Pharmacological properties

Pharmacodynamics. the combination ramiprit and diuretic of a hydrochlorothiazide has antihypertensive and diuretic effect. antihypertensive effects of both substances supplement each other, and the gipokaliyemichesky effect of a hydrochlorothiazide reduces ramiprit.

Ramipril

Ramiprilat — the active metabolite of a ramipril, oppresses enzyme dipeptidil-carboxypeptidase I (synonyms: APF, a kininaza of II), angiotensin II and also disintegration of an active vazodilatator of bradykinin catalyzing transformation of angiotensin I in fabrics in an active vasoconstrictor. Reduction of amount of angiotensin II and oppression of disintegration of bradykinin causes vasodilatation.

As angiotensin II also stimulates with

secretion of Aldosteronum, ramiprilat leads to decrease in level of Aldosteronum. Increase in activity of bradykinin enhances cardiotyre-tread effect of a ramipril and protects an endothelium of vessels.

Use of a ramipril leads

to the significant decrease in peripheric arterial resistance. Usually do not note significant change of speed of a renal blood-groove and glomerular filtration.

Ramipril lowers the arterial blood pressure without compensatory increase in ChSS. The antihypertensive effect is reached in 1–2 h after reception of a single dose. The maximum effect is reached in 3–6 h after reception. As a rule, the antihypertensive effect after single use lasts not less than 24 h. At long treatment ramiprily the maximum antihypertensive effect is usually reached in 2–4 weeks and he manages to be supported for 2 years. The sharp termination of reception of a ramipril does not cause fast and excessive increase in the ABP.

Hydrochlorothiazide

Hydrochlorothiazide — thiazide diuretic. Oppresses a reabsorption of sodium and chlorine in distal tubules. The strengthened renal excretion of these ions is followed by increase in an uropoiesis (in connection with osmotic binding of water). Excretion of potassium and magnesium increases, and uric acid decreases. In a high dose medicament causes bicarbonate excretion strengthening, and long reception reduces calcium excretion.

Probable mechanisms of antihypertensive action include change of sodium balance, reduction of volume of extracellular water and blood plasma, change of resistance of renal vessels or decrease in reactions to noradrenaline and angiotensin II.

Excretion of electrolytes and water begins

approximately in 2 h after reception, the maximum effect is reached in 3–6 h and lasts for 6–12 h. The antihypertensive effect is reached in 3–4 days of treatment and lasts for 1 week after the end of use of drug.

decrease in the ABP is reached by

At long therapy at use of medicament in lower dose, than it is necessary for diuretic effect. Decrease in the ABP is followed by slight increase of glomerular filtration rate, vascular resistance of the renal course and activity of renin in blood plasma.

Thiazide diuretics can break secretion of breast milk.

Pharmacokinetics. Ramipril is quickly absorbed in a GIT (not less than 56% of the entered dose), the C _max in blood plasma is reached for 1 h Ramipril almost completely is metabolized (generally in a liver) with formation of active and inactive metabolites. Its active metabolite ramiprilat is 6 times more active than a ramipril. The C _max in blood plasma is reached in 2–4 h. Among the known inactive metabolites — diketopiperazine ether, diketopiperazine acid and also glucuronides of a ramipril and the ramiprilat. Linking of a ramipril and the ramiprilat with blood proteins makes about 73 and 56% respectively. At use in usual doses (1 time a day) equilibrium concentration in blood plasma is reached for the 4th day of reception. After use of 60% of a dose about 40% are removed with urine (generally in the form of metabolites), and — with a stake. Nearly 2% of the entered dose are removed with urine in not changed look.

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After oral administration of 70% of a hydrochlorothiazide it is soaked up in a duodenal and upper colon. The C _max in blood plasma is reached in 1.5-4 h. It contacts proteins of blood plasma approximately for 40%. 95% of a hydrochlorothiazide are allocated with kidneys by canalicular excretion. T _½ — 5–15 h. Usually therapeutic effect of a hydrochlorothiazide is reached in 2 h after reception, maximum — in 2–4 h

Action of this combination of the medicament Hartil-N usually lasts up to 24 h. Optimum decrease in the ABP is noted in 3–4 weeks of treatment.

