Lipromak-LF

General characteristics. Structure:

Active ingredient: 10 mg, 20 mg and 40 mg of an atorvastatin.

Excipients: calcium carbonate, кросповидон, sodium lauryl sulfate, aerosil, talc, cellulose microcrystallic, опадрай the II pink (talc, polyethyleneglycol, titanium dioxide, polyvinyl alcohol, ferrous oxide yellow, ferrous oxide red, ferrous oxide black).

The hypolipidemic drug reducing cholesterol level in blood.

Pharmacological properties:

Pharmacodynamics. Atorvastatin is the selection competitive inhibitor of GMG-KOA-reduktazy - enzyme which regulates the speed of the GMG-KOA transformation in мевалонат - the predecessor of sterol (including cholesterol (XC)). At patients with homozygous and heterozygous family giperkho-a lesterinemiy, not hereditary form of a hypercholesterolemia and the mixed dislipidemiya аторвастатин reduces concentration of the general of XC, lipoproteids of the low density (L11NP) and apolipoprotein B (Apo In). Atorvastatin also reduces concentration of lipoproteids of very low density (LPONP) and triglycerides (TG), and also increases the maintenance of the XC lipoproteids of the high density (LPVP) a little.

Atorvastatin reduces level XC and lipoproteids in a blood plasma by oppression ГМГ-КоА-of reductase, synthesis of XC in a liver and increases in number of receptors of LPNP at surfaces gepa-totsit that is followed by strengthening of capture and a catabolism of LPNP. Atorvastatin reduces products of LPNP, causes the expressed and long increase in activity of receptors of LPNP. Atorvastatin effectively reduces the LPNP level at patients with a homozygous family hypercholesterolemia which does not give in to standard therapy by hypolipidemic sredstyova.

Primary scene of action of an atorvastatin is the liver which plays a major role in a sinyoteza of XC and clearance of LPNP. Decrease in the LPNP level XC correlates with a dose of drug and its kontsenyotration in an organism.

Atorvastatin in a dose of 10-80 mg reduced the level of the general XC (by 30-46%), the XC LPNP (for 41-61%), Apo In (for 34-50%) and TG (for 14-33%). This result is steady at patients with the heterozygous family hypercholesterolemia acquired by a form of a hypercholesterolemia and the mixed foryomy lipidemia including at patients with a non-insulin-dependent diabetes mellitus.

At patients with the isolated gipertriglitseridemiya аторвастатин reduces the level of the general XC, XC LPNP, the XC LPONP, Apo of V, TG and increases the LPVP level XC a little. At patients with dis-a betalipoproteinemiya аторвастатин reduces the LPSP level XC.

At patients with a giperlipoproteinemiya like Pa and N (on Fredrikson's classification) the average level of increase in the XC LPVP at use of an atorvastatin in a dose of 10-80 mg made 5,1-8,7% irrespective of a dose. Besides, significant dozozavisimy reduction of ratios the general XC/XC LPVP and the XC LPNP/HS LPVP was noted. Use of an atorvastatin reduces risk of development of ischemia and death at patients with a myocardial infarction without tooth with Q and unstable stenocardia (не­зависимо from gender and age) in direct ratio to the LPNP level XC.

Heterozygous related hypercholesterolemia in pediatrics. At boys and girls at the age of 10-17 years with a heterozygous family hypercholesterolemia or a heavy hypercholesterolemia аторвастатин in a dose of 10-20 mg of 1 times a day significantly reduced the level of the general XC, XC LPNP, TG and Apo In in a blood plasma. At the same time the significant effect on growth and puberty at boys or on duration of a menstrual cycle at girls was not revealed. Safety and efficiency of use in doses higher than 20 mg for treatment of children was not studied. Influences of a proyodolzhitelnost of therapy atorvastatiny in the childhood on reduction of incidence and mortality at adult age it is not established.

