Ramizes Côme

General characteristics. Structure:

Active ingredient: ramipril, hydrochlorothiazide;

1 tablet contains a ramipril of 5 mg and a hydrochlorothiazide of 25 mg or a ramipril of 2,5 mg and a hydrochlorothiazide of 12,5 mg;

 excipients: lactoses monohydrate, cellulose microcrystallic 102, кросповидон, gipromeloza, magnesium stearate.

Pharmacological properties:

Action mechanism.

Ramipril. Ramiprilat, an active metabolite of pro-drugs-ramiprila, is dipeptidilkarboksipeptidaza enzyme inhibitor І (also known as an angiotensin-converting enzyme, or a kinase ІІ). In a blood plasma and fabrics this enzyme catalyzes angiotensin transformation І in angiotensin ІІ, active vasoconstrictive agent, and splitting of bradykinin which is an active vazodilatator. Reduction of formation of angiotensin II and oppression of splitting of bradikinin lead to vasodilatation.

As angiotensin II also stimulates release of Aldosteronum, рамиприлат causes reduction of secretion of Aldosteronum. Patients of negroid race (the Afro-Caribbean origin) with arterial hypertension (population of which the low level of activity of a renin is, as a rule, characteristic) APF inhibitors on average had less expressed reaction to monotherapy, than at patients who are representatives of other races.

Hydrochlorothiazide. The hydrochlorothiazide is a thiazide diuretic. As for thiazide diuretics, the mechanism of their anti-hypertensive action meanwhile is finally not found out. They oppress a reabsorption of ions of sodium and chlorine in distal tubules. The strengthened renal excretion of these ions is followed by increase in an uropoiesis (owing to osmotic binding of water). Removal of potassium and magnesium also increases whereas removal of uric acid decreases. Possible mechanisms of hypotensive action of a hydrochlorothiazide consist in change of sodium balance, reduction of volume of extracellular liquid and plasma, change of resistance of renal vessels or decrease in reactions to noradrenaline and angiotensin II.

Pharmacodynamics. Ramipril. Use of a ramipril leads to considerable decrease in peripheric arterial resistance. As a rule, considerable changes of a renal plazmotok or glomerular filtration rate do not happen. At patients with arterial hypertension purpose of a ramipril leads to a lowering of arterial pressure both in horizontal, and in vertical position that is not followed by compensatory increase in heart rate.

At most of patients the anti-hypertensive effect occurs approximately in 1-2 hours after oral administration of a single dose of drug. The maximum effect after oral administration of a single dose usually occurs in 3-6 hours. The anti-hypertensive effect after reception of a single dose usually remains within 24 hours.

At prolonged treatment using a ramipril the maximum anti-hypertensive effect develops in 3-4 weeks. It is proved that at long therapy the anti-hypertensive effect remains within 2 years.

The sudden termination of reception of a ramipril does not render bystry and excessive increase in arterial pressure (a ricochet phenomenon).

Hydrochlorothiazide. As for a hydrochlorothiazide, the beginning of diuretic effect comes approximately in 2 hours and lasts for 6-12 hours, and the maximum effect occurs in 4 hours.

The anti-hypertensive effect occurs in 3-4 days of treatment and can lasts for 1 week after completion of treatment.

The anti-hypertensive effect is followed by insignificant increase in a glomerular filtration rate, vascular resistance of a renal bed and activity of a renin in plasma.

Simultaneous use of a ramipril and hydrochlorothiazide. Use of this combination leads to more considerable lowering of arterial pressure, than use of each of active ingredients separately. Simultaneous use of a ramiril and hydrochlorothiazide reduces potassium loss which accompanies diuretic effect probably owing to activity oppression system renin-angiotensin-aldosteronovoy. The APF inhibitor combination with thiazide diuretic renders synergistic effect, and also reduces risk of emergence of the hypopotassemia caused by use of the diuretic.

Pharmacokinetics. Ramipril.

Absorption. After oral administration ramiprit quickly it is soaked up from digestive tract. The maximum concentration of a ramipril in a blood plasma is reached within 1 hour. Absorption makes минумум 56%, and for it significantly existence of food in digestive tract does not influence. Bioavailability of an active metabolite of a ramiprilat after oral administration of drug in a dose of 2,5 mg and 5 mg makes 45%.

