Atoris - instructions for use, doses, side effects, contraindications

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Dosage form: & nbspfilm-coated tablets

Composition:

1 tablet, film-coated, contains:

CORE

Active substance: 30 mg 60 mg 80 mg

Atorvastatin calcium 31.08 mg 62.16 mg 82.88 mg

(equivalent to atorvastatin) 30.00 mg 60.00 mg 80.00 mg

Excipients:

Lactose monohydrate 175.24 mg 350.49 mg 467.32 mg

Cellulose microcrystalline 52.50 mg 105.00 mg 140.00 mg

Giprolose 6.00 mg 12.00 mg 16.00 mg

Croscarmellose sodium 15.00 mg 30.00 mg 40.00 mg

Crospovidone, type A 15.00 mg 30.00 mg 40.00 mg

Polysorbate 80 0.68 mg 1.35 mg 1.80 mg

Sodium hydroxide 1.50 mg 3.00 mg 4.00 mg

Magnesium stearate 3.00 mg 6.00 mg 8.00 mg

Film Sheath:

* Opadrai II HP 85F28751 white 9.00 mg 18.00 mg 24.00 mg

* Foam II HP 85F28751 white consists of:

Polyvinyl alcohol 3.60 mg 7.20 mg 9.60 mg

Titanium dioxide (E171) 2.25 mg 4.50 mg 6.00 mg

Macrogol 3000 1.82 mg 3.64 mg 4.85 mg

Talc 1.33 mg 2.66 mg 3.55 mg

Description:

tablets 30 mg; Round, slightly biconcave tablets, covered with a film shell of white or almost white color, with a bevel.

tablets 60 mg: Oval, biconvex tablets covered with a film coating of white or almost white color.

tablets 80 mg: The capsule-shaped, biconvex tablets covered with a film shell of white or almost white color.

Pharmacotherapeutic group:Hypolipidemic agent - inhibitor of HMG-CoA reductase

Pharmacodynamics:

Atorvastatin is a lipid-lowering drug from the statin group.The main mechanism of action of atorvastatin is inhibition of the activity of 3-hydroxy-3-methylglutaryl-coenzyme A- (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid. This transformation is one of the early stages in the cholesterol synthesis chain in the body. The suppression of cholesterol by atorvastatin results in an increased reactivity of low-density lipoprotein (LDL) receptors in the liver, as well as in extrahepatic tissues. These receptors bind LDL particles and remove them from the blood plasma, which leads to a decrease in LDL cholesterol (LDL-C) in the blood.

The antisclerotic effect of atorvastatin is a consequence of its effect on the walls of blood vessels and blood components. Atorvastatin Suppresses the synthesis of isoprenoids, which are the growth factors of the cells of the inner shell of the vessels. Under the influence of atorvastatin, the endothelium-dependent dilatation of blood vessels improves, the content of LDL-C, apolipoprotein B, triglycerides decreases, high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A are increased.

Atorvastatin reduces the viscosity of the blood plasma and the activity of certain clotting factors and platelet aggregation. Due to this, it improves hemodynamics and normalizes the state of the coagulation system. HMG-CoA reductase inhibitors also have an effect on the metabolism of macrophages, blocking their activation and prevent plaque rupture.

Typically, the therapeutic effect of atorvastatin develops after two weeks of use of the drug Atoris®, and the maximum effect is achieved in four weeks.

Significantly reduces the risk of ischemic complications (including death from myocardial infarction) by 16%, the risk of re-hospitalization for angina, accompanied by signs of myocardial ischemia - by 26%.

Pharmacokinetics:

Atorvastatin absorption is high, approximately 80% is absorbed from the gastrointestinal tract. The degree of absorption and concentration in the blood plasma increase in proportion to the dose. The time of the maximum concentration (TC_m_ax)> on average, 1-2 hours. For women, the TC_m_ax is higher by 20%, and the area under the curve "concentration-time" (AUC) - lower by 10%. Differences in pharmacokinetics in patients by age and sex are insignificant and do not require dose adjustment.

In patients with alcoholic cirrhosis of the liver, the time to achieve TC_m_Oh in 16 times above the norm.Food slightly reduces the speed and duration of absorption of the drug (by 25 % and 9%, respectively), but the reduction in LDL cholesterol is similar to that of atorvastatin without food.

