ANVISTAT

Active material: Atorvastatin
When ATH: C10AA05
CCF: Lipid-lowering drugs
ICD-10 codes (testimony): E78.0, E78.1, E78.2
When CSF: 16.01.01
Manufacturer: Antiviral NPO ZAO (Russia)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, Film-coated white or white with weak yellowish Sheen colors, oblong, with Valium on one side.

Excipients: colloidal silicon dioxide, Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose.

The composition of the coating film: gipromelloza, talc, Titanium dioxide (E171).

7 PC. – packings Valium planimetric (2) – packs cardboard.
10 PC. – packings Valium planimetric (3) – packs cardboard.

Pills, Film-coated white or white with weak yellowish Sheen colors, oblong, with Valium on one side.

Excipients: colloidal silicon dioxide, Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose.

The composition of the coating film: gipromelloza, talc, Titanium dioxide (E171).

7 PC. – packings Valium planimetric (2) – packs cardboard.
10 PC. – packings Valium planimetric (3) – packs cardboard.

Pills, Film-coated white or white with weak yellowish Sheen colors, oblong, with Valium on one side.

Excipients: colloidal silicon dioxide, Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose.

The composition of the coating film: gipromelloza, talc, Titanium dioxide (E171).

7 PC. – packings Valium planimetric (2) – packs cardboard.
10 PC. – packings Valium planimetric (3) – packs cardboard.

Pharmacological action

Synthetic drug-lowering. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase – enzyme, defines the speed limit of the biosynthesis of cholesterol, responsible for the conversion of 3-Hydroxy-3-methyl-gljutaril-Coenzyme a in mevalonat, the predecessor of sterols, including cholesterol.

In the liver, triglycerides and cholesterol are included in the very low density lipoprotein (VLDL), arrive in blood plasma and are transported to the peripheral tissues. From VLDL formed low-density lipoproteins (LDL), which katabolizirujutsja mainly through interaction with vysokoaffinnymi LDL receptor.

Atorvastatin reduces levels of cholesterol and lipoproteins in the blood plasma through inhibition of HMG-CoA reductase inhibitors and the synthesis of cholesterol in the liver, as well as by increasing the number of “Hepatic” LDL receptors on the surface of cells, increases grip and LDL katabolizaciju.

Atorvastatin reduces LDL products and the number of LDL particles. Atorvastatin calls and persistent increase in LDL receptor activity coupled with favorable changes in the quality of circulating LDL particles.

Dozozawisimo reduces the level of LDL in patients with homozygous hypercholesterolemia is hereditary, resistant to therapy with other lipid means.

Study dose and response showed, that atorvastatin reduces total cholesterol (on 30-46%), LDL cholesterol (on 41-61%), apolipoprotein B (on 34-50%) and triglycerides (on 14-33%), at the same time causing, in varying degrees,, increased levels of cholesterol-HDL and apolipoprotein (a). These results were similar in patients with heterozygous Familial Hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed Hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus.

Due to lower levels of total cholesterol, LDL cholesterol and apolipoprotein in decreases the risk of cardiovascular disease and, respectively, decreases the risk of death. Study of the effect of atorvastatin on mortality and morbidity has not yet completed.

Pharmacokinetics

Absorption and distribution

Absorption – high. C_max plasma levels achieved after 1-2 no. Food reduces the speed and duration of drug absorption (on 25% and 9% respectively), However lowering cholesterol-LDL is similar to that in the application of atorvastatin without food. Concentrations of atorvastatin when applied in the evening below, than in the morning (approximately 30%). Revealed a linear relationship between the degree of suction and dose of medication.

Bioavailability – 12%, System bioavailability inhibiting activity against HMG-CoA reductase inhibitors – 30%. Low system bioavailability due to presistemnym metabolism in GASTROINTESTINAL mucosa and in the first passage through the liver.

Average V_d – 381 l, the link with blood plasma proteins – 98 %.

