Дальнева®

General characteristics. Structure:

Active ingredients: безилат (that is equivalent to 5 mg of an amlodipin) + 21,0 mg of substance granules perindoprit 6,935 mg of an amlodipin эрбумин And (that is equivalent to 4,0 mg of a perindopril); безилат (that is equivalent to 10 mg of an amlodipin) + 21,0 mg of substance granules perindoprit 13,870 mg of an amlodipin эрбумин And (that is equivalent to 4,0 mg of a perindopril); безилат (that is equivalent to 5 mg of an amlodipin) + 42,0 mg of substance granules perindoprit 6,935 mg of an amlodipin эрбумин And (that is equivalent to 8,0 mg of a perindopril); безилат (that is equivalent to 10 mg of an amlodipin) + 42,0 mg of substance granules perindoprit 13,870 mg of an amlodipin эрбумин And (that is equivalent to 8,0 mg of a perindopril).

Excipients: cellulose microcrystallic, starch prezhelatinizirovanny, sodium carboxymethylstarch, Natrii hydrocarbonas, silicon dioxide colloid, magnesium stearate.

The combined anti-hypertensive and anti-anginal drug.

Pharmacological properties:

Pharmacodynamics. Perindopril – inhibitor of an angiotensin-converting enzyme (APF). APF or a kininaza of II is ekzopeptidazy, carrying out transformation of angiotensin I into vasoconstrictive substance - angiotensin II, besides APF is destroyed by the bradikinin possessing vasodilating action to an inactive gektapeptid. Suppression of activity of APF leads to decrease in angiotensin II, increase in activity of a renin in a blood plasma and to weakening of secretion of Aldosteronum. As APF is also destroyed by bradikinin, suppression of APF leads also to increase in activity of kallikrein-kinin system.

Perindopril acts by means of the active metabolite, a perindoprilat. Other metabolites have no inhibiting effect on APF in vitro. Perindopril renders therapeutic effect at any degree of the arterial hypertension (AH), reducing the systolic and diastolic arterial pressure (AP) in situation "lying" and "standing".

Reduces the general peripheric vascular resistance (GPVR) therefore the peripheral blood stream without changes of the heart rate (HR) amplifies.

The renal blood stream, as a rule, amplifies while the glomerular filtration rate (GFR) does not change.

The hypotensive effect reaches the maximum in 4-6 h after a single dose of a perindopril inside and remains during 24 h. Hypotensive action in 24 h after a single dose inside makes about 87-100% of the maximum hypotensive effect.

Decrease in the ABP develops quickly. The therapeutic effect occurs less than in 1 month from the beginning of therapy and is not followed by tachycardia.

The termination of therapy does not lead to development of a syndrome of "cancellation".

Perindopril has vasodilating effect, promotes recovery of elasticity of large arteries and structures of a vascular wall of small arteries, and also reduces a hypertrophy of a left ventricle.

Amlodipin. Derivative dihydropyridine – the blocker of "slow" calcium channels, has anti-anginal and hypotensive effect. 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 OPSS, reduces an afterload by a myocardium, reduces the need of a myocardium for oxygen, expanding 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 a spasm of coronary arteries (including caused by smoking). At patients with stable stenocardia the single daily dose increases tolerance to an exercise stress, increases time before an attack of stenocardia and a "ischemic" depression of a segment of ST by an ECG, 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 decrease in the 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 fraction of emission of a left ventricle.

Reduces degree of a hypertrophy of a myocardium of a left ventricle. Does not exert impact on contractility and conductivity of a myocardium, does not cause reflex increase in ChSS, 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 h, effect duration - 24 h.

Pharmacokinetics. The size of absorption of an amlodipin and perindopril at drug Dalneva® use significantly does not differ from that at use of monodrugs.

Perindopril. After intake perindoprit quickly it is soaked up and reaches the maximum concentration in a blood plasma during 1 h. The perindoprila makes an elimination half-life (Т½) of a blood plasma, about, 1 h.

Perindopril has no pharmacological activity, is pro-medicine. About 27% of the total quantity accepted in a perindopril get to a blood stream in the form of an active metabolite – a perindoprilat. In addition to a perindoprilat 5 more metabolites which do not have pharmacological activity are formed. The maximum concentration of a perindoprilat (Cmax) in a blood plasma is reached in 3-4 h after intake.

Meal reduces bioavailability of a perindopril therefore it is necessary to accept drug 1 time a day, in the morning, before meal.

