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Active ingredients
Atorvastatin
Release form
Pills
Composition
Atorvastatin (in the form of atorvastatin calcium) 20 mg adjuvants: lactose monohydrate - 34.8 mg, croscarmellose sodium - 19.2 mg, hyprolosis - 2 mg, polysorbate 80 - 2.6 mg, magnesium oxide, heavy - 26 mg, silicon dioxide colloid - 1.2 mg, magnesium stearate - 1 mg, microcrystalline cellulose - up to 250 mg. Of the composition: hypromellose - 2.976 mg, hyprolosis - 0.744 mg, titanium dioxide (e171) - 1.368 mg, macrogol 6000 - 0.6 mg, talc - 0.3 mg, ferric oxide yellow (e172) - 0.012 mg.
Pharmacological effect
Lipid-lowering agent. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase - an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, which is a precursor of sterols, including cholesterol. very low density (VLDL) during synthesis in the liver, enter the blood plasma and are transported to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL during interaction with LDL receptors. Studies have shown that increased concentrations of total Xc, LDL and apolipoprotein B (apo-B) in the blood plasma contribute to the development of atherosclerosis and are among the risk factors for cardiovascular diseases, while increasing the concentration of high-density lipoprotein (HDL) reduces the risk of developing cardiovascular diseases. Atorvastatin reduces the concentration of Xc and lipoproteins in the blood plasma due to inhibition I have HMG-CoA reductase, cholesterol synthesis in the liver and an increase in the number of hepatic LDL receptors on the cell surface, which leads to increased uptake and catabolism of LDL (according to preclinical studies). Atorvastatin reduces the synthesis and concentration of Xc-LDL, total Xc, apo In patients with homozygous and heterozygous familial hypercholesterolemia, primary hypercholesterolemia and mixed hyperlipidemia. It also causes a decrease in the concentration of cholesterol-VLDL and TG and an increase in the concentration of cholesterol-HDL and apolipoprotein A-1 (an -A). In patients with dysbetalipoproteinemia, the concentration of lipoproteins of intermediate density Xc-LppP decreases. Attorney doses of 10 mg and 20 mg reduces the concentration of total Xc by 29% and 33%, LDL - by 39% and 43%, apo-B - by 32% and 35% and TG - by 14% and 26%, respectively; causes an increase in the concentration of cholesterol-HDL and apo-A.Atorvastatin in doses of 40 mg reduces the concentration of total cholesterol by 37%, LDL - 50%,Apo-B - by 42% and TG - by 29%; causes an increase in the concentration of Xc-HDL and apo-A.Dose-dependently reduces the concentration of LDL in patients with homozygous familial hypercholesterolemia resistant to other lipid-lowering drugs. It has no carcinogenic and mutagenic effects. The therapeutic effect develops 2 weeks after the start of therapy, reaches a maximum after 4 weeks and lasts for the entire period of treatment.
Pharmacokinetics
Absorption and distribution Absorption is high. Cmax in the blood plasma after ingestion is achieved after 1-2 hours. Eating a little reduces the rate and extent of absorption of the drug (by 25% and 9%, respectively), but the decrease in Xc-LDL is similar to that of atorvastatin without simultaneous ingestion of food. ingestion of atorvastatin in the evening its plasma concentration is lower (Cmax and AUC by about 30%) than after taking it in the morning, while the decrease in the concentration of Xc-LDL does not depend on the time of day the drug is taken. A linear relationship was found between the degree of absorption and the dose of the drug. The bioavailability is 12-14%, the systemic bioavailability of the inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability due to presystemic metabolism in the gastrointestinal tract and the effect of the first passage through the liver. Average Vd - 381 l, binding to plasma proteins - 98%. The ratio of atorvastatin concentration in erythrocytes / plasma is about 0.25, which indicates poor penetration of atorvastatin into erythrocytes Metabolism and excretionAtorvastatin is metabolized primarily in the liver by the action of CYP3A4, CYP3A5 and CYP3A7 isoenzymes with the formation of pharmacologically active metabolites (ortho- and parahydroxylated dnyh, products of beta-oxidation). In vitro, ortho and parahydroxylated metabolites have an inhibitory effect on HMG-CoA reductase comparable to that of atorvastatin. The inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites, which persists for approximately 20-30 h due to their presence. In vitro studies suggest that the liver isoenzyme CYP3A4 plays an important role in metabolism atorvastatin.This is confirmed by an increase in plasma levels of atorvastatin while taking erythromycin, which is an inhibitor of this isoenzyme. In vitro studies also showed that atorvastatin is a weak inhibitor of the CYP3A4 isoenzyme. It is eliminated mainly through the intestine after hepatic and / or extrahepatic metabolism (the drug is not expressed expressed enterohepatic recirculation). T1 / 2 - 14 hours. T1 / 2 of the inhibitory activity of HMG-CoA reductase is 20-30 hours. Less than 2% of the ingested dose is determined in urine. It is not displayed during hemodialysis due to intensive binding to plasma proteins. Pharmacokinetics in special clinical situations in women Cmax is higher by 20%, AUC is lower by 10% than in men, which has no clinical significance. In patients with alcoholic cirrhosis (class B on the Child-Pugh scale), the Cmax liver is 16 times, and the AUC is 11 times higher than the norm. The Cmax and AUC in older patients (≥65 years) are 40% and 30% higher, respectively, than in younger patients, but this is not affects the degree of lowering LDL cholesterol. Impaired kidney function does not affect the concentration of the drug in Lazma blood level of LDL cholesterol reduction.
