2010/09/20

Anvistat

Composition, structure and packing

Tablets, film-coated white or white with a slight yellowish tint, oblong shape, with risks on one side.

1 tab. atorvastatin calcium trihydrate 10,823 mg, which corresponds to the content of atorvastatin 10 mg.

Other ingredients: silicon dioxide colloidal, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose.

The composition of the shell membrane: gipromelloza, talc, titanium dioxide (E171).

Tablets, film-coated white or white with a slight yellowish tint, oblong shape, with risks on one side.

1 tab. atorvastatin calcium trihydrate 21,646 mg, which corresponds to the content of atorvastatin 20 mg.

Other ingredients: silicon dioxide colloidal, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose.

The composition of the shell membrane: gipromelloza, talc, titanium dioxide (E171).

Tablets, film-coated white or white with a slight yellowish tint, oblong shape, with risks on one side.

1 tab. - Atorvastatin calcium trihydrate 43,293 mg, which corresponds to the contents of atorvastatin 40 mg.

Other ingredients: silicon dioxide colloidal, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose.

The composition of the shell membrane: gipromelloza, talc, titanium dioxide (E171).

Clinico-pharmacological group

Lipid lowering drugs.

Pharmacological action

Synthetic lipid lowering drugs. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase - the enzyme that determines the ultimate speed of cholesterol biosynthesis, responsible for the transformation of 3-hydroxy-3-methyl-glyutaril-coenzyme A to mevalonate, the precursor of sterols, including cholesterol.

In the liver, triglycerides and cholesterol are included in the very low density lipoproteins (VLDL), enter the blood plasma and transported to peripheral tissues. Because VLDL formed low-density lipoprotein (LDL), which kataboliziruyutsya primarily through interaction with the high affinity LDL.

Atorvastatin reduces levels of cholesterol and lipoproteins in blood plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver, as well as by increasing the number of "liver" of LDL receptors on the cell surface, which increases the capture and katabolizatsiyu LDL.

Atorvastatin decreases the production of LDL and LDL particle number. Atorvastatin is pronounced and persistent increase in LDL receptor activity coupled with favorable changes in the quality of circulating LDL particles.

Dose-dependent manner reduces the level of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.

Research dose ratio and the reaction showed that atorvastatin reduced total cholesterol (by 30-46%), LDL cholesterol (by 41-61%), apolipoprotein B (by 34-50%) and triglycerides (by 14-33%), simultaneously causing, in varying degrees, increased levels of HDL cholesterol and apolipoprotein A. These results were similar in patients with heterozygous familial hypercholesterolemia, non-family forms of hypercholesterolemia and mixed hyperlipidemia, including patients with insulin-dependent diabetes mellitus.

In connection with the reduction in total cholesterol, LDL cholesterol and apolipoprotein B decreased risk of cardiovascular disease and, consequently, decreases the risk of death. Study the impact of atorvastatin on morbidity and mortality has not yet been completed.

Pharmacokinetics

Absorption and distribution

Absorption - high. Cmax plasma levels achieved in 1-2 hours on a meal reduces the rate and duration of the absorption of the drug (25% and 9% respectively), but the decrease in LDL cholesterol similar to that in the application of atorvastatin without food. The concentration of atorvastatin when used in the evening is lower than in the morning (approximately 30%). Revealed a linear relationship between absorption rate and dose of the drug.

Bioavailability - 12%, systemic bioavailability of inhibitory activity against HMG-CoA reductase - 30%. The low systemic bioavailability due presistemnym metabolism in the mucosa of the gastrointestinal tract and the first passage through the liver.

The average Vd - 381 hp, the relationship with blood plasma proteins - 98%.

Metabolism

Metabolised mainly in the liver under the influence of isoenzymes CYP 3A4, CYP 3A5 and CYP 3A7 to the formation of pharmacologically active metabolites (ortho-and paragidroksilirovannyh derivatives, products of beta-oxidation). In vitro ortho-and paragidroksilirovannye metabolites exert an inhibitory effect on HMG-CoA reductase, comparable with that of atorvastatin. Inhibitory effect of the drug on HMG-CoA reductase by about 70% is determined by the activity of circulating metabolites.

Withdrawal

Is derived from the bile after liver and / or extrahepatic metabolism (not subject to pronounced enterohepatic recirculation). T1 / 2 - 14 hours inhibitory activity against HMG-CoA reductase saved about 20-30 h due to the presence of active metabolites. Less than 2% of the accepted oral dose of the drug determined in the urine. Not shown in the course of hemodialysis.

