Hartil®-A 2.5 mg / 12.5 mg tablets coated 28's
- $17.80
Sku:
15318e900c6d
The instruction for medical use
of HARTIL®-medicine D
Trade name
of Hartil® - D
International unlicensed name
Is not present
the Dosage form
of Tablet 2.5mg/12.5 of mg, 5mg/25 mg
Structure
One tablet 2.5mg/12.5 of mg contains
active agents:
the hydrochlorothiazide of 12.5 mg ramiprit 2.5 mg
One tablet 5mg/25mg contains
active agents: ramiprit 5 mg
a hydrochlorothiazide of 25 mg,
excipients: lactoses monohydrate, a gipromelloza, krospovidon, cellulose microcrystalline, the sodium stearylfumarating.
The description
of Tablet 2.5mg/12.5mg - white, oval, with risky on both parties, on one party of a tablet – an engraving of numbers 2.5 and 12.5 on different sides from risks
of Tablet 5mg/25mg - white, oval, with risky on both parties, on one party of a tablet – an engraving of numbers 5 and 25 on different sides from risks
Pharmacotherapeutic group
the Enzyme Angiotensin-converting (EAC) inhibitors in a combination with diuretics.
The code of automatic telephone exchange C09BA05
The pharmacological
Ramipril Pharmacokinetics properties after intake is quickly soaked up from digestive tract (50-60% of the dose accepted inside). Food does not influence extent of absorption, but slows down drug absorption. Ramipril is pro-medicine. Is exposed to metabolism of the first passing through a liver with formation of an active metabolite - the ramiprilat (inhibits AKF 6 times more actively, than ramiprit) and inactive metabolites. Among the known inactive metabolites - diketopiperazine ether, diketopiperazine acid and also glucuronides of a ramipril and the ramiprilat. Bioavailability after intake 2.5-5mg the ramiprila makes about 20%, for the ramiprilat about 45%. The maximum concentration of a ramipril in blood plasma is reached within 1 hour, and the ramiprilat within 2-4 hours after intake. Concentration increase in blood of a ramipril and the ramiprilat at increase in a dose, but are not strictly proportional to it. Linking with proteins of plasma for a ramipril - 73%, the ramiprilat - 56%. Decrease in concentration of the ramiprilat in plasma has multiphase character. A phase of initial distribution and removal with elimination half-life of the ramiprilat 2-4 hours. Then an intermediate phase with elimination half-life of the ramiprilat of 9-18 hours. A final phase of removal from very low concentration of the ramiprilat in plasma and long elimination half-life - more than 50 hours. The final phase is connected with slow dissociation of the ramiprilat from communication with AKF receptors. Steady concentration of the ramiprilat in plasma after single daily dose of a ramipril in a dose of 5 mg is reached approximately by 4th day. Stationary concentration of the ramiprilat are slightly higher, than observed after reception of the first dose of a ramipril, especially in low doses (2.5 mg), but the distinction is not clinically significant. After multiple dose of daily doses of a ramipril 5-10mg the therapeutic range of elimination half-life of concentration of the ramiprilat is 13-17 hours (the parameter influencing the choice of a dose). After intake about 60% of a dose are removed with urine (mainly in the form of metabolites), about 40% with a stake, less than 2% are allocated with urine in not changed look.
In renal failures the removal of a ramipril and its metabolites slows down in proportion to decrease to the clearance of creatinine (CC). It leads to increase in plasma concentration of the ramiprilat and their slower decrease unlike patients with normal function of kidneys.
In an abnormal liver function the reception of a ramipril in high doses (10 mg) slows down transformation of a ramipril in ramiprilat, concentration of a ramipril in blood plasma can increase by 3 times, at the same time the maximum concentration in blood plasma of the ramiprilat does not change.
At reception of a ramipril in a dose of 5 mg of 1 times a day by the patients with heart failure and arterial hypertension after 2 weeks of treatment did not observe clinically significant accumulation of a ramipril and the ramiprilat.
At elderly people the drug pharmacokinetics significantly does not change.
Ramipril is excreted with breast milk.
