Vasator, 10 mg 30 pcs.

Pharmacotherapeutic group: Hypolipidemic drug – HMG-CoA reductase inhibitor

Pharmacological action

Hypolipidemic drug of the statin group. Selective competitive inhibitor of HMG-CoA reductase – enzyme, converting Z-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, which is the precursor of sterols, including cholesterol. Triglycerides (TG) and cholesterol in the liver are incorporated into very low density lipoproteins (VLDL), enter the blood plasma, and are transported to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL through interaction with LDL receptors.

Atorvastatin reduces plasma concentrations of cholesterol and lipoproteins by inhibiting HMG-CoA reductase, cholesterol synthesis in the liver and increasing the number of “hepatic” LDL receptors on the cell surface, which leads to increased capture and catabolism of LDL. Reduces LDL formation and causes a marked and persistent increase in LDL receptor activity. Reduces LDL concentration in patients with homozygous familial hypercholesterolemia, which usually does not respond to therapy with hypolipidemic agents. Reduces total cholesterol concentration by 30-46%, LDL concentration by 41-61%, apolynoprotein B concentration by 34-50% and TG concentration by 14-33%; causes increase in HDL cholesterol (high-density linoprotensin) and apolipoprotein A concentration. Dose-dependently reduces LDL levels in patients with homozygous hereditary hypercholesterolemia resistant to therapy with other hypolipidemic agents.

Pharmacokinetics

Absorption is high. C_max in plasma is reached after 1-2 h, C_max in women is 20% higher, area under the concentration-time curve (AUC) is 10% lower; C_max in patients with alcoholic cirrhosis is 16 times higher, AUC- 11 times higher than normal.

Eating slightly reduces speed and duration of drug absorption (by 25% and 9% respectively), but decrease of LDL cholesterol is similar to that with atorvastatin without food. Concentration of atorvastatin when administered in the evening is lower than in the morning (approximately by 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%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and during “first passage” through the liver.

V_d – 381 liters, binding to plasma proteins – 98%. It is metabolized mainly in liver under the influence of CYP3A4, CYP3A5 and CYP3A7 isoenzymes with formation of pharmacological active metabolites (ortho- and para-hydroxylated derivatives, beta-oxidation products). In vitro, ortho- and parahydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable with that of atorvastatin. The inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites.

Extracted through the intestine with bile after hepatic and/or extrahepatic metabolism (not subject to marked intestinal-hepatic recirculation). T_1/2 – 14 h. Inhibitory activity against HMG-CoA reductase persists for about 20-30 hours due to the presence of active metabolites. Less than 2% of the oral dose is detected in the urine. It is not excreted during hemodialysis.

Indications

Active ingredient

Composition

Film coating composition: hypromellose – 4.1 mg, macrogol 6000 – 1.2 mg, titanium dioxide – 0.6 mg, talc – 1.2 mg, iron oxide red dye – 0.07 mg.

How to take, the dosage

People should be advised of a standard hypolipidemic diet before prescribing Vasator, which they should continue to follow for the duration of therapy.

The initial dose is on average 10 mg once daily. The dose varies from 10 to 80 mg once daily.

The drug can be taken at any time of the day with food or regardless of the time of meals. The dose is adjusted with regard to baseline cholesterol/LDL levels, the goal of therapy and individual effect. At the beginning of treatment and/or during dose increase of atorvastatin it is necessary to monitor plasma lipid concentrations every 2-4 weeks and adjust the dose accordingly.

Primary hypercholesterolemia and mixed hyperlipidemia as well as type III and IV according to Fredrickson: In most cases the dosage of 10 mg of Vasator once daily is enough. Significant therapeutic effect is observed after 2 weeks, as a rule, and the maximum therapeutic effect is usually observed after 4 weeks. This effect persists with long-term treatment.

Homozygous familial hypercholesterolemia: The drug is used in a dose of 80 mg (4 tablets of 20 mg) once daily.Do not use more than 4 tablets of 10 mg daily – the dosage of 20 mg must not be changed to 10 mg at a daily dose of 80 mg

The use of the drug in patients with renal insufficiency and renal diseases does not influence the plasma atorvastatin level or the degree of cholesterol/LDL reduction with its use; therefore no change in the drug dose is required.

