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

Excipients: lactose monohydrate - 0.09514 g or 0.1233 g Microcrystalline cellulose - or 0.01015 g 0.02080 g of calcium carbonate - or 0.02175 g 0.03120 g sodium croscarmellose (primelloza) - 0.00072 g or 0.00104 g, magnesium stearate 0.00145 g or 0.00208 g;

composition of the shell:

for dosage of 10 mg: Opadrai II White - 0.0049 g (polyvinyl alcohol, titanium dioxide, talc, macrogol (polyethylene glycol)), silicone emulsion - 0.0001 g;

for dosage of 20 mg: Opadrai II Blue - 0.00785 g (polyvinyl alcohol, titanium dioxide, talc, macrogol (polyethylene glycol), aluminum lacquer based on indigo carmine), silicone emulsion - 0.00015 g.

Description:The film-coated tablets are white (for 10 mg dosage) or blue (for a dosage of 20 mg), round, biconvex. Insignificant roughness of the surface is permissible. Color of tablets on a cross-section - from white to white with a yellow shade.

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 hypolipidemic agent from the group of statins. A selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, a precursor of sterols, including cholesterol. Triglycerides (TG) 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. Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma, inhibiting 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 TG by 14-33%; causes an increase in concentration cholesterol-HDL (high-density lipoprotein) and apolipoprotein A. Dose-dependent lowers the concentration of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.

Pharmacokinetics:

Absorption is high. The maximum concentration (Cmah) in the blood plasma is achieved after 1-2 hours, Cmah in women is higher by 20%, the area under the curve "concentration-time" (AUC) - lower by 10%; With hepatic insufficiency in patients with alcoholic cirrhosis of the liver (on the scale Child-Pugh B) Cmah and AUC increase by 16 and 11 times, respectively.

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. 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.

Bioavailability - 12%, systemic bioavailability of inhibitory activity against HMG-CoA reductase - 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 distribution is 381 liters, communication with plasma proteins is 98%. Metabolized mainly in the liver under the action of the isoenzyme CYP3A4 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 circulating metabolites.

It is excreted with bile after hepatic and / or extrahepatic metabolism (it does not undergo significant intestinal hepatic recirculation).

Half-life is 14 hours. The inhibitory activity against HMG-CoA reductase is maintained for about 20-30 hours due to the presence of active metabolites. Less than 2% of the dose taken internally is determined in the urine. It is not excreted during hemodialysis.

Indications:

Atorvastatin is used:

- in combination with a diet to reduce the elevated concentrations of total cholesterol, cholesterol / LDL, apolipoprotein B and triglycerides, and increase HDL cholesterol in patients with primary hypercholesterolemia, heterozygous familial and non-family hypercholesterolemia, and combined hyperlipidemia (types IIa and IIb by Fredrickson);

- in combination with a diet for the treatment of patients with elevated serum concentrations of triglycerides (type IV according to Fredrickson) and patients with disbetalipoproteinemia (type III according to Fredrickson),in which diet therapy does not provide an adequate effect;

- to reduce the concentration of total cholesterol and cholesterol / LDL in patients with homozygous familial hypercholesterolemia, when diet therapy and other non-pharmacological treatments are not effective enough.

Contraindications:

- hypersensitivity to the components of the drug;

- active liver disease or increased activity of "hepatic" enzymes of unknown origin (more than 3 times compared with the upper limit of the norm);

- hepatic insufficiency (degree of severity on the scale Child-Pugh A and B)

- pregnancy;

- lactation period;

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

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

Carefully:Alcohol abuse, liver disease in history, severe electrolyte imbalance, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, extensive surgical interventions, injuries, skeletal muscle diseases.

Pregnancy and lactation:

Atorvastatin is contraindicated for use during pregnancy and lactation (breastfeeding). 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.

Women of reproductive age during treatment should use adequate methods of contraception. Atorvastatin can be used in 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.

Dosing and Administration:

Before using atorvastatin, the patient should be recommended a standard lipid-lowering diet, which he must continue to observe during the entire period of therapy.

The initial dose is on average 10 mg 1 time / day. The dose varies from 10 to 80 mg 1 pac / d. The drug can be taken at any time of the day with food or whatever time it takes to eat. 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 atorvastatin, it is necessary to monitor the concentration of lipids in the blood plasma every 2-4 weeks and adjust the dose accordingly.

