Ator - instructions for use, dose, side effects, contraindications

Excipients: calcium hydrogen phosphate 9.0 / 36.0 mg, lactose monohydrate 48.0 / 192.0 mg, microcrystalline cellulose 75.0 / 300.0 mg, croscarmellose sodium 6.0 / 24.0 mg, magnesium stearate 1.15 / 4.6 mg;

auxiliary substances of the film shell: Opadry II white (85 F 18378) 7.5 mg / 30.0 mg (polyvinyl alcohol 40%, titanium dioxide (E171) 25%, macrogol-4000 20.2%, talc 14.8%).

Description:

For the dosage of 10 mg:

Oval, biconvex tablets coated with a coat, white with a risk on one side, 10 mm x 5 mm; a kind of tablets on a break - from white to white-yellow color.

For a dosage of 40 mg:

Oval, biconvex tablets coated with a coat, white with a risk on one side, 18 mm x 8 mm; a kind of tablets on a break - from white to white-yellow color.

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

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.05 Atorvastatin

Pharmacodynamics:

A selective competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, a precursor of sterols, including cholesterol.

Triglycerides and cholesterol in the liver are included in the composition of very low density lipoproteins (VLDL), enter the blood plasma and transport to peripheral tissues. Low density lipoproteins (LDL) are formed from VLDL in the course of interaction with LDL receptors.

Reduces the concentration of cholesterol and lipoproteins in the blood plasma due to the inhibition of HMG-CoA reductase, the synthesis of cholesterol in the liver and the increase in the number of "liver" LDL receptors on the cell surface, which leads to increased capture and catabolism of LDL.

Reduces the formation of LDL, causes a pronounced and persistent increase in the activity of LDL receptors. Reduces the concentration of LDL in patients with homozygous familial hypercholesterolemia, which usually does not respond to lipid-lowering therapy.

Reduces the concentration of total cholesterol by 30-46%, LDL by 41-61%, apolipoprotein B - by 34-50% and triglycerides by 14-33%; increases the concentration of cholesterol-HDL and apolipoprotein A.

Dose-dependent decreases the concentration of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.

Reliably reduces the risk of developing ischemic complications (including the development of mortality from myocardial infarction) by 16%, the risk of re-hospitalization for angina pectoris accompanied by signs of myocardial ischemia - by 26%.

Does not have a carcinogenic and mutagenic effect.

The therapeutic effect is achieved 2 weeks after the initiation of therapy, reaches a maximum after 4 weeks, and persists throughout the treatment period.

Pharmacokinetics:

Suction

Absorption is high. Time to reach the maximum concentration (TC_m_Oh) - 1-2 hours. Eating somewhat reduces the speed and duration of absorption of the drug (by 25% and 9%, respectively), but the decrease in LDL cholesterol is similar to that with atorvastatin without simultaneous ingestion. The concentration of atorvastatin when used in the evening is lower than in the morning (about 30%). A linear relationship between the degree of absorption and the dose of the drug has been revealed.

Absolute bioavailability is 14%, 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 (GIT) and in the "primary passage" through the liver.

Distribution

Average volume of distribution (V_d) - 381 l, communication with blood plasma proteins - more than 98%. The ratio of the erythrocyte / plasma content is about 0.25, i.e. atorvastatin poorly penetrates into red blood cells.

Metabolism

Metabolized mainly in the liver under the action of cytochrome isoenzymes CYP3A4, CYP3A5 and CYP3A7 with the formation of pharmacologically active metabolites (ortho- and para-hydroxylated derivatives, beta-oxidation products). In vitro ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin. The inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of the circulating metabolites and remains about 20-30 hours due to their presence.

Excretion

It is excreted with bile after hepatic and / or extrahepatic metabolism (it does not undergo significant intestinal hepatic recirculation). Half-life (T₁_/2) - 14 hours.

Less than 2% of the dose taken internally is determined in the urine.

It is not excreted during hemodialysis due to intensive binding to plasma proteins.

Pharmacokinetics in special clinical cases

Elderly patients. The maximum concentration (C_m_Oh) and the area under the pharmacokinetic curve "concentration-time" (AUC) of the drug in elderly patients (65 years older) by 40% and 30%, respectively, higher than those in adult patients of young age (of clinical importance).

Children. Studies of the pharmacokinetics of the drug in children have not been conducted.

FROMmah Women are 20% higher, a AUC 10% lower than those of men (it has no clinical significance).

