Atorvastatin-OBL - instructions for use, dose, side effects, contraindications

Atorvastatin calcium	- 10.83 mg	-21.66 mg	- 43.32 mg	- 86.64 mg
in terms of atorvastatin	-10 mg	- 20 mg	- 40 mg	- 80 mg
Excipients:
mannitol	- 63.5 mg	-127.0 mg	- 254.0 mg	- 508.0 mg
macrogol 6000 (polyethylene glycol 6000)	- 2.17 mg	- 4.34 mg	- 8.68 mg	- 17.36 mg
crospovidone	- 10.0 mg	- 20.0 mg	- 40.0 mg	- 80.0 mg
sodium croscarmellose	- 2.6 mg	- 5.2 mg	-10.4 mg	- 20.8 mg
magnesium stearate	0.9 mg	-1.8 mg	- 3.6 mg	- 7.2 mg
Average tablet weight	- 90 mg	-180 mg	360 mg	- 720 mg

Excipients for the shell:

Opadrai II (series 85)

polyvinyl alcohol; 1.2 mg

macrogol 0.606 mg

talc 0.444 mg

titanium dioxide 0.708 mg

Aluminum lacquer based on

indigo carmine dye 0.0381 mg

dye iron oxide yellow 0.0039 mg

Opadrai II (series 85)

polyvinyl alcohol 2.4 mg

macrogol 1.212 mg

talc 1.888 mg

titanium dioxide 1.367 mg

Aluminum lacquer based on

dye quinoline yellow 0.132 mg

Aluminum lacquer based on

indigo carmine dye 0.001 mg

Opadrai II (series 85)

polyvinyl alcohol 4.8 mg

macrogol 2.424 mg

talc 1.776 mg

titanium dioxide 2.809 mg

Aluminum lacquer based on

dye of charming red 0.0697 mg

Aluminum lacquer based on

dye azorubin 0.044 mg

Aluminum lacquer based on

dye sunset yellow 0.0673 mg

Opadrai II (series 85)

polyvinyl alcohol 9.6 mg

macrogol 4.846 mg

talc 3.552 mg

titanium dioxide 6.0 mg

Average weight of coated tablet - 93 mg -186 mg - 372 mg - 744 m

Description:

Tablets coated with a film membrane 10 mg: light blue, biconvex, oblong with rounded ends, with a risk on one side of the tablet.

Tablets, film-coated 20 mg: yellow, round, biconvex form.

The tablets covered with a film cover of 40 mg: pink, biconvex, oblong with rounded ends, with a risk on one side of the tablet.

Tablets coated with a film membrane 80 mg: white, biconvex, oblong with rounded ends, with a risk on one side of the tablet.

On the cross-section of tablets of all dosages, the nucleus is white or almost white in color.

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.

Triglycerides (TG) and cholesterol are included in the composition of very low density lipoproteins (VLDL) in liver synthesis, enter the blood plasma and are transported in peripheral tissues. Low density lipoproteins (LDL) are formed from VLDL in the course of interaction with LDL receptors.Studies have shown that an increase in the concentration of total cholesterol in the blood plasma, LDL and apolipoprotein B - (apo-B) promotes the development of atherosclerosis and is part of a group of risk factors for cardiovascular disease, while an increase in the concentration of high-density lipoprotein (HDL) reduces risk of developing cardiovascular diseases.

Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase, an inhibitor of cholesterol synthesis in the liver, and an increase in the number of "liver" LDL receptors on the cell surface, which leads to an increase in the capture and catabolism of LDL.

Atorvastatin reduces the synthesis and concentration of cholesterol-LDL, total cholesterol, apo-B in patients with homozygous and heterozygous familial hypercholesterolemia, primary hypercholesterolemia and mixed hyperlipidemia.

It also causes a decrease in the concentration of cholesterol-VLDL and TG and an increase in the concentration of cholesterol-HDL and apolipoprotein A (apo-A).

In patients with disbetalipoproteinemia, the concentration of lipoproteins in the intermediate density of cholesterol-LDLP decreases.

Atorvastatin in doses of 40 mg reduces the concentration of total cholesterol by 37 %, LDL - by 50%, apo-B - by 42% and TG - by 29% %; causes an increase in the concentration of cholesterol-HDL and apo-A.

