Amvastan 20 mg tablets # 30

Author Ольга Кияница

2017-05-11

Amount in a package 30
Product form Pills
Manufacturer Bilim Pharmaceuticals (Turkey)
Registration certificate UA/7376/01/02
The main medicament Amvastan
morion code 331960

Amvastan (AMVASTAN) instructions for use

Composition

active ingredient: atorvastatin; 1 tablet contains atorvastatin calcium 10,338 mg 20,675 mg, or 41,35 mg, or 82,7 mg, equivalent to 10 mg or 20 mg, or 40 mg or 80 mg of atorvastatin;
auxiliary substances: polysorbate; hydroxypropyl cellulose; calcium carbonate; cellulose microcrystalline lactose monohydrate, sodium croscarmellose; magnesium stearate color white Opadry YS-1-7040 White (dye composition: hypromellose, polyethylene glycol, titanium dioxide (E 171), talc).

Dosage form

Film-coated tablets.

Basic physical and chemical properties:

for 10 mg, 20 mg and 40 mg: white, oblong, biconvex tablets, film-coated
for 80 mg: white, oblong, biconvex tablets, film-coated, labeled "bilim" on one side.

Pharmacological group

Drugs that lower the level of cholesterol and triglycerides in the blood serum. Inhibitors of HMG-CoA reductase.ATX Code C10A A05.

Pharmacological properties

Pharmacodynamics.

Amvastane is a synthetic lipid-lowering drug. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA into mevalonate, the early stage of cholesterol biosynthesis, which limits the rate of its formation.

Amvastane is a selective competitive inhibitor of HMG-CoA reductase, an enzyme on which the rate of conversion of 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, the precursor substance of sterols, including cholesterol, depends.Cholesterol and triglycerides circulate in the bloodstream in a complex with lipoproteins. These complexes are separated by ultracentrifugation into high density lipoprotein (HDL) fractions, intermediate density lipoproteins, LDL (low density lipoproteins) and VLDLP (very low density lipoproteins). Triglycerides (TG) and cholesterol in the liver are included in the VLDL and released into the blood plasma for transport to peripheral tissues. LDL are formed by VLDL and are catabolized by interaction with high-affinity LDL receptors. There have been reports of clinical and pathoanatomical studies that show that elevated levels of total cholesterol (OX), LDL cholesterol (LDL-C) and apolipoprotein B (apo B) in the blood plasma contribute to the development of atherosclerosis in humans and are risk factors for the development of cardiovascular disease, cardiovascular disease, while elevated HDL cholesterol levels are associated with a reduced risk of cardiovascular disease.

In experimental models in animals, Amvastan lowers cholesterol and lipoprotein levels in the plasma by inhibiting the HMG-CoA reductase and cholesterol in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance absorption and catabolism of LDL; Amvastane also reduces the production of LDL and the amount of these particles. Amvastane reduces the level of LDL cholesterol in some patients with homozygous familial hypercholesterolemia, that is, groups of people who rarely respond to treatment with other lipid-lowering medications.

There are reports of numerous clinical studies that have shown that elevated levels of total cholesterol, LDL cholesterol and apo B (a membrane complex for LDL cholesterol) provoke the development of atherosclerosis. Likewise, the levels of HDL cholesterol (and its transport complex - a for A) are lowered due to the development of atherosclerosis.Epidemiological studies have established that cardiovascular morbidity and mortality change in direct proportion to the level of total cholesterol and LDL cholesterol and inversely proportional to the level of HDL cholesterol.

Amvastan reduces the level of total cholesterol, LDL cholesterol and apo B in patients with homozygous and heterozygous familial hypercholesterolemia, non-family forms of hypercholesterolemia, and mixed dyslipidemia.Amvastane also reduces cholesterol levels in VLDL and TG, and also leads to an unstable increase in HDL cholesterol and apolipoprotein A-1. Amvastan reduces total cholesterol, LDL cholesterol, VLDLP cholesterol, apo B, triglycerides and cholesterol-lowering HDL-C, and also increases HDL cholesterol in patients with isolated hypertriglyceridemia.Amvastan reduces cholesterol lowering in patients with disbetalipoproteinemia.

Like LDL, lipoproteins enriched with cholesterol and triglycerides, including VLDL, LTR and residues, can also contribute to the development of atherosclerosis. Elevated levels of triglycerides in the blood plasma are often found in a triad with low levels of HDL cholesterol and small slices of LDL, and in combination with non-lipid metabolic risk factors for coronary heart disease. It has not been consistently proven that the total plasma triglyceride level as such is an independent risk factor for the development of coronary heart disease. In addition, an independent effect of increasing the level of HDL cholesterol or lowering the level of triglycerides on the risk of coronary and cardiovascular morbidity and mortality was established.

Amvastane, like some of its metabolites, is pharmacologically active in humans. The main place of action of atorvastatin is the liver, which plays a major role in the synthesis of cholesterol and the clearance of LDL. The dose of the drug, in contrast to the systemic concentration of the drug, better correlates with a decrease in the level of LDL cholesterol.Individual dose selection should be performed depending on the therapeutic response (see Section "Method of administration and dose").

Pharmacokinetics.