Indication

Essential hypertensia at patients to whom combination therapy is recommended (ramiprit also a hydrochlorothiazide).

Use

For oral administration.

recommends to take the Drug 1 time a day at the same time, it is desirable in the morning.

can take the Drug to, in time and after a meal as meal does not affect bioavailability of medicament (see Pharmacokinetics). It is necessary to swallow of tablets entirely, washing down with water. They cannot be chewed or crushed.

Adult. To adjust a dose individually, depending on features of the patient (see. Special INSTRUCTIONS) and ABP levels. Use of the fixed combination of a ramipril and a hydrochlorothiazide, as a rule, is recommended only after titration of doses of each of its separate components.

Begin with

treatment with the lowest possible dose. In case of need the dose can be raised to achievement of a target indicator of the ABP gradually. The maximum daily dose makes 10 mg of a ramipril and 25 mg of a hydrochlorothiazide a day that corresponds to 2 tablets Hartil-N of 5 mg / 12.5 mg.

Special groups of patients

Patients receiving diuretics. It is recommended to show care as the patients receiving diuretics in an initiation of treatment can have an arterial hypotension. Before beginning medicament treatment, it is necessary to lower a dose of diuretic or to stop its use.

Patients with a renal failure. Because of existence of a hydrochlorothiazide component medicament is contraindicated to patients with a heavy renal failure (clearance of creatinine of 30 ml/min. (see CONTRAINDICATIONS). Low doses of medicament can be shown to patients with a renal failure. Patients with clearance of creatinine of 30-60 ml/min. should be treated only using a low dose of the fixed combination ramiprila / a hydrochlorothiazide after monotherapy ramiprily. The maximum daily dose * makes 5 mg of a ramipril and 25 mg of a hydrochlorothiazide.

Patients with an abnormal liver function. At patients with a slight and moderate abnormal liver function the treatment should be begun only under careful control. The maximum daily dose * in such cases makes 2.5 mg of a ramipril and 12.5 mg of a hydrochlorothiazide. Drug is contraindicated in cases of a heavy abnormal liver function (see CONTRAINDICATIONS).

Patients of advanced age. The initial dose has to be lower, especially at very old and weak patients, and further titration of a dose should be carried out gradually, considering a high probability of emergence of side reactions.

Contraindication

Hypersensitivity to active ingredient to a ramipril or other inhibitors apf, to a hydrochlorothiazide, other thiazide diuretics, streptocides or to any of the excipients which are a part of medicament (see structure).

Existence in the anamnesis of a Quincke's disease (the hereditary, idiopathic or earlier postponed against the background of use APF inhibitors or antagonists of receptors of angiotensin II).

Arterial hypotension or hemodynamically unstable states.

Simultaneous use of APF inhibitors and extracorporal methods of treatment at which there is a contact of blood with negatively charged surfaces as such use can lead to anaphylactic reactions of heavy degree. Such extracorporal methods of treatment include dialysis or haemo filtration with use of certain membranes with high hydraulic permeability (for example polyacrylonitrile) and aferez LDL using a sulfate dextran (see INTERACTIONS).

Considerable bilateral stenosis of renal arteries or a unilateral renal artery stenosis in the presence of the only kidney.

Heavy renal failures (clearance of creatinine of 30 ml/min.) at patients to whom the hemodialysis is not carried out.

Clinically significant disturbances of electrolytic balance which course can worsen during treatment (see. Special INSTRUCTIONS).

hypopotassemia, Resistant to treatment, or hypercalcemia.

Refractory hyponatremia.

Symptomatic hyperuricemia (gout).

Anury.

Heavy abnormal liver function, hepatic encephalopathy.

Simultaneous use with the medicaments containing aliskiren for patients with diabetes or at patients with a moderate or heavy renal failure (clearance of creatinine of 60 ml/min.).

