Anvistat^® (Tablets) Instructions for Use

Marketing Authorization Holder

AnviLab, LLC (Russia)

Manufactured By

Vizag Pharmaceuticals (P), Ltd. (India)

ATC Code

C10AA05 (Atorvastatin)

Active Substance

Atorvastatin (Rec.INN WHO registered)

Dosage Forms

	Anvistat®	Film-coated tablets, 10 mg: 14 or 30 pcs.
		Film-coated tablets, 20 mg: 14 or 30 pcs.
		Film-coated tablets, 40 mg: 14 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or white with a slight yellowish tint, oblong in shape, with a score on one side.

Excipients: colloidal silicon dioxide – 1.546 mg, croscarmellose sodium – 1.546 mg, lactose monohydrate – 123.715 mg, magnesium stearate – 1.546 mg, microcrystalline cellulose – 15.464 mg.

Film coating composition: hypromellose – 4.8 mg, talc – 0.16 mg, titanium dioxide (E171) – 0.4 mg.

7 pcs. – non-cell contour packs (2) – cardboard packs.
10 pcs. – non-cell contour packs (3) – cardboard packs.

Film-coated tablets white or white with a slight yellowish tint, oblong in shape, with a score on one side.

Excipients: colloidal silicon dioxide – 3.092 mg, croscarmellose sodium – 3.092 mg, lactose monohydrate – 247.43 mg, magnesium stearate – 3.092 mg, microcrystalline cellulose – 30.928 mg.

Film coating composition: hypromellose – 9.6 mg, talc – 0.32 mg, titanium dioxide (E171) – 0.8 mg.

7 pcs. – non-cell contour packs (2) – cardboard packs.
10 pcs. – non-cell contour packs (3) – cardboard packs.

Film-coated tablets white or white with a slight yellowish tint, oblong in shape, with a score on one side.

Excipients: colloidal silicon dioxide – 6.1856 mg, croscarmellose sodium – 6.1856 mg, lactose monohydrate – 494.856 mg, magnesium stearate – 6.1856 mg, microcrystalline cellulose – 61.856 mg.

Film coating composition: hypromellose – 19.2 mg, talc – 0.64 mg, titanium dioxide (E171) – 1.6 mg.

7 pcs. – non-cell contour packs (2) – cardboard packs.
10 pcs. – non-cell contour packs (3) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

A synthetic hypolipidemic drug. Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the enzyme that determines the rate-limiting step in cholesterol biosynthesis, responsible for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

In the liver, triglycerides and cholesterol are incorporated into very low-density lipoproteins (VLDL), enter the plasma, and are transported to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL and are catabolized primarily via interaction with high-affinity LDL receptors.

Atorvastatin reduces plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver, as well as by increasing the number of hepatic LDL receptors on the cell surface, which increases LDL uptake and catabolism.

Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin causes a pronounced and sustained increase in LDL receptor activity combined with beneficial changes in the quality of circulating LDL particles.

It dose-dependently reduces LDL levels in patients with homozygous hereditary hypercholesterolemia resistant to therapy with other hypolipidemic agents.

Dose-response studies have shown that Atorvastatin reduces total cholesterol (by 30-46%), LDL cholesterol (by 41-61%), apolipoprotein B (by 34-50%), and triglycerides (by 14-33%), while causing, to varying degrees, an increase in HDL cholesterol and apolipoprotein A levels. 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 the reduction in total cholesterol, LDL cholesterol, and apolipoprotein B levels, the risk of cardiovascular diseases and, accordingly, the risk of death is reduced. Studies on the effect of atorvastatin on mortality and morbidity are not yet completed.

Pharmacokinetics

Absorption and Distribution

Absorption is high. C_max in plasma is reached in 1-2 hours. Food slightly reduces the rate and extent of drug absorption (by 25% and 9%, respectively), but the reduction in LDL cholesterol is similar to that with atorvastatin taken without food. The concentration of atorvastatin when taken in the evening is lower than in the morning (by approximately 30%). A linear relationship between the degree of absorption and the drug dose was found.

