Pharmacological properties of the drug Tulip
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). CS and TG circulate in the blood as part of lipoprotein molecules. Using ultracentrifugation, these molecules can be separated into intermediate-density lipoprotein (MDL) fractions, as well as HDL, LDL and VLDL. VLDL is synthesized from TG and cholesterol in the liver. From the liver they enter the blood plasma and are transported to peripheral tissues. LDL is formed from VLDL and is catabolized mainly through interaction with LDL receptors. An increase in the level of total cholesterol, LDL cholesterol and apolipoprotein B (apo-B) in the blood plasma causes the development of atherosclerosis and is a risk factor for the development of diseases of the cardiovascular system, while an increase in the level of HDL cholesterol is associated with a decrease in the degree of this risk. Atorvastatin reduces the level of cholesterol in the blood plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of LDL receptors on the outer membranes of hepatocytes, which enhances the uptake and catabolism of LDL. Atorvastatin also reduces LDL synthesis. In some patients with homozygous familial hypercholesterolemia, a disease difficult to treat with other lipid-lowering drugs, it reduces serum LDL concentrations. An increase in the level of total cholesterol, LDL cholesterol and apo-B in the blood plasma contributes to the development and progression of atherosclerosis. A decrease in HDL cholesterol levels, as well as apo-A, is associated with the development of atherosclerosis. Epidemiological studies have established a direct relationship between the incidence of cardiovascular diseases and mortality from them with the level of total cholesterol and LDL cholesterol, and the inverse relationship with the level of HDL cholesterol. The effect of increasing the level of HDL cholesterol or decreasing the level of TG in the blood plasma on the risk of developing cardiovascular diseases and mortality from them has not been established. Atorvastatin reduces the level of total cholesterol, LDL cholesterol and apo-B in patients with homozygous and heterozygous familial hypercholesterolemia, primary hypercholesterolemia and mixed hyperlipidemia. It also causes a decrease in the levels of VLDL cholesterol and TG and an increase in the levels of HDL cholesterol and apo-A. Atorvastatin reduces the levels of total cholesterol, LDL cholesterol, VLDL cholesterol, apo-B, TG and increases the level of HDL cholesterol in patients with isolated hypertriglyceridemia. Reduces LPSP cholesterol levels in patients with dysbetalipoproteinemia. Like LDL cholesterol, lipoproteins enriched in cholesterol and TG, including VLDL and LPSP, can also contribute to the progression of the atherosclerotic process. Elevated levels of TG in the blood plasma are often detected as part of a triad that also includes low levels of HDL cholesterol and small particles of LDL cholesterol, as well as along with non-lipid metabolic risk factors for the development of cardiovascular diseases. The total level of TG in blood plasma is not an independent risk factor for the development of coronary artery disease. Moreover, the effect of independent increases in HDL cholesterol or decreases in TG levels on cardiovascular morbidity and mortality has not been established. The point of application of the pharmacological activity of atorvastatin and its metabolites is the liver, the main organ in which cholesterol is synthesized and LDL clearance occurs. The use of atorvastatin (at a dose of 10 and 20 mg) causes a decrease in the level of total cholesterol by 29 and 33%, LDL cholesterol by 39 and 43%, apo-B by 32 and 35%, and TG by 14 and 26%. The level of HDL cholesterol increases by 6 and 9%, respectively. Atorvastatin is rapidly absorbed after oral administration; the maximum concentration in blood plasma is reached after 1–2 hours. The degree of absorption increases in proportion to the dose of atorvastatin. The absolute bioavailability of atorvastatin is approximately 14%, the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. Low systemic availability is associated with first-pass metabolism in the gastrointestinal mucosa and during the first pass through the liver. Although the presence of food reduces the rate and extent of absorption of atorvastatin by approximately 25 and 9%, respectively, the extent of the reduction in LDL cholesterol levels is independent of food intake. After taking atorvastatin in the evening, its concentration in the blood plasma is lower (by about 30%) compared to taking it in the morning; Despite this, the degree of reduction in LDL cholesterol levels does not depend on the time of taking the drug during the day. Atorvastatin is approximately 98% bound to plasma proteins. The distribution ratio in whole blood and plasma is about 0.25, indicating weak binding of the drug to erythrocytes. It has been experimentally established that atorvastatin can be excreted in breast milk. Atorvastatin is metabolized to form various ortho- and parahydroxylated derivatives and β-oxidation products. In vitro, the degree of inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of the inhibitory activity against HMG-CoA reductase is associated with active metabolites. in vitro studies indicate an important role of cytochrome P450 3A4 in the metabolism of atorvastatin. Atorvastatin and its metabolites are excreted mainly in bile; not included in the enterohepatic recirculation. The