Metabolism

Metabolised mainly in the liver under the influence of the CYP 3A4 Isoenzymes, CYP 3A5 and 3A7 CYP with the formation of pharmacologically active metabolites (ortho- paragidroksilirovannyh and derivatives, beta-oxidation products). In vitro Ortho- and paragidroksilirovannye metabolites have an inhibitory effect on the g-KOA-reduktazu, comparable to that of atorvastatin. Ingibiruty effect of the drug in respect of the HMG-CoA reductase inhibitors by approximately 70% is determined by the activity of circulating metabolites.

Deduction

Return to jelchew after liver and/or vnepechenochnogo metabolism (It does not undergo pronounced enterohepatic recirculation). T_1/2 – 14 no. Inhibiting activity against g-KOA-reduktaza about 20-30 h thanks to active metabolites. Less 2% from the inside of the dosage is determined in the urine. Not displayed during hemodialysis.

Pharmacokinetics in special clinical situations

C_max women up 20%, а AUC – below on the 10 %.

C_max in patients with alcoholic cirrhosis 16 time, а AUC – in 11 times higher than normal.

Testimony

— combined with a diet to reduce elevated total cholesterol levels, cholesterol-LDL, Apolipoprotein b and triglycerides and increase HDL cholesterol in patients with primary hypercholesterolemia, heterozygous Familial Hypercholesterolemia and precluded from accompanying and combination (mixed) hyperlipidaemia (Types IIa and IIb of Fredrickson).

— in combination with diet for the treatment of patients with elevated serum triglyceride levels (Type IV by Fredriksonu) and patients with disbetalipoproteinemiej (Type III by Fredriksonu), whose diet does not give adequate effect;

-to reduce the levels of total cholesterol and LDL-cholesterol in patients with homozygous Familial Hypercholesterolemia, When diet and other non-pharmacological therapies are insufficient.

Dosage regimen

Is inwards at any time of the day regardless of the meal. Before starting therapy with Anvistat^® You should try to control hypercholesterolemia through diet, exercise and lower body mass index in patients with obesity, as well as the treatment of the underlying disease.

Before applying the product the patient must be transferred to a standard diet, cholesterol, and should continue to enforce this diet during treatment with.

The initial dose is 10 mg 1 time / day. Daily dose of the drug varies from 10 to 80 mg. Dose should be selected individually, taking into account the source of cholesterol-LDL, the goal of therapy and the patient's response to treatment. The maximum daily dose of the drug – 80 upon receipt mg 1 time / day. At the beginning and/or during the rise of the dosage must be every 2-4 weeks to monitor levels of lipids in the blood plasma and the dose adjusted accordingly.

At intervals of not less than 4 weeks should be a correction dose.

For patients with established CHD and other patients, with a high risk of coronary attacks, We recommend setting the following goals the correction of lipid levels: cholesterol LDL cholesterol less than 3.0 mmol / l (or less 115 mg / dL) and total cholesterol less than 5.0 mmol / l (or less 190 mg / dL).

At primary hypercholesterolemia and combined (mixed) giperlipidemii necessary control lipid levels in most patients is provided by reception 10 mg 1 time / day. Therapeutic effect is observed during 2 weeks and usually reaches its peak during 4 weeks.

At heterozygous Familial Hypercholesterolemia treatment should start with the appointment of 10 mg / day. Realizing individual dose every correction 4 of the week, should bring it to the 40 mg / day. You can then increase the dose up to a maximum level, equal 80 mg / day, or use a combination of the value 40 mg Anvistat^® and sekvestranta bile acids.

At homozygous Familial Hypercholesterolemia administered at a dose of 80 mg 1 time / day.

Any dose adjustment at patients renal failure not required, tk. violations of the kidney do not affect the concentrations of atorvastatin in plasma or reduction of LDL-Cholesterol with drug therapy Anvistat^®.

At hepatic insufficiency doses should be reduced under the constant supervision of transaminaz liver (ACT and ALT).

