Amlodipin

General characteristics. Structure:

Active ingredient: 6,9 mg and 13,8 mg of an amlodipin of a bezilat that there correspond 5 mg and 10 mg of an amlodipin.

Excipients: lactoses monohydrate, povidone, кросповидон, calcium stearate.

Drug for treatment of arterial hypertension, stenocardia, an effective lowering of arterial pressure. Drug is an antagonist of calcium of the third generation – i.e. slows down receipt of calcium ions in cells of smooth muscles of vessels of heart and myocardium. Reduces a tone of unstriated muscles of vessels, reduces resistance in peripheral vessels, thereby lowering arterial pressure.

Drug possesses vasodilating action.

At expansion of peripheral vessels heart rate remains almost invariable, and decrease in load of heart leads to reduction of amount of the consumed energy and decrease in need of a myocardium for intake of oxygen. Respectively, the cause of ischemia of a myocardium is removed that allows to warn, block stenocardia attacks.

At the same time, амлодипин still increases delivery of oxygen to ischemic sites.

Drug noticeably reduces arterial pressure within 24 hours after its reception, working gradually.

Pharmacological properties:

Pharmacodynamics. Derivative dihydropyridine – the blocker of "slow" calcium channels (BMKK) of the II generation, has anti-anginal and hypotensive effect. Contacting dihydropyridinic receptors, blocks calcium channels, reduces transmembrane transition of calcium ions to a cell (more in smooth muscle cells of vessels, than in cardiomyocytes).

Anti-anginal action is caused by expansion of coronary and peripheral arteries and arterioles: at stenocardia reduces expressiveness of ischemia of a myocardium; expanding peripheral arterioles, reduces the general peripheric vascular resistance (GPVR), reduces preload of heart, reduces the need of a myocardium for oxygen. Expands the main coronary arteries and arterioles in not changed and ischemic zones of a myocardium, increases intake of oxygen in a myocardium (especially at vasospastic stenocardia); prevents development of a spasm of coronary arteries (including caused by smoking). At patients with stable stenocardia the single daily dose increases tolerance to an exercise stress, slows down development of stenocardia and "ischemic" depression of a segment of ST, reduces the frequency of attacks of stenocardia and consumption of nitroglycerine and other nitrates.

Renders long-term dozozavisimy hypotensive effect. Hypotensive action is caused by direct vazodilatiruyushchy impact on unstriated muscles of vessels. At arterial hypertension the single dose provides clinically significant lowering of arterial pressure (ABP) for 24 h (in position of the patient "lying" and "standing"). Orthostatic hypotension at purpose of an amlodipin meets rather seldom. Does not cause decrease in tolerance to an exercise stress, fraction of emission of a left ventricle. Reduces degree of a hypertrophy of a myocardium of a left ventricle, has anti-atherosclerotic and cardiotyre-tread effect at the coronary heart disease (CHD). Does not exert impact on contractility and conductivity of a myocardium, does not cause reflex increase in the heart rate (HR), slows down aggregation of thrombocytes, raises a glomerular filtration rate, possesses a weak natriuretic effect.

At a diabetic nephropathy does not increase expressiveness of a microalbuminuria. Does not exert any adverse impact on a metabolism and concentration of lipids of a blood plasma and it can be applied at treatment of patients with bronchial asthma, a diabetes mellitus and gout. Significant decrease in the ABP is observed in 6-10 hours, effect duration 24 hours. At long therapy the maximum decrease in the ABP occurs in 6-12 hours after reception of an amlodipin inside. If after long treatment амлодипин to cancel, effective decrease in the ABP remains within 48 hours after reception of the last dose. Then the ABP indicators gradually are returned to initial level within 5-6 days.

Pharmacokinetics. After intake амлодипин it is slowly absorbed from the digestive tract (DT). Average absolute bioavailability makes 64%, the maximum concentration (Cmax) in blood serum is observed in 6-9 hours. Equilibrium serumal concentration (Css) are reached after 7-8 days of therapy. Meal does not influence absorption of an amlodipin.

The average volume of distribution makes 21 l/kg of body weight that indicates that the most part of drug is in fabrics, and rather smaller – in blood. The most part of the drug which is in blood (95%) contacts proteins of a blood plasma.

Amlodipin is exposed to slow, but active metabolism in a liver in the absence of significant effect of "the first passing". Metabolites have no essential pharmacological activity.

After a single dose inside the elimination half-life (T1/2) varies from 31 to 48 hours, at repeated purpose of T1/2 makes about 45 hours. About 60% of the dose accepted inside are allocated with kidneys preferential in the form of metabolites, 10% - in an invariable look, and 20-25% - through intestines, and also with breast milk. The general clearance of an amlodipin makes 0,116 ml / with/kg (7 ml/min., 0,42 l/h/kg).