Bioavailability is 12%, systemic bioavailability of HMG-CoA reductase inhibitory activity is 30%. The low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and during first-pass through the liver.

Mean V_d is 381 L, plasma protein binding is 98%.

Metabolism

It is metabolized mainly in the liver by the action of isoenzymes CYP 3A4, CYP 3A5, and CYP 3A7 to form pharmacologically active metabolites (ortho- and para-hydroxylated derivatives, beta-oxidation products). In vitro, the ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase comparable to that of atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites.

Excretion

It is excreted in bile after hepatic and/or extrahepatic metabolism (does not undergo significant enterohepatic recirculation). T_1/2 is 14 hours. The inhibitory activity against HMG-CoA reductase persists for about 20-30 hours due to the presence of active metabolites. Less than 2% of the orally administered dose is detected in urine. It is not excreted during hemodialysis.

Pharmacokinetics in Special Clinical Cases

C_max in women is 20% higher, and AUC is 10% lower.

C_max in patients with alcoholic liver cirrhosis is 16 times, and AUC is 11 times higher than normal.

Indications

• In combination with diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides and to increase HDL cholesterol levels in patients with primary hypercholesterolemia, heterozygous familial and non-familial hypercholesterolemia, and combined (mixed) hyperlipidemia (Fredrickson types IIa and IIb).
• In combination with diet for the treatment of patients with elevated serum triglyceride levels (Fredrickson type IV) and patients with dysbetalipoproteinemia (Fredrickson type III), in whom diet therapy does not provide an adequate effect;
• To reduce total cholesterol and LDL cholesterol levels in patients with homozygous familial hypercholesterolemia when diet therapy and other non-pharmacological treatments are insufficiently effective.

ICD codes

Dosage Regimen

Take orally at any time of the day, regardless of meals. Before starting therapy with Anvistat^®, an attempt should be made to control hypercholesterolemia with diet therapy, physical exercise, and weight reduction in obese patients, as well as treatment of the underlying disease.

Before starting the drug, the patient should be switched to a standard cholesterol-lowering diet and must continue to follow this diet during the treatment period.

The initial dose is 10 mg once a day. The daily dose of the drug ranges from 10 to 80 mg. The dose should be selected individually, taking into account the baseline LDL cholesterol level, the goal of therapy, and the patient’s response to treatment. The maximum daily dose of the drug is 80 mg taken once a day. At the beginning and/or during dose increase, plasma lipid levels should be monitored every 2-4 weeks and the drug dose should be adjusted accordingly.

Dose adjustment should be made at intervals of at least 4 weeks.

For patients with established coronary heart disease and other patients at high risk of coronary events, the following lipid level correction goals 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).

In primary hypercholesterolemia and combined (mixed) hyperlipidemia, the necessary control of lipid levels in most patients is provided by taking 10 mg of the drug once a day. The therapeutic effect is observed within 2 weeks and usually reaches a maximum within 4 weeks.

In heterozygous familial hypercholesterolemia, treatment of patients should be started with 10 mg/day. By individually adjusting the dose every 4 weeks, it should be increased to 40 mg/day. After that, the dose can be increased to a maximum level of 80 mg/day, or a combination of 40 mg of Anvistat^® and a bile acid sequestrant can be used.

In homozygous familial hypercholesterolemia, it is prescribed at a dose of 80 mg once a day.

No dose adjustment is required for patients with renal insufficiency, since impaired renal function does not affect the plasma concentration of atorvastatin or the degree of LDL-C reduction during therapy with Anvistat^®.

In hepatic insufficiency, doses must be reduced under constant monitoring of liver transaminase activity (AST and ALT).

When using the drug in elderly patients, no differences in safety, efficacy, or achievement of the goal of hypolipidemic therapy compared to the general population were noted; no dose adjustment is required.

If concomitant use with cyclosporine is necessary, the dose of Anvistat^® should not exceed 10 mg.

