LIPRIMAR

Active material: Atorvastatin
When ATH: C10AA05
CCF: Lipid-lowering drugs
ICD-10 codes (testimony): E78.0, E78.1, E78.2, i20, I21, I25.1, I61, I63
When CSF: 01.12.11.03
Manufacturer: GOOD DECK GmbH (Germany)

Pharmaceutical form, composition and packaging

Pills, Film-coated white, elliptical, Engraved “10” on one side and “PD 155” – another; of presentations – White core.

Excipients: calcium carbonate, microcrystalline cellulose, lactose monohydrate, Croscarmellose sodium, polysorbate-80, giproloza, magnesium stearate.

The composition of the coating film: opadraj white YS-1-7040 (gipromelloza, polyethylene glycol, Titanium dioxide, talc), simethicone emulsion (simethicone, stearinovyj emulsifier, sorbic acid, water), wax kandelila.

7 PC. – blisters (2) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (10) – packs cardboard.

Pills, Film-coated white, elliptical, Engraved “20” on one side and “PD 156” – another; of presentations – White core.

Excipients: calcium carbonate, microcrystalline cellulose, lactose monohydrate, Croscarmellose sodium, polysorbate-80, giproloza, magnesium stearate.

The composition of the coating film: opadraj white YS-1-7040 (gipromelloza, polyethylene glycol, Titanium dioxide, talc), simethicone emulsion (simethicone, stearinovyj emulsifier, sorbic acid, water), wax kandelila.

7 PC. – blisters (2) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (10) – packs cardboard.

Pills, Film-coated white, elliptical, Engraved “40” on one side and “PD 157” – another; of presentations – White core.

Excipients: calcium carbonate, microcrystalline cellulose, lactose monohydrate, Croscarmellose sodium, polysorbate-80, giproloza, magnesium stearate.

The composition of the coating film: opadraj white YS-1-7040 (gipromelloza, polyethylene glycol, Titanium dioxide, talc), simethicone emulsion (simethicone, stearinovyj emulsifier, sorbic acid, water), wax kandelila.

7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (10) – packs cardboard.

Pills, Film-coated white, elliptical, Engraved “80” on one side and “PD 158” – another; of presentations – White core.

Excipients: calcium carbonate, microcrystalline cellulose, lactose monohydrate, Croscarmellose sodium, polysorbate-80, giproloza, magnesium stearate.

The composition of the coating film: opadraj white YS-1-7040 (gipromelloza, polyethylene glycol, Titanium dioxide, talc), simethicone emulsion (simethicone, stearinovyj emulsifier, sorbic acid, water).

7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.
10 PC. – blisters (3) – packs cardboard.
10 PC. – blisters (10) – packs cardboard.

Pharmacological action

Synthetic drug-lowering. Atorvastatin-selective competitive inhibitor of HMG-CoA reductase, a key enzyme, converting 3-Hydroxy-3-HMG CoA mevalonat-the predecessor of steroids, including cholesterol.

In patients with homozygous and heterozygous Familial Hypercholesterolemia, non-familial forms of hypercholesterolemia and Mixed Dyslipidemia atorvastatin lowers plasma total cholesterol in the blood (Hs), XC-LDL and apolipoprotein in (APO-), as well as the contents of the XC-VLDL and TG, raises the delicate increased level HDL-Xc.

Atorvastatin reduces the concentration of cholesterol and lipoprotein in plasma, inhibiting HMG-KOA-reduktazu and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors 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. Calls and persistent increase in LDL receptor activity, coupled with favorable qualitative changes LDL particles. Reduces the level of Cholesterol-LDL in patients with hereditary homozygous hypercholesterolemia, resistant to therapy with other lipid means.

Atorvastatin in doses 10-80 mg reduces total cholesterol at 30-46%, LDL-C – on 41-61%, APO- – on 34-50% and TG – on 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 non-insulin dependent diabetes mellitus.