average half-life of atorvastatin is 14 hours, while the half-life of the inhibitory effect on HMG-CoA reductase is 20–30 hours (due to the action of active metabolites). Less than 2% of atorvastatin taken is excreted in the urine. In healthy individuals over the age of 65 years, the plasma concentration of atorvastatin is higher than in younger patients (maximum concentration by 40%, AUC by 30%). When taking atorvastatin in the same doses, a decrease in LDL cholesterol levels is observed, compared with that in younger patients. The plasma concentration of atorvastatin in women differs from that in men (the maximum concentration is approximately 20% higher and the AUC value is 10% lower than in men); Despite this, clinically significant differences in the degree of reduction in LDL cholesterol levels when treated with atorvastatin in patients of different sexes were not identified. In the presence of kidney disease, the degree of reduction in the level of LDL cholesterol in the blood plasma under the influence of atorvastatin does not change; dose adjustment is not required for patients with impaired renal function. Hemodialysis does not appear to have a significant effect on the clearance of atorvastatin, since the drug is largely bound to plasma proteins. In patients with chronic forms of alcoholic liver damage, the concentration of atorvastatin in the blood plasma is significantly increased. The value of the maximum plasma concentration and AUC in patients with liver cirrhosis of functional class A according to the Child-Pugh classification is 4 times higher than in healthy individuals usually, and with functional class B these indicators exceed the norm by 16 and 11 times, respectively.
Tulip tablets p/o 10 mg No. 10x3
Name
Tulip table p/capt. about. 10 mg per bl. pack №10x3
Main active ingredient
Atorvastatin
Release form
pills
Compound
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 – yellow iron oxide (E172).
Description
Tulip 10 mg: white or off-white, round, biconvex, film-coated tablets with “HLA 10” printed on one side. Tulip 20 mg: light yellow, round, biconvex, film-coated tablets with “HLA 20” printed on one side. Tulip 40 mg: light yellow, round, biconvex, film-coated tablets with “HLA 40” printed 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 to sterols, including cholesterol. Atorvastatin reduces plasma cholesterol 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 promotes enhanced uptake and catabolism of LDL. As a result of the action of atorvastatin, the concentrations of total cholesterol are reduced by 30-46%, LDL cholesterol by 41-61%, apolipoprotein B by 34-50% and triglycerides by 14-33%, while simultaneously increasing the concentration of HDL cholesterol and apolipoprotein A-I , which has been proven to reduce the risk of cardiovascular events and mortality from cardiovascular diseases. Atorvastatin significantly reduced total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B levels in children aged 6 to 17 years with heterozygous familial hypercholesterolemia or severe hypercholesterolemia compared with placebo and colestipol.
Pharmacokinetics
Absorption After administration, atorvastatin is rapidly absorbed from 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%, the absolute bioavailability is 12-14%, the systemic HMG-CoA reductase inhibitory activity is approximately 30%. Distribution The average volume of distribution of atorvastatin is 381 l, the degree of binding to plasma proteins is about 98%. Metabolism Atorvastatin is metabolized with the participation of 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. Elimination Atorvastatin and its metabolites are substrates for P-glycoprotein. Atorvastatin and its metabolites are eliminated primarily in bile. The average 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 elderly (age >65 years) compared with young volunteers, while lipid-lowering effects were comparable between the two age groups. Children. In an open-label 8-week study, pediatric patients at stage I of sexual development according to Tanner (n = 15) and stage II of sexual development according to Tanner (n = 24) aged 6-17 years with heterozygous hereditary hypercholesterolemia and an initial level of LDL-C of ? 4 mmol/l received atorvastatin, respectively, 5 or 10 mg in chewable tablets, or 10 and 20 mg in film-coated tablets, once a day. In the population model of atorvastatin pharmacokinetics, the only significant covariate was body weight. The apparent oral clearance of atorvastatin in pediatric patients was similar to that in adults when data were allometrically scaled by body weight. Over the exposure range of atorvastatin and o-hydroxyatorvastatin, there was a sustained decrease in LDL-C and total cholesterol levels. 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 between men and women. Patients with renal failure. Kidney disease had no effect on plasma concentrations of atorvastatin and its 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-fold and AUC approximately 11-fold). 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 developing rhabdomyolysis. Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) was associated with an increase in atorvastatin AUC by 2.4 times compared to atorvastatin AUC in individuals who do not have this genotype variant (C.521TT). Also, these patients may have a genetically determined disorder in the hepatic uptake of atorvastatin. The possible effects on the effectiveness of the drug are unknown.
