TORVAKARD

Active material: Atorvastatin
When ATH: C10AA05
CCF: Lipid-lowering drugs
ICD-10 codes (testimony): E78.0, E78.1, E78.2
When CSF: 16.01.01
Manufacturer: ZENTIVA a.s. (Czech Republic)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, coated from white to almost white, Oval, lenticular.

Excipients: magnesium oxide, heavy, microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, Low-substituted hydroxypropylcellulose LH21, colloidal silicon dioxide, magnesium stearate.

The composition of the shell: gipromelloza 2910/5, macrogol 6000, Titanium dioxide, talc.

10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (3) – foil sachet (1) – packs cardboard.
10 PC. – blisters (9) – packs cardboard.
10 PC. – blisters (9) – foil sachet (1) – packs cardboard.
30 PC. – vials of dark glass (1) – packs cardboard.
90 PC. – vials of dark glass (1) – packs cardboard.

Pharmacological action

Lipid-lowering drugs. Selective competitive inhibitor of HMG-CoA reductase inhibitors – main enzyme, converting 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, a steroid precursor, including cholesterol. In the liver, triglycerides and cholesterol are included in VLDL, arrive in blood plasma and transported in peripheral tissues. LDL is formed from VLDL, which are catabolized by interaction with high-affinity LDL receptors. Atorvastatin lowers cholesterol levels (Hs) and lipoproteins in blood plasma, inhibiting HMG-CoA reductase in the liver and, increasing the number of LDL receptors in the liver on the surface of cells, that leads to increased grip and catabolism of LDL-Cholesterol.

Atorvastatin reduces LDL-Cholesterol Education and the number of particles of LDL. The drug causes a pronounced and persistent increase in the activity of LDL receptors, and also has a beneficial effect on the quality of circulating LDL. Atorvastatin effectively reduces LDL-C levels in patients with homozygous hypercholesterolemia, which usually does not respond to treatment with other lipid-lowering drugs.

When studying the dose dependence of the effect of atorvastatin, it was shown, what drug (dose 10-80 mg) decreased the level of total cholesterol (on 30-46%), LDL-C (on 41-61%), apolipoprotein B (on 34-50%) and triglycerides (on 14-33%). Treatment results were similar in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed Hyperlipidemia (incl. in patients with non-insulin dependent diabetes mellitus). Atorvastatin reduces total cholesterol levels, LDL-C, Hs-LPONP, apolipoprotein B, triglycerides and cholesterol, not included in the PAP, and increases HDL-C levels in patients with isolated hypertriglyceridemia. Atorvastatin reduces intermediate-density lipoprotein cholesterol levels (Xc-DILI) in patients with dysbetalipoproteinemia. Like LDL, lipoproteins, containing triglycerides (incl. VLDL, LPPP and their remains) also accelerate the development of atherosclerosis. Increased plasma triglyceride levels are often found in combination with decreased HDL-C levels and the presence of small LDL particles, and also in combination with non-lipid metabolic risk factors for coronary heart disease. Not proven yet, that an increase in total plasma triglyceride levels is an independent risk factor for coronary artery disease. It is also not proven, that an increase in HDL-C levels or a decrease in triglyceride levels in itself affects the risk of coronary and other cardiovascular complications and mortality of patients.

Atorvastatin and some of its metabolites are pharmacologically active. The primary target organ of action of atorvastatin is the liver., where cholesterol synthesis and LDL clearance occurs.

Dynamics of LDL-C levels correlates better with the dose of atorvastatin, than its concentration in the blood plasma. The dose of the drug should be selected taking into account the therapeutic effect.

Pharmacokinetics

Absorption

After oral administration, atorvastatin is rapidly absorbed from the gastrointestinal tract.. C_max plasma levels achieved after 1-2 no. Absorption and concentration of atorvastatin in plasma increases proportionally with the dose.

The bioavailability of atorvastatin tablets compared to solution is 95-99%.