Dose-dependently reduces the concentration of LDL in patients with homozygous familial hypercholesterolemia, resistant to therapy with other lipid-lowering drugs.

Therapeutic effect develops 2 weeks after the initiation of therapy and reaches a maximum after 4 weeks and persists throughout the treatment period.

Pharmacokinetics:

Absorption and distribution

Absorption is high. The maximum concentration (Cmah) in the blood plasma after ingestion is achieved in 1-2 hours Cmah in women is higher by 20%, the area under the curve "concentration-time" (AUC) - 10% lower than in men, which has no clinical significance. FROMmah in patients with alcoholic liver cirrhosis (class B on the Child-Pugh scale) 16 times, a AUC - 11 times higher than normal.

Eating somewhat reduces the speed and degree of absorption of the drug (approximately 25% and 9%, respectively), but the reduction in LDL-cholesterol is similar to that of atorvastatin without simultaneous ingestion.

After oral administration of atorvastatin in the evening, the concentration in the blood plasma is lower (Cmah and AUC approximately 30%) than after taking in the morning, however, a decrease in the concentration of LDL cholesterol does not depend on the time of day in which take the drug. A linear relationship between the degree of absorption and the dose of the drug has been revealed.

Bioavailability is 12%, systemic bioavailability of inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal tract and "primary passage" through the liver.

The average volume of distribution is 381 liters, the connection with blood plasma proteins -98%.

The ratio of atorvastatin concentration in erythrocytes / plasma is about 0.25, that is atorvastatin poorly penetrates into red blood cells.

Metabolism and excretion

Atorvastatin is metabolized predominantly in the liver by isozymes CYP3A4, CYP3A5 and CYP3A7 with the formation of pharmacologically active metabolites (ortho- and para-hydroxylated derivatives, beta-oxidation products). In vitro ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin. Inhibitory the effect of the drug on HMG-CoA reductase by about 70 % is determined by the activity of circulating metabolites, which persists for about 20-30 hours, due to their presence.

Isozyme CYP3A4 The liver plays an important role in the metabolism of atorvastatin. This is confirmed by an increase in the concentration of atorvastatin in plasma, blood with the simultaneous administration of erythromycin, which is also an inhibitor of this isoenzyme.

Atorvastatin is a weak isoenzyme inhibitor CYP3 A4.

It is derived mainly through the intestine after hepatic and / or extrahepatic metabolism (the drug is not subjected to severe intestinal hepatic recirculation). The half-life (T1 / 2) is about 14 hours. Less than 2% of the ingested dose is determined in urine.

It is not excreted during hemodialysis due to intensive binding to blood plasma proteins.

FROMmah and AUC of the drug in elderly patients (65 years and older) by 40 and 30%, respectively, higher than in young patients, but this has no clinical significance.

Impaired renal function does not affect the concentration of the drug in the blood plasma.

Indications:

In combination with a diet to reduce elevated concentrations of total cholesterol, cholesterol / LDL,apolipoprotein B and triglycerides and increasing the concentration of HDL cholesterol in patients with primary hypercholesterolemia, heterozygous familial and non-family hypercholesterolemia, and combined hyperlipidemia (types IIa and IIb by Fredrickson).

In combination with a diet for the treatment of patients with elevated serum concentrations of triglycerides (type IV Fredrickson) and patients with disbetalipoproteinemia (type III Fredrickson), in which diet therapy does not provide an adequate effect.

To reduce the concentration of total cholesterol and cholesterol / LDL in patients with homozygous familial hypercholesterolemia, when diet therapy and other non-pharmacological methods of treatment are not effective enough.

Contraindications:

Hypersensitivity to any of the components of the drug; active liver disease or increased activity of "hepatic" enzymes of unknown origin (more than 3 times compared with the upper limit of the norm); myopathy; pregnancy and the period of breastfeeding, as well as the use in women of reproductive age not using adequate methods of contraception; age to 18 years (efficacy and safety of use not established).

Carefully:

Alcoholism, liver disease in the anamnesis, diseases of the muscular system (in the anamnesis from the use of other group representatives, inhibitors of HMG-CoA reductase), severe water-electrolyte balance disorders, endocrine (hyperthyroidism) and metabolic disorders, arterial hypotension, severe acute infections (sepsis ), uncontrolled epilepsy, extensive surgical interventions, trauma.