There is a linear dependence of concentration of a perindopril in a blood plasma from the size of its dose.

The volume of distribution of a free perindoprilat makes about 0,2 l/kg. Communication of a perindoprilat with proteins of a blood plasma (generally with APF) makes 20%, and depends on its concentration. Perindoprilat is brought by kidneys, Т½ untied fraction makes about 17 h therefore equilibrium concentration is reached within 4 days after intake.

Removal of a perindoprilat is slowed down at patients of advanced age and at patients with a heart and renal failure therefore observation of such patients has to include regular control of concentration of creatinine and potassium in a blood plasma.

The dialysis clearance of a perindoprilat is equal to 70 ml/min.

The pharmacokinetics of a perindopril is changed at patients with cirrhosis: the hepatic clearance decreases twice, but the quantity of the formed perindoprilat does not decrease therefore dose adjustment is not required.

Amlodipin. Amlodipin is well soaked up at intake in therapeutic doses and reaches Cmax in a blood plasma in 6-12 h. Absolute bioavailability makes 64-80%. Distribution volume - about 21 l/kg. Meal does not influence bioavailability of an amlodipin. The researches in vitro showed that about 97,5% of the circulating amlodipin are connected with proteins of a blood plasma.

Final Т½ from a blood plasma - 35-50 h that allows to accept drug of 1 times a day.

Amlodipin is metabolized in a liver with formation of inactive metabolites. About 60% of the accepted dose are removed by kidneys, 10% - in not changed look.

Patients of advanced age: time of achievement of Cmax (TCmax) in a blood plasma is identical at patients of advanced age and young people. It is tended to decrease in clearance of an amlodipin at patients of advanced age that "concentration time" (AUC) is followed by increase in the area under a curve. The recommended dosing mode for patients of advanced age same, as for patients of younger age though increase in a dose has to be carried out with care.

Liver failure: Т½ the amlodipina is extended at patients with abnormal liver functions.

Indications to use:

Arterial hypertension and/or coronary heart disease: a stable angina of exertion at patients who need therapy perindoprily and amlodipiny.

Route of administration and doses:

Inside, on one tablet once a day, it is preferable in the morning before meal. The dose of the drug Dalneva® is selected after earlier carried out titration of doses of separate components of drug: a perindoprila and an amlodipina at patients with arterial hypertension and stable stenocardia.

If necessary, the dose of the drug Dalneva® can be changed, on the basis of individual selection of doses of separate components:

(амлодипин 5 mg + perindoprit 4 mg) OR (амлодипин 10 mg + perindoprit 4 mg) OR (амлодипин 5 mg + perindoprit 8 mg) OR (амлодипин 10 mg + perindoprit 8 mg).

Maximum daily dose: амлодипин 10 mg + perindoprit 8 mg.

The drug Dalneva® can be used at patients with KK more than 60 ml/min.

The drug Dalneva® is contraindicated to use for patients with KK less than 60 ml/min. Individual selection of doses of a perindopril and amlodipin is recommended to such patients. Change of concentration of an amlodipin in a blood plasma does not correlate with degree of manifestation of a renal failure.

It is necessary to be careful at drug Dalneva® use by patients with a liver failure since there are no recommendations about drug doses at such patients.

At use of the drug Dalneva® for patients of advanced age of dose adjustment it is not required.

Children and teenagers should not appoint the drug Dalneva® 18 years since there are no data on efficiency and safety of use of a perindopril and amlodipin for these groups of patients both in monotherapy, and as a part of a combination therapy are younger.

Features of use:

The special instructions relating to an amlodipin and to a perindopril are applicable also to the drug Dalneva®.

Perindopril. The increased sensitivity / a Quincke's disease (Quincke's edema)

At use of APF inhibitors, including perindoprit, development of a Quincke's disease of the person, lips, language, voice folds, and/or throats in rare instances can be observed. At emergence of these symptoms use of the drug Dalneva® has to be immediately stopped, the patient has to be observed until symptoms of hypostasis do not disappear completely.

If the Quincke's disease affects only a face and lips, then its manifestations usually take place independently or for treatment of its symptoms antihistaminic drugs can be used. The Quincke's disease which is followed by a paraglossa or throats can lead to obstruction of respiratory tracts and a lethal outcome.

At emergence of such symptoms it is necessary to enter immediately subcutaneously Epinephrinum (adrenaline) in cultivation 1:1000 (0,3 or 0,5 ml) and/or to provide passability of respiratory tracts. The patient has to be under medical observation before total and permanent disappearance of symptoms.

