Atorvox - instructions for use, dose, side effects, contraindications

Excipients: microcrystalline cellulose, lactose monohydrate, calcium carbonate, giprolose, polysorbate 80, silicon colloidal dioxide, croscarmellose sodium, vegetable hydrogenated oil, magnesium stearate,

shell: Opapray II 31F58914 white (a complex component consisting of hypromellose, lactose monohydrate, titanium dioxide, macrogol 4000, and sodium citrate).

Description:White, round, biconvex tablets, covered with a film membrane.

Pharmacotherapeutic group:Hypolipidemic agent - inhibitor of HMG-CoA reductase

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.05 Atorvastatin

Pharmacodynamics:

Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A into mevalonic acid, a precursor of sterols, including cholesterol. In the liver, triglycerides and cholesterol are included in very low density lipoproteins (VLDL), enter the plasma and are transported to peripheral tissues. Low-density lipoproteins (LDL) are formed from VLDL when interacting with LDL receptors.

Atorvastatin lowers cholesterol and lipoprotein levels in the blood plasma, inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of "liver" LDL receptors on the cell surface, which leads to increased cholesterol / LDL cholesterol uptake and catabolism. Atorvastatin reduces the formation of LDL. It 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 the level of cholesterol / LDL in patients with homozygous hypercholesterolemia, which usually does not respond to therapy with other lipid-lowering drugs.

When studying the dose-dependent effect of atorvastatin, it was shown that the drug (in a dose of 10-80 mg) reduced total cholesterol levels (by 30-46%), cholesterol / LDL (by 41-61%), apolipoprotein B (by 34-50%) and triglycerides (by 14 - 33%). The results of treatment were similar in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed hyperlipidemia, incl. in patients with insulin-dependent diabetes mellitus.

Pharmacokinetics:

Suction

Atorvastatin is rapidly absorbed after oral administration. The maximum concentration (Cmah) is achieved in 1 to 2 hours.

The degree of absorption and concentration of atorvastatin in the blood plasma increases in proportion to the dose. The absolute bioavailability of atorvastatin is about 14%, and the systemic bioavailability of inhibitory activity against HMG-CoA reductase is about 30%.Low systemic bioavailability is explained by presystemic clearance in the mucous membrane of the gastrointestinal tract (GIT) and / or by the primary metabolism in the liver.

Distribution

The average volume of atorvastatin distribution is about 381 liters. The degree of binding to plasma proteins is 98% or more.

Metabolism

Atorvastatin is actively metabolized with the participation of cytochrome P450 ZA4 with the formation of ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro the inhibitory effect of ortho- and para-hydroxylated metabolites on HMG-CoA reductase is equivalent to that of atorvastatin. The inhibitory activity against HMG-CoA reductase in the blood plasma is approximately 70% due to active metabolites.

Excretion

Atorvastatin and its metabolites are excreted mainly with bile after hepatic and / or extrahepatic metabolism; but atorvastatin, apparently, does not undergo intestinal hepatic recirculation. The half-life (T1 / 2) in the blood plasma is about 14 hours, but the T1 / 2 inhibitory activity against HMG-CoA reductase is 20-30 hours, which is explained by the presence of active metabolites. After ingestion, less than 2% of the dose of atorvastatin is detected in the urine.

The concentration of atorvastatin and its active metabolites in the blood plasma in elderly people is higher than in older adults, but there was no difference in safety, efficacy, or achievement of lipid-lowering therapy goals in the elderly compared to the general population.

The presence of renal failure in the patient does not affect the concentration of atorvastatin in the blood plasma or its hypolipidemic activity. In this regard, dose adjustment in patients with impaired renal function is not required.

The concentration of atorvastatin and its active metabolites in blood plasma is significantly increased (Cmah and AUC0-24 approximately 16 and 11 times, respectively) in patients with chronic alcoholic liver cirrhosis and / or other liver diseases, incl. in the anamnesis.

Indications:

Atorvosk is applied:

in combination with diet and other non-pharmacological methods of treatment with their insufficient effectiveness.

- primary hypercholesterolemia,

- heterozygous familial and non-family hypercholesterolemia,

- combined (mixed) hyperlipidemia,

homozygous familial hypercholesterolemia

- hypertriglyceridemia, disbetalipoproteinemia

Contraindications:

- Hypersensitivity to the drug, excipients;

- liver disease in the active stage, increased activity of "hepatic" enzymes (more than 3 times compared with the upper limit of the norm) of an unknown genesis

- pregnancy,

- lactation period

- age under 18 years (effectiveness and safety not established),

- Women of childbearing age who do not use adequate methods of contraception.