Indications
- in combination with a cholesterol-lowering diet to reduce elevated concentrations of total Xc, Xc-LDL, apo-B and TG and increase the concentration of Xc-HDL in patients with primary hypercholesterolemia, heterozygous familial and non-familial hypercholesterolemia and combined (mixed) hyperlipidemia (type IIa) according to the Fredrickson classification), when diet therapy and other non-pharmacological treatment methods are not effective enough - to reduce the concentration of total Xc and Xc-LDL in patients with homozygous familial hypercholesterol when diet therapy and other non-pharmacological treatment methods are not effective enough - primary prevention of cardiovascular complications in patients without clinical signs of CHD, but having several risk factors for its development: age over 55 years old, nicotine dependence, arterial hypertension, diabetes mellitus, retinopathy , albuminuria, low concentrations of HDL-HDL in plasma, genetic predisposition, including on the background of dyslipidemia; - secondary prevention of cardiovascular complications in patients with coronary artery disease in order to reduce the total mortality rate, myocardial infarction, stroke, re-hospitalization for angina and the need for revascularization.
Contraindications
- liver disease in the active stage or increased activity of hepatic transaminases in the blood plasma (more than 3 times compared to VGN) of unknown origin; - pregnancy; - lactation period; - age up to 18 years (efficacy and safety not established); - deficiency lactase, lactose intolerance, glucose-galactose malabsorption syndrome (because the composition contains lactose); - hypersensitivity to atorvastatin and other auxiliary components of the drug. With caution, you should prescribe the drug for alcohol abuse, a history of liver diseases, muscular system diseases (in history from the use of other members of the HMG-CoA reductase inhibitor group), severe electrolyte imbalance, endocrine (hyperthyroidism) and metabolic disorders, arterial hypotension, diabetes mellitus, severe acute infections (sepsis), uncontrolled epilepsy, extensive surgical interventions, injuries, aggressive lipid-lowering therapy (atorvastatin in a dose of 80 mg) in the secondary prevention of stroke in patients with hemorrhagic or lacunae history of artery stroke.
Precautionary measures
Application for violations of liver functionWith caution, you should prescribe the drug for violations of the liver.It is not necessary to change the dose in case of renal dysfunction. The concentration of amplodipine in the blood plasma does not depend on the degree of reduction of renal function. Use in children It is contraindicated in children and adolescents under the age of 18. Application in elderly patients With caution in elderly patients.
Use during pregnancy and lactation
Tulip drug is contraindicated for use during pregnancy. Since cholesterol and substances synthesized from cholesterol are important for the development of the fetus, the potential risk of inhibition of HMG-CoA reductase exceeds the use of the drug during pregnancy. If pregnancy is diagnosed during therapy with Tulip, it should be stopped as soon as possible. the patient must be warned of the potential risk to the fetus. The Tulip preparation can be used in women of reproductive age only if the probability of pregnancy is very low,and the patient is informed about the possible risk to the fetus during treatment. Women of reproductive age during treatment with Tulip should use reliable methods of contraception. Atorvastatin is excreted in breast milk, therefore it is contraindicated for use during breastfeeding. If necessary, the use of the drug Tulip during lactation breastfeeding should be stopped.
