Amlostat

General characteristics. Structure:

Active ingredient: 1 tablet contains S (-) of an amlodipin of a besilat in terms of              
S (-) амлодипин 2,5 mg, an atorvastatina of calcium in terms of аторвастатин 10 mg.

Auxiliary veshchestva:tsellyuloza microcrystallic, lactoses monohydrate, calcium carbonate, gipromelloz, sodium of a kroskarmelloz, silicon dioxide colloid anhydrous, magnesium stearate, Opadry 04F82783 yellow: polyethyleneglycol, gipromelloz, titanium dioxide    (Е 171), ferrous oxide yellow (Е 172).

Pharmacological properties:

Pharmacodynamics. Амлостат® is the combined drug which combines two medicines: the dihydropyridinic antagonist of calcium – S (-) амлодипин and GMG-KOA-reduktazy inhibitor – аторвастатин. In this combination of S (-) амлодипин is a blocker of slow calcium channels of cellular membranes in smooth muscle fibers of vessels and hearts; аторвастатин has the powerful selection inhibiting effect on GMG-KOA-reduktazu, key enzyme of converting GMG-KOA in мевалонат – substance which is a predecessor of stirol including XC.
The mechanism of anti-hypertensive action of S (-) of an amlodipin consists in relaxation of smooth muscle fibers of vessels. S (-) амлодипин: a) expands peripheral arterioles and at the expense of it reduces OPSS (afterload). As heart rate practically does not change, decrease in load of heart leads to decrease in consumption of energy and need of a myocardium for oxygen; b) assists expansion of big coronary arteries and coronary arterioles both in not changed, and in ischemic zones of a myocardium. Such dilatation increases intake of oxygen to a myocardium at patients with vasospastic stenocardia (stenocardia of Printsmetall or alternative stenocardia) and prevents development of coronary vasoconstriction.

At patients with arterial hypertension the single dose of S (-) of an amlodipin provides clinically meaning lowering of arterial pressure for 24 hours in situation both lying, and standing. Thanks to the slow beginning of action of S (-) амлодипин does not predetermine acute arterial hypotension. At patients with S stenocardia (-) амлодипин promotes increase in tolerance to an exercise stress, reduces the frequency of attacks of stenocardia and the need for reception of Tabulettaes Nitroglycerini.
S (-) амлодипин does not cause metabolic disturbances or change of lipids in a blood plasma thanks to what it is possible to appoint drug the patient with bronchial asthma, a diabetes mellitus or gout.

Atorvastatin – the selection powerful inhibitor of GMG-KOA-reduktazy which regulates the speed of the GMG-KOA transformation in мевалонат – the predecessor of stirol (including XC). At patients with a homozygous and heterozygous hereditary and not hereditary form of a hypercholesterolemia and the mixed dislipidemiya аторвастатин reduces concentration of the general of XC, HS-LPNP and apolipoprotein B, concentration of HS-LPDNP and TG and in insignificant degree is increased by the HS-LPVP level. Also reduces levels XC and lipoproteins in a blood plasma due to oppression of GMG-KOA-reduktazy and synthesis of XC in a liver and increases in number of hepatic receptors of LPNP at surfaces of cells that predetermines increase in hobby and a catabolism of LPNP.

Atorvastatin reduces synthesis of LPNP and reduces quantity of parts of LPNP. It causes the expressed and permanent increase in activity of LPNP-receptors in connection with positive changes of quality of the circulating LPNP-parts. Atorvastatin reduces the LPNP level at patients with a homozygous hereditary hypercholesterolemia at whom therapy by usual hypolipidemic means is often ineffective.
At the person shows pharmacological activity as аторвастатин, and some of his metabolites. Primary scene of action of an atorvastatin is the liver that plays a major role in synthesis of XC and clearance of LPNP. Decrease in the HS-LPNP level well correlates with a dose of drug and its concentration in an organism. The individual drug dosing is based on a therapeutic effectiveness.
Atorvastatin (10–80 mg) reduces the level of the general XC (30–46%), HS-LPNP (41–61%), apolipoprotein B (34–50%) and TG (14–33%). Such result is resistant at patients with heterozygous hereditary and not hereditary forms of a hypercholesterolemia and the mixed lipidemia form, including patients with an insulin-dependent diabetes mellitus.
At patients with the isolated gipertriglitseridemiya аторвастатин reduces the level of the general XC, HS-LPNP, HS-LPONP, apolipoprotein B, TG, HS-LPNP and raises HS-LPVP. At patients with a disbetalipoproteinemiya аторвастатин reduces the HS-LPNP level. At patients with a giperlipoproteinemiya of the IIA and IIB type across Fredrikson the average percent of increase in HS-LPVP at use of 10-80 mg of an atorvastatin makes 5,1–8,7% irrespective of a dose. Besides, considerable dozozavisimy reduction of ratios of the general HS/HS-LPVP and HS-LPNP/HS-LPVP is noted.