At patients in whose anamnesis the Quincke's edema which is not connected using APF inhibitors was noted the risk of its development against the background of use of drugs of this group can be increased.

In rare instances against the background of therapy by APF inhibitors the intestinal Quincke's disease (a Quincke's disease of intestines) develops. At the same time at patients the abdominal pain as the isolated symptom or in combination with nausea and vomiting, in certain cases without the previous Quincke's disease of the person is noted and at the normal S-1-esterazy level. The diagnosis is established by means of a computer tomography of an abdominal cavity, ultrasonography or at the time of surgical intervention. Symptoms disappear after phase-out of APF inhibitors. At the patients with an abdominal pain receiving APF inhibitors when carrying out the differential diagnosis it is necessary to consider a possibility of development of an intestinal Quincke's disease.

Anaphylactoid reactions when holding procedures of desensitization. There are separate messages on development of long, life-threatening anaphylactoid reactions in the patients receiving APF inhibitors during the desensibilizing therapy by poison of hymenopterous insects (Hymenoptera). APF inhibitors need to be applied with care at the patients inclined to allergic reactions undergoing procedures of desensitization. It is necessary to avoid purpose of APF inhibitor to the patients receiving an immunotherapy poison of hymenopterous insects. Nevertheless, development of anaphylactoid reactions can be avoided by temporary cancellation of APF inhibitor not less than in 24 hours prior to holding a procedure of desensitization.

Anaphylactoid reactions when carrying out an aferez of LPNP with the help a sulfate dextran. In rare instances at the patients receiving APF inhibitors when carrying out an aferez of lipoproteins of the low density (LPNP) with use a dextran of sulfate life-threatening anaphylactoid reactions can develop. For prevention of anaphylactoid reaction it is necessary to stop therapy by APF inhibitor before each procedure of an aferez of LPNP with use of high-flowing membranes.

Hemodialysis. At the patients receiving APF inhibitors when carrying out a hemodialysis with use of high-flowing membranes (for example, AN69®) noted anafilaktodny reactions. Therefore it is desirable to use a membrane of other type or to use hypotensive drug of other pharmakoterapevtichesky group.

Neutropenia/agranulocytosis, thrombocytopenia and anemia. At the patients accepting APF inhibitors, chances of development of a neutropenia/agranulocytosis, thrombocytopenia and anemia. At patients with normal function of kidneys for lack of other complications the neutropenia develops seldom and passes independently after cancellation of APF inhibitors.

Perindopril it is necessary to apply carefully at patients with diseases of connecting fabric and at the same time receiving immunosuppressive therapy, Allopyrinolum or procaineamide, especially at the existing renal failures. At some patients the heavy infections which are not giving in to an intensive antibioticotherapia can develop. In case of purpose of a perindopril control of quantity of leukocytes in a blood plasma is recommended. The patient has to be warned that in case of any symptoms of an infectious disease (a pharyngalgia, fervescence) it is necessary to see a doctor immediately.

Risk of arterial hypotension and/or renal failure (at patients with HSN, disturbance of water and electrolytic balance, etc.). At cirrhosis, by followed hypostases and ascites, arterial hypotension, HSN considerable activation the system renin-angiotensin-aldosteronovoy (SRAA) can be noted, especially at the expressed hypovolemia and decrease in content of electrolytes in a blood plasma (against the background of a diet with restriction of table salt or long reception of diuretics).

Use of APF inhibitor causes blockade of RAAS, in this regard perhaps sharp decrease in the ABP and/or increase in concentration of creatinine in a blood plasma, testimonial of development of an acute renal failure that is more often observed at reception of the first dose or within the first two weeks of therapy by the drug Dalneva®.

APF inhibitors can cause sharp decrease in the ABP. Symptomatic arterial hypotension seldom arises at patients without associated diseases. The risk of excessive decrease in the ABP is increased at patients with reduced OTsK that can be noted against the background of therapy by diuretics, at observance of a rigid diet about restriction of table salt, a hemodialysis, at diarrhea or vomiting, or at patients with heavy degree arterial hypertension with high activity of a renin. At patients with high risk of development of symptomatic arterial hypotension it is necessary to control carefully the ABP, function of kidneys and content of potassium in blood serum during therapy by the drug Dalneva®.

The same precautionary measures concern to patients with stenocardia or cerebrovascular diseases at which the expressed decrease in the ABP can lead to development of a myocardial infarction or disturbance of cerebral circulation.