Simultaneous use with medicaments of antagonists of receptors of angiotensin II for patients with a diabetic nephropathy.

Side effects

safety Profile ramiprila / a hydrochlorothiazide includes side reactions which occur in the context of arterial hypotension and/or loss of liquid at increase in a diuresis. ramiprit active agent can cause persistent dry cough whereas active agent can lead a hydrochlorothiazide to deterioration in metabolism of glucose, lipids and uric acid. two active agents have reversible influence on potassium level in blood. serious side reactions include a Quincke's edema or anaphylactoid reactions, a renal or liver failure, pancreatitis, skin reactions and a neutropenia/agranulocytosis.

from the system of blood and a lymph: decrease in hemoglobin and hematocrit, leukopenia, thrombocytopenia, reduction of quantity of erythrocytes; an agranulocytosis, a pancytopenia, an eosinophilia, hemolytic anemia at patients with deficit glyukozo-6-fosfatdegidrogenazy, a neutropenia, haemo concentration in case of a liquid delay.

from the immune system: on ramiprit anaphylactic or anaphylactoid reactions, anaphylactic reactions to a hydrochlorothiazide, increase in antinuclear antibodies are possible.

from an endocrine system: syndrome of disturbance of secretion of antidiuretic hormone.

from metabolism and food: uncontrollable diabetes, decrease in tolerance to glucose, increase in level of glucose, uric acid in blood, gout, increase in level XC and/or TG in blood at the expense of a hydrochlorothiazide; anorexia, a loss of appetite, decrease in level of potassium in blood, the increased feeling of thirst due to action of a hydrochlorothiazide; increase in level of potassium in blood due to action of a ramipril; a glucosuria, a metabolic alkalosis, a hypochloraemia, a hypomagnesiemia, a hypercalcemia, dehydration due to action of a hydrochlorothiazide.

Mental disturbances: suppressed mood, apathy, concern, nervousness, sleep disorders (including drowsiness); fear, confusion of consciousness, disturbance of attention.

Dysfunction of nervous system and sense bodys: dizziness, fatigue, headache, weakness, drowsiness, conjunctivitis, blepharitis, concern, disturbance of sense of smell, disturbance of taste (dysgeusia), loss of taste (ageusia), feeling of heat, disturbance of balance, paresthesia; passing short-sightedness, illegibility of sight, sonitus, brain ischemia, including ischemic stroke and tranzitorny ischemic attack, vertigo, tremor.

from organs of hearing: sonitus, hearing disorder.

from organs of sight: a disorder of vision, including illegibility of sight, conjunctivitis, a xanthopsia, reduction of a slezootdeleniye as a result of action of a hydrochlorothiazide.

from a cardiovascular system: myocardium ischemia, including stenocardia, tachycardia, arrhythmia, feeling of the strengthened heartbeat, peripheral hypostases, a myocardial infarction, orthostatic arterial hypotension, arterial hypotension, orthostatic hypotension, a syncope, inflows, thrombosis owing to considerable reduction OCK, a vascular stenosis, hypoperfusion, Reynaud's syndrome, a vasculitis, a necrotizing angiitis.

from a respiratory system: dry cough, bronchitis; dispnoe, pharyngitis, sinusitis, rhinitis, a tracheobronchitis, laryngitis, a bronchospasm, including OH, an asthma, congestion of a nose; the allergic alveolitis, a hydrochlorothiazide can cause not cardiogenic fluid lungs.

from digestive system: the inflammatory phenomena in a GIT, digestion disturbances, unpleasant feelings in a stomach, dyspepsia, gastritis, nausea, a constipation, an ulitis owing to action of a hydrochlorothiazide, vomiting, stomatitis, a glossitis, diarrhea, pain in an upper part of a stomach, dryness in a mouth, thirst, pancreatitis (it was in rare instances reported about lethal consequences at use of APF inhibitors), increase in level of enzymes of a pancreas, a Quincke's disease of a small intestine, a sialadenitis owing to action of a hydrochlorothiazide.