If you are using the drug in elderly patients differences in security, efficiency or achieving the goal of cholesterol-lowering treatment in comparison with the general population not noted, dose adjustment is required.

If necessary, the joint use of ziklosporinom dose Anvistat^® should not exceed 10 mg.

Side effect

Frequently (≥1%)

CNS: insomnia, headache, asthenic syndrome.

From the digestive system: nausea, diarrhea, abdominal pain, dyspepsia, flatulence, constipation.

On the part of the musculoskeletal system: myalgia.

Less often (<1%)

CNS: malaise, dizziness, amnesia, paresthesia, perifericheskaya neuropathy, gipesteziya.

From the digestive system: vomiting, anorexia, hepatitis, pancreatitis, holestatitcheskaja jaundice.

On the part of the musculoskeletal system: backache, muscle cramps, myositis, myopathy, myalgia, arthralgia, raʙdomioliz.

Allergic reactions: hives, itching, rash, anaphylactic reactions, bullous rash, polymorphous ekssoudatus Erythema (incl. Stevens-Johnson syndrome), Lyell's syndrome (toxic epidermal necrolysis).

From the hematopoietic system: thrombocytopenia.

Metabolism: Hypo- or hyperglycemia, increased activity of serum CPK.

Other: impotence, peripheral edema, weight gain, chest pain, secondary renal failure, alopecia, noise in ears, fatigue.

Contraindications

— active liver disease or liver transaminaz (more than 3 fold compared with CAH) unknown origin;

- Liver failure (the severity of a and b for classification of Child-Pugh);

- Pregnancy;

- Lactation (breast-feeding);

- Up to 18 years (efficacy and safety have not been established);

- Hypersensitivity to the drug.

C caution should be used in patients, alcohol abusers; with indications the disease on liver disease.

Pregnancy and lactation

Anvistat^® contraindicated during pregnancy. Women of reproductive age at the time of treatment must use reliable methods of contraception.

The preparation may be nominated women of reproductive age only, if the probability of pregnancy have a very low, and the patient informed of possible risks of treatment for fetus.

The drug is contraindicated during breast-feeding. Unknown, whether the drug in breast milk. In view of the possibility of adverse events in infants, If necessary, use during lactation should decide the issue of termination of breastfeeding.

Cautions

Before starting therapy with Anvistat^® the patient you want to assign standard gipoholesterinovu diet, which he must comply during the entire treatment period.

The use of inhibitors of HMG-CoA reductase to reduce the level of lipids in the blood can lead to changes in biochemical parameters, reflecting liver function. Liver function should be monitored before therapy, through 6 weeks, through 12 weeks after you start taking the drug, and after each dose increase, and periodically, eg, every 6 months. Increase in liver enzymes in the serum may occur during drug therapy. Patients, have noted increased activity of enzymes, should be controlled prior to returning to normal enzymes. In the case of strong ALT activity or ACT to the level, exceeding more than 3 times the upper limit of, It is recommended that you reduce the dose or stop treatment.

Anvistat^® should be used with caution in patients, alcohol and/or have liver disease. Active liver disease or persistent increase in liver transaminaz ambiguous Genesis serves as a contraindication to prescription drug. Drug treatment, like other inhibitors of HMG-CoA reductase inhibitors, can cause myopathy. Diagnosis of myopathy (pain and weakness in the muscles, combined with the increased activity of the KLF more than 10 times compared with FHG) should be considered in patients with common mialgijami, pain or weakness of muscles and/or expressed by increased activity of KFK.

Patients should be warned about that, that they should immediately inform the doctor about the emergence of unexplained pain or weakness in the muscles, If they are accompanied by malaise or fever.

Therapy should be discontinued in the case of explicit activity KLF or if there is a confirmed or suspected myopathy. The risk of myopathy during treatment of other drugs of this class has increased, while the use of Cyclosporine, fibrate, Erythromycin, Nicotinic Acid in lipidsnizhajushhih doses or azole antifungals. Many of these drugs inhibit the metabolism of, mediated cytochrome P450 3A4, and/or transport drugs. Atorvastatin biotransformiroetsa under the influence of izofermenta CYP3A4.