In case of development of arterial hypotension the patient has to be transferred to situation "lying" on spin with the raised legs. If necessary to fill OTsK with intravenous administration of 0,9% of solution of sodium of chloride. Tranzitorny arterial hypotension is not a contraindication for further administration of drug of Dalneva®. After recovery of OTsK and the ABP treatment by the drug Dalneva® can be continued.

Aortal stenosis / Mitral stenosis / Hypertrophic subaortic stenosis. APF inhibitors have to be applied with care at patients with obstruction of an output path of a left ventricle (an aortal stenosis, a hypertrophic subaortic stenosis), and also to patients with a mitral stenosis.

Kaliysberegayushchy diuretics and drugs of potassium. Simultaneous use of a perindopril and kaliysberegayushchy diuretics, and also drugs of potassium and kaliysoderzhashchy substitutes of table salt is not recommended.

Cough. Against the background of therapy dry unproductive cough which disappears after cancellation of drugs of this group can arise APF inhibitor. At emergence of dry cough it is necessary to remember possible communication of this symptom using APF inhibitor.

Children and teenagers are younger than 18 years. The drug Dalneva® is contraindicated to children and teenagers more young than 18 years due to the lack of data on efficiency and safety of drug at this age group.

Renal failure. At a renal failure (KK less than 60 ml/min.) recommends individual selection of doses of a perindopril and amlodipin. Regular control of content of potassium and creatinine in a blood plasma are a necessary condition in treatment of such patients.

Some patients with a bilateral stenosis of renal arteries or a stenosis have arteries of the only kidney, accepting APF inhibitors, increase in concentration of urea and creatinine in a blood plasma, reversible after therapy cancellation was noted. These changes are more probable at patients with a renal failure. Patients with renovascular hypertensia have an increased risk of heavy arterial hypotension and renal failure. At some patients with arterial hypertension without obvious symptoms of the existing diseases of kidneys which accepted perindoprit along with diuretic, small and temporary increase in concentration of urea and creatinine in blood serum was noted. These changes develop at patients with the previous renal failure more often.

Abnormal liver function. Seldom use of APF inhibitors is followed by a syndrome which development begins with cholestatic jaundice and which then progresses to a fulminantny necrosis of a liver, sometimes with a lethal outcome. The mechanism of development of this syndrome is not clear. If during use of APF inhibitor there is jaundice or activity of "hepatic" transaminases increases, APF inhibitor should be cancelled immediately, and the patient has to remain under the corresponding medical observation.

Ethnic features. At patients of negroid race more often than at representatives of other races, against the background of use of APF inhibitors the Quincke's disease develops. Perindopril, as well as other APF inhibitors, perhaps, has less expressed hypotensive effect at patients of negroid race in comparison with representatives of other races. Perhaps, this distinction is caused by the fact that at patients with arterial hypertension of negroid race low activity of a renin of a blood plasma is more often noted.

Surgical interventions / general anesthesia. Use of APF inhibitors for the patients who are exposed to extensive surgical intervention and/or the general anesthesia can lead to the expressed decrease in the ABP if means are applied to the general anesthesia with hypotensive action. It is connected with blocking of formation of angiotensin II against the background of compensatory increase in activity of a renin. If development of arterial hypotension is connected with the described mechanism, it is necessary to increase OTsK. It is recommended to stop use of drug for 24 h to surgical intervention.

Hyperpotassemia. Against the background of therapy by APF inhibitors, including perindoprit, at some patients the content of potassium in a blood plasma can increase. Risk factors of development of a hyperpotassemia are the renal failure, depression of function of kidneys, advanced age (70 years), a diabetes mellitus, intercurrent states, in particular, dehydration, an acute decompensation of cordial activity, a metabolic acidosis, simultaneous use of kaliysberegayushchy diuretics (for example, Spironolactonum, эплеренон, Triamterenum or amiloride), medicines or additives with the content of potassium, kaliysoderzhashchy substitutes of edible salt or simultaneous use of other drugs increasing the content of potassium in a blood plasma (for example, heparin are more senior). The hyperpotassemia can cause serious, sometimes life-threatening arrhythmias. In need of simultaneous use of a perindopril and one of the substances stated above, it is necessary to be careful and to regularly control the content of potassium in a blood plasma.

Patients with a diabetes mellitus. At the patients with a diabetes mellitus accepting hypoglycemic means for intake and/or insulin in the first several months of therapy by APF inhibitors the strengthened control of concentration of glucose in blood is necessary.