Absolute bioavailability is approx. 14%, and system bioavailability inhibiting activity against HMG-CoA reductase inhibitors – about 30%.

Low systemic bioavailability is explained by presystemic clearance in the gastrointestinal mucosa and/or metabolism during “first pass” through the liver.

Although food reduces the rate and extent of absorption by approximately 25% and 9% respectively (as evidenced by the results of (C)_max and AUC values), However, CHS level of LDL cholesterol when taken on an empty stomach and atorvastatin during meals is reduced to the same extent. After taking atorvastatin in the evening, its plasma levels are lower (C_max and AUC by approximately 30%), than after taking in the morning. However, the degree of reduction in LDL-C levels does not depend on the time of taking the drug during the day.

Distribution

Average V_d is about 381 l. The binding to plasma proteins – 98%. The ratio of atorvastatin levels in red blood cells/plasma is approximately 0.25, which indicates low permeability of atorvastatin into red blood cells.

Metabolism

Atorvastatin is actively metabolized to form ortho- and paragidroksilirovannyh derivatives and various products beta oxidation. In vitro inhibitory effect of ortho- and parahydroxylated metabolites in relation to HMG-CoA reductase is comparable to that of atorvastatin. Inhibitory activity against HMG-CoA reductase in blood plasma is approximately 70% caused by active metabolites. In vitro studies indicate the importance of metabolism of atorvastatin by the CYP3A4 isoenzyme in the liver; this is confirmed by an increase in atorvastatin concentrations in human plasma during concomitant administration of erythromycin, that is an inhibitor of the izofermenta. In vitro studies have also shown, that atorvastatin is a weak inhibitor of the CYP3A4 isoenzyme.

In animals, the orthohydroxy metabolite undergoes further glucuronidation.

Deduction

Atorvastatin and its metabolites are excreted primarily in bile after hepatic and/or extrahepatic metabolism; however atorvastatin, apparently, does not undergo enterohepatic recirculation. T_1/2 is about 14 no, However, T_1/2 active metabolite, determining inhibitory activity against HMG-CoA reductase, is 20-30 no. Intake in the urine detected less 2% dose.

Pharmacokinetics in special clinical situations

Plasma atorvastatin concentrations in the elderly (the age 65 years) higher (C_max about 40%, AUC approximately 30%), than in younger adult patients. However, differences in safety, The effectiveness or achievement of goals of lipid-lowering therapy in elderly patients compared with the general population was not found.

Research pharmacokinetics of the drug in children have not been conducted.

Atorvastatin concentration in the blood plasma in women differs (C_max about 20% higher, (a) the AUC on 10% below) on concentration in men. However, clinically significant differences influence on lipid metabolism in both men and women is not revealed.

Kidney disease does not affect the plasma concentration of atorvastatin or its effect on lipid parameters. In this regard, no dose change is required in patients with impaired renal function..

Although studies have not been conducted in patients with end-stage renal disease, however, hemodialysis is unlikely to significantly increase the clearance of atorvastatin, tk. it actively binds to plasma proteins.

Atorvastatin concentrations increase significantly (C_max and AUC approximately 16 and 11 times, respectively,) in patients with alcoholic cirrhosis of the liver (Class B of Child-Pugh).

Testimony

- in combination with diet to reduce elevated levels of total cholesterol, LDL-C, apolipoprotein B and triglycerides and increased HDL-C levels in patients with primary hypercholesterolemia, heterozygous Familial Hypercholesterolemia and precluded from accompanying and combination (mixed) hyperlipidaemia (types IIa and IIb on Fredriksonu);

— in combination with diet for the treatment of patients with elevated serum triglyceride levels (Type IV by Fredriksonu) and patients with disbetalipoproteinemiej (Type III by Fredriksonu), whose diet does not give adequate effect;

- to reduce the levels of total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, When diet and other non-pharmacological therapies are insufficient.