Pregnancy and lactation:

The drug Atorvastatin-OBL contraindicated during pregnancy.

In the case of diagnosing pregnancy during atorvastatin therapy, the drug should be discontinued as soon as possible, and the patient is warned about the potential risk to the fetus.

The drug Atorvastatin-OBL contraindicated during breastfeeding. Atorvastatin is excreted in breast milk, so if you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside at any time of the day, regardless of time of food intake.

The dose of the drug ranges from 10 mg to 80 mg per day, and is selected taking into account the initial concentrations of cholesterol-LDL, the purpose of therapy and individual therapeutic response to the therapy.For most patients, the initial dose is 10 mg once a day.

At the beginning of treatment, and / or during a dose increase atorvastatin-OBL, it is necessary to monitor the lipid levels in the blood plasma every 2-4 weeks and adjust the dose accordingly.

Primary hypercholesterolemia and mixed hyperlipidemia, and type III and IV according to Fredrickson

In most cases, it is sufficient to use a dose of 10 mg once a day. A significant therapeutic effect is observed after 2 weeks, as a rule, and the maximum therapeutic effect is usually observed after 4 weeks. When long-term treatment this effect persists. The maximum daily dose is 80 mg / day.

Homozygous familial hypercholesterolemia

The drug Atorvastatin-OBL apply in a dose of 80 mg once a day.

Correction of the dose of atorvastatin-OBL in patients with impaired renal function and in patients older than 65 years is not required.

Dose of Atorvastatin-OBL in patients with insufficient liver function, it is necessary to decrease with the constant monitoring of the activity of "hepatic" transaminases: aspartate aminotransferase (ACT) and alanine aminotransferase (ALT).

Side effects:

To assess the incidence of adverse reactions, the following criteria were used: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000), including individual messages.

Allergic reactions: often - itchy skin, skin rash; infrequently - hives; very rarely - angioedema, bullous rash, polymorphic exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

From the nervous system: often - headache, dizziness, insomnia, asthenic syndrome, drowsiness, nightmares, depression, malaise, weakness, paresthesia, hypoesthesia; infrequently - peripheral neuropathy, amnesia, a violation of taste perception.

From the digestive system: often - constipation, flatulence, indigestion, nausea, diarrhea, abdominal pain; infrequently - anorexia, vomiting, belching, pancreatitis; rarely - hepatitis, cholestatic jaundice (including obstructive jaundice).

From the side of the musculoskeletal and connective tissue: often - myalgia, joint pain, back pain,pain in the neck, limbs, swelling of the joints; infrequently - myopathy, muscle cramps, arthralgia, muscle weakness, tendopathy (in some cases with a rupture of the tendon); rarely - myositis, rhabdomyolysis.

From the side of the hearing organ and labyrinthine disorders: infrequently, noise in the ears.

Laboratory indicators: infrequently - hyperglycemia, hypoglycemia, increased activity of serum creatinine phosphokinase (CK), increased activity of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT), leukocyturia.

From the side of the blood and lymphatic system: infrequently - thrombocytopenia.

Other: often - chest pain, peripheral edema; infrequently - increased fatigue, fever, nasopharyngitis, weight gain, potency disorders, alopecia, secondary renal failure; there are separate reports on development of atonic fasciitis (a link with the use of atorvastatin is not exactly installed).

If any of the side effects specified in the instruction are aggravated, or you notice any other side effects not listed in the instructions, this doctor.

Overdose:

Treatment: There is no specific antidote.In case of an overdose, symptomatic treatment should be given. Hemodialysis is ineffective (because atorvastatin binds to blood plasma proteins).

Interaction:

During treatment with HMG-CoA reductase inhibitors, while using cyclosporine, fibrates, erythromycin / clarithromycin, antifungal agents, azole derivatives and nicotinic acid in lipid-lowering doses (> 1 g / day) increased risk of myopathy.

Inhibitor inhibitors CYP3A4

Because the atorvastatin metabolized by isoenzyme CYP3A4, combined use of atorvastatin with isozyme inhibitors CYP3A4 can lead to an increase in the concentration of atorvastatin in the blood plasma. Power interaction and potentiation effect are determined by the variability of the effect on the isoenzyme CYP3A4.