At elderly patients (65 years are more senior) removal of an amlodipin is slowed down (T1/2 - 65 h) in comparison with young patients, however this difference has no clinical value. Lengthening of T1/2 at patients with a liver failure assumes that at long appointment cumulation of drug in an organism will be higher (T1/2 - to 60 h). The renal failure has no significant effect on kinetics of an amlodipin. Drug gets through a blood-brain barrier. At a hemodialysis is not removed.

Indications to use:

• Arterial hypertension (monotherapy or in a combination with other anti-hypertensive means).

• A stable angina of exertion and vasospastic stenocardia (Printsmetal's stenocardia) (monotherapy or in a combination with other anti-hypertensive means).

Route of administration and doses:

Inside, the initial dose for treatment of arterial hypertension and stenocardia makes 5 mg of drug once a day. The maximum daily dose - 10 mg once.

At arterial hypertension the maintenance dose can be 2,5 – 5 mg (1/2 tablets on 5 mg - 1 tablet on 5 mg) in days.

At an angina of exertion and vasospastic stenocardia – 5-10 mg a day, once. For the purpose of prevention of attacks of stenocardia – 10 mg/days.

The patient with an abnormal liver function as an antihypertensive Amlodipin appoint with care, in an initial dose of 2,5 mg (1/2 tablets on 5 mg), as anti-anginal means – 5 mg.

At patients of advanced age Amlodipin's T1/2 can increase and decrease the clearance of creatinine (CC). Change of doses is not required, but more careful observation of patients is necessary.

Change of a dose at co-administration with thiazide diuretics, beta adrenoblockers and inhibitors of an angiotensin-converting enzyme (APF) is not required.

Change of a dose is not required from patients with a renal failure.

Features of use:

During treatment by Amlodipin it is necessary to control the body weight and consumption of sodium, purpose of the corresponding diet. Maintenance of hygiene of teeth and observation at the stomatologist is necessary (for prevention of morbidity, bleeding and a hyperplasia of gums).

To patients of low growth and patients with the expressed abnormal liver function the smaller dose can be required by patients with small body weight.

At elderly patients T1/2 and clearance of drug can be extended. Change of doses for elderly patients is not required; at increase in a dose more careful observation of patients is necessary.

At an abnormal liver function drug T1/2 can be also extended. Therefore such patients Amlodipin need to appoint with care.

In spite of the fact that the termination of reception of Amlodipin is not followed by development of a syndrome of "cancellation", it is desirable to carry out the termination of treatment, gradually reducing a drug dose.

Efficiency and safety of drug at hypertensive crisis is not established.

Influence on ability to driving and other difficult mechanisms: there were no messages on Amlodipin's influence on driving or work with mechanisms. Nevertheless, at some patients, it is preferential in an initiation of treatment, there can be a drowsiness and dizziness. At their emergence the patient has to observe special precautionary measures during the driving and work with difficult mechanisms.

Teratogenecity of an amlodipin in a research on animals was not revealed, however there is no clinical experience of its use at pregnancy and in the period of a lactation. Therefore амлодипин it is not necessary to appoint pregnant and in the period of a lactation, and also to women of childbearing age if they do not use reliable methods of contraception.

Side effects:

Classification of frequency of development of side effects of the World Health Organization (WHO):

very often  > 1/10

often             from> 1/100 to <1/10

sometimes          from> 1/1000 to <1/100

seldom             from> 1/10000 to <1/1000

very seldom from <1/10000, including separate messages.

From cardiovascular system: often – heartbeat, peripheral hypostases (puffiness of anklebones and feet), "inflows" of blood to face skin; sometimes – excessive decrease in the ABP; very seldom – a syncope, an asthma, a vasculitis, orthostatic hypotension, development or aggravation of heart failure, disturbance of a heart rhythm (including bradycardia, ventricular tachycardia and atrial fibrillation), a myocardial infarction, thorax pains.

From the central and peripheral nervous system: often – a headache, dizziness, increased fatigue, drowsiness; sometimes – an adynamy, a febricula, a hypesthesia, paresthesias, peripheral neuropathy, a tremor, sleeplessness, lability of mood, unusual dreams, nervousness, a depression, uneasiness, it is very rare – migraine, the increased sweating, apathy.

From the alimentary system: often - nausea, abdominal pains; sometimes – vomiting, a lock or diarrhea, a meteorism, dyspepsia, anorexia, dryness in a mouth, thirst;
seldom – a hyperplasia of gums, increase in appetite; very seldom – the pancreatitis, gastritis, jaundice (caused by a cholestasia), a hyperbilirubinemia, increase in activity of "hepatic" transaminases, hepatitis.

From bodies кроветворения:очень it is rare – a Werlhof's disease, a leukopenia, thrombocytopenia.

From urinogenital system: sometimes – the speeded-up urination, an urodynia, a nocturia, impotence, is very rare – a dysuria, a polyuria, a gynecomastia.

From respiratory system: sometimes – short wind, rhinitis, it is very rare – cough.

From integuments: seldom – dermatitis, it is very rare – an alopecia, a xerodermia, "cold" sweat, disturbance of a xanthopathy.