The maximum concentration in a blood plasma of a ramiprilat, the only active metabolite of a ramipril, are reached in 2-4 hours after reception of a ramipril. After use of usual doses of a ramipril of 1 times a day equilibrium concentration of a ramiprilat in a blood plasma is reached approximately in 4 days of treatment.

Distribution. Linkng with proteins of a blood plasma makes about 73% for a ramipril and 56% for a ramiprilat.

Metabolism. Ramipril is almost completely metabolized to a ramiprilat and to diketopiperazine ether, diketopiperazine acid and glucuronides of a ramipril and a ramiprilat.

Removal. Removal of metabolites happens preferential by renal excretion. Decrease in concentration of a ramiprilat in a blood plasma is multiphase. In view of powerful accumulative linkng with APF and slow dissociation from communication with enzyme рамиприлат has a prolongovanny terminal phase of removal at very low concentration in a blood plasma. The effective elimination half-life of a ramipril after reception of repeated doses of 5-10 mg of a ramipril of 1 times a day makes 13-17 hours and longer at use of low doses (1,25-2,5 mg). The difference is caused by the fact that ability of enzyme to binding with ramiprilaty is sating. After oral administration of a single dose of a ramipril ramiprit, its metabolite were not found in breast milk. However it is unknown what effect has reception of repeated doses.

Patients with a renal failure (see the section "Route of Administration and Doses"). At patients with a renal failure renal excretion of a ramiprilat is lowered, and the renal clearance of a ramiprilat is proportional to clearance of creatinine. It leads to increase in concentration of a ramiprilat in plasma which decreases more slowly, than at persons with normal function of kidneys.

Patients with an abnormal liver function (see the section "Route of Administration and Doses"). At patients with an abnormal liver function transformation of a ramipril in рамиприлат happens more slowly because of decrease of the activity of hepatic esterases. At such patients increase in levels of a ramipril in a blood plasma is observed. However the maximum concentration of a ramiprilat in a blood plasma of these patsint did not differ from such at persons with normal function of a liver.

Hydrochlorothiazide.

Absorption. After oral administration from digestive tract 70% of a hydrochlorothiazide are soaked up. The maximum concentration of a hydrochlorothiazide in a blood plasma I am reached within 1,5-5 hours.

Distribution. For a hydrochlorothiazide linkng with proteins of a blood plasma makes about 40%.

Metabolism. The hydrochlorothiazide is metabolized in a liver in very insignificant quantities.

Removal. The hydrochlorothiazide is removed by kidneys almost completely (> 95%) in not changed look; 50-70% of a single dose are removed within 24 hours. The elimination half-life makes 5-6 hours.

Patients with a renal failure (see the section "Route of Administration and Doses"). At patients with a renal failure renal excretion of a hydrochlorothiazide is lowered, and the renal clearance of a hydrochlorothiazide is proportional to clearance of creatinine. It leads to increase in concentration of a hydrochlorothiazide in plasma which decreases more slowly, than at persons with healthy kidneys.

Patients with an abnormal liver function (see the section "Route of Administration and Doses"). At patients with cirrhosis the pharmacokinetics of a hydrochlorothiazide does not undergo essential changes.

Any research of pharmacokinetics of a hydrochlorothiazide at patients with heart failure was not conducted.

Ramipril and hydrochlorothiazide. Simultaneous use of a ramipril and hydrochlorothiazide did not influence their bioavailability. The combined drug can be considered to bioequivalent drugs which contain separate active ingredients.                                                                            

Pharmaceutical characteristics

 

Main physical and chemical properties:

tablets of 5 mg / 25 mg: tablets of white or almost white color, a round form with a flat surface with risky and a facet;

tablets of 2,5 mg / 12,5 mg: tablets of white or almost white color, a round form with a biconvex surface with risky or tablets of white color, a round form with a flat surface with risky and a facet.

Indications to use:

Treatment of essential hypertensia at patients to whom the combination therapy is recommended (ramiprit also a hydrochlorothiazide).

Route of administration and doses:

For oral administration.

