Atoris^® (Tablets) Instructions for Use

ATC Code

C10AA05 (Atorvastatin)

Active Substance

Atorvastatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

A hypolipidemic agent from the group of statins. Through the principle of competitive antagonism, the statin molecule binds to the part of the coenzyme A receptor where HMG-CoA reductase attaches. Another part of the statin molecule inhibits the process of converting hydroxymethylglutarate to mevalonate, an intermediate product in the synthesis of the cholesterol molecule. Inhibition of HMG-CoA reductase activity leads to a series of sequential reactions, resulting in a decrease in intracellular cholesterol content and a compensatory increase in LDL receptor activity and, accordingly, an acceleration of LDL cholesterol (C) catabolism.

The hypolipidemic effect of statins is associated with a decrease in total C levels due to LDL-C. The reduction in LDL levels is dose-dependent and not linear but exponential. The inhibitory effect of atorvastatin on HMG-CoA reductase is approximately 70% determined by the activity of its circulating metabolites.

Statins do not affect the activity of lipoprotein and hepatic lipases, nor do they significantly affect the synthesis and catabolism of free fatty acids; therefore, their effect on TG levels is secondary and mediated through their primary effects of lowering LDL-C levels. The moderate reduction in TG levels during statin treatment is likely associated with the expression of remnant (apo E) receptors on the surface of hepatocytes, involved in the catabolism of IDL, which contain approximately 30% TG. Compared to other statins (except for rosuvastatin), Atorvastatin causes a more pronounced reduction in TG levels.

In addition to the hypolipidemic effect, statins have a positive effect on endothelial dysfunction (a preclinical sign of early atherosclerosis), on the vascular wall, the state of atheroma, improve the rheological properties of blood, and possess antioxidant and antiproliferative properties.

Atorvastatin reduces cholesterol levels in patients with homozygous familial hypercholesterolemia, which is usually resistant to therapy with hypolipidemic agents.

Pharmacokinetics

Atorvastatin is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability is low – about 12%, due to presystemic clearance in the gastrointestinal mucosa and/or due to first-pass metabolism in the liver, primarily at the site of action.

Atorvastatin is metabolized with the participation of the CYP3A4 isoenzyme to form a number of substances that are inhibitors of HMG-CoA reductase.

The plasma T_1/2 is about 14 hours, although the T_1/2 of HMG-CoA reductase inhibitory activity is approximately 20-30 hours, due to the participation of active metabolites.

Plasma protein binding is 98%.

Atorvastatin is excreted in the form of metabolites mainly with bile.

Indications

Primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia (Fredrickson type IIa); combined (mixed) hyperlipidemia (Fredrickson types IIa and IIb); dysbetalipoproteinemia (Fredrickson type III) (as an adjunct to diet); familial endogenous hypertriglyceridemia (Fredrickson type IV), resistant to diet; homozygous familial hypercholesterolemia with insufficient effectiveness of diet therapy and other non-pharmacological treatment methods.

Primary prevention of cardiovascular complications in patients without clinical signs of coronary artery disease (CAD), but with several risk factors for its development – age over 55 years, nicotine dependence, arterial hypertension, diabetes mellitus, low plasma HDL-C concentrations, genetic predisposition, including against the background of dyslipidemia.

Secondary prevention of cardiovascular complications in patients with CAD to reduce the overall mortality rate, myocardial infarction, stroke, rehospitalization for angina, and the need for revascularization.

ICD codes

Dosage Regimen

Tablets

Treatment is carried out against the background of a standard diet for patients with hypercholesterolemia. The dose is set individually, depending on the initial cholesterol level. It is taken orally. The initial dose is usually 10 mg once a day. The effect appears within 2 weeks, and the maximum effect within 4 weeks. If necessary, the dose can be gradually increased at intervals of 4 weeks or more. The maximum daily dose is 80 mg.

Adverse Reactions

Nervous system disorders > 1% – insomnia, dizziness; < 1% - headache, asthenia, malaise, drowsiness, nightmares, paresthesia, peripheral neuropathy, amnesia, emotional lability, ataxia, facial nerve palsy, hyperkinesis, migraine, depression, hypoesthesia, loss of consciousness.

Sensory organ disorders:< 1% - amblyopia, tinnitus, conjunctival dryness, accommodation disorder, retinal hemorrhage, deafness, glaucoma, parosmia, loss of taste, taste perversion; frequency unknown - ocular myasthenia.

Cardiovascular system disorders: > 1% – chest pain; < 1% - palpitations, vasodilation symptoms, orthostatic hypotension, increased blood pressure, phlebitis, arrhythmia, angina pectoris.

Hematopoietic system disorders:< 1% - anemia, lymphadenopathy, thrombocytopenia.

Respiratory system disorders: > 1% – bronchitis, rhinitis; < 1% - pneumonia, dyspnea, exacerbation of bronchial asthma, epistaxis.

Digestive system disorders: > 1% – nausea; < 1% - heartburn, constipation or diarrhea, flatulence, gastralgia, abdominal pain, decreased or increased appetite, dry mouth, belching, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosive and ulcerative lesions of the oral mucosa, gastroenteritis, hepatitis, biliary colic, cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, liver function impairment, rectal bleeding, melena, gum bleeding, tenesmus.