Indications for use
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 (types IIa and IIb according to the Fredrickson classification) in addition to a 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 are not possible. Prevention of cardiovascular diseases Tulip is used for the prevention of cardiovascular diseases in patients at high risk of a first cardiovascular event as an adjunct to the correction of other risk factors.
Contraindications
– Hypersensitivity to the active or excipients of the drug; – active liver disease or persistent unexplained increase in serum transaminases, three times the upper limit of normal; – pregnancy and breastfeeding. The drug is also contraindicated in women of childbearing age who do not use contraception.
Use during pregnancy and lactation
During treatment, women of childbearing age should use reliable contraception. 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 pregnancy or suspect pregnancy should not take Tulip. Its use should be delayed during pregnancy or until its absence is established. Excretion into breast milk is unknown. The use of Tulip during breastfeeding is contraindicated.
Directions for use and doses
For oral administration. Take once a day at any time of the day, regardless of meals. Before starting and throughout the entire period of treatment, you should adhere to a standard hypocholesterol diet. The dose is individualized based on baseline LDL cholesterol levels, treatment goals, and response to 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 with a dose of 10 mg once daily. Therapeutic effectiveness appears within two weeks and usually reaches a maximum after four weeks. With long-term 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 the maximum (80 mg per day), or combined with atorvastatin 40 mg (once daily) 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 drugs (eg, LDL apheresis) or when it is impossible to use other drugs. 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 recommendations. Kidney failure. No dose adjustment is required. Liver failure. Use with caution. Do not use if you have active liver disease. Elderly persons. When taken at recommended doses, safety and effectiveness 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 doctor with experience in the treatment of hyperlipidemia in children and with regular examination. The recommended starting dose of atorvastatin for patients with heterozygous familial hypercholesterolemia aged 10 years and older is 10 mg per day. The dose can be increased to 80 mg daily based on individual response to treatment and tolerability. Doses should be individualized according to the purpose of therapy. Adjustments should be made at intervals of 4 weeks or more. Dose titration to 80 mg daily is supported by data from studies in adult patients and limited clinical data from studies in children with heterozygous familial hypercholesterolemia. There are limited data on efficacy and safety from open studies in children with heterozygous familial hypercholesterolemia aged 6–10 years. Atorvastatin is not indicated for the treatment of patients under 10 years of age. The currently available data is presented in the sections “Side effects”, “Pharmacodynamics”, “Pharmacokinetics”, but recommendations regarding dosing cannot be given. In patients in this category, it may be advisable 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.
Side effect
Adverse reactions are classified by frequency of occurrence and listed in descending order: frequent (?1/100, 30 kg/m2, elevated triglycerides, history of arterial hypertension). Providing information about suspected adverse reactions Providing information about suspected adverse reactions after registration of a medicinal product is of great importance. This allows continued monitoring of the benefit-risk ratio of the 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 atorvastatin overdose. Treatment of overdose is symptomatic and, if necessary, supportive. It is necessary to monitor the levels of liver enzymes and CPK. Hemodialysis is ineffective.
