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

Excipients: cellulose microcrystalline - 52.51 mg; corn starch pregelatinized starch - 52.51 mg; silicon dioxide colloidal - 0.38 mg; magnesium carbonate - 33.00 mg; magnesium stearate - 0.75 mg.

Composition of the tablet shell: fall off II white (85F18422) - 4.50 mg (polyvinyl alcohol 40.0%, titanium dioxide 25.0 %, macrogol-3350 - 20.2 %, talcum - 14,8%.)

1 tablet, film-coated 20 mg, contains:

Tablet core composition:

Active substance: atorvastatin calcium trihydrate 21.70 mg, calculated as atorvastatin 20.00 mg;

Excipients: cellulose microcrystalline - 105.02 mg; corn starch pregelatinized starch - 105.02 mg; silicon dioxide colloidal - 0.76 mg; magnesium carbonate - 66.00 mg; magnesium stearate - 1.50 mg.

Composition of the tablet shell: fall off II white (85F18422) - 9.00 mg (polyvinyl alcohol - 40.0 %, titanium dioxide - 25.0 %, Macrogol-3350 - 20,2%, talc - 14,8 %.)

Description:

Tablets 10 mg

The tablets are round, biconvex, covered with a film coat of white or almost white color. On the cross section - the core is white or almost white.

Tablets 20 mg

Tablets are round, biconcave, film-coated, white or almost white, with a risk on one side. On the cross section - the core is white or almost white.

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:

Atorvastatin is a selective competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme involved in the conversion of 3-hydroxy-3-methyl-glutaryl coenzyme A to mevalonic acid, a sterol precursor, including number of cholesterol. Cholesterol and triglycerides circulate in the vascular bed of lipoprotein molecules. Triglycerides (TG) and cholesterol in the liver synthesize very low-density lipoproteins (VLDL). From the liver they enter the blood plasma and are delivered to the peripheral tissues. Lipoproteins of low density (LDL) are formed from VLDL, catabolism is carried out, mainly through interaction with LDL receptors. Atorvastatin reduces the synthesis and concentration of cholesterol and LDL, the concentration of total cholesterol, apolipoprotein B in patients with homozygous and heterozygous familial hypercholesterolemia, primary hypercholesterolemia and mixed hyperlipidemia. It also causes a decrease in the concentration of VLDL cholesterol and triglycerides and an increase in the concentration of high-density lipoprotein cholesterol (HDL) and apolipoprotein A.Like LDL, lipoproteins enriched with cholesterol and rich in triglycerides (VLDL, intermediate-density lipoproteins and chylomicron residues) can also contribute to the progression of atherosclerosis. An increase in plasma triglyceride concentration is often combined with a decrease in HDL cholesterol and the appearance of small-size LDL particles, as well as other non-lipid metabolic risk factors for coronary heart disease (CHD).

Pharmacokinetics:

Absorption is high. Time to reach the maximum concentration (t_max) in the blood plasma after oral administration for 1-2 hours. tmax in women is higher by 20%, the area under the curve (AUC) is lower by 10%. t_max in patients with alcoholic cirrhosis of the liver 16 times, and AUC - 11 times higher than normal. Food slightly reduces the rate and degree of absorption of the drug (by 25% and 9%, respectively), but the reduction in LDL cholesterol is similar to that of atorvastatin without food. After taking atorvastatin in the evening, its concentration in the blood plasma is lower (t_max and AUC approximately 30%) than after taking in the morning. A linear relationship between the degree of absorption and the dose of the drug has been revealed.Bioavailability is 12%, the systemic bioavailability of inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to presystemic metabolism in the mucous membrane of the gastrointestinal tract and during the "primary passage" through the liver. The average volume of distribution is 381 liters, communication with plasma proteins is 98%. Metabolised mainly in the liver under the action of the isoenzyme CYP3A4 with the formation of pharmacologically active metabolites (ortho- and parahydroxylated derivatives, beta-oxidation products). It is excreted mainly with bile after hepatic and / or extrahepatic metabolism (atorvastatin not subject to severe intestinal hepatic recirculation, not excreted by hemodialysis). Half-life (T_1/2) - 14 hours. The inhibitory activity against HMG-CoA reductase persists for about 20-30 hours due to the presence of active metabolites. Approximately 46% of atorvastatin is excreted through the intestine and less than 2% by the kidneys.

Indications:

- Primary hypercholesterolemia (heterozygous familial and non-family hypercholesterolemia (IIand the Fredrickson type);

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

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

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

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

- 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 concentration of HDL-C in blood plasma, genetic predisposition, including number on the background of 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);

- increased activity of alanine aminotransferase (ALT) or aspartate aminotransferase (ACT) (more than 3 times as compared with the upper limit of the norm) of unknown origin;

- cirrhosis of the liver of any etiology;

- use in women of reproductive age who do not use adequate methods of contraception.