Dosage regimen

Before prescribing Torvacard, the patient should be recommended a standard lipid-lowering diet, which he must continue to observe throughout the entire period of therapy.

Initial dose is averaged 10 mg 1 time / day. The dose varies from 10 to 80 mg 1 time / day. The drug can be taken at any time of the day with food or regardless of the time of the meal. The dose is selected taking into account the initial levels of LDL-C, the goal of therapy and individual effect. At the beginning of treatment and/or while increasing the dose of Torvacard, it is necessary every 2-4 weeks to monitor levels of lipids in the blood plasma and appropriately correct dose.

At primary hypercholesterolemia and mixed Hyperlipidemia in most cases, a dose is sufficient 10 mg of the drug Torvacard 1 time / day. A significant therapeutic effect is observed through 2 of the week, usually, and the maximum therapeutic effect is usually observed after 4 of the week. In long-term care, this effect is.

The following guidelines can be used to determine treatment goals:.

A. National Cholesterol Education Program Guidelines (United States)

* IHD or peripheral vascular atherosclerosis (including damage to the carotid arteries, accompanied by clinical symptoms).

** age (men ≥45 years old, women ≥55 years or early menopause, in which estrogen replacement therapy is not carried out), cases of early development of ischemic heart disease in relatives, smoking, arterial hypertension, confirmed HDL-C level<35 mg / dL (<0.91 mmol / l) and diabetes mellitus. One risk factor should be subtracted, if HDL-C level is ≥60 mg/dL (≥1.6 mmol/l).

*** in patients with coronary artery disease with LDL-C levels from 100 to 129 mg/dL the question of prescribing drug therapy is decided by the doctor taking into account clinical experience.

B. Goals of lipid-lowering therapy of the European Atherosclerosis Society

In patients with a confirmed diagnosis of coronary artery disease and other patients at high risk of ischemic complications, the goal of treatment is to reduce LDL-C levels<115 mg / dL (<3 mmol / l) and General Cs<190 mg / dL (<5 mmol / l).

IN. National treatment guidelines

Homozygous familial hypercholesterolemia

In the study, Adult patients with homozygous familial hypercholesterolemia are treated with atorvastatin at a dose 80 mg in most cases led to a decrease in LDL-C levels by more than 15% (18-45%).

Use of the drug in patients with renal failure and kidney disease does not affect the level of atorvastatin in the blood plasma or the degree of reduction in LDL-C levels when used, therefore, no change in the dose of the drug is required.

In applying the drug in elderly patients differences in security, performance or achievement of the objectives of the cholesterol-lowering treatment in comparison with the general population not noted.

Side effect

From the central and peripheral nervous system: headache, dizziness, asthenic syndrome, insomnia or drowsiness, nightmares, amnesia, paresthesia, perifericheskaya neuropathy, emotional lability, ataxia, hyperkinesis, depression, giperesteziya.

From the senses: amblyopia, tinnitus, dryness of the conjunctiva, ccomodation, bleeding in the eye, deafness, increased intraocular pressure, parosmija, dysgeusia, loss of taste.

Cardio-vascular system: chest pain, heartbeat, vasodilation, orthostatic hypotension, phlebitis, arrhythmia.

From the hematopoietic system: anemia, lymphadenopathy, thrombocytopenia.

The respiratory system: bronchitis, rhinitis, dyspnoea, bronchial asthma, nose bleed.

From the digestive system: nausea, heartburn, constipation or diarrhea, flatulence, gastralgia, abdominal pain, Anorexia or increased appetite, dry mouth, belching, dysphagia, vomiting, stomatitis, esophagitis, glossitis, gastroenteritis, hepatitis, pečenočnaâ how, cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, increase in liver enzymes, rectal bleeding, ground, krovotochivosty right, tenesmus.

On the part of the musculoskeletal system: arthritis, cramping of the leg muscles, ʙursit, myositis, myopathy, arthralgia, myalgia, raʙdomioliz, joint contractures, backache.