Interaction with other drugs
Atorvastatin is metabolized by cytochrome P4503A4 and is a substrate of transport proteins, in particular the hepatic organic anion transporter OATP1B1. Concomitant use of atorvastatin and inhibitors of cytochrome P4503A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and increase the risk of myopathy, which can also be observed when combined 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 cytochrome P4503A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir) should be avoided. , indinavir, darunavir, etc.). If concomitant use of the above-mentioned drugs with atorvastatin is unavoidable, a reduction in the initial and maximum dose of atorvastatin should be considered and patients should be monitored accordingly. Moderate cytochrome P4503A4 inhibitors, such as erythromycin, diltiazem, verapamil, amiodarone and fluconazole, may increase plasma concentrations of atorvastatin, therefore a reduction in the maximum dose of Tulip and clinical observation is recommended. When erythromycin is combined with statins, the risk of developing myopathy increases. Particular attention of the physician 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 coadministration is unavoidable, dose reduction and careful evaluation of clinical effectiveness are recommended. Inducers of cytochrome P4503A4 (eg, efavirenz, rifampicin, St. John's wort) may 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 administration of 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 assessed. Gemfibrozil/fibrates, ezetimibe. Muscle damage, including rhabdomyolysis, sometimes occurs with fibrates and ezetimibe monotherapy, and the risk increases when used together with atorvastatin. If co-administration is necessary, the minimum therapeutic dose of atorvastatin is used, treatment is carried out under the supervision of a physician. Colestipol. Co-administration with colestipol reduces the concentration of atorvastatin and its active metabolites (atorvastatin concentration ratio: 0.74), however, the antihyperlipidemic effectiveness of the combination exceeds that of each drug separately. Fusidic acid. Concomitant use of systemic fusidic acid with statins may increase the risk of myopathy, including rhabdomyolysis. The mechanism of this interaction (whether pharmacodynamic or pharmacokinetic, or both) is not yet known. Rhabdomyolysis (including some deaths) has been reported in patients receiving this combination. If the use of systemic fusidic acid is considered necessary, atorvastatin should be discontinued during fusidic acid treatment. Colchicine. Although interaction studies between atorvastatin and colchicine have not been conducted, there are reports of the development of myopathy with simultaneous use of atorvastatin with colchicine, and therefore caution should be exercised when prescribing atorvastatin in combination with colchicine. Digoxin. Repeated administration of digoxin and 10 mg of atorvastatin was accompanied by a slight increase in the steady-state concentration of digoxin. While taking digoxin, the patient should be under medical supervision. Oral contraceptives. Concomitant use of atorvastatin and oral contraceptives increased plasma levels of norethindrone and ethinyl estradiol. 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 normalized by the 15th day of treatment with atorvastatin. Therefore, when taking coumarin anticoagulants, it is recommended to determine the prothrombin time 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 changes in prothrombin time in patients not taking anticoagulants. Children. Interaction studies with other drugs were conducted only in adults. The extent 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 concomitantly used drugs on the pharmacokinetics of atorvastatin Concomitantly taken drug and dosage regimen Atorvastatin Dose (mg) AUC+ ratio Clinical recommendations # Tipranavir 500 mg 2 times / day / ritonavir 200 mg 2 times / day, 8 days (from 14 to 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 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 2 times / day, 14 days 20 mg 1 time / day for 4 days 5.9 In cases where it is necessary to carry out treatment simultaneously with atorvastatin, it is recommended to reduce the maintenance dose of atorvastatin. When using atorvastatin in doses exceeding 20 mg, clinical monitoring is indicated. Clarithromycin 500 mg 2 times/day, 9 days 80 mg 1 time/day for 8 days 4.5 Saquinavir 400 mg 2 times/day / ritonavir (300 mg 2 times/day 5-7 days, followed by increasing the dose 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 it is necessary to carry out treatment simultaneously with taking atorvastatin, it is recommended to reduce maintenance atorvastatin dose. When using atorvastatin in doses exceeding 40 mg, clinical monitoring is indicated. Darunavir 300 mg 2 times/day / ritonavir 100 mg 2 times/day, 9 days 10 mg 1 time/day for 4 days 3.4 Itraconazole 200 mg 1 time/day, 4 days 40 mg once 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 2 times/day, 14 days 10 mg 1 time/day for 28 days 1.74 No special recommendations Grapefruit juice, 240 ml 1 time/day* 40 mg once 1.37 It is not recommended to use atorvastatin simultaneously with amount of grapefruit juice. Diltiazem 240 mg once a day, 28 days 40 mg once 1.51 After starting diltiazem or adjusting