Atoris film-coated tablets 20 mg No. 90

Instructions for Atoris film-coated tablets 20 mg No. 90

Composition

active ingredient: 1 film-coated tablet contains 20 mg of atorvastatin in the form of atorvastatin calcium;

excipients: povidone, sodium lauryl sulfate, calcium carbonate, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate;

shell: talc, polyvinyl alcohol, macrogol 3000, titanium dioxide (E 171).

Dosage form

Film-coated tablets.

Main physicochemical properties: white, round, slightly convex, film-coated tablets.

Pharmacotherapeutic group

Lipid-lowering agents. HMG-CoA reductase inhibitors. Atorvastatin. ATC code C10A A05.

Pharmacological properties

Pharmacodynamics

The drug contains the active substance atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that determines the rate of conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, which is a precursor of sterols, in particular cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low density lipoprotein (VLDL) molecules, enter the blood plasma and are transported to peripheral tissues. Low density lipoprotein (LDL) is formed from VLDL and is catabolized mainly by interaction with high-affinity LDL receptors (LDL receptors).

Atorvastatin reduces plasma cholesterol and serum lipoprotein concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver, and also increases the number of hepatic LDL receptors on the cell surface, leading to increased uptake and catabolism of LDL.

Atorvastatin reduces LDL formation and LDL particle number. Atorvastatin causes a marked and sustained increase in LDL receptor activity combined with favorable changes in the quality of circulating LDL particles. Atorvastatin effectively lowers LDL cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia, a group that has not always responded to lipid-lowering therapy.

In addition to its effect on plasma lipids, atorvastatin has other effects that enhance its antiatherosclerotic effect. It inhibits the synthesis of isoprenoids - substances that act as growth factors on the proliferation of vascular smooth muscle cells, reduces plasma viscosity and the activity of some coagulation and aggregation factors. Due to this action, it improves hemodynamics and contributes to the normalization of blood coagulation processes. In addition, HMG-CoA reductase inhibitors affect the metabolism of macrophages and, thus, inhibit their activation, which reduces the risk of rupture of atherosclerotic plaques.

Atorvastatin has been shown to reduce total cholesterol (30–46%), LDL-C (41–61%), apolipoprotein B (34–50%), and triglycerides (14–33%), with variable increases in HDL-C and apolipoprotein A in a dose-response study. These results are consistent with data in patients with heterozygous familial hypercholesterolemia, nonfamilial hypercholesterolemia, and mixed hyperlipidemia, including patients with noninsulin-dependent diabetes mellitus.

It has been proven that lowering levels of total cholesterol, LDL-C, and apolipoprotein B reduces the risk of cardiovascular complications and mortality from cardiovascular disease.

Pharmacokinetics

Absorption

Atorvastatin is rapidly absorbed after oral administration and reaches peak plasma concentrations within 1–2 hours. The extent of absorption and plasma concentrations of atorvastatin depend on the dose of atorvastatin. The bioavailability of atorvastatin in tablet form compared to the solution is 95 and 99%, respectively. The absolute bioavailability of atorvastatin is approximately 12–14%, and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is due to presystemic clearance in the gastrointestinal mucosa and biotransformation during first-pass metabolism in the liver.

Distribution

The mean volume of distribution of atorvastatin is approximately 381 L. Plasma protein binding is >98%. The blood/plasma concentration ratio of approximately 0.25 indicates poor penetration of the drug into erythrocytes.

Metabolism

Atorvastatin is extensively metabolized to form ortho- and parahydroxylated derivatives and various β-oxidation products. In vitro, ortho- and parahydroxylated metabolites exhibit inhibitory activity against HMG-CoA reductase equivalent to that of atorvastatin. The inhibitory effect of the drug on HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites.

Selection

Atorvastatin and its metabolites are mainly excreted in the bile after hepatic and/or extrahepatic biotransformation, but do not undergo gastrohepatic recirculation. The mean elimination half-life of atorvastatin in humans is approximately 14 hours. Inhibitory activity against HMG-CoA reductase is maintained for 20–30 hours due to the presence of active metabolites. After oral administration, less than 2% of the dose is excreted in the urine.