from a gepatobiliarny system: cholestatic or cytolytic hepatitis, increase in level of liver enzymes and/or bilirubin, the calculous cholecystitis connected with a hydrochlorothiazide, an acute liver failure, cholestatic jaundice, hepatocellular disturbances.

from skin and hypodermic fabrics: a Quincke's edema as an exception, obstruction of airways, psoriazopodobny dermatitis, the increased sweating, makulopapulezny rash, an itching, an alopecia, a toxic epidermal necrolysis, Stephens's syndrome — Johnson, a multiformny erythema, a bladderwort, exacerbation of psoriasis, exfoliative dermatitis, a photosensitization, onikholizis, psoriazoformny or a pemfigoidny dieback or an enantema, a small tortoiseshell, a system lupus erythematosus owing to action of a hydrochlorothiazide can result.

from the musculoskeletal system and connective tissue: myalgia, an arthralgia, muscular spasms, the weakness of muscles, musculoskeletal constraint, a tetany connected with a hydrochlorothiazide.

from kidneys and urinary tract: a renal failure, including OPN, increase in a diuresis, increase in content of urea and creatinine in blood plasma, strengthening of already existing proteinuria, an oliguria, hypostases, interstitial nephrite it is connected with a hydrochlorothiazide.

from a reproductive system and mammary glands: decrease in a libido, temporary disturbance of an erection, gynecomastia.

Disturbance of the general state: increased fatigue, weakness, stethalgia, hyperthermia.

Special instructions

Special groups of patients

Pregnancy. Treatment by APF inhibitors or antagonists of receptors of angiotensin II should not be begun during pregnancy. Except for cases when treatment continuation by inhibitor by APF/antagonists of receptors of angiotensin II is absolutely necessary, the patients who are going to become pregnant, it is necessary to transfer to other antihypertensive medicament which use during pregnancy is recognized as safe. As soon as pregnancy is diagnosed, treatment by inhibitors by APF/antagonists of receptors of angiotensin II should be stopped immediately and, in case of need, to begin treatment with other medicament (see CONTRAINDICATIONS and Use during pregnancy and feeding by a breast).

Special cautions

Patients with possible risk of developing of arterial hypotension

Patients with the significant activity system renin-angiotensin-aldosteronovoy. At patients with the significant activity perhaps sharp decrease in the ABP and deterioration in function of kidneys connected with use of APF inhibitors, especially when APF inhibitor or the accompanying diuretic medicine appoint system renin-angiotensin-aldosteronovoy for the first time, or at increase in a dose.

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Medical observation and control of the ABP system renin-angiotensin-aldosteronovoy as is necessary for such patients with the significant activity:

• patients from heavy AG;
• patients with dekompensirovanny stagnant heart failure;
• patients with hemodynamically significant disturbance of inflow and outflow of blood in a left ventricle (for example a stenosis of the aortal or mitral valve);
• patients with a unilateral renal artery stenosis of the second functioning kidney;
• patients at whom risk of development excessive removal of liquid or sodium chloride (including the patients accepting diuretics) from an organism exists or is possible;
• patients with cirrhosis and/or ascites;
• patients who transferred serious surgeries or at which during anesthesia used the medicaments causing hypotension.

is recommended to eliminate with

Before an initiation of treatment conditions of dehydration, a hypovolemia or excessive removal of sodium chloride (however at patients with heart failure the possibility of holding such corrective actions should be weighed carefully concerning risk of development of a volume overload).

Surgery. It is recommended that treatment by APF inhibitors, such as ramiprit, was whenever possible stopped in 1 day prior to operation.

If it is possible, before surgical intervention (including stomatology) medicament treatment it is necessary to stop or lower a dose. When performing immediate surgeries of a dose of the medicines applied to premedication and anesthesia it is necessary to reduce.

Patients with risk of developing cardiac or cerebral ischemia in acute arterial hypotension. The initial phase of treatment demands special medical observation.

Primary hyper aldosteronism. The combination ramiprit and the hydrochlorothiazide is not choice medicament for treatment of primary hyper aldosteronism. If this combination is used for treatment of patients with primary hyper aldosteronism, then control of level of potassium in blood plasma is not required.

