Atoris film-coated tablets 30 mg No. 90

Instructions for Atoris film-coated tablets 30 mg No. 90

Composition

active ingredient: atorvastatin;

1 tablet contains 30 mg or 60 mg or 80 mg of atorvastatin as atorvastatin calcium;

excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, croscarmellose sodium, crospovidone, polysorbate 80, sodium hydroxide, magnesium stearate;

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

Dosage form

Film-coated tablets.

Main physicochemical properties:

30 mg: white or almost white, round, slightly convex, film-coated, beveled edge tablets;

60 mg: white or almost white, oval, biconvex, film-coated tablets;

80 mg: white or almost white, capsule-shaped, biconvex, film-coated tablets.

Pharmacotherapeutic group

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

Pharmacological properties

Pharmacodynamics.

Atoris® 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 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 size. 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 factors 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, non-familial hypercholesterolemia, and mixed hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus.

It has been proven that lowering levels of total cholesterol, LDL-C, and apolipoprotein B reduces the risk of developing 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.

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.

Atorvastatin is a substrate of the hepatic transporters organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin has also been identified as a substrate of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), which may limit intestinal absorption and biliary clearance of atorvastatin.

Patient populations

Elderly patients

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 (ages 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 adult 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 adult patients with clinically significant ischemic heart disease, the drug is indicated for:

reducing the risk of non-fatal myocardial infarction;

reducing the risk of fatal and non-fatal stroke;

reducing the risk of needing myocardial revascularization procedures;

reducing the risk of needing hospitalization for congestive heart failure;

reducing the risk of angina pectoris.

Hyperlipidemia

In adult patients

Primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to the Fredrickson classification). As an adjunct to diet to reduce elevated levels of 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 triglyceride levels.

Primary dysbetalipoproteinemia (type III according to the Fredrickson classification). For the treatment of patients in cases where diet is not effective enough.

Homozygous familial hypercholesterolemia. To reduce total cholesterol and LDL-C as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if 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 postmenarcheal girls aged 10 to 17 years, if, after appropriate diet therapy, the test results are as follows:

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

family history of early cardiovascular disease or

two or more other risk factors for cardiovascular disease are present in the pediatric patient.

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 three or more times.

The drug is contraindicated in pregnant women, women who are breastfeeding, and women of reproductive age who do not use adequate contraception (see section “Use during pregnancy or breastfeeding”).

Treatment with antiviral drugs glecaprevir/pibrentasvir against hepatitis C.

Interaction with other medicinal products and other types of interactions

Atorvastatin is a substrate of CYP3A4 and transporters (e.g. OATP1B1/1B3, P-gp or BCRP). Plasma levels of atorvastatin may be significantly increased by concomitant use of inhibitors of CYP3A4 and transporters. Table 1 lists drugs that may increase the exposure of Atoris® and the risk of myopathy and rhabdomyolysis with concomitant use, and recommendations for the treatment and prevention of such risks (see sections 4.4 and 5.1).

Table 1

Interaction of the drug Atoris® with other drugs, which increases the risk of developing myopathy and rhabdomyolysis Atoris®.

Table 2

Interaction with drugs that may reduce the exposure of the drug Atoris®

Table 3

The effect of the drug Atoris® on other drugs

Diltiazem hydrochloride.

Simultaneous administration of atorvastatin (40 mg) and diltiazem (240 mg) is accompanied by an increase in the concentration of atorvastatin in the blood plasma.

Cimetidine.

As a result of the conducted studies, no signs of interaction between atorvastatin and cimetidine were detected.

Antacids.

Simultaneous oral administration of atorvastatin and an antacid suspension containing magnesium and aluminum hydroxide is accompanied by a decrease in the concentration of atorvastatin in the blood plasma by approximately 35%. The hypolipidemic effect of atorvastatin was not changed.

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

Transporter protein inhibitors may increase the systemic exposure of atorvastatin (see Table 1). Cyclosporine and letermovir are inhibitors of transporters involved in the distribution of atorvastatin, including OATP1B1/1B3, P-gp, and BCRP, which leads to systemic exposure of atorvastatin (see Table 1). The effect of inhibition of storage transporters on the exposure of atorvastatin in liver cells is unknown. If concomitant administration cannot be avoided, it is recommended to reduce the dose and conduct clinical monitoring of the effectiveness of treatment (see Table 1).

The use of atorvastatin in patients taking letermovir concomitantly with cyclosporine is not recommended (see Precautions).

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

Ezetimibe alone has been associated with muscle-related events, including rhabdomyolysis. Therefore, the risk of these events may be increased when ezetimibe and atorvastatin are co-administered. Appropriate clinical monitoring of these patients is recommended.

Colestipol

Plasma concentrations of atorvastatin and its active metabolites were lower (approximately 25%) when colestipol was administered concomitantly with atorvastatin. However, the lipid effects were greater when atorvastatin and colestipol were administered concomitantly than when either drug was administered alone.

Fusidic acid

Interaction studies with atorvastatin and fusidic acid have not been performed. As with other statins, muscle complications, including rhabdomyolysis, have been observed with concomitant use of atorvastatin and fusidic acid. The mechanism of this interaction is unknown. Patients should be closely monitored and temporary discontinuation of atorvastatin may be appropriate.

Colchicine

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

With simultaneous use of multiple doses of the drug and digoxin, the equilibrium plasma concentrations of digoxin increase by approximately 20%. Patients taking digoxin should be appropriately monitored.