Suction. Amvastan is rapidly absorbed after oral intake and its maximum concentration in blood plasma is reached within 1-2 hours. The degree of absorption increases in proportion to the dose of Amvastan. The bioavailability of atorvastatin (the starting drug) is approximately 14%, and the systemic bioavailability of the inhibitory activity against HMG-CoA reductase is approximately 30%. Low system availability of the drug is associated with pre-systemic clearance in the mucosa of the gastrointestinal tract and / or pre-system biotransformation in the liver. Although food reduces the rate and extent of drug absorption by about 25% and 9%, respectively, based on C max and AUC, lowering LDL cholesterol is similar regardless of whether Amvastan is taken with food or separately. When using atorvastatin in the evening, its concentration in the blood plasma is lower (about 30% for C max and AUC) than in the morning reception. However, the decrease in LDL cholesterol is the same regardless of the time of taking the drug (see Section "Method of administration and dose").

Distribution. The average volume of distribution of the drug Amvastan is approximately 381 liters. More than 98% of the drug binds to blood plasma proteins. The blood / plasma concentration ratio is approximately 0.25, indicating a poor penetration of the drug into the erythrocytes. Based on observations in rats it is believed that Amvastan is able to penetrate into breast milk (see Sections "Contraindications", "Use during pregnancy or lactation" and "Features of use").

Metabolism. Amvastane is extensively metabolized in ortho and para-hydroxylated derivatives and various beta-oxidation products. In vitro studies of inhibition of HMG-CoA reductase ortho and parahydroxylated metabolites is equivalent to inhibition by Amvastan. Approximately 70% of the circulating inhibitory activity against HMG-CoA reductase is associated with active metabolites. In vitro studies indicate the importance of the metabolism of Amvastan cytochrome P450 3A4, which is consistent with increased concentrations of Amvastan in human blood plasma after simultaneous use with erythromycin, a known inhibitor of this enzyme (see Section "Interaction with other drugs").

Excretion. Amvastane and its metabolites are excreted mainly with bile after hepatic and / or extrahepatic metabolism, but this drug obviously does not experience gastrohepatic recirculation. The half-life of Amvastan from human plasma is approximately 14 hours, but the period of substitution of inhibitory activity against HMG-CoA reductase is from 20 to 30 hours through the contribution of active metabolites. After taking the drug with urine, less than 2% of the dose is released.

Patient populations

Patients of advanced age. The concentration of Amvastan in plasma is higher (about 40% for Cmax and 30% for AUC) in healthy elderly patients (over 65 years) than in young adults. Published data on clinical trials indicate a greater degree of lowering of LDL when using any dose of the drug in elderly patients compared with young people (see section "Features of application").

Children

Pharmacokinetic data for a group of patients of childhood are absent.

Floor. The concentration of Amvastan in women's blood plasma differs from that in blood plasma (about 20% higher for Cmax and 10% lower for AUC). However, there is no clinically significant difference in the reduction of LDL cholesterol when using Amvastan in men and women.

The time of the kidney function. Kidney disease does not affect the concentration of the drug Amvastan in blood plasma or a decrease in LDL cholesterol, and, consequently, correction of the dose of the drug for patients with impaired renal function is not required (see Sections "Method of administration and dose", "features of application").

Hemodialysis. Despite the fact that patients with terminal stage of kidney disease have not been studied, it is believed that hemodialysis does not significantly increase the clearance of Amvastane, since the drug binds intensely to plasma proteins.

Liver failure. The concentration of Amvastan in plasma is markedly increased in patients with chronic alcoholic liver disease. The values of Cmax and AUC are 4 times higher in patients with class A liver disease on the Child-Pugh scale.In patients with liver disease class on the Child-Pugh scale, the values of Cmax and AUC increase approximately 16-fold and 11-fold, respectively (see Section "Contraindications").

Table 1.

The effect of concurrently used drugs on the pharmacokinetics of atorvastatin

Simultaneously used drugs and dosing regimen Atorvastatin
Dose (mg) Change in AUC * Change C max *
** Cyclosporine 5.2 mg / kg / day, stable dose 10 mg once daily for 28 days 8.7 times 10.7 times
** Tipranavir 500 mg twice daily / ritonavir 200 mg twice daily, 7 days 10 mg of RD 9.4 times 8.6 times
** Telaprevir 750 mg every 8:00, 10 days 20 mg of RD 7,88 times 10.6 times
**, ****** Saquinavir 400 mg twice daily / ritonavir 400 mg twice daily, 15 days 40 mg once a day for 4 days 3.9 times 4.3 times
** Clarithromycin 500 mg twice daily, 9 days 80 mg once a day for 8 days 4.4 times 5,4 times
** Darunavir 300 mg twice daily / ritonavir 100 mg twice daily, 9 days 10 mg once a day for 4 days 3,4 times 2.25 times
** Itraconazole 200 mg 1 time / day, 4 days 40 mg of RD 3.3 times 20%
** Fosamprenavir 700 mg twice daily / ritonavir 100 mg twice daily, 14 days 10 mg once a day for 4 days 2.53 times 2.84 times
** Fosamprenavir 1400 mg 2 times a day, 14 days 10 mg once a day for 4 days 2.3 times 4.04 times
** Nelfinavir 1250 mg 2 times a day, 14 days 10 mg once a day for 28 days 74% 2.2 times
** Grapefruit juice, 240 ml once a day *** 40 mg once a day 37% 16%
Diltiazem 240 mg once a day, 28 days 40 mg once a day 51% without change
Erythromycin 500 mg 4 times a day, 7 days 10 mg once a day 33% 38%
Amlodipine 10 mg, single dose 80 mg once daily 15% 12%
Cimetidine 300 mg once a day, 4 weeks 10 mg once a day for 2 weeks ¯ Less than 1% eleven%
Colestipol 10 mg twice daily, 28 weeks 40 mg once a day for 28 weeks indefined ¯ 26% ****
Maalox TC 30 ml once a day, 17 days 10 mg once a day for 15 days ¯ 33% ¯ 34%
Efavirenz 600 mg once a day, 14 days 10 mg for 3 days ¯ 41% 1%
** Rifampin 600 mg once a day, 7 days (with simultaneous administration) ***** 40 mg once a day thirty% 2.7 times
** Rifampin 600 mg once a day, 5 days (in separate doses) ***** 40 mg once a day ¯ 80% ¯ 40%
** Gemfibrozil 600 mg twice daily, 7 days 40 mg once a day 35% ¯ Less than 1%
** Fenofibrate 160 mg once a day, 7 days 40 mg once a day 3% 2%
** Boceprivir 800 mg 3 times a day, 7 days 40 mg once a day 2.30 times 2.66 times