Bioavailability of atorvastatin is low (12%), systemic bioavailability of inhibitory activity against HMG-CoA reductase is 30%. Low systemic bioavailability is due to presystemic metabolism in the mucous membrane of the gastrointestinal tract and "first pass" through the liver.

The average volume of atorvastatin distribution is 381 liters. More than 98% of atorvastatin binds to plasma proteins. Atorvastatin does not penetrate the blood-brain barrier. It is metabolized mainly in the liver under the action of the isoenzyme ZA4 cytochrome P450 with the formation of pharmacologically active metabolites (ortho- and parahydroxylated metabolites, beta-oxidation products), which account for approximately 70% of the inhibitory activity against HMG-CoA reductase, for 20-30 hours.

The half-life (T1 / 2) of atorvastatin is 14 hours. It is excreted mainly with bile (does not undergo significant intestinal hepatic recirculation, is not excreted during hemodialysis). Approximately 46 % Atorvastatin is excreted through the intestine and less than 2 % - the kidneys.

Special patient groups

Children

Studies of pharmacokinetics in children have not been conducted.

Elderly patients

FROMmOh u AUC of the drug in elderly patients (over 65 years) by 40% and 30%, respectively, higher than those in adult patients of young age (of clinical importance).

Impaired renal function

Violation of the kidney function does not affect the concentration of atorvastatin in the blood plasma or its effect on lipid metabolism, so the dose change in patients with impaired renal function is not required.

Impaired liver function

The concentration of the drug is significantly increased (Cmah about 16 times, AUC approximately 11 times) in patients with alcoholic cirrhosis of the liver (class B according to the Child-Pugh classification).

Indications:

- Primary hypercholesterolemia (heterozygous familial and non-family hypercholesterolemia (type II according to Fredrickson);

- Combined (mixed) hyperlipidemia (IIa and IIb types by Fredrickson);

- Disbetalipoproteinemia (type III according to Fredrickson) (as a supplement to the diet);

- Family endogenous hypertriglyceridemia (type IV according to Fredrickson), resistant to diet;

- Homozygous familial hypercholesterolemia with insufficient effectiveness of diet therapy and other non-pharmacological methods of treatment;

- Prevention of cardiovascular diseases:

- Primary prophylaxis of cardiovascular complications in patients without clinical signs of IHD, but having several risk factors for its development: age over 55, nicotine dependence, arterial hypertension, diabetes mellitus, low HDL-C level in blood plasma, genetic predisposition, including against dyslipidemia;

- Secondary prophylaxis of cardiovascular complications in patients with ischemic heart disease in order to reduce the total death rate, myocardial infarction, stroke, re-hospitalization for angina pectoris and the need for revascularization.

Contraindications:

- Hypersensitivity to any of the components of the drug;

- liver disease in the active stage (including active chronic hepatitis, chronic alcoholic hepatitis); liver failure; cirrhosis of the liver of any etiology;

- increased activity of "hepatic" transaminases of unknown origin more than 3 times compared with the upper limit of the norm;

- diseases of skeletal muscles;

- pregnancy and the period of breastfeeding;

- age to 18 years (effectiveness and safety of application not established);

- Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Carefully:Alcoholism, liver disease in the anamnesis.

Pregnancy and lactation:

The drug Atoris® is contraindicated in pregnancy and during breastfeeding. The results of animal studies suggest that the risk to the fetus may exceed any possible benefit to the mother.

In women of reproductive age who do not use reliable methods of contraception, the use of Atoris® is not recommended. When planning pregnancy, it is necessary to stop using Atoris® at least 1 month before the planned pregnancy.

There is no information about the isolation of atorvastatin with breast milk. However, in some animal species, the concentration of atorvastatin in blood and breast milk is similar. If you need to use Atoris® during lactation, to avoid the risk of developing adverse events in infants, breastfeeding should be discontinued.

Dosing and Administration:

Prior to the use of Atoris®, the patient should be switched to a diet that provides a reduction in lipid levels in the blood, which must be observed during therapy with the drug. Before starting therapy, you should try to achieve control of hypercholesterolemia with exercise and weight loss in obese patients, as well as therapy for the underlying disease.

The drug is taken orally, regardless of food intake. Treatment begins with the recommended initial dose of 10 mg.

The dose of the drug varies from 10 mg to 80 mg once a day and is selected taking into account the baseline level of LDL-C, the purpose of therapy and the individual therapeutic effect.