Adverse Reactions

Most frequently (≥1%)

From the central nervous system insomnia, headache, asthenic syndrome.

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

From the musculoskeletal system myalgia.

Less frequently (<1%)

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

From the digestive system 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, polymorphous exudative erythema (including Stevens-Johnson syndrome), Lyell’s syndrome (toxic epidermal necrolysis).

From the hematopoietic system: thrombocytopenia.

From metabolism hypo- or hyperglycemia, increased serum CPK activity.

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

Contraindications

• Active liver diseases or unexplained persistent elevation of serum transaminases (more than 3 times the upper limit of normal);
• Liver failure (severity A and B according to the Child-Pugh classification);
• Pregnancy;
• Lactation period (breastfeeding);
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to the components of the drug.

Use with caution in patients who abuse alcohol; with a history of liver disease.

Use in Pregnancy and Lactation

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

The drug can be prescribed to women of reproductive age only if the probability of pregnancy is very low, and the patient is informed about 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. Given the possibility of adverse events in infants, if it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

The drug is contraindicated in active liver diseases or unexplained persistent elevation of serum transaminases (more than 3 times the upper limit of normal); in liver failure (severity A and B according to the Child-Pugh classification).

Use with caution in patients with a history of liver disease.

Use in Renal Impairment

No dose adjustment is required for patients with renal insufficiency.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age (efficacy and safety not established).

Geriatric Use

When using the drug in elderly patients, no differences in safety, efficacy, or achievement of the goal of hypolipidemic therapy compared to the general population were noted; no dose adjustment is required.

Special Precautions

Before starting therapy with Anvistat^®, the patient must be prescribed a standard hypocholesterolemic diet, which he must follow throughout the entire treatment period.

The use of HMG-CoA reductase inhibitors to lower blood lipid levels may lead to changes in biochemical parameters reflecting liver function. Liver function should be monitored before starting therapy, 6 weeks and 12 weeks after starting the drug, after each dose increase, and periodically, for example, every 6 months. An increase in serum liver enzyme activity may be observed during therapy with the drug. Patients with elevated enzyme activity should be monitored until the enzyme levels return to normal. In case of a persistent increase in ALT or AST activity to a level exceeding 3 times the upper limit of normal, it is recommended to reduce the drug dose or discontinue treatment.

Anvistat^® should be used with caution in patients who abuse alcohol and/or have liver disease. Active liver disease or unexplained persistent elevation of serum transaminases is a contraindication to the prescription of the drug. Treatment with the drug, like other HMG-CoA reductase inhibitors, can cause myopathy. The diagnosis of myopathy (muscle pain and weakness combined with an increase in CPK activity more than 10 times the upper limit of normal) should be considered in patients with widespread myalgia, muscle tenderness or weakness, and/or a marked increase in CPK activity.

Patients should be warned to immediately inform their doctor of the appearance of unexplained muscle pain or weakness, if they are accompanied by malaise or fever.

Drug therapy should be discontinued in case of a marked increase in CPK activity or in the presence of confirmed or suspected myopathy. The risk of myopathy during treatment with other drugs of this class increased with the simultaneous use of cyclosporine, fibrates, erythromycin, nicotinic acid in lipid-lowering doses, or azole antifungals. Many of these drugs inhibit metabolism mediated by cytochrome P450 3A4 and/or drug transport. Atorvastatin is biotransformed by the action of the CYP3A4 isoenzyme.

When prescribing Anvistat^® in combination with fibrates, erythromycin, immunosuppressive agents, azole antifungals, or nicotinic acid in lipid-lowering doses, the expected benefit and risk of treatment should be carefully weighed and patients should be regularly monitored for the appearance of muscle pain or weakness, especially during the first months of treatment and during dose increase of any drug. In such situations, periodic determination of CPK activity can be recommended, although such monitoring does not prevent the development of severe myopathy.

When using Anvistat^®, as with other agents of this class, cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described. Drug therapy should be temporarily interrupted or completely discontinued if signs of possible myopathy appear or if there is a risk factor for the development of renal failure against the background of rhabdomyolysis (for example, severe acute infection, arterial hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disturbances, and uncontrolled seizures).