Influence of an atorvastatin in a dose of 80 mg a day for 16 weeks on developing of ischemia and the general mortality at patients with unstable stenocardia or myocardial infarction without tooth of Q is shown by considerable decrease in risk of ischemia of a myocardium and a lethality, risk of cases of a regospitalization because of stenocardia and the confirmed myocardium ischemia. Atorvastatin reduces risk of development of ischemia and a lethal outcome in inverse proportion to concentration of HS-LPNP, the risk of ischemia and a lethal outcome at patients with a myocardial infarction without tooth Q and unstable stenocardia to the same extent at patients of both floors age up to 65 years and is more senior.
Atorvastatin considerably reduces the frequency of lethal cardiovascular diseases and a non-lethal myocardial infarction, the general frequency of cardiovascular diseases, frequency of a lethal and non-lethal stroke, reduced need of performance of revascularization of a myocardium. At use of an atorvastatin the over-all mortality owing to cardiovascular diseases in insignificant degree decreased. The effect of therapy did not depend on a sex, age or the HS-LPNP initial level.

Pharmacokinetics. Absorption. At oral administration of a combination of S (-) the amlodipina/atorvastatin is noted by two separate maxima of plazmovy concentration. The first, within 1–2 hours after reception, connected with atorvastatiny; the second, within 6–12 hours after reception, connected with             S (-) amlodipiny. Absorption speed (bioavailability) of S (-) of an amlodipin and an atorvastatin as a part of S combination (-) of an amlodipina/atorvastatin does not differ from bioavailability of S (-) of an amlodipin and an atorvastatin which were accepted separately in the form of tablets that is visible from indicators of the maximum concentration in a blood plasma (Cmax) 101% and the areas under a curve "concentration time" (AUC) of 100% for S (-) of an amlodipin as a part of S combination (-) of an amlodipina/atorvastatin and Cmax of 94% and AUC of 105% – for an atorvastatin as a part of S combination (-) of an amlodipina/atorvastatin.
Bioavailability of S (-) of an amlodipin as a part of S combination (-) of an amlodipina/atorvastatin does not worsen at use of drug after meal that Cmax – 105% and AUC – 101% in comparison with indicators is confirmed at administration of drug on an empty stomach. In spite of the fact that meal lowers indicators of speed and volume of absorption of an atorvastatin at use of the combined drug almost by 32% and 11% respectively that is confirmed to Cmax – 68% and AUC – 89% in comparison with indicators at administration of drug on an empty stomach. Similar decrease in concentration in a blood plasma at use of an atorvastatin after reception is noted also at monotherapy atorvastatiny, but it is not followed by reduction of influence on decrease in HS-LPNShch.

After intake in therapeutic doses of S (-) амлодипин it is well soaked up, reaching Cmax in 6–12 hours. Absolute bioavailability reaches 64–80%. The volume of distribution makes about 21 l/kg. About 97,5% of S (-) of an amlodipin contact proteins of a blood plasma. Meal does not influence absorption of S (-) of an amlodipin.
Atorvastatin is quickly soaked up after oral administration; concentration it in a blood plasma reaches a maximum for 1–2 hours. Absorption and concentration in a blood plasma increase in proportion to a drug dose. Atorvastatin in tablets has bioavailability of 95-99% in comparison with solution. Absolute bioavailability of an atorvastatin – about 12%, and system availability of the inhibiting activity concerning GMG-KOA-reduktazy – about 30%. Low system bioavailability is connected with presistemny clearance in a mucous membrane of a digestive tract and/or biotransformation at the first passing through a liver. In spite of the fact that the particle and extent of absorption of drug decrease at reception together with food approximately by 25% and 9% (for Cmax and AUC) respectively, decrease in the HS-LPNP level did 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 is lower (about 30% for Cmax and AUC), than at reception in the morning. However decrease in the HS-LPNP level does not depend on time of administration of drug.