its dosage, appropriate clinical monitoring is indicated. Erythromycin 500 mg 4 times a day, 7 days 10 mg, once 1.33 A lower maximum dose is recommended, as well as clinical monitoring. Amlodipine 10 mg, once 80 mg once 1.18 No special recommendations Cimetidine 300 mg 4 times/day, 2 weeks 10 mg 1 time/day for 2 weeks 1.00 No special recommendations Colestipol 10 g, 2 times/day, 28 weeks 40 mg 1 time/day for 28 weeks 0.74** No special recommendations Antacid, in the form of a suspension, containing magnesium and aluminum hydroxides, 30 ml 4 times/day, 17 days 10 mg 1 time/day for 15 days 0.66 No special recommendations 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 doses) 40 mg once 0.20 Gemfibrozil 600 mg 2 times / day, 7 days 40 mg once 1.35 A lower initial dosage and clinical monitoring is recommended Fenofibrate 160 mg 1 time/day, 7 days 40 mg once 1.03 A lower initial dosage and clinical monitoring is recommended Boceprevir 800 mg 3 times/day, 7 days 40 mg once 2,3 Lower initial dosage and clinical monitoring are recommended. When used concomitantly with boceprevir, the daily dose of atorvastatin should not exceed 20 mg + Shows the relationship between drug combinations with atorvastatin compared to atorvastatin alone. #Information on clinical significance is provided in the sections “Special instructions and precautions” and “Interaction with other drugs and other types of interactions.” *The composition contains one or more components that inhibit the activity of CYP3A4, which may increase the 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. Drinking significant amounts of grapefruit juice (more than 1.2 liters per day for 5 days) resulted in a 2.5-fold increase in the AUC of atorvastatin and the AUC of active compounds (atorvastatin and its metabolites). **Ratios are based on one sample taken 8-16 hours after ingestion. Table 2. Effect of atorvastatin on the pharmacokinetics of concomitantly taken drugs Atorvastatin and dosage regimen Co-administered drug Drug / dose (mg) AUC+ ratio Clinical recommendations 80 mg 1 time / day for 10 days Digoxin 0.25 mg 1 time / day, 20 days 1.15 The condition of patients taking digoxin 40 mg 1 time / day for 22 days should be properly monitored. Oral contraceptive, 1 time / day, 2 months - norethindrone 1 mg - ethinyl estradiol 35 mcg 1.28 1.19 Special no recommendations 80 mg 1 time/day for 15 days * Phenazone, 600 mg, once 1.03 No special recommendations 10 mg once Tipranavir 500 mg 2 times/day / ritonavir 200 mg 2 times/day, 7 days 1.08 Special no recommendations 10 mg 1 time/day for 4 days Fosamprenavir 1400 mg 2 times/day, 14 days 0.73 No special recommendations 10 mg 1 time/day for 4 days Fosamprenavir 700 mg 2 times/day / ritonavir 100 mg 2 times/day, 14 days 0.99 No special recommendations+Displays the relationship between the combination of drugs with atorvastatin compared to taking atorvastatin as monotherapy. *The simultaneous repeated use of atorvastatin and phenazone had little or no effect on the clearance of phenazone.
Precautionary measures
Effect on the liver Liver function should be checked before starting treatment and regularly monitored during treatment, as well as if any clinical signs of liver damage appear. Patients who experience increased transaminase levels should be monitored until enzyme levels normalize. If transaminase values are persistently three times or more higher than the upper limit of normal (ULN), it is recommended to reduce the dose of Tulip or discontinue the drug. For patients who abuse alcohol and/or have a history of liver disease, Tulip is prescribed with caution. Stroke Prevention with Intensive Cholesterol Lowering In a secondary analysis of stroke subtypes in patients without coronary artery disease who had a recent stroke or transient cerebrovascular accident, a higher incidence of hemorrhagic stroke was observed with an initial dose of atorvastatin 80 mg compared with placebo. The risk of its occurrence was especially high in patients who had suffered a hemorrhagic stroke or lacunar infarction before inclusion 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 in them. Effect on skeletal muscle 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 level of creatine phosphokinase (CPK), myoglobinemia and myoglobinuria, which is fraught with the development of renal failure. There are very rare case reports of immune-mediated necrotizing myopathy (IONM) 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 When prescribing Tulip to patients with a predisposition to rhabdomyolysis, caution should be exercised. The level of CPK should be determined before starting treatment in the following cases: - renal failure; - hypothyroidism; - hereditary muscle diseases in the patient or his relatives; - previous toxic muscle damage due to the use of a statin or fibrate; - pre-existing liver disease and/or alcohol abuse; — in patients over 70 years of age, the need to determine CPK levels is determined by the presence of other predisposition factors to rhabdomyolysis; - with an expected increase in plasma levels of the drug, in particular due to interaction with other drugs, as well as in special groups of patients, including genetically predisposed ones. In such cases, it is necessary to compare the potential benefits of treatment and the degree of risk and carry out clinical monitoring