Amlodipin. Abnormal liver function. At patients with an abnormal liver function of T1/2 of an amlodipin it is extended. At purpose of drug such patients should be careful and to regularly control activity of "hepatic" enzymes.

Patients with heart failure. At patients with HSN (III and the IV functional class on NYHA classification) treatment is carried out with care, in connection with a possibility of edematization of lungs.

Influence on ability of control of motor transport and other technical devices: in connection with possibility of dizziness, etc. side effects against the background of use of the drug Dalneva® it is necessary to be careful at control of vehicles and work with other technical devices demanding the increased concentration of attention and speed of psychomotor reactions.

Use of the drug Dalneva® is contraindicated at pregnancy. The drug Dalneva® should not be used in the I trimester of pregnancy. When planning pregnancy or at its approach against the background of drug Dalneva® use, it is necessary to stop administration of drug as soon as possible and to appoint other hypotensive therapy allowed for use at pregnancy. The corresponding controlled researches of use of APF inhibitors for pregnant women were not conducted. The available limited data on impact of drug on a fruit in the I trimester of pregnancy demonstrate that use of APF inhibitors does not lead to fruit malformations, however increase in risk cannot be excluded.

It is known that impact of APF inhibitors on a fruit in II and III trimesters of pregnancy can lead to disturbance of its development (to depression of function of kidneys, an oligogidramnion, delay of ossification of bones of a skull) and to development of complications in the newborn (a renal failure, arterial hypotension, a hyperpotassemia). If the patient received APF inhibitors in II or III trimesters of pregnancy, it is recommended to conduct ultrasonography for assessment of a condition of bones of a skull and function of kidneys of a fruit.

Newborns whose mothers received APF inhibitors during pregnancy have to be under careful medical observation because of risk of development of arterial hypotension, an oliguria and a hyperpotassemia.

Breastfeeding period. It is not recommended to use the drug Dalneva® in the period of a lactation since there is no corresponding clinical experience of use of an amlodipin and perindopril both in monotherapy, and as a part of a combination therapy. In need of use of the drug Dalneva® in the period of a lactation breastfeeding should be stopped.

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

infrequently                                  from ≥1/1000 to <1/100

seldom                                      from ≥1/10000 to <1/1000

very seldom                           from <1/10000

frequency               should be unknown is estimated on the basis of the available data.

In each group undesirable effects are presented as reduction of their gravity.

From circulatory and lymphatic system: very seldom: a leukopenia/neutropenia, an agranulocytosis, a pancytopenia, thrombocytopenia, hemolitic anemia at patients with inborn deficit glyukozo-6-fosfatdegidrogenazy, decrease in concentration of hemoglobin and a hematocrit.

From immune system: infrequently: small tortoiseshell.

Metabolic disturbances: infrequently: increase in body weight, body degrowth; very seldom: the hyperglycemia, frequency is unknown: hypoglycemia.

From a nervous system: often: drowsiness, dizziness, headache, paresthesias, вертиго; infrequently: sleeplessness, lability of mood, sleep disorder, tremor, hypesthesias; very seldom: peripheral neuropathy, confusion of consciousness.

From sense bodys: often: vision disorders, sonitus;

From cardiovascular system: often: a heart consciousness, "inflows" of blood to face skin, the expressed decrease in the ABP; infrequently: syncope; seldom: pain behind a breast; very seldom: stenocardia, a myocardial infarction, perhaps, owing to excess decrease in the ABP at patients from group of high risk, arrhythmia (including, bradycardia, ventricular tachycardia and a ciliary arrhythmia), a stroke, perhaps, owing to excess decrease in the ABP at patients from group of high risk, a vasculitis.

From respiratory system: often: short wind, cough; infrequently: rhinitis, bronchospasm; very seldom: eosinophilic pneumonia.

From the alimentary system: often: abdominal pain, nausea, vomiting, dyspepsia, diarrhea, lock; infrequently: dryness of a mucous membrane of an oral cavity, disturbance of flavoring perception, change of a rhythm of defecation; very seldom: pancreatitis, hyperplasia of gums, gastritis, hepatitis, cholestatic jaundice, cytolytic or cholestatic hepatitis.

From integuments: often: skin itch, skin rash; infrequently: a Quincke's disease of the person, extremities, lips, mucous membranes, language, voice folds and/or throats, an alopecia, hemorrhagic rash, a photosensitization, the increased perspiration; very seldom: Quincke's edema, multiformny erythema, Stephens-Johnson's syndrome.