- pregnancy and the period of breastfeeding;

- age to 18 years (efficacy and safety of application not established).

Carefully:Liver diseases in history, alcohol abuse, severe water-electrolyte balance disorders, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, skeletal muscle diseases, extensive surgical interventions, injuries, diabetes mellitus.

Pregnancy and lactation:

Application during pregnancy and during breastfeeding is contraindicated.

Since cholesterol and substances synthesized from cholesterol are important for the development of the fetus, the potential risk of inhibiting HMG-CoA reductase exceeds the use of the drug Atorvastatin during pregnancy.In the case of pregnancy diagnosis, the drug should be discontinued as soon as possible, and the patient is warned about the potential risk to the fetus. Women of reproductive age during treatment should use adequate means of contraception. Atorvastatin can be prescribed to women of reproductive age only if the probability of pregnancy is very low, and the patient is informed of the possible risk of treatment for the fetus. It is not known whether atorvastatin with breast milk. Considering the possibility of undesirable phenomena in infants, if it is necessary to use the drug during breastfeeding, the question of stopping breastfeeding should be resolved.

Dosing and Administration:

Before starting the use of the drug, the patient should be transferred to a diet with a low cholesterol content, which must be observed during therapy with the drug.

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

Treatment begins with a recommended initial dose of 10 mg once daily.

The dose of the drug varies from 10 to 80 mg once a day, selecting it taking into account the initial concentrations of LDL cholesterol,purpose of therapy and individual therapeutic effect. Change the dose should be at intervals of at least 4 weeks.

Primary hypercholesterolemia and mixed hyperlipidemia

The recommended initial dose of atorvastatin is 10 mg once daily. Then individually selected dose of 10 - 80 mg of the drug per day, depending on the target concentration of cholesterol and the effectiveness of the drug. After 2 to 4 weeks after the start of treatment and / or dose selection, a determination of blood lipid concentration should be made and, in accordance with the results, adjust the dose of the drug.

Family hypercholesterolemia

- heterozygous

The initial dose is 10 mg per day, the dose can be increased to 80 mg per day.

- homozygous

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. The maximum daily dose is 80 mg.

With simultaneous use with cyclosporine, the dose of atorvastatin should not exceed 10 mg per day.

In patients with hepatic insufficiency, care must be taken in connection with the delay in the excretion of the drug.Clinical and laboratory indicators should be closely monitored and, if abnormalities are detected, reduce the dose or discontinue treatment. If the patient has renal insufficiency, the concentration of atorvastatin in the blood plasma and its effect on the concentration of LDL cholesterol do not change. In this regard, dose adjustment for patients with kidney disease is not required. Dose adjustments for patients older than 70 years are not required.

Side effects:

To determine the incidence of side effects of the drug, the following classification is used:

Often (≥1/10)

Often (≥1/100 and <1/10)

Infrequently (≥1/1000 and <1/100)

Rarely (≥1/10 000 and <1/1000)

Very rarely (<10 000)

Allergic reactions: often - itchy skin, skin rash, contact dermatitis, rarely - urticaria, anaphylaxis, Quincke's edema, erythema multiforme exudative (Stevens-Johnson syndrome), toxin epidermal necrolysis (Lyell's syndrome), angioedema, anaphylactic shock, bullous eruptions. photosensitization.

From the central nervous system: often - insomnia, headache, asthenic syndrome; infrequently - dizziness, drowsiness, nightmarish dreams,paresthesia, amnesia, peripheral neuropathy, depression, hyperesthesia, malaise, fatigue, migraine.

From the skin: infrequently - alopecia.

From the genitourinary system: rarely - erectile dysfunction, secondary renal failure.

From the side of the musculoskeletal system: often - myalgia, arthralgia, back pain, joint swelling, pain in the limbs, muscle weakness, knee pain; infrequently - myopathy, convulsions; rarely - myositis, rhabdomyolysis, bursitis, myositis, tenosynovitis, tendopathy (in some cases with a rupture of the tendon).

From the digestive system: often - nausea, infrequently - heartburn, constipation or diarrhea, flatulence, abdominal pain, anorexia, belching, dysphagia, vomiting, hepatitis, pancreatitis, cholestatic jaundice, dysgeusia (a violation of taste perception).

On the part of the organs of hematopoiesis: rarely - thrombocytopenia.

From the side of the cardiovascular system: often - pain in the chest; rarely - palpitations, vasodilation, orthostatic hypotension, phlebitis, arrhythmia, increased blood pressure.

Laboratory indicators: rarely hyperglycemia, hypoglycemia, increase in the concentration of creatine phosphokinase (CK), increased serum aminotransferase (ACT, ALT), leukocyturia.

