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

Excipients: calcium carbonate - 33.00 / 66.00 mg. cellulose microcrystalline - 48,00 / 96,00 mg, lactose monohydrate (sugar milk) - 23,85 (47,70 mg,starch pregelatinized (starch 1500) - 32.80 / 65.60 mg, silicon colloidal dioxide (aerosil) 0.75 / 1.50 mg, magnesium stearate 0.75 / 1.50 mg, polyvinyl alcohol 2.50 / 5.00 mg, macrogol (polyethylene glycol) 1.26 / 2.52 mg, talc 0.93 / 1.86 mg, titanium dioxide -1.56 / 3.12 mg.

Description:Biconvex tablets coated with a white film coating.

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 cholesterol and lipoprotein levels in the blood plasma by 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 level of LDL in patients with homozygous familial hypercholesterolemia, which usually does not respond to lipid-lowering drugs. Reduces the level of total cholesterol by 30-46%, LDL by 41-61%, apolipoprotein B by 34-50% and TG by 14-33%; causes an increase in HDL cholesterol (high-density lipoprotein) and apolipoprotein A. Dozozavisimo reduces the level 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%; 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 of Atorvastatin without food. Atorvastatin concentrations are lower in evening use than in the morning (approximately 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 influence of cytochrome 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 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 elevated levels of total cholesterol, cholesterol / LDL, apolipoprotein B and triglycerides, and 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 the treatment of patients with elevated serum triglyceride levels (Fredrickson type IV) and patients with disbetalipoproteinemia (type III Fredrickson), in whom 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-Pug A and B classification)

- Pregnancy;

- lactation period;

- age under 18 years (efficiency 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 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 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.

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

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.

Homozygous familial hypercholesterolemia.

Assign 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:

From the nervous system: more often 2% - insomnia, dizziness; less than 2% - headache, asthenia, malaise, drowsiness, nightmarish dreams, paresthesia, peripheral neuropathy, amnesia, emotional lability, ataxia, facial paralysis, hyperkinesia, migraine, depression, hypoesthesia, loss of consciousness.

From the sense organs: less than 2% - amblyopia, ringing in the ears, dryness of the conjunctiva, disruption of accommodation, bleeding in the retina, deafness, glaucoma, parosmia, loss of taste, taste distortion.

From the cardiovascular system: more often 2% - chest pain; less than 2% - palpitation, symptoms of vasodilation, orthostatic hypotension, increased blood pressure, phlebitis, arrhythmia, angina.

On the part of the hematopoiesis system: less than 2% - anemia, lymphadenopathy, thrombocytopenia.

From the respiratory system: more often 2% - bronchitis, rhinitis; less than 2% - pneumonia, dyspnoea, exacerbation of bronchial asthma, nosebleeds.

Co side of the digestive system: more often 2% - nausea; less than 2% - heartburn, constipation or diarrhea, meteorism, gastralgia, abdominal pain, decreased or increased appetite, dry mouth, belching, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosive ulcerous lesions of the oral mucosa, gastroenteritis, hepatitis, biliary colic, cheilitis, ulcer Duodenum, pancreatitis, cholestatic jaundice, impaired liver function, rectal bleeding, melena, bleeding gums, tenesmus.

From the musculoskeletal system: more often 2% - arthritis; less than 2% - leg muscle cramps, bursitis, tendosinovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonia, joint contractures.

From the genitourinary system: more often 2% - urogenital infections, peripheral edema; less often 2% - 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 2% - alopecia, xeroderma, increased sweating, eczema, seborrhea, ecchymosis, petechiae.

Allergic reactions: less often 2% - skin itching, skin rash, contact dermatitis, rarely urticaria, angioedema, facial edema, photosensitivity, anaphylaxis, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Laboratory indicators: less than 2% - hyperglycemia, hypoglycemia, increased serum CK, albuminuria.

Other: less than 2% - weight gain, gynecomastia, mastodynia, exacerbation of gout.

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, antifungal agents,related to azoles and nicotinic acid.

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 the antipyrine (phenazone), so 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 digoxin concentration 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 ZA4,an increase in the concentration of atorvastatin in blood plasma was observed.

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 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.

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.

No clinically significant adverse effects of atorvastatin and antihypertensive agents have been observed.

The simultaneous use of atorvastatin with protease inhibitors, known as cytochrome P450 inhibitors of ZA4, was accompanied by an increase in the concentration of atorvastatin in 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.Increased activity of "liver" enzymes in the blood serum may occur during therapy with atorvastatin. Patients with elevated levels of enzymes should be monitored until the enzyme level returns to normal. In that case, if the values of alanine aminotransferase (ALT) or asparaginaminotransferazy (ACT) more than 3 times higher than the level of the upper allowable limit, it is advisable to reduce the dose of atorvastatin or discontinue 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. Diagnosis myopathy (pain and weakness in the muscles in combination with increased activity of creatine phosphokinase (CK) more than 10 times compared with the upper limit of normal) should be discussed in patients with advanced myalgia, pain, or muscle weakness, and / or a marked increase of CPK 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 in treatment with other drugs of this class was increased with the simultaneous use of cyclosporine, fibrates, erythromycin, nicotinic acid or azole antifungal agents. Many of these drugs inhibit cytochrome P450 mediated metabolism of AP4, and / or drug transport. Atorvastatin biotransformed by action CYP AP4. Assigning Atorvastatin in combination with fibrates, erythromycin, immunosuppressive agents, 50 antifungal agents or nicotinic acid in lipid-lowering / doses, the expected benefit and risk of treatment should be carefully weighed and monitored regularly patients with the purpose of revealing 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 diet therapy, increased physical activity, weight loss in obese patients and treatment of 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:

On the adverse effects of atorvastatin on the ability to drive and work with mechanisms were not reported.

Form release / dosage:

Tablets film-coated 10 mg and 20 mg.

Packaging:

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

1, 2, 3, 4 or 5 contour squares 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:LSR-005205/08

Date of registration:03.07.2008 / 02.04.2013

Expiration Date:Unlimited

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

Manufacturer: & nbsp

ALSI Pharma, ZAO Russia

Information update date: & nbsp05.10.2017

Illustrated instructions

Instructions

Atorvastatin (Atorvastatin)