Primary hypercholesterolemia and mixed hyperlipidemia, and type III and IV according to Fredrickson.

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

Homozygous familial hypercholesterolemia.

Apply in a dose of 80 mg (4 tablets of 20 mg) once a day.

The use of the drug in patients with renal insufficiency and kidney disease does not affect the level of Atorvastatin in blood plasma or the degree of decrease in cholesterol / LDL when it is used, therefore, a change in the dose of the drug is not required.

For hepatic insufficiency, the dose should be reduced (see "With caution" and "Special instructions").

When using the drug in elderly patients, there were no differences in safety, effectiveness, or achievement of lipid-lowering therapy goals in comparison with the general population.

Side effects:

According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1 / 10000, <1/1000) and very rarely (<1/10000), including individual messages; frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

From the immune system: often - allergic reactions; very rarely anaphylaxis.

From the central and peripheral nervous system: often - headache; infrequent - dizziness, sleep disturbances, including insomnia and nightmarish dreams, asthenic syndrome, weakness, paresthesia, hypesesthesia, loss or loss of memory; rarely: peripheral neuropathy.

From the digestive tract: often - constipation, flatulence. dyspepsia, nausea, diarrhea; infrequently - anorexia, vomiting, pancreatitis, hepatitis. abdominal pain; rarely - cholestatic jaundice (including obstructive); very rarely liver failure.

From the musculoskeletal system and connective tissue: often - myalgia, arthralgia, "swelling" joints, joint pain, back pain; infrequently - muscle cramps, pain in the muscles of the neck; rarely - myopathy, myositis, rhabdomyolysis,Tendonopathy (sometimes complicated by a rupture of the tendon).

From the senses: infrequently - noise in the ears, blurred vision; very rarely: hearing loss.

From the skin and subcutaneous fat: rarely - hives, skin rash and itching, alopecia; rarely - angioedema, bullous rash, polymorphic exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

On the part of the endocrine system: often - hyperglycemia, increased activity of serum creatinine phosphokinase (CK), increased activity of "liver" transaminases; infrequently - hypoglycemia.

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

From the respiratory system: often - nasopharyngitis, sore throat, nosebleed.

Other: often - peripheral edema; infrequently - increased fatigue, weight gain, potency, leukocyturia, secondary renal failure, fever, chest pain; very rarely - gynecomastia, diabetes mellitus; frequency is unknown - depression, interstitial lung disease (especially with prolonged therapy), sexual dysfunction, increased glycosylated hemoglobin.There are separate reports on the development of atonic fasciitis (a connection with the use of atorvastatin is not exactly established).

Overdose:

Treatment: there is no specific antidote, symptomatic therapy is performed.

Hemodialysis is ineffective.

Interaction:

The risk of myopathy during treatment with other drugs of this class is increased with the simultaneous use of cyclosporine, fibrates, erythromycin, clarithromycin, immunosuppressive, antifungal agents related to azoles, and nicotinic acid in lipid-lowering doses.

With simultaneous administration of atorvastatin and a suspension containing magnesium and aluminum hydroxide, Atorvastatin concentrations in the blood plasma were reduced by approximately 35%, however, the degree of decrease in cholesterol / LDL concentration remained unchanged.

With simultaneous application Atorvastatin does not affect the pharmacokinetics of phenazone (antipyrine), so the interaction with other agents metabolized by the same isoenzymes of cytochrome CYP AP4 is not expected.

With the simultaneous use of colestipol, the concentration of atorvastatin in the blood plasma was reduced by approximately 25%.However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.

With repeated use of digoxin and atorvastatin in a dose. 10 mg the equilibrium concentrations of digoxin in the plasma of 1 fev did not change. However, when using digoxin in combination with Atorvastatin in a dose of 80 mg / day. The concentration of digoxin increased by about 20%. Patients receiving digoxin in combination with Atorvastatin should be observed.

With the simultaneous use of atorvastatin and erythromycin (500 mg 4 times / day) or clarithromycin (500 mg 2 times / day), which inhibit the isoenzyme CYP ZA4, there was an increase in the concentration of atorvastatin in the blood plasma.

With the simultaneous use of atorvastatin (10 mg 1 time / day) and azithromycin (500 mg 1 time / day), the concentration of atorvastatin in plasma did not change.