Pharmacokinetics. Atorvastatin is quickly soaked up after oral administration; its concentration in a blood plasma reaches the maximum level for 1-2 h. Relative bioavailability of an atorvastayotin makes 95-99%, absolute - 12-14%, system (the reductase GMG-KOA providing inhibition) - about 30%. Low system bioavailability is explained with a presistemny kliyorens in a mucous membrane of digestive tract and/or metabolism at the first proyokhozhdeniye through a liver. Absorption and concentration in a blood plasma increase proportsioyonalno to a drug dose. In spite of the fact that at reception with food drug absorption уменьшает­ся (the maximum concentration and AUC - approximately for 25 and 9% respectively), decrease in the LPNP level XC does not depend on that, was accepted аторвастатин together with food or not. At reception of an atorvastatin in the evening its concentration in a blood plasma was lower (about 30% for the maximum concentration and AUC), than at morning reception. However decrease in the LPNP level XC does not depend on time of administration of drug.

More than 98% of drug contact proteins of a blood plasma. эритро­цит / plasma makes ratio coefficient about 0,25 that demonstrates weak penetration of a prepayorat into erythrocytes.

Atorvastatin is metabolized to orto-and parahydroxylated derivatives and various beta oxidized products. The inhibiting effect of drug concerning GMG-KOA-reduktazy approximately for 70% is implemented due to activity of the circulating metabolites. Ustanovleyono, that аторвастатин is weak inhibitor of P450 ZA4 cytochrome.

Atorvastatin and his metabolites are allocated mainly with bile after hepatic and/or extrahepatic metabolism. However drug is not subject to essential enterohepatic recirculation. The average elimination half-life of an atorvastatin makes nearly 14 h, but the period of inhibitory activity concerning GMG-KOA-reduktazy thanks to the circulating aktivyony metabolites makes 20-30 h. Less than 2% of the dose of an atorvastatin accepted orally vydeyolyatsya with urine.

Concentration of an atorvastatin in a blood plasma of healthy faces of advanced age (65 years) higher (about 40% for the maximum concentration and 30% - for AUC are more senior), than at young people. Distinctions in efficiency of treatment atorvastatiny at patients of advanced age and patients of other age groups are not revealed.

Concentration of an atorvastatin in a blood plasma at women differs from concentration in kroyova plasma at men (at women the maximum concentration about 20% higher, an AUC - is 10% less). However whether it is revealed clinically reliable difference in influence on level - pvd at men and women.

Diseases of kidneys do not influence concentration of drug in a blood plasma or on influence atorva-statine on the level of lipids therefore patients have no need for dose adjustment of drug with a renal failure. The conducted researches did not cover patients with a termiyonalny stage of a renal failure; possibly, the hemodialysis significantly does not change кли­ренс an atorvastatin as drug almost completely contacts proteins of a blood plasma. Concentration of an atorvastatin in a blood plasma significantly increases (the maximum kontsentrayotion - approximately by 16 times, AUC - by 11 times) at patients with cirrhosis of an alcoholic etioloyogiya.

Indications to use:

Hypercholesterolemia. Atorvastatin is appointed as addition to a diet for treatment of patients with the increased level of the general XC, XC LPNP, Apo In and triglycerides, and also for increase in the LNVP level XC at patients with primary hypercholesterolemia (a hereditary heterozygous and not hereditary hypercholesterolemia) combined (mixed) lipidemia (the IIA and IIb type on Fredrikson's classification), the increased TG level in plasma (type III on Fredrikson's classification) when the diet does not render sufficient effect.

Atorvastatin is also shown for lowering of the level of the general XC and XC LPNP at patients with a homozygous hereditary hypercholesterolemia when there is no sufficient reaction to a diet or other not medicinal actions.

Prevention warmly - vascular diseases. Warmly - a vascular disease, with a dislipidemiya or without it, but with multiple factors of risk of coronary heart disease, such as smoking, arterial hypertension, a diabetes mellitus, low XC LPVP (H-LPVP), or with early coronary heart disease in the family anamnesis, use of an atorvastatin is shown to patients without clinical signs for

- reduction of risk of a lethality at coronary heart disease and not fatal myocardial infarction;

- reduction of risk of development of a stroke;

- reduction of risk to undergo operation of revascularization and risk of development of stenocardia;

- reduction of risk of hospitalization concerning chronic heart failure;

- reduction of risk of development of stenocardia.