Distribution of an atorvastatin. The average volume of distribution of an atorvastatin makes about 381 l. More than 98% of drug contact proteins of a blood plasma. The erythrocyte/blood plasma makes ratio coefficient about 0,25 that demonstrates weak penetration of drug into erythrocytes.
Metabolism and excretion of S (-) an amlodipin. Resistant equilibrium concentration in a blood plasma is reached in 7–8 days of regular reception of S (-) of an amlodipin. S (-) амлодипин is extensively transformed in a liver with formation of inactive metabolites. It is removed with urine: 10% of the entered dose – in not changed look, 60% – in the form of metabolites. Plasma elimination half-life of blood makes about 35-50 hours that allows to appoint drug of 1 times in sutku.
Atorvastatin is metabolized in orto-both parahydroxylated derivatives and different the beta oxidized products. In vitro oppression of GMG-KOA-reduktazy for the account orto-and parahydroxylated metabolites practically equals to action of an atorvastatin. The inhibiting effect of drug concerning GMG-KOA-reduktazy approximately for 70% is implemented due to activity of the circulating metabolites. Results of the researches in vitro showed importance of hepatic P450 ZA4 cytochrome for metabolism of an atorvastatin that can influence increase in concentration of an atorvastatin in a blood plasma of the person owing to the general use with erythromycin which is inhibitor of the specified enzyme. At the researches in vitro it is also established that аторвастатин – weak inhibitor of P450 ZA4 cytochrome. Simultaneous use of an atorvastatin and terfenadin – connection which is generally metabolized by P450 ZA4 cytochrome did not give the meaning effect of increase in concentration of a terfenadin in a blood plasma. It is improbable that аторвастатин will change considerably pharmacokinetics of other substrates of P450 ZA4 cytochrome. Atorvastatin and his metabolites are removed, mainly, with bile owing to hepatic and/or ekstrapechenochny metabolism. However drug is not exposed to considerable enterohepatic recirculation. The average elimination half-life of an atorvastatin makes about 14 hours, but the average period of inhibitory activity concerning GMG-KOA-reduktazy, thanks to the circulating active metabolites, makes 20–30 hours. Less than 2% of a dose of an atorvastatin after oral administration are removed with urine.
Liver failure. Level of concentration of an atorvastatin in a blood plasma considerably increases (Cmax approximately by 16 times, an AUC – by 11 times) at patients with alcoholic cirrhosis (severity on classifications of Chayld-Pyyu, a class B).
Renal failure. Changes of concentration in S blood plasma (-) of an amlodipin do not correlate with degree of a renal failure. S (-) амлодипин is not removed at a hemodialysis.

Diseases of kidneys do not influence concentration in a blood plasma of an atorvastatin or its influence on lipids therefore there is no need for change of concentration of an atorvastatin for patients with a renal failure.
Floor. Level of concentration of an atorvastatin in a blood plasma at women differs from concentration level in a blood plasma at husband's (about 20% higher for Cmax and is 10% less for AUC). However clinically reliable difference of effect of influence on lipids at men and women is not revealed.
Patients of advanced age. Time of achievement of equilibrium concentration of S (-) of an amlodipin in a blood plasma is similar both at elderly patients, and at adults.
Clearance of S (-) an amlodipin. At patients of advanced age and patients with congestive heart failure note a tendency to decrease in clearance of S (-) of an amlodipin that leads to increase in AUC and an elimination half-life of drug. Identical doses of S (-) of an amlodipin were well transferred as patients of young, and advanced age.
Level of concentration of an atorvastatin in a blood plasma at healthy elderly faces (65 years) higher (approximately for 40% for Cmax and for 30% – for AUC are more senior), than at young people.