The hydrochlorothiazide after intake is quickly soaked up from gastrointestinal (60-80%). Bioavailability of-70%. The average time of achievement of the maximum concentration in plasma-1.5-4 hours. Linking with proteins of blood plasma about 40-60%. Absorption speed practically does not depend on a dose. Elimination half-life - 6-8 hours. It is not metabolized in a liver, removed mainly by kidneys: 95% - in not changed look and about 4% - in the form of a metabolite. In an hour after intake it is noted in urine and during 24 h about 50-70% of the entered dose are allocated. Removal with bile is insignificant. The hydrochlorothiazide in small amounts is excreted with breast milk.
The renal clearance of a hydrochlorothiazide finds high correlation with clearance of creatinine. At patients at whom the glomerular filtration rate (GFR) less than 10 ml/min. only 10% of the accepted dose are defined in urine.
In a renal failure the excretion of a hydrochlorothiazide decreases and extended elimination half-life.
Significant changes of pharmacokinetics in cirrhosis are not noted.
Regular reception of a combination of a ramipril and hydrochlorothiazide does not influence or slightly affects bioavailability of each of them. Use of the combined tablet of drug Hartil-D 5mg/25mg bioekvivalentno to a concomitant use of its ingredients in separate dosage forms.
The hypotensive effect begins in 1-2 hours after intake of a single dose of drug, the maximum effect develops in 3-6 hours after reception and remains within 24 hours. At daily use the hypotensive activity gradually increases within 3-4 weeks and remains at long-term treatment within 1-2 years. At short-term cancellation the significant increase in arterial blood pressure is not observed (there is no withdrawal).
A pharmacodynamics
Hartil-D - the combined antihypertensive drug which part are AKF inhibitor (ramiprit) also thiazide diuretic (hydrochlorothiazide). Has antihypertensive and diuretic effect.
Ramiprilat, an active metabolite of a ramipril, competitively inhibits activity the angiotensin-the converting enzyme (ACE), reduces the speed of transformation of angiotensin I into angiotensin II. Reduction of concentration of angiotensin II is resulted by secondary increase in activity of renin of plasma due to elimination of negative feedback at release of renin and direct decrease in secretion of Aldosteronum. Reduces degradation of bradykinin and increases synthesis of prostaglandins. Reduction of formation of angiotensin II and increase in activity of bradykinin leads to vasodilatation and makes the contribution to cardioprotective and endotelioprotektivny action of a ramipril. Thanks to the high lipophilicity, ramiprit in comparison with enalapril gets into fabrics better that well influences interaction about angiotensin - the converting system of various fabrics and bodies and also the AKF level in plasma. Drug causes antihypertensive effect both in position of the patient standing, and in a prone position without compensatory increase in heart rate. Thanks to vasodilating action reduces the general peripheric vascular resistance (afterload), pressure in pulmonary capillaries (preloading) and resistance in pulmonary vessels. Causes increase in minute volume of blood and increase in tolerance to loadings. Usually does not cause significant changes in a renal blood-groove (in some cases it raises) and glomerular filtration rate. At long-term treatment contributes to involution of a hypertrophy of a myocardium at patients with arterial hypertension and reduces the frequency of arrhythmias at reperfusion of a myocardium. Improves blood supply of an ischemic myocardium. Reduces aggregation of thrombocytes. Prevents the contractilny changes of an endothelium of vessels caused by a high-cholesteric diet.
The hydrochlorothiazide suppresses a reabsorption of sodium and chlorine in distal tubules of nephron. The strengthened renal excretion of these ions is followed by the raised uropoiesis (because of osmotic binding of water). Increases removal of potassium ions, magnesium, bicarbonate, delays removal of calcium ions, uric acid. The mechanism of antihypertensive action is definitely not installed and perhaps consists of the next moments: change of sodium balance, reduction of volume of extracellular water and plasma, change of resistance of renal vessels, decrease in reactions to noradrenaline and angiotensin II. At long-term treatment the lowering of arterial pressure is reached at reception of smaller doses, than it is necessary for achievement of diuretic effect. The lowering of arterial pressure is followed by small increase in SKF, vascular resistance of the renal course and activity of renin in plasma. Single dose of high doses of a hydrochlorothiazide leads to reduction of volume of plasma, SKF, renal blood-groove and average arterial blood pressure. At long reception of small doses the volume of plasma remains reduced while the minute volume and SKF return to the initial level preceding an initiation of treatment. Average arterial blood pressure and system vascular resistance remain reduced. Thiazide diuretics can break development of breast milk.
