Tulip tablets p/o 20mg №10×3

Name:
Tulip tabl p / captivity. about. 20mg in bl. pack. No. 10×3 Main active ingredient Atorvastatin Release formtablets Composition Active ingredient: atorvastatin. Each tablet contains 10 mg, 20 mg, 40 mg of atorvastatin as calcium salt, respectively. Excipients. Core: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, polysorbate 80, heavy magnesium oxide, colloidal silicon dioxide, magnesium stearate; shell: hypromellose, hydroxypropylcellulose, titanium dioxide (E171), macrogol 6000, talc; additionally in tablets of 20 mg, 40 mg – iron oxide yellow (E172).
Description:
Tulip 10 mg: white or off-white, round biconvex film-coated tablets, debossed “HLA 10” on one side. Tulip 20 mg: light yellow, round biconvex film-coated tablets, debossed “HLA 20” on one side. Tulip 40 mg: light yellow, round biconvex film-coated tablets, debossed “HLA 40” on one side. Pharmacological properties Pharmacodynamics Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme involved in the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin reduces plasma cholesterol levels and serum lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver, as well as increasing the number of surface LDL receptors on hepatocytes, which contributes to increased uptake and catabolism of LDL. As a result of the action of atorvastatin, the concentration of total cholesterol is reduced by 30-46%, LDL cholesterol – by 41-61%, apolipoprotein B – by 34-50% and triglycerides – by 14-33%, while increasing the concentration of HDL cholesterol and apolipoprotein A-I , which has been shown to reduce the risk of cardiovascular events and mortality from cardiovascular disease. Atorvastatin significantly reduced total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B in children aged 6 to 17 years with heterozygous familial hypercholesterolemia or severe hypercholesterolemia compared with placebo and colestipol. PharmacokineticsAbsorption After administration, atorvastatin is rapidly absorbed in the gastrointestinal tract, the maximum plasma concentration (Cmax) is reached after 1-2 hours. The degree of absorption increases in proportion to the dose taken. The relative bioavailability of atorvastatin is 95-99%, absolute – 12-14%, systemic HMG-CoA reductase inhibitory activity – approximately 30%. Distribution The mean volume of distribution of atorvastatin is 381 liters, the degree of binding to plasma proteins is about 98%. Metabolism Atorvastatin is metabolized by cytochrome CYP3A4 to ortho- and para-hydroxylated derivatives, as well as beta-oxidation products. About 70% of the inhibitory activity of the drug is due to ortho- and para-hydroxylated active metabolites. Excretion Atorvastatin and its metabolites are substrates for P-glycoprotein. Atorvastatin and its metabolites are eliminated mainly in the bile. The mean elimination half-life of atorvastatin is approximately 14-15 hours. Due to the presence of pharmacological activity in metabolites, the period of inhibitory activity against HMG-CoA reductase is 20-30 hours. Special groups of patients Elderly patients. Plasma concentrations of atorvastatin were higher in the elderly (>65 years of age) compared with younger volunteers, while the lipid-lowering effect was comparable between the two age groups. Children. In an open 8-week study, pediatric patients of Tanner stage I (n = 15) and Tanner stage II (n = 24) aged 6-17 years with heterozygous hereditary hypercholesterolemia and baseline LDL-C ? 4 mmol/l received atorvastatin, respectively, 5 or 10 mg in chewable tablets, or 10 and 20 mg in coated tablets, once a day. In a population model of the pharmacokinetics of atorvastatin, body weight was the only significant covariate. The apparent clearance of atorvastatin after oral administration in pediatric patients was similar to that in adults with allometric scaling of data by body weight. In the exposure range of atorvastatin and o-hydroxyatorvastatin, there was a steady decrease in the levels of LDL-C and total cholesterol. Floor. Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC). However, there are no clinically significant differences in the effect on lipids in men and women. Patients with renal insufficiency. Kidney disease had no effect on plasma concentrations of atorvastatin and lipid-lowering effect. Patients with liver failure. In patients with chronic alcoholic liver disease, there was a significant increase in plasma concentrations of atorvastatin (Cmax approximately 16 times and AUC approximately 11 times). Polymorphism SLOC1B1. Hepatic uptake of all HMG-CoA reductase inhibitors, including atorvastatin, is carried out using the OATP1B1 transporter. Patients with polymorphisms in the SLCO1B1 gene are at risk of increased exposure to atorvastatin, which may lead to an increased risk of rhabdomyolysis. Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) was associated with a 2.4-fold increase in atorvastatin AUC compared to atorvastatin AUC in individuals without this genotype variant (C.521TT). Also in these patients, a genetically determined violation of the hepatic uptake of atorvastatin is possible. Possible consequences for the effectiveness of the drug are unknown. Indications Hypercholesterolemia Tulip is used to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides in adults, adolescents and children 10 years of age and older with primary hypercholesterolemia (including heterozygous familial hypercholesterolemia) or combined hyperlipidemia (Fredrickson type IIa and IIb) in addition to diet in case of an unsatisfactory response to diet therapy and other non-drug treatment. Tulip is also used to lower total and LDL cholesterol in patients with homozygous familial hypercholesterolemia in addition to other lipid-lowering agents (eg, LDL-apheresis) or when other agents cannot be used. Prevention of cardiovascular disease Tulip is used for the prevention of cardiovascular disease in patients at high risk of a first cardiovascular event as an adjunct to the management of other risk factors. Contraindications – Hypersensitivity to the active or excipients of the drug; – liver disease in the active phase or persistent unexplained increase in serum transaminases, three times the upper limit of normal; – Pregnancy and breastfeeding. Also, the drug is contraindicated in women of childbearing age who do not use contraceptives. Use during pregnancy and lactation During treatment, women of childbearing age should use reliable contraceptives. The use of Tulip during pregnancy is contraindicated. There have been isolated reports of the development of congenital fetal anomalies due to exposure to HMG-CoA reductase inhibitors during fetal development. Women who are pregnant, planning a pregnancy or suggesting a pregnancy should not take Tulip. Its use should be delayed for the duration of pregnancy or until the fact of its absence is established. Excretion into breast milk is unknown. The use of Tulip during breastfeeding is contraindicated. Method of administration and doses For oral administration. Take once a day at any time of the day, with or without food. Prior to the start and throughout the entire period of treatment, a standard hypocholesterol diet should be followed. The dose is selected individually in accordance with the initial levels of LDL cholesterol, goals of treatment and response to the use of the drug. The usual starting dose is 10 mg once daily. The dose must be adjusted at intervals of four weeks or more. The maximum daily dose is 80 mg once a day. Primary hypercholesterolemia and combined (mixed) hyperlipidemia. In most patients, the effect occurs at a dose of 10 mg once a day. Therapeutic efficacy appears within two weeks and usually reaches a maximum after four weeks. With prolonged treatment, the effect persists. Heterozygous familial hypercholesterolemia. The initial dose is 10 mg per day. The dose is selected individually and, if necessary, adjusted every four weeks until a daily dose of 40 mg is reached, after which the dose can be increased to a maximum (80 mg per day), or combined with 40 mg of atorvastatin (once a day) with a bile acid sequestrant. Homozygous familial hypercholesterolemia. The daily dose for patients with homozygous familial hypercholesterolemia varies between 10-80 mg. Tulip is used in combination with other lipid-lowering agents (eg, LDL-apheresis) or when other agents cannot be used. Prevention of cardiovascular diseases. The dose is 10 mg per day. Higher doses may be required to achieve target LDL cholesterol levels consistent with current guidelines. Renal failure. Dose adjustment is not required. Liver failure. Apply with caution. Do not use in active liver disease. The elderly. When taken at recommended doses, safety and efficacy in patients over 70 years of age do not differ from those in the general population. Children Hypercholesterolemia Treatment should be carried out by a physician experienced in the treatment of hyperlipidemia in children and under regular supervision. The recommended starting dose of atorvastatin for patients with heterozygous