It is possible to use the drug Atoris® at another registered dosage (film-coated tablets, 10 mg, 20 mg and 40 mg).

The drug Atoris ® can be taken once at any time of the day, but at the same time every day. Therapeutic effect is observed after two weeks of treatment, and the maximum effect develops in four weeks. Therefore, dosage should not be changed earlier than four weeks after the start of the drug in the previous dose.

At the beginning of therapy and / or during a dose increase, it is necessary to monitor the level of lipids in the blood plasma every 2-4 weeks and adjust the dose accordingly.

Primary (heterozygous hereditary and polygenic) hypercholesterolemia (type II a) and mixed hyperlipidemia (type IIb)

Treatment begins with the recommended initial dose, which is increased after four weeks, depending on the patient's response. The maximum daily dose is 80 mg.

Homozygous hereditary hypercholesterolemia

The range of doses is the same as for other types of hyperlipidemia.

The initial dose is selected individually depending on the severity of the disease. In the majority of patients with homozygous hereditary hypercholesterolemia, the optimal effect was observed when the drug was used in a daily dose of 80 mg (once). Atoris® is used as adjunctive therapy for other treatments (plasmapheresis) or as a primary treatment if therapy with other methods is not possible.

Have elderly patients and patients with kidney disease Do not change the dose of Atoris®.Impaired renal function does not affect the level of atorvastatin in the blood plasma or the degree of decrease in the content of LDL-C during application of atorvastatin, therefore, a change in the dose of the drug is not required.

Have patients with impaired hepatic function caution is needed (due to the delay in removing the drug from the body). In such a situation, clinical and laboratory indicators should be carefully monitored (regular activity monitoring ACT and ALT) and, if significant pathological changes are detected, the dose of Atoris® should be reduced or treatment should be discontinued.

Use in combination with other medicines

If a simultaneous application with cyclosporine is necessary, the daily dose of Atoris® should not exceed 10 mg.

Recommendations for determining the purpose of treatment.

A. Recommendations of the National Cholesterol Education Program NCEP,

USA.

Risk Category	The target content of Xc-LDL (mg / dl)	The content of X-LDL, in which a lifestyle change is recommended (mg / dl)	The content of Xc-LDL, in which it is recommended pharmacotherapy (mg / dL)
CHD or risk of developing CHD (10-year risk> 20%)	<100	>100	> 130 (100-129 possible pharmacotherapy) *
more than 2 risk factors (10-year-old risk <20%)	<130	>130	10-year risk of 10-20%:> 130
more than 2 risk factors (10-year-old risk <20%)	<130	>130	10-year risk <10%:> 160
0-1 factor risk **	<160	>160	> 190 (160-189: prescribe a drug that reduces the content of LDL-C)

* Some experts recommend the use of lipid-lowering drugs,

which reduce the content of LDL-C, if a change in lifestyle does not lead to a decrease in its content to a level of <100 mg / dl. Others prefer drugs that have a predominant effect on Tg and HDL-C, such as a nicotinic acid in lipid-lowering doses (more than 1 g / day) and fibrates. The doctor may also postpone the pharmacotherapy in this subgroup.

** In the absence of risk factors or the presence of only 1 risk factor, almost all people have a 10-year risk of <10 %, so its evaluation is not required.

If the target LDL-C content is reached and the triglyceride content is> 200 mg / dl, the secondary goal of the therapy is to reduce the cholesterol content, excluding the HDL-C, to a level exceeding the target LDL-C-value by 30 mg / dl in each risk category .

B. Recommendations of the European Society of Atherosclerosis

In patients with confirmed diagnosis of ischemic heart disease and other patients with a high risk of ischemic complications, the goal of treatment is to reduce the levelX-LDL <3 mmol / L (or <115 mg / dL) and total XC <5 mmol / L (or <190 mg / dL).

Side effects:

Classification of the frequency of development of side effects of the World Organization Health (WHO):

very often> 1/10

often from> 1/100 to <1/10

infrequently from> 1/1000 to <1/100

rarely from> 1/10000 to <1/1000

very rarely from <1/10000, including individual messages.