Assigning product Anvistat^® in combination with fibratami, Erythromycin, immunosupressivei means, azole fungicide or Nicotinic Acid at doses of lipidsnizhajushhih, You should carefully weigh the expected benefits and risks of treatment and regularly monitor patients with the aim of identifying pain or weakness in the muscles, especially during the first months of treatment and dose of any drug enhancement period. In such situations, it is possible to recommend periodic determination of activity of KFK, Although such control does not allow you to prevent the development of severe myopathy.

In applying the drug Anvistat^®, like other tools of this class, Describes cases of rhabdomyolysis with acute renal failure, caused by myoglobinuria. Drug therapy should temporarily suspend or Cancel when you see signs of possible myopathy or the existence of a risk factor for the development of renal failure on the background of rhabdomyolysis (eg, severe acute infection, hypotension, a serious operation, trauma, heavy Exchange, metabolic and electrolyte disorders and uncontrolled convulsions).

Effects on ability to drive vehicles and management mechanisms

Information on the adverse effects of the drug on the ability to drive and to engage in potentially hazardous activities, require high concentration and speed of psychomotor reactions, no.

Overdose

Treatment: No specific antidote; simptomaticescuu and supportive care as needed. Needed to be monitored liver and serum CPK level. Hemodialysis nyeeffyektivyen.

Drug Interactions

The risk of myopathy during treatment of inhibitors of HMG-CoA reductase inhibitors is increased when you use them in combination with cyclosporin, fiʙratami, makrolidnymi antibiotics (including erythromycin, clarithromycin), azole fungicide or Nicotinic Acid at doses of lipidosnizhajushhih. In some rare cases the data combinations cause rhabdomyolysis, accompanied by renal insufficiency in connection with by myoglobinuria. Concerning, a thorough assessment of the risk and benefits of combined treatment.

Atorvastatin metabolism is carried out with the participation of izofermenta zitohroma r450 3A4. When using atorvastatin in combination with inhibitors izofermenta zitohroma r450 3A4 (eg, cyclosporine, makrolidnymi antibiotics, eg, Erythromycin and clarithromycin, nefazodone, azole antifungal drugs, eg, itraconazole, and HIV protease inhibitors) drug interactions can occur. The combined use of drugs can be elevated concentrations of atorvastatin in plasma. Concerning, You should exercise extreme caution when using atorvastatin combined with the aforementioned means of.

The simultaneous use of drugs, reduces the concentration of endogenous steroid hormones (incl. cimetidine, ketoconazole, spironolactone), It increases the risk of reducing the endogenous steroid hormones (Caution should be exercised).

Atorvastatin and its metabolites are substrates for p-glycoprotein. P-glycoprotein inhibitors (eg, cyclosporine) may increase the bioavailability of atorvastatin.

Together with the use of atorvastatin and erythromycin (500 mg 4 times / day) or == (500 mg 2 times / day), that inhibit CYP cytochrome P450 3A4, There was an increase in concentrations of atorvastatin in plasma.

Together with the use of atorvastatin (10 mg 1 time / day) and azithromycin (500 mg 1 time / day) plasma atorvastatin concentrations did not change.

The combined application of atorvastatin dose 40 mg of itraconazole in dose 200 mg 1 times/SUT revealed an increase in AUC to the level, exceeded the norm by 3 times.

The combined application of atorvastatin with protease inhibitors, known as inhibitors izofermenta zitohroma r450 3A4, accompanied by increases in the concentrations of atorvastatin in plasma (together with the use of erythromycin (C)_max Atorvastatin is increased by 40%).

Combined application of atorvastatin dose 40 mg with diltiazem dose 240 mg leads to increased concentrations of atorvastatin in plasma.

