Anvistat - instructions for use, doses, side effects, contraindications

Active substance: atorvastatin calcium trihydrate 10.823 mg / 21.646 mg / 43.293 mg (equivalent to 10 mg / 20 mg / 40 mg atorvastatin, respectively).

Excipients: silicon dioxide colloidal - 1,546 mg / 3,092 mg / 6,1856 mg, croscarmellose sodium 1.546 mg / 3.092 mg / 6.1866 mg, lactose monohydrate 123.715 mg / 247.430 mg / 494.856 mg, magnesium stearate 1.546 mg / 3.092 mg / 6.1856 mg, microcrystalline cellulose - 15.464 mg / 30.928 mg / 61.856 mg.

Film Sheath: hypromellose - 4,800 mg / 9,600 mg / 19,200 mg, talc 0.160 mg / 0.320 mg / 0.640 mg, titanium dioxide (E171) 0.400 mg / 0.800 mg / 1.600 mg.

Description:Tablets white or white with a weak yellowish tinge of color, oblong form, covered with a film membrane, with a risk on one side.

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:

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that determines the limiting rate of cholesterol biosynthesis responsible for the conversion of 3-hydroxy-3-methyl-glutaryl coenzyme A to mevalonate, a precursor of sterols, including cholesterol; synthetic hypolipidemic agent. In the liver, triglycerides and cholesterol are included in very low density lipoproteins (VLDL), enter the blood plasma and are transported to peripheral tissues. Low density lipoproteins (LDL) are formed from VLDL, which are catabolized primarily through interaction with high-affinity LDL receptors.

Atorvastatin lowers cholesterol and lipoprotein levels in the blood plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver,as well as by increasing the number of "hepatic" LDL receptors on the surface of cells, increasing the uptake and catabolization of LDL. Atorvastatin reduces the production of LDL and the number of particles of LDL. Atorvastatin causes a pronounced and persistent increase in the activity of LDL receptors in combination with favorable changes in the quality of the circulating LDL particles.

Dose-dependent decreases the level of LDL in patients with homozygous hereditary hypercholesterolemia, resistant to therapy with other hypoglycemic agents.

Dose-response studies have shown that atorvastatin reduces the level of total cholesterol (by 30-46%), LDL cholesterol (by 41-61%), apolipoprotein B (by 34-50%) and triglycerides (by 14-33%), simultaneously causing, to some extent, an increase in HDL cholesterol 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.

In connection with a decrease in the level of total cholesterol, LDL cholesterol and apolipoprotein B reduces the risk of cardiovascular diseases and, accordingly, reduces the risk of death.Studies of the effects of atorvastatin on mortality and morbidity have not yet been completed.

Pharmacokinetics:

Absorption is high. Maximum concentration (C_max) in the blood plasma is achieved in 1-2 hours. C_max in women higher by 20%, the area under the curve "concentration-time" (AUC) - lower by 10%; C_max 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. 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 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 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:

In combination with a diet to reduce elevated levels of total cholesterol, LDL cholesterol, 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 by Fredrickson), in which diet 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 effective enough.

Contraindications:

Hypersensitivity to the components of the drug.

Active liver disease or increased activity of "liver" enzymes of unknown origin (more than 3 times compared with the upper limit of the norm).

Hepatic insufficiency (degree of severity according to Child-Pugh A and B classification).

Pregnancy.

Lactation period.

Age to 18 years (effectiveness and safety not established).

Carefully:

Abuse of alcohol, liver disease in history.

Pregnancy and lactation:

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

The drug 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

The drug is contraindicated for use during breastfeeding. It is not known whether the drug is excreted in breast milk. Considering the possibility of undesirable phenomena in infants, if it is necessary to use the drug during lactation, the question of stopping breastfeeding should be solved.

Dosing and Administration:

Inside. Take at any time of the day, regardless of food intake.

Before starting therapy, the drug should try to achieve control of hypercholesterolemia with diet, exercise and weight loss in obese patients, as well as therapy for the underlying disease.

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

Usually, the initial dose is 10 mg once a day. The dose varies from 10 to 80 mg / day. Doses should be selected individually, taking into account the initial level of LDL cholesterol, the purpose of therapy and the patient's response to treatment.The maximum daily dose of the drug for a single dose is 80 mg.

At the beginning and / or during an increase in the dose of the drug, it is necessary to monitor the levels of lipids in the blood plasma every 2-4 weeks and adjust the dose accordingly.

At intervals of at least 4 weeks, dose adjustment should be performed. The maximum daily dose is 80 mg.

For patients with established ischemic heart disease and other patients at high risk of coronary attacks, the following goals for correcting lipid levels are recommended: LDL cholesterol less than 3.0 mmol / L (or less than 115 mg / dL) and total cholesterol less than 5.0 mmol / l (or less than 190 mg / dL).

Primary hypercholesterolemia and combined (mixed hyperlipidemia

In most patients, the necessary control of lipid levels is provided by taking 10 mg of the drug 1 time per day. The therapeutic effect is observed for 2 weeks and usually reaches a maximum within 4 weeks.