Patient populations

Plasma concentrations of atorvastatin in healthy elderly volunteers (aged > 65 years) are higher than in younger subjects, while the lipid-lowering effects were comparable to those observed in young subjects.

Children

Apparent oral clearance of atorvastatin in children was similar to that in adults when scaled allometrically for body weight, as body weight was the only significant covariate in a population pharmacokinetic model of atorvastatin with data that included children with heterozygous familial hypercholesterolemia (aged 6 to 17 years).

Sex

The plasma concentration of atorvastatin in women differs from that in men (the maximum plasma concentration (Cmax) is approximately 20% higher and the area under the curve (AUC) is 10% lower). However, these differences are not clinically significant, and the lipid-lowering effect of the drug in men and women is almost the same.

Kidney failure

Renal disease does not affect the plasma concentrations or lipid-lowering effects of atorvastatin and its active metabolites.

Hemodialysis: Although studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly increase clearance of the drug, as atorvastatin is extensively bound to plasma proteins.

Liver failure

Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease. Cmax and AUC values are 4-fold higher in patients with Child-Pugh Class A liver disease.

In patients with Child-Pugh Class B liver disease, Cmax and AUC values are increased approximately 16-fold and 11-fold, respectively (see Contraindications).

Indication

Prevention of cardiovascular disease

In adult patients without clinically significant coronary heart disease (CHD) but with multiple risk factors for CHD, such as older age, smoking, hypertension, low HDL, or a family history of early CHD, the drug is indicated for:

reducing the risk of myocardial infarction; reducing the risk of stroke; reducing the risk of angina and the need for myocardial revascularization procedures.

In patients with type 2 diabetes mellitus and without clinically significant coronary heart disease, but with several risk factors for the development of coronary heart disease, such as retinopathy, albuminuria, smoking or arterial hypertension, the drug is indicated for:

reducing the risk of myocardial infarction; reducing the risk of stroke.

In patients with clinically significant ischemic heart disease, the drug is indicated for:

reduced risk of non-fatal myocardial infarction; reduced risk of fatal and non-fatal stroke; reduced risk of need for myocardial revascularization procedures; reduced risk of need for hospitalization for congestive heart failure; reduced risk of angina.

Hyperlipidemia

Primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb). As an adjunct to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B and triglycerides, and to increase high-density lipoprotein cholesterol (HDL-C). Hypertriglyceridemia (Fredrickson type IV). As an adjunct to diet for the treatment of patients with elevated serum triglycerides. Primary dysbetalipoproteinemia (Fredrickson type III). For the treatment of patients when dietary adherence is insufficient. Homozygous familial hypercholesterolemia. To reduce total cholesterol and LDL-C as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or when such treatments are unavailable. Heterozygous familial hypercholesterolemia in pediatric patients (aged 10-17 years). As an adjunct to diet to reduce total cholesterol, LDL-C and apolipoprotein B in adolescent boys and postmenarche girls aged 10 to 17 years, if, after appropriate diet therapy, the test results are as follows:

a) LDL cholesterol remains ≥ 190 mg/dL (³ 4.91 mmol/L) or

b) LDL cholesterol ≥ 160 mg/dL (≥ 4.14 mmol/L) and:

There is a family history of early cardiovascular disease or two or more other risk factors for cardiovascular disease are present in the patient as a child.

Contraindication

Hypersensitivity to any ingredient of the drug. Liver disease in the acute phase or a persistent increase (of unknown origin) in serum transaminase levels by 3 times or more. The drug is contraindicated in pregnant women, women who are breastfeeding, and women of reproductive age who do not use adequate methods of contraception (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions

Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a substrate for transport proteins, such as the hepatic transporter OATP1B1. Concomitant administration of medicinal products that are inhibitors of CYP3A4 or transport proteins may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy. This risk may also be increased by concomitant administration of atorvastatin with other medicinal products that may cause myopathy, such as cyclosporine, fibrates, nicotinic acid or inhibitors of cytochrome P450 3A4 (e.g. erythromycin, azole antifungals) (see section 4.4).