Atorvastatin did not have a clinically significant effect on the concentration of terfenadine in the blood plasma, which is metabolized mainly by the isoenzyme CYP ZA4; in this connection it seems unlikely that Atorvastatin can significantly affect the pharmacokinetic parameters of other isoenzyme substrates CYP 3A4.

With the simultaneous use of atorvastatin and a contraceptive for oral administration, containing norethisterone and ethinyl estradiol, there was a significant increase AUC norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively. This effect should be considered when choosing an oral contraceptive for a woman receiving Atorvastatin.

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

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

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

There was no clinically significant undesirable interaction of Atorvastatan and hypotensive drugs.

The simultaneous use of atorvastatin with protease inhibitors, known as isoenzyme inhibitors CYP ZA4, was accompanied by an increase in the concentration of atorvastatin in blood plasma.

Pharmaceutical incompatibility is unknown.

Special instructions:

Before starting therapy with atorvastatin, the patient should be assigned a standard hypocholesterolemic diet, which he must observe during the entire treatment period. 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 therapy, 6 weeks, 12 weeks after the start of Atorvastatin and after each dose increase, and periodically, for example, every 6 months. An increase in the activity of "hepatic" enzymes in the serum can be observed during therapy with Atorvastatin. Patients with a marked increase in enzyme activity should be monitored before the enzyme activity returns to normal. In the event that the values of alanine aminotransferase (ALT) or aspartate aminotransferase (ACT) more than 3 times higher than the upper limit, it is recommended to reduce the dose of atorvastatin or stop treatment.

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

Treatment with atorvastatin may cause myopathy. The diagnosis of myopathy (pain and weakness in muscles combined with an increase in CKK activity by more than 10 times compared with the upper limit of normal) should be observed in patients with common myalgias, tenderness or weakness of the muscles and / or a marked increase in CKK activity. Patients should be warned that they should immediately inform the doctor of unexplained pain or weakness in the muscles if they are accompanied by a malaise or fever.

Therapy with Atorvastatin should be discontinued in the event of a marked increase in the activity of CKK or in the presence of confirmed or suspected myopathy. The risk of myopathy during treatment with other drugs of this class increases with simultaneous use with cyclosporine, fibrates, erythromycin, clarithromycin, immunosuppressive, antifungal agents related to azoles, and nicotinic acid in lipid-lowering doses.Many of these drugs inhibit isoenzyme mediated metabolism CYP AP4, and / or transport of medicinal products. Atorvastatin biotransformed by isoenzyme CYP AP4. Applying Atorvastatin simultaneously with fibrates, erythromycin, immunosuppressive agents, azole antifungal agents or nicotinic acid in lipid-lowering doses, the expected benefit and risk of treatment should be carefully weighed and patients monitored regularly to identify pain or weakness in the muscles, especially during the first months of treatment and during the period of increase dose of any drug. In such situations, it is possible to recommend a periodic determination of the activity of CKK, although such control does not prevent the development of severe myopathy.

When using Atorvastatin, as well as other drugs of this class, cases of rhabdomyolysis with acute renal failure due to myoglobinuria are described. Therapy Atorvastatin should be temporarily discontinued or completely, canceled if there is evidence of possible myopathy or the presence of a risk factor for developing renal failure against rhabdomyolysis (for example, severe, acute infection,Arterial hypotension, extensive operative surgical interventions, trauma, severe metabolic, endocrine and electrolyte disorders and uncontrolled convulsions).

Before starting therapy with atorvastatin, it is necessary to try to achieve control of hypercholesterolemia by adequate dietotherapy, increased physical activity, weight loss in obese patients and treatment of other conditions.

There are reports of the development of atonic fasciitis in the background of Atorvastatin, however, the association with the drug is possible, but has not been proven to date, the etiology is unknown.

Effect on the ability to drive transp. cf. and fur:The adverse effect of atorvastatin on the ability to drive vehicles and work with mechanisms was not reported.

Form release / dosage:

Tablets, film-coated, 10 mg and 20 mg.

Packaging:

For 7 or 10 tablets in a contour mesh package.

By 1,2,3 or 4 contour mesh packages together with instructions for use in a cardboard pack.

Storage conditions:

In a dry, 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 after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000142

Date of registration:12.01.2011

The owner of the registration certificate:BIOKOM, CJSC BIOKOM, CJSC Russia

Manufacturer: & nbsp

BIOKOM, CJSC Russia

Information update date: & nbsp26.06.2014

Illustrated instructions

Instructions

Atorvastatin (Atorvastatin)