of patients. Treatment should not be started if baseline CPK levels are significantly elevated (>5 times the ULN). Determination of CPK levels Do not measure CPK levels after heavy physical activity or in the presence of any factors leading to an increase in enzyme levels, as this will complicate the interpretation of the test results. If the initial CPK level is significantly elevated (>5 times the ULN), the analysis is repeated after 5-7 days to confirm the results. During treatment, patients should immediately report pain, cramps or muscle weakness to the doctor, 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. If it increases significantly (>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. Once symptoms disappear and CPK levels normalize, treatment with the lowest doses of statins can be resumed under close medical supervision. If there is a clinically significant increase in CPK levels (>10 times relative to ULN), as well as if rhabdomyolysis is suspected or confirmed, treatment with Tulip is discontinued. Interstitial lung disease Exceptional cases of interstitial lung disease have been reported with the use of some statins, especially with long-term therapy. If the development of interstitial lung disease is suspected (shortness of breath, nonproductive cough, weakness, weight loss, fever), statin treatment is discontinued. Children. No clinically significant effects on growth and puberty were observed in a three-year study based on assessment of general maturation and development, Tanner stage assessment, and height and weight measurements. Diabetes mellitus Statins, as a class, have the ability to increase blood glucose and may cause hyperglycemia in some patients at high risk of developing diabetes, requiring standard diabetes management measures. At the same time, the reduction in the risk of cardiovascular complications by 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 monitoring and biochemical tests. Concomitant use with other medicinal products When atorvastatin is co-administered with a number of medicinal products that can lead to an increase in its plasma levels, such as strong inhibitors of cytochrome P4503A4 or transport proteins (for example, cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.), the risk of rhabdomyolysis increases. Concomitant use of gemfibrozil and other fibrates, boceprevir, erythromycin, niacin, ezetimibe, telaprevir, or the tipranavir/ritonavir combination may also increase the risk of developing myopathy. Instead, if possible, other drugs that do not interact with atorvastatin should be considered. If it is necessary to use the above-mentioned drugs together with atorvastatin, the benefits and risks of such therapy should be carefully weighed. In cases of use of 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 cytochrome P4503A4 inhibitors, a lower initial dose of atorvastatin should be considered and patients should be monitored accordingly. Atorvastatin should not be used concomitantly with fusidic acid or within 7 days after stopping treatment with fusidic acid. If the use of systemic fusidic acid is considered necessary, the statin should be discontinued during fusidic acid treatment. Cases of rhabdomyolysis (including some deaths) have been reported in patients receiving combinations of fusidic acid and statins. You should contact your doctor immediately if you experience any symptoms of muscle weakness, pain, or tenderness. Statin therapy can be resumed 7 days after the last dose of fusidic acid. In exceptional cases where long-term treatment with systemic fusidic acid is necessary, such as severe infections, the need for co-administration of atorvastatin and fusidic acid should only be considered on a case-by-case basis and under close medical supervision. Tulip contains lactose. The drug should not be used in patients with such rare types of hereditary pathology as galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.
Storage conditions
Keep out of the reach of children! Store in original packaging at a temperature not exceeding 25°C.
Use of the drug Tulip
The patient should be placed on a cholesterol-lowering diet before prescribing the drug; it must be observed throughout the entire period of drug treatment. Primary hypercholesterolemia and mixed hyperlipidemia The recommended initial dose of Tulip is 10 mg 1 time per day. In the future, the dose is selected individually; it can be 10–80 mg/day, depending on the level of cholesterol. After 2–4 weeks after the start of treatment, the level of lipids in the blood serum should be determined and the dose of the drug should be adjusted accordingly. Familial hypercholesterolemia The initial dose of Tulip for heterozygous familial hypercholesterolemia is 10 mg/day, subsequently it can be increased to 80 mg/day. In case of homozygous familial hypercholesterolemia, the use of Tulip at a dose of 80 mg/day reduces the level of LDL cholesterol by 17–31%. Dosing in patients with renal failure If a patient has kidney disease, the concentration of atorvastatin in the blood plasma and its effect on LDL cholesterol levels do not change. In this regard, no dose adjustment is required for patients with kidney disease. Use in Elderly Patients The safety and effectiveness of atorvastatin in persons over 70 years of age do not differ from those in younger patients.