Route of administration and doses:

For intake. Tablets are washed down with enough water.

Use of this medicine is possible only after consultation with the doctor. If you forgot to accept Lipromak-LF, take a pill as soon as possible, time of the next reception did not come yet. If time was suitable for reception of the following dose of medicine, do not accept the passed dose. It is impossible to double a medicine dosage for compensation missed! Further drug is used according to the recommended dosing mode.

Do not stop reception Lipromaka-LF without preliminary consultation with the attending physician.

If you had doubts or questions, see the attending physician.

Before therapy Lipromakom-LF it is necessary to determine level XC in blood against the background of the corresponding diet, to appoint physical exercises and to hold the events directed to decrease in body weight at patients with obesity and also to carry out treatment of basic diseases. During treatment Lipromakom-LF patients should adhere to a standard gipokholeste-rinemichesky diet. Drug appoint in a dose 10-80 mg of 1 times a day daily, in any, but at the same time day, irrespective of meal. The initial and supporting doses can be individualized according to the LPNP initial level XC, tasks and efficiency of therapy. In 2 — 4 weeks from an initiation of treatment and/or Lipromaka-LF the lipidogramm should carry out dose adjustments and as appropriate to correct a dose.

Primary hypercholesterolemia and the combined (mixed) lipidemia. In most cases it is enough to appoint drug in a dose of 10 mg of 1 times a day daily. The effect of treatment develops in 2 weeks, the maximum effect - in 4 weeks. Positive changes are supported by long use of drug.

Homozygous family hypercholesterolemia. Drug is appointed in a dose from 10 mg to 80 mg of 1 times a day daily, at any time, irrespective of meal. The initial and supporting doses are established individually. In most cases at patients with a homozygous family hypercholesterolemia the result is achieved by Lipromak's use - LF in a dose of 80 mg of 1 times a day.

Lipromak-LF apply as additional therapy to other methods of treatment (plasmapheresis) or as the main way of treatment if therapy by other methods is impossible. Use for patients with a renal failure. Diseases of kidneys do not influence concentration of an atorvastatin or decrease in the LPNP level XC in a blood plasma therefore there is no need for dose adjustment.

To patients with abnormal liver functions drug is appointed with care in connection with delay of removal of drug from an organism. Control of clinical and laboratory indicators is shown and at identification of considerable pathological changes, the dose has to be reduced or treatment is stopped.

Co-administration with SURZA4 inhibitors. Always to begin treatment with the minimum dose (10 mg), it is obligatory to control blood serum lipids before titration of a dose.

It is possible to cancel temporarily reception Lipromaka-LF if CYP3A4 inhibitors are appointed a short course (for example, a short course of an antibiotic, such as кларитромицин.

Recommendations of the maximum doses Lipromaka-LF when using: with cyclosporine - the dose should not exceed 10 mg; with klaritromitsiny - the dose should not exceed 20 mg; with itrakonazoly - the dose should not exceed 40 mg.

Heterozygous family hypercholesterolemia in pediatrics (patients at the age of 10-17 years). Lipromak - LF in an initial dose of 10 mg of 1 times a day daily is recommended to appoint. The maximum recommended dose makes 20 mg of 1 times a day daily (the doses exceeding 20 mg at patients of this age group did not study). The dose is established individually taking into account problems of therapy, it is possible to korrigirovat a dose with an interval of 4 weeks and more.

Use for patients of advanced age. In safety and efficiency of drug in treatment of a hypercholesterolemia patients of advanced age and adult patients aged up to 60 years have no distinctions.

Features of use:

As well as at use of other hypolipidemic means of the same class, at treatment by drug Lipromak-LF perhaps moderate (more than by 3 times in comparison with VGN) increase in serumal activity of hepatic transaminases.

Before, in 6 weeks and 12 weeks later began uses of drug or after increase in a dose, and also during all course of treatment it is necessary to control indicators of function of a liver. Function of a liver should be investigated also at emergence of clinical signs of damage of a liver. In case of increase in level of hepatic transaminases their activity should be controlled until it is not normalized. If increase in activity of nuclear heating plant or ALT more than by 3 times in comparison with VGN remains, recommended a dose decline or drug withdrawal.