From the nervous system: often: headache, insomnia, dizziness, paresthesia, asthenic syndrome; infrequently: peripheral neuropathy, amnesia, hypoesthesia, "nightmarish" dreams;

From the sense organs: infrequently: noise in the ears; rarely: nasopharyngitis, epistaxis;

From the cardiovascular system: heart beat, vasodilation, migraine, postural hypotension, increased blood pressure, phlebitis, arrhythmia;

On the part of the hematopoiesis system: infrequently: thrombocytopenia;

From the respiratory system: often: chest pain;

From the digestive system: often: constipation, indigestion, nausea, diarrhea, flatulence (bloating), abdominal pain; infrequently: anorexia, a violation of taste perception, vomiting, pancreatitis; rarely: hepatitis, cholestatic jaundice;

From the musculoskeletal system: often: myalgia, arthralgia, back pain, swelling of the joints; infrequently: myopathy, muscle cramps; rarely: myositis, rhabdomyolysis, tendopathy (in some cases with a rupture of tendons);

From the genitourinary system: infrequently: impotence, secondary renal failure;

From the skin: often: skin rash, itching; infrequently: urticaria; very rarely: angioedema, alopecia, bullous rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis;

Allergic reactions: often: allergic reactions; very rarely: anaphylaxis;

Laboratory indicators: infrequently: increased serum aminotransferase activity (ACT, ALT), increased serum creatine phosphokinase (CKF) activity; Very rarely: hyperglycemia, hypoglycemia;

Other: often: peripheral edema; infrequently: malaise, fatigue, fever, weight gain. Causal relationship of some of the undesirable effects with the use of the drug Atoris®, which are regarded as "very rare", is not established.

If severe undesirable effects occur, use of Atoris should be discontinued.

Overdose:

Cases of overdose are not described.

In case of an overdose, the following general measures are necessary: monitoring and maintaining the vital functions of the body, as well as preventing further absorption of the drug (gastric lavage, intake of activated charcoal or laxatives).

With the development of myopathy followed by rhabdomyolysis and acute renal failure (a rare but severe side effect), the drug should be immediately discontinued and an infusion of the diuretic and sodium bicarbonate should begin. If necessary, hemodialysis should be performed. Rhabdomyolysis can lead to hyperkalemia, which requires intravenous administration of calcium chloride solution or calcium gluconate solution, infusion of 5% dextrose (glucose) solution with insulin, the use of potassium-exchange resins or, in severe cases, hemodialysis. Hemodialysis is ineffective.

Interaction:

The simultaneous use of atorvastatin with cyclosporine, antibiotics (erythromycin, clarithromycin, quinupristin / delfopristin), HIV protease inhibitors (indinavir, ritonavir), antifungal agents (fluconazole, itraconazole, ketoconazole) or with nefazodone can lead to an increase in the content of atorvastatin in the serum, which increases the risk of myopathy with rhabdomyolysis and renal failure. Thus, when applied simultaneously with erythromycin TS_max Atorvastatin is increased by 40%. All these drugs inhibit the cytochrome isoenzyme CYP450 ZA4, which takes part in the metabolism of atorvastatin in the liver.

A similar interaction is possible with simultaneous use of atorvastatin with fibrates and nicotinic acid in lipid-lowering doses (more than 1 g per day). Simultaneous use of atorvastatin in a dose of 40 mg with diltiazem in a dose of 240 mg, leads to an increase in the concentration of atorvastatin in blood plasma.

The simultaneous use of atorvastatin with phenytoin, rifampicin, which are inducers of the cytochrome isoenzyme CYP4503A4, may lead to a decrease in the efficacy of atorvastatin. Because the atorvastatin is metabolized by cytochrome isoenzyme CYP4503A4, simultaneous use of atorvastatin with inhibitors of the cytochrome isoenzyme CYP4503A4 can lead to an increase in the concentration of atorvastatin in the blood plasma.

Inhibitors of transport protein OAT31B1 (for example, ciclosporin) may increase the bioavailability of atorvastatin.

With simultaneous application antacids (a suspension of magnesium hydroxide and aluminum hydroxide) reduce the content of atorvastatin in blood plasma.

With simultaneous use of atorvastatin with colestipol the concentration of atorvastatin in plasma is reduced by 25%, but the therapeutic effect of the combination is higher than that of atorvastatin alone.

Simultaneous use of atorvastatin with drugs that reduce the concentration of endogenous steroid hormones (incl. cimetidine, ketoconazole, spironolactone), increases the risk of reducing endogenous steroid hormones (caution should be exercised).

In patients who simultaneously receive 80 mg of atorvastatin and digoxin, the content of digoxin in the blood plasma increases by about 20%, so these patients should be monitored.

