Pharmacological properties

Pharmacodynamics. amlodipin — the antagonist of calcium (derivative dihydropyridine) blocking receipt of calcium ions in a myocardium and in cells of unstriated muscles.

Mechanism of hypotensive action of an amlodipin is caused by the direct weakening influence on unstriated muscles of vessels. The exact mechanism of anti-anginal effect of an amlodipin is studied insufficiently, however effects stated below play a part.

peripheral arterioles and thus reduces the peripheric resistance (afterload). As the warm rhythm remains stable, decrease in load of heart leads to reduction of consumption of energy and need of a myocardium for oxygen.

Expansion of the main coronary arteries and coronary arterioles (normal and ischemic), perhaps, also plays a role in the mechanism of action of an amlodipin. Such expansion increases myocardium saturation oxygen at patients with a spasm of a coronary artery (Printsmetal's stenocardia or alternative stenocardia).

At patients with AG clinically significant decrease in the ABP during 24 h in situation both lying, and standing. Due to the slow beginning of action of an amlodipin the acute arterial hypotension usually is not observed.

At patients with stenocardia at use of 1 daily dose of medicament the general time of physical activity, time prior to the beginning of stenocardia and time up to 1 mm of a depression of a segment of ST raises. Drug reduces the frequency of attacks of stenocardia and reduces the need for nitroglycerine use.

Amlodipin is not associated with any side metabolic effects or changes of level of lipids in blood plasma and can be applied at patients with asthma, diabetes and gout.

Pharmacokinetics

Absorption/distribution. After oral administration in therapeutic doses amlodipin it is gradually absorbed in blood plasma. The absolute bioavailability of not changed molecule is about 64-80%. The C _max in blood plasma is reached during 6–12 h after use. The volume of distribution is about 21 l/kg of body weight; the dissociation constant of acid (rka) of an amlodipin makes 8.6. Linking of an amlodipin with proteins of blood plasma — about 97.5%.

Simultaneous consumption of food does not influence absorption of an amlodipin.

Metabolism/removal. T _½ makes about 35-50 h of blood plasma. Equilibrium concentration in blood plasma is reached after 7–8 days of continuous use of drug. Amlodipin is mainly metabolized with formation of inactive metabolites. About 60% of the entered dose are removed with urine of which about 10% make amlodipin in not changed look.

Patients of advanced age. Time of achievement of equilibrium concentration of an amlodipin in blood plasma is similar at patients of advanced age and at adult patients. The clearance of an amlodipin is usually a little reduced that at elderly people "concentration/time" (AUC) and T _{½ leads to increase in the area under a curve} .

Patients with disturbance of functions of kidneys. Amlodipin biotransformirutsya extensively to inactive metabolites. 10% of an amlodipin are allocated in not changed view with urine. Changes of concentration of an amlodipin in blood plasma do not correlate with extent of disturbance of functions of kidneys. Patients with disturbance of functions of kidneys can apply amlodipin in usual doses. Amlodipin does not leave by dialysis.

Patients with an abnormal liver function. Information on use of an amlodipin for patients with an abnormal liver function is very limited. At patients with a liver failure the clearance of an amlodipin is reduced that leads to increase in duration of a half-life period and to increase in AUC approximately by 40–60%.

Children. Usually the clearance at oral administration to children at the age of 6–12 and 13–17 years was 22.5 and 27.4 l/h respectively for boys and 16.4 and 21.3 l/h — respectively for girls. The considerable variability of exposure at different patients is observed. Information concerning patients is aged younger than 6 years is limited.

Indication

Ag, chronic stable stenocardia, vasospastic stenocardia (stenocardia printsmetat).

Use

Adult. for treatment of patients with ag and stenocardia the usual initial dose of medicament aladin makes 5 mg of 1 times a day. depending on reaction of the patient to therapy the dose can be raised to maximum, making 10 mg of 1 times a day.

to Patients with stenocardia can use medicament in monotherapy or in a combination with other anti-anginal medicines at resistance to nitrates and/or adequate doses of blockers of beta adrenoceptors.

experience of use of medicament in a combination with thiazide diuretics, blockers alpha and beta adrenoceptors or APF inhibitors at patients with AG Exists.

need for selection of a dose of medicament at simultaneous use with thiazide diuretics, blockers of beta adrenoceptors and APF inhibitors.

Children aged from 6 years with AG. The recommended initial dose of the medicament Aladin for this category of patients makes 2.5 mg of 1 times a day. If the AD necessary level is not reached during 4 weeks, the dose can be raised to 5 mg/days. Use of medicament in doses of 5 mg for this category of patients was not investigated.

Patients of advanced age. There is no need for selection of a dose for this category of patients. Increase in a dose needs to be carried out with care.