Use of a combination of a ramipril and hydrochlorothiazide leads to more significant decrease in the ABP in comparison with monotherapy by each drug separately and allows to maintain antihypertensive effect of drug at least during 24 h. Antihypertensive effects of both substances supplement each other, and the gipokaliyemichesky effect of a hydrochlorothiazide decreases ramiprily.
Indications
- treatment of arterial hypertension when use
of combination therapy
the Route of administration is required and doses
Is recommended to take the drug on 1-2 tablet a day at the same time, it is preferable in the morning. Tablets can be halved, breaking after risk, washing down with a large amount of liquid, irrespective of meal. The dose of drug and duration of therapy are established individually. Treatment of arterial hypertension should not be begun with use of the fixed combination. Before therapy it is necessary to determine by the drug Hartil-D the corresponding dose of separate components.
The initial recommended dose – tablets 2.5mg/12.5mg. It is possible to increase a dose with an interval not less than 3 weeks. A maintenance dose - tablets 2.5mg/12.5mg or 5mg/25mg. The maximum daily dose - 10 mg of a ramipril and 50 mg of a hydrochlorothiazide.
Patients of advanced age and patients with a renal failure (KK of 30 - 60 ml/min.) Hartil-D should apply only after preliminary selection of doses of each of components. The maintenance dose has to be lower.
To patients with a renal failure (KK of 30-60 ml/min.) an initial dose - 1.25 mg of a ramipril and 6.25 mg of a hydrochlorothiazide. The recommended daily dose - tablets 2.5mg/12.5mg 1 of times a day. The maximum daily dose - tablets 5mg/25mg, divided into 2 receptions (in the morning and in the evening).
Patients with a slight or moderate abnormal liver function Hartil-D should apply only after preliminary selection of a dose of a ramipril.
Side effects
Often of 1 - 9.9% (> 1/100,
- dizziness, fatigue, a headache, weakness
- arterial hypotension (in an initiation of treatment and after increase in a dose)
- bronchitis, the dry cough passing after drug withdrawal
- nausea, vomiting, an abdominal pain, digestion disturbance
- rash on skin and mucous
- a hypopotassemia, a hyperglycemia, increase in level of uric acid, urea and
creatinine in blood
- gout
Infrequently of 0.1 - 0.9% (> 1/1000,
- drowsiness, apathy, nervousness
- a hyperpotassemia, a hyponatremia, a hypomagnesiemia, a hyperchloremia,
a hypercalcemia
- a proteinuria
- conjunctivitis, blepharitis
- a photosensitization
- an itching, urticaria
- peripheral hypostases (in ankle joints)
- spasms in epigastric area, thirst, a loss of appetite, a constipation, diarrhea,
- decrease in potency
is rare 0.01 - 0.09% (> 1/10000,
- uneasiness, confusion of consciousness, a sleep disorder, sonitus, faints,
concern, paresthesias
- disturbance of sense of smell, taste
- balance disturbance
- a disorder of vision, passing short-sightedness
- a thrombembolia
- short wind
- rhinitis, sinusitis, pharyngitis, a glossitis, a bronchospasm (at patients with
hyperexcitability of a tussive reflex), eosinophilic pneumonia
- dryness in a mouth, vomiting, inflammation of mucous membranes of a mouth and language, a sialadenitis
- feeling of rush of blood with feeling of heat on certain sites of skin,
the strengthened sweating, swelled
- muscular spasms, muscle weakness, myalgias, arthralgias
- arthritis
- a renal failure
- decrease in level of hemoglobin and a hematocrit, a leukopenia, thrombocytopenia
- increase in residual nitrogen and serumal creatinine, increase
in activity of liver enzymes, a hyperbilirubinemia, disturbances of water
electrolytic balance (especially at patients with a renal failure),
a hypochloraemia, a metabolic alkalosis
- disturbance of potency
is Very rare
- arrhythmias, heart consciousness, tachycardia, in the profound