Effect on ability to drive vehicles and mechanisms

There are no data on the adverse effect of the drug on the ability to drive a car and engage in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

Treatment there is no specific antidote; symptomatic and supportive therapy is carried out as needed. Monitoring of liver function and serum CPK levels is necessary. Hemodialysis is not effective.

Drug Interactions

The risk of myopathy during treatment with HMG-CoA reductase inhibitors increases when they are 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 failure due to myoglobinuria. In this regard, a thorough assessment of the risk-benefit ratio of combination therapy is necessary.

Atorvastatin metabolism is carried out with the participation of the CYP3A4 isoenzyme. When using atorvastatin in combination with inhibitors of the CYP3A4 isoenzyme (for example, cyclosporine, macrolide antibiotics, such as erythromycin and clarithromycin, nefazodone, azole antifungal drugs, such as itraconazole, and HIV protease inhibitors), drug interactions may occur. With the combined use of drugs, increased concentrations of atorvastatin in the blood plasma may be observed. In this regard, special caution should be exercised when using atorvastatin in combination with the above agents.

Concomitant 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 exercised).

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

With simultaneous use of atorvastatin and erythromycin (500 mg 4 times/day) or clarithromycin (500 mg 2 times/day), which inhibit the CYP3A4 isoenzyme, an increase in the plasma concentration of atorvastatin was observed.

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

With the combined use of atorvastatin at a dose of 40 mg and itraconazole at a dose of 200 mg once/day, an increase in AUC to a level exceeding the norm by 3 times was detected.

Simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the CYP3A4 isoenzyme, was accompanied by an increase in the plasma concentration of atorvastatin (with simultaneous use with erythromycin, the C_max of atorvastatin increases by 40%).

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

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

The effect of drugs that induce CYP3A4 (for example, rifampicin or efavirenz) on Atorvastatin is unknown. Interaction with atorvastatin and other substrates of this isoenzyme is unknown, but the possibility of this interaction should be taken into account when using drugs with a low therapeutic index – in particular, class III antiarrhythmic drugs, for example, amiodarone.

The risk of atorvastatin-induced myopathy may increase with concomitant use of fibrates. In vitro studies indicate that gemfibrozil may also interact with atorvastatin by inhibiting its glucuronidation, which may lead to increased plasma concentrations of atorvastatin.

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

Taking atorvastatin in combination with an oral contraceptive containing norethisterone and ethinyl estradiol caused an increase in the plasma concentrations of norethisterone and ethinyl estradiol. These increases in concentrations should be taken into account when selecting doses of oral contraceptives. With simultaneous use of atorvastatin and an oral contraceptive containing norethisterone and ethinyl estradiol, a significant increase in the AUC of norethisterone and ethinyl estradiol by approximately 30% and 20%, respectively, was observed. This effect should be taken into account when choosing an oral contraceptive for a woman receiving Atorvastatin.

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

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

With simultaneous use of atorvastatin and terfenadine, no clinically significant changes in pharmacokinetic parameters were identified.

With simultaneous oral administration of atorvastatin and a suspension containing magnesium and aluminum hydroxides, the plasma concentration of atorvastatin decreased by approximately 35%; however, the degree of reduction in LDL-C levels did not change.

When taking atorvastatin in combination with warfarin, a slight decrease in prothrombin time was noted in the first days of taking atorvastatin; however, within the next 15 days the prothrombin time returned to normal. Nevertheless, in case of concomitant use of atorvastatin and warfarin, patients should be carefully monitored.

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

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

With combined administration of 80 mg atorvastatin and 10 mg amlodipine, no changes in the steady-state pharmacokinetic parameters of atorvastatin were identified.

No clinically significant adverse interaction between atorvastatin and antihypertensive agents has been noted. Interaction studies with all specific drugs have not been conducted.

Storage Conditions

List B. The drug should be stored in a dry place, protected from light, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.