In patients with isolated hypertriglyceridemia atorvastatin reduces total cholesterol, LDL-C, Hs-LPONP, APO-, TG and HS-LPneVP and increases the level of HDL Cholesterol. In patients with disbetalipoproteinemiej reduces cholesterol OTHER.

In patients with giperlipoproteinemiej type IIA and IIb Fredrickson average value increase the level of HDL Cholesterol in the treatment of atorvastatin is appropriate (10-80 mg), compared to the benchmark is 5.1-8.7% and does not depend on the dose. There is a significant reduction in dose-dependent values of ratios: total cholesterol/HDL-Xc and XC-LDL/HDL-Xc on 29-44% and 37-55% respectively.

Atorvastatin dose 80 mg reliably reduces the risk of ischaemic complications and death on 16% After a 16-week course, and the risk of repeated hospitalization about angina, accompanied by signs of myocardial ischemia, – on 26%. In patients with different source levels of Hs-LDL atorvastatin reduces risk of ischaemic complications and death (in patients with myocardial infarction without zubza Q and unstable angina, men and women, patients aged under or over 65 years).

Decrease in plasma Cholesterol-LDL is better correlated with the dose of the drug, than its concentration in the blood plasma.

Therapeutic effect was achieved through the 2 weeks after start of therapy, reaches through 4 weeks and lasts for the whole period of therapy.

Prevention of cardiovascular diseases

In the Anglo-Scandinavian cardiac outcomes study, lipidosnižaûŝaâ branch (ASCOT-LLA), influence of atorvastatin on fatal and non-fatal CORONARY HEART DISEASE outcomes found, the effect of atorvastatin is appropriate therapy at a dose 10 mg significantly exceeded the effect of placebo, in connection with the decision on early termination of research through 3.3 years instead of the anticipated 5 years.

Atorvastatin significantly reduced the development of the following complications:

Significant reduction of total and cardiovascular mortality has not been pointed out, Although the observed positive trends.

In a joint study on the impact of atorvastatin in patients with diabetes 2 type (CARDS) in deadly and non-fatal cardiovascular disease outcomes shown, Atorvastatin is appropriate therapy reduced the risk of developing the following cardiovascular complications, regardless of gender, the age of the patient or the initial level of LDL-Cholesterol.

Effect of atorvastatin on development of cardiovascular complications are described in the following table.

Atherosclerosis

The study of reverse development of coronary atherosclerosis in intensive lipid-lowering therapy (REVERSAL) Atorvastatin is appropriate in a dose 80 mg in patients with ischemic heart disease found, the average decrease in the total atheroma (the primary criterion of effectiveness) Since the beginning of the study amounted to 0.4%.

Recurrent stroke

The programme of intensive cholesterol-lowering (SPARCL) It was found, that atorvastatin dose 80 mg/day reduces the risk of repeated fatal or nonfatal stroke in patients, a history of stroke or transient ischemic attack without ISCHEMIC HEART DISEASE in history 15%, compared to placebo. This significantly decreased the risk of major cardiovascular complications and revascularization procedures. Reducing the risk of cardiovascular disorders in atorvastatin is appropriate therapy was observed in all groups except the, which included patients with primary or recurrent haemorrhagic stroke (7 in the Group of atorvastatin against 2 placebo).

Hemorrhagic stroke

Patients, receiving treatment at the dose of atorvastatin is appropriate 80 mg, the incidence of hemorrhagic or ischemic stroke (265 against 311) or IBS (123 against 204) was less, than in the control group.

Secondary prevention of cardiovascular complications

In the interpretation of the new target Research (TNT) Comparing the effect of atorvastatin in doses 80 mg / day 10 mg/day on the risk of cardiovascular complications in patients with clinically confirmed CORONARY HEART DISEASE.