Patients with a renal failure. It is recommended to use medicament in usual doses as changes of concentration of an amlodipin in blood plasma are not connected with severity of a renal failure. Amlodipin is not brought by dialysis.

Patients with a liver failure. Drug doses for use for patients with a liver failure from easy to moderate severity are not established therefore selection of a dose should be carried out with care and to begin use with the smallest dose (see. Special INSTRUCTIONS and PHARMACOLOGICAL PROPERTIES, Pharmacokinetics).

Pharmacokinetics of an amlodipin was not investigated at patients with an abnormal liver function of heavy degree. For persons with an abnormal liver function of heavy degree the use of an amlodipin should be begun with the lowest dose and gradually to raise it.

Contraindication

Known hypersensitivity to dihydropyridines, an amlodipin or to any other component of drug, arterial hypotension of heavy degree, shock (including cardiogenic shock), obstruction of the removing path of a left ventricle (for example a stenosis of an aorta of heavy degree), hemodynamically unstable heart failure after an acute myocardial infarction.

Side effects

from blood and lymphatic system: thrombocytopenia, leykotsitopeniya;

from the immune system: allergic reactions;

disturbance of metabolism and alimentary disorders: hyperglycemia;

from mentality: insomnia, change of mood (including uneasiness), a depression, confusion of consciousness;

from nervous system: drowsiness, dizziness, a headache (mainly in an initiation of treatment), a tremor, a dysgeusia, a syncope, a hypesthesia, paresthesia, a hyper tone, peripheral neuropathy;

from an organ of sight: a disorder of vision (including a diplopia), dacryagogue;

from an organ of hearing and a labyrinth: a ring in ears;

from heart: the strengthened heartbeat, a myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation);

from vessels: inflows, arterial hypotension, vasculitis;

respiratory, thoracic and mediastinal disturbances: dispnoe, rhinitis, cough;

from digestive tract: nausea, vomiting, an abdominal pain, dyspepsia, dryness in a mouth disturbance of a vermicular movement of intestines (including a constipation and diarrhea), pancreatitis, gastritis, a hyperplasia of gums;

from a gepatobiliarny system: hepatitis, jaundice, increase in level of liver enzymes (that most often was associated with a cholestasia);

from skin and hypodermic fabrics: a Quincke's disease (Quincke's edema), rash, an itching, a multiformny erythema, a dieback, a small tortoiseshell, an alopecia, a purpura, discoloration of skin, the increased sweating, photosensitivity, exfoliative dermatitis, Stephens's syndrome — Johnson;

from skeletal and muscular and connecting fabrics: puffiness of shins, arthralgia, myalgia, myotonia, dorsodynia;

from kidneys and an urinary path: nocturia, urination disturbance, increase in frequency of urination;

from a reproductive system and mammary glands: gynecomastia, impotence;

general disturbances: hypostasis, fatigue, asthenia, pain, stethalgia, indisposition;

a research: increase or degrowth of a body.

It was reported about exceptional cases of development of an extrapyramidal syndrome.

Special instructions

use of medicament with the smallest dose. it is required to be careful both at the beginning of medicament use, and at increase in a dose. slow selection of a dose and careful health surveillance of the patient can be necessary for patients with a heavy liver failure.

throughout the entire period of treatment needs to control the body weight and the use of sodium, purpose of the corresponding diet and also daily control of the ABP.

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Use for patients with heart failure. This category of patients Aladin should apply with care. At patients with heart failure of heavy degree (class III and IV on classification of NYHA) at use of an amlodipin the frequency of cases of edematization of lungs was higher in comparison with that at placebo use. Patients with stagnant heart failure, including amlodipin, should apply blockers of calcium channels with care as they increase risk of cardiovascular events and lethal cases in the future.

Use for patients with an abnormal liver function. The amlodipina and the AUC parameters are more than t _½ at patients with an abnormal liver function, there are no recommendations concerning doses of drug. Therefore this category of patients should begin use of medicament with the lowest dose. It is necessary to be careful both at the beginning of medicament use, and during increase in a dose. Slow selection of a dose and careful observation of their state of health can be necessary for patients with a heavy liver failure.

Use for patients of advanced age. It is necessary to raise a dose of medicament of this category of patients with care.

Use for patients with a renal failure. Aladin to apply to this category of patients in usual doses. Change of concentration of an amlodipin in blood plasma does not correlate with severity of a renal failure. Amlodipin is not brought by dialysis. Amlodipin does not affect results of laboratory researches.

is not recommended to be applied amlodipin together with grapefruit or with grapefruit juice as at some patients the bioavailability can be increased that will lead to strengthening of hypotensive effect of drug.

