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

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 the concentration of cholesterol (Xs) of LDL-C (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 expansion of blood vessels improves, the concentration of LDL-C, apolipoprotein B, triglycerides (TG) decreases, the concentration of high-density lipoprotein cholesterol (Xc-HDL) and apolipoprotein A increases.

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. Inhibitors of HMG-CoA reductase also have an effect on the metabolism of macrophages, block their activation and prevent the rupture of atherosclerotic plaque.

As a rule, the therapeutic effect of atorvastatin develops after two weeks of using atorvastatin, and the maximum effect is achieved in four weeks.

Atorvastatin at a dose of 80 mg significantly reduces the risk of developing ischemic complications (incl.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. Time to reach the maximum concentration (TCmax), on average, 1-2 hours. In women, TCmax is 20% higher, and the area under the concentration-time curve (AUC) is 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, TCmax is 16 times higher than normal. Eating slightly reduces the speed and duration of absorption of the drug (by 25% and 9%, respectively), however, a decrease in the concentration of LDL-C 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 "primary passage" 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.

Metabolised mainly in the liver under the action of the isoenzyme ZA4 cytochrome P450 to form pharmacologically active metabolites (ortho- and para-hydroxylated 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% of atorvastatin is excreted through the intestine and less than 2% by the kidneys.

Special patient groups

Children

Studies of pharmacokinetics in children have not been conducted.

Elderly patients

The maximum concentration in blood plasma (Cmax) and AUC of the drug in elderly patients (over 65 years) is 40% and 30%, respectively, higher than those in adult patients of young age (of clinical significance).

Impaired renal function

Impaired renal function does not affect the concentration of atorvastatin in the blood plasma or its effect on lipid metabolism,in this regard, a change in the dose of the drug in patients with impaired renal function is not required.

Impaired liver function

The concentration of the drug is significantly increased (Cmax - about 16 times, AUC - about 11 times) in patients with alcoholic cirrhosis (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 (III type by Fredrickson) (as an adjunct to the diet);

Family endogenous hypertriglyceridemia (type IV through 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 prevention of cardiovascular complications in patients without clinical signs of IHD, but having several risk factors for its development: age over 55, nicotine dependence, hypertension. diabetes, low HDL-C level in blood plasma, genetic predisposition, including against the background of dyslipidemia;

Secondary prophylaxis of cardiovascular complications in patients with coronary heart disease (CHD) in order to reduce the total death rate, myocardial infarction, stroke. repeated 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);

- 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 the blood serum and in the milk of lactating animals 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 the drug Atoris®, the patient should be transferred to a diet that reduces the concentration of lipids in the blood, which must be observed during the entire 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.The dose of the drug varies from 10 mg to 80 mg once a day and is selected taking into account the initial concentration of LDL-C, the purpose of therapy and individual therapeutic effect.

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 concentration of lipids in the blood plasma every 2-4 weeks and adjust the dose accordingly.

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

Treatment begins with a recommended initial dose of 10 mg, 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 most patients with homozygous hereditary hypercholesterolemia, the optimal effect is observed when the drug is 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.

At patients of advanced age and at patients with diseases of kidneys the dose of preparation Atoris® should not be changed. The renal dysfunction does not affect the concentration of atorvastatin in the blood plasma or the degree of decrease in the concentration of LDL-C in the use of atorvastatin, so a dose change is not required.

Care should be taken in patients with violations of the liver function (due to the delay in the removal of the drug from the body). In such a situation, clinical and laboratory indicators should be closely monitored (regular monitoring of activity of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT)). With a significant increase in the activity of "hepatic" transaminases, 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 Education Program for Cholesterol NCEP, USA

Category risk	Target concentration Xc-LDL (mg / dL)	Concentration Xc-LDL, at which recommended change image life (mg / dL)	Concentration of LDL-C, at which it is recommended pharmacotherapy (mg / dL)
CHD
or
risk			>130 (100-
development of			129
CHD	<100	>100	is possible
(10-			pharmacotherapy *
summer
risk> 2
0 %)
more than 2			10-year-old
factors			risk of 10-
			20%;>130
risk
	<130	>130
(10-			10-year-old
summer			risk
risk <			<10%:>160
20 %)
0-1			>190 (160-
factor	<160	>160	189:
risk **			appoint a drug, decreasing concentration Xs-LDL)

* Some experts recommend the use of lipid-lowering drugs that reduce the concentration of LDL-C, if lifestyle changes do not lead to a decrease in its concentration to <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 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 patients have a 10-year risk of <1%, so its evaluation is not required.

If the target concentration of LDL-C is reached, and the TG concentration is> 200 mg / dL, the secondary goal of the therapy is to lower the cholesterol concentration (excluding HDL-C) to a concentration of 30 mg / dL higher than the target in each risk category.

B. Recommendations of the European Society of Atherosclerosis:

In patients with confirmed diagnosis of coronary heart disease and other patients with a very high risk of ischemic complications, the goal of treatment is to reduce the concentration of LDL-C <1.8 mmol / L (or <70 mg / dL) or lower LDL-C> 50%.