Dosage and administration
Before starting the use of Tulip, the patient should be advised to recommend a standard cholesterol-lowering diet, which he should continue to follow throughout the entire period of drug therapy. The drug is taken orally, regardless of the meal time. The dose of Tulip varies from 10 mg to 80 mg per day, and is selected based on the initial concentrations of Xc-LDL, the goal of therapy and the individual therapeutic response to therapy. For most patients, the initial dose is 10 mg 1 time / day. At the beginning treatment, after 2-4 weeks of therapy and / or after increasing the dose of the drug Tulip, it is necessary to monitor plasma lipid concentrations and, if necessary, adjust the dose of the drug. The maximum daily dose is 80 mg / day. Primary (heterozygous hereditary and oligennaya), hypercholesterolemia (type IIa) and mixed hyperlipidaemia (type IIb) In most cases, it is enough of the drug Tulip 10 mg 1 time / day (possibly use of atorvastatin in the pills of 10 and 20 mg). If necessary, it is possible to gradually increase the dose to 80 mg (2 tab. 40 mg), depending on the patient's response with an interval of 2-4 weeks, since the therapeutic effect is observed after 2 weeks, and the maximum therapeutic effect - after 4 weeks. With long-term treatment, this effect is preserved. Homozygous hereditary hypercholesterolemia Tulip preparation in most cases is used in a dose of 80 mg (2 tab. 40 mg) 1 time per day. If the optimal plasma LDL concentration is not reached, an increase in the dose of the drug up to 80 mg / day is possible, depending on the patient's response with an interval of 2-4 weeks. Correction of the dose of Tulip in patients with impaired renal function and in elderly patients is not required. abnormal liver function slows down the excretion of atorvastatin from the body, so it is recommended to use it with caution with constant monitoring of the activity of hepatic transaminases: ACT and ALT.If the observed increase in the activity of ACT or ALT is more than 3 times compared with VGN is maintained, a dose reduction or withdrawal of the drug Tulip is recommended.
Side effects
According to the WHO, undesirable effects are classified according to their development frequency as follows: often (more than 1/100, less than 1/10), infrequently (more than 1/1000, less than 1/100), rarely (more than 1 / 10,000, less than 1/1000) and very rarely (less than 1/10 000), including individual messages; frequency is unknown - according to the available data it was not possible to establish the frequency of occurrence. From the immune system: often - allergic reactions; very rarely - anaphylaxis. From the nervous system: often - headache; infrequently - dizziness, sleep disturbances, including insomnia and nightmares, asthenic syndrome, weakness, paresthesia, hypoesthesia, taste disturbance, loss or loss of memory; rarely, peripheral neuropathy. From the sense organs: infrequently, tinnitus, blurred vision; rarely - visual impairment; very rarely - hearing loss. From the digestive system: often - constipation, flatulence, dyspepsia, nausea, diarrhea; infrequently - anorexia, vomiting, pancreatitis, hepatitis, abdominal pain, belching; rarely - cholestatic jaundice (including obstructive); very rarely - liver failure. From the musculoskeletal system: often - myalgia, arthralgia, joint swelling, joint pain, back pain, muscle spasm; infrequently - pain in the muscles of the neck, muscle weakness; rarely - myopathy, myositis, rhabdomyolysis, tendinopathy (sometimes complicated by tendon rupture); frequency is unknown - immune-mediated necrotizing myopathy. On the side of the skin and subcutaneous tissues: infrequently - urticaria, skin rash and itching, alopecia; rarely - angioedema, bullous rash, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome). On the metabolic side: often - hyperglycemia; infrequently - hypoglycemia. From the hematopoietic system: infrequently - thrombocytopenia. From the respiratory system: often - nasopharyngitis, sore throat, nosebleeds. Laboratory indicators: often - increased activity of serum CFC, increased activity of hepatic transaminases; infrequently - leukocyturia; the frequency is unknown - an increase in the concentration of glycated hemoglobin. Other: infrequently - increased fatigue, impaired potency, secondary renal failure, fever, chest pain, peripheral edema, weight gain; very rarely - gynecomastia, diabetes.There are separate reports on the development of atonic fasciitis (the association with the use of atorvastatin has not been established exactly); frequency is unknown - depression, interstitial lung disease (especially with long-term therapy), sexual dysfunction.