Indications to use:

For prevention of cardiovascular disturbances at patients with arterial hypertension with three concurrent factors of cardiovascular risk: with cholesterol levels from normal to moderately raised, without clinical displays of coronary heart disease when according to the existing instructions concerning treatment it is considered corresponding the combined use of S (-) of an amlodipin and a low dose of an atorvastatin.
In case of inefficiency of a diet and other not pharmacological measures.

Route of administration and doses:

Drug is intended for oral administration.
The usual initial dose makes 2,5 mg / 10 mg of 1 times a day.
Drug can be accepted with food or without it at any time.
Амлостат® it is possible to apply as separately, and in a combination with antihypertensives, but it cannot be applied with other blocker of calcium channels or with other statine.
It is necessary to avoid a drug combination from fibrata.
Patients with a renal failure: for patients with disturbance of renal function in dose adjustment there is no need.
Patients with a liver failure: drug is contraindicated to patients with an active disease of a liver.
Patients of advanced age: dose adjustment is not necessary.

Features of use:

Influence on a liver. Results of hepatic tests need to be defined before an initiation of treatment, periodically after treatment, and also at patients at whom any signs or symptoms which demonstrate damage of a liver are shown. In case of the increased levels of transaminases it is necessary to conduct their monitoring before normalization of indicators.
If the increased ALT or nuclear Heating Plant levels more than 3 times higher than the upper bound of norm (UBN) keep, treatment needs to be stopped.
Because of existence of an atorvastatinovy component patients who in a significant amount take alcohol, to patients with a liver failure and/or with a liver disease in the anamnesis need to use drug with care.
Influence on skeletal muscles. As well as other inhibitors of GMG-KOA-reduktazy, аторвастатин can influence skeletal muscles and cause a mialgiya, a miositis and a myopathy which in isolated cases can progress to an acute necrosis of skeletal muscles which is characterized much by the increased KFK levels (more than 10 times higher than VGN), a myoglobinemia and a myoglobinuria which can lead to a renal failure and seldom or never can be lethal.
In the absence of symptomatology at patients who are treated by statine regular control of the KFK levels or other muscular enzymes is not recommended. For patients with factors of tendency to an acute necrosis of skeletal muscles and patients with muscular symptoms before any treatment statine, and also during treatment by statine recommends monitoring of KFK (see below).
Before treatment
Patients with tendency to an acute necrosis of skeletal muscles need to appoint drug with care. Before an initiation of treatment statine the KFK level needs to be measured in the following cases:
- to elderly people (70 years are more senior);
- at a renal failure;
- at a gipoterioza;
- at inherited muscular disorders in the personal or family anamnesis;
- at the muscular toxicity connected using statines or fibrat in the anamnesis;
- at an alcohol abuse.
In such cases it is necessary to analyze risk in comparison with possible positive effect and to carry out clinical monitoring.
If at the initial stage the KFK levels are considerably increased (more than 5 times higher than VGN), it is impossible to begin treatment.

Measurement of KFK
It is impossible to measure KFK after an intensive exercise stress or in the presence of any other reason of probable increase in KFK as it complicates interpretation of the received results. If the KFK levels at the initial stage are significantly increased (more than 5 times higher than VGN), they need to be measured systematically in 5–7 days for confirmation of results. If the KFK levels which by 5 times exceed VGN at the initial stage are confirmed, it is impossible to begin treatment.