At the patients receiving аторвастатин mialgiya were observed. The diagnosis of a myopathy should be assumed at patients with widespread mialgiya, morbidity or weakness of muscles and/or the expressed increase in activity of KFK. Therapy Lipromakom-LF should be stopped in case of the expressed increase in activity of KFK or in the presence of the confirmed or estimated myopathy.

Increase in risk of a myopathy at simultaneous use of cyclosporine, derivatives of fibroyevy acid, erythromycin, niacin or antifungal drugs from group of azoles is possible. Appointing Lipromak-LF in a combination with fibrata, erythromycin, immunodepressants, antifungal drugs from group of azoles or niacin in hypolipidemic doses, it is necessary to weigh carefully expected advantage and risk of treatment and to regularly observe patients for the purpose of detection of pains or weakness in muscles, especially within the first months of treatment and during the periods of increase in a dose of any drug. In similar situations it is possible to recommend periodic definition of activity of KFK.

Atorvastatin is capable to cause increase in activity of KFK. At use of an atorvastatin, as well as other drugs of this class, exceptional cases of a rabdomioliz with the acute renal failure caused by a myoglobinuria are described. Therapy by drug Lipromak-LF should be stopped temporarily or to cancel completely at emergence of signs of a possible myopathy or existence of risk factors of development of a renal failure against the background of a rabdomioliz (for example, a heavy acute infection, arterial hypotension, serious operation, an injury, metabolic, endocrine and electrolytic disturbances and uncontrollable spasms).

At use of an atorvastatin in a dose of 80 mg there is a risk of a repeated hemorrhagic stroke in comparison with placebo.

It is necessary to see immediately a doctor at emergence of inexplicable pains or weakness in muscles, especially if they are followed by an indisposition or fever.

Messages on very exceptional cases developments of intersticial diseases of lungs at use of statines were gained, especially at long therapy. At emergence of symptoms of intersticial diseases of lungs, such as breath disturbance, short wind, unproductive cough, deterioration in the general state (fatigue, decrease in body weight, fever), therapy by statines should be stopped.

Some data demonstrate that statines increase the content of glucose in blood, and with high risk of development of diabetes can cause increase in content of glucose in blood which demands the corresponding treatment in patients. However advantages of statines concerning decrease in risks of cardiovascular diseases are exceeded by small increase in risk of development of diabetes therefore it is not necessary to stop use of statines. It is necessary to control periodically the content of glucose in blood at the patients accepting statines, especially at patients from risk group (glucose on an empty stomach of 5.6-6.9 mmol/l, a body weight index> 30 kg/sq.m, increase in level of triglycerides or hypertensia).

Influence on ability to driving of motor transport and to control of mechanisms. It is unknown.

You are pregnant or nurse if you assume that you are pregnant or do not exclude at yourself probability of approach of pregnancy, report about it to the attending physician. Lipromak-LF is contraindicated at pregnancy and feeding by a breast.

Women of reproductive age during treatment have to use reliable methods of contraception. Lipromak-LF women of reproductive age can appoint only if probability of pregnancy at them very low, and the patient is informed on possible risk for a fruit during treatment.

Planning of pregnancy is possible 1 month later after the termination of reception of an atorvastatin Lipromak-LF is contraindicated when feeding by a breast. It is unknown whether drug with breast milk is removed. Considering a possibility of undesirable reactions at babies, the women receiving this drug have to stop feeding by a breast.

Side effects:

From TsNS and peripheral nervous system: sleeplessness or drowsiness, dreadful dreams, indisposition, dizziness, depression, amnesia, headache, asthenic syndrome, paresthesias, peripheral neuropathy, hypesthesia.

From cardiovascular system: stethalgia, heartbeat, vazodilatation, migraine, postural hypotension, increase in the ABP, phlebitis, arrhythmia, stenocardia, repeated hemorrhagic stroke.

From sense bodys: an amblyopia, a ring in ears, dryness of a conjunctiva, accommodation disturbance, hemorrhage in eyes, deafness, glaucoma, a parosmiya, loss of flavoring feelings.