Interaction with other drugs
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 in the blood. Ritonavir - increases the risk of myopathy. Similar interaction is possible with simultaneous use of atorvastatin with fibrates and nicotinic acid in lipids dsnizhayuschih doses (more than 1 g / day) .Ingibitory isoenzyme CYP3A4Poskolku atorvastatin is metabolized by the isoenzyme CYP3A4, Tulip drug combined use with the inhibitors of this isoenzyme may increase atorvastatin plasma concentration. The degree of interaction and the effect of increasing the concentration of atorvastatin are determined by the variability of the effect on the CYP3A4 isoenzyme. OATP1B1 transport inhibitorsAtorvastatin and its metabolites are substrates of the OATP1B1 transport protein. OATR1B1 inhibitors (for example, cyclosporin) can 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 plasma concentration of atorvastatin 7.7 times. Erythromycin / clarithromycin. When simultaneously used atorvastatin 10 mg and erythromycin (500 mg 4 times / day) or clarithromycin (500 mg 2 times / day), which inhibit the cytochrome CYP3A4 isoenzyme, an increase in plasma plasma levels of atorvastatin is observed (by 40% when used with erythromycin and by 56% when used with clarithromycin). Protease inhibitors Simultaneous use of atorvastat Ina with protease inhibitors, known as inhibitors of the cytochrome CYP3A4 isoenzyme, is accompanied by an increase in plasma plasma levels of atorvastatin (when used simultaneously with erythromycin - Cmax atorvastatin is increased by 40%). DiltiazemAtorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in plasma concentration of atorvastatin. Cimetidine Clinically significant interaction of atorvastatin with cimetidine was not detected. a multiple increase in the AUC value of atorvastatin. Grapefruit juice Because grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme, its excessive use (more than 1.2 liters per day for 5 days ) Can cause an increase in the plasma concentration of atorvastatin krovi.Induktory isoenzyme CYP3A4Sovmestnoe use with atorvastatin SURZA4 isoenzyme inducers (e.g., efavirenz or rifampicin) may reduce the concentration of atorvastatin in plasma. Due to the dual mechanism of interaction with rifampicin (CYP3A4 isoenzyme inducer and hepatocyte transport protein inhibitor OATP1B1), simultaneous use of atorvastatin and rifampicin is not recommended, since delayed taking of atorvastatin after taking rifampicin leads to a significant decrease in atorvastatin concentration in the blood plasma. containing magnesium and aluminum hydroxides, the concentration of atorvastatin in plasma decreases by about 35%, however, the degree of decrease in the concentration of Xc-LDL does not change. Phenazone Atorvastatin does not affect the pharmacokinetics of phenazone, therefore, the interaction with other drugs metabolized by the same isoenzymes is not expected. to reduce the concentration of atorvastatin by 25% with its simultaneous use with colestipol. Fusidic acid Studies on the interaction of atorvastatin and fusidic acid was not conducted. As with other statins, post-marketing studies of the combined use of atorvastatin and fusidic acid reported side effects on the muscles, including rhabdomyolysis. The mechanism of interaction is unknown. Such patients require careful observation and, perhaps,temporary discontinuation of atorvastatin. ColchicineAlthough studies of the interaction of atorvastatin and colchicine have not been conducted, cases of myopathy have been reported when used together with colchicine, and with the simultaneous appointment of atorvastatin and colchicine, caution should be exercised. Digoxin. 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 about 20%. Patients taking digoxin in combination with atorvastatin require monitoring of the concentration of digoxin in the blood plasma. Azithromycin In case of 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 the use of atorvastatin and oral contraceptive containing norethisterone and ethinyl estradiol, there is a significant increase in the AUC of norethisterone and ethinyl estradiol by about 30% and 20%, respectively, It should be considered when choosing an oral contraceptive. TerfenadinAtorvastatin, when used simultaneously with terfenadine, does not have a clinically significant effect on the pharmacokinetics of terfenadine. This effect disappears after 15 days of simultaneous use of these drugs. Although cases of clinically significant changes in the anticoagulant effect were reported very rarely, prothrombin time should be measured in patients taking coumarin anticoagulants before and, often enough, at the beginning of treatment with atorvastatin, to ensure that there are no significant changes in the prothrombin time. As soon as a stable prothrombin time is recorded, it can be checked at intervals usual for patients taking coumarin anticoagulants. When changing the dose or discontinuation of treatment, these measures should be repeated. There was no association between atorvastatin use and bleeding or a change in prothrombin time in patientsAmlodipine When used simultaneously with atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg, the pharmacokinetics of atorvastatin does not change in equilibrium. Other lipid-lowering preparations the risk of developing rhabdomyolysis increases. Other concomitant therapyWhen using atorvastatin together with antihypertensive drugs and estrogen (as replacement therapy) - no clinically significant interaction has been identified.