Inhibitors of transport protein OATP1B1

Atorvastatin and its metabolites are substrates of the transport protein OATP1B1. Inhibitors of OATP1B1 (for example, ciclosporin) may increase the bioavailability of atorvastatin. The combined use of atorvastatin 10 mg and cyclosporine at a dose of 5.2 mg / kg / day led to an increase in the concentration of atorvastatin in blood plasma at 7.7 times.

Erythromycin / clarithromycin

With simultaneous use of atorvastatin and erythromycin (500 mg 4 times per day) or clarithromycin (500 mg twice a day), inhibitors of isoenzyme CYP3A4, an increase in the concentration of atorvastatin in the blood plasma was observed.

Inhibitors of proteases

Simultaneous use of atorvastatin with protease inhibitors, known isoenzyme inhibitors CYP3A4, is accompanied by an increase in the concentration of atorvastatin in the blood plasma (with simultaneous use with erythromycin CmAtorvastatin increases by 40%).

Diltiazem

The combined use of atorvastatin in a dose of 40 mg with diltiazem at a dose of 240 mg, leads to an increase in the concentration of atorvastatin in blood plasma.

Cimetidine

Clinically significant interaction of atorvastatin with cimetidine was not detected.

Itraconazole

Simultaneous use of atorvastatin in doses from 20 mg to 40 mg and itraconazole at a dose of 200 mg conducted to an increase in the value AUC atorvastatin.

Grapefruit juice

Because grapefruit juice contains one or more components that inhibit the isoenzyme CYP3A4, its excessive consumption (more than 1.2 liters within 5 days) can increase AUC atorvastatin 2.5 times and the concentration of atorvastatin and its active metabolites in blood plasma is 1.3 times.

Inductors of isoenzyme CYP3A4

Combined use of atorvastatin with isoenzyme inducers CYP3A4 (eg, efavirenz or rifampicin) can lead to a decrease in the concentration of atorvastatin in the blood plasma. Due to the dual mechanism of interaction with rifampicin (isoenzyme inducer CYP3A4 and inhibitor of the hepatocyte transport protein OATP1B1) simultaneous use of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after taking rifampicin results in a significant decrease in the concentration of atorvastatin in blood plasma.

Antacids

Simultaneous ingestion of a suspension containing magnesium hydroxide and aluminum hydroxide reduced the concentration of atorvastatin in the blood plasma by approximately 35%, but the degree of decrease in the LDL content did not change.

Fenazone

Atorvastatin does not affect the pharmacokinetics of phenazone, so interactions with other drugs metabolized by the same cytochrome isoenzymes are not expected.

Kolestypol

With simultaneous application of colestipol, the concentration of atorvastatin in the blood plasma decreased by about 25 %; However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.

Gemfibrosil / fibroic acid derivatives

The risk of atorvastatin-induced myopathy may increase with simultaneous use of atorvastatin and fibrolic acid derivatives (fibrates), due to inhibition by gemfibrozil (according to data in vitro) glucuronide pathway of atorvastatin metabolism.

Digoxin

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. However, when using digoxin in combination with atorvastatin at a dose of 80 mg / day, the digoxin concentration increased by about 20%. Patients receiving digoxin in combination with atorvastatin, require appropriate monitoring.

Azithromycin

With the simultaneous use of atorvastatin 10 mg once a day and azithromycin 500 mg once a day, the concentration of atorvastatin in the blood plasma did not change.

Oral contraceptives

With simultaneous use of atorvastatin and oral contraceptives containing norethisterone and ethinyl estradiol, there was a significant increase AUC norethisterone and ethinyl estradiol by approximately 30% and 20%, respectively. This effect should be considered when choosing an oral contraceptive for a woman receiving atorvastatin.

Terfenadine

With the simultaneous use of atorvastatin and terfenadine, clinically significant changes in the pharmacokinetics of terfenadine have not been identified.

Warfarin

There were no signs of a clinically significant interaction of atorvastatin with warfarin.

Amlodipine

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

Fusidic acid

During postmarketing studies, there have been cases of rhabdomyolysis in patients taking both fusidic acid and atorvastatin. Patients should be carefully monitored and accounted for that the temporary cancellation of atorvastatin may be appropriate.