Special instructions for the use of Tulip
The use of HMG-CoA reductase inhibitors to reduce blood lipid levels can lead to changes in biochemical parameters reflecting liver function. Liver function parameters should be monitored before starting treatment and 12 weeks after starting the drug, 12 weeks after each dose increase, and also periodically, for example every six months. Changes in liver enzyme activity are usually observed within the first 3 months after starting atorvastatin. Patients who experience increased transaminase activity should be under medical supervision until these indicators normalize. If the activity of ALT or AST is more than 3 times higher than the upper limit of normal, it is recommended to reduce the dose of atorvastatin or discontinue treatment. Atorvastatin should be used with caution in patients who abuse alcohol or have a history of liver disease. Active liver disease or an unexplained increase in serum transaminase activity is a contraindication for the use of atorvastatin. Patients with diffuse myalgia, myasthenia gravis, or a significant increase in CPK levels are at risk for the development of myopathy (manifested by myalgia or muscle weakness in combination with a concomitant increase in CPK levels of more than 10 times the upper limit of normal). Treatment with atorvastatin should be temporarily suspended or discontinued in the acute development of a condition that can be regarded as a myopathy, as well as in the presence of risk factors for the development of renal failure due to rhabdomyolysis (for example, acute severe infection, arterial hypotension, recent major surgery, trauma, severe metabolic and endocrine disorders, as well as electrolyte imbalances and uncontrolled seizures). CS and other compounds formed during its biosynthesis are important for the normal development of the fetus (including the synthesis of steroid hormones and cell membrane components). HMG-CoA reductase inhibitors inhibit the synthesis of cholesterol and, possibly, the synthesis of other biologically active substances that are derivatives of cholesterol; therefore, their use during pregnancy may have a negative effect on the fetus. The use of HMG-CoA reductase inhibitors during pregnancy and breastfeeding is contraindicated. Tulip can be prescribed to women of childbearing age only if they are certain that pregnancy is impossible and after explaining to them the possible consequences of using the drug during pregnancy. If pregnancy occurs during treatment with Tulip, you should stop taking it and inform the patient about the possible negative effect of the drug on the fetus. Due to the possibility of negative effects on infants, women taking Tulip are advised to stop breastfeeding.
Interactions of the drug Tulip
The risk of developing myopathy in patients taking statins increases while taking cyclosporine, fibric acid derivatives, erythromycin, nicotinic acid and azole antifungals. When prescribing combination therapy with atorvastatin and cyclosporine, fibric acid derivatives, erythromycin, immunosuppressants, azole antifungals and nicotinic acid in lipid-lowering doses, the potential benefits and risks of this treatment regimen should be compared and the patients’ condition monitored for timely detection of myalgia and muscle weakness and other manifestations of myopathy, especially during the first months of treatment and when the dose of any of the drugs is increased. With the simultaneous administration of atorvastatin and antacid drugs in the form of a suspension containing magnesium and aluminum hydroxides, the concentration of atorvastatin in the blood plasma is reduced by approximately 35%, while the degree of reduction in LDL cholesterol levels remains unchanged. With the simultaneous use of atorvastatin and colestipol, the concentration of atorvastatin in the blood plasma is reduced by approximately 25%, while the degree of reduction in LDL cholesterol levels exceeds that when taking each drug separately. With repeated concomitant use of atorvastatin and digoxin, the concentration of digoxin in the blood plasma increases by approximately 20%, and therefore patients taking digoxin should be monitored. With simultaneous administration of atorvastatin and erythromycin, which has an inhibitory effect on cytochrome P450 3A4, the concentration of atorvastatin in the blood plasma of healthy volunteers increased by approximately 40%. When atorvastatin was coadministered with oral contraceptives, the AUC increased by approximately 30% for norethindrone and by 20% for ethinyl estradiol. These data should be taken into account when selecting contraceptives for patients taking atorvastatin. In patients taking warfarin for a long time, atorvastatin slightly reduces the prothrombin time in the first days after the start of its use, but after 15 days this indicator returns to normal. After prescribing Tulip to patients taking warfarin, they should check their prothrombin time more often than usual.
Tulip®
The risk of myopathy during treatment with HMG-CoA reductase inhibitors increases with simultaneous use with cyclosporine, erythromycin, clarithromycin, immunosuppressive, antifungal drugs (azole derivatives)
due to a possible increase in serum concentrations of atorvastatin.
When used simultaneously with HIV protease inhibitors - indinavir, ritonavir -
the risk of developing myopathy increases.
A similar interaction is possible with simultaneous use of atorvastatin with fibrates and nicotinic acid
in lipid-lowering doses (more than 1 g/day).
Inhibitors of the
CYP3A4 isoenzyme Since
atorvastatin is metabolized by the CYP3A4 isoenzyme, concomitant use of the drug Tulip®
with inhibitors of this isoenzyme may lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and the effect of increasing the concentration of atorvastatin is determined by the variability of the effect on the CYP3A4 isoenzyme.
OATP1B1 transport protein inhibitors
Atorvastatin and its metabolites are substrates of the transport protein OATP1B1. OATP1B1 inhibitors (eg, cyclosporine) may increase the bioavailability of atorvastatin. Thus, the use of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg/kg/day leads to an increase in the concentration of atorvastatin in the blood plasma by 7.7 times.
Erythromycin/clarithromycin
With the simultaneous use of atorvastatin 10 mg and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg 2 times a day), which inhibit the cytochrome CYP3A4 isoenzyme, an increase in the concentration of atorvastatin in the blood plasma is observed (by 40% when used with erythromycin and by 56% when used with clarithromycin).