With the genitourinary system: urogenital infections, peripheral edema, dizurija (incl. thamuria, nocturia, urinary incontinence or urinary retention, urgent need to urinate), jade, cystitis, hematuria, vaginal bleeding, uterine bleeding, urolithiasis disease, metrorragija, epididymitis, decreased libido, impotence, abnormal ejaculation.

Dermatological reactions: alopecia, Sweating, eczema, seborrhea, ecchymosis, photosensitivity.

Allergic reactions: itching, skin rash, contact dermatitis; rarely – hives, angioedema, swelling of the face, anaphylaxis, erythema multiforme exudative, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

From the laboratory parameters: giperglikemiâ, gipoglikemiâ, Increase serum CPK, albuminuria, increased AST activity, GOLD.

Other: weight gain, gynecomastia, exacerbation of gout, fever.

Contraindications

- active liver disease or increased transaminase activity in the blood serum (more than 3 fold compared with CAH) unknown origin;

- Pregnancy;

- Lactation;

- Childhood and adolescence up 18 years (efficacy and safety have not been established);

- Hypersensitivity to the drug.

FROM caution should be used for chronic alcoholism, a history of liver disease, heavy violations elektrolitnogo balance, endocrine and metabolic irregularities, When arterial hypotension, severe acute infections (sepsis), uncontrolled epilepsy, in case of extensive surgical interventions and injuries, diseases of skeletal muscle.

Pregnancy and lactation

Atorvastatin is contraindicated for use in pregnancy and lactation (breast-feeding).

Unknown, is allocated whether atorvastatin with breast milk. In view of the possibility of adverse events in infants, If necessary, use during lactation should decide the issue of termination of breastfeeding.

Women of reproductive age at the time of treatment must use adequate contraception methods. Atorvastatin can be assigned to women of reproductive age only, if the probability of pregnancy have a very low, and the patient informed of possible risks of treatment for fetus.

Cautions

Before starting Torvacard therapy, the patient must be prescribed a standard cholesterol-lowering diet, which he must comply during the entire treatment period.

The use of inhibitors of HMG-CoA reductase to reduce the level of lipids in the blood can lead to changes in biochemical parameters, reflecting liver function. Liver function should be monitored before therapy, through 6 weeks, 12 weeks after starting Torvacard and after each dose increase, and periodically (eg, every 6 Months). An increase in the activity of liver enzymes in the blood serum may be observed during therapy with Torvacard.. Patients, in which there is an increase in transaminase levels, should be controlled prior to returning to normal enzymes. In that case, if AST or ALT values ​​over 3 times those of VGN, it is recommended to reduce the dose of Torvacard or stop treatment.

Torvacard should be used with caution in patients, alcohol and/or have liver disease. Active liver disease or persistent increase in aminotransferase activity of unknown origin are contraindications to the use of Torvacard.

Treatment with Torvacard may cause myopathy. In patients with common mialgijami, muscle soreness or weakness and/or a pronounced increase in CPK activity should keep in mind the possibility of developing myopathy (pain and weakness in the muscles, combined with the increased activity of the KLF more than 10 times compared with FHG). Patients should be warned about that, that they should immediately inform the doctor about the emergence of unexplained pain or weakness in the muscles, If they are accompanied by malaise or fever. Treatment with Torvacard should be discontinued in the event of a marked increase in CPK activity or in the presence of confirmed or suspected myopathy. The risk of myopathy during treatment of other drugs of this class has increased, while the use of Cyclosporine, fibrate, Erythromycin, Nicotinic Acid or azole antifungals. Many of these drugs inhibit the metabolism of, mediated by the CYP3A4 isoenzyme, and/or transport drugs. Atorvastatin biotransformiroetsa under the influence of CYP3A4. Prescribing atorvastatin in combination with fibrates, Erythromycin, immunosupressivei means, azole antifungal drugs or Nicotinic Acid in lipid lowering doses, You should carefully weigh the expected benefits and risks of treatment and regularly monitor patients with the aim of identifying pain or weakness in the muscles, especially during the first months of treatment and during periods of increasing doses of any medication. In such situations, it is possible to recommend periodic determination of activity of KFK, Although such control does not allow you to prevent the development of severe myopathy.