Atorvastatin dose 80 mg reliably reduced the development of the following complications:

Pharmacokinetics

Absorption

Atorvastatin is rapidly absorbed after administration inwards; C_max achieved through 1-2 no. Absorption and concentration of atorvastatin in plasma increases proportionally with the dose. Absolute bioavailability of atorvastatin is approximately 14%, and system bioavailability inhibiting activity against g-KOA-reduktaza-about 30%. Low system bioavailability due to presistemnym metabolism in GASTROINTESTINAL mucosa and/or “first pass” through the liver. Food reduces the rate and extent of absorption by approximately 25% and 9% respectively (as evidenced by the results of (C)_max и AUC), However, CHS level of LDL cholesterol when taken on an empty stomach and atorvastatin during meals is reduced almost to the same extent. Despite, that after administration of atorvastatin in the evening in the plasma levels below (C_max and AUC by approximately 30%), than after taking in the morning, lowering LDL cholesterol Cholesterol does not depend on the time of day, which take the drug.

Distribution

Average V_d Atorvastatin is approximately 381 l. Linking of atorvastatin to plasma proteins is not less 98%. Relevant levels of atorvastatin in erythrocyte/plasma is about 0.25, ie. Atorvastatin poorly crosses in red blood cells.

Metabolism

Atorvastatin is largely metabolized with the formation of Ortho- and paragidroksilirovannyh derivatives and various products beta oxidation. In vitro Ortho- and paragidroksilirovannye metabolites have an inhibitory effect on HMG-CoA reductase inhibitors, comparable to that of atorvastatin. Inhibiting activity against g-KOA-reduktaza approximately 70% due to the activity of circulating metabolites. Results of in vitro studies suggest, that CYP3A4 CYP plays an important role in the metabolism of atorvastatin. This is confirmed by the increased concentrations of atorvastatin in human plasma while receiving erythromycin, that is an inhibitor of the izofermenta.

In vitro studies have also shown, that atorvastatin is a weak inhibitor of CYP3A4 izofermenta. Atorvastatin had no clinically significant effect on concentration terfenadina in plasma, which is metabolized mainly CYP3A4 izofermentom; in this regard, the substantial influence of atorvastatin on farmakokinetiku izofermenta CYP3A4 substrates other unlikely.

Deduction

Atorvastatin and its metabolites are excreted, mainly, with bile after liver and/or vnepečenočnogo metabolism (Atorvastatin is not subject to pronounced kishechno-pechenocna recycling). T_1/2 is about 14 no, , While ingibiruty effect drug in relation to HMG-CoA- approximately reductase 70% is determined by the activity of circulating metabolites and is about 20-30 h due to their presence. Intake in the urine detected less 2% doses of atorvastatin.

Pharmacokinetics in special clinical situations

Age

Plasma atorvastatin concentrations in the elderly (aged ≥ 65 years) higher (C_max about 40%, AUC approximately 30%), than in adult patients of young age. Differences in security, performance or achievement of the objectives of the cholesterol-lowering therapy in the elderly compared with the general population have not been.

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

Paul

Atorvastatin concentrations in plasma from women differ (C_max about 20% higher, and AUC by 10% below) from those in men. However, clinically significant differences influence on lipid metabolism in both men and women is not revealed.

Renal failure

Violation of kidney function has no effect on the concentration of plasma atorvastatin or its effect on the indices of lipid metabolism. In this regard, changes dosage in patients with renal impairment is not required.

Atorvastatin is not displayed during hemodialysis due to intensive binding to plasma proteins.

Hepatic failure

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

Testimony

- Primary Hypercholesterolemia (heterozygous familial hypercholesterolemia and non-family (type Iia Fredrickson);

-combined (mixed) hyperlipidemia (types IIA and IIb Fredrickson);

— disbetalipoproteinemiâ (Fredrickson type III) (as an adjunct to diet);

-family endogenous hypertriglyceridemia (Fredrickson type IV), resistant to diet;

-homozygous Familial Hypercholesterolemia with inefficiency diet and other non-pharmacological treatments;

— the primary prevention of cardiovascular complications in patients without clinical signs of ISCHEMIC HEART DISEASE, but with several risk factors of its development – older than 55 years, Nicotine addiction, arterial hypertension, diabetes, low concentrations of HDL Cholesterol in the blood plasma, genetic predisposition, incl. against the backdrop of Dyslipidemia;

-secondary prevention of cardiovascular complications in patients with ischemic heart disease to reduce the total death rate, myocardial infarction, stroke, rehospitalization for angina and the need for revascularization.