Carefully:With severe violations of electrolyte balance, endocrine and metabolic disorders, alcohol abuse, liver diseases in history, the presence of factors, including hereditary complications, predisposing to the development of rhabdomyolysis, arterial hypotension, severe acute infections, uncontrolled convulsions, extensive surgical interventions, trauma.

Dosing and Administration:During treatment with Atorvox it is recommended to follow a standard lipid-lowering diet.

Inside. The drug can be taken at any time of the day, regardless of food intake. The dose is selected taking into account the baseline levels of cholesterol / LDL,purpose of therapy and individual effect. The initial dose is an average of 10 mg once a day. The maximum dose is 80 mg once a day. At the beginning of treatment and / or during an increase in Atorvox dose, it is necessary to monitor the level of lipids in the plasma every 2-4 weeks and adjust the dose accordingly.

Primary hypercholesterolemia and combined (mixed) hyperlipidemia

In most patients, the required effect can be achieved with the use of Atorvox in a dose of 10 mg 1 time per day. Therapeutic effect manifests itself within 2 weeks and usually reaches a maximum within 4 weeks. With prolonged treatment, the effect persists.

Heterozygous familial hypercholesterolemia

The recommended initial dose of Atorvox is 10 mg per day. Doses are selected individually, increasing every 4 weeks to a maximum dose of 80 mg / day.

Homozygous familial hypercholesterolemia

In a study in adult patients with homozygous familial hypercholesterolemia, an adequate dose is 80 mg / day.

Side effects:

From the nervous system: more often 2% - insomnia, dizziness; less than 2% - headache, asthenia, malaise, drowsiness,abnormal dreams, amnesia, paresthesia, peripheral neuropathy, amnesia, emotional lability, facial paralysis, hyperkinesis, depression, hypersensitivity, impaired consciousness.

From the sense organs: less than 2% - amblyopia, tinnitus, dryness conjunctiva ccomodation, eye hemorrhage, deafness, glaucoma, parosmiya, loss of taste, taste perversion.

From the cardiovascular system: more often 2% - chest pain; less than 2% - palpitation, vasodilation, migraine, postural hypotension, increased blood pressure, phlebitis, arrhythmia, angina.

On the part of the hematopoiesis system: less than 2% - Anemia, lymphadenopathy, thrombocytopenia.

From the respiratory system: more often 2% - bronchitis, rhinitis; less than 2% - pneumonia, dyspnea, bronchial asthma, epistaxis.

From the digestive system: more often 2% - nausea; less than 2% - heartburn, constipation or diarrhea, flatulence, gastralgia, abdominal pain, anorexia, decreased or increased appetite, dry mouth, regurgitation, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosive and ulcerative lesions of the oral mucosa, gastroenteritis, hepatitis, biliary colic,cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, impaired liver function, rectal bleeding, melena, bleeding gums, tenesmus.

From the musculoskeletal system: more often 2% - arthritis; less than 2% - leg muscle cramps, bursitis, tendosinovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonia, joint contractures.

From the genitourinary system: more often 2% - urogenital infections, peripheral edema; less than 2% - dysuria (including pollakiuria, nocturia, urinary incontinence or urinary retention, urgency to urinate), nephritis, hematuria, vaginal bleeding, nefrourolitiaz, metrorrhagia, epididymitis, decreased libido, impotence, abnormal ejaculation.

From the skin: more often 2% - alopecia, xeroderma, increased sweating, eczema, seborrhea, ecchymosis, petechiae.

Allergic reactions: less often 2% - skin itching, skin rash, contact dermatitis, rarely urticaria, angioedema, facial edema, photosensitivity, anaphylaxis, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Laboratory indicators: less than 2% - hyperglycemia, hypoglycemia, increased serum CK, albuminuria.

Other: less than 2% - weight gain, gynecomastia, mastodynia, exacerbation of gout.

Overdose:

Treatment: there is no specific antidote, symptomatic therapy is performed. Given the active binding of atorvastatin to plasma proteins, hemodialysis is ineffective.

Interaction:

The risk of myopathy during treatment with atorvastatin and other drugs of this class is increased with the simultaneous use of cyclosporine, fibrates, erythromycin, antifungal drugs related to azoles, and niacin.

With simultaneous ingestion of atorvastatin and a suspension containing magnesium and aluminum hydroxides, atorvastatin concentrations in the plasma decreased by approximately 35%, however, the level of cholesterol / LDL-lowering did not change.

With simultaneous application atorvastatin does not affect the pharmacokinetics of antipyrine, therefore interaction with other drugs metabolized by the same isoenzymes of cytochrome is not expected.

With simultaneous application of colestipol, concentrations of atorvastatin in blood plasma decreased by approximately 25%.However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug individually.