In the application of atorvastatin, like other drugs of this class, Describes cases of rhabdomyolysis with acute renal failure, caused by myoglobinuria. Torvacard therapy should be temporarily discontinued or completely discontinued if signs of possible myopathy appear or if there is a risk factor for the development of renal failure due to rhabdomyolysis (eg, severe acute infection, hypotension, a serious operation, trauma, heavy Exchange, metabolic and electrolyte disorders and uncontrolled convulsions). Before starting therapy with Torvacard, it is necessary to try to control hypercholesterolemia through adequate diet therapy, increasing physical activity, lower body mass index in patients with obesity and treat other conditions. Patients should be warned about, they should immediately consult a doctor if you have unexplained pain or weakness in muscles, especially if they are accompanied by malaise or fever.

Effects on ability to drive a car and operate machinery

No adverse effects of Torvacard on the ability to drive or operate machines have been reported..

Overdose

Symptoms: possible arterial hypotension.

Treatment: symptomatic therapy. No specific antidote. Hemodialysis nyeeffyektivyen.

Drug Interactions

The risk of myopathy during treatment with other drugs of this class increases with concomitant use of cyclosporine, fibrate, Erythromycin, antifungals, belonging to azolam, and niacin.

While ingestion of atorvastatin and suspension, containing magnesium and aluminum hydroxide, plasma concentrations of atorvastatin decreased by approximately 35%, However, the degree of lowering LDL-Cholesterol while not changed.

When used concomitantly, atorvastatin does not affect the pharmacokinetics of antipyrine., therefore interactions with other drugs, those same cytochrome izofermentami is not expected.

With simultaneous use of colestipol, plasma concentrations of atorvastatin decreased by approximately 25%. However, lowering atorvastatin combination effects and kolestipola surpassed such each drug separately.

The readmission of Digoxin and atorvastatin dose 10 mg equilibrium concentration of Digoxin in plasma is not changed. However, when applied in combination with digoxin dose of atorvastatin is appropriate 80 mg/day concentration of Digoxin increased by about 20%. Patients, receiving digoxin in combination with atorvastatin, supervision required.

Together with the use of atorvastatin and erythromycin (500 mg 4 times / day) or == (500 mg 2 times / day), that inhibit CYP3A4 CYP, There was an increase in concentrations of atorvastatin in plasma.

Together with the use of atorvastatin (10 mg 1 time / day) and azithromycin (500 mg 1 time / day) plasma atorvastatin concentrations did not change.

Atorvastatin had no clinically significant effect on concentration terfenadina in plasma, which is metabolized mainly by CYP3A4; In this regard, it is unlikely, that atorvastatin can significantly affect the pharmacokinetic parameters of other CYP3A4 substrates.

Together with the use of atorvastatin and oral contraceptive, containing norethindrone and ethinyl estradiol, There was a significant increase in AUC norethindrone and ethinyl estradiol by about 30% and 20% respectively. This effect should be taken into account when choosing oral contraceptive for women, receiving atorvastatin.

When studying the interaction of atorvastatin with warfarin and cimetidine, no signs of clinically significant interaction were found.

Together with the use of atorvastatin dose 80 mg and amlodipine dose 10 mg pharmacokinetics of atorvastatin in equilibrium has not changed.

The combined application of atorvastatin with protease inhibitors, known as inhibitors of the CYP3A4 isoenzyme, accompanied by increases in the concentrations of atorvastatin in plasma.

No clinically significant interactions atorvastatin and antigipertenziveh funds, and also with estrogens. Research of interaction with all specific drugs have been conducted.

No known pharmaceutical incompatibilities.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children at temperature from 10 ° to 30 ° C. Shelf life – 2 year.