familial hypercholesterolemia aged 10 years and older is 10 mg daily. The dose may be increased to 80 mg daily according to individual response to treatment and tolerability. Doses should be adjusted individually according to the purpose of therapy. Adjustments should be made at intervals of 4 weeks or more. Dose titration up to 80 mg daily is supported by studies in adults and limited clinical data from studies in children with heterozygous familial hypercholesterolemia. There are limited data on efficacy and safety obtained from open studies in children with heterozygous familial hypercholesterolemia aged 6-10 years. Atorvastatin is not indicated for the treatment of patients younger than 10 years of age. The data available to date are presented in the sections “Side effect”, “Pharmacodynamics”, “Pharmacokinetics”, but recommendations regarding dosing cannot be given. In patients in this category, it may be appropriate to use other dosage forms / dosages. If you miss a dose, do not double the dose of the drug, but simply take the next one at the usual time for taking it. Adverse reactions are classified by frequency of occurrence and listed in descending order: frequent (?1/100, <1/10), infrequent (?1/1000, <1/100), rare (?1/10000, <1/10 1000), very rare (<1/10000), the frequency is unknown (cannot be established from the available data). Infectious and parasitic diseases Common: nasopharyngitis. Circulatory and lymphatic system disorders Rare: thrombocytopenia. Immune system disorders Common: allergic reactions; very rare: anaphylaxis. Metabolic and nutritional disorders Common: hyperglycemia; infrequent: hypoglycemia, weight gain, anorexia. Psychiatric disorders Uncommon: nightmares, insomnia. Nervous system disorders Common: headache; infrequent: dizziness, paresthesia, hypesthesia, taste perversion, amnesia; rare: peripheral neuropathy. On the part of the organ of vision Infrequent: deterioration in visual acuity; rare: visual impairment. Hearing and labyrinth disorders Uncommon: tinnitus; very rare: hearing loss. Respiratory, thoracic and mediastinal disorders Common: pain in the pharynx and larynx, epistaxis. Gastrointestinal disorders Common: constipation, flatulence, dyspepsia, nausea, diarrhea; infrequent: vomiting, pain in the upper and lower abdomen, belching, pancreatitis. Liver and biliary tract disorders Uncommon: hepatitis; rare: cholestasis; very rare: liver failure. Skin and subcutaneous tissue disorders Uncommon: urticaria, skin rash, pruritus, alopecia; rare: angioedema, bullous dermatitis, including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. Musculoskeletal and connective tissue disorders Common: myalgia, arthralgia, pain in limbs, muscle spasms, joint swelling, back pain; infrequent: neck pain, muscle weakness; rare: myopathy, myositis, rhabdomyolysis, tendon pathology, sometimes complicated by their rupture; frequency unknown: immune-mediated necrotizing myopathy. Reproductive and breast disorders Very rare: gynecomastia. General disorders and disorders at the injection site Uncommon: malaise, asthenia, chest pain, peripheral edema, fatigue, fever. Laboratory and instrumental data Frequent: violations of liver function tests, increased plasma levels of creatine phosphokinase; infrequent: leukocyturia. Against the background of taking Tulip (as well as against the background of taking other HMG-CoA reductase inhibitors), a transient slight increase in the level of serum transaminases is possible, which does not require discontinuation of the drug. It was dose-dependent and reversible in all cases. Adverse effects in children In pediatric patients aged 10 to 17 years who were treated with atorvastatin, the adverse event profile was generally similar to that in patients treated with placebo. The most frequently observed adverse events in both groups, regardless of the assessment of causality, were infections. There was no clinically significant effect on growth and puberty during a three-year study based on assessment of general maturation and development, Tanner score, and measurements of height and body weight. The safety and tolerability profile in pediatric patients was similar to the known safety profile in adult patients. The Clinical Safety Database includes safety data from 520 pediatric patients treated with atorvastatin, of which 7 patients were <6 years of age, 121 patients were 6 to 9 years of age, and 392 patients were 10 to 17 years of age. According to the available data, the frequency, type and severity of adverse reactions in children are similar to those in adults. When using some statins, the following adverse reactions were noted: sexual dysfunction, depression, isolated cases of interstitial lung disease, especially with long-term treatment, diabetes mellitus (the frequency of development depends on the presence of risk factors - fasting glucose ? 