From the alimentary system: vomiting, anorexia, abdominal pain, dyspepsia, nausea, loss of appetite, meteorism, lock, diarrhea, hepatitis, pancreatitis, cholestatic jaundice.

From a musculoskeletal system: dorsodynia, myotonia, miositis, myopathy, arthralgias, рабдомиолиз.

Allergic reactions: urticaria, itch, skin rash, anaphylactic reactions, violent rash, mnogoformny exudative erythema, toxic epidermal necrolysis (Lyell's disease), malignant exudative erythema (Stephens-Johnson's syndrome).

From a metabolism: a hypoglycemia, a hyperglycemia, increase in level of serumal KFK, a diabetes mellitus (frequency of development will depend on existence or lack of risk factors - glucose on an empty stomach ≥ 5.6, a body weight index> 30 kg/sq.m, increase in level of triglycerides, arterial hypertension in the anamnesis).

From respiratory system: bronchitis, rhinitis, pneumonia, диспноэ, bronchial asthma, nasal bleeding, exceptional cases of development of intersticial diseases of lungs, especially at prolonged use.

From system of a hemopoiesis: anemia, limfoadenopatiya, thrombocytopenia.

From an urinary system: urogenital infections, peripheral hypostases, a dysuria (including a pollakiuria, a nocturia, an incontience of urine or a delay of an urination, imperative desires on an urination), nephrite, a hamaturia, нефроуролитиаз.

From a reproductive system: vaginal bleeding, metrorrhagia, epididymite, decrease in a libido, impotence, disturbance of an ejaculation.

Dermatological reactions: an alopecia, a xerodermia, the increased sweating, eczema, seborrhea, ecchymomas, petechias.

Others: increase in body weight, fervescence.

Interaction with other medicines:

The risk of a myopathy during treatment by other drugs of this class increases at simultaneous use of cyclosporine, derivatives of fibroyevy acid, erythromycin, the antifungal drugs relating to azoles and niacin.

At simultaneous use of antiacid drugs in the form of the suspension containing magnesium hydroxide and aluminum hydroxide, concentration of an atorvastatin in a blood plasma decreased approximately by 35%, however extent of reduction of the Hs-LPNP level at the same time did not change.

Lipromak-LF does not influence antipyrine pharmacokinetics therefore interaction with other drugs, the metabolized same isoenzymes of CYP450, is not expected.

In a research of medicinal interaction at healthy faces the concomitant use of an atorvastatin in a dose of 80 mg and an amlodipina in a dose of 10 mg led to increase in bioavailability of an atorvastatin by 18% that has no clinical value.

Due to the increased risk of development of a myopathy / рабдомиолиза at simultaneous use of inhibitors of GMG-KOA-reduktazy with gemfibrozily co-administration of the specified medicines should be avoided.

At simultaneous use of inhibitors of GMG-KOA-reduktazy from fibrata the risk of development of a myopathy / рабдомиолиза therefore at use of fibrat аторвастатин it is necessary to appoint with care increases.

At use of an atorvastatin in a combination with niacin the risk of development of a myopathy / рабдомиолиза therefore in this situation it is necessary to consider a question of a dose decline of an atorvastatin can increase.

At simultaneous use of a kolestipol concentration of an atorvastatin in a blood plasma decreased approximately by 25%. However the hypolipidemic effect of a combination of an atorvastatin and kolestipol surpassed that of each drug separately.

At repeated reception of digoxin and an atorvastatin in a dose of 10 mg of Css of digoxin in a blood plasma did not change. However at use of digoxin in a combination with atorvastatiny in a dose of 80 mg/days concentration of digoxin increased approximately by 20%. The patients receiving digoxin in combination with atorvastatiny need clinical control.

At simultaneous use of an atorvastatin and erythromycin (500 mg of 4 times/days) or a klaritromitsina (500 mg of 2 times/days) which are CYP3A4 isoenzyme inhibitors increase in concentration of an atorvastatin in a blood plasma was observed.

At simultaneous use of an atorvastatin (10 mg of 1 times/days) and azithromycin (500 mg of 1 times/days) concentration of an atorvastatin in plasma did not change.