Other: rarely - weight gain, peripheral edema, tinnitus, gynecomastia, fever (fever), hearing loss, nasopharyngitis, epistaxis, sore throat, interstitial lung disease, immuno-mediated necrotising myopathy (there are several cases of development use of statins), blurred vision.

Overdose:Specific treatment in case of an overdose there. Treatment is symptomatic; take measures to maintain vital functions and prevent further absorption of the drug (gastric lavage, intake of activated charcoal). Due to the fact that the drug actively binds to blood plasma proteins, hemodialysis does not seem to be an effective way to accelerate its excretion from the body.

Interaction:

Because the atorvastatin is metabolized by the CYP3A4 isoenzyme in the liver, simultaneous use of atorvastatin with inhibitors of the isoenzyme CYP3A4 (ciclosporin, antibiotics (erythromycin, clarithromycin, quinupristin / delfopristin), HIV protease inhibitors (indinavir, ritonavir), antifungal agents (fluconazole, itraconazole, ketoconazole) or nefazodone) can 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 use with erythromycin tmax, atorvastatin increases by 40%.

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 CYP3A4 isoenzyme, may lead to a decrease in the efficacy of atorvastatin. Inhibitors of transport protein OAT31B1 (for example, ciclosporin) may increase the bioavailability of atorvastatin.

With the simultaneous use of antacids (a suspension of magnesium hydroxide and aluminum hydroxide) reduce the concentration of atorvastatin in the 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 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. It is necessary to control the choice of female contraceptives in women receiving atorvastatin.

The simultaneous use of atorvastatin with warfarin may in the first days increase the effect of warfarin on the coagulation factors (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 of protease with HIV inhibitors leads to an increase in the concentration of atorvastatin in 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.

The consumption of grapefruit juice during the period of application of atorvastatin may lead to an increase in the concentration of atorvastatin in the blood plasma. In this regard, patients receiving atorvastatin, should avoid the use of grapefruit juice more than 1.2 liters per day.

Special instructions:

Impaired liver function

The use of HMG-CoA reductase inhibitors to reduce lipid levels in the blood can lead to a change in biochemical parameters that reflect the function of the liver.The liver function should be monitored before treatment, 6 weeks, 12 weeks after the initiation of atorvastatin and after each dose increase, and periodically, for example, every 6 months. The change in hepatic transaminase activity is usually observed within the first three months after the onset of atorvastatin. Patients who have increased transaminase activity should be monitored until the transaminase activity returns to normal. In the event that ALT or ACT values are more than 3 times higher than the upper allowable limit, it is recommended to reduce the dose of atorvastatin or discontinue treatment.

Skeletal musculature

Patients with diffuse myalgia, lethargy or muscle weakness and / or a significant increase in CKK activity represent a risk group for the development of myopathy (defined as muscle pain with concomitant increase in CKK activity by more than 10 times the upper limit of normal). When prescribing combined therapy of atorvastatin with cyclosporine, fibrolic acid derivatives, erythromycin, clarithromycin, immunosuppressants, and antifungal drugs of azole structure,as well as nicotinic acid in lipid-lowering doses, it is necessary to compare the potential benefit and the degree of risk in this treatment and to monitor patients who show signs or symptoms of muscle pain, weakness or weakness, especially during the first months of treatment and with an increase in the dose of some from preparations. 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. With a differential diagnosis of chest pain, consideration should be given to the possibility of an increase in serum CPK activity when atorvastatin is used. The patient should immediately consult a doctor if unexplained pain or weakness in the muscles occurs, especially if accompanied by malaise and fever.

Women of reproductive age should use reliable methods of contraception.

Statins can increase the concentration of glucose in the blood plasma and lead to the manifestation of diabetes,However, in patients at risk of cardiovascular disease, the benefits of therapy exceed the risk of developing diabetes. Patients in the risk group need regular monitoring.

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

Care must be taken when driving vehicles and other technical devices that require a high concentration of attention and speed of psychomotor reactions.

Form release / dosage:Tablets, film-coated 10 mg, 20 mg.

Packaging:

For 10 or 15 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil.

By 2, 3, 4, 6, 9 or 10 contour mesh packages together with instructions for medical use are placed in a pack of cardboard box.

Storage conditions:In the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002326

Date of registration:12.12.2013 / 20.10.2014

Expiration Date:10.12.2018

The owner of the registration certificate:IZVARINO PHARMA, LLC IZVARINO PHARMA, LLC Russia

Manufacturer: & nbsp

IZVARINO PHARMA, LLC Russia

Information update date: & nbsp20.10.2014

Illustrated instructions

Instructions

Atorvastatin (Atorvastatin)