* Data indicated as a change of x times is a simple relationship between cases of simultaneous use of drugs and the use of only atorvastatin (i.e., 1-fold = unchanged). The data indicated in the% change are% the difference in the ratio of the indices when using atorvastatin alone (i.e., 0% = unchanged).

** For information on clinical significance, see the sections on "Features of Use" and "Interaction with Other Drugs and Other Interactions".

*** A large increase in AUC (up to 2.5 times) and / or C max (up to 71%) was reported with excessive consumption of grapefruit juice (0.75-1.2 liters per day or more).

**** Single sample, taken 8-16 hours after taking the drug.

***** The simultaneous use of atorvastatin with rifampin is recommended through the mechanism of double interaction of rifampin, as it was shown that the delayed use of atorvastatin after rifampin is associated with a significant decrease in concentrations of atorvastatin in the blood plasma.

****** The dose of saquinavir + ritonavir combination in this study is not a clinically applicable dose. Increasing the exposure of atorvastatin when used in clinical settings is likely to be higher than that observed in this study. Therefore, it is necessary to use the drug with caution in a low required dose.

Table 2.

The effect of atorvastatin on the pharmacokinetics of concomitantly used drugs

Atorvastatin Simultaneously, the drug used and the dosing regimen
The drug / dose (mg) AUC change Changing Cmax
80 mg once a day for 15 days Antipyrine, 600 mg once a day 3% ↓ 11%
80 mg once a day for 14 days ** Digoxin 0.25 mg once a day, 20 days 15% 20%
40 mg once a day for 22 days Oral contraceptives once a day, 2 months

    • norethisterone 1 mg
    • ethinylestradiol 35 μg
28%

19%
23%

thirty%
10 mg once daily Tipranavir 500 mg twice daily / ritonavir 200 mg 2 times a day, 7 days without change without change
10 mg once a day for 4 days Fosamprenavir 1400 mg 2 times a day, 14 days ¯ 27% 18%
10 mg once a day for 4 days Fosamprenavir 700 mg twice daily / ritonavir 100 mg twice daily, 14 days without change without change

** For information on clinical significance, see "Interaction with Other Drugs and Other Interactions".

Indications

Prevention of cardiovascular disease

For adults without clinically severe coronary heart disease, but with several risk factors for developing coronary heart disease, such as age, smoking, hypertension, low HDL cholesterol, or the presence of an early ischemic heart disease in a family history, Amvastan is indicated for:

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

For patients with type II diabetes and without clinically severe coronary heart disease, but with several risk factors for developing coronary heart disease, such as retinopathy, albuminuria, smoking or hypertension, Amvastan is indicated for:

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

For patients with clinically severe ischemic heart disease, Amvastan is indicated for:

  • decrease in the risk of non-lethal myocardial infarction
  • reduction in the risk of lethal and non-lethal stroke;
  • reducing the risk of revascularization procedures;
  • reduction in the risk of hospitalization due to congestive heart failure,
  • reduction in the risk of angina pectoris.

Hyperlipidemia

In addition to diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides, and also to increase HDL cholesterol in patients with primary hypercholesterolemia (heterozygous familial and non-family) and mixed dyslipidemia (type IIa and IIb according to Fredrickson classification) .

As a supplement to the diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson type IV).

For the treatment of patients with primary dysbetalipoproteinemia (type III according to Fredrikson's classification), in cases when diet compliance is not effective enough.

In order to reduce total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

As an adjunct to diet to reduce total cholesterol, LDL cholesterol and apolipoprotein B in boys and girls after the onset of menstruation at the age of 10 to 17 years with heterozygous familial hypercholesterolemia if after an appropriate test results of diet therapy are as follows:

a) ³ LDL cholesterol is 190 mg / dl or

b) ³ LDL cholesterol 160 mg / dl:

family history, there are early heart disease or two or more other risk factors for cardiovascular disease are present in childhood patients.

Contraindications

Active liver disease, which can include sustained increase in liver transaminases of unknown etiology.

Hypersensitivity to any of the drug components.

Application features

Skeletal muscles

There have been rare reports of rhabdomyolysis with acute renal failure due to myoglobinuria Amvastan when using the drug and other drugs in this class. A history of renal dysfunction may be a risk factor for the development of rhabdomyolysis. Such patients need closer monitoring to detect violations of the skeletal muscles.

Atorvastatin, like other drugs of the statin group sometimes cause myopathy, defined as muscle pain or weakness of muscles in conjunction with an increase in CPK indicators (CK) more than 10 times the upper limit of normal. The simultaneous use of high doses of atorvastatin with certain drugs such as cyclosporin and potent inhibitors of CYP3A4 (e.g. clarithromycin, itraconazole and HIV protease inhibitors) increases the risk of myopathy / rhabdomyolysis.