5.6 mmol / l, body mass index > 30 kg/m2, elevated triglycerides, history of arterial hypertension). Reporting Suspected Adverse Reactions Reporting suspected adverse reactions after drug registration is important. This allows you to continue monitoring the balance between benefit and risk when using this drug. Healthcare professionals are asked to report any suspected adverse reactions using the national adverse reaction reporting system. Overdose There is no specific treatment for overdose of atorvastatin. Treatment of overdose is symptomatic and, if necessary, supportive. It is necessary to control the levels of liver enzymes and CPK. Hemodialysis is ineffective. Interactions with other drugs Atorvastatin is metabolized by cytochrome P4503A4 and is a substrate for transport proteins, in particular the hepatic organic anion transporter OATP1B1. The combined use of atorvastatin and inhibitors of cytochrome P4503A4 or transport proteins can lead to an increase in plasma concentrations of atorvastatin and increase the risk of myopathy, which can also be observed when it is used together with other drugs that lead to the development of myopathy, such as fibrates and ezetimibe. Cytochrome P4503A4 inhibitors. Due to a significant increase in plasma concentrations of atorvastatin, co-administration with strong inhibitors of cytochrome P4503A4 (eg, cyclosporine, telithromycin, clarithromycin, delavirdine, styripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir) should be avoided. , indinavir, darunavir, etc.). If co-administration of the above-mentioned medicinal products with atorvastatin is unavoidable, a reduction in the initial and maximum dose of atorvastatin should be considered and appropriate monitoring of patients should be carried out. Moderate inhibitors of cytochrome P4503A4, such as erythromycin, diltiazem, verapamil, amiodarone and fluconazole, can increase the plasma concentration of atorvastatin, therefore, a reduction in the maximum dose of Tulip and clinical observation is recommended. The combination of erythromycin with statins increases the risk of myopathy. Particular attention of the doctor is required at the initial stage of treatment with cytochrome P4503A4 inhibitors and when adjusting their dose. Transport protein inhibitors (eg, cyclosporine) may increase the systemic exposure of atorvastatin. The effect of inhibition of hepatic uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If co-administration is unavoidable, dose reduction and careful assessment of clinical efficacy are recommended. Cytochrome P4503A4 inducers (eg, efavirenz, rifampicin, St. John’s wort) can lead to a variable decrease in plasma concentrations of atorvastatin. Due to the dual mechanism of interaction of rifampicin (induction of cytochrome P4503A4 and inhibition of the hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after rifampicin caused a significant decrease in plasma concentrations of atorvastatin. However, the effect of rifampicin on hepatocyte concentrations of atorvastatin is unknown, and therefore, if co-administration is unavoidable, clinical efficacy should be carefully evaluated. Gemfibrozil/fibrates, ezetimibe. Muscle damage, including rhabdomyolysis, sometimes occurs with monotherapy with fibrates and ezetimibe, and when used together with atorvastatin, the risk increases. If necessary, a joint intake is used the minimum therapeutic dose of atorvastatin, treatment is carried out under the supervision of a physician. Colestipol. Co-administration with colestipol reduces the concentration of atorvastatin and its active metabolites (the concentration ratio of atorvastatin: 0.74), however, the antihyperlipidemic efficacy of the combination exceeds that of each of the drugs separately. Fusidic acid. With the simultaneous use of systemic fusidic acid with statins, the risk of myopathy, including rhabdomyolysis, may be increased. The mechanism of this interaction (whether pharmacodynamic or pharmacokinetic, or both) is not yet known. Rhabdomyolysis (including some deaths) has been reported in patients treated with this combination. If the use of systemic fusidic acid is considered necessary, atorvastatin should be discontinued during treatment with fusidic