Insufficient function baked. FROM_m_Oh in patients with alcoholic cirrhosis of the liver 16 times, AUC - 11 times higher than normal.

Lack of kidney function. Renal failure does not affect the concentration of the drug in the blood plasma.

Indications:

- Primary hypercholesterolemia (heterozygous familial and non-family hypercholesterolemia (type IIbut according to Fredrickson's classification);

- combined (mixed) hyperlipidemia (types IIa and IIb according to Fredrickson's classification);

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

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

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

- primary prevention of cardiovascular complications in patients without clinical signs of IHD, but having several risk factors for its development - age over 55,nicotinic dependence, arterial hypertension, diabetes mellitus, low concentrations of cholesterol-HDL in the blood plasma, genetic predisposition, incl. 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 procedures.

Contraindications:

Hypersensitivity to any of the components of the drug; liver diseases in the active stage (including active chronic hepatitis, chronic alcoholic hepatitis); cirrhosis of the liver of any etiology; an increase in the activity of "hepatic" transaminases (more than 3 times as compared with the upper limit of the norm) of an unknown genesis; pregnancy and lactation, as well as the use of women of reproductive age who do not use reliable methods of contraception; children's age till 18 years; lactose intolerance, lactase deficiency, glucose-galactose malabsorption (because the preparation contains lactose).

Carefully:Alcoholism; liver failure; liver disease in history; hypothyroidism; renal impairment; diseases of skeletal muscles.

Pregnancy and lactation:

Use of the drug Ator is contraindicated during pregnancy and lactation (breastfeeding).

Women of reproductive age during treatment should use reliable methods of contraception. The potential risk of inhibiting HMG-CoA reductase exceeds the benefit of using the drug during pregnancy, since cholesterol and cholesterol-derived substances are important for fetal development, Athor can be prescribed to women of reproductive age only if the probability of pregnancy is very low. In the case of diagnosing pregnancy during therapy, the drug should be taken immediately terminated, and the patient is informed of the potential risk to the fetus.

It is not known whether atorvastatin with breast milk. Given the potential for adverse effects in infants, if necessary, use during lactation should decide the issue of termination of breastfeeding.

Dosing and Administration:

Inside, at any time of the day, regardless of food intake.

Before starting therapy with Ator, try to control hypercholesterolemia with a diet,physical exercises and weight loss in obese patients, as well as the treatment of the underlying disease. Before using the drug Ator patient should recommend a standard lipid-lowering diet, which he must continue to observe during the entire period of therapy.

The initial dose of the drug Ator is 10 mg once a day. The dose varies from 10 to 80 mg 1 time / day. The dose is selected taking into account the initial concentrations of cholesterol / LDL, the purpose of therapy and individual effect. At the beginning of treatment and / or during an increase in the dose of the drug, it is necessary to monitor the concentration of lipids in the blood plasma every 2-4 weeks and adjust the dose accordingly. The maximum daily dose is 80 mg per 1 dose.

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

In most cases, it is sufficient to use a dose of 10 mg of the drug Ator 1 time per day. A significant therapeutic effect is observed after 2 weeks, as a rule, the maximum therapeutic effect is usually observed after 4 weeks. With prolonged treatment, this effect persists.

Homozygous hereditary hypercholesterolemia.

Assign 80 mg once a day (lowering the LDL content by 18-45%).

With hepatic insufficiency dose should be reduced, due to the slowdown of the removal of the drug from the body.

Use of the drug in patients with renal insufficiency does not affect the concentration of atorvastatin in the blood plasma or the degree of reduction the content of cholesterol / LDL when it is used, therefore, a change in the dose of the drug is not required.

For elderly patients correction of the dose is not required.

When simultaneous application is required with cyclosporine the daily dose of the drug Ator should not exceed 10 mg.

Side effects:

Classification of the World Health Organization (WHO) of unwanted adverse reactions according to the frequency of development:

very frequent 1/10 appointments (≥ 10 %);

frequent 1/100 appointments (≥ 1%, but <10%);

infrequent 1/1000 appointments (≥ 0.1%, but <1%);

rare 1 / 10,000 appointments (≥ 0.01%, but <0.1%);

very rare less than 1/10000 prescriptions (<0.01%)

Allergic reactions: infrequently - skin itching, rash, hives, anaphylactic reactions, polymorphic exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome),bullous rash; rarely - contact dermatitis, angioedema, facial edema, lupus-like syndrome, vasculitis, photosensitivity, multiforme exudative erythema.