During treatment.
Patients have to report at once about muscular pain, a myotonia or weakness for the unclear reason, especially if these symptoms are followed by weakness or temperature increase.
If such symptoms arise during treatment, it is necessary to measure the KFK level. If it turns out that this level is considerably increased (more than 5 times higher than VGN), treatment needs to be stopped.
If muscular symptoms heavy also serve as the reason of daily inconveniences, it is necessary to consider the treatment termination even if the increased KFK levels do not exceed VGN less than by 5 times.
If symptoms disappeared and the KFK levels returned to norm, it is possible to consider the possibility of repeated use of drug at careful monitoring.
Prevention of a stroke by aggressive decrease in levels of cholesterol (SPARCL)
For patients with the previous hemorrhagic stroke or a lacunary heart attack the balance of risk and positive effect at use of 80 mg of an atorvastatin is unknown therefore before an initiation of treatment it is necessary to analyze potential risk of a hemorrhagic stroke carefully.
Intersticial disease of lungs: for some statines it was reported about exceptional cases of an intersticial disease of lungs, especially at long treatment. Features of manifestation can include диспноэ, dry cough and deteriorations in the general state of health (fatigue, loss of body weight and temperature increase). If there is a suspicion that at the patient the intersticial disease of lungs develops, treatment by statine needs to be stopped.
Drug contains lactose that needs to be meant at appointment as his patient with intolerance of a galactose, deficit of lactase of Lapp or malabsorption of a glucose/galactose.

Ability to influence speed of response at control of motor transport or work with other mechanisms.
As during use of drug effects of drowsiness and dizziness are possible, during this period it is necessary to refrain from management of transport and work with difficult mechanisms.

Side effects:

The following undesirable phenomena are shown separately for S (-) of an amlodipin and an atorvastatin: very widespread (> 1/10), extended (> 1/100, <1/10), not widespread (> 1/1000, <1/100), seldom widespread (> 1/1000, <1/100), very seldom widespread (<1/10 000), unknown (it is impossible to estimate according to the available data).

 

Interaction with other medicines:

The accompanying drug treatment
The drug combination with dantroleny (infusion), gemfibrozily and other fibrata is not recommended.
As well as at use of other medicines of a class of statines, the risk of an acute necrosis of muscles and a myopathy increases at joint administration of drug and certain medicines which can increase concentration of an atorvastatin in plasma, such as immunosuppressors (for example, cyclosporine); makrolidny antibiotics (for example, erythromycin, кларитромицин); azolny antifungal means (for example, итраконазол, кетоконазол, нефазодон); lipidomodifitsiruyushchy doses of Niacinum; gemfibrozit, other derivatives of fibroyevy acid or inhibitors of HIV protease.
The combination of an atorvastatin and fuzidovy acid is not recommended. At treatment by fuzidovy acid, perhaps, it will be reasonablly temporary to suspend reception of an atorvastatin.
The interactions connected with the combined drug
The researches of interaction of medicines given relatively which included reception of 10 mg of S (-) of an amlodipin and 80 mg of an atorvastatin by healthy volunteers, demonstrate that S pharmacokinetics (-) of an amlodipin does not change when these drugs accept jointly. No influence of S (-) of an amlodipin on Cmax of an atorvastatin, but AUC of an atorvastatin in the presence of S was shown (-) the amlodipina increased for 18% (DI of 90% [109-127%]).
Researches of medicinal interaction of a combination of S (-) of an amlodipina/atorvastatin with other drugs were not conducted though researches of separately taken     S (-) of amlodipinovy and atorvastatinovy components were conducted as it is described below:
The interactions connected with S (-) amlodipiny.

Undesirable combination
Dantrolen (infusion): at intravenous administration of verapamil and a dantrolen there is a risk of development of lethal fibrillation of ventricles.
Extrapolating results, it is necessary to avoid S combination (-) of an amlodipin and a dantrolen.
Combinations which demand care
Baclofenum: strengthens hypotensive action. It is necessary to conduct monitoring of arterial pressure and to adjust if necessary a dose of hypotensive drug.
Inductors CYP3A4 (anticonvulsant drugs, such as carbamazepine, phenobarbital, Phenytoinum, фосфенитоин, Primidonum, Rifampinum): risk of decrease in levels of blockers of calcium channels in plasma owing to strengthening by these inductors of hepatic metabolism. It is necessary to conduct clinical monitoring. Dose adjustment of S (-) of an amlodipin is in case of need possible during treatment by such inductors and after the termination of their reception.
Combination which needs to be considered
Alpha 1 - blockers in urology (Prazozinum, алфузозин, доксазозин, тамзулозин, теразозин): strengthening of hypotensive action; risk of heavy orthostatic hypotension.
Amifostin: strengthening of hypotensive action owing to addition of undesirable effects.
Imipraminovy antidepressants, neuroleptics: hypotensive action and risk of strengthening of orthostatic hypotension (additive effect).
Beta-blockers at heart failure (бисопролол, карведилол, метопролол): risk of arterial hypotension and heart failure at patients with latent or uncontrollable heart failure (a negative inotropic effect of in vitro dihydropyridines changeable depending on drugs which can strengthen a negative inotropic effect of beta-blockers). Treatment in the presence of beta-blockers can minimize the acting group of nice reflexive reactions in case of excessive hemodynamic repercussion.