In case of hepatic impairment, the dose should be reduced (see sections “Caution” and “Special Precautions”).

There were no differences in safety, efficacy, or achievement of hypolipidemic therapy goals when using the drug in elderly patients compared to the general population.

Interaction

The risk of myopathy during treatment with other drugs of this class is increased with concomitant use of cyclosporine, fibrates, erythromycin, azole antifungals and nicotinic acid.Concomitant administration of atorvastatin and suspension containing magnesium and aluminum hydroxide decreased concentrations of atorvastatin in blood plasma by approximately 35%, but the degree of cholesterol/LDL level decrease in this case did not change. In concomitant use atorvastatin does not affect pharmacokinetics of antipyrine (phenazone), therefore interaction with other drugs metabolized by the same cytochrome isoenzymes is not expected.

Concomitant use of colestipolacconcentrations of atorvastatin in plasma were decreased by approximately 25%. However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug alone. When repeated administration of digoxin and atorvastatin at a dose of 10 mg, equilibrium plasma concentrations of digoxin did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg/day, digoxin concentrations increased by approximately 20%. Patients receiving digoxin in combination with atorvastatin should be observed. In concurrent use of atorvastatin and erythromycin (500 mg 4 times per day) or clarithromycin (500 mg 2 times per day), which inhibit CYPZA4 isoenzyme, increased Atorvastatin concentration in plasma was observed. Concomitant administration of atorvastatin (10 mg 1 time/day) and azithromycin (500 mg 1 time/day) did not change concentration of atorvastatin in plasma.

Atorvastatin had no clinically significant effect on terfenadine plasma concentration, which is metabolized primarily by CYPZA4; in this regard it seems unlikely that atorvastatin can significantly affect pharmacokinetic parameters of other CYPZA4 substrates.

In concomitant use of atorvastatin and oral contraceptive containing norethisterone and ethinylestradiol, a significant increase in AUC of norethindrone and ethinylestradiol by approximately 30% and 20% respectively was observed. This effect should be considered when choosing an oral contraceptive for a woman receiving atorvastatin.

Concomitant use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of reduction of endogenous steroid hormones (caution should be exercised).

In the study of interactions of atorvastatin with warfarin and cimetidine no clinically significant interaction was found.

The pharmacokinetics of atorvastatin 80 mg and amlodipine 10 mg in equilibrium has not changed in concomitant use.

There have been no clinically significant adverse interactions between atorvastatin and antihypertensives.

The concomitant use of atorvastatin with protease inhibitors, known as CYPCA4 isoenzyme inhibitors, was accompanied by an increase in plasma concentration of atorvastatin. Pharmaceutical incompatibility is not known.

Special Instructions

Before starting therapy with Vazazator, the patient should be prescribed a standard hypocholesterolemic diet, which should be followed during the entire period of treatment.

The use of HMG-CoA reductase inhibitors to decrease blood lipid concentrations may lead to changes in biochemical parameters reflecting liver function. Liver function should be monitored before the start of therapy, at 6 weeks, 12 weeks after the start of Vasator and after each dose increase, as well as periodically, e.g., every 6 months. Elevated serum hepatic enzyme activity may be observed during therapy with Vasator. Patients with elevated enzyme activity should be monitored until enzyme activity returns to normal. If ALT or ACT values are more than 3 times higher than the upper limit, it is recommended to decrease the dosage of Vazazator or discontinue therapy.

Vasator 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” transferases of unknown genesis are contraindications to the prescription of Vasator.

The treatment with Vasator may cause myopathy. The diagnosis of myopathy (muscle pain and weakness combined with an increase in CPK activity of more than 10 times the upper limit of normal) should be discussed in patients with widespread myalgia, muscle soreness or weakness and/or marked increase in CPK activity. Patients should be warned to inform their physician immediately of unexplained muscle pain or weakness if accompanied by malaise or fever. Vasator therapy should be discontinued if there is a marked increase in CPK activity or if there is confirmed or suspected myopathy. The risk of myopathy during treatment with other drugs of this class was increased with concomitant use of cyclosporine, fibrates, erythromycin, nicotinic acid in lipid-lowering doses or azole antifungals. Many of these drugs inhibit CYPCA4 isoenzyme-mediated metabolism and/or drug transport.