There have been rare reports of an immunologically mediated necrotising myopathy (IONM) - autoimmune myopathy associated with statin use. IONM is characterized by the following features: proximal muscle weakness and elevated levels of creatine kinase in the blood serum, which persist despite discontinuation of statin therapy; Muscle biopsy reveals necrotizing myopathy without significant inflammation; the application of immunosuppressive agents observed a positive trend.

The possibility of developing myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness, and / or a significant increase in CPK. Patients should be advised to immediately report cases of muscle pain, tenderness, or weakness of the muscles of unknown etiology, particularly if it is accompanied by a feeling of malaise or fever or if signs and symptoms of muscle disease persist after discontinuation of the drug Amvastan. Treatment should be discontinued in case of increase of CPK, diagnosis or suspicion of myopathy.

The risk of myopathy during treatment with this class of drugs is increased while the use of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, protease inhibitors of hepatitis C virus telaprevir, combinations of HIV protease inhibitors, including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir, and fosamprenavir + ritonavir, and niacin or antimycotic azole group. Doctors who are considering the possibility of combination drug therapy Amvastan and fibric acid derivatives, erythromycin, clarithromycin, combinations saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, antimycotics group azoles or lipidomodifitsiruyuschey doses of niacin should carefully weigh the potential benefits and risksand carefully monitor the condition of patients for any signs or symptoms of pain, tenderness, or weakness in the muscles, especially in the initial months of therapy and during any periods of dose titration in the direction of increase of any of the drugs. Should consider the use of low initial and maintenance doses of atorvastatin while taking the above drugs (see. Section "interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.especially in the initial months of therapy and during any periods of dose titration in the direction of increasing any of the drugs. Should consider the use of low initial and maintenance doses of atorvastatin while taking the above drugs (see. Section "interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.especially in the initial months of therapy and during any periods of dose titration in the direction of increasing any of the drugs. Should consider the use of low initial and maintenance doses of atorvastatin while taking the above drugs (see. Section "interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.CATEGORY "Interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.CATEGORY "Interaction with other drugs and other types of interactions"). In such situations, it may be considered for periodic determination of CK, but there is no assurance that such monitoring will prevent cases of severe myopathy.

It reported cases of myopathy, including rhabdomyolysis, while the use of atorvastatin with colchicine, so atorvastatin with colchicine should be administered with caution to patients (see. Section "Interaction with other medicinal products and other forms of interaction").

Therapy Amvastan should be temporarily or permanently discontinued in any patient with an acute, serious condition, it indicates the development of myopathy, or if there is a risk factor for renal disease development due to rhabdomyolysis (eg severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

Impaired liver function

It has been shown that statins as hypolipidemic and some other therapeutic agents associated with abnormal biochemical indicators of liver function.

Before starting therapy with Amvastan, it is recommended to get the results of analyzes of the liver enzymes to be tested again in the case of clinical need. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking drugs of statins, including atorvastatin. In case of severe liver disease with clinical symptoms and / or hyperbilirubinaemia or jaundice should be stopped immediately when applying Amvastan preparation. If an alternate etiology is not defined, do not re-start the treatment with the drug.

Amvastan should be used with caution in patients taking significant amounts of alcohol and / or have a history of liver disease. Amvastan contraindicated with active liver disease or persistent elevations in liver transaminases of unknown etiology (see. Section: "Contra ').

endocrine function

It reported an increased level of HbA1c concentration and serum fasting glucose when using the HMG-CoA reductase inhibitors, including Amvastan preparation.

Statins inhibit cholesterol synthesis and theoretically may reduce the secretion of adrenal and / or gonadal steroids. There are reports of clinical studies, which showed that Amvastan does not reduce basal plasma cortisol concentration and does not damage the adrenal reserve. The effect of statins on sperm fertilizing ability have not investigated in a sufficient number of patients. It is not known how the drug affects, and indeed affects the system "sex glands-pituitary-hypothalamus" in women in the premenopausal period. Caution must be exercised while the use of the drug with the statin drugs, which may reduce the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.

The use in patients with recent cases of stroke or transient ischemic attack

There are reports of increased incidence of non-fatal hemorrhagic stroke when using atorvastatin. Reported increased incidence of fatal hemorrhagic stroke with no use of atorvastatin.

There was no no general differences in safety and efficacy between elderly patients and younger patients, but greater sensitivity can not exclude some older patients. Since older age (65 years) is a factor of predisposition to myopathy, should be used with caution in elderly Amvastan.

Liver failure

Amvastan contraindicated in patients with active liver disease, including persistent elevation of liver transaminases of unknown etiology (see. Sections "Contra" and "Pharmacological properties").

Prior to treatment

Atorvastatin should be used with caution in patients with a propensity for the development of rhabdomyolysis. Prior to initiating treatment with statins in patients who are prone to the development of rhabdomyolysis, should determine the level of the Criminal Code when:

  • impaired renal function
  • hypothyroidism;
  • hereditary muscular system disorders in a family history or personal
  • endured in the past cases, the toxic effects of statins or fibrates in the muscles;
  • endured in the past liver disease and / or use of large amounts of alcohol.

For elderly patients (over 70 years), the need for these measures should be evaluated taking into account the presence of other factors predisposing to the development of rhabdomyolysis.

Increasing the plasma level of the drug may, in particular, in the case of interaction and the application of special populations of patients, including patients with hereditary diseases.

In such cases it is advisable to evaluate the ratio of risk and potential benefit from the treatment and to conduct clinical monitoring of patients. If CC before treatment level significantly increased (BMH exceeds more than 5 times), the treatment should not begin.