At simultaneous use of an atorvastatin and terfenadin of clinically significant changes of pharmacokinetics of a terfenadin it is not revealed.

At simultaneous use of the atorvastatin and oral contraceptive containing norethindrone and ethinylestradiol substantial increase of AUC norethindrone and ethinylestradiol approximately for 30% and 20% respectively was observed. This effect should be considered at the choice of an oral contraceptive for the woman accepting аторвастатин.

When studying interaction of an atorvastatin with warfarin of symptoms of clinically significant interaction it is not revealed.

When studying interaction of an atorvastatin with Cimetidinum of symptoms of clinically significant interaction it is not revealed.

At simultaneous use of an atorvastatin with inhibitors of proteases which are CYP3A4 inhibitors concentration of an atorvastatin in a blood plasma increases.

Recommendations of the combined use of an atorvastatin and inhibitors of HIV protease

HIV protease inhibitors	Recommendations about combined use
Tipranavir + ритонавир Telaprevir	Joint reception is not recommended
Lopenavir + ритонавир	To apply аторвастатин with care and in a minimal effective dose
Darunavir + ритонавир Fosamprenavir Fosamprenavir + ритонавир Sakvinavir + ритонавир	The dose of an atorvastatin should not exceed 20 mg/days
Nelfinavir	The dose of an atorvastatin should not exceed 40 mg/days

Atorvastatin and metabolites of an atorvastatin are OATP1B1 carrier substrates. OATP1B1 inhibitors (for example, cyclosporine) are capable to increase bioavailability of an atorvastatin. The concomitant use of an atorvastatin in a dose of 10 mg and cyclosporine in a dose of 5.2 mg/kg/days led to 7.7 multiple increase in bioavailability of an atorvastatin.

At simultaneous use of an atorvastatin (40 mg) and diltiazem (240 mg) higher are observed by concentration of an atorvastatin in plasma.

At simultaneous use of an atorvastatin (in a dose from 20 mg) and the itrakonazola (200 mg) increases to 40 mg AUC of an atorvastatin.

Grapefruit juice contains one or more components which inhibit CYPZA4 and can increase concentration of an atorvastatin in plasma, especially at the excess use of grapefruit juice (more than 1.2 l/days).

At simultaneous use of an atorvastatin and inductors of an isoenzyme CYP3A4 (for example, an efavirenza, rifampicin) various extent of decrease in concentration of an atorvastatin in plasma is possible. Because of the dual mechanism of interaction of rifampicin (induction of an isoenzyme CYP3A4 and inhibition of a carrier of OATP1B1 providing capture with hepatocytes), the simultaneous combined purpose of an atorvastatin and rifampicin since purpose of an atorvastatin after use of rifampicin was followed by considerable decrease in concentration of an atorvastatin in plasma is recommended.

Contraindications:

- hypersensitivity to active agent or any of auxiliary components;

- active diseases of a liver or increase in activity of transaminases of serum (more than by 3 times in comparison with the upper bound of norm) not clear genesis;

- period of pregnancy and lactation;

- the women of reproductive age who are not using reliable methods of contraception;

- age up to 18 years.

Overdose:

Treatment: if necessary carry out symptomatic therapy (a gastric lavage, reception of absorbent carbon or laxative drugs).

At development of a myopathy with the subsequent rabdomioliz and an acute renal failure drug should be cancelled immediately. Administration of diuretic and solution of Natrii hydrocarbonas is shown. Rabdomioliz can lead to a hyperpotassemia for which elimination it is required in/in introduction of Calcii chloridum or calcium of a gluconate, infusion of glucose with insulin, a hemodialysis.

There is no specific antidote. As аторвастатин contacts proteins of plasma, the hemodialysis is ineffective.

Storage conditions:

Drug should be stored in the unavailable to children, protected from moisture place at a temperature not above 25 °C. Period of validity 2 years.

Issue conditions:

According to the recipe

Packaging:

On 10  tablets in   a blister strip packaging. On three or six   blister strip packagings a dosage of 10 mg or 20 mg together with the application instruction in a pack from a cardboard. On three blister strip packagings a dosage of 40 mg together with the application instruction in a pack from a cardboard.