Other interactions

In clinical trials, the use of atorvastatin simultaneously with antihypertensive andhypoglycemic drugs did not reveal a clinically significant interaction.

Special instructions:

Before using Atorvastatin-OBL the patient should be recommended a standard hypocholesterolemic diet, which he must continue to observe throughout the period of therapy.

The drug can be used in women of reproductive age only if they are likely to have a pregnancy highly low, and the patient is informed of the possible risk to the fetus during treatment. Women of reproductive age during the treatment should use reliable methods of contraception.

Effects on the liver

As with other lipid-lowering agents in this class, after treatment with atorvastatin noted moderate (more than 3 times compared with the upper limit of normal) increased activity of "liver" transaminases ACT and ALT, which was usually not accompanied by jaundice or other clinical manifestations.

With a reduced dose, temporary or complete withdrawal of the drug, the activity of "liver" transaminases returns to the initial level.

Before the start of therapy,After 6 weeks and 12 weeks after the beginning of the use of the drug or after increasing the dose, as well as the appearance of clinical signs of liver damage, it is necessary to monitor the liver function parameters. In the case of increased activity of "hepatic" transaminases, control is performed until the activity 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 drug. The drug should be used with caution in patients who abuse alcohol and / or liver disease in an anamnesis.

Action on skeletal muscles

In patients who received atorvastatin, there were cases of myalgia. Myopathy should be diagnosed in patients with diffuse myalgia, muscle soreness or weakness, and / or a marked increase in CKK activity (more than 10 times the upper limit of normal). The drug should be discontinued if there is a marked increase in the activity of CK, with confirmed myopathy or suspected development. The risk of myopathy when treated with other drugs of this class is increased with the simultaneous use of cyclosporine, fibrates, erythromycin,nicotinic acid in lipid-lowering doses (more than 1 g / day) or azole antifungal agents. Many of these drugs inhibit isoenzyme mediated metabolism CYP3A4, and / or the transport of drugs. Isozyme CYP3A4 - the main isoenzyme of the liver involved in the biotransformation of atorvastatin. If necessary simultaneous administration with fibrates, erythromycin, immunosuppressants, azole antifungal agents or nicotinic acid in lipid-lowering doses (more than 1 g / day), the physician should carefully correlate the expected benefit of treatment and the possible risk of myopathy. Patients should be observed regularly to identify pain or weakness in the muscles, especially during the first months of therapy and during the period of increasing the dose of any of these agents. If necessary, combination therapy should consider the possibility of using lower initial and maintenance doses of the above funds. Temporary cancellation of atorvastatin may be appropriate during treatment with fusidic acid. In such situations it is possible to recommend periodic monitoring of the activity of CKK, although such monitoring does not prevent the development of severe myopathy.When the drug is used, rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria are described. The risk factor for advanced rhabdomyolysis may be a previous impairment of renal function. Such patients should ensure a more thorough control of the skeletal musculature. If symptoms of a possible myopathy or presence of risk factors for the development of renal failure against rhabdomyolysis (eg severe acute infection, arterial hypotension, extensive surgery, trauma, metabolic, endocrine and electrolyte disturbances, uncontrolled convulsions), drug therapy should be temporarily discontinued or completely abolished. Patients should be warned about the need to immediately consult a doctor if unexplained pain or Muscular weakness, especially if they are accompanied by malaise or fever.

Effect on the ability to drive transp. cf. and fur:Data on the effect of atorvastatin on the ability to drive vehicles, to service moving machinery, and to engage in potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions are lacking.However, given the possibility of advanced dizziness, care should be taken when performing the listed activities.

Form release / dosage:

Tablets, film-coated 10 mg, 20 mg, 40 mg, 80 mg.

Packaging:

By 7, 10, 14, 15, 20 or 30 tablets into the cell loop packaging of the film polyvinylchloride and aluminum foil printed lacquered.

By 1,2,3,4,5 or 6 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Storage conditions:

In dry, dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001245

Date of registration:17.11.2011

The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Manufacturer: & nbsp

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Information update date: & nbsp17.11.2011

Illustrated instructions

Instructions

Atorvastatin-OBL (Atorvastatin-OBL)