acid. Colchicine. Although interaction studies between atorvastatin and colchicine have not been conducted, there are reports of the development of myopathy with the simultaneous use of atorvastatin with colchicine, and therefore, when prescribing atorvastatin in combination with colchicine, care must be taken. Digoxin. Repeated administration of digoxin and 10 mg of atorvastatin was accompanied by a slight increase in the equilibrium concentration of digoxin. At the time of taking digoxin, the patient should be under medical supervision. Oral contraceptives. With the simultaneous use of atorvastatin and oral contraceptives, plasma levels of norethindrone and ethinylestradiol increased. Warfarin. On the 4th day of treatment with atorvastatin (80 mg/day), against the background of long-term previous therapy with warfarin, a slight decrease in prothrombin time was observed, which returned to normal by the 15th day of treatment with atorvastatin. Therefore, when taking coumarin anticoagulants, the determination of prothrombin time is indicated before starting and regularly in the early stages of treatment with atorvastatin, as well as when changing the dose or discontinuing the drug. Atorvastatin therapy did not cause bleeding or a change in prothrombin time in patients not taking anticoagulants. Children. Interaction studies with other medicinal products have only been performed in adults. The degree of interaction in children is unknown. The above interactions in adults and precautions should be taken into account when used in children. Table 1 Effect of concomitant medicinal products on atorvastatin pharmacokinetics Co-administered medicinal product and dosing regimen Atorvastatin Dose (mg) AUC+ ratio 21 days) 40 mg on day 1, 10 mg on day 20 9.4 In cases where it is necessary to carry out treatment simultaneously with taking atorvastatin, the daily dose of atorvastatin should not exceed 10 mg. Clinical monitoring is recommended. Telaprevir 750 mg 1 time / 8 hours, 10 days 20 mg once 7.9 Cyclosporine 5.2 mg / kg / day, stable dose 10 mg 1 time / day for 28 days 8.7 Lopinavir 400 mg 2 times / day / ritonavir 100 mg twice daily for 14 days 20 mg once daily for 4 days 5,9 In cases where treatment is required concomitantly with atorvastatin, it is recommended to reduce maintenance doses of atorvastatin. When using atorvastatin in doses exceeding 20 mg, clinical monitoring is indicated. Clarithromycin 500 mg twice daily for 9 days 80 mg once daily for 8 days 4.5 Saquinavir 400 mg twice daily/ritonavir (300 mg twice daily on days 5-7, then increased to 400 mg 2 times / day on day 8), on days 4-18, 30 minutes after taking atorvastatin 40 mg 1 time / day for 4 days 3.9 In cases where treatment is necessary simultaneously with taking atorvastatin, it is recommended to reduce maintenance doses of atorvastatin. When using atorvastatin in doses exceeding 40 mg, clinical monitoring is indicated. Darunavir 300 mg twice daily / ritonavir 100 mg twice daily for 9 days 10 mg once daily for 4 days 3.4 Itraconazole 200 mg once daily for 4 days 40 mg once daily 3.3 Fosamprenavir 700 mg 2 times/day / ritonavir 100 mg 2 times/day, 14 days 10 mg 1 time/day for 4 days 2.5 Fosamprenavir 1400 mg 2 times/day, 14 days 10 mg 1 time/day for 4 days 2, 3 Nelfinavir 1250 mg twice daily for 14 days 10 mg once daily for 28 days 1.74 No special recommendations Grapefruit juice 240 ml once daily* 40 mg once daily 1.37 amount of grapefruit juice. Diltiazem 240 mg once daily, 28 days 40 mg once daily 1.51 Appropriate clinical monitoring is indicated after diltiazem is started or dose adjusted. Erythromycin 500 mg 4 times a day, 7 days 10 mg, single dose 1.33 A lower maximum dose is recommended, as well as clinical monitoring. Amlodipine 10 mg single dose 80 mg single dose 1.18 No special recommendation Cimetidine 300 mg 4 times a day, 2 weeks 10 mg 1 time a day for 2 weeks 1.00 No special recommendation Colestipol 10 g, 2 times a day, 28 weeks 40 mg 1 time / day for 28 weeks 0.74** No special recommendations Antacids, in the form of suspension, containing magnesium and aluminum hydroxides, 30 ml 4 times / day, 17 days days 0.66 No special recommendation Efavirenz 600 mg 1 time / day, 14 days 10 mg for 3 days 0.59 No special recommendations Rifampin 600 mg 1 time / day, 7 days (simultaneous use) 40 mg once 1.12 If simultaneous use cannot be avoided, it is recommended to use atorvastatin and rifampin simultaneously and conduct clinical monitoring of the patient’s condition Rifampin 600 mg 1 time / day, 5 days (separate