Grapefruit juice contains at least one ingredient, the inhibitor izofermenta CYP3A4, and may cause an increase in the concentration of plasma products, which are metabolized izofermentami CYP 3A4. Daily consumption 240 ml grapefruit juice increased the AUC of atorvastatin on 37% and AUC of the active-metabolita ortogidroksi on 20.4%. Consumption of large amounts of grapefruit juice (more 1.2 l/day for 5 days) increased AUC of atorvastatin in 2.5 times, (a) the AUC of the active inhibitor of HMG-CoA reductase inhibitors (Atorvastatin + its metabolites) – in 1.3 times. The consumption of large quantities of grapefruit juice during treatment is not recommended atorvastatin is appropriate.

Effect of drugs, inducing cytochrome P450 3A4 (eg, rifampicin or jefavirenz), on atorvastatin is unknown. Interaction with atorvastatin is appropriate and other substrates this izofermenta unknown, However, the possibility of these interactions should be considered when using drugs with a low therapeutic index – in particular, class III antiarrhythmics, eg, amiodarona.

The risk of myopathy, called atorvastatin is appropriate, may increase with concomitant use of fibrate. In vitro studies suggest that, What is gemfibrozil may interact with atorvastatin is appropriate through his inhibiting glukuronirovania, What can cause increased concentrations of atorvastatin in plasma.

The readmission of Digoxin and atorvastatin dose 10 mg equilibrium concentration of Digoxin in plasma is not changed. But, in the application of Digoxin in combination with atorvastatin is appropriate in a dose 80 mg/day concentration of Digoxin increased by about 20%. Sick, receiving digoxin combined with atorvastatin is appropriate, require appropriate monitoring.

Reception of atorvastatin in combination with oral contraceptive, contains norethisterone and ethinyl estradiol, caused increased concentrations of norethisterone and ethinyl estradiol in the blood plasma. These increasing concentrations should be considered when selecting doses of oral contraceptives. Together with the use of atorvastatin and oral contraceptive, contains norethisterone and ethinyl estradiol, There was a significant increase in AUC of ethinyl estradiol and norethisterone approximately 30% and 20% respectively. This effect should be taken into account when choosing oral contraceptive for women, receiving atorvastatin.

When taking kolestipola in combination with atorvastatin is appropriate it was noted reduced concentrations of atorvastatin in plasma approximately 25%. But, the combined application of atorvastatin and kolestipola effects on lipids was more pronounced, than using each of these drugs individually.

Together with the use of atorvastatin dose 10 mg 1 times/day and dose of azithromycin 500 mg 1 times/SUT atorvastatin concentration in plasma is not changed.

Together with the use of atorvastatin and clinically significant changes of terfenadine indicators pharmacokinetics not detected.

While ingestion of atorvastatin and suspension, containing magnesium and aluminium hydroxides, Atorvastatin concentration in plasma decreased by approximately 35%; However, the degree of decline in the level of LDL-Cholesterol while not changed.

When taking atorvastatin in combination with varfarinom noted a slight reduction of prothrombin time in the early days of admission of atorvastatin; However, in the coming 15 days indicator protrombinovogo time returning to normal. Nonetheless, in the case of a joint application of atorvastatin and warfarin, patients should be carefully monitored.

Together with the use of atorvastatin does not affect the farmakokinetiku Phenazone, Therefore, interaction with other tools, those same cytochrome izofermentami is not expected.

Study of the combined introduction of cimetidine and atorvastatin not identified meaningful interaction between drugs.

When combined with the introduction 80 mg atorvastatin and 10 mg amlodipina changes farmakokineticeskih parameters of atorvastatin in equilibrium have been identified.

No clinically significant interactions atorvastatin and antigipertenziveh funds. Research of interaction with all specific drugs have been conducted.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

B. list the drug should be stored in a dry, protected from light, inaccessible to children at temperature not exceeding 25 ° C. Shelf life – 3 year.