From the nervous system: often - headache, asthenic syndrome; infrequent - dizziness, malaise, loss or loss of memory, paresthesia, peripheral neuropathy, hypoesthesia; rarely - sleep disturbances, including insomnia and nightmarish dreams, emotional lability, ataxia, hyperkinesia, depression, weakness.

From the skin: often - alopecia; increased sweating, eczema, seborrhea, ecchymosis, xeroderma, petechiae.

From the genitourinary system: often - urogenital infections, peripheral edema, rarely dysuria (including pollakiuria, nocturia, urinary incontinence or urinary retention, mandatory urges to urinate), cystitis, hematuria, vaginal bleeding, urolithiasis, metrorrhagia, epididymitis, decreased libido, impotence impaired ejaculation.

From the musculoskeletal system: often - rheumatic polymyalgia, myalgia; infrequently - back pain, leg muscle cramps, myositis, myopathy, arthralgia,rhabdomyolysis; rarely arthritis, bursitis, muscle hypertonus, tendosynovitis, joint contractures, swelling of the joints, tendopathy (in some cases with a rupture of the tendon).

From the digestive system: often - nausea, diarrhea, abdominal pain, indigestion, flatulence, constipation; infrequent - vomiting, anorexia or increased appetite, hepatitis, pancreatitis, cholestatic jaundice; rarely heartburn, gastralgia, dryness of the oral mucosa, belching, dysphagia, stomatitis, esophagitis, glossitis, gastroenteritis, hepatic colic, cheilitis, duodenal ulcer, increased activity of "liver" enzymes, rectal bleeding, melena, bleeding gums, erosive- ulcerous lesions of the oral mucosa, tenesmus.

From the hematopoiesis: infrequently - thrombocytopenia; rarely - anemia, lymphadenopathy.

From the respiratory system: rarely - bronchitis, rhinitis, dyspnoea, exacerbation of bronchial asthma, nosebleeds.

From the sense organs: infrequently, noise in the ears; rarely - amblyopia, dry conjunctiva, disruption of accommodation, eye hemorrhage, deafness, glaucoma, parosmia, loss of taste, taste distortion.

From the cardiovascular system: rarely - a feeling of palpitations, symptoms of vasodilation, migraine, postural hypotension, increased blood pressure, phlebitis, arrhythmia, angina pectoris, vasculitis.

Laboratory indicators: infrequently hyperglycemia, hypoglycemia, increased serum creatine phosphokinase (CKF) activity; rarely - albuminuria, increased concentration of glycosylated hemoglobin, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR).

Other: infrequently - peripheral edema, weight gain, increased fatigue, tinnitus; rarely - sexual dysfunction, gynecomastia, exacerbation of gout, fever, single cases of interstitial lung disease (especially with prolonged use), cases of immunosuppressed necrotizing myopathy.

Overdose:

Symptoms: development of myopathy with subsequent rhabdomyolysis and acute renal failure (a rare but severe side effect). The drug should be immediately canceled.

Treatment: there is no specific antidote, symptomatic therapy.The patient must enter a diuretic and a solution of sodium bicarbonate. If necessary, hemodialysis should be performed. Rhabdomyolysis can lead to hyperkalemia, which requires the intravenous administration of calcium chloride or calcium gluconate, glucose infusion with insulin, the use of potassium ion exchangers, or, in severe cases, hemodialysis. Because the atorvastatin is largely associated with blood plasma proteins, hemodialysis is a relatively ineffective way of removing this substance from the body.

Interaction:

The risk of myopathy increases with the simultaneous use of cyclosporine, fibrates, erythromycin, clarithromycin, immunosuppressive, antifungal preparations (belonging to azoles) and nicotinic acid in lipid-lowering doses (more than 1 g / day).

With simultaneous ingestion of atorvastatin and a suspension containing magnesium and aluminum hydroxide, the concentrations of atorvastatin in the plasma decreased by approximately 35%, but the degree of decrease in the level of cholesterol / LDL did not change.

The hypolipidemic effect of the combination with colestipol exceeds that for each drug alone,despite a decrease in the concentration of atorvastatin by 25% with its simultaneous use with colestipol.

With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma do not change. However, when applying digoxin in combination with atorvastatin at a dose of 80 mg per day, the concentration of digoxin increases by about 20%. Patients receiving digoxin in combination with atorvastatin should be observed.

With simultaneous use of atorvastatin and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg twice a day), which inhibit the cytochrome isoenzyme CYP3A4 an increase in the concentration of atorvastatin in the blood plasma is observed.