Pharmacokinetics in special clinical situations

Cmax in women above 20%, and AUC - below 10%.

Cmax in patients with alcoholic liver cirrhosis in 16 times, and the AUC - 11 times above normal.

Indications for use of the drug
in combination with diet to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides and raising HDL-cholesterol in patients with primary hypercholesterolemia, heterozygous familial and non-family hypercholesterolemia and combined (mixed) hyperlipidemia (Types IIa and IIb of Fredrickson) .
in combination with diet for treatment of patients with elevated serum levels of triglycerides (type IV according to Fredrickson) and patients with disbetalipoproteinemiey (type III according to Fredrickson), in which nutritional therapy does not provide an adequate effect;
to reduce the levels of total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, when diet therapy and other non-pharmacological treatments are not sufficiently effective.

Dosage regimen

Is the inside at any time regardless of the meal. Before therapy with Anvistat ® should try to control hypercholesterolemia with diet, exercise and weight loss in patients with obesity, as well as treating the underlying disease.

Prior to the use of the drug the patient should be transferred to a standard diet, lowers cholesterol, and should continue to respect this diet during drug treatment.

The initial dose is 10 mg 1 time / daily dose ranges from 10 to 80 mg. The dose should be selected individually based on the initial level of LDL cholesterol, the goals of therapy and patient response to treatment. The maximum daily dose - 80 mg when receiving 1 time / At the beginning and / or while increasing the dose every 2-4 weeks is necessary to control lipid levels in blood plasma and to adjust dose.

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

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

When the primary hypercholesterolemia and combined (mixed) hyperlipidemia necessary control lipid levels in most patients provided 10 mg of the drug 1 times. The therapeutic effect was observed within 2 weeks and usually reaches a maximum within 4 weeks.

In heterozygous familial hypercholesterolemia patients treated should begin with the appointment of 10 mg. Through individual dose adjustment every 4 weeks, you should bring it up to 40 mg. You can then increase the dose to a maximum level equal to 80 mg / or use a combination of the appointment of 40 mg of the drug Anvistat ® and sekvestranta bile acids.

In homozygous familial hypercholesterolemia prescribed a dose of 80 mg 1 time.

There was no dose adjustment in patients with renal insufficiency is not required because renal dysfunction does not affect the concentration of atorvastatin in plasma or the degree of reduction of Tc-LDL in the treatment of drug Anvistat.

When liver failure dose should be reduced under the constant supervision of the activity of hepatic transaminases (ACT and ALT).

When using the drug in elderly patients differences in the safety, efficacy or goal lipid-lowering therapy compared with the general population is not mentioned, dose adjustment is required.

If necessary, a joint application with cyclosporine dose Anvistat ® should not exceed 10 mg.

Side effect

The most common (≥ 1%)
From the CNS: insomnia, headache, asthenia syndrome.
On the part of the digestive system: nausea, diarrhea, abdominal pain, dyspepsia, flatulence, constipation.
The part of the musculoskeletal system: myalgia.

Less frequently (<1%)
From the CNS: malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia.
On the part of the digestive system: vomiting, anorexia, hepatitis, pancreatitis, jaundice holestatitcheskaya.
On the part of the musculoskeletal system: back pain, muscle cramps, myositis, myopathy, myalgia, arthralgia, rhabdomyolysis.

Allergic reactions: rash, itching, rash, anaphylactic reactions, bullous eruption, polymorphic exudative erythema multiforme (including Stevens-Johnson syndrome), Lyell syndrome (toxic epidermal necrolysis).
The part of the hemopoietic system: thrombocytopenia.
From the Metabolic: hypo-or hyperglycemia, increased activity of serum CK.

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

Contraindications to the use of the drug
active liver disease or increased activity of hepatic transaminases (more than 3 times compared with FHG) of unknown origin;
hepatic impairment (severity of A and B on the classification of Child-Pugh);
Pregnancy
Lactation (breastfeeding);
the age of 18 years (effectiveness and safety have not been established);
Hypersensitivity to the drug's components.

C should be used cautiously in patients who abuse alcohol, with indications in the history of the disease of the liver.

Pregnancy and lactation

Anvistat contraindicated in pregnancy. Women of reproductive age during treatment should use reliable methods of contraception.

The drug can be given to women of childbearing age only if the probability of pregnancy among them is very low, and the patient informed of the risks of treatment for the fetus.

The drug is contraindicated during breastfeeding. It is not known whether the drug is derived from breast milk. Given the possibility of adverse effects in infants, if necessary, use during lactation should decide on the termination of breastfeeding.