Measurement of CK

CPK levels should not be determined after intense exercise or in the presence of any possible alternative causes of increased levels of the Criminal Code, as it may complicate the interpretation of the results. If a significant increase in the Criminal Code (exceeding the upper limit of normal in more than 5 times) was observed at the initial level, then after 5-7 days it is necessary to re-determination to confirm the result.

During treatment

Patients should be aware of the need to immediately report on the development of muscle pain, court or weakness, particularly if accompanied by malaise or fever.

In case of these symptoms during treatment with atorvastatin is necessary to determine the level of QC in this patient. If CC level is significantly elevated (BMH exceeds more than 5 times), treatment should cease.

The expediency of treatment discontinuation should also be considered, if the rise of the Criminal Code does not reach the level of fivefold excess capital punishment, but by muscle symptoms are severe in nature and every day can become a cause of discomfort.

After the disappearance of symptoms and normalization CC level can consider resuming atorvastatin or alternative start of treatment with statins provided use the lowest possible dose and careful monitoring of the patient.

Treatment with atorvastatin should be discontinued if there is a clinically significant increase in the level of the Criminal Code (exceeding the upper limit of normal in more than 10 times) or in the case of diagnosis of rhabdomyolysis (or suspected rhabdomyolysis).

The simultaneous use of other drugs

The risk of rhabdomyolysis is increased while the application of atorvastatin with certain drugs which can increase the concentration of atorvastatin in plasma. Examples of such drugs can act potent inhibitors of CYP3A4 or transport proteins cyclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir. While the use of gemfibrozil and other fibric acid derivatives, erythromycin, niacin and ezetimibe as the risk of myopathy. If possible, it is necessary to use other drugs (not interact with atorvastatin) instead of the above.

If you want to carry out simultaneous treatment with atorvastatin and mentioned drugs should carefully weigh the benefits and risks of simultaneous treatment. If patients are taking medicines that increase the concentration of atorvastatin in plasma, it is recommended to reduce the dose of atorvastatin to a minimum. Furthermore, in the case of strong CYP3A4 inhibitors should consider the possibility of using a lower initial dose of atorvastatin. It is also recommended to carry out a proper clinical monitoring of the condition of these patients.

It is not recommended to appoint both atorvastatin and fusidic acid, so it is worth considering the possibility of temporary suspension of atorvastatin during fusidic acid treatment.

Interstitial lung disease

During treatment certain statins (especially during long-term treatment) were disclosed exceptional cases of interstitial lung disease. By manifestations of the disease may include dyspnea, nonproductive cough and general health deterioration (fatigue, weight loss and fever). In the event of a suspicion of interstitial lung disease should discontinue treatment with statins.

fillers

The composition of the drug Amvastan includes lactose. This drug should not be taken to patients with rare hereditary diseases associated with galactose intolerance, Lappease lactase deficiency, or malabsorption of glucose-galactose.Therapy lipidomodifikatsiiimy drugs should be one of the components of complex therapy for patients with a significantly increased risk of atherosclerotic vascular disease through hypercholesterolemia. Drug therapy is recommended as a supplement to a diet, when the result of adherence to a diet that restricts the intake of saturated fats and cholesterol, as well as from the use of other non-medicament measures was not enough. Patients with coronary heart disease or several risk factors for developing coronary heart disease can receive Amvastan along with a diet.

Restriction of use

There is no data on the use of Amvastan in conditions where the main deviation from the norm from lipoproteins is an increase in the level of chylomicrons (types I and V according to Fredrikson's classification).

Interaction with other drugs and other interactions

The risk of developing myopathy during statin treatment is increased when concomitant use of fibrolic acid derivatives, lipidomodification doses of niacin, cyclosporine, or potent inhibitors of CYP 3A4 (eg clarithromycin, HIV protease inhibitors and itraconazole) (see Sections "Features of Use" and "Pharmacological Properties"). .

Powerful inhibitors of CYP 3A4. Amvastan is metabolized by cytochrome P450 3A4. Simultaneous use of Amvastan with powerful CYP 3A4 inhibitors can lead to an increase in the concentration of atorvastatin in the blood plasma (see Table 3 and detailed information below). The degree of interaction and enhancement of action depends on the variability of the effect on CYP 3A4. If possible, simultaneous use with potent inhibitors of CYP3A4 should be avoided (for example, with cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir). If simultaneous use of these drugs with atorvastatin can not be avoided, consideration should be given to the use of lower initial and maximum doses of atorvastatin. It is also recommended that proper clinical monitoring of the patient's condition be performed (see Table 3).

Moderate inhibitors of CYP3A4 (eg erythromycin, diltiazem, verapamil and fluconazole) can increase the concentration of atorvastatin in blood plasma (see Table 3). Simultaneous use of erythromycin and statins is accompanied by an increased risk of myopathy. The study of the interaction of drugs to assess the effect of amiodarone or verapamil on atorvastatin was not conducted. It is known that amiodarone and verapamil suppress the activity of CYP3A4, and consequently, the simultaneous administration of these drugs with atorvastatin may lead to an increase in exposure to atorvastatin. Thus, with the simultaneous use of atorvastatin and these moderate inhibitors of CYP3A4, consideration should be given to the possibility of assigning smaller maximum doses of atorvastatin. Clinical monitoring of the patient's condition is also recommended. After starting treatment with an inhibitor or after adjusting its dose, it is recommended to conduct clinical monitoring of the patient's condition.