Heterozygous familial hypercholesterolemia

Treatment of patients should begin with the appointment of 10 mg of the drug per day. Carrying out individual correction of the dose every 4 weeks, it should be brought to 40 mg / day.After this, you can increase the dose to a maximum level of 80 mg / day, or use the combined administration of 40 mg of the drug Anvistat® and the sequestrant of bile acids.

Homozygous familial hypercholesterolemia

Assign a dose of 80 mg once a day.

In patients with renal insufficiency

Renal impairment does not affect the concentration of atorvastatin in the blood plasma or the degree of decrease in LDL-C during treatment with the drug Anistat®, therefore, there is no need for any dose adjustment in patients with kidney disease.

In patients with hepatic insufficiency

In case of hepatic insufficiency, the dose should be reduced, with the constant monitoring of the activity of "liver" transaminases: aspartate aminotransferase (ACT) and alanine aminotransferase (ALT) (see "With caution" and "Special instructions").

In elderly patients

When using the drug in elderly patients, there was no difference in safety, effectiveness, or achievement of the goal of lipid-lowering therapy in comparison with the general population, no dose adjustment is required.

Use in combination with other medicines

If a joint application with cyclosporine is required, the dose of the drug should not exceed 10 mg (see section "Special instructions").

Side effects:

Most often (1% or more): insomnia, headache, asthenic syndrome; nausea, diarrhea, abdominal pain, indigestion, flatulence, constipation; myalgia.

Less often (less than 1%):

From the central nervous system: malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia.

From the digestive tract: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.

From the musculoskeletal system: back pain, muscle cramps, myositis, myopathy, myalgia, arthralgia, rhabdomyolysis.

Allergic reactions: urticaria, skin itching, rash, anaphylactic reactions, bullous rash, polymorphic exudative erythema (including Stevens-Johnson syndrome), Lyell's syndrome (toxic epidermal necrolysis).

From the hematopoiesis: thrombocytopenia.

From the side of metabolism: hypo- or hyperglycemia, increased serum creatine phosphokinase (CK) activity.

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

Overdose:

There is no specific antidote. In case of an overdose, the necessary symptomatic and supportive therapy should be carried out as necessary. It is necessary to monitor the function of curing the level of CK in serum. Hemodialysis is ineffective.

Interaction:

The risk of myopathy when treated with HMG-CoA reductase inhibitors is increased when used in combination with cyclosporine, fibrates, macrolide antibiotics (including erythromycin, clarithromycin), azole antifungal agents or nicotinic acid in lipid-lowering doses.

In some rare cases, these combinations cause rhabdomyolysis, accompanied by renal insufficiency in connection with myoglobinuria. AT Due to this, a thorough evaluation of the risk-benefit ratio of the combined treatment is necessary (see section "Special instructions").

Inhibitors of cytochrome P450 isoenzymes ZA4

The metabolism of atorvastatin is carried out with the participation of the cytochrome P450 isoenzyme ZA4. When using atorvastatin in combination with cytochrome P450 ZA4 isoenzyme inhibitors (for example, cyclosporine, macrolide antibiotics, for example, erythromycin and clarithromycin, nefazodone,azole antifungals, for example, itraconazole, and HIV protease inhibitors), drug interactions may occur. With combined use of drugs, there may be increased concentrations of atorvastatin in the blood plasma. In this regard, caution should be exercised when using atorvastatin in combination with the aforementioned agents (see section "Special instructions").

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).

P-glycoprotein inhibitors

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

Erythromycin, clarithromycin

With the simultaneous use of atorvastatin and erythromycin (500 mg 4 times / day) or clarithromycin (500 mg 2 times / day), which inhibit the isoenzyme of cytochrome P450 3A4, 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.

Itraconazole

With the combined use of atorvastatin 40 mg and itraconazole at a dose of 200 mg once a day, an increase AUC To a level that exceeded the norm by three times.

Inhibitors of proteases

Simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the cytochrome P450 isoenzyme ZA4, was accompanied by an increase in the concentration of atorvastatin in the blood plasma (with simultaneous use with erythromycin CmAtorvastatin increases by 40%).

Diltiazem

Joint use of atorvastatin in a dose of 40 mg with diltiazem at a dose of 240 mg, leads to an increase in the concentration of atorvastatin in blood plasma.

Grapefruit juice

Grapefruit juice contains at least one ingredient that is an inhibitor of the isoenzyme CYP3A4, and can cause an increase in the concentration in the plasma of those drugs that are metabolized by isoenzymes CYP3A4. Daily intake of 240 ml of grapefruit juice increased AUC by 37% and reduced the area under the curve "concentration of active orthohydroxy metabolite in plasma-time" by 20.4%.Consumption of a large amount of grapefruit juice (more than 1.2 liters per day for 5 days) increased AUC atorvastatin 2.5 times, and AUC the active inhibitor of HMG-CoA reductase (atorvastatin + its metabolites) - in 1,3 times. Consumption of large quantities of grapefruit juice during treatment with atorvastatin is not recommended.

Inductors of the cytochrome isoenzyme P450 3A4

The effect of drugs inducing cytochrome P450 A3 (for example, rifampicin or efavirenz), on atorvastatin is unknown. Interactions with atorvastatin and other substrates of this isoenzyme are not known; however, the possibility of these interactions should be taken into account when using drugs with a low therapeutic index - in particular, class III antiarrhythmics, for example, amiodarone.