Use during pregnancy or feeding by a breast. Safety of use of an amlodipin for women during pregnancy is not established.

is recommended to be Applied amlodipin during pregnancy only in cases, when there is no safer alternative, and the risk connected with a disease exceeds possible harm from treatment for mother and a fruit.

during tests on animals at use of medicament in high doses observed reproductive toxicity.

feeding Period breast. It is unknown whether gets amlodipin into breast milk. At making decision on feeding continuation by a breast or about use of an amlodipin it is necessary to estimate advantage of feeding by a breast for the child and advantage of use of medicament for mother.

Fertility. It was reported about reversible biochemical changes of a head of a spermatozoon at some patients at use of blockers of calcium channels. Clinical information on potential influence of an amlodipin on fertility is not enough.

Children. To use medicament at children aged from 6 years. Influence of an amlodipin on the ABP of patients aged up to 6 years is unknown.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Aladin can slightly or moderately affect ability to run vehicles or to work with other mechanisms. It is necessary to be careful, especially at the beginning of therapy.

in the presence of such symptoms as dizziness, a headache, confusion of consciousness or nausea.

Interaction

Influence of other medicines on amlodipin

CYP Inhibitors 3A4. Simultaneous use of an amlodipin and CYP inhibitors 3A4 of powerful or moderate action (inhibitors of proteases, azolny antifungal means, macroleads, such as erythromycin or klaritromitsin, verapamil or diltiazem) can lead to significant increase in exposure of an amlodipin that increases risk of developing of hypotension. Patients of advanced age can have more expressed clinical value of such changes. Clinical observation of a condition of the patient and selection of a dose can be necessary.

is not recommended to be applied at the same time amlodipin and to use grapefruits or grapefruit juice as at some patients the bioavailability of an amlodipin can increase that, in turn, leads to strengthening of hypotensive action.

Inductors CYP 3A4. There is no information on influence of inductors CYP 3A4 on amlodipin. Simultaneous use of an amlodipin and the substances which are inductors CYP 3A4 (for example rifampicin, a St. John's wort), can lead to decrease in concentration of an amlodipin in blood plasma therefore it is necessary to apply such combinations with care.

Dantrolen (infusions). At animals noted ventricular fibrillations with a lethal outcome and cardiovascular collapse which were associated with a hyperpotassemia, after use of verapamil and a dantrolen in / century. Due to the risk of development of a hyperpotassemia it is recommended to avoid use of blockers of calcium channels, such as amlodipin, to patients, inclined to a malignant hyperthermia, and at treatment of a malignant hyperthermia.

Influence of an amlodipin on other medicines. The hypotensive effect of an amlodipin exponentiates hypotensive effect of other antihypertensive drugs.

Takrolimus. There is a risk of increase in level of a takrolimus in blood at simultaneous use with amlodipiny, however the pharmacokinetic mechanism of such interaction is completely not installed. To avoid toxicity of a takrolimus at the accompanying use of an amlodipin, it is necessary to control levels of a takrolimus in blood and if necessary — to korrigirovat a dosage.

Cyclosporine. Researches of interaction of cyclosporine and an amlodipin at use for healthy volunteers or in other groups were not conducted, except for use to patients with a transplantirovanny kidney at whom noted variable increase in residual concentration of cyclosporine (on average for 0–40%). For the patients with a transplantirovanny kidney applying amlodipin it is necessary to consider the possibility of monitoring of concentration of cyclosporine and if necessary — to lower a cyclosporine dose.

Simvastatin. Simultaneous use of reusable doses of an amlodipin of 10 mg and a simvastatin in a dose of 80 mg led to increase in exposure of a simvastatin by 77% in comparison with use only a simvastatin. For the patients applying amlodipin the dose of a simvastatin should be limited up to 20 mg/days

Results of clinical trials of interaction of medicament demonstrate what amlodipin does not influence pharmacokinetics of an atorvastatin, digoxin, ethanol (alcohol), warfarin.

Experience of deliberate overdose of medicament is limited to

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overdose Symptoms: the available information allows to consider that the considerable overdose of the medicament Aladin will lead to an excessive peripheral vazodilatation and, perhaps, to reflex tachycardia. It was reported about development considerable and, perhaps, long system hypotension, including shock with a lethal outcome.

Treatment: clinically significant hypotension caused by overdose of an amlodipin demands active support of activity of a cardiovascular system, including frequent monitoring of functions of heart and breath, a raising of extremities, monitoring of OCK and urination.

For restoration of a tone of vessels and the ABP can use vasoconstrictive drugs, having convinced of lack of contraindications to their use. Gluconate calcium use in/in can be useful to leveling of effects of blockade of calcium channels.

In certain cases useful. Use of activated carbon to healthy volunteers during 2 h after introduction of 10 mg of an amlodipin considerably reduced the level of its absorption.

As amlodipin substantially contacts proteins, the effect of dialysis is insignificant.

Storage conditions

In original packing at a temperature not above 25 °C.