Grapefruit juice. Contains one or more components that inhibit CYP 3A4 and can increase the concentration of atorvastatin in the blood plasma, especially with excessive consumption of grapefruit juice (more than 1.2 liters per day).

Clarithromycin. The value of AUC of atorvastatin increased significantly with the simultaneous use of Amvastan at a dose of 80 mg and clarithromycin (500 mg twice daily) compared with the use of Amvastane alone (see Section "Pharmacological properties"). So, patients who take clarithromycin should use caution with Amvastan at a dose of 20 mg (see Sections "Features of application" and "Method of administration and dose").

Combination of protease inhibitors. The value of AUC of atorvastatin increased significantly when Amvastane was used simultaneously with several combinations of HIV protease inhibitors, as well as with the protease inhibitor of hepatitis C virus, telaprevir, compared with the use of Amvastan alone (see Section "Pharmacological properties"). Therefore, for patients taking a protease inhibitor tipranavir + ritonavir or a protease inhibitor of hepatitis C virus, telaprevir, simultaneous use with Amvastan should be avoided. The drug should be administered with caution to patients who take the HIV protease inhibitor lopinavir + ritonavir and apply it in the most appropriate dose. For patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir, the dosage of Amvastan should not exceed 20 mg and be administered with caution (see Sections "Features of Use" and "Dosage and Administration") for patients taking HIV protease inhibitors. When using nelfinavir or a hepatitis C protease inhibitor bocheprivir in patients taking a protease inhibitor HIV, the dose of Amvastan should not exceed 40 mg, and careful clinical monitoring of patients is recommended.

Itraconazole. The value of AUC of atorvastatin increased significantly with the simultaneous use of Amvastan in a dose of 40 mg and itraconazole at a dose of 200 mg (see Section "Pharmacological properties"). Thus, patients taking itraconazole should be careful if the dose of Amvastan exceeds 20 mg (see Sections "Features of application" and "Method of administration and dose").

Cyclosporine. Atorvastatin and its metabolites are the substrates of the OATP1B1 transporter. Inhibitors of OATP1B1 (eg, cyclosporin) may increase the bioavailability of atorvastatin. The value of AUC of atorvastatin increased significantly with the simultaneous use of Amvastan at a dose of 10 mg and cyclosporine at a dose of 5.2 mg / kg / day compared to the use of Amvastane alone (see Section "Pharmacological properties"). It is necessary to avoid the simultaneous use of Amvastane and cyclosporine (see section "Features of application").

Medical recommendations for the use of medications interacting are summarized in Table 2 (see also the sections "Dosing and Administration", "Features of Use", "Pharmacological Properties").

Table 3.

Drug interactions associated with an increased risk of myopathy / rhabdomyolysis

Preparations interact Medical recommendations for use
Cyclosporine, HIV protease inhibitors (tipranavir + ritonavir), hepatitis C virus protease inhibitor (telaprevir) Avoid the use of atorvastatin
The HIV protease inhibitor (lopinavir + ritonavir) Use with caution and in lesser dosage
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir + ritonavir * darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir) Exceed the dose of 20 mg of atorvastatin per day

HIV protease inhibitor (nelfinavir)

The protease inhibitor of the hepatitis C virus (bocetrevir)

Exceed the dose of 40 mg of atorvastatin per day

* Use with caution and in lesser dosage.

Gemfibrozil. In view of the increased risk of myopathy / rhabdomyolysis with concomitant administration of HMG-CoA reductase inhibitors with gemfibrozil, joint use of Amvastan with gemfibrozil should be avoided (see "Features of use" section).

Other fibrates. Since it is known that the risk of developing myopathy during treatment with HMG-CoA reductase inhibitors is increased with simultaneous administration of other fibrates, Amvastane should be used with caution when used in conjunction with other fibrates (see Section "Features of Use").

Niacin. The risk of side effects from skeletal muscles may increase when used in combination with niacin, and therefore, under such conditions, the possibility of reducing the dose of Amvastan should be considered (see Section "Application Features").

Rifampicin or other inducers of cytochrome P450 3A4. Simultaneous use of the drug with cytochrome P450 3A4 inducers (eg efavirenz, rifampicin) can lead to an unstable decrease in the concentration of atorvastatin in the blood plasma. Through the mechanism of double interaction of rifampin, the simultaneous use of Amvastan with rifampin is recommended, since it has been shown that the delayed use of the drug after administration of rifampin is associated with a significant decrease in the concentrations of atorvastatin in the blood plasma.

Diltiazema hydrochloride. Simultaneous administration of atorvastatin (40 mg) and diltiazem (240 mg) is accompanied by an increase in the concentration of atorvastatin in blood plasma.

Cimetidine. As a result of the studies, no signs of interaction between atorvastatin and cimetidine have been identified.

Antacids. Simultaneous oral administration of atorvastatin and a suspension of an antacid preparation containing magnesium and aluminum hydroxide is accompanied by a decrease in the concentration of atorvastatin in blood plasma by 35%. In this case, the hypolipidemic effect of atorvastatin is unchanged.

Kolestipol. The concentration of atorvastatin in the blood plasma is lower (by approximately 25%) with concurrent administration of atorvastatin and colestipol. In this case, the hypolipidemic effect of the combination of atorvastatin and colestipol exceeded the effect that gives the reception of each of these drugs separately.

Azithromycin. Simultaneous administration of atorvastatin (10 mg once a day) and azithromycin (500 mg once a day) was not accompanied by changes in the concentration of atorvastatin in the blood plasma.

