atorvastatin should be considered and appropriate clinical monitoring of the patient is recommended when concomitantly used with moderate CYP3A4 inhibitors. Appropriate clinical monitoring is recommended after initiation or following dose adjustments of the inhibitor. Grapefruit juice contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 litres per day). Clarithromycin. Atorvastatin AUC was significantly increased with concomitant administration of Atorvakor 80 mg with clarithromycin (500 mg twice daily) compared to that of Atorvakor alone (see Pharmacological properties). Therefore, in patients taking clarithromycin, caution should be used when the Atorvakor dose exceeds 20 mg (see Special warnings and precautions for use, Posology and method of administration). Combination of protease inhibitors. Atorvastatin AUC was significantly increased with concomitant administration of Atorvakor with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitortelaprevir, compared to that of Atorvakor alone (see Pharmacological properties). Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of Atorvakor should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing Atorvakor and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of Atorvakor should not exceed 20 mg and should be used with caution (see Special warnings and precautions for use, Posology and method of administration). In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of Atorvakor should not exceed 40 mg and close clinical monitoring is recommended. Itraconazole. Atorvastatin AUC was significantly increased with concomitant administration of Atorvakor 40 mg with itraconazole 200 mg (see Pharmacological properties). Therefore, in patients taking itraconazole, caution should be used when the Atorvakor dose exceeds 20 mg (see Special warnings and precautions for use, Posology and method of administration). Cyclosporine. Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of Atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of Atorvastatin alone (see Pharmacological properties). The co-administration of Atorvakor with cyclosporine should be avoided (see Special warnings and precautions for use). Medical recommendations for the use of interacting drugs are given in Table 3 (see sections Posology and method of administration, Special warnings and precautions for use, Pharmacological properties). Table 3. Drug interactions which increase the risk of myopathy/rhabdomyolysis Interacting drugsMedical recommendations for use Cyclosporine, HIV protease inhibitors (tipranavir + ritonavir), hepatitis C virus protease inhibitor (telaprevir)Avoid the use of atorvastatinHIV protease inhibitor (lopinavir + ritonavir)Caution should be applied and the lowest dose necessary should be usedClarithromycin, itraconazole, HIV protease inhibitors (saquinavir + ritonavir*, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir)Do not exceed the atorvastatin dose of 20 mg/dayHIV protease inhibitor (nelfinavir) Hepatitis C virus protease inhibitor (boceprevir)Do not exceed the atorvastatin dose of 40 mg/day*Caution should be applied and the lowest dose necessary should be used. Gemfibrozil. Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of Atorvakor with gemfibrozil should be avoided (seeSpecial warnings and precautions for use). Other fibrates. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, Atorvakor should be administered with caution when used concomitantly with other fibrates (seeSpecial warnings and precautions for use). Niacin. The risk ofskeletal muscleeffects may be enhanced when Atorvakor is used in combination with niacin; a reduction in Atorvakor dosage should be considered in this setting (seeSpecial warnings and precautions for use). Rifampin or other inducers of cytochrome P450 3A4. Concomitant administration of Atorvakor with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of Atorvakor with rifampin is recommended, as delayed administration of Atorvakor after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Diltiazem hydrochloride. Co-administration of atorvastatin (40 mg) and diltiazem (240 mg) may increase plasma concentrations of atorvastatin. Cimetidine. During interaction studies atorvastatin and cimetidine interaction were not detected. Antacids. Oral co-administration of atorvastatin and antacid suspension of magnesium and aluminium hydroxides is accompanied by decrease in the concentration of atorvastatin in the blood plasma by approximately 35%. The hypolipidemic effect of atorvastatin did not change. Colestipol. Plasma concentrations of atorvastatin were lower (about 25%) when colestipol was co-administered with atorvastatin. However, lipid effects were greater when atorvastatin and colestipol were co-administered than when either medicinal product was given alone. Azithromycin. Co-administration of atorvastatin (10 mg once a day) and azithromycin (500 mg once a day) was not accompanied by changes in the concentration of atorvastatin in the blood plasma. Transport protein inhibitors. Inhibitors of transport proteins (e.g. cyclosporine) can increase the systemic exposure of atorvastatin (see Table 1). The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If concomitant administration cannot be avoided, a dose reduction and clinical monitoring for efficacy is recommended (see Table 1). Ezetimibe. The use of ezetimibe alone is associated with muscle related events, including rhabdomyolysis. The risk of these events may therefore be increased with concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring of these patients is recommended. Fusidic acid. Interactions of atorvastatin and fusidic acid have not been studied. As