administration) 40 mg once 0.20 Gemfibrozil 600 mg 2 times / day, 7 days 40 mg once 1.35 Lower starting dosage and clinical trial recommended. Fenofibrate 160 mg OD, 7 days 40 mg OD 1.03 Lower initial dose and clinical monitoring recommended Boceprevir 800 mg 3 Times/day, 7 days 40 mg OD 2.3 Lower initial dosage and clinical monitoring recommended monitoring. When used simultaneously with boceprevir, the daily dose of atorvastatin should not exceed 20 mg + Displays the ratio between the combination of drugs with atorvastatin compared with taking atorvastatin as monotherapy. #Information on clinical significance is provided in the sections “Special instructions and precautions” and “Interaction with other medicinal products and other forms of interaction”. *The composition contains one or more components that inhibit the activity of CYP3A4, which can increase plasma concentrations of drugs that undergo metabolic transformations under the influence of this enzyme. Drinking one glass of grapefruit juice (240 ml) also resulted in a 20.4% decrease in the AUC of the ortho-hydroxylated active metabolite. The use of a significant amount of grapefruit juice (more than 1.2 liters per day for 5 days) led to a 2.5-fold increase in the AUC of atorvastatin and the AUC of active compounds (atorvastatin and its metabolites). ** Ratio based on one sample taken 8-16 hours after ingestion. Table 2. Effect of atorvastatin on the pharmacokinetics of concomitant medicinal products Atorvastatin and dosing regimen Co-administered drug Drug/dose (mg) AUC+ Ratio Clinical guidelines 80 mg 1 time/day for 10 days Digoxin 0.25 mg 1 time/day, 20 days 1 ,15 Patients treated with digoxin 40 mg once daily for 22 days should be monitored appropriately Oral contraceptive once daily for 2 months – norethindrone 1 mg – ethinyl estradiol 35 mcg 1.28 1.19 No specific recommendation 80 mg 1 time / day for 15 days * Phenazone, 600 mg, single dose 1.03 No special recommendation 10 mg once Tipranavir 500 mg 2 times / day / ritonavir 200 mg 2 times / day, 7 days 1.08 No special recommendation 10 mg 1 time/day for 4 days Fosamprenavir 1400 mg 2 times/day, 14 days 0.73 No special recommendation 10 mg 1 time/day for 4 days Fosamprenavir 700 mg 2 times/day/ritonavir 100 mg 2 times/day , 14 days 0.99 Special re no recommendations+Displays the ratio between the combination of drugs with atorvastatin compared with taking atorvastatin as monotherapy. * Simultaneous repeated use of atorvastatin and phenazone had little or no effect on the clearance of phenazone. Precautions Effects on the liver Liver function should be checked prior to initiation of treatment and regularly monitored during treatment, as well as any clinical signs of liver damage. Patients who have an increase in transaminase levels should be monitored until the normalization of the level of enzymes. With a stable three-fold or more excess of transaminase values of the upper limit of normal (ULN), it is recommended to reduce the dose of Tulip or stop the drug. For patients who abuse alcohol and / or with a history of liver disease, Tulip is prescribed with caution. Prevention of stroke by intensive cholesterol lowering In patients without coronary artery disease who had a recent stroke or transient cerebrovascular accident, a higher incidence of hemorrhagic stroke was observed in a secondary stroke subtype analysis with an initial dose of atorvastatin 80 mg compared with placebo. The risk of its occurrence was especially high in patients who had a hemorrhagic stroke or lacunar infarction prior to enrollment in the study. Before starting treatment, it is necessary to carefully weigh the potential risk of developing hemorrhagic stroke in this group of patients, since the risk / benefit ratio when using Tulip at a dose of 80 mg has not been precisely established. Influence on skeletal muscles Like other HMG-CoA reductase inhibitors, Tulip in rare cases can affect skeletal muscles, causing myalgia, myositis and myopathy, which, when progressing to rhabdomyolysis, become a life-threatening condition with a pronounced (more than 10 times relative to ULN) increase levels of creatine phosphokinase (CPK), myoglobinemia and myoglobinuria, which is fraught with the development of renal failure. There are very rare reports of cases of immune-mediated necrotizing myopathy (IMNM) during or after treatment with certain statins. IONM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin treatment. Before starting treatment Caution should be exercised when prescribing Tulip to patients with