Inhibitors of transport proteins. Inhibitors of transport proteins (eg, cyclosporin) are able to increase the level of systemic exposure to atorvastatin (see Table 3). The effect of inhibition of storage transport proteins on the concentration of atorvastatin in the liver cells is unknown. If simultaneous administration of these drugs is not possible, a dose reduction and clinical monitoring of the efficacy of atorvastatin is recommended (see Table 3).

Ezetimibe. The use of ezetimibe as monotherapy is associated with the development of phenomena from the muscular system, including rhabdomyolysis. Thus, with the simultaneous use of ezetimibe and atorvastatin, the risk of developing these phenomena increases. It is recommended to conduct proper clinical monitoring of the condition of such patients.

Fusidic acid. The interaction of atorvastatin and fusidic acid has not been studied. As in the case of other statins, in the postmarketing period with the simultaneous administration of atorvastatin and fusidic acid, phenomena from the muscular system (including rhabdomyolysis) were observed. The mechanism of this interaction remains unknown.Patients need careful monitoring; temporary suspension of treatment with atorvastatin may be required.

Digoxin. With the simultaneous use of multiple doses of Amvastan and digoxin, the equilibrium concentrations of digoxin in the blood plasma are increased by about 20%. Properly monitor the condition of patients taking digoxin.

Oral contraceptives. Simultaneous use of Amvastan with oral contraceptives increased the AUC value for norethisterone and ethinylestradiol (see Section "Pharmacological properties"). These increases should be considered when choosing an oral contraceptive for a woman who takes Amvastane.

Warfarin. Amvastane did not have a clinically significant effect on prothrombin time when used in patients undergoing long-term treatment with warfarin.

Colchicine. With the simultaneous use of atorvastatin with colchicine, there have been reports of cases of myopathy, including rhabdomyolysis, so caution should be given to atorvastatin with colchicine.

Other medicines. There have been reports of clinical trials that showed that the simultaneous use of atorvastatin and antihypertensive drugs and their use during estrogen replacement therapy were not accompanied by clinically significant side effects. Studies of interaction with other drugs have not been conducted.

Use during pregnancy and lactation

Pregnancy.

Amvastan is contraindicated in pregnant women and women who may become pregnant. Statins can harm the fetus when administered to pregnant women. Amvastane can be used in women of reproductive age only if it is very unlikely that such patients will become pregnant and have been informed of potential risk factors. If a woman becomes pregnant during the treatment period for Amvastan, the drug should be stopped immediately and the patient should be re-advised on the potential risk factors for the fetus and the clinical benefit of continuing the drug during pregnancy is not known.

With a normal course of pregnancy, serum cholesterol and triglyceride levels increase. Admission of lipid-lowering drugs during pregnancy will not have a beneficial effect, since cholesterol and its derivatives are necessary for normal fetal development. Atherosclerosis is a chronic process, and, consequently, a break in taking lipid-lowering drugs during pregnancy should not have a significant effect on the results of long-term treatment of primary hypercholesterolemia.

Adequate and well-controlled studies of the use of atorvastatin during pregnancy have not been conducted. There were rare reports of congenital anomalies after intrauterine exposure to statins. In a prospective study of approximately 100 pregnancies in women treated with other statin drugs, the incidence of congenital fetal abnormalities, miscarriages and fetal deaths / stillbirths did not exceed the frequency expected for the general population. However, this study could only rule out a 3-4 fold increase in the risk of congenital fetal anomalies compared to the background frequency. In 89% of these cases, treatment began before pregnancy and stopped at I trimester after pregnancy was detected.

The period of breastfeeding.

It is not known whether atorvastatin penetrates breast milk, but it is known that a small amount of another drug of this class penetrates into breast milk. Since statins are potentially capable of causing serious adverse reactions in infants who are breastfeeding, women who need treatment with Amvastan should not breast-feed their infants (see Section "Contraindications").

The ability to influence the reaction rate when driving vehicles or other mechanisms

Has very little effect on the reaction rate when driving vehicles or working with other mechanisms.

Dosing and Administration

Hyperlipidemia (heterozygous family and non-family) and mixed dyslipidemia (type IIa and IIb according to Fredrickson classification)

The recommended initial dose of Amvastan is 10 or 20 mg once a day. For patients who require a significant reduction in LDL cholesterol (more than 45%), therapy can be started at a dosage of 40 mg once a day. The dosage range of the drug Amvastan is in the range of 10 to 80 mg once daily. The drug can be taken in a single dose at any time and regardless of food intake. Initial and maintenance doses of Amvastan should be selected individually depending on the purpose of treatment and response. After starting treatment and / or after titrating the dose of Amvastan, lipid levels should be analyzed for a period of 2 to 4 weeks and the dose adjusted accordingly.

Heterozygous familial hypercholesterolemia in pediatric patients (aged 10-17 years)

The recommended initial dose of Amvastan is 10 mg / day, the maximum recommended dose is 20 mg / day (doses exceeding 20 mg in this group of patients have not been studied). Doses of the drug should be selected individually in accordance with the recommended goal of treatment. The dose adjustment should be done at intervals of 4 weeks or more.

Homozygous familial hypercholesterolemia

The dose of Amvastane for patients with homozygous familial hypercholesterolemia ranges from 10 to 80 mg per day.Amvastane should be used as an adjunct to other lipid-lowering treatments (eg, LDL apheresis), or if lipid-lowering treatments are not available.

Simultaneous lipid-lowering therapy

Amvastane can be used with bile acid sequestrants. The combination of inhibitors of HMG-CoA reductase (statins) and fibrates should generally be used with caution (see Sections "Features of Use", "Interaction with Other Drugs and Other Interactions").