From a musculoskeletal system: often: spasms of muscles; infrequently: arthralgia, mialgiya, dorsodynia.

From an urinary system: infrequently: disturbance of an urination, a nocturia, the speeded-up urination, a renal failure; very seldom: acute renal failure.

From reproductive system: infrequently: impotence, gynecomastia.

Other: often: peripheral hypostases, adynamy, increased fatigue; infrequently: thorax pain, indisposition.

Laboratory indicators: seldom: increase in concentration of bilirubin; very seldom: increase in activity of "hepatic" transaminases: aspartate aminotransferases (nuclear heating plant), alaninaminotranspherase (ALT) (it is the most frequent – in combination with a cholestasia); frequency is unknown: increase in concentration of urea and creatinine in blood serum.

Additional data on an amlodipin: separate cases of an extrapyramidal syndrome at use of blockers of "slow" calcium channels are registered.

Interaction with other medicines:

Perindopril. Simultaneous use is not recommended:

Kaliysberegayushchy diuretics, drugs of potassium or substitutes of edible salt containing potassium: in spite of the fact that the content of potassium in blood serum remains within norm, at some patients at use of a perindopril the hyperpotassemia can be observed. Kaliysberegayushchy diuretics (for example, Spironolactonum, Triamterenum or amiloride), can lead drugs of potassium or substitutes of edible salt containing potassium to essential increase in content of potassium in a blood plasma therefore their use along with APF inhibitors is not recommended. If simultaneous therapy is necessary (in case of the confirmed hypopotassemia), it is necessary to be careful and carry out regular control of content of potassium in a blood plasma and the ECG parameters.

Lithium drugs: at simultaneous use of drugs of lithium and APF inhibitors cases of reversible increase in concentration of lithium in blood serum and the toxic effects connected with it were registered. Simultaneous therapy perindoprily and drugs of lithium is not recommended. In need of such combination therapy it is necessary to carry out it under regular control of concentration of lithium in a blood plasma.

Estramustinum: simultaneous use is followed by the increased risk of development of a Quincke's disease.

The simultaneous use demanding extra care:

Non-steroidal anti-inflammatory drugs (NPVP), including inhibitors of cyclooxygenase-2 (TsOG-2), acetylsalicylic acid in high doses (more than 3 g/days) and non-selective NPVP): use of NPVP can lead to decrease in diuretic, natriuretic and hypotensive effect of APF inhibitors. Simultaneous use of APF and NPVP inhibitors can lead to deterioration in function of kidneys, including development of an acute renal failure and to increase in content of potassium in blood serum, especially at patients with reduced function of kidneys. It is necessary to be careful at use of this combination, especially at patients of advanced age. Patients in this case need to offset liquid loss carefully to control function of kidneys, both in an initiation of treatment, and in the course of treatment.

Hypoglycemic drugs (hypoglycemic means for intake and/or insulin): use of APF inhibitors can strengthen hypoglycemic effect of insulin or derivatives of sulphonylurea at patients with a diabetes mellitus. Development of episodes of a hypoglycemia was noted very seldom (the increase in tolerance to glucose leading to reduction of need for insulin perhaps takes place).

The simultaneous use requiring attention:

Diuretics (thiazide and "loopback"): at the patients accepting diuretics, especially at excess removal of liquid and/or electrolytes at the beginning of use of APF inhibitors considerable decrease in the ABP can be observed. The risk of development of arterial hypotension can be reduced by diuretic cancellation, increase in consumption of liquid and/or table salt before therapy, beginning therapy with low doses of a perindopril with their further gradual increase.

Sympathomimetics: sympathomimetics can weaken hypotensive effect of APF inhibitors.

Gold drugs: at the patients receiving simultaneous injection therapy by gold drugs (sodium ауротиомалат) and APF inhibitors, including perindoprit, nitratopodobny reactions are seldom noted ("inflows" of blood to face skin, nausea, vomiting, decrease in the ABP).

Allopyrinolum, cytostatic and immunosuppressive means, glyukokortikosteroda (at system use) and procaineamide: simultaneous use with APF inhibitors can be followed by the increased risk of a leukopenia.

Means for the general anesthesia: simultaneous use of APF inhibitors and means for the general anesthesia can lead to strengthening of hypotensive effect.