lowering of arterial pressure, generally at patients with coronary heart disease
and clinically significant vasoconstriction of a brain,
myocardium ischemia (stenocardia, a myocardial infarction) and brain ischemia
(passing disturbance of cerebral circulation, an ischemic stroke)
- Reynaud's syndrome, a vasculitis, thrombosis, a thrombembolia
- anaphylactic reactions, a Quincke's disease, a fluid lungs owing to
hypersensitivity to a hydrochlorothiazide
- intestinal impassability, hemorrhagic pancreatitis, cholestatic
jaundice, hepatitis, acute cholecystitis (against the background of cholelithiasis),
liver necrosis
- a multiformny erythema, Stephens-Johnson's syndrome, a toxic
epidermal necrolysis, psoriazopodobny or pemfigoidny skin reactions,
a system lupus erythematosus, an alopecia, exacerbation of psoriasis, an onycholysis
- paralysis
- an oliguria, an acute renal failure, a nephrotic syndrome,
interstitial nephrite
- an agranulocytosis, a pancytopenia, an eosinophilia, hemolytic anemia against the background of
deficiency of glyukozo-6-phosphate-dehydrogenase
- a gipertriglitseridemiya, a hypercholesterolemia, increase in serumal amylase
of the Contraindication
- hypersensitivity to a ramipril or to other components of drug
and also to other AKF inhibitors, tiazida or derivatives of sulfonamide
- the Quincke's disease in the anamnesis connected with use before
AKF inhibitors
- a hereditary or idiopathic Quincke's disease
- the profound renal failures (KK less 30ml/min/1.73m2
body surface areas) or an anury
- the profound abnormal liver functions and/or a cholestasia
- hemodynamically significant bilateral (or unilateral at patients with
one kidney) a renal artery stenosis
- arterial hypotension or instability of a hemodynamics
- the emergency hemodialysis or haemo filtration with use
of high-permeability dialysis membranes
- aferez LDL dextran sulfate
- a concomitant use Hartil-D with the desensibilizing therapy by poison
of Hymenoptera
- pregnancy and the period of a lactation
- children's and teenage can develop the age up to 18 years (due to the lack of data on
safety and efficiency of use)
Medicinal interactions
of Hartil® - D reduces lithium excretion by kidneys and increase risk of development litiye-
howl intoxications. The increase in level of lithium developing as a result of it
in serum increase risk it kardio- and nephrotoxicity. Lithium drugs
are not appointed, as a rule, along with diuretics or AKF inhibitors.
In need of purpose of such combination of drugs, it is necessary to carry out
regular control of level of lithium in serum.
Simultaneous use of Hartila® - D with Trimethoprimum increases risk of a hyperpotassemia.
The hydrochlorothiazide weakens hypoglycemic effect of oral anti-diabetic means and insulin while ramiprit exponentiates it, up to development of a hypoglycemia. Risk of development of such phenomena is especially high within the first weeks of simultaneous use of these drugs with AKF inhibitors and also at patients with a renal failure.
At simultaneous use with sodium chloride the easing of antihypertensive effect of Hartila® - is possible.
Simultaneous long administration of drug with non-steroidal anti-inflammatory drugs (NPVS), including acetylsalicylic acid in high doses (to 3g/days), can weaken hypotensive effect of AKF inhibitors, and the hydrochlorothiazide can enhance neurotoxicity of salicylates. Effects of NPVS and AKF inhibitors on increase in level of potassium in serum are summarized that can lead to a renal failure. These effects are usually reversible. In rare instances, mainly at elderly patients or in dehydration, the acute renal failure can be observed. Хартил®-Д it is possible to apply against the background of intake of acetylsalicylic acid in cardiological doses, trombolitik, beta-blockers and/or nitrates.