Corticosteroid, тетракозактид: weakening of hypotensive action (effect of deduction of water and sodium of corticosteroids).
Other hypotensive drugs: combined use of S (-) of an amlodipin with other hypotensive drug (a beta-blocker, an angiotensin blocker ІІ, diuretic, APF inhibitor) can strengthen hypotensive action of S (-) of an amlodipin. It is necessary to consider with care treatment by trinitrate, nitrates or other vazodilatator.
Sildenafil: the single dose of a sildenafil of 100 mg did not influence pharmacokinetic parameters S (-) of an amlodipin at patients with idiopathic hypertensia. At use of a combination of S (-) of an amlodipin and a sildenafila each drug influenced a lowering of arterial pressure independently.
In researches of interaction it is shown also that Cimetidinum, аторвастатин, salts of aluminum/magnesium and digoxin did not influence S pharmacokinetics (-) of an amlodipin.
The interaction connected with atorvastatiny

Contraindicated combinations
Intrakonazol, кетоконазол: the increased risk of undesirable effects (dozozavisimy), such as acute necrosis of skeletal muscles (the lowered metabolism of an atorvastatin).
Telitromitsin: the increased risk of undesirable effects (dozozavisimy), such as acute necrosis of skeletal muscles (the lowered metabolism of an atorvastatin).
Undesirable combination
Gemfibrozil and other fibrata: the increased risk of undesirable effects (dozozavisimy), such as acute necrosis of skeletal muscles.
Combinations which demand care
Inhibitors of P450 3A4 cytochrome: аторвастатин it is metabolized by P450 3A4 cytochrome. Interaction can take place when аторвастатин accept with inhibitors of P450 3A4 cytochrome (for example, immunosuppressors, such as cyclosporine, makrolidny antibiotics, for example, erythromycin and klaritromitsiny, nefazodony, azolny antifungal means and inhibitors of HIV protease). Joint reception can result in the increased plazmovy concentration of an atorvastatin. Therefore if аторвастатин it is applied in combination with such medicines, it is necessary to apply the special warning measures.
In case joint reception of these medicines along with atorvastatiny is considered necessary, it is necessary to analyze a ratio advantage/risk of such accompanying treatment. Therefore at reception with the drugs stated above it is necessary to consider the lowered initial and maintenance doses of an atorvastatin.
Inhibitors of conveyors: аторвастатин and its metabolites are substrates of conveyors which can be oppressed by the accompanying medicines, such as cyclosporine that as a result increases bioavailability of an atorvastatin. Joint reception of 10 mg of an atorvastatin and 5,2 mg/kg/days of cyclosporine leads to growth by 7,7 times of exposure of an atorvastatin. If joint reception of an atorvastatin and cyclosporine is considered necessary, the dose of an atorvastatin should not exceed 10 mg.
Inductors of P450 3A4 cytochrome: joint reception of an atorvastatin with inductors of P450 3A4 cytochrome (for example, efavirentsy, Rifampinum, carbamazepine, Phenytoinum, phenobarbital, rifabutiny or a St. John's Wort) can lead to variable decrease in plazmovy concentration of an atorvastatin. This decrease can reach the maximum value of 80% at use of Rifampinum. For ensuring efficiency it is necessary to conduct monitoring of levels of cholesterol.
Protease inhibitors: joint reception of an atorvastatin and inhibitors of protease, the known inhibitors of P450 3A4 cytochrome, was connected with the increased plazmovy concentration of an atorvastatin.