Amlodipin. Simultaneous use is not recommended:

Dantrolen (intravenous administration): in experiments on animals after administration of verapamil and a dantrolen cases of fibrillation of ventricles with a lethal outcome and cardiovascular insufficiency, associated with a hyperpotassemia were (intravenously) observed. Considering risk of development of a hyperpotassemia, it is necessary to avoid simultaneous use of blockers of "slow" calcium channels, including and an amlodipin and a dantrolen.

The simultaneous use demanding extra care:

The inductors CYP3A4 (rifampicin, drugs of the St. John's Wort which is made a hole, anticonvulsants, such as carbamazepine, phenobarbital, Phenytoinum, фосфенитоин, Primidonum): decrease in plasma concentration of an amlodipin in a consequence of strengthening of his metabolism in a liver is possible. It is necessary to be careful at simultaneous use of an amlodipin and inductors of a microsomal oxidation and if necessary to adjust a dose of an amlodipin.

Strong and moderate inhibitors of an isoenzyme CYP3A4 (inhibitors of proteases, azolny antifungal drugs (итраконазол and кетоконазол), macroleads, such as erythromycin and кларитромицин, verapamil and diltiazem): increase in plasma concentration of an amlodipin and strengthening of risk of development of side effects, especially at patients of advanced age is possible. It is necessary to be careful at simultaneous use and, if necessary, to adjust a dose of an amlodipin.

The simultaneous use requiring attention:

Simultaneous use of beta adrenoblockers (бисопролол, метопролол) and alpha and beta adrenoblocker of a karvedilol, applied at the chronic heart failure (CHF): increases risk of development of arterial hypotension and deterioration in a current of HSN at patients from uncontrollable or latentnoprotekayushchy HSN (strengthening of an inotropic effect). Besides, beta adrenoblockers can reduce excessive reflex cordial sympathetic activation against the background of the accompanying HSN.

Other combinations:

In monotherapy амлодипин it is safe to apply along with thiazide diuretics, beta adrenoblockers, APF inhibitors, nitrates of the prolonged action, nitroglycerine (to hypoglossal use), digoxin, warfarin, atorvastatiny, sildenafily, antacids (aluminum hydroxide colloid, magnesium hydroxide), симетикон, Cimetidinum, NPVP, antibiotics and hypoglycemic means for intake.

There is no interaction of the following medicines with amlodipiny:

- at simultaneous use of an amlodipin and Cimetidinum pharmacokinetic parameters of an amlodipin did not change;

- at simultaneous use of an amlodipin and sildenafil strengthening of hypotensive effect of each of drugs is noted;

- grapefruit juice: reception of 240 ml of grapefruit juice together with a single dose of an amlodipin (10 mg inside) did not exert significant impact on pharmacokinetics of an amlodipin.

Amlodipin does not influence pharmacokinetics of the following medicines:

- аторвастатин: reception of repeated doses of an amlodipin of 10 mg in a combination with atorvastatiny in a dose of 80 mg does not lead to essential change of equilibrium pharmacokinetic parameters of an atorvastatin;

- digoxin: simultaneous use of an amlodipin and digoxin is not followed by change of concentration of digoxin in blood serum and renal clearance of digoxin at healthy volunteers;

- warfarin: at healthy volunteers is a male, accepting warfarin, addition of an amlodipin has no significant effect on change of an indicator of the prothrombin time caused by warfarin;

- cyclosporine: амлодипин has no significant effect on pharmacokinetic parameters of cyclosporine.

Дальнева®. The simultaneous use requiring special attention:

Baclofenum: potentiation of hypotensive action is possible. Control of the ABP and function of kidneys, and also dose adjustment of an amlodipin is necessary.

The simultaneous use requiring attention:

Antihypertensives (for example, beta adrenoblockers) and vazodilatator: strengthening of hypotensive effect of a perindopril and amlodipin is possible.

It is necessary to be careful at simultaneous use with nitroglycerine, other nitrates or other vazodilatator as at the same time perhaps additional decrease in the ABP.

Corticosteroids (mineralo-and glucocorticosteroids), тетракозактид: decrease in hypotensive action (a delay of liquid and ions of sodium as a result of action of corticosteroids).

Alpha adrenoblockers (Prazozinum, альфузозин, доксазозин, тамсулозин, теразозин):

strengthening of hypotensive action and increase in risk of orthostatic hypotension.

Amifostin: can exponentiate hypotensive effect of an amlodipin.

Tricyclic antidepressants / neuroleptics / means for the general anesthesia: strengthening of hypotensive effect and increase in risk of development of orthostatic hypotension.