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

Drug can be accepted to, in time and after food as meal does not influence bioavailability of drug (see the section "Pharmacokinetics"). It is necessary to swallow of tablets whole, washing down with water. They cannot be chewed or crushed.

Adults. The dose should be korrigirovat individually, depending on severity of arterial hypertension and existence of other concurrent factors of risk. Use of the fixed combination of a ramipril and a hydrochlorothiazide is, as a rule, recommended only after titration of doses of each of its separate components.

Begin treatment with the lowest possible dose. If necessary the dose can be increased gradually before achievement of a target indicator of arterial pressure. The maximum admissible dose makes 10 mg of a ramipril and 50 mg of a hydrochlorothiazide a day.

Special groups of patients.

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

Patients with a renal failure. Due to the existence of a hydrochlorothiazide component drug is contraindicated to patients with a heavy renal failure (clearance of creatinine <30 ml/min.) (see the section "Contraindications"). Lower doses of drug can be shown to patients with renal failures. Patients with clearance of creatinine of 30-60 ml/min. should be treated only using the lowest dose of the fixed combination рамиприла / a hydrochlorothiazide after monotherapy ramiprily. The maximum admissible daily dose makes 5 mg of a ramipril and 25 mg of a hydrochlorothiazide.

Patients with an abnormal liver function. At patients with an easy and moderate abnormal liver function treatment by drug should be begun only under careful medical observation. The maximum daily dose in such cases makes 2,5 mg of a ramipril and 12,5 mg of a hydrochlorothiazide. Drug is contraindicated at a heavy abnormal liver function (see the section "Contraindications").

Patients of advanced age. The initial dose has to be lower, and further titration of a dose should be carried out more gradually in connection with higher probability of emergence of side reactions.

Features of use:

Special groups of patients

Patients who have a high risk of developing of arterial hypotension.

Patients with a superactivity system renin-angiotensin-aldosteronovoy. At patients with a superactivity renin-angiotensin-aldosteronovoy of system exists risk of a sudden considerable lowering of arterial pressure and deterioration in function of kidneys owing to oppression of APF. It especially concerns cases when APF inhibitor or the accompanying diuretic is appointed for the first time or for the first time raise a dose. The increase in activity system renin-angiotensin-aldosteronovoy demanding medical observation, including constant control of arterial pressure can be expected, for example, at patients:
with heavy arterial hypertension;
with congestive heart failure;
with hemodynamically significant obstruction of ways of inflow or outflow of blood from a left ventricle (for example with a stenosis of the aortal or mitral valve);
with a unilateral renal artery stenosis in the presence of other functioning kidney;
with the expressed or latent shortage of liquid or electrolytes (including those patients who receive diuretics);
with cirrhosis and/or ascites;
by which carry out extensive surgical interventions or during anesthesia using drugs which can cause arterial hypotension.

Before an initiation of treatment it is, as a rule, recommended to carry out correction of dehydration, a hypovolemia or shortage of electrolytes (however at patients with heart failure such corrective measures should be weighed carefully from the point of view of risk of reloading volume).

Surgical intervention. If it is possible, then treatment by APF inhibitors, such as ramiprit, it is necessary to stop in 1 day prior to carrying out surgical intervention.

Patients who have a risk of developing of cardiac or cerebral ischemia in case of acute arterial hypotension. In an initial phase of treatment the patient needs careful medical observation.

Primary hyper aldosteronism. A combination ramiprit + the hydrochlorothiazide is not choice drug at treatment of primary hyper aldosteronism. However if     ramiprit + a hydrochlorothiazide apply to the patient with primary hyper aldosteronism, it is necessary to control carefully potassium level in a blood plasma.

Patients of advanced age. See the section "Route of Administration and Doses".

Patients with liver diseases. Patients with diseases of a liver have disturbances of electrolytic balance arising owing to treatment by diuretics, such as a hydrochlorothiazide, can lead to development of hepatic encephalopathy. When developing hepatic encephalopathy treatment should be cancelled immediately.

Control of function of kidneys. Function of kidneys needs to be controlled to and during performing treatment and as appropriate to korrigirovat a dose, especially in the first weeks of treatment. Patients with a renal failure (see the section "Route of Administration and Doses") need especially careful control. There is a risk of deterioration in renal function, especially at patients with congestive heart failure or after renal transplantation.