The concomitant use of kaliysberegayushchy diuretics (Spironolactonum, Triamterenum or amiloride) or other drugs promoting increase in potassium concentration in blood plasma (heparin) with Hartilom® - D can lead to a hyperpotassemia.
At simultaneous use of Hartila® - D with diuretics strengthening of antihypertensive effect is possible. Reception of Hartila® - D can sometimes cause arterial hypotension in patients who already accept diuretics.
Intake of other antihypertensive drugs, vazodilatator, nitroglycerine and other nitrates exponentiates hypotensive effect of Hartila®-.
Tricyclic antidepressants, antipsychotic means, anesthetics can enhance hypotensive effect of Hartila®-.
Sympathomimetics can weaken hypotensive effect of AKF inhibitors therefore patients in such cases need careful observation.
At simultaneous use of Hartila® - D with Allopyrinolum or cyclosporine the risk of developing a renal failure and a leukopenia increases.
Simultaneous use of Hartila® - D with lovastatiny increases risk of a hyperpotassemia.
Simultaneous use of Hartila® - D with procaineamide, cytostatics and immunodepressants increases risk of a leukopenia.
Хартил® - D at its appointment together with Amphotericinum B (parenterally), karbenoksolony, GKS, AKTG, depletive increases risk of development of a hypopotassemia.
At simultaneous use with cardiac glycosides the risk of developing glikozidny intoxication and a thiazide hypopotassemia increases.
At simultaneous use of Hartila® - D with the drugs extending QT interval (some antipsychotic means, quinidine, Amiodaronum, sotalol and other drugs) the hypopotassemia and development of ventricular arrhythmia like 'pirouette' is possible.
Thiazide diuretics reduce calcium excretion therefore their concomitant use can increase calcium level in serum.
Colestyraminum and kolestipol reduce absorption of Hartila®-. Therefore sulphonamide diuretics should be accepted, at least, in 1 hour prior to or in 4-6 hours after intake of the anion-exchange pitches.
Хартил® - D can strengthen action of not depolarizing muscle relaxants.
Special instructions
during the Hartil-D drug treatment the regular medical control is necessary that is caused by clinical effects of both active components of drug. Periodically it is necessary to control the level of arterial blood pressure, function of kidneys, the content of hemoglobin, creatinine, urea, level of electrolytes and activity of liver enzymes in blood plasma. Prior to administration of drug it is necessary to correct dehydration, a hypovolemia, decrease in number of erythrocytes.
Symptomatic arterial hypotension seldom occurs at treatment of Hartilom® - D in patients with uncomplicated arterial hypertension, however it can develop as a result of therapy by AKF inhibitors at patients with a reduced volume of the circulating blood (for example, against the background of therapy by diuretics, at restriction of consumption of liquid and salt with food, when carrying out dialysis, at insufficient completion of losses of liquid and salts in diarrhea, vomiting or the increased sweating) and also at severe forms renin - dependent hypertensia.
In the beginning treatments and at selection (increase) of a dose the careful medical observation of a state is required from patients with high risk of developing hypotension and also from patients with coronary heart disease or cerebrovascular insufficiency at which the profound arterial hypotension can lead to a myocardial infarction or disturbance of cerebral circulation.
In case of an excessive lowering of arterial pressure the patient should give horizontal position with sublime position of legs, if necessary to correct the volume of the circulating blood by intravenous infusion of normal saline solution and other measures.
At patients with chronic heart failure, with the normal or low level of arterial blood pressure, ramiprit can cause an additional lowering of arterial pressure. This predictable effect, usually is not the basis for the treatment termination. In long and clinically apparent hypotension the reduction of a dose or cancellation of administration of drug can be required. At patients with chronic heart failure the frequency of development of hypotension does not depend on existence or absence of the accompanying renal failure. More often hypotension is observed at patients with heavy chronic heart failure, as a result of reception of high doses of diuretics, against the background of a hyponatremia or in a functional renal failure.
At patients with chronic heart failure in an initiation of treatment AKF inhibitors deterioration in function of kidneys is possible. Development cases in such situations of an acute renal failure, usually passing are described.