Warfarin: the concomitant use of an atorvastatin can strengthen anticoagulating effect of warfarin that leads to risk of bleeding. Patients need to carry out often monitoring as there can be a need for correction of dosing of peroral anticoagulant.
Fuzidovy acid: it was reported about connected with muscles the phenomena, including an acute necrosis of skeletal muscles, as well as for other statines. The mechanism of this interaction is unknown. Patients have to undergo careful monitoring and, perhaps, reasonable will be temporary to stop treatment.
Niacinum: the risk of a myopathy during treatment by GMG-KOA-reduktazy inhibitors at a concomitant use of lipidomodifitsiruyushchy doses of Niacinum increases, and in isolated cases the acute necrosis of skeletal muscles with renal dysfunction, a myoglobinuria secondary relatively becomes result. Therefore it is necessary to weigh comprehensively a ratio advantage/risk of the accompanying treatment.

Combinations which should be considered
Antacid: joint reception of an atorvastatin with peroral suspension of an antacid (aluminum hydroxides and magnesium) reduces plazmovy concentration of an atorvastatin and its active metabolite approximately by 35%. However decrease in LPNP cholesterol did not change.
Grapefruit juice: growth of plazmovy concentration of hypolipidemic drugs with risk of approach of the undesirable phenomena, such as the muscular phenomena.
Oral contraceptives: joint reception of an atorvastatin with an oral contraceptive predetermines growth of plazmovy concentration of norethindrone and ethinylestradiol. At the choice of doses of oral contraceptives it is necessary to consider these increased concentration.
Kolestipol: at joint reception of a kolestipol with an atorvastatiny plazmovy of concentration of an atorvastatin and its active metabolite were lower (approximately for 25%). However lipidic effects were stronger when аторвастатин and колестипол were accepted jointly than when they were accepted separately.

Other interactions
HSL diltiazem: joint reception of 40 mg of an atorvastatin from 240 mg of diltiazem leads to 51% to growth of exposure of an atorvastatin.
Phenazone: joint reception of reusable doses of an atorvastatin and phenazone showed insignificant or imperceptible influence on clearance of phenazone.
No interaction with NPVP, antibiotics, hypoglycemic means, Cimetidinum and digoxin was observed.

Contraindications:

Hypersensitivity to dihydropyridines, active ingredients – S (-) to an amlodipin and an atorvastatin or any component of drug. Liver diseases in an active phase or the levels of serumal transaminases which are constantly increased for the unclear reasons which by 3 times exceed the upper bound of norm, combinations with itrakonazoly, ketokonazoly and telitromitsiny, heavy arterial hypotension, shock (including cardiogenic shock), obstruction of outflow tracts of a left ventricle (for example, an aortal stenosis of high degree), hemodynamically unstable heart failure after an acute myocardial infarction.

Overdose:

Information on overdose of a combination of S (-) of an amlodipina/atorvastatin is absent.
For S (-) of an amlodipin experience of rather deliberate overdose at people is limited. The considerable overdose can lead to an excessive vazodilatation with following noticeable and probably long system arterial hypotension. Any arterial hypotension caused by overdose of S (-) of an amlodipin, demands monitoring in department of intensive cardiological care. It is possible to apply a vasoconstrictor to recovery of a vascular tone and arterial pressure. S (-) амлодипин is not exposed to dialysis.
Specific treatment for overdose atorvastatiny is absent. In case of overdose of the patient it is necessary to treat symptomatic and to begin, if necessary, the supporting measures. It is necessary to conduct monitoring of function of a liver and the KFK levels. Because of considerable binding of drug proteins of plasma did not expected that the hemodialysis will significantly improve clearance of an atorvastatin.

Use during pregnancy or feeding by a breast. Drug is contraindicated during pregnancy or feeding by a breast.

Children. Safety and efficiency of use of drug are not established to children therefore this age category of patients is not recommended to appoint it.

Storage conditions:

To store at a temperature not above 25 °C in the dry, protected from light place. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 14 tablets in the blister, on 1 or 2 blisters in cardboard packaging.