Patients with a renal failure. At patients with a disease of kidneys of a tiazida can provoke sudden emergence of uraemia. Patients with a renal failure can have cumulative effects of active ingredients. If progressing of renal dysfunction becomes obvious what points increase in amount of residual nitrogen to, then it is necessary to weigh carefully the decision concerning treatment continuation. It is necessary to consider the possibility of the termination of treatment by diuretic (see the section "Contraindications").

Disturbances of electrolytic balance. As well as at all patients receiving treatment by diuretics it is necessary regularly, through the corresponding periods to measure the level of electrolytes in a blood plasma. Tiazida, including a hydrochlorothiazide, disturbances of water and electrolytic balance (a hypopotassemia, a hyponatremia and a gipokhloremichesky alkalosis) can cause.

Though at use of thiazide diuretics the hypopotassemia can develop, simultaneous use of a ramipril can reduce the hypopotassemia caused by diuretic. The risk of emergence of a hypopotassemia is the highest at patients with cirrhosis, patients with the increased diuresis, the patients receiving insufficient amount of electrolytes and also at patients who at the same time receive treatment by corticosteroids and AKTG (see the section "Interaction with Other Medicines and Other Types of Interactions"). Within the first week of treatment it is necessary to determine initial levels of potassium in a blood plasma. At identification of reduced levels of potassium it is necessary to carry out correction.

There can be a dillyutsionny hyponatremia. Low levels of sodium at first can be asymptomatic therefore regular determination of its quantity is very important. At patients of advanced age and patients with cirrhosis such analyses should be carried out much more often.

Was prodemonstrovano that tiazida increase removal of magnesium with urine that can lead to a gipomagneziyemiya.

Hyperpotassemia. At some patients who received APF inhibitors emergence of a hyperpotassemia was observed. Patients with a renal failure, elderly people (70 years are more senior), patients with not treated or insufficiently controlled diabetes mellitus or those who accept potassium salts, kaliysberegayushchy diuretics, and also other active agents increasing the content of potassium in a blood plasma or patients with such states as dehydration, an acute cordial decompensation or a metabolic acidosis treat risk group of emergence of a hyperpotassemia. If simultaneous use of the above-stated drugs is shown, it is regularly recommended to control potassium level in a blood plasma (see the section "Interaction with Other Medicines and Other Types of Interactions").

Hypercalcemia. The hydrochlorothiazide stimulates a calcium reabsorption in kidneys that can lead to emergence of a hypercalcemia. It can distort results of tests which carry out with a research objective of function of epithelial bodies.

Quincke's disease. At patients who received APF inhibitors such as ramiprit, the Quincke's disease was noted (see the section "Side reactions"). At emergence of a Quincke's disease treatment Ramizes Côme it is necessary to stop and begin with drug emergency treatment immediately. The patient has to be under medical observation within at least 12-24 hours and can be written out only after total disappearance of symptoms.

At the patients receiving APF inhibitors, such as Ramizes Côme cases of a Quincke's disease of intestines were noted (see the section "Side reactions"). These patients complained of an abdominal pain (with nausea/vomiting or without them).

Anaphylactic reactions during desensitization. At use of APF inhibitors the probability of emergence and weight of anaphylactic and anaphylactoid reactions to poison of insects and other allergens increases. Before carrying out desensitization it is necessary to stop temporarily administration of drug Ramizes Côme.

Neutropenia/agranulocytosis. Cases of a neutropenia/agranulocytosis were noted seldom. Also it was reported about oppression of function of marrow. For the purpose of identification of a possible leukopenia it is recommended to control quantity of leukocytes in blood. It is desirable to carry out more frequent control in an initiation of treatment and for patients with an impaired renal function, patients with the accompanying collagenoses (for example a system lupus erythematosus or a scleroderma) and for those who at the same time accept other medicines which can cause changes of a picture of blood (see the sections "Interaction with Other Medicines and Other Types of Interactions" and "Side reactions").

Ethnic differences. APF inhibitors cause a Quincke's disease in patients of negroid race much more often, than in representatives of other races. As well as at use of other APF inhibitors, hypotensive action of a ramipril can be less expressed at patients of negroid race, than at representatives of other races. It can be caused by the fact that at black patients with arterial hypertension arterial hypertension with low activity of a renin is more often observed.