B. Recommendations of the Russian cardiological society, The National Society for the Study of Atherosclerosis (NOA) and the Russian Society of Cardiosomal rehabilitation and secondary prevention (RosOKR) (V revision 2012):

The optimal values for the levels of Xc-LPS and total cholesterol (OXc) for high-risk patients are: <2.5 mmol / L (or <100 mg / dl) and <4.5 mmol / L (or <175 mg / dL) , respectively, for patients with a very high risk: <1.8 mmol / L (or <70 mg / dL) and <4 mmol / L (or <150 mg / dl), respectively.

Side effects:

Classification of the frequency of development of side effects of the World Health Organization (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

frequency is unknown: can not be estimated from the available data.

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

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

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

From the respiratory system: often: chest pain;

From the digestive system: often: constipation, dyspepsia, 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: decreased potency, secondary renal failure;

From the skin: often: skin rash, itchy skin; 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 activity of aminotransferases (ACT, ALT), increased serum creatine phosphokinase (CK) 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 be started. 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.

There is no specific antidote.

Interaction:

Simultaneous use of atorvastatin with cyclosporine, antibiotics (erythromycin, clarithromycin, quinupristin / delfopristin), HIV protease inhibitors (indinavir, ritonavir), antifungal agents (fluconazole, itraconazole, ketoconazole) or with nefazodone may lead to an increase in the concentration of atorvastatin in the blood plasma, which increases the risk of myopathy with rhabdomyolysis and renal failure. Thus, with simultaneous application of erythromycin TSmax, atorvastatin is increased by 40%.All these drugs inhibit the cytochrome isoenzyme CYP4503A4, which takes part in the metabolism of atorvastatin in the liver.

A similar interaction is possible with the 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 the 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.

When used simultaneously with antacids (a suspension of magnesium hydroxide and aluminum hydroxide), the concentration of atorvastatin in the blood plasma decreases.

With the simultaneous use of atorvastatin with colestipol, the concentration of atorvastatin in blood 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 concentration of digoxin in the blood plasma increases by about 20%, so these patients should be monitored.

With the 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 the blood plasma. Control over the choice of contraceptives in women using atorvastatin.

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

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

Atorvastatin does not affect the pharmacokinetics of phenazone.

Simultaneous use 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 substitution therapy, no clinically significant undesirable interaction was observed.

The consumption of grapefruit juice during the period of application of the drug Atoris® can lead to an increase in the concentration of atorvastatin 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 follow throughout the treatment period.

It is necessary to monitor liver function. During the period of therapy with the drug Atoris®, an increase in the activity of "hepatic" enzymes in blood plasma 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 blood plasma before the start of therapy, after 6 weeks, 12 weeks and with an increase in the dose of Atoris. If there is a threefold increase in the activity of ACT and / or ALT relative to the upper limits of the norm, treatment with Atoris® should be stopped.

The increase in serum aminotransferase activity depends on the dose of the drug and is reversible in all patients. Atoris® should be used with caution in patients who abuse alcohol and patients with a history of liver disease.

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

The diagnosis of myopathy (muscle pain or muscle weakness in combination 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. caused by myoglobinuria. The risk of this complication increases with the simultaneous use of the following drugs with Atoris®: fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day), cyclosporine (daily dose of Atoris® should not exceed 10 mg), nefazodone, certain antibiotics, antifungal funds 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.

The patient must be warned that he should immediately consult a doctor if unexplained pain or muscle weakness occurs, especially if accompanied by malaise or fever.

The drug Atoris® contains lactose, therefore, its use for 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 possibility of developing dizziness, care should be taken when driving vehicles and other technical devices that require increased concentration and speed of psychomotor reactions.

Form release / dosage:Tablets, film-coated, 40 mg.

Packaging:When manufacturing at JSC "Krka, dd, Novo mesto", Slovenia:
10 tablets per blister (contour mesh packaging) of a combined material polyamide / aluminum foil / PVC - aluminum foil (Coldforming OPA / A1 / PVC-A1).
For 1, 3, 6 or 9 blisters (contour cell packs), together with the instructions for use are put in a cardboard box.
When packing the Russian company LLC Krka-Rus:
For 1, 3, 6 or 9 blisters (contour cell packs), together with the instructions for use are put in a cardboard box.
When produced at OOO Krka-Rus, Russia:
10 tablets in a contour mesh package (blister) from the combined material polyamide / aluminum foil / PVC according to GOST 52145-2003 and aluminum foil according to GOST 745-2003, or TU 48-21-270-94, or according to the specifications of JSC "Krka, New Place, Slovenia (Coldforming OPA / A1 / PVC-A1).
For 1, 3, 6 or 9 contour squares (blisters) together with the instruction for use are placed in a pack of cardboard in accordance with GOST 7933-89.

Storage conditions:At a temperature of no higher than 25 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:LSR-002153/07

Date of registration:13.08.2007

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

Manufacturer: & nbsp

KRKA-RUS, LLC Russia

Representation: & nbspKRKA KRKA Slovenia

Information update date: & nbsp17.06.2015

Illustrated instructions

Instructions

Atoris® (Atoris®)