Use for patients of advanced age. This category of patients should carry out increase in a dose with care. When prescribing this medicament to patients of advanced age, accepting diuretics and/or for which heart failure is diagnosed and also the patient with abnormal liver functions or kidneys, the special attention is required. The dose is established by the doctor individually, depending on reaction of the patient to drug.

Use for patients with an abnormal liver function. Diuretics, including a hydrochlorothiazide, can lead electrolytic disturbances owing to therapy to hepatic encephalopathy at patients with liver diseases.

Monitoring of function of kidneys. Function of kidneys should be estimated before and during treatment. The dose should be adjusted, especially in the first weeks of treatment. Especially careful control is necessary for patients with a renal failure. There is a risk of a renal failure, especially at patients with stagnant heart failure or after transplantation of a kidney.

Renal failure. At patients with a disease of kidneys of a tiazida can accelerate development of uraemia. Patients with a disease of kidneys can also have an effect of cumulation of active agent. If development of a renal failure progresses what growth of nonprotein nitrogen testifies to, it is necessary to reconsider and overestimate carefully treatment taking into account the therapy termination by diuretics.

Disturbance of electrolytic balance. As well as for any patients at therapy by diuretics, it is necessary to carry out definition of electrolytes in blood plasma through the corresponding periods. Tiazida, including a hydrochlorothiazide, can cause an imbalance of liquid or electrolytes (hypopotassemia, a hyponatremia, a gipokhloremichesky alkalosis). Though the hypopotassemia can develop at use of thiazide diuretics, the accompanying therapy ramiprily can reduce effect of diuretic which caused a hypopotassemia. Risk of development of a hypopotassemia the highest at patients with cirrhosis, is observed increase in a diuresis at the patients receiving insufficient amount of electrolytes and receiving therapy of GKS or AKTG. The first measurement of level of potassium in blood plasma should be taken within 1 week after an initiation of treatment. If potassium level low, is not required to dose adjustment.

Decrease in level of sodium can proceed asymptomatically therefore regular control is of great importance. The thicket should carry out control of level of sodium in blood plasma at patients of advanced age and at patients with cirrhosis.

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It was shown that tiazida increase magnesium removal that can lead to a hypomagnesiemia.

Hyperpotassemia. The hyperpotassemia was noted at some patients accepting APF inhibitors including Hartil-N. Patients who can have a risk of development of a hyperpotassemia make the following groups of patients: patients with a renal failure, patients are aged more senior than 70 years, patients with uncontrollable diabetes, patients who apply potassium salts, kaliysberegayushchy diuretics and other means which lead to increase in level of potassium in blood serum, to increase in level of active agents or at the expense of such conditions as dehydration, an acute heart failure, a metabolic acidosis. If simultaneous observance of the above-stated conditions is reasonable, then regular control of level of potassium in blood serum is recommended.

Hepatic encephalopathy. The electrolytic imbalance owing to therapy by diuretics, including a hydrochlorothiazide, can lead to hepatic encephalopathy at patients with liver diseases, symptoms of an abnormal liver function are observed in the first weeks or months. In case of developing of hepatic encephalopathy the treatment needs to be stopped.

Hypercalcemia. The hydrochlorothiazide stimulates a calcium reabsorption in kidneys and can lead to a hypercalcemia. It can lead to false indicators of the test of function of an epithelial body.

Quincke's disease. The Quincke's disease was registered at patients who were treated by APF inhibitors, including ramiprily. In case of developing of a Quincke's disease the Hartil-N medicament treatment should be stopped. Treatment of symptoms should be begun as soon as possible. Patients have to be under observation of the doctor during from 12 to 24 h. The intestinal Quincke's disease was registered at patients who were treated APF inhibitors. Such patients complained of an abdominal pain (with nausea and vomiting or without them).