Athletes. The hydrochlorothiazide can yield a positive take when carrying out a doping test.

Metabolic and endocrine effects. Treatment of a tiazidama can cause disturbance of tolerance to glucose. In certain cases dose adjustment of insulin and peroral hypoglycemic means can be necessary for patients with a diabetes mellitus. At treatment of a tiazidama the latent form of a diabetes mellitus can develop into manifest.

Therapy by thiazide diuretics can be followed by increase in levels of cholesterol and triglycerides. At some patients use of thiazide diuretics can provoke development of a hyperuricemia or bad attack of gout.

Cough. At use of APF inhibitors it was reported about developing of cough. As a rule, this cough is unproductive, long and disappears after the treatment termination. At differential diagnosis of cough it is necessary to remember possibility of the cough caused by APF inhibitors.

Others. Patients, irrespective of existence in the anamnesis of an allergy or bronchial asthma, can have hypersensitivity reactions. It was reported about a possibility of an aggravation or activation of a system lupus erythematosus.

To syncope. If the patient has a state to a syncope, it should stop treatment and to see a doctor.

Ability to influence speed of response at control of motor transport or work with other mechanisms

 

Some side effects (for example symptoms of a lowering of arterial pressure, such as dizziness) can break ability of the patient to concentration of attention and speed of its reaction. It especially concerns an initiation of treatment or transition to use of other drugs.

Within several hours after reception of the first dose or further increase in a dose it is undesirable to manage the vehicle or to work with other mechanisms.

Side effects:

Profile of safety of drug Ramizes Côme contains data on side effects which arise owing to arterial hypotension and/or reduction of OTsK owing to increase in a diuresis. Ramiprit active ingredient can cause constant cough while active ingredient a hydrochlorothiazide can break metabolism of glucose, fats and uric acid. Both substances have irreversible effect on potassium level in a blood plasma. The Quincke's disease or anaphylactoid reactions, abnormal liver functions or kidneys, pancreatitis, heavy reactions belong to heavy side reactions from skin and a neutropenia/agranulocytosis.

Frequency of emergence of side effects is classified as follows: very often (≥ 1/10); often (from ≥ 1/100 to <1/10); infrequently (from ≥ 1/1 000 to <1/100); seldom (from ≥ 1/10 000 to < 1/1 000); very seldom (< 1/10 000); it is unknown (it cannot be calculated according to the available data). In each group side reactions are presented as reduction of degree of their gravity.

 