Dosage regimen

Before starting treatment Liprimarom^® You should try to control hypercholesterolemia through diet, exercise and lower body mass index in patients with obesity, as well as the treatment of the underlying disease.

In appointing the drug, the patient should recommend a standard gipoholesterinemičeskuû diet, He must observe during treatment.

The drug is taken orally at any time of the day regardless of the meal. Dose ranges from 10 mg 80 mg 1 time / day, selection of doses should be carried out taking into account baselines XC-LDL, the goal of therapy and individual effect. The maximum dose – 80 mg 1 time / day.

At the beginning of treatment and/or during the rise of the dose Liprimara^® must every 2-4 weeks to monitor content of lipids in plasma and adjust the dose accordingly.

At primary hypercholesterolemia and combined (mixed) giperlipidemii for most patients, the dose of Liprimara^® is 10 mg 1 time / day. Therapeutic effect manifests itself within 2 weeks and usually reaches its peak during 4 weeks. In long-term care effect lasts.

At homozygous Familial Hypercholesterolemia the drug is prescribed in a dose 80 mg 1 time / day (lowering the level of LDL-Cholesterol in the 18-45%).

At hepatic insufficiency dose Liprimara^® should be reduced under the constant supervision of the activity of ACT and ALT.

Impaired renal function has no effect on the concentration of plasma atorvastatin or the degree of reduction of LDL-Cholesterol in the application Liprimara^®, Therefore, do not require dose adjustment.

In applying the drug in elderly patients differences in security, effectiveness compared to the overall population is not detected, and dose adjustment is not required.

If necessary, joint application with ziklosporinom dose Liprimar^® should not exceed 10 mg

Recommendations for determining treatment goals

A. The recommendations of the national educational programmes to obstruct the NCEP, United States

* Some experts recommend the use of lipid means, reduce the content of Cholesterol-LDL, If a lifestyle change does not reduce its content to a level < 100 mg / dL. Others prefer drugs, which have a preferential effect on TG and HDL-Xc, such as niacin and Fibrates. The doctor may also defer pharmacotherapy in this subgroup.

** In the absence of risk factors or available only 1 risk factor in virtually all people 10-year risk < 10%, Therefore, his score is not required.

If you have reached your target LDL-Cholesterol content, but the content remains TG ≥ 200 mg / dL, the secondary goal of therapy – lowering cholesterol, excluding XC-HDL, up to the level, exceeding the target LDL cholesterol on Cholesterol content 30 mg/dl in each risk category.

B. Recommendations of the European society of atherosclerosis

In patients with a confirmed diagnosis of IHD and other patients with a high risk of ischaemic complications the aim of treatment is to reduce the level of Cholesterol-LDL < 3 mmol / l (or <115 mg / dL) and General Cs < 5 mmol / l (or <190 mg / dL).

Side effect

Liprimar^® generally well tolerated. Side effects, usually, light and fleeting.

The most frequent adverse reactions (≥1%)

CNS: insomnia, headache, asthenic syndrome.

From the digestive system: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.

On the part of the musculoskeletal system: myalgia.

Less frequent adverse reactions (≤1%)

From the central and peripheral nervous system: malaise, dizziness, amnesia, paresthesia, perifericheskaya neuropathy, gipesteziya.

From the digestive system: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.

On the part of the musculoskeletal system: backache, muscle cramps, myositis, myopathy, artralgii, raʙdomioliz.

Allergic reactions: hives, itch, skin rash, anaphylactic reactions, bullous rash, erythema multiforme exudative, toxic epidermal necrolysis (Lyell's syndrome), malignant exudative erythema (Stevens-Johnson syndrome).

Metabolism: gipoglikemiâ, giperglikemiâ, increased level of serum CPK.

From the hematopoietic system: thrombocytopenia.

Other: impotence, peripheral edema, weight gain, chest pain, secondary renal failure, alopecia, noise in ears, fatigue.