CYP3A4 inhibitors

Potent CYP3A4 inhibitors are known to significantly increase atorvastatin concentrations (see Table 1 and detailed information below). Co-administration with potent CYP3A4 inhibitors (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided whenever possible. If co-administration of these drugs with atorvastatin cannot be avoided, lower (initial and maximum) doses of atorvastatin should be considered. Appropriate clinical monitoring of the patient is also recommended (see Table 1).

Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin (see Table 1). Concomitant use of erythromycin and statins is associated with an increased risk of myopathy. Drug interaction studies to evaluate the effects of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil are known to inhibit CYP3A4 activity, and therefore, co-administration of these drugs with atorvastatin may result in increased exposure to atorvastatin. Therefore, lower maximum doses of atorvastatin should be considered when atorvastatin is co-administered with these moderate CYP3A4 inhibitors. Clinical monitoring of the patient is also recommended after initiation of treatment with the inhibitor or after dose adjustment.

CYP3A4 stimulators

Concomitant administration of atorvastatin with cytochrome P450 3A inducers (e.g. efavirenz, rifampin, St. John's wort) may result in erratic decreases in atorvastatin plasma concentrations. Due to the dual interaction mechanism of rifampin (cytochrome P450 3A induction and inhibition of the hepatic transporter OATP1B1), concomitant administration of atorvastatin and rifampin is recommended, as administration of atorvastatin at a significant interval after rifampin is associated with a significant decrease in atorvastatin plasma concentrations. However, the effect of rifampin on atorvastatin concentrations in liver cells is unknown, and if concomitant administration cannot be avoided, the patient's response to treatment should be closely monitored.

Azithromycin

Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) was not accompanied by changes in atorvastatin plasma concentrations.

Transport protein inhibitors

Inhibitors of transport proteins (e.g. cyclosporine) may increase the systemic exposure of atorvastatin (see Table 1). The effect of inhibition of storage transport proteins on the concentration of atorvastatin in liver cells is unknown. If concomitant administration of these drugs cannot be avoided, a dose reduction and clinical monitoring of the effectiveness of atorvastatin is recommended (see Table 1).

Gemfibrozil/fibric acid derivatives

The use of fibrates as monotherapy is associated with the development of muscular events, including rhabdomyolysis. The risk of such events may be increased by concomitant administration of fibric acid derivatives and atorvastatin. If concomitant administration cannot be avoided, the lowest dose of atorvastatin should be used to achieve a therapeutic dose and patients should be monitored appropriately (see section 4.4).

Ezetimibe

The use of ezetimibe as monotherapy has been associated with the development of muscular events, including rhabdomyolysis. Therefore, the risk of these events is increased when ezetimibe and atorvastatin are co-administered. Appropriate clinical monitoring of these patients is recommended.

Colestipol

Plasma concentrations of atorvastatin were lower (approximately 25%) when atorvastatin and colestipol were coadministered. The lipid-lowering effects of the combination of atorvastatin and colestipol were greater than those of either drug alone.

Fusidic acid

Interaction studies with atorvastatin and fusidic acid have not been conducted. As with other statins, muscle-related events (including rhabdomyolysis) have been reported in the post-marketing setting with concomitant use of atorvastatin and fusidic acid. The mechanism of this interaction remains unknown. Patients should be monitored closely and temporary discontinuation of atorvastatin may be necessary.

Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin with colchicine, therefore atorvastatin should be prescribed with caution with colchicine.

Effect of atorvastatin on concomitant medications

Digoxin

When multiple doses of the drug are administered simultaneously with digoxin, steady-state plasma concentrations of digoxin increase by approximately 20%. Patients taking digoxin should be monitored closely.

Oral contraceptives

Concomitant use of atorvastatin with oral contraceptives has been shown to increase plasma concentrations of norethisterone and ethinyl estradiol. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.