Dosing for patients with impaired renal function

Kidney disease does not affect either the concentration in the blood plasma, or the lowering of LDL cholesterol when using Amvastan; consequently, correction of the dose of the drug for patients with impaired renal function is unnecessary (see the sections "Features of application", "Pharmacokinetics").

Dosing for patients receiving cyclosporin, clarithromycin, itraconazole or certain protease inhibitors

Amvastan treatment should be avoided in patients receiving cyclosporin, or HIV protease inhibitors (tipranavir + ritonavir), or a viral protease inhibitor, Hepatitis C (telaprevir). Amvastan should be used with caution in patients with HIV who are taking lopinavir + ritonavir and apply the most necessary dose. Patients taking clarithromycin, itraconazole or in patients with HIV who take in combination with saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir, or fosamprenavir + ritonavir therapeutic dose Amvastan should limit the dose to 20 mg, and the required clinical examination is recommended for ensure the application of the smallest dose necessary Amvastan. Patients taking an HIV protease inhibitor nelfinavir or an inhibitor of HCV protease With boceprevir,Amvastan treatment should limit the dose to 40 mg, and holding the respective recommended clinical examinations to ensure application of the least required dose Amvastan (see. Section "Features of application" and "interaction with other drugs and other types of interactions").

Children

Known data on the safety and efficacy of atorvastatin in patients aged 10-17 years with heterozygous familial hypercholesterolemia in a controlled clinical trial of 6 months in adolescent boys and girls after the onset of menstruation. Patients who were treated with atorvastatin had overall shaped profile of adverse reactions in patients receiving placebo. Infectious diseases were the adverse events most frequently observed in both groups, regardless of the assessment of the causal link. In this group of patients we studied doses 20 mg. In this narrow, controlled trial found no significant effect of the drug on growth or sexual maturation of boys or girls in the duration of the menstrual cycle (see.CATEGORY "Dosage and administration"). Teenage girls should be consulted for suitable methods of contraception during the treatment with atorvastatin (see. Section "use during pregnancy and lactation" and "Application in certain patient groups").

No data on the use of atorvastatin in controlled clinical trials, which included adolescent patients or patients younger than 10 years.

There are reports of clinical efficacy of atorvastatin in doses up to 80 mg / day for 1 year, was evaluated in an uncontrolled study in patients with homozygous familial hypercholesterolemia, in which 8 pediatric patients were included (see. Section "homozygous familial hypercholesterolemia").

Overdose

Specific treatment of drug overdose Amvastan not. In the case of an overdose the patient should be treated symptomatically and apply supportive measures if necessary. For a high degree of binding of drug with plasma proteins should not expect a significant increase in drug clearance Amvastan via hemodialysis.

Adverse Reactions

There are reports of five of the most common side effects in patients receiving treatment with atorvastatin, which led to discontinuation of the drug: myalgia, diarrhea, nausea, increased alanine aminotransferase (ALT) and liver enzymes.

Also, adverse reactions, of which data are available include:

  • general disorders: malaise, pyrexia;
  • From the digestive system: abdominal discomfort, belching, flatulence, hepatitis, cholestasis,
  • on the part of the musculoskeletal system: musculoskeletal pain, fatigue muscles, neck pain, joint swelling, tendinopathy (sometimes difficult tendon rupture)
  • on the part of metabolism and nutrition: increased transaminases, abnormal liver function tests, increased levels of alkaline phosphatase in the blood, increased CPK activity, hyperglycemia;
  • on the part of the nervous system: nightmares;
  • The respiratory system: nose bleeding;
  • of the skin and its appendages: urticaria
  • by the organs of vision: blurred vision, blurred vision;
  • by hearing and balance organs: tinnitus
  • genitourinary: leykotsitouriya;
  • Reproductive system and breast: Gynecomastia.

The frequency of adverse reactions by frequency of occurrence is classified into categories often (> 1/100, <1/10), uncommon (> 1/1000, <1/100), rare (> 1/10000, <1/1000), very rare (<1/10000).

Violation of the nervous system: frequent headache Uncommon: dizziness, paresthesia, hypoesthesia, dysgeusia, amnesia rare: peripheral neuropathy.

Dysfunction of the gastrointestinal tract: constipation often infrequent pancreatitis, vomiting.

Impaired function of the musculoskeletal system and connective tissue: often joint pain, back pain uncommon: myopathy, myositis, rhabdomyolysis.

General disorders: Infrequent: asthenia, chest pain, peripheral edema, fatigue.

Metabolic disorders and nutritional: Infrequent hypoglycemia, weight gain, anorexia.

The liver and gall bladder: extremely rare: hepatic insufficiency.

On the part of the skin and connective tissues: skin rash, pruritus, alopecia rare angioneurotic edema, bullous dermatitis (including erythema multiforme), Stevens-Johnson syndrome and toxic epidermal necrolysis.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders: common: pain in the throat and larynx.

Disorders of the blood system and lymphatic system: Infrequent: thrombocytopenia.

Immune system disorders: allergic reactions often; are extremely rare: anaphylaxis.

Disorders of organs of vision: rarely blurred vision.

Changes in laboratory results: often: deviation liver function tests results, elevated blood CK infrequently positive content analysis of leukocytes in urine.

Shelf life

3 years.

Storage conditions

Stored in original package at a temperature not higher than 25 ° C in the reach of children.

Packaging

To 10 mg, 20 mg and 40 mg tablets in the blister 10, 3 blisters in a carton.
6 To 80 mg tablets in a blister, 5 blisters per box.

Category of leave

On prescription.


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