Causal link with the admission of the drug is not for all of the above reactions.

Contraindications

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

- Up to 18 years (insufficient clinical data on efficacy and safety for this age group);

- Hypersensitivity to the drug.

C caution should be used in patients, alcohol abusers; with indications the disease on liver disease.

Pregnancy and lactation

Liprimar^® contraindicated during pregnancy and lactation (breast-feeding).

Women of reproductive age at the time of treatment must use adequate contraception methods. Liprimar^® You can assign women of reproductive age only, if the probability of pregnancy have a very low, and the patient informed of possible risks to the fetus during treatment.

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

Cautions

Effect on the liver

As with other funds of the same class of lipid-lowering, After treatment with Liprimar^® noted moderate (more than 3 fold compared with CAH) increase serum activity of AST and ALT. Persistent increase whey transaminaz liver (more than 3 fold compared with CAH) observed in 0.7% patients, receiving Liprimar^® in clinical studies,. The frequency of such changes in the application of the drug in doses 10 mg, 20 mg, 40 mg 80 mg was 0.2%, 0.2%, 0.6% and 2.3% respectively. The increase in the liver transaminaz usually not accompanied by jaundice or other clinical manifestations. By reducing the dose Liprimara^®, temporary or complete lifting preparation activity transaminaz liver returned to the original level. The majority of patients continued receiving Liprimara^® in the reduced dose without any consequences.

Before the beginning, through 6 weeks 12 weeks after the beginning of drug or after an increase in dose, as well as during the entire course of treatment to control the liver. Liver function should be explored also with the appearance of clinical signs of liver damage. An increase in liver transaminaz activity should be monitored until the, While it is not normalized. If there has been an increase in the activity of AST or ALT more than 3 compared to the VGN remains, recommended dose reduction or elimination product.

Effect on skeletal muscle

Patients, receiving Liprimar^®, There was myalgia. Diagnosis of myopathy (pain and weakness in the muscles, combined with the increased activity of the KLF more than 10 times compared with FHG) assume in patients with common mialgiâmi, pain or weakness of muscles and/or expressed by increased activity of KFK. Liprimarom Therapy^® should stop in case of explicit activity KLF or if there is a 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 in lipid lowering doses (more 1 g) or azole antifungals. Many of these drugs inhibit the metabolism of, indirect izofermentom CYP3A4, and/or transport drugs. Known, What CYP cytochrome CYP3A4 – primary hepatic CYP, involved in the biotransformation of atorvastatin. Assigning Liprimar^® in combination with fibratami, Erythromycin, immunosuppressants, azole antifungal drugs or Nicotinic Acid in lipid lowering doses, You should carefully weigh the expected benefits and risks of treatment; should regularly observe patients in order to identify pain or weakness in the muscles, especially during the first months of treatment and during periods of increasing doses of any medication. In case of need combination therapy should consider the use of these drugs in lower primary and supporting doses. In such situations, it is possible to recommend periodic determination of activity of KFK, Although such monitoring does not allow you to prevent the development of severe myopathy.

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 vehicles and management mechanisms

Data on the effects of atorvastatin on the ability to drive and to other potentially hazardous activities, require high concentration and speed of psychomotor reactions, not available.

Overdose

Treatment: if necessary, symptomatic therapy. Atorvastatin is highly associated with blood plasma proteins, Therefore, hemodialysis is ineffective. No specific antidote.

Drug Interactions

The risk of myopathy during treatment with other drugs of this class is increased, while the use of Cyclosporine, fibrate, Erythromycin, antifungal drugs derivatives azola and Nicotinic Acid in lipid lowering doses.

Izofermenta CYP3A4 inhibitors

As atorvastatin is metabolized by CYP3A4 izofermentom, combined use of Liprimara^® the inhibitors izofermenta can lead to increased concentrations of atorvastatin in plasma. The degree of interaction and effect potenzirovania defined variability effects on CYP CYP3A4.