It is required to be careful when assigning a ramipril, to patients with an aortal and mitral stenosis or difficulty of emission of blood from a left ventricle, for example, at a hypertrophic cardiomyopathy. In some cases hemodynamic disturbances can make inadmissible a concomitant use of a ramipril and a hydrochlorothiazide.
Patients with primary aldosteronism (Kronn's disease) are not sensitive to antihypertensive drugs which effect is based on suppression system renin-angiotenzinovoy. Therefore use of the fixed combinations of a ramipril and a hydrochlorothiazide is not shown.
At some patients with arterial hypertension without pathology of vessels of kidneys the reception of a ramipril in combination with diuretic, usually causes slight and passing increase of level of urea in blood and creatinine in serum. Probability of their emergence is higher at patients, with the available renal failure. In such cases the dose decline and/or the termination of reception of each of components separately can be required.
At some patients with defeat of vessels of kidneys (narrowing of both renal arteries or a stenosis of an artery of the only kidney) the intake of AKF inhibitors can lead to a renal failure and an acute renal failure, increase in level of urea in blood and creatinine in serum. Usually these changes take place after the termination of administration of drugs. Probability of it is especially high at the existing renal failure.
In the presence of renovascular hypertensia the risk of developing heavy hypotension and renal failure increases. At such patients the treatment should be begun with low doses under careful medical observation.
The patients who recently transferred transplantation of a kidney are not recommended to apply ramiprit, due to the lack of experience of its use for such patients.
In rare instances during reception of a ramipril there can be a Quincke's disease of the face, lips, language, phonatory bands and/or throats, extremities. Hypostasis can arise at any stage of therapy. In this case reception of a ramipril should be stopped immediately, to carry out the corresponding treatment and to establish observation of a state by the patient. Even when hypostasis extends only to language, and signs of disturbance of breath are absent, patients need rather long observation as out-patient treatment by antihistaminic drugs and corticosteroids can be insufficient. There are rare messages about a lethal outcome in connection with a Quincke's disease of a throat or language.
If the Quincke's disease extends to area of language, a glottis and/or throat and accepts life-threatening character, it is necessary to take urgent measures: monitoring of the ECG and arterial blood pressure to provide passability of airways and adequate ventilation of the lungs, immediate hypodermic introduction 0.3-0.5ml adrenaline or slow intravenous administration of adrenaline, intravenous or intramuscular administration of glucocorticoids, parenteral administration of antihistaminic drugs. The patient has to be under careful medical observation before total and permanent disappearance of symptomatology.
At the instruction in the anamnesis on the Quincke's disease which is not connected with intake of AKF inhibitors the risk of developing a Quincke's disease against the background of therapy by AKF inhibitors increases.
At the patients of negroid race accepting AKF inhibitors a Quincke's disease more often develops, than at other patients. Ramipril can render smaller hypotensive effect at patients of negroid race, in comparison with persons of other race, perhaps owing to higher frequency of persons with the low level of renin in population of patients of negroid race, with arterial hypertension.
It was reported about several cases of development of an acute liver failure with cholestatic jaundice, necrosis of a liver and a lethal outcome during treatment by AKF inhibitors. The reason of these syndromes is completely not clear. During the developing of jaundice and increase in activity of liver enzymes the treatment has to be immediately stopped, and patients have to be under observation.
At extensive surgical interventions or during the general anesthesia with use of the drugs reducing arterial blood pressure ramiprit, blocks the formation of angiotensin II caused by compensatory release of renin. If at the same time the profound arterial hypotension explained with the similar mechanism it develops it is possible to correct increase in volume of the circulating blood.
At some patients accepting ramiprit, increase in level of potassium in serum is possible. Patients, with a renal failure or diabetes, the accepting kaliysberegayushchy diuretics (Spironolactonum, Triamterenum or amiloride) or kaliysoderzhashchy drugs and also the patients taking other drugs increasing potassium level in blood serum (heparin) treat risk group of development of a hyperpotassemia. Use of potassium additives, kaliysberegayushchy diuretics or kaliysoderzhashchy salts can lead to substantial increase of level of potassium in serum, especially at patients with a renal failure. If reception above the listed drugs along with AKF inhibitor is necessary, regular control of level of potassium in serum is recommended.