Application for violations of liver function

The drug is contraindicated in active liver disease or increased activity of hepatic transaminases (more than 3 times compared to FHG) of unknown origin, with liver failure (severity of A and B on the classification of Child-Pugh).

C caution should be used when specifying a history of the disease of the liver.

Application for violations of renal function

Dosage adjustment in patients with renal insufficiency is not required.

Cautions

Before therapy with Anvistat ® patient must assign standard hypolipidemic diet, which he must comply during the whole period of treatment.

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 starting therapy, after 6 weeks, 12 weeks after starting the drug and after each increasing dose, and periodically, eg every 6 months. Increased activity of liver enzymes in blood serum can be observed during drug therapy. Patients in whom there is an increase of enzyme activity should be under control until the return of enzyme levels back to normal. In the case of a persistent increase the activity of ALT or ACT to a level that exceeds more than 3 times the upper FHG, it is recommended to reduce the dose or stop treatment.

Anvistat should be used with caution in patients who abuse alcohol and / or have liver disease. Active liver disease or a persistent increase in liver transaminases of unknown origin is a contraindication to the use of the drug. Treatment of drug, like other inhibitors of HMG-CoA reductase may cause myopathy. The diagnosis of myopathy (pain and weakness in the muscles, combined with increased activity of CK more than 10 times compared to FHG) should be discussed in patients with widespread myalgia, tenderness or weakness of muscles and / or a pronounced increase in the activity of CK.

Patients need to warn that they should immediately inform your doctor about the appearance of unexplained pain or weakness in muscles, if they are accompanied by malaise or fever.

Drug therapy should be discontinued in the event of a pronounced increase in the activity of CK or in the presence of confirmed or suspected myopathy. The risk of myopathy during treatment with other drugs of this class increased, while use of cyclosporine, fibrates, erythromycin, nicotinic acid lipidsnizhayuschih doses or azolnyh antifungals. Many of these drugs inhibit the metabolism mediated by cytochrome P450 3A4, and / or transport of drugs. Atorvastatin biotransformiruetsya under the action of isoenzyme CYP3A4.

Appointing Anvistat drug in combination with fibrates, erythromycin, immunosuppressive means azolnymi antifungal medicines or nicotinic acid in lipidsnizhayuschih doses should carefully weigh the potential benefits and risks of treatment and regularly monitor patients to identify pain or weakness in muscles, especially during the first months of treatment and during increasing doses of any drug. In such situations, you can recommend a periodic determination of CK activity, although such control does not prevent the development of severe myopathy.

In applying the drug Anvistat, as other tools of this class, described cases of rhabdomyolysis with acute renal failure caused mioglobinuriey. Drug therapy should be suspended or completely cancel when the signs of a possible myopathy or presence of risk factors for renal insufficiency on the background of rhabdomyolysis (eg severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances and uncontrolled seizures).

Effects on ability to drive vehicles and management mechanisms

Data on the adverse effect of the drug on driving ability and engage in potentially hazardous activities that require high concentration and speed of psychomotor reactions, no.

Overdose

Treatment: No specific antidote; spend symptomatic and supportive therapy as needed. Required monitoring of liver function and levels of CK in serum. Hemodialysis is ineffective.

Drug Interactions

The risk of myopathy during treatment of inhibitors of HMG-CoA reductase is increased when used in combination with cyclosporine, fibrates, macrolide antibiotics (including erythromycin, clarithromycin), antifungal medicines azolnymi or nicotinic acid in the lipid-lowering doses. In some rare cases, these combinations cause rhabdomyolysis, accompanied by renal failure in connection with mioglobinuriey. In this connection, the need to carefully assess the ratio of risks and benefits of combined treatment.

Metabolism of atorvastatin carried out with the participation of CYP3A4 isoenzyme. When using atorvastatin in combination with the CYP3A4 isoenzyme inhibitors (eg, cyclosporine, macrolide antibiotics such as erythromycin and clarithromycin, nefazodonom, azolnymi antifungal agents, for example, itraconazole, and inhibitors of HIV protease) may have drug interactions. With the combined use of drugs may be elevated concentrations of atorvastatin in plasma. In this regard, it should be particularly cautious when using atorvastatin in combination with the aforementioned means.

The simultaneous use of drugs, which reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone), increases the risk reduction of endogenous steroid hormones (caution).