Warfarin

In a clinical study in patients receiving long-term warfarin therapy, co-administration of 80 mg of atorvastatin daily with warfarin resulted in a small decrease (approximately 1.7 seconds) in prothrombin time during the first 4 days of therapy, but this index returned to normal within the next 15 days of atorvastatin therapy. Although only very rare cases of clinically significant anticoagulant interactions have been reported, prothrombin time should be determined before initiating atorvastatin therapy in patients receiving coumarin anticoagulants and quite often at the beginning of therapy to confirm that there is no significant change in the index. Once a stable prothrombin time has been established, the index can be monitored at intervals usually recommended for patients receiving coumarin anticoagulants. In the event of discontinuation of therapy or a change in the dose of atorvastatin, this procedure should be repeated. In patients not taking anticoagulants, atorvastatin therapy was not associated with bleeding or changes in prothrombin time.

Table 1. Effect of concomitant medications on the pharmacokinetics of atorvastatin

1 Ratio of cases of use of combination drugs with atorvastatin to atorvastatin monotherapy.

2 For information on clinical relevance, see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”.

3 Contains one or more components that inhibit CYP3 A4 and may increase plasma concentrations of drugs. Consumption of one 240 mL glass of grapefruit juice also resulted in a 20.4% decrease in AUC of the active orthohydroxy metabolite. Large amounts of grapefruit juice (>1.2 L/day for 5 days) increased the AUC of atorvastatin 2.5-fold and the AUC of active HMG-CoA reductase inhibitors (atorvastatin and metabolites) 1.3-fold.

4 Single sample taken 8–16 h after drug dose.

5 Accompanied by a decrease in the concentration of atorvastatin in the blood plasma by approximately 35%, but the hypolipidemic effect of atorvastatin did not change.

Table 2. Effect of atorvastatin on the pharmacokinetics of concomitantly administered drugs

1 Ratio of cases of use of combination drugs with atorvastatin to atorvastatin monotherapy.

2 Atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized by the same isomeric cytochromes are not expected.

3 With simultaneous use of multiple doses of atorvastatin and phenazone, changes in phenazone clearance are insignificant or not detected.

Application features

Liver dysfunction

It is recommended that liver enzyme tests be obtained before initiating therapy and periodically thereafter. Patients who develop symptoms suggestive of liver injury should have liver function tests performed. Patients who develop elevated transaminases should have liver function monitored until the abnormalities resolve. If persistent elevations of serum transaminases to 3 or more times the upper limit of normal (ULN) occur, discontinuation of therapy is recommended (see Adverse Reactions).

Atorvastatin should be prescribed with caution to patients who abuse alcohol and/or have a history of liver disease.

Stroke Prevention by Dramatically Lowering Cholesterol Levels (SPARCL)

In a post-hoc analysis of stroke subtypes in patients without coronary artery disease (CAD) who had a recent stroke or transient ischemic attack (TIA), a higher rate of hemorrhagic stroke was reported in the atorvastatin 80 mg group compared with the placebo group. The increased risk was particularly pronounced in patients with prior hemorrhagic stroke or lacunar infarction at study entry. For patients with prior hemorrhagic stroke or lacunar infarction, the balance of risks and benefits of atorvastatin 80 mg has not been established, and the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment.

Atorvastatin, like other HMG-CoA reductase inhibitors, may occasionally affect skeletal muscle and cause myalgia, myositis, and myopathy, which may progress to rhabdomyolysis, a potentially life-threatening condition characterized by markedly elevated creatine kinase (CK) (> 10 times the upper limit of normal), myoglobinemia, and myoglobinuria, which may lead to renal failure. There have been very rare reports of immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin therapy.

Before starting treatment

Atorvastatin should be used with caution in patients with a predisposition to rhabdomyolysis. Before initiating statin treatment in patients with a predisposition to rhabdomyolysis, CK levels should be determined in:

impaired renal function; hypothyroidism; hereditary disorders of the muscular system in family or personal history; previous cases of toxic effects of statins or fibrates on muscles; previous liver disease and/or alcohol abuse;

When treating elderly patients (over 70 years of age), the need for these measures should be assessed taking into account the presence of other predisposing factors for the development of rhabdomyolysis.

Increased plasma levels of the drug are possible, in particular, in the event of interaction (see section "Interaction with other medicinal products and other types of interactions") and use in special groups of patients, including patients with hereditary diseases (see section "Pharmacokinetics").

In such cases, it is recommended to assess the risk-benefit ratio of treatment and conduct clinical monitoring of the patient's condition.