Anaphylactic reactions at desensitization. Probability and weight of anaphylactic and anaphylactoid reactions to poison of insects and other allergens increase at use of APF inhibitors. Treatment of Hartilom-N needs to be stopped before performing desensitization.

Neutropenia/agranulocytosis. A neutropenia/agranulocytosis it was observed seldom, information on oppression of marrow did not arrive. It is recommended to control the level of leukocytes in blood, emergence of a leukopenia is possible. Control is recommended to be carried out in an initiation of treatment and at patients with a renal failure and also especially at patients with collagenic vascular diseases (for example a system lupus erythematosus or a scleroderma) and also at the patients accepting medicines which caused changes of a picture of blood.

Ethnic distinctions. APF inhibitors cause a Quincke's disease in representatives of negroid race more often, than in the Caucasian.

As well as other APF inhibitors, ramiprit it can be less effective for decrease in the ABP at patients of negroid race, perhaps, because of high prevalence of AG with the low level of renin at this category of patients.

Athletes. The hydrochlorothiazide can yield positive take at test for doping control.

Metabolism and endocrine effects. Thiazide diuretics can lead to decrease in tolerance to glucose. Sick diabetes dose adjustment of insulin or oral hypoglycemic medicament can be required. During treatment by thiazide diuretics latent diabetes can pass into an active form.

Thiazide diuretics can also increase level XC and TG.

development of a hyperuricemia or bad attack of gout in some patients at use of thiazide diuretics Is possible

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Cough. At use of APF inhibitors the appearance of cough is possible. It is characteristic that cough is unproductive, resistant and passes after the therapy termination. The possibility of appearance of the cough caused by APF inhibitors has to be considered at implementation of differential diagnosis of cough.

Others. Reaction to medicament can arise at patients with / or an allergy or OH in the anamnesis. Information on aggravation of a system lupus erythematosus did not arrive.

Double blockade system renin-angiotensin-aldosteronovoy by means of the medicines containing aliskiren.

Double blockade system renin-angiotensin-aldosteronovoy by the combined use of the medicament Hartil-N and aliskireny is not recommended to

as at the same time there is an increased risk of developing arterial hypotension, a hyperpotassemia and emergence of changes in function of kidneys (including OPN).

to Patients with diabetes or renal failures (glomerular filtration rate of 60 ml/min.) the combined use of the medicament Hartil-N and an aliskiren contraindicated (see CONTRAINDICATIONS).

If therapy by double blockade is considered by

as a necessary measure, treatment should be carried out under observation of experts and to carry out monitoring of function of kidneys, to control the level of electrolytes and the ABP.

APF Inhibitors and blockers of receptors of angiotensin II should not be applied at patients with a diabetic nephropathy.

Lactose intolerance. Drug contains lactose monohydrate. Patients should not appoint it with rare inherited disorders of tolerance to a galactose, hereditary deficiency of lactase the Sami or a glucose galactose absorption disturbance syndrome.

is not recommended to take alcoholic beverages during treatment.

With care is appointed the patient with gout and also diabetes, especially that which applies insulin and oral antidiabetic means.

Extracorporal methods of treatment which give in contact of blood with negatively charged surfaces, such as dialysis or haemo filtration with certain membranes with high hydraulic permeability (for example polyacrylonitrile) and also aferez LDL about a dextrin sulfate, owing to the increased risk of heavy anaphylactic reactions. If such treatment is necessary, it is necessary to consider a question of use of other type of a dialysis membrane or other class of antihypertensive drugs.

Period of pregnancy and feeding by a breast. Ramipril is not recommended to apply in the I trimester of pregnancy and is contraindicated during II and III trimester of pregnancy.