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

With simultaneous use of atorvastatin and erythromycin (500 mg 4) or clarithromycin (500 mg, 2), which inhibit the CYP3A4 isoenzyme, there was an increased concentration of atorvastatin in plasma.

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

With the combined use of atorvastatin at a dose of 40 mg and itraconazole in a dose of 200 mg 1 time / increase in AUC were found to levels that exceeded the rate of 3 times.

The simultaneous use of atorvastatin with inhibitors of proteases, known as inhibitors of CYP3A4 isoenzyme, was accompanied by an increase in the concentration of atorvastatin in plasma (with simultaneous application with erythromycin Cmax of atorvastatin increased by 40%).

The combined use of atorvastatin 40 mg with diltiazem 240 mg leads to increased concentrations of atorvastatin in plasma.

Grapefruit juice contains at least one ingredient, is an inhibitor of isoenzyme CYP3A4, and may cause an increase in plasma concentrations of those drugs that are metabolized by isoenzymes CYP 3A4. Daily consumption of 240 ml grapefruit juice increased the AUC of atorvastatin by 37% and AUC of active metabolite ortogidroksi-20.4%. Consuming large quantities of grapefruit juice (more than 1.2 l / 5 days) increased the AUC of atorvastatin 2.5-fold, a AUC of the active inhibitor of HMG-CoA reductase inhibitors (atorvastatin + its metabolites) - 1.3 times. Consumption of large quantities of grapefruit juice during treatment with atorvastatin is not recommended.

Effects of drugs that induce CYP3A4 (eg, rifampin or efavirenz) for atorvastatin is unknown. Interaction with atorvastatin and other substrates of this isoenzyme is not known, but the possibility of this interaction should be considered when using drugs with low therapeutic index - in particular, class III antiarrhythmics, such as amiodarone.

The risk of myopathy caused by atorvastatin may increase with concomitant use of fibrates. Studies in vitro suggest that gemfibrozil may also interact with atorvastatin through inhibition of its glyukuronirovaniya that can cause increasing concentrations of atorvastatin in plasma.

If readmission of digoxin and atorvastatin 10 mg equilibrium concentrations of digoxin in the blood plasma did not change. However, the application of digoxin in combination with atorvastatin at a dose of 80 mg / concentration of digoxin increased by about 20%. Patients receiving digoxin in combination with atorvastatin, require appropriate monitoring.

Acceptance of atorvastatin in combination with oral contraceptives containing norethisterone and ethinylestradiol caused an increase in the concentrations of norethisterone and ethinyl estradiol in the blood plasma. These increasing concentrations should be considered when choosing doses of oral contraceptives. With simultaneous use of atorvastatin and contraceptives for oral administration containing norethisterone and ethinylestradiol showed a significant increase in AUC norethisterone and ethinyl estradiol by approximately 30% and 20% respectively. This effect should be considered when selecting oral contraceptive for women receiving atorvastatin.

When receiving colestipol in combination with atorvastatin had decreased concentrations of atorvastatin in plasma by approximately 25%. However, the combined use of atorvastatin and colestipol effects on lipids was more pronounced than when using each of these drugs individually.

With simultaneous use of atorvastatin at a dose of 10 mg 1 time / and azithromycin 500 mg 1 time / concentration of atorvastatin in plasma did not change.

With simultaneous use of atorvastatin and terfenadina clinically significant changes in pharmacokinetic parameters were found.

In simultaneous ingestion of atorvastatin, and the suspension containing magnesium hydroxide and aluminum, the concentration of atorvastatin in plasma decreased by about 35%, but the degree of reduction of Tc-LDL is not changed.

When receiving atorvastatin in combination with warfarin noted a slight decrease in prothrombin time in the first days of receiving atorvastatin, but, in the next 15 days measure prothrombin time returned to normal. Nevertheless, in the case of joint use of atorvastatin and warfarin, patients should be carefully monitored.

With simultaneous use of atorvastatin does not affect the pharmacokinetics fenazona, so interaction with other drugs, is metabolized by the same cytochrome isoenzymes are not expected.

The study combined the introduction of cimetidine and atorvastatin did not reveal significant interaction between these drugs.

In the combined administration of atorvastatin 80 mg and 10 mg of amlodipine changes in pharmacokinetic parameters of atorvastatin in the equilibrium state has been identified.

There was no clinically significant undesirable interactions of atorvastatin and antihypertensive agents. Studies of interaction with all the specific drugs were not conducted.

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Drug prescription.

Terms and Conditions of storage

List B. The drug should be stored in dry, protected from light, away from children at or above 25 ° C. Shelf life - 3 years.