Protease inhibitors
The simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the cytochrome CYP3A4 isoenzyme, is accompanied by an increase in the concentration of atorvastatin in the blood plasma (when used simultaneously with erythromycin, the Cmax of atorvastatin increases by 40%).
Diltiazem
Co-administration of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in the concentration of atorvastatin in the blood plasma.
Cimetidine
No clinically significant interaction of atorvastatin with cimetidine has been identified. Itraconazole
The simultaneous use of atorvastatin in doses from 20 mg to 40 mg and itraconazole in a dose of 200 mg leads to a 3-fold increase in the AUC value of atorvastatin.
Grapefruit juice
Since grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme, excessive consumption (more than 1.2 L per day for 5 days) may cause an increase in plasma concentrations of atorvastatin.
Inducers of the CYP3A4 isoenzyme
: Concomitant CYP3A4 )
may lead to a decrease in the concentration of atorvastatin in the blood plasma. Due to the dual mechanism of interaction with rifampicin (an inducer of the CYP3A4 isoenzyme and an inhibitor of the hepatocyte transport protein OATP1B1), the simultaneous use of atorvastatin and rifampicin is not recommended, since delayed administration of atorvastatin after taking rifampicin leads to a significant decrease in the concentration of atorvastatin in the blood plasma.
Antacids
With simultaneous oral administration of atorvastatin and a suspension containing magnesium and aluminum hydroxides, the plasma concentration of atorvastatin is reduced by approximately 35%, but the degree of reduction in LDL-cholesterol concentration does not change.
Phenazone
Atorvastatin does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same isoenzymes is not expected.
Colestipol
The lipid-lowering effect of the combination with colestipol is superior to that of each drug separately, despite a 25% decrease in the concentration of atorvastatin when used simultaneously with colestipol.
Fusidic acid
No interaction studies have been conducted between atorvastatin and fusidic acid. As with other statins, muscle side effects, including rhabdomyolysis, have been reported in post-marketing studies of concomitant use of atorvastatin and fusidic acid. The mechanism of interaction is unknown. Such patients require careful monitoring and, possibly, temporary discontinuation of atorvastatin.
Colchicine
Although interaction studies between atorvastatin and colchicine have not been conducted, cases of myopathy have been reported when coadministered with colchicine, and caution should be used when atorvastatin and colchicine are coadministered.
Digoxin
With repeated use of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma do not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg/day. The concentration of digoxin in the blood plasma increases by approximately 20%. Patients taking digoxin in combination with atorvastatin require monitoring of digoxin plasma concentrations.
Azithromycin
With simultaneous use of atorvastatin at a dose of 10 mg 1 time / day and azithromycin at a dose of 500 mg 1 time / day, the concentration of atorvastatin in the blood plasma does not change.
Oral contraceptives
When atorvastatin is used concomitantly with an oral contraceptive containing norethisterone and ethinyl estradiol, there is a significant increase in the AUC of norethisterone and ethinyl estradiol by approximately 30% and 20%, respectively, which should be taken into account when choosing an oral contraceptive.
Terfenadine
Atorvastatin, when used simultaneously with terfenadine, does not have a clinically significant effect on the pharmacokinetics of terfenadine.
Warfarin
In patients who take warfarin for a long time, atorvastatin at a dose of 80 mg per day slightly shortens the prothrombin time in the first days of joint use. This effect disappears after 15 days of simultaneous use of these drugs. Although clinically significant changes in the anticoagulant effect have been reported very rarely, the prothrombin time should be determined in patients taking coumarin anticoagulants before and frequently during the initiation of treatment with atorvastatin to ensure that there are no significant changes in the prothrombin time. Once a stable prothrombin time has been recorded, it can be checked at intervals usual for patients taking coumarin anticoagulants. If the dose is changed or treatment is stopped, these measures should be repeated. There was no association between atorvastatin use and bleeding or changes in prothrombin time in patients not taking anticoagulants.
Amlodipine
With simultaneous use of atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg, the pharmacokinetics of atorvastatin at steady state does not change.
Other lipid-lowering
drugs
When atorvastatin is used concomitantly with other lipid-lowering drugs (for example, ezetimibe, gemfibrozil, fibric acid derivative)
in lipid-lowering doses, the risk of developing rhabdomyolysis increases.
Other concomitant therapy
When atorvastatin is used together with antihypertensive drugs and estrogens (as replacement therapy), no clinically significant interaction has been identified.