If the CK level is significantly elevated (more than 5 times the upper limit of normal) before starting treatment, treatment should not be started.

Creatine kinase level measurement

The CK level should not be measured after intense exercise or in the presence of any possible alternative causes of the CK level increase, as this may complicate the interpretation of the results. If the CK level is significantly elevated at baseline (more than 5 times the ULN), a repeat measurement should be performed after 5–7 days to confirm the result.

During treatment

Patients should be advised to report immediately any muscle pain, cramps or weakness, especially if accompanied by malaise or fever. If these symptoms occur during treatment with atorvastatin, the patient's CK level should be measured. If CK levels are significantly elevated (>5 times the ULN), treatment should be discontinued. Discontinuation of treatment should also be considered if the CK level is less than 5 times the ULN but the muscle symptoms are severe and cause daily distress. Once symptoms resolve and CK levels return to normal, resuming atorvastatin or initiating an alternative statin may be considered, provided that the lowest possible dose is used and the patient is closely monitored. Atorvastatin treatment should be discontinued if a clinically significant increase in CK levels is observed (more than 10 times the upper limit of normal) or if rhabdomyolysis is diagnosed (or suspected).

Concomitant use with other medications

The risk of rhabdomyolysis is increased when atorvastatin is used concomitantly with certain medicinal products that may increase atorvastatin plasma concentrations. Examples of such medicinal products include potent CYP3A4 inhibitors or transporter proteins: cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole - and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc. Concomitant use with gemfibrozil and other fibric acid derivatives, erythromycin, niacin and ezetimibe also increases the risk of myopathy. If possible, other medicinal products (that do not interact with atorvastatin) should be used instead of the above.

Atorvastatin should not be used concomitantly with systemic fusidic acid or within 7 days of discontinuation of fusidic acid. In patients for whom fusidic acid treatment is considered essential, statin therapy should be discontinued for the duration of fusidic acid treatment. Rhabdomyolysis (including some fatalities) has been reported in patients receiving concomitant fusidic acid and statins (see section 4.5). Patients should seek medical advice immediately if they experience signs of muscle weakness, pain or tenderness.

Statin therapy can be resumed 7 days after the last dose of fusidic acid.

In exceptional cases where prolonged therapy with fusidic acid is necessary, for example for the treatment of severe infections, the possibility of concomitant use of atorvastatin and fusidic acid should be considered on a case-by-case basis and carried out under constant medical supervision.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, particularly with long-term treatment (see section 4.8). Features may include dyspnoea, dry cough and deterioration in general health (fatigue, weight loss and fever). If a patient is suspected of developing interstitial lung disease, statin treatment should be discontinued.

Diabetes mellitus

Some evidence suggests that statins as a class increase HbA1c and serum glucose levels and may cause hyperglycemia to a level that warrants appropriate treatment of diabetes in some patients at high risk of developing diabetes. However, this risk is outweighed by the reduction in vascular risk associated with statin use and is therefore not a reason to discontinue statin therapy. According to national guidelines, clinical and biochemical monitoring of patients at risk (fasting glucose 5.6 to 6.9 mmol/L, body mass index > 30 kg/m2, elevated triglycerides, hypertension) is required.

Excipients

The drug contains lactose, so patients with congenital galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency should not use it.

Ability to influence reaction speed when driving vehicles or other mechanisms

There are no reports of the effect of atorvastatin on the ability to drive a car or use technical devices. However, some patients may experience dizziness and muscle cramps while taking the drug. Therefore, caution should be exercised when driving or operating other machinery during treatment.

Use during pregnancy or breastfeeding

Women of reproductive age

During treatment, women of childbearing potential should use adequate contraception (see section "Contraindications"). If the patient decides to become pregnant during treatment with atorvastatin, she should stop taking the drug no later than one month before the planned pregnancy.

Pregnancy

Atoris® is contraindicated during pregnancy, as the safety of administration has not been established and there are no controlled studies of the use of atorvastatin in pregnant women. There have been rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. Animal studies have shown reproductive toxicity.

Atorvastatin treatment may reduce intrauterine levels of mevalonate, which is required for biosynthesis