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

Excipients: calcium carbonate 35.4 / 70.8 mg, cellulose microcrystalline 24.0 / 48.0 mg, StarKap1 500 [corn starch and pregelatinized starch] 53.6 / 107.2 mg, silicon dioxide colloid (aerosil) 400/800 μg, talc 1.6 / 3.2 mg, magnesium stearate 1.6 / 3.2 mg,opadrai II (series 85) (polyvinyl alcohol 2.56 / 5.12 mg, macrogol 1.29 / 2.58 mg, talc 0.94 / 1.89 mg, titanium dioxide 1.56 / 3.13 mg, dye iron oxide yellow 0.032 / 0.064 mg, ferric oxide red oxide 0.00128 / 0.00256 mg) 6.4 / 12.8 mg.

Description:Round biconvex tablets covered with a film coat of light yellow color with a brownish tinge. On the cross-section - the inner layer of white or white with a cream color 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 converting 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 interaction with the LDL receptor. Atorvastatin reduces the levels of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase,the synthesis of cholesterol in the liver and the increase in the number of "liver" receptors of LDL on the surface of cells, 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 level of LDL in patients with homozygous familial hypercholesterolemia, which usually does not respond to lipid-lowering therapy. Reduces the level of total cholesterol by 30-46%, LDL by 41-61%, apolipoprotein B by 34-50% and TG by 14-33%; increases the level of cholesterol-HDL cholesterol (high-density lipoproteins density) and apolipoprotein A. Dose-dependent decreases the level of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering agents.

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%; FROMmah in patients with alcoholic cirrhosis of the liver 16 times, AUC - 11 times higher than normal.

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 with atorvastatin without food.Concentration of atorvastatin when used in the evening 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 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 during the "primary passage" through the liver.

Average - volume of distribution - 381 l, communication with blood plasma proteins - 98%. Metabolized mainly in the liver with the participation 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 parahydroxylated 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.

If the liver function is significantly impaired (Cmax approximately 16 times, AUC approximately 11 times) in patients with alcoholic liver cirrhosis (class B on the Child-Pugh scale); Atorvastatin concentrations in elderly patients over 65 years of age are higher (Cmah about 40%, AUC approximately 30%) than in adult patients of a young age; renal dysfunction does not affect the concentration of atorvastatin in the blood plasma or its effect on the lipid profile, therefore, dose adjustments in patients with impaired renal function are not required.

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 elevated levels of total cholesterol, cholesterol / LDL, apolipoprotein B and triglycerides, and an increase in 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, treatment of patients with elevated serum levels of triglycerides (type IV by Fredrickson) and patients with disbetalipoproteinemia (type III according to Fredrickson), in which diet therapy does not provide an adequate effect;

- to reduce total cholesterol and cholesterol / LDL cholesterol 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 according to Child-Piuga A and B classification);

- pregnancy;

- lactation period;

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

Carefully:Alcohol abuse, liver disease in history, severe water-electrolyte balance disorders, 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 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.

Dosing and Administration:

Before the appointment of 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 time / day. The maximum daily dose of the drug is 80 mg.

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 levels 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 levels of lipids in the blood plasma every 2-4 weeks and adjust the dose accordingly. To ensure the following dosage regimen, the drug can be used

Atorvastatin in another dosage form: film-coated tablets, 10 and 20 mg each.

When administered simultaneously with cyclosporine, the daily dose of atorvastatin should not exceed 10 mg.

Primary hypercholesterolemia and mixed hyperlipidemia

In most cases, it may be sufficient to prescribe 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.

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

In case of liver failure, the dose should be reduced (see "With caution" and "Special instructions").

When the drug is used in elderly patients, differences in safety, efficacy, or achievement of lipid-lowering therapy goals in comparison with the general the population was not noted.

Side effects:

From the nervous system: more often 1% - insomnia, dizziness; less than 1% - headache, asthenia, malaise, drowsiness, nightmarish dreams, paresthesia, peripheral neuropathy, amnesia, emotional lability, ataxia, facial nerve paralysis, hyperkinesia, depression, hyperesthesia, loss of consciousness.

From the sense organs: less than 1% - amblyopia, ringing in the ears, dryness of the conjunctiva, disruption of accommodation, eye hemorrhage, deafness, glaucoma, parosmia, loss of taste sensations, perversion of taste.

From the cardiovascular system: more often 1% - chest pain; less than 1% - palpitations, vasodilation, migraine, orthostatic hypotension, increased blood pressure, phlebitis, arrhythmia, angina.

On the part of the hematopoiesis system: less than 1% - anemia, lymphadenopathy, thrombocytopenia, leukocyturia.

From the respiratory system: more often 1% - bronchitis, rhinitis; less than 1% - pneumonia, dyspnea, bronchial asthma, nosebleeds.

From the digestive system: more often 1% - nausea; less than 1% - heartburn, constipation or diarrhea, meteorism, gastralgia, abdominal pain, anorexia, a decrease or increase in appetite, dryness of the oral mucosa, belching, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosive ulcerative lesions of the oral mucosa, gastroenteritis, hepatitis, biliary colic , cheilitis, ulcer of duodenum, pancreatitis, cholestatic jaundice, impaired liver function, rectal bleeding, melena, bleeding gums, tenesmus.

From the musculoskeletal system: more often 1% - arthritis; less than 1% - leg muscle cramps, bursitis, tendosinovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonia, joint contractures, joint swelling, tendonitis (in some cases with tendon rupture).