with the use of other statins, co-administration of atorvastatin and fusidic acid in the postmarketing period is associated with muscle related events, including rhabdomyolysis. The mechanism of this interaction is yet unknown. Patients need careful monitoring. They may require temporary discontinuation of atorvastatin. Digoxin. When multiple doses of Atorvakor and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately. Oral contraceptives. Co-administration of atorvastatin and an oral contraceptive increased AUC values for norethisterone and ethinyl estradiol (see Pharmacological properties). These increases should be considered when selecting an oral contraceptive for a woman taking Atorvakor. Warfarin. Atorvakor had no clinically significant effect onprothrombin timewhen administered to patients receiving chronic warfarin treatment. Colchicine. Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered withcolchicine, and caution should be exercised when prescribing atorvastatin with colchicine. Other medicinal products. Clinical studies have shown that co-administration of atorvastatin and antihypertensive drugs and its use in the course of estrogen replacement therapy is not accompanied by clinically significant adverse effects. No drug interaction studies have been conducted. Special warnings and precautions for use Skeletal muscles Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class.A history of renal impairment may be arisk factorfor the development ofrhabdomyolysis. Such patients need closer monitoring for skeletal muscle effects. Atorvastatin, like otherstatins, occasionally causesmyopathy, defined as muscle aches or muscle weakness in conjunction with increases increatine phosphokinase (CPK) values >10 times ULN. Theconcomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, andHIVprotease inhibitors) increases the risk of myopathy/rhabdomyolysis. There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by:proximalmuscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied bymalaiseor fever or if muscle signs and symptoms persist after discontinuingAtorvakor. Atorvakor therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives,erythromycin, clarithromycin, thehepatitis C HYPERLINK "http://www.rxlist.com/script/main/art.asp?articlekey=5080" protease inhibitortelaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir,niacin, or azole antifungals. Physicians considering combined therapy with Atorvakor and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, orlipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs (seeInteraction with other medicinal products and other forms of interaction). Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered withcolchicine, therefore caution should be exercised when prescribing atorvastatin with colchicine (see Interaction with other medicinal products and other forms of interaction). Atorvakor therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures). Hepatic impairment Statins, like some other lipid-lowering therapies, have been associated withbiochemicalabnormalities of liver function.Persistent elevations (>3 times the upper limit of normal) in serum transaminases can occur. It is recommended that liver enzyme tests be obtained prior to initiating therapy with Atorvakor and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/orhyperbilirubinemiaor jaundice occurs during treatment with Atorvakor, promptly interrupt therapy. If an alternateetiologyis not found, do not restart Atorvakor. Atorvakor should be used with caution in patients who consume substantial quantities of alcohol and/or have a history ofliver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of Atorvakor (see Contraindications). Endocrine function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, includingatorvastatin. Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma  HYPERLINK "http://www.rxlist.com/script/main/art.asp?articlekey=2850" cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on thepituitary-gonadalaxisin premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity ofendogenoussteroid hormones, such as ketoconazole, spironolactone, and cimetidine. Since advanced age (>65 years) is a predisposing factor for myopathy, Atorvakor should be prescribed with caution in the elderly. Hepatic insufficiency Atorvakor is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels (see sections Contraindications and Pharmacological properties). Before treatment Atorvastatin should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be measured before starting statin treatment in the following situations: - renal impairment; - hypothyroidism; - personal or familial history of hereditary muscular disorders; - previous history of muscular toxicity with a statin or fibrate; - previous history of liver disease and/or where substantial quantities of alcohol are consumed. In elderly (age > 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis. An increase in plasma levels may occur particularly with interactions (see section Interaction with other medicinal products and other forms of interaction) and in special populations including genetic subpopulations. In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started. Creatine kinase measurement Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results. During treatment Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever. If such symptoms occur whilst a patient is receiving treatment with atorvastatin, their CK levels should be measured. If these levels are found to be significantly elevated (> 5 times ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to d" 5 x ULN, treatment discontinuation should be considered. If symptoms resolve and CK levels return to normal, then re-introduction of atorvastatin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring. Atorvastatin must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected. Concomitant treatment with other medicinal products Risk of rhabdomyolysis is increased when atorvastatin is administered concomitantly with certain medicinal products that may increase the plasma concentration of atorvastatin such as potent inhibitors of CYP3A4 or transport proteins (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.). The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivatives, erythromycin, niacin and ezetimibe. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products. In cases where co-administration of these medicinal products with atorvastatin is necessary, the benefit and the risk of concurrent treatment should be carefully considered.When patients are receiving medicinal products that increase the plasma concentration of atorvastatin, a dose of atorvastatin should be decreased to the lowest dose. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of atorvastatin should be considered and appropriate clinical monitoring of these patients is recommended. Atorvastatin must not be co-administered with fusidic acid. In patients where the use of fusidic acid is considered essential, atorvastatin treatment should be discontinued throughout the duration of fusidic acid treatment. Interstitial lung disease Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued. Excipients Atorvakor contains sorbitol. If the patient is intolerant of some sugars, medical consultation is needed before taking this drug. This product contains less than 1 mmol/dose sodium, i.e. is essentially sodium free. Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacological measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, Atorvakor can be started simultaneously with diet. Limitations of use Atorvakor has not been studied in conditions where the majorlipoprotein abnormality is elevation of chylomicrons (FredricksonTypes I and V). Use during pregnancy and in nursing women Pregnancy Atorvakor is contraindicated in women who are pregnant or may become pregnant. Statins may cause foetal harm when administered to a pregnant woman. Atorvakor should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, Atorvakor should be discontinued immediately and the patient should be re-advised of the potential hazard to the foetus and the lack of a known clinical benefit from continued use of the drug during pregnancy. Serum cholesterol and triglycerides increase during normal pregnancy. Hypolipidemic medicinal products will not have a beneficial effect during pregnancy, as cholesterol or cholesterol derivatives are essential for foetal development.Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of Atorvastatin use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and foetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a 3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Lactation It is not known whether Atorvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require Atorvakor treatment should not breastfeed their infants (see section Contraindications). Effects on ability to drive and use machines Atorvakor has negligible influence on the ability to drive and use machines. Posology and method of administration Hyperlipidaemia (heterozygous familial and nonfamilial) and mixed dyslipidaemia (Fredrickson types IIa and IIb) The recommended starting dose of Atorvakor is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of Atorvakor is 10 to 80 mg once daily. Atorvakor can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of Atorvakor should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or upon titration of Atorvakor, lipid levels should be analysed within 2 to 4 weeks and dosage adjusted accordingly. Heterozygous familial hypercholesterolemia in paediatric patients (10 - 17 years of age) The recommended starting dose of Atorvakor is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more. Homozygous familial hypercholesterolemia The dosage of Atorvakor in patients with homozygous FH is 10 to 80 mg daily. Atorvakor should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. Concomitant lipid-lowering therapy Atorvakor may be used withbile acidresins. The combination of HMG-CoA reductase inhibitors ( HYPERLINK "http://www.rxlist.com/statins/drugs-condition.htm" statins) and fibrates should generally be used with caution (see section Special warnings and precautions for use, Interaction with other medicinal products and other forms of interaction). Dosage in patients with renal impairment Renal disease does not affect the plasma concentrations nor LDL-C reduction of Atorvakor; thus, dosage adjustment in patients with renal dysfunction is not necessary (see sections Special warnings and precautions for use, Pharmacokinetics). Dosage in patients taking cyclosporine, clarithromycin, itraconazole, or certain protease inhibitors In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor(telaprevir), therapy with Atorvakor should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing Atorvakor and the lowest dose should be employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with Atorvakor should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of Atorvakor is employed. In patients taking the HIV protease inhibitor nelfinavir or thehepatitis Cprotease inhibitor boceprevir, therapy with Atorvakor should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of Atorvakor is employed (see section Special warnings and precautions for use and Interaction with other medicinal products and other forms of interaction). Paediatric patients Safety and effectiveness in patients 10-17 years of age withheterozygous familialhypercholesterolemia have been evaluated in a 6-month controlled clinical trial in adolescent boys and postmenarchal girls. Patients treated with atorvastatin had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections.Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls (see Undesirable effects, Posology and method of administration). Adolescent females should be counselled on appropriate contraceptive methods while on atorvastatin therapy (see Use during pregnancy and in nursing women). Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients withhomozygousFH including 8 paediatric patients (see section Posology and method of administration). Overdose There is no specific treatment for Atorvakor overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins,haemodialysisis not expected to significantly enhance Atorvakor clearance. Undesirable effects The five most common adverse reactions in patients treated with Atorvastatin that led to treatment discontinuation: myalgia, diarrhoea, nausea, alanine aminotransferase (ALT) increased and hepatic enzyme increased. The following adverse reactions were also observed: nasopharyngitis, arthralgia, diarrhoea, pain in extremity, urinary tract infection, dyspepsia, muscle spasms, insomnia, pharyngolaryngeal pain. Other adverse reactions are: Psychiatric disorders: nightmare; Ear and labyrinth disorders: tinnitus; Urinary disorders: leukocyturia; Reproductive system and breast disorders: gynecomastia; Nervous system disorders: headache, dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia, peripheral neuropathy. 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As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving atorvastatin. These changes were usually mild, transient, and did not require interruption of treatment. These elevations were dose related and were reversible in all patients. Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal were observed. Adverse reactions occurred during clinical trials: urinary tract infection, diabetes mellitus, stroke. Post-marketing experience of atorvastatin The following adverse reactions have been identified during postapproval use of atorvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions associated with atorvastatin therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following:anaphylaxis, angioneurotic oedema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis,myositis, fatigue,tendonrupture, fatal and non-fatal hepatic failure, dizziness, depression,peripheral neuropathy, andpancreatitis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use (see section Special warnings and precautions for use). There have been rare postmarketing reports ofcognitiveimpairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for allstatins and were not considered serious adverse reactions. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptomresolution(median of 3 weeks). The following adverse effects were described with some statins: sexual disorders; single cases of interstitial lung disease, especially during prolonged treatment. The following adverse reactions have been identified during postapproval use of Atorvastatin. Blood and lymphatic system disorders: thrombocytopenia. Immune system disorders: allergic reactions, anaphylaxis including anaphylactic shock. Metabolism and nutrition disorders: weight increased. Nervous system disorders: headache, hypoesthesia, dysgeusia. Gastrointestinal disorders: abdominal pain. Ear disorders: tinnitus. Skin and subcutaneous tissue: urticaria. Musculoskeletal and connective tissue disorders: arthralgia, back pain. General disorders: chest pain, peripheral swelling, malaise, fatigue. Investigations: alanine aminotransferase increased, blood creatine phosphokinase increased. Shelf-life 2 years. Do not use after expiry date indicated on the carton. Storage Store in the original package below 25 C. Keep out of reach of children. Nature and contents of container 10 mg tablets: No.30 (10E3), No.60 (10E6) in blisters inserted into a carton. 20 mg tablets: No.30 (10E3), No.40 (10E4) in blisters inserted into a carton. 40 mg tablets: No.30 (10E3) in blisters inserted into a carton. 80 mg tablets: aQ{yo)S=>ISdgdz d1$gdz d1$gd%iouxy'()ĵėӗӗyjZJh>h%i>*CJaJmH sH h>hH<>*CJaJmH sH h>hCJaJmH sH h>hfCJaJmH sH h>hVMCJaJmH sH h>hZ,hCJaJmH sH h>h|CJaJmH sH h>h}FCJaJmH sH h>h%iCJaJmH sH h>hzCJaJmH sH h>h>CJaJmH sH h>h!CJaJmH sH 01no()FGQS<=>H࢓o"h>h1TH56CJaJmH sH "h>hX056CJaJmH sH h>hzCJaJmH sH h>h1THCJaJmH sH h>h1TH6CJaJmH sH h>h%i6CJaJmH sH h>hH<CJaJmH sH h>h%iCJaJmH sH h>hH<6CJaJmH sH *HIQRSϿ߰n^nKn8ϐ$h>hy]}CJOJQJaJmH sH $h>hy]}CJOJQJaJmH sH h&+5CJOJQJaJmH sH $h>h1THCJOJQJaJmH sH h>hy]}CJaJmH sH h>h1TH5CJaJmH sH h>hy]}5CJaJmH sH h>hM5CJaJmH sH h>h]5CJaJmH sH h>hM55CJaJmH sH h>h1THCJaJmH sH "h>hz56CJaJmH sH 6`bLN$d]^a$gdz d1$gdzdgdzd1$5$9D]gdz d]gdz  ,246BDRTV\^`bǵǦǗǵǦǗǵǦǗǵǦǗxkh>hzCJmH sH h>h1THCJmH sH h>h{.CJmHnHsH uUh>h{.CJaJmH sH h>hVMCJaJmH sH #h>h{.CJaJmHnHsH uh>h1THCJaJmH sH hHCJaJmH sH h>hHCJaJmH sH h>hUPCJaJmH sH %No.30 (6E5) in blisters inserted into a carton. Prescription status Prescription only. Manufacturer JSC Farmak. Location 74, Frunze str., Kyiv, Ukraine, 04080 Date of the last revision 22.12.2016. >HLNͽkWH9ͽh>hzCJaJmH sH h>heFCJaJmH sH &h>hot5CJaJmHnHsH u&h>hM55CJaJmHnHsH uh>hM5CJaJmH sH h>h1THCJaJmH sH h>hy]}5CJaJmH sH h>hM55CJaJmH sH h>h1TH5CJaJmH sH &h>hu5CJaJmHnHsH uh>hM5CJmHnHsH uh>h1TH5CJmH sH h>hTsCJaJmH sH h>hm.CJaJmH sH h>hb5CJaJmH sH ;0P:pM5|. 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