Transport inhibitors of protein OATR1V1

Atorvastatin and its metabolites are substrates of the transport protein OATR1V1. OATR1V1 Inhibitors (eg, cyclosporine) may increase the bioavailability of atorvastatin. So, combined application of atorvastatin dose 10 mg and Cyclosporine dose 5.2 mg/kg/day resulted in increased concentrations of atorvastatin in the blood plasma in 7.7 times.

Erythromycin/clarithromycin

If you are applying to Liprimara^® and erythromycin (by 500 mg 4 times / day) or == (by 500 mg 2 times / day), that inhibit CYP3A4, There was an increase in concentrations of atorvastatin in plasma.

Protease inhibitors

Simultaneous application Liprimara^® protease inhibitors, known as CYP3A4 inhibitors, accompanied by increases in the concentrations of atorvastatin in plasma.

Diltiazem

Combined use of Liprimara^® dose 40 mg with diltiazem dose 240 mg leads to increased concentrations of atorvastatin in plasma.

Cimetidine

Clinically meaningful interaction Liprimara^® with cimetidine does not detected.

Itraconazole

Simultaneous application Liprimara^® in doses of 20 mg 40 mg of itraconazole in dose 200 mg conducted to increase the values of AUC atorvastatin.

Grapefruit juice

Because grapefruit juice contains one or more components, that inhibit CYP3A4 CYP, his excessive consumption (more 1.2 liters per day) can cause increased concentrations of atorvastatin in plasma.

Inductive izofermenta zitohroma CYP3A4

Combined use of Liprimara^® with inducers of izofermenta zitohroma CYP3A4 (eg, èfavirenzom or rifampicin) can reduce concentrations of atorvastatin in plasma. Because of the dual interaction mechanism with rifampicin (inducer izofermenta zitohroma CYP3A4 inhibitor protein hepatocytes transport and OATR1V1) recommended simultaneous application of atorvastatin and rifampicin, because deferred admission atorvastatin after taking rifampicin leads to a significant decrease in concentrations of atorvastatin in plasma

Antacids

While ingestion Liprimara^® and suspension, containing magnesium and aluminium hydroxides, Atorvastatin concentration in plasma decreased by approximately 35%, However, the degree of lowering LDL-Cholesterol while not changed.

Fenazon

While applying Liprimar^® does not affect the farmakokinetiku Phenazone, Therefore, interaction with other drugs, those same cytochrome izofermentami, It is not expected.

Colestipol

While applying kolestipola atorvastatin concentration in plasma decreased by approximately 25%. However, lowering atorvastatin combination effects and kolestipola surpassed such each drug separately.

Digoxin

The readmission of Digoxin and Liprimara^® dose 10 mg equilibrium concentration of Digoxin in plasma is not changed. However, when applied in combination with digoxin Liprimarom^® dose 80 mg/day concentration of Digoxin increased by about 20%. Patients, receiving digoxin combined with Liprimarom^®, requires clinical monitoring.

Azithromycin

If you are applying to Liprimara^® dose 10 mg 1 times/day and dose of azithromycin 500 mg 1 times/day plasma atorvastatin concentrations did not change.

Oral contraceptives

If you are applying to Liprimara^® and oral contraceptive, contains norethisterone and ethinyl estradiol, There was a significant increase in AUC of ethinyl estradiol and norethisterone approximately 30% and 20% respectively. This effect should be taken into account when choosing oral contraceptive for women, receiving Liprimar^®.

Terfenadin

Liprimar^® While applying had no clinically significant effect on farmakokinetiku terfenadina.

Warfarin

Symptoms clinically meaningful interaction of atorvastatin with warfarin is not detected.

Amlodipine

If you are applying to Liprimara^® dose 80 mg and amlodipine dose 10 mg pharmacokinetics of atorvastatin in equilibrium has not changed.

Other concomitant therapy

In clinical studies Liprimar^® used in combination with antigipertenzivei means and estrogens, who appointed as replacement therapy; symptoms of clinically significant interactions have been noted. Research of interaction with specific drugs have been conducted.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored at temperatures not exceeding 25 ° C, out of reach of children. Shelf life – 3 year.