From the genitourinary system: more often 1% - urogenital infections, peripheral edema; less than 1% - dysuria (including pollakiuria, nocturia,urinary incontinence or urinary retention, mandatory urges to urinate), nephritis, hematuria, vaginal bleeding, nephrourolythiasis, metrorrhagia, epididymitis, decreased libido, impotence, ejaculatory impairment.

From the skin: more often 1% - alopecia, xeroderma, increased sweating, eczema, seborrhea, ecchymosis, petechiae.

Allergic reactions: less often 1% - skin itching, skin rash, contact dermatitis, rarely - hives, angioedema, edema localized in the face, photosensitivity, anaphylaxis, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (syndrome Lyell).

Laboratory indicators: less than 1% hyperglycemia, hypoglycemia, increased serum CK, albuminuria.

Other: less often 1%,- weight gain, gynecomastia, mastodynia, exacerbation of gout.

Overdose:

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

Hemodialysis is ineffective.

Interaction:

With simultaneous use of atorvastatin with cyclosporine, HIV protease inhibitors (indinavir, ritonavir), antibiotics (erythromycin, clarithromycin, quinupristin / dalfopristin), antifungal agents from the group of azoles (fluconazole, itraconazole, ketoconazole), nefazodone, fibroblast derivatives acid, nicotinic acid or diltiazem - the concentration of atorvastatin in the plasma increases, which increases the risk of myopathy with rhabdomyolysis and acute renal failure.

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

With simultaneous application Atorvastatin does not affect the pharmacokinetics of antipyrine, therefore interaction with other agents metabolized by the same isoenzymes of cytochrome is not expected.

With simultaneous application of colestipol, concentrations of atorvastatin in blood plasma decreased by approximately 25%. However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug individually. With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma 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 cytochrome P450 3A4, there was an increase in the concentration of atorvastatin in blood plasma.

Atorvastatin had no clinically significant effect on the concentration of terfenadine in the blood plasma, which is metabolized mainly by cytochrome P450 3A4; in this connection, it seems unlikely that Atorvastatin can significantly affect the pharmacokinetic parameters of other substrates of cytochrome P450 3A4. With the simultaneous use of atorvastatin and a contraceptive for oral administration containing norethindrone 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.

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.

The simultaneous use of atorvastatin with protease inhibitors, known as cytochrome P450 inhibitors of ZA4 (grapefruit juice), was accompanied by an increase concentration of atorvastatin in the blood plasma, in this regard, you should avoid the use of this juice.

There was no clinically significant undesirable interaction between Atorvastatin and antihypertensives, as well as with estrogens. Studies of interaction with all specific drugs have not been conducted.

The simultaneous use of atorvastatin with isoenzyme inducers CYP3A4 (efavirenz, rifampicin) leads to an increase in the concentration of the drug in the blood plasma.

Pharmaceutical incompatibility is not known.

Special instructions:

Before starting therapy with atorvastatin, the patient should be prescribed 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 indicators that reflect liver function.The liver function should be monitored before the start of therapy, 6 weeks, 12 weeks after the initiation 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 who have an increase in enzyme activity should be monitored before the enzyme level returns to normal. In the event that the values of alanine aminotransferase (ALT) or asparagine 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 the activity of aminotransferases of unknown origin serve as contraindications to the administration of atorvastatin.

Treatment with atorvastatin may cause myopathy. The diagnosis of myopathy (pain and weakness in muscles combined with an increase in activity of creatine phosphokinase (CK) more than 10 times compared with the upper limit of the norm) should be discussed in patients with common myalgia,muscle soreness or weakness and / or a marked increase in CKK activity. Patients should be warned that they should immediately inform the doctor about the occurrence of unexplained pain or weakness in the muscles, if they are accompanied by 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 in the treatment of other drugs in this class are increased while the use of cyclosporine, fibrates, erythromycin, nicotinic acid or antifungal agents, azole derivatives. Many of these drugs inhibit metabolism mediated by cytochrome P450 ZA4, and / or transport of drugs. Atorvastatin biotransformed by action CYP AP4. Assigning Atorvastatin in combination with fibrates, erythromycin, immunosuppressive agents, antifungal agents, an azole derivative or nicotinic acid in the lipid-lowering doses should carefully weigh the potential benefits and risks of treatment and regularly monitor patients to detect pain or weakness in muscles, especially during the first months of treatment and during periods of increasing the 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. Atorvastatin should be temporarily discontinued or completely discontinued if there is evidence of possible myopathy or the presence of a risk factor for developing renal failure against rhabdomyolysis (eg, severe acute infection, arterial hypotension, severe surgery, trauma, severe metabolic, endocrine and electrolyte disturbances and uncontrolled convulsions).

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

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

Care should be taken when driving and working with machines, as there is a risk of dizziness.

Form release / dosage:

The film coated tablets are 40 mg and 80 mg.

Packaging:

For 10 tablets in a contour mesh box made of PVC film and aluminum foil printed lacquered. 100 tablets per can of polymer.

1, 2, 3, 4 or 5 contour mesh packages with instructions in a pack of cardboard or 1 can of polymer with instruction in a pack of cardboard.

Storage conditions:

In a dry, protected from light 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-001283

Date of registration:25.11.2011

The owner of the registration certificate:ALSI Pharma, ZAO ALSI Pharma, ZAO Russia

Manufacturer: & nbsp

ALSI Pharma, ZAO Russia

Information update date: & nbsp25.11.2011

Illustrated instructions

Instructions

Atorvastatin (Atorvastatin)