Classes of systems of bodies	Often	Infrequently		Very seldom	It is unknown
From cardiovascular system		Myocardium ischemia, including stenocardia; tachycardia; arrhythmia; feeling of the strengthened heartbeat; peripheral hypostases; arterial hypotension, orthostatic hypotension, syncope, heat inflows			Myocardial infarction; thrombosis owing to considerable reduction OTsK, a vascular stenosis, hypoperfusion, Reynaud's syndrome, a vasculitis
From blood and lymphatic system		Reduction of quantity of leukocytes, reduction of quantity of erythrocytes, decrease in level of hemoglobin, hemolitic anemia, decrease in quantity of thrombocytes			Oppression of function of marrow; neutropenia, including agranulocytosis, pancytopenia, eosinophilia; a gemokontsen-tration at a liquid delay
From a nervous system	Headache, dizziness	Paresthesia, tremor, balance disturbance, feeling of burning, dysgeusia, ageusia			Cerebral ischemia, including ischemic stroke and tranzi-even ischemic attack; disturbance of psychomotor functions, parosmiya
From organs of sight		Vision disorders, including a sight illegibility, conjunctivitis			Xanthopsia, reduction of lacrimation owing to action of a hydrochlorothiazide
From acoustic organs and a labyrinth		Ring in ears			Hearing disorder
From respiratory system	The unproductive irritating cough, bronchitis	Sinusitis, short wind, nose congestion			Bronchospasm, including exacerbation of bronchial asthma; allergic alveolitis; not cardiogenic fluid lungs owing to action of a hydrochlorothiazide
From a digestive tract		The inflammatory phenomena in a digestive tract, digestive disturbances, an abdominal pain, dyspepsia, gastritis, nausea, a lock, an ulitis owing to action of a hydrochlorothiazide	Vomiting, aphthous stomatitis, glossitis, diarrhea, dryness in a mouth		Pancreatitis (in isolated cases it was reported about lethal outcomes at use of APF inhibitors), increase in level of enzymes of a pancreas, Quincke's disease of thin intestines, sialadenitis owing to action of a hydrochlorothiazide
From kidneys and urinary tract		Renal failures, including an acute renal failure; increase in an uropoiesis; increase in level of urea in blood and creatinine			Deterioration in a current of a background proteinuria, intersticial nephrite owing to action of a hydrochlorothiazide
From skin and its derivatives		Quincke's disease; in very exceptional cases – disturbance of passability of respiratory tracts owing to a Quincke's disease which can lead to a lethal outcome; psoriasis dermatitis; hyperhidrosis; dieback, in particular makulo-papular; itch; alopecia			Stephens-Johnson's syndrome, multi-formnaya erythema, aggravation of a course of psoriasis, exfoliative dermatitis, photosensitivity, онихолизис, a pemfigoidny or lichenoid dieback or an enantema, a small tortoiseshell, a system red lupus owing to action of a hydrochlorothiazide
From a musculoskeletal system and connecting fabric		Mialgiya			Arthralgia, muscular spasms, muscular weakness, musculoskeletal constraint, tetanic spasms owing to action of a hydrochlorothiazide
Metabolic and alimentary frustration	Diabetes mellitus decompensation, reduction of tolerance to glucose, increase in level of glucose in blood, increase in level of uric acid, an exacerbation of gout, increase in level of cholesterol and/or triglycerides owing to action of a hydrochlorothiazide	Anorexia, loss of appetite, reduction of level of potassium			Decrease in level of sodium in plasma, glucosuria, metabolic alkalosis, hypochloraemia, hypomagnesiemia, hypercalcemia, dehydration owing to action of a hydrochlorothiazide
Disturbances of the general state	Fatigue, adynamy	Stethalgia, pyrexia
From immune system					On ramiprit anaphylactic or anaphylactoid reactions or anaphylactic reactions to a hydrochlorothiazide, increase in level of antinuclear antibodies
From a liver and biliary tract		Cholestatic or cytolytic hepatitis (in very exceptional cases – with a lethal outcome), increase in level of liver enzymes and/or conjugates of bilirubin, calculous cholecystitis owing to action of a hydrochlorothiazide			Acute liver failure, cholestatic jaundice, damage of hepatic cells
From reproductive system and mammary glands		Tranzitorny erectile impotence			Decrease in a libido, gynecomastia
From mentality		Decrease in mood, apathy, uneasiness, nervousness, sleep disorder, including drowsiness			Confusion of consciousness, disturbance of attention

 

Interaction with other medicines:

Contraindicated combinations.

Methods of extracorporal therapy therefore there is a contact of blood with negatively loaded surfaces, such as dialysis or haemo filtering with имембран from polyacrylonitrile) and аферез lipoproteins of low density with use of a dextran of sulfate – because of the increased risk of development of heavy anaphylactoid reactions (see the section "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 anti-hypertensive means.

The combinations demanding extra care.

The potassium salts, heparin, kaliysberegayushchy diuretics and other active agents increasing potassium level in a blood plasma (including antagonists of angiotensin ІІ, Trimethoprimum, такролимус, cyclosporine). There can be a hyperpotassemia therefore it is necessary to control carefully potassium level in a blood plasma.

Anti-hypertensive medicines (for example diuretics) and other active ingredients which can reduce arterial pressure (for example nitrates, tricyclic antidepressants, anesthetics, alcohol, Baclofenum, альфузозин, доксазозин, Prazozinum, тамсулозин, теразозин). Increase in risk of developing of arterial hypotension is possible (see the section "Route of Administration and Doses" concerning diuretics).

Angiotonic sympathomimetics and other active ingredients (for example Epinephrinum) which can reduce anti-hypertensive effect of a ramipril. It is recommended to control arterial pressure regularly.