Atorvastatin is biotransformed by the CYPZA4 isoenzyme. When prescribing Vasazar in combination with fibrates, erythromycin, immunosuppressive agents, azole antifungals or nicotinic acid in lipid-lowering doses, the expected benefits and risks of treatment should be carefully weighed and patients should be regularly observed for muscle pain or weakness, especially during the first months of treatment and during dose increases of any drug. Periodic determination of CPK activity may be recommended in such situations, although such monitoring does not prevent the development of severe myopathy.

In case of rhabdomyolysis with acute renal failure due to myoglobinuria has been described with Vasator as well as other agents of this class. Therapy with Vasator should be temporarily stopped or completely discontinued if there are signs of possible myopathy or if there are risk factors of renal failure with rhabdomyolysis (e.g., severe acute infection, arterial hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders and uncontrolled convulsions).

Before initiating therapy with Vasator, an attempt should be made to control hypercholesterolemia through adequate diet therapy, increasing physical activity, reducing body weight in obese patients, and treating other conditions. Patients should be warned to seek immediate medical attention if they experience unexplained muscle pain or weakness, especially if accompanied by malaise or fever.

Impact on driving and operating machinery

In some patients, the drug may cause dizziness and other side effects that may affect driving and operating machinery. In this regard, caution should be exercised while treating with Vasator while driving vehicles and other complex mechanisms requiring increased attention.

Contraindications

With caution: alcohol abuse, history of liver disease, severe electrolyte-water balance disorders, endocrine and metabolic disorders, arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, major surgical interventions, trauma, skeletal muscle diseases.

Side effects

CNS disorders: insomnia, dizziness, headache, asthenia, malaise, somnolence, nightmares, paresthesias, peripheral neuropathy, amnesia, emotional lability, ataxia, facial nerve paralysis, hyperkinesias, migraine, depression, hypoesthesia, loss of consciousness.

Senses: amblyopia, tinnitus, dry conjunctiva, accommodation disorder, retinal hemorrhage, deafness, glaucoma, parosmia, loss of sense of taste, perversion of taste.

Cardiovascular system: chest pain, palpitations, symptoms of vasodilation, orthostatic hypotension, increased BP, phlebitis, arrhythmia, angina pectoris.

Hematopoietic system disorders: anemia, lymphoadenopathy, thrombocytopenia.

Respiratory system disorders: bronchitis, rhinitis, pneumonia, dyspnea, exacerbation of bronchial asthma, nasal bleeding.

In the digestive system: Nausea, 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, 12 duodenal ulcer, pancreatitis, cholestatic jaundice, liver dysfunction, rectal bleeding, melena, bleeding gums, tenesmus.

Musculoskeletal system: arthritis; leg muscle cramps, bursitis, tenosynovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonicity, joint contractures.

Urogenital system disorders: urogenital infections, peripheral edema; dysuria (including nephritis, hematuria, vaginal bleeding, nephrourolithiasis, metrorrhagia, epididymitis, decreased libido, impotence, ejaculation disorders.

Skin disorders: alopecia, xeroderma, increased sweating, eczema, seborrhea, ecchymoses, petechiae.

Allergic reactions: skin itching, skin rash, contact dermatitis, urticaria, aegioneurotic edema, facial edema, photosensitization, anaphylaxis, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

Laboratory measures: hyperglycemia, hypoglycemia, increased serum creatine phosphokinase (CPK), albuminuria.

Others: weight gain, gynecomastia, mastodynia, gout exacerbation.

Overdose

Pregnancy use

Vasator is contraindicated in pregnancy and during lactation (breastfeeding).

It is unknown whether atorvastatin is excreted with breast milk. Taking into account the possibility of developing adverse events in breastfed children, if it is necessary to use the drug during lactation, discontinuation of breastfeeding should be considered.

Women of reproductive age should use adequate contraceptive methods during treatment with Vasator.

Vasator should only be prescribed to women of reproductive age if they are very unlikely to become pregnant and the patient has been informed of the possible risks of the treatment to the fetus.

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