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, patients taking coumarin anticoagulants should have their prothrombin time measured frequently enough to ensure that there is no significant change in the index before initiating atorvastatin therapy. Once a stable prothrombin time has been achieved, the index can be monitored at intervals usually recommended for patients taking coumarin anticoagulants. This procedure should be repeated if atorvastatin therapy is discontinued or the dose is changed. In patients not taking anticoagulants, atorvastatin therapy was not associated with bleeding or changes in prothrombin time.

Application features

Myopathy and rhabdomyolysis

The drug may cause myopathy (muscle pain, tenderness, or weakness in association with an elevation of creatine kinase (CK) greater than 10 times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare cases of fatal rhabdomyolysis have been reported with statins, including Atoris®.

Risk factors for developing myopathy

Risk factors for the development of myopathy include age 65 years and older, uncontrolled hypothyroidism, impaired renal function, concomitant use with certain other drugs, and use of increased doses of Atoris® (see section “Interaction with other medicinal products and other types of interactions”).

Measures to avoid or reduce the risk of developing myopathy and rhabdomyolysis

The simultaneous intake of grapefruit juice in large quantities (more than 1.2 liters per day) is not recommended for patients taking Atoris® (see section “Interaction with other medicinal products and other types of interactions”).

Atoris® should be discontinued if markedly elevated CK levels are observed or myopathy is diagnosed or suspected. Muscle symptoms and elevated CK levels resolve after discontinuation of atorvastatin. Atoris® should be temporarily discontinued in patients with acute or serious conditions at high risk of developing renal failure caused by rhabdomyolysis (e.g. sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine or electrolyte disturbances; uncontrolled epilepsy).

Patients should be informed of the risk of myopathy and rhabdomyolysis at the beginning of treatment or when the dose of Atoris® is increased. Patients should be advised to immediately report any unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever.

Immune-mediated necrotizing myopathy

Rare cases of immune-mediated necrotizing myopathy (IMNM) have been reported during or after treatment with some statins. Clinically, IMNM is characterized by persistent proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin therapy; positive HMG-CoA reductase antibodies; muscle biopsy reveals necrotizing myopathy and improvement with immunosuppressant therapy. Additional neuromuscular and serological studies may be necessary. Immunosuppressant therapy may be required. The risk of IMNM should be carefully weighed before initiating another statin. If another statin is initiated, monitoring for signs and symptoms of IMNM is necessary.

Effect on the liver

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 Intensive Cholesterol Lowering (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 with atorvastatin 80 mg compared with placebo. The increased risk was particularly pronounced in patients with prior hemorrhagic stroke or lacunar infarction at study entry. The balance of risks and benefits of atorvastatin 80 mg in patients with prior hemorrhagic stroke or lacunar infarction has not been established, and the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment.

Skeletal muscles

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) levels (> 10 times the upper limit of normal), myoglobinemia, and myoglobinuria, which may lead to renal failure.

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 kidney function;

hypothyroidism;

hereditary disorders of the muscular system in family or personal history;

previous cases of muscle toxicity from statins or fibrates;

history of liver disease and/or alcohol abuse.

When treating elderly patients (70 years and older), 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.

The CK level should not be measured after intense exercise or in the presence of any possible alternative causes of the CK level elevation, as this may complicate the interpretation of the results. If a significant elevation of CK is observed at baseline (>5 times the upper limit of normal), a repeat measurement should be performed after 5–7 days to confirm the result.

During treatment

Patients should be advised to immediately report the development of muscle pain, cramps, or weakness, especially when accompanied by malaise or fever.

If these symptoms occur during treatment with atorvastatin, the patient's CK level should be determined. If the CK level is significantly elevated (more than 5 times the upper limit of normal), treatment should be discontinued.

Discontinuation of treatment should also be considered if the CK level is less than five times the upper limit of normal, but muscle symptoms are severe and cause daily discomfort.

After symptoms resolve and CK levels normalize, resuming atorvastatin treatment or starting an alternative statin may be considered, provided 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 by concomitant use of atorvastatin with certain medicinal products that may increase atorvastatin plasma concentrations, such as potent CYP3A4 inhibitors or transport proteins (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, strypentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc.). The risk of myopathy may also be increased by concomitant use of gemfibrozil and other fibric acid derivatives, antiviral agents for the treatment of hepatitis C (HCV) (e.g., boceprevir, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir), erythromycin, niacin, or ezetimibe. If possible, alternative (non-interacting) treatments should be considered instead of these medications.

If concomitant treatment with atorvastatin and these drugs is necessary, the benefits and risks of their concomitant use should be carefully weighed. If patients are taking drugs that increase the concentration of atorvastatin in the blood plasma, it is recommended to reduce the dose of atorvastatin to the minimum. In addition, in the case of the use of potent CYP3A4 inhibitors, a lower initial dose of atorvastatin should be considered and appropriate clinical monitoring of these patients should be carried out (see section "Interaction with other medicinal products and other forms of interaction").

Atorvastatin should not be used concomitantly with systemic fusidic acid or within 7 days of stopping 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 fusidic acid and statins concomitantly (see section 4.5). Patients should seek medical advice immediately if they experience muscle weakness, pain or tenderness.

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

In exceptional cases where prolonged fusidic acid therapy is necessary, e.g. for the treatment of severe infections, the possibility of concomitant use of atorvastatin and fusidic acid should be considered.