At the patients with diabetes taking the oral antidiabetic drugs or insulin it is regularly necessary to control glycemia level during treatment by AKF inhibitor.
There are messages about life-threatening anaphylactic reactions, sometimes up to development of shock, for patients during a hemodialysis with use of certain high-flowing membranes (for example, polyacrylonitrile) at simultaneous use of AKF inhibitors. Similar reactions were observed at a LDL afereza using dextran sulfate.
In rare instances at the patients accepting AKF inhibitors at the desensibilizing therapy for the purpose of prevention or treatment of allergic reaction to a sting of insects (for example, bees and wasps) heavy, life-threatening anaphylactic reactions (falling of arterial blood pressure, breath disturbance, vomiting, skin reactions) developed.
Intake of AKF inhibitors can be followed by dry cough with continuous increase in a tussive reflex. Cough amplifies at night and in a prone position more often, to a thicket is observed at women and not smokers. The cough caused by intake of AKF inhibitor should be considered differential diagnostic character. Cough can stops after drug withdrawal or at conversion of the patient to other AKF inhibitor.
With renal failures thiazide diuretics can cause an azotemia in patients. At such patients cumulative effects of tiazid can be shown. In case of progressing of the renal failure which is characterized by increase in nonprotein nitrogen it is necessary to estimate carefully need of therapy and to consider the possibility of the termination of intake of diuretics.
Drug is appointed with care at patients with the moderated or progressing abnormal liver function as Hydrochlorthiazidum can cause a hepatic coma even at insignificant disturbances of water and electrolytic balance.
The hydrochlorothiazide can reduce tolerance to glucose that Therapy of a tiazidama can demand dose adjustment of hypoglycemic means at treatment of diabetes can cause manifestation of latent diabetes.
Thiazide diuretics connect increase in levels of cholesterol and triglycerides with therapy.
Constant reception of a hydrochlorothiazide reduces excretion of uric acid and can contribute to the development of gout in some patients. However ramiprit can strengthen excretion of uric acid and by that to weaken giperurikemichesky effect of a hydrochlorothiazide. Therefore at a concomitant use of these drugs the attacks of gout do not arise.
Intake of thiazide diuretics, including a hydrochlorothiazide, can cause disturbance of water and electrolytic balance (hypopotassemia, a hyponatremia and a gipokhloremichesky alkalosis). At the patients accepting diuretics it is necessary to reveal signs of disturbance of water or electrolytic balance, such as dryness in a mouth, thirst, weakness, a lethargy, drowsiness, concern, myalgia or muscular spasms, fatigue of muscles, hypotension, an oliguria, tachycardia and disorders from digestive tract, nausea, vomiting.
Potassium loss which is caused by diuretics of a tiazidovy row, as a rule, decreases under the influence of a ramipril. Risk of development of a hypopotassemia increases in cirrhosis, at patients with the raised diuresis, at inadequate oral administration of electrolytes, against the background of therapy of GKS and AKTG.
The hyponatremia can develop in hot weather at patients with peripheral hypostases.
Reception of tiazid increases renal excretion of magnesium that can lead to a hypomagnesiemia.
The deficiency of chlorides connected with therapy by thiazide diuretic is usually mild and does not demand special treatment.
Reception of tiazid can reduce excretion of calcium with urine and also cause an insignificant and passing hypercalcemia, even in the absence of obvious disturbances of calcic metabolism. At development of a hypercalcemia it is necessary to exclude the latent hyperparathyreosis. Reception of tiazid should be stopped before carrying out researches of function of epithelial bodies.
It is necessary to stop reception of a combination of the fixed doses of a ramipril and a hydrochlorothiazide in case of emergence or suspicion on emergence of a neutropenia (quantity of neutrophils less than 1000/mm3).
The hydrochlorothiazide gives positive reaction when conducting doping control.
During drug treatment, hypersensitivity reactions at patients without the previous allergy or bronchial asthma can be noted.