Epidemiological data on risk of teratogenecity after use of APF inhibitors in the I trimester of pregnancy were not convincing, however it is impossible to exclude slight increase of risk. If therapy continuation by APF inhibitor is considered necessary, patients who plan pregnancy need to pass to alternative antihypertensive medicament which has the established safety profile for use during pregnancy. If pregnancy is diagnosed, treatment it is necessary to stop and begin with APF inhibitors alternative therapy immediately. It is known that use of APF inhibitors in II and III trimester of pregnancy causes in the person a fetotoksichnost (depression of function of kidneys, oligogidramnion, a delay of ossification of bones of a skull) and neonatal toxicity (renal failure, arterial hypotension, a hyperpotassemia). If APF inhibitor is applied in the II trimester of pregnancy, ultrasonography of function of kidneys and a skull is recommended. Newborns whose mothers accepted APF inhibitors should be examined carefully regarding hypotension, an oliguria and a hyperpotassemia. There is a limited experience of use of medicine during pregnancy, especially in the I trimester of pregnancy. Researches on animals are insufficient. The hydrochlorothiazide gets through a placenta. On the basis of the pharmacological mechanism of action the hydrochlorothiazide and its use in II and III trimester of pregnancy can result in such side effects at a fruit and the newborn as jaundice, disturbance of electrolytic balance and thrombocytopenia. The hydrochlorothiazide is contraindicated in gestational hypostasis, gestational hypertensia or a preeclampsia, use of medicament can lead to reduction of amount of blood plasma and placentary hypoperfusion. The hydrochlorothiazide is contraindicated at AG at pregnant women except for rare situations when the advantage exceeds risk. As there is no sufficient information concerning use of a ramipril during feeding by a breast, it do not recommend to apply and appoint alternative remedies with the established safety profile, especially if just or prematurely the kid was born.

Feeding by a breast. It is contraindicated to use the medicament Hartil-N during feeding by a breast. Quantity of the ramipril and hydrochlorothiazide getting into breast milk such is that at use of therapeutic doses of a ramipril and hydrochlorothiazide the baby who is on breastfeeding can undergo their influence. As there are no appropriate data on use of a ramipril during feeding by a breast, it is desirable to give preference to other medicines which use during feeding by a breast is safer, especially when breastfeeding newborn or premature babies. The hydrochlorothiazide gets into breast milk. Use of a tiazid at nursing was followed by reduction or even complete cessation of development of milk. There can be hypersensitivity to sulfonamide derivatives, a hypopotassemia and a kernicterus. As the combination of their active ingredients can result in heavy undesirable effects at the babies who are on breastfeeding it is necessary to make the decision on the termination either chest feeding, or treatment depending on importance of this therapy for mother.

Children. Children are not recommended to appoint medicament due to the lack of data on safety and efficiency in this age group.

Ability to influence speed of response at control of vehicles or other mechanisms. Some side effects (for example such symptoms of decrease in the ABP as dizziness) can affect speed of response at control of vehicles or other mechanisms. These side reactions were observed in an initiation of treatment or upon transition from other drugs. After reception of the first dose or at increase in a dose it is not recommended to drive the car or to work with mechanisms within several hours.

Interaction

Food. the concomitant use of food has no considerable impact on absorption of a ramipril.

Contraindicated combinations. Methods of extracorporal therapy which use is resulted by contact of blood with negatively charged surfaces, such as dialysis or haemo filtration with use of certain membranes with high intensity of a stream (for example membranes from polyacrylonitrile) and aferez LDL using a sulfate dextran, considering the increased risk of development of heavy anaphylactic reactions (see CONTRAINDICATIONS). If such treatment is necessary, it is necessary to consider a question of use of other type of a dialysis membrane or use of other class of antihypertensive drugs.

Simultaneous use with the medicaments containing aliskiren is contraindicated to

to use for patients with diabetes or patients with a moderate or heavy renal failure (clearance of creatinine of 60 ml/min.) and is not recommended to use for all other patients.

Simultaneous use with medicaments of antagonists of receptors of angiotensin II is contraindicated to

to use for patients with a diabetic nephropathy, but it is not recommended to use for all other patients.

Salt of potassium, the heparin, kaliysberegayushchy diuretics and other active agents increasing potassium level in blood plasma (including antagonists of angiotensin II, Trimethoprimum, takrolimus, cyclosporine): there can be a hyperpotassemia therefore careful monitoring of level of potassium in blood plasma is necessary.

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