Gemfibrosil / Fibrates

The risk of myopathy caused by atorvastatin may increase with the concomitant use of fibrates. Research in vitro suggest that gemfibrozil can also interact with atorvastatin by inhibiting its glucuronation, which can cause an increase in the concentrations of atorvastatin in the blood plasma (cf.section "Special instructions").

Digoxin

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, with the use of digoxin in combination with atorvastatin at a dose of 80 mg / day, the digoxin concentration increased by about 20%. Patients receiving digoxin in combination with atorvastatin, require appropriate monitoring.

Oral contraceptives

The administration of atorvastatin in combination with an oral contraceptive containing norethisterone and ethinyl estradiol, caused an increase in the concentrations of norethisterone and ethinyl estradiol in blood plasma. These increases in concentration should be considered when choosing doses of oral contraceptives. With the simultaneous use of atorvastatin and a contraceptive for oral administration containing norethisterone and ethinyl estradiol, there was a significant increase AUC norethisterone and ethinyl estradiol by approximately 30% and 20%, respectively. This effect should be considered when choosing an oral contraceptive for a woman receiving atorvastatin.

Kolestypol

When taking colestipol in combination with atorvastatin, there was a decrease in the concentration of atorvastatin in the blood plasma by approximately 25%.However, with the combined use of atorvastatin and colestipol, the effect on lipids was more pronounced than with each of these drugs alone.

Azithromycin

With the simultaneous use of atorvastatin 10 mg once a day and azithromycin 500 mg once a day, the concentration of atorvastatin in the blood plasma did not change.

Terfenadine

With the simultaneous use of atorvastatin and terfenadine, clinically significant changes in pharmacokinetics were not detected.

Antacids

With simultaneous ingestion of atorvastatin and a suspension containing magnesium and aluminum hydroxide, the concentration of atorvastatin in blood plasma decreased by approximately 35%; but the degree of decrease in the level of LDL-C was not changed.

Warfarin

When taking atorvastatin in combination with warfarin, there was a slight decrease in prothrombin time in the first days of atorvastatin administration; However, in the next 15 days the prothrombin time returned to normal. However, in the case of combined use of atorvastatin and warfarin, patients should be carefully monitored.

Fenazone

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

Cimetidine

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

Amlodipine

With the combined administration of 80 mg of atorvastatin and 10 mg of amlodipine, there was no change in the pharmacokinetic parameters of atorvastatin in the equilibrium state.

Other

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

Special instructions:

Before starting therapy with the drug Anistat®, the patient should be assigned a standard hypocholesterol 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 start of the drug 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 the drug. Patients who have an increase in enzyme activity should be monitored before the enzyme level returns to normal. 3 cases of persistent increase in ALT activity or ACT to a level that exceeds the upper limit by more than 3 times, it is recommended to reduce the dose of the drug or stop treatment.

Anvistat® 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 "hepatic" transaminases of an unknown genesis serves as a contraindication to the administration of the drug.

Treatment with the drug, like other inhibitors of HMG-CoA reductase, can cause myopathy. The diagnosis of myopathy (pain and weakness in muscles combined with an increase in CKK activity of more than 10 times compared with the upper limit of normal) should be discussed in patients with common myalgia, 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 about the appearance of unexplained pains or weakness in the muscles, if they are accompanied by malaise or fever!

The drug should be discontinued in the event of a marked increase in the activity of CK 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 in lipid-lowering doses or azole antifungal agents. Many of these drugs inhibit cytochrome P450 mediated metabolism of AP4, and / or drug transport. Atorvastatin biotransformed by isoenzyme CYP3A4.

When prescribing the drug Anvistat® in combination 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 treatment and during the period 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 the drug Anvistat®, as well as other drugs of this class, cases of rhabdomyolysis with acute renal failure due to myoglobinuria are described. The drug should be temporarily discontinued or completely discontinued if there is evidence of possible myopathy or a risk factor for developing renal failure with rhabdomyolysis (eg severe acute infection, arterial hypotension, severe surgery, trauma, severe metabolic, endocrine and electrolyte disturbances and uncontrolled seizures).

Before starting therapy with the drug, 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.

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

Data on the adverse effect of the drug on the ability to drive and engage in potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions, no.

Form release / dosage:

Tablets coated with a film membrane 10, 20, 40 mg.

Packaging:

For 7 or 10 tablets in a contour non-jammed package.

2 contour non-jawed packs of 7 tablets or 3 contour non-jawed packages of 10 tablets together with instructions for use 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-007167/09

Date of registration:10.09.2009 / 18.10.2012

Expiration Date:Unlimited

The owner of the registration certificate:Anvilab, OOO Anvilab, OOO Russia

Manufacturer: & nbsp

VIZAG PHARMACEUTICALS (P), Ltd. India

Representation: & nbspAnviLab Ltd AnviLab Ltd Russia

Information update date: & nbsp02.09.2017

Illustrated instructions

Instructions

Anvistat® (Anvistat®)