Allopyrinolum, immunodepressants, corticosteroids, procaineamide, cytostatics and other substances which can cause changes of a picture of blood. The probability of emergence of hematologic reactions is increased (see the section "Features of Use").

Lithium salts. As APF inhibitors are capable to reduce lithium excretion, it can lead to increase in toxicity of lithium. It is regularly necessary to control lithium level in a blood plasma. At simultaneous use of thiazide diuretics the risk of emergence of toxicity of lithium can increase and raise already increased risk of emergence of toxicity of lithium caused by use of APF inhibitors. Therefore it is not recommended to apply at the same time a combination рамиприл / a hydrochlorothiazide and lithium.

Antidiabetic means, including insulin. There can be hypoglycemic reactions. The hydrochlorothiazide can weaken effect of antidiabetic drugs. Therefore at the beginning of simultaneous use of these drugs it is necessary to control especially carefully glucose level in blood.

Non-steroidal anti-inflammatory drugs (NPVP) and acetylsalicylic acid.: Decrease in anti-hypertensive effect of drug Ramizes Côme is expected. Moreover, simultaneous use of APF and NPVP inhibitors can be followed by the increased risk of a renal failure and increase in level of potassium in blood.

Peroral anticoagulants. At simultaneous use with a hydrochlorothiazide the anticoagulating effect can be weakened.

Corticosteroids, AKTG, Amphotericinum In, карбеноксолон, the use of a large number of a liquorice, purgatives (at prolonged use) and other potassiumuretic drugs or active ingredients which reduce amount of potassium in a blood plasma. The increased risk of emergence of a hypopotassemia.

The foxglove drugs, active ingredients capable to increase QT interval duration, antiarrhytmic means. In the presence of disturbances of electrolytic balance (for example hypopotassemias, hypomagnesiemia) pro-arhythmic effects can amplify, and antiarrhytmic effects − to be weakened.

Methyldopa. The hemodialysis is possible.

Holestiramin or other ion-exchange resins which apply inside. Disturbance of absorption of a hydrochlorothiazide. Sulphonamide diuretics it is necessary to accept a minimum in 1 hour prior to or in 4-6 hours after the use of these drugs.

Kurarepodobny muscular relaxants. Strengthening and increase in duration of action of muscular relaxants is possible.

Salts of calcium and drugs which increase calcium level in a blood plasma. At simultaneous use with a hydrochlorothiazide it is possible to expect increase in concentration of calcium in a blood plasma therefore it is necessary to control carefully calcium level in plasma.

Carbamazepine. There is a risk of emergence of a hyponatremia owing to strengthening of effect of a hydrochlorothiazide.

The contrast agents containing iodine. In case of dehydration caused by use of diuretics, including a hydrochlorothiazide there is an increased risk of development of an acute renal failure, especially in case considerable doses of the contrast agent containing iodine are entered.

Penicillin. Excretion of a hydrochlorothiazide occurs in distal tubules of nephron in this connection excretion of penicillin decreases.

Quinine. The hydrochlorothiazide reduces quinine excretion.

Contraindications:

Hypersensitivity to a ramipril or to other APF inhibitors, a hydrochlorothiazide, other thiazide diuretics, sulfonamides or to any of the excipients which are a part of drug.

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 ІІ).

Use of methods of extracorporal therapy therefore there is a contact of blood with negatively charged surfaces (see the section "Interaction with Other Medicines and Other Types of Interactions").

Bilateral stenosis of renal arteries or unilateral renal artery stenosis in the presence of the only functioning kidney.

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

Clinically significant disturbances of electrolytic balance which course can worsen during treatment by drug (see the section "Features of Use").

Heavy abnormal liver function, hepatic encephalopathy, cholestasia.

Overdose:

Symptoms of overdose of APF inhibitors is the excessive peripheral vazodilatation (with the expressed arterial hypotension, shock), bradycardia, disturbance of electrolytic balance, a renal failure, disturbance of a cordial rhythm, consciousness disturbance, including a coma, epileptic attacks, paresis and paralytic intestinal impassability.

The overdose of a hydrochlorothiazide can lead to an acute ischuria at the patients inclined to it (for example at patients with a prostate hyperplasia).

It is necessary to watch a condition of the patient attentively.