special instructions
Impact on the liver As with the use of other HMG-Co-reductase inhibitors (statins), therapy with Tulip may have a moderate (more than 3 times compared to VGN) elevation of serum activity of hepatic transaminases: ACT and ALT. weeks and 12 weeks after the start of taking Tulip or after increasing its dose, it is necessary to monitor indicators of liver function (ACT, ALT). Liver function should also be monitored when clinical signs of liver damage appear. In the case of increased activity of ACT and ALT, their activity should be monitored until it normalizes. Tulip should be used with caution in patients who abuse alcohol and / or have a history of liver disease. Liver disease in the active stage or increased activity of hepatic plasma transaminases of obscure genesis are contraindicated for the use of Tulip.Pulmonary therapy using intensive lipid-lowering therapy (SPARCL) In a retrospective analysis of various subspecies of stroke in persons not suffering from coronary heart disease, who recently had a stroke or transient ischemic attack (TIA), n higher risk of hemorrhagic stroke in patients taking atorvastatin at a dose of 80 mg compared with placebo. Especially high risk was observed in patients who had hemorrhagic stroke or lacunar infarction at the time of the study. For patients who have had a hemorrhagic stroke or lacunar infarction and taking atorvastatin at a dose of 80 mg, the risk / benefit ratio is ambiguous, and the potential risk of hemorrhagic stroke should be carefully assessed before the treatment. Skeletal muscles may develop myalgia when using Tulip.The diagnosis of myopathy (pain and weakness in the muscles in combination with an increase in the activity of CPK more than 10 times compared with VGN) may be suggested in patients with diffuse myalgia, muscle soreness or weakness and / or a pronounced increase in the activity of CPK. Tulip therapy should be discontinued if there is a pronounced increase in CPK activity or in the presence of confirmed or suspected myopathy. With the use of other HMG Co-reductase inhibitors (statins), myopathy may be increased while being used with cyclosporine, fibrates, erythromycin, nicotinic acid in lipid-lowering (more than 1 g / day) or antifungal drugs of the azoles group. When using Tulip in combination with fibrates, erythromycin, immunosuppressants, antifungals of the azoles group or nicotinic acid in lipid-lowering doses (more than 1 g / day), it is necessary to weigh the expected benefits and the risk from treatment with Tulip. I have rarely reported cases of immune-mediated infections. time or after treatment with statins, including atorvastatin. Immune-mediated necrotizing myopathy is clinically characterized by muscle weakness in the upper extremities and an increase in plasma CPK concentration that persists despite discontinuation of treatment with statins. If necessary, combination therapy should consider using these drugs in lower initial and maintenance doses. Periodic monitoring of CPK activity is recommended. Combined use of atorvastatin and fusidic acid is not recommended, therefore, temporary discontinuation of atorvastatin therapy during the use of fusidic acid should be considered. Patients should be warned that they should immediately consult a doctor if unexplained pain or muscle weakness, especially , if they are accompanied by malaise or fever. When using the drug Tulip, as well as other HMG-Co-reductase inhibitors (statins), described us Rare cases of rhabdomyolysis with acute renal failure caused by mioglobinuriey.Pri possible symptoms of myopathy or presence of renal failure risk factors in the background of rhabdomyolysis (eg,severe acute infection, arterial hypotension, extensive surgery, trauma, serious metabolic, electrolyte and endocrine disorders and uncontrolled seizures) Tulip therapy should be stopped or completely canceled. with prolonged therapy. Clinical manifestations include shortness of breath, unproductive cough, and worsening of general health (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin treatment should be stopped. Diabetes mellitus Some studies have shown that the use of statins as a class can lead to an increase in blood glucose concentration, and in some patients with an increased risk of developing diabetes can cause hyperglycemia, which requires standard anti-diabetic therapy. However, this risk is insignificant compared with a decrease in vascular risk when taking statins, and, therefore, should not be a cause of discontinuation of treatment with statins. Patients at risk (with a fasting glucose concentration of 5.6–6.9 mmol / l, a BMI greater than 30 kg / m2, elevated triglycerides, elevated blood pressure) should be controlled, both clinical and biochemical, in accordance with national standards of care. Impact on the ability to drive vehicles and control mechanisms. During the period of treatment with Tulip, care must be taken when driving and taking on other potentially hazardous activities that require There is no specific antidote for the treatment of overdose. In case of overdose, symptomatic treatment should be carried out. Hemodialysis is not effective (because the drug is significantly associated with plasma proteins).