With simultaneous use of 10 mg of atorvastatin per day and erythromycin (500 mg 4 times a day) or 10 mg of atorvastatin per day and clarithromycin 500 mg twice a day, which inhibit cytochrome P450 3A4, an increase in the concentration of atorvastatin in the blood plasma is observed. On the background of combined treatment with atorvastatin and clarithromycin Cmah and AUC Atorvastatin increased by 56% and 80%, respectively. Probably an increase in the concentration of atorvastatin against a background of combined therapy with other drugs that inhibit cytochrome P450 ZA4, for example, cyclosporine, macrolide antibiotics, nefazodone, antifungal agents related to azoles, incl. itraconazole, as well as protease inhibitors, as well as grapefruit juice in large quantities.

With the simultaneous use of atorvastatin at a dose of 10 mg per day and azithromycin at a dose of 500 mg once daily, the concentrations of atorvastatin in blood plasma did not change.

When digoxin is used in combination with atorvastatin at a dose of 80 mg / day, the digoxin concentration increases by about 20%However, with repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma did not change.

Atorvastatin had no clinically significant effect on the concentration of terfenadine in plasma, which is metabolized mainly by cytochrome P450 3A4; in this connection, it seems unlikely that atorvastatin can significantly affect the pharmacokinetic parameters of other substrates of cytochrome P450 3A4.

With simultaneous use of atorvastatin and oral contraceptives containing norethisterone and ethinyl estradiol, there is a significant increase in their concentration in the blood plasma. This effect should be taken into account when choosing an oral contraceptive.

Clinically significant interaction of atorvastatin with warfarin and cimetidine was not detected.

With the simultaneous use of atorvastatin 80 mg and amlodipine 10 mg, the pharmacokinetics of atorvastatin did not change in the equilibrium state.

Simultaneous use with ethanol increases the risk of increased "liver" transaminases (contraindicated in liver diseases).

Grapefruit juice in large quantities is not recommended during treatment with atorvastatin.

Special instructions:

Atorvox may cause an increase in serum creatinophosphokinase (CK), which should be taken into account in the differential diagnosis of chest pain.

As with other hypolipidemic drugs of the same class, after treatment with atorvox, a moderate increase in the serum activity of "liver" enzymes was noted, which is usually not accompanied by jaundice or other clinical manifestations. With a decrease in the dose of atorvox, a temporary or complete withdrawal of the drug, the activity of the "hepatic" enzymes returned to the initial level. Before and periodically during treatment, it is necessary to monitor indicators of liver function. The liver function should also be investigated when there are clinical signs of impairment. In the case of an increase in the level of liver enzymes, their activity should be monitored before it is normalized. If the increase in activity ACT or ALT more than 3 times compared with the upper limit of the norm is maintained, it is recommended to reduce the dose or cancel the atorvox.

It is necessary to temporarily stop the use of atorvox in the development of clinical symptoms, suggesting the presence of acute myopathy,or in the presence of factors predisposing to the development of acute renal failure against rhabdomyolysis (severe infections, arterial hypotension, traumatic surgeries, trauma, metabolic, endocrine or severe electrolyte disturbances). Patients should be warned that they should immediately consult a doctor if unexplained pain, weakness and muscle cramps occur, especially if they are accompanied by a malaise or fever. When these symptoms appear, it is necessary to measure the level of creatine phosphokinase (CK) in the blood. With a significant increase (more than 5 times higher than the upper limit of the norm), treatment should be stopped. If there are severe symptoms from the muscular system, and the level of CK is equal to or less than the fivefold increase in the value of the upper limit of normal values, treatment should be discontinued.

After the level of CPK returns to normal, and symptoms disappear from the muscles, it is possible to resume therapy atorvsom in smaller doses under strict medical supervision.

Women of reproductive age should use reliable methods of contraception.

The presence of kidney disease or kidney failure does not affect the level of atorvastatin in the plasma or the degree of lowering of cholesterol / LDL when it is used, so no dose adjustment is required.

When using the drug in elderly patients, there were no differences in safety, effectiveness, or achievement of lipid-lowering therapy goals in comparison with the general population.

Effect on the ability to drive transp. cf. and fur:There was no impact on the ability to drive and engage in activities that require concentration.

Form release / dosage:

Tablets, film-coated, 10 mg, 20 mg and 40 mg.

Packaging:

10 tablets per blister from OPA / aluminum foil / PVC / aluminum foil.

For 3 or 6 blisters together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

1,5 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-001350/08

Date of registration:29.02.2008

Expiration Date:Unlimited

The owner of the registration certificate:Pliva of Hrvatska dooPliva of Hrvatska doo Croatia

Manufacturer: & nbsp

PLIVA HRVATSKA, d.o.o. Croatia

Representation: & nbspPliva of Hvartska dooPliva of Hvartska doo

Information update date: & nbsp05.10.2017

Illustrated instructions

Instructions

Atorvox (Atorvox)