With the simultaneous use of atorvastatin (10 mg once a day) and azithromycin (500 mg once a day), the concentration of atorvastatin in the blood plasma does not change.

With simultaneous use of atorvastatin and oral contraceptive containing norethindrone and ethinyl estradiol, there is a significant increase AUC Approximately 30 and 20 ethinylestradiol %, respectively. This effect should be considered when choosing an oral contraceptive for a woman receiving atorvastatin.

When studying the interaction of atorvastatin with warfarin, phenazone and cimetidine, no signs of clinically significant interaction were found.

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

Because grapefruit juice contains one or more components that inhibit the cytochrome isoenzyme CYP3A4, its excessive consumption (more than 1.2 liters per day) can cause an increase in the concentration of atorvastatin in the blood plasma.

The simultaneous use of atorvastatin with protease inhibitors, known as cytochrome inhibitors CYP3A4, is accompanied by an increase in the concentration of atorvastatin in the blood plasma by about 40%.

In clinical trials atorvastatin used in combination with antihypertensive agents and estrogens within the framework of substitution therapy; signs of clinically significant undesirable interaction were not observed. Atorvastatin and its metabolites are substrates of transport protein OAT31B1. OAT31B1 inhibitors (e.g., ciclosporin) can increase bioavailability of atorvastatin.Thus, simultaneous use of atorvastatin 10 mg and cyclosporine at a dose of 5.2 mg / kg / day leads to an increase in the concentration of atorvastatin in blood plasma by 7.7 times (see section "Method of administration and dose").

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.

Atorvastatin does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same isoenzyme is not expected. There have been cases of rhabdomyolysis in patients taking both fusidic acid and atorvastatin. Patients should be observed and considered that the temporary cancellation of atorvastatin may be appropriate.

Special instructions:

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

The use of the drug ator can cause an increase in the activity of CK, which should be taken into account in the differential diagnosis of chest pain. It should be borne in mind that an increase in the activity of CK 10 times compared with the norm, accompanied by myalgia and muscle weakness, may be associated with myopathy - treatment should be discontinued.

It is necessary to regularly monitor the liver function before treatment, 6 and 12 weeks after the start of the use of the drug Ator, or after an increase in the dose, and periodically (every 6 months) during the entire period of use (until the patients normalize their activity "hepatic" transaminases exceed normal ones). Increased activity of "liver" transaminases is observed mainly in the first 3 months of the drug. It is recommended to cancel the drug or reduce the dose with increasing activity ACT and ALT more than 3 times.

Ator should be used with caution in patients who abuse alcohol and / or have liver disease. Active liver disease or persistent increase in the activity of "hepatic" transaminases of unknown origin serve as a contraindication to the use of the drug Ator.

It is necessary to temporarily stop the use of the drug Ator in the development of clinical symptoms, suggesting the presence of acute myopathy, or in the presence of factors predisposing to the development of acute renal insufficiency on the background of rhabdomyolysis (severe infections, lower blood pressure,extensive surgical interventions, trauma, metabolic, endocrine or severe water-electrolyte disturbances).

Patients should be warned that they should immediately consult a doctor if unexplained pain or weakness in the muscles occurs, especially if they are accompanied by a malaise or fever.

The risk of myopathy increases with simultaneous use of cyclosporine, fibrolic acid derivatives, fusidic acid, erythromycin, nicotinic acid in lipid-lowering doses or azole antifungal drugs.

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

An adverse effect on the ability to drive vehicles and work with mechanisms was not reported.

Form release / dosage:Tablets, film-coated, 10 mg, 40 mg.

Packaging:

Tablets, film-coated 10 mg.

For 7 tablets in aluminum (aluminum / aluminum) blister; 4 blisters together with instructions for use in a pack of cardboard.

Tablets, film-coated 40 mg.

4 tablets in aluminum (aluminum / aluminum) blister; 7 blisters together with instructions for use in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Special precautions for the destruction of unused medications

If the medicine has become unusable or the expiration date has expired, do not throw it into sewage or into the street! Place the drug in a bag and put it in the trash. These measures will help protect the environment!

Terms of leave from pharmacies:On prescription

Registration number:LP-002418

Date of registration:03.04.2014

Expiration Date:03.04.2019

The owner of the registration certificate:Laboratories Medis, TunisiaLaboratories Medis, Tunisia Tunisia

Manufacturer: & nbsp

Les Laboratoires MediS, S.A. Tunisia

Information update date: & nbsp08.10.2017

Illustrated instructions

Instructions

Ator (Ator)