With simultaneous use of atorvastatin with oral contraceptives (norethisterone and ethinyl estradiol) it is possible to increase the absorption of contraceptives and increase their concentration in blood plasma. The choice of contraceptives should be monitored in women receiving atorvastatin.

The simultaneous use of atorvastatin with warfarin may in the first days increase the effect of warfarin on the parameters of blood coagulation (reduction of prothrombin time). This effect disappears after 15 days of simultaneous application of these drugs.

With the simultaneous use of atorvastine and terfenadine, clinically significant changes in the pharmacokinetics of terfenadine have not been identified.

Atorvastatin does not affect the pharmacokinetics phenazone.

Simultaneous application with protease inhibitors leads to an increase in the concentration of atorvastatin in the blood plasma.

With simultaneous use of atorvastatin in a dose of 80 mg and amlodipine at a dose of 10 mg the pharmacokinetics of atorvastatin did not change in the equilibrium state.

There have been cases of rhabdomyolysis in patients using atorvastatin and fusidic acid.

Concomitant therapy

When using atorvastatin with antihypertensive agents and estrogens within the framework of the substitution therapy, no clinically significant undesirable interaction was observed.

Use grapefruit juice During the period of application of the drug Atoris® can lead to an increase in the concentration of the drug in the blood plasma.In this regard, patients taking the drug Atoris® should avoid the use of grapefruit juice more than 1.2 liters per day.

Special instructions:

Before starting therapy with Atoris®, the patient should be given a standard hypocholesterolemic diet, which he must observe during the entire treatment period.

It is necessary to monitor liver function. During the period of therapy with Atoris, an increase in the activity of "hepatic" enzymes in serum can be observed. This increase, as a rule, is small and clinically insignificant. However, it is recommended to monitor the activity of "hepatic" enzymes in the serum prior to therapy, after 6 weeks, 12 weeks and with an increase in the dose of Atoris.

If there is a triple, relative to the upper limits of the norm, an increase in activity ACT and / or ALT, treatment with Atoris® should be discontinued. The increase in serum levels of aminotransferases depends on the dose of the drug and is reversible in all patients.

It is possible that the upper limit of the CKK level is about 10 times higher.

Atoris® should be used with caution in patients who abuse alcohol and patients with liver disease.

On the background of the use of the drug Atoris ®, myalgia is possible.

The diagnosis of myopathy (muscle pain or muscle weakness, combined with an increase in CKK activity) is likely in patients with diffuse myalgia, muscle soreness or weakness, and / or a marked increase in CKK activity. When using the drug Atoris ®, as with the use of other statins, it is rare, but it is possible to develop rhabdomyolysis with acute renal failure due to myoglobinuria. The risk of this complication increases with the simultaneous use of the following drugs with the drug Atoris: fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), cyclosporine (the daily dose of the drug Atoris® should not exceed 10 mg), nefazodone, some antibiotics, antifungal agents from the group "azoles", HIV-protease inhibitors.

When there are symptoms of myopathy or the presence of risk factors for the development of renal failure, it is recommended to determine the serum activity of CK. If the activity of CK exceeds the upper limit of the norm by more than 10 times, treatment should be discontinued. In the differential diagnosis of chest pain, consideration should be given to the possibility of increasing the serum activity of CKK when using the drug Atoris®.

Patients should be observed regularly to identify pain or weakness in the muscles, especially during the first months of therapy and during the period of increasing the dose of any of the above.

Patients should be warned that they should seek medical attention immediately if unexplained pain or muscle weakness occurs, especially if they are accompanied by a malaise or fever.

The drug Atoris® contains lactose, therefore, its use by patients with lactase deficiency, lactose intolerance and glucose-galactose malabsorption syndrome is contraindicated.

Effect on the ability to drive transp. cf. and fur:

Given the potential for dizziness, caution in the management of vehicles and other technical devices that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Film-coated tablets, 30 mg, 60 mg and 80 mg.

Packaging:

10 tablets in blister from combined material OPA / A1 / PVC - aluminum foil (OPA/Al/PVC-aluminium foil).

For 3, 6 or 9 blisters are placed in a pack of cardboard along with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001644

Date of registration:12.04.2012

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, d.d. Slovenia

Representation: & nbspKRKA KRKA Slovenia

Information update date: & nbsp12.04.2012

Illustrated instructions

Instructions

Atoris® (Atoris®)