a predisposition to rhabdomyolysis. It is necessary to determine the level of CPK before starting treatment in the following cases: – renal failure; – hypothyroidism; – hereditary muscle diseases in a patient or his relatives; – previous toxic damage to the muscles in connection with the use of a statin or fibrate; – previous liver disease and/or alcohol abuse; – in patients older than 70 years, the need to determine the level of CPK is determined by the presence of other predisposition factors for rhabdomyolysis; – with an expected increase in plasma levels of the drug, in particular due to interactions with other drugs, as well as in special groups of patients, including those who are genetically predisposed. In such cases, it is necessary to compare the potential benefit of treatment with the degree of risk and to carry out clinical monitoring of patients. Treatment should not be initiated if baseline CPK levels are markedly elevated (>5 times ULN). Determining the level of CPK Do not measure the level of CPK after heavy exercise or in the presence of any factors leading to an increase in the level of the enzyme, as this will complicate the interpretation of the results of the analysis. If the initial level of CPK is significantly increased (> 5 times relative to ULN), the analysis is repeated after 5-7 days to confirm the results. During treatment, patients should immediately inform the doctor of pain, cramps or weakness in the muscles, especially if accompanied by malaise or fever. If the symptoms listed above appeared during treatment with Tulip, it is necessary to determine the level of CPK. With its significant increase (> 5 times relative to ULN), treatment should be discontinued. If muscle symptoms are severe and cause daily discomfort to the patient, discontinuation of the drug should be considered, even if the CPK level is ?5 ULN. After the disappearance of symptoms and normalization of CPK levels, treatment with the lowest doses of statins can be resumed under close medical supervision. With a clinically significant increase in the level of CPK (> 10 times relative to ULN), as well as if rhabdomyolysis is suspected or confirmed, treatment with Tulip is stopped. Interstitial lung disease Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy. If interstitial lung disease is suspected (shortness of breath, non-productive cough, weakness, weight loss, fever), statin treatment is stopped. Children. No clinically significant effect on growth and puberty was observed in a three-year study based on assessment of general maturation and development, assessment of Tanner stage, and measurement of height and weight. Diabetes mellitus As a class, statins are capable of elevating blood glucose, and in some patients at high risk of developing diabetes, they can cause hyperglycemia requiring standard diabetes management. At the same time, the reduction in the risk of cardiovascular events with statins prevails over the risk of diabetes, so discontinuation of statin therapy is not required. Patients at risk of developing diabetes (fasting glucose 5.6 – 6.9 mmol / l, body mass index> 30 kg / m2, elevated triglycerides, arterial hypertension) require clinical observation and biochemical analyzes. Co-administration with other medicinal products When atorvastatin is co-administered with certain medicinal products that may increase plasma levels, such as strong inhibitors of cytochrome P4503A4 or transport proteins (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine, styripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.), the risk of rhabdomyolysis is increased. Co-administration of gemfibrozil and other fibrates, boceprevir, erythromycin, niacin, ezetimibe, telaprevir, or the tipranavir/ritonavir combination may also increase the risk of myopathy. Instead, if possible, other medicinal products that do not interact with atorvastatin should be considered. If it is necessary to co-administer the above-mentioned medicinal products with atorvastatin, the benefits and risks of such therapy should be carefully weighed. In cases of using drugs that increase the concentration of atorvastatin in plasma, it is recommended to reduce the maximum dose of the latter. In addition, when using strong inhibitors of cytochrome P4503A4, a lower initial dose of atorvastatin should be considered and appropriate monitoring of patients should be carried out. Do not use atorvastatin concomitantly with fusidic acid or within 7 days of discontinuing fusidic acid treatment. If the use of systemic fusidic aci