Musculoskeletal system disorders: > 1% – arthritis; < 1% - leg muscle cramps, bursitis, tenosynovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonia, joint contractures, joint swelling, tendinopathy (in some cases with tendon rupture); frequency unknown - occurrence or exacerbation of myasthenia.

Urinary and reproductive system disorders: > 1% – urogenital infections, peripheral edema; < 1% - dysuria (including pollakiuria, nocturia, urinary incontinence or retention, imperative urination urges), leukocyturia, nephritis, hematuria, vaginal bleeding, nephrourolithiasis, metrorrhagia, epididymitis, decreased libido, impotence, ejaculation disorder.

Dermatological reactions: > 1% – alopecia, xeroderma, photosensitivity, increased sweating, eczema, seborrhea, ecchymosis, petechiae.

Endocrine system disorders< 1% - gynecomastia, mastodynia.

Metabolism and nutrition disorders< 1% - weight gain, exacerbation of gout.

Allergic reactions:< 1% - skin itching, skin rash, contact dermatitis, rarely - urticaria, angioedema, facial edema, anaphylaxis, exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Laboratory parameters:< 1% - hyperglycemia, hypoglycemia, increased serum CPK, albuminuria.

Contraindications

Active liver disease, unexplained persistent elevation of serum transaminases (more than 3 times the upper limit of normal), pregnancy, lactation (breastfeeding), women of reproductive age not using reliable contraception; children and adolescents under 18 years of age; hypersensitivity to atorvastatin.

Use in Pregnancy and Lactation

Atorvastatin is contraindicated for use during pregnancy and during lactation (breastfeeding).

It is not known whether Atorvastatin 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 considered.

Women of reproductive age should use adequate contraceptive methods during treatment. Atorvastatin can be used in 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.

Use in Hepatic Impairment

Contraindication: active liver disease.

Before starting and during treatment with atorvastatin, especially if symptoms of liver damage appear, liver function parameters must be monitored. If transaminase levels increase, their activity should be monitored until normalization. If the activity of AST or ALT, more than 3 times the upper limit of normal, persists, a dose reduction or discontinuation of atorvastatin is recommended.

Pediatric Use

Experience with atorvastatin in children at doses up to 80 mg/day is limited.

Special Precautions

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

Before starting and during treatment with atorvastatin, especially if symptoms of liver damage appear, liver function parameters must be monitored. If transaminase levels increase, their activity should be monitored until normalization. If the activity of AST or ALT, more than 3 times the upper limit of normal, persists, a dose reduction or discontinuation of atorvastatin is recommended.

If symptoms of myopathy appear during treatment, CPK activity should be determined. If a significant increase in CPK level persists, it is recommended to reduce the dose or discontinue Atorvastatin.

The risk of myopathy during treatment with atorvastatin increases with the simultaneous use of cyclosporine, fibrates, erythromycin, antifungal drugs belonging to azoles, and niacin.

There is a possibility of the following adverse reactions, although a clear causal relationship with atorvastatin intake has not been established in all cases: muscle cramps, myositis, myopathy, paresthesia, peripheral neuropathy, pancreatitis, hepatitis, cholestatic jaundice, anorexia, vomiting, alopecia, itching, rash, impotence, hyperglycemia and hypoglycemia.

Experience with atorvastatin in children at doses up to 80 mg/day is limited.

Atorvastatin should be used with caution in patients with chronic alcoholism.

Drug Interactions

With simultaneous use of atorvastatin with digoxin, the plasma concentration of digoxin slightly increases.

Diltiazem, verapamil, isradipine inhibit the CYP3A4 isoenzyme, which is involved in the metabolism of atorvastatin, therefore, with simultaneous use with these calcium channel blockers, an increase in the plasma concentration of atorvastatin and an increased risk of myopathy are possible.

With simultaneous use of itraconazole, the plasma concentration of atorvastatin significantly increases, apparently due to inhibition of its metabolism in the liver by itraconazole, which occurs with the participation of the CYP3A4 isoenzyme; increased risk of myopathy.

With simultaneous use of colestipol, a decrease in the plasma concentration of atorvastatin is possible, while the hypolipidemic effect is enhanced.

With simultaneous use of antacids containing magnesium hydroxide and aluminum hydroxide, the concentration of atorvastatin is reduced by approximately 35%.

With simultaneous use of cyclosporine, fibrates (including gemfibrozil), antifungal drugs of the azole derivatives, nicotinic acid, the risk of myopathy increases.

With simultaneous use of erythromycin, clarithromycin, the plasma concentration of atorvastatin moderately increases, the risk of myopathy increases.

With simultaneous use of ethinyl estradiol, norethisterone (norethindrone), the plasma concentration of ethinyl estradiol, norethisterone (norethindrone) slightly increases.

With simultaneous use of protease inhibitors, the plasma concentration of atorvastatin increases, because protease inhibitors are inhibitors of the CYP3A4 isoenzyme.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.