Allergic reactions: skin itch, rash (including erythematic, makulopapulezny rash, small tortoiseshell), Quincke's disease, multiformny erythema.

From a musculoskeletal system: sometimes – muscular spasms, a mialgiya, an arthralgia, a dorsodynia, arthrosis, it is rare - a myasthenia.

Others: sometimes – a ring in ears, a diplopia, accommodation disturbance, a xerophthalmia, conjunctivitis, eye pain, a fever, nasal bleeding, it is very rare – a parosmiya, a hyperglycemia.

Interaction with other medicines:

Amlodipin can safely be applied to treatment of arterial hypertension together with thiazide diuretics, alpha adrenoblockers, beta adrenoblockers or APF inhibitors. At patients with stable stenocardia drug can be combined with other anti-anginal means, for example, with nitrates of the prolonged action, beta adrenoblockers or nitrates of short action.

Amlodipin it is possible to apply at the same time with non-steroidal anti-inflammatory drugs (NPVP) (especially indometacin), antibacterial agents and hypoglycemic means to intake.

Strengthening of anti-anginal and hypotensive action of BMKK at combined use with thiazide and "loopback" diuretics, verapamil, APF inhibitors, beta adrenoblockers and nitrates, and also strengthening of their hypotensive action at combined use with alfa1-adrenoblockers, neuroleptics is possible.

Though when studying an amlodipin of negative inotropic effect usually did not observe, nevertheless, some BMKK can increase expressiveness of negative inotropic effect of the antiarrhytmic means causing lengthening of an interval of QT (for example, Amiodaronum and quinidine).

The single dose of 100 mg of a sildenafil at patients with essential hypertensia does not exert impact on parameters of pharmacokinetics of an amlodipin.

Repeated use of an amlodipin in a dose of 10 mg and an atorvastatina in a dose of 80 mg is not followed by considerable changes of indicators of pharmacokinetics of an atorvastatin.

Ethanol (the drinks containing alcohol): амлодипин at single and repeated use in a dose of 10 mg does not influence ethanol pharmacokinetics.

Antiviral means (ритонавир) increases plasma concentration of BMKK, including amlodipin.

Neuroleptics and изофлуран – strengthening of hypotensive action of derivatives of dihydropyridine.

Drugs of calcium can reduce effect of BMKK.

At combined use of an amlodipin with drugs of lithium strengthening of manifestation of a neurotoxicity (nausea, vomiting, diarrhea, an ataxy, a tremor, a sonitus) is possible.

Amlodipin does not change cyclosporine pharmacokinetics.

Also its renal clearance does not exert impact on concentration in blood serum of digoxin.

Has no significant effect on effect of warfarin (prothrombin time).

Cimetidinum does not influence pharmacokinetics of an amlodipin.

In the researches invitro амлодипин does not influence linkng with blood proteins of digoxin, Phenytoinum, warfarin and indometacin.

Grapefruit juice: the concomitant single dose of 240 mg of grapefruit juice and 10 mg of an amlodipin inside is not followed by essential change of pharmacokinetics of an amlodipin.

Contraindications:

• Hypersensitivity to an amlodipin, derivatives of dihydropyridine and other components of drug;
• the expressed arterial hypotension (systolic the ABP less than 90 mm hg);
• collapse, cardiogenic shock;
• unstable stenocardia (except for Printsmetal's stenocardia);
• clinically significant stenosis of an aorta;
• pregnancy and period of a lactation;
• age up to 18 years (efficiency and safety are not studied);
• deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption.

With care to apply at: abnormal liver functions, the sick sinus syndrome (SSS) (the expressed bradycardia, tachycardia), chronic heart failure of not ischemic etiology of the III-IV functional class on classification of NYHA, arterial hypotension, an aortal stenosis, a mitral stenosis, a hypertrophic subaortic stenosis (GOKMP), an acute myocardial infarction (and within 1 month after a myocardial infarction), at advanced age.

Overdose:

Symptoms: excessive peripheral vazodilatation svyrazhenny and perhaps long decrease in the ABP, collapse, shock.

Treatment: the gastric lavage, purpose of absorbent carbon, maintenance of function of cardiovascular system, control of indicators of function of heart and lungs raised is higher than the level of head, position of the lower extremities, control of volume of the circulating blood and a diuresis. For recovery of a tone of vessels – use of vasoconstrictors (in the absence of contraindications to their use); for the purpose of elimination of effects of blockade of calcium channels – intravenous administration of calcium of a gluconate. The hemodialysis is inefficient.

Storage conditions:

In the dry, protected from light place, at a temperature not over 25 ˚С. To store in the place, unavailable to children. Period of validity 3 years. Not to use after expiry date.

Issue conditions:

According to the recipe

Packaging:

Tablets on 5 mg or 10 mg.

On 10 tablets in a blister strip packaging. 1, 2, 3, 4 or 5 blister strip packagings together with the application instruction place in a pack from a cardboard.

On 100 tablets in bank polymeric, each can together with the application instruction is placed in a pack from a cardboard.