Symptomatic treatment and supporting. Primary detoxication (a gastric lavage, administration of adsorbents), and also measures directed to recovery of a stable hemodynamics, including introduction of agonists alfa-1 adrenoceptors or angiotensin ІІ (Angiotensinamidum) belong to medical actions. Ramiprilat, an active metabolite of a ramipril, is badly brought by a hemodialysis. Removal from an organism of thiazide diuretics by means of dialysis insignificant.

If nevertheless carrying out dialysis or haemo filtering is provided, it is necessary to consider danger of development of anaphylactoid reactions at use of high-flowing membranes (see the section "Features of Use").

Use during pregnancy or feeding by a breast

Pregnancy. APF inhibitors can cause a disease and death of a fruit and the newborn if they are appointed to pregnant women. Several tens of cases in the different countries were described in literature. When diagnosing pregnancy drug use Ramizes Côme should be stopped as soon as possible.

In isolated cases (less than 1 on each one thousand pregnancies), when there is no an alternative for therapy by APF inhibitor, the pregnant woman should be informed on possible harming a fruit. For assessment of fetation, a state and volume of amniotic liquid it is necessary to conduct serial ultrasonic examinations of the pregnant woman.

At identification of an oligogidramnion it is necessary to stop administration of drug Ramizes Côme if it is not vital for the woman. Depending on duration of gestation there can be useful a beznagruzochny test (BNT) and (or) definition of the profile of biophysical parameters (PBP). If safety for a fruit, as well as earlier, remains, then it is necessary to think of conducting load test on labor pains (PRS). Both patients, and doctors should know what олигогидрамнион can remain not distinguished until the irreversible damage of a fruit is created.

Strict observation of children with existence of inutero of APF inhibitors in the anamnesis is necessary for detection of arterial hypotension, an oliguria and a hyperpotassemia. If the oliguria develops, it is necessary to watch the arterial pressure and renal perfusion carefully. The exchange transfusion or dialysis as means can be necessary for reduction of arterial hypotension and (or) recovery of the broken renal function. However the available brief experience on holding these procedures was not followed by essential clinical result. Remains to unknown whether it is possible to remove by means of a hemodialysis from an organism ramiprit and рамиприлат.

As drug use Ramizes Côme during pregnancy can render harm to a fruit which is in a development stage, or even to cause his death, it is necessary to advise women of reproductive age that they immediately reported to the doctor about pregnancy approach.

Data of researches. It is unknown whether the exposure relating to the I trimester of pregnancy can affect result of fetation. Use of APF inhibitors during II and III trimesters of pregnancy is connected with defeat of a fruit and the newborn, including arterial hypotension, a hypoplasia of a skull of the newborn, an anury, a reversible or irreversible renal failure and death. It is also registered and олигогидрамнион which probably developed owing to deterioration in renal function of a fruit; олигогидрамнион in such cases was followed by development of contractures of extremities of a fruit, craniofacial deformations and hypoplasias of lungs. Premature births and an open arterial channel though it is unknown whether these phenomena are caused by APF inhibitor reception were also registered.

Feeding by a breast. Drug Ramizes Côme is contraindicated during feeding by a breast. The quantity of a ramipril and hydrochlorothiazide which gets to breast milk is such that at use of therapeutic doses of a ramipril and hydrochlorothiazide the child who is on breastfeeding can undergo their influence. As there are no sufficient data concerning use of a ramipril during feeding by a breast, it is desirable to prefer as other medicines which use during a lactation is safer. The hydrochlorothiazide gets into breast milk. Use of a hydrochlorothiazide to mothers nursing was followed by reduction or even complete cessation of production of milk. There can be hypersensitivity to sulfonamide derivatives, a hypopotassemia and a kernicterus. As use of both active ingredients can result in heavy undesirable effects at children who are on breastfeeding, it is necessary to make the decision on the termination or breastfeeding, or treatment, depending on importance of this therapy for mother.

Children

Drug is not recommended to be used to children (aged up to 18 years) as there are not enough data on its efficiency and safety for such patients.

Storage conditions:

 Period of validity 2 years. Not to use drug after the termination of the period of validity specified on packaging. To store at a temperature not above 25 °C. To store in  the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister. On 3 blisters in a pack.