Contraindications:

Perindopril:

- hypersensitivity to a perindopril or other APF inhibitors;

- a Quincke's disease (Quincke's edema) in the anamnesis (including against the background of reception of other APF inhibitors);

- hereditary/idiopathic Quincke's disease;

- age up to 18 years (efficiency and safety are not established);

Amlodipin:

- hypersensitivity to an amlodipin or other derivatives of dihydropyridine;

- the expressed arterial hypotension (systolic the ABP less than 90 mm of mercury.), shock, including cardiogenic shock;

- obstruction of an output path of a left ventricle (for example, the expressed aorta stenosis);

- unstable stenocardia (except for Printsmetal's stenocardia);

- age up to 18 years (efficiency and safety are not established);

- hemodynamically unstable heart failure after an acute myocardial infarction.

Дальнева®:

- hypersensitivity to the excipients which are a part of drug;

- renal failure (clearance of creatinine (CC) less than 60 ml/min.);

- age up to 18 years (efficiency and safety are not established).

With care: liver failure, the chronic heart failure (CHF), aortal and/or mitral stenosis, hypertrophic subaortic stenosis (GOKMP), advanced age, bilateral stenosis of renal arteries, stenosis of an artery of the only functioning kidney, renal failure (KK less than 60 ml/min.), general diseases of connecting fabric (including, a system lupus erythematosus, a scleroderma), therapy by immunodepressants, Allopyrinolum, procaineamide (risk of development of a neutropenia, agranulocytosis), the reduced the volume of the circulating blood (VCB) (reception of diuretics, a diet with restriction of table salt, vomiting, diarrhea), atherosclerosis, cerebrovascular diseases, renovascular hypertensia, a diabetes mellitus, use of a dantrolen, estramustinum, kaliysberegayushchy diuretics, drugs of potassium, kaliysoderzhashchy substitutes of edible salt and drugs of lithium, a hyperpotassemia, surgical intervention / the general anesthesia, use for patients of negroid race, carrying out a hemodialysis with use of high-flowing poliakrilnitrilovy membranes – risk of development of anaphylactoid reactions; before the procedure of an aferez of lipoproteins of the low density (LPNP) with the help a sulfate dextran, simultaneous performing the desensibilizing therapy by allergens (for example, poison of Hymenoptera), a state after transplantation of a kidney (lack of clinical data).

Overdose:

Information on overdose by the drug Dalneva® is absent.

Perindopril. Data on overdose perindoprily are limited.

Symptoms: the expressed decrease in the ABP, shock, disturbances of water and electrolytic balance, a renal failure, a hyperventilation of lungs, tachycardia, a heart consciousness, bradycardia, dizziness, concern and cough.

Treatment: measures of acute management come down to removal of drug from an organism: to a gastric lavage and/or purpose of absorbent carbon with the subsequent recovery of OTsK.

 At the expressed decrease in the ABP it is necessary to transfer the patient to situation "lying" on spin with the raised legs, if necessary to hold events for recovery of OTsK (for example, intravenous infusion of 0,9% chloride sodium solution). Also perhaps intravenous administration of catecholamines. By means of a hemodialysis it is possible to remove perindoprit from a system blood-groove. At bradycardia, resistant to therapy, installation of an artificial pacemaker can be required. Dynamic control of the general state, concentration of creatinine and electrolytes in a blood plasma is necessary.

Amlodipin. Information on overdose amlodipiny is limited.

Symptoms: the expressed decrease in the ABP with possible development of reflex tachycardia and an excessive peripheral vazodilatation (risk of development of the expressed and persistent arterial hypotension, including with development of shock and a lethal outcome).

Treatment: a gastric lavage, purpose of absorbent carbon (especially in the first 2 h after overdose), maintenance of function of cardiovascular system, sublime position of the lower extremities, control of OTsK and a diuresis, a symptomatic and maintenance therapy. For recovery of a tone of vessels - use of vasoconstrictors (in the absence of contraindications to their use); for elimination of effects of blockade of calcium channels - intravenous administration of solution of calcium of a gluconate. The hemodialysis is inefficient.

Storage conditions:

At a temperature not above 25 °C, in original packaging. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets of 5 mg + 4 mg, 10 mg + 4 mg, 5 mg + 8 mg, 10 mg + 8 mg.

On 10 tablets in a blister strip packaging from the combined material OOPS / PVC (aluminum polyamide/foil / polyvinylchloride) and aluminum foil Is scarlet/.

3 or 9 blister strip packagings together with the application instruction place in a pack from a cardboard.