There are messages about cases of aggravation of a system lupus erythematosus.
If skin reactions are pronounced, urgent consultation of the doctor is necessary.
In inherited disorders of tolerance to a galactose and a lactose intolerance it is necessary to consider its contents in each tablet: Hartil-D of 2.5 mg/12.5 mg – 25 mg of lactose, Hartil-D 5mg/25mg – 50 mg of lactose.
Pregnancy and the period of a lactation
Hartil-D is contraindicated at pregnancy therefore before his reception it is necessary to be convinced of lack of pregnancy. If reception Hartil-D is absolutely necessary, it is necessary to avoid pregnancy. If the patient is going to have the child, she should stop intake of AKF inhibitors and a hydrochlorothiazide and to replace them with other antihypertensive drugs. At pregnancy approach administration of drug Hartil-D follows as soon as possible (before termination I of a trimester) to replace with the drug which is not cont
of HARTIL®-medicine D
Trade name
of Hartil® - D
International unlicensed name
Is not present
the Dosage form
of Tablet 2.5mg/12.5 of mg, 5mg/25 mg
Structure
One tablet 2.5mg/12.5 of mg contains
active agents:
the hydrochlorothiazide of 12.5 mg ramiprit 2.5 mg
One tablet 5mg/25mg contains
active agents: ramiprit 5 mg
a hydrochlorothiazide of 25 mg,
excipients: lactoses monohydrate, a gipromelloza, krospovidon, cellulose microcrystalline, the sodium stearylfumarating.
The description
of Tablet 2.5mg/12.5mg - white, oval, with risky on both parties, on one party of a tablet – an engraving of numbers 2.5 and 12.5 on different sides from risks
of Tablet 5mg/25mg - white, oval, with risky on both parties, on one party of a tablet – an engraving of numbers 5 and 25 on different sides from risks
Pharmacotherapeutic group
the Enzyme Angiotensin-converting (EAC) inhibitors in a combination with diuretics.
The code of automatic telephone exchange C09BA05
The pharmacological
Ramipril Pharmacokinetics properties after intake is quickly soaked up from digestive tract (50-60% of the dose accepted inside). Food does not influence extent of absorption, but slows down drug absorption. Ramipril is pro-medicine. Is exposed to metabolism of the first passing through a liver with formation of an active metabolite - the ramiprilat (inhibits AKF 6 times more actively, than ramiprit) and inactive metabolites. Among the known inactive metabolites - diketopiperazine ether, diketopiperazine acid and also glucuronides of a ramipril and the ramiprilat. Bioavailability after intake 2.5-5mg the ramiprila makes about 20%, for the ramiprilat about 45%. The maximum concentration of a ramipril in blood plasma is reached within 1 hour, and the ramiprilat within 2-4 hours after intake. Concentration increase in blood of a ramipril and the ramiprilat at increase in a dose, but are not strictly proportional to it. Linking with proteins of plasma for a ramipril - 73%, the ramiprilat - 56%. Decrease in concentration of the ramiprilat in plasma has multiphase character. A phase of initial distribution and removal with elimination half-life of the ramiprilat 2-4 hours. Then an intermediate phase with elimination half-life of the ramiprilat of 9-18 hours. A final phase of removal from very low concentration of the ramiprilat in plasma and long elimination half-life - more than 50 hours. The final phase is connected with slow dissociation of the ramiprilat from communication with AKF receptors. Steady concentration of the ramiprilat in plasma after single daily dose of a ramipril in a dose of 5 mg is reached approximately by 4th day. Stationary concentration of the ramiprilat are slightly higher, than observed after reception of the first dose of a ramipril, especially in low doses (2.5 mg), but the distinction is not clinically significant. After multiple dose of daily doses of a ramipril 5-10mg the therapeutic range of elimination half-life of concentration of the ramiprilat is 13-17 hours (the parameter influencing the choice of a dose). After intake about 60% of a dose are removed with urine (mainly in the form of metabolites), about 40% with a stake, less than 2% are allocated with urine in not changed look.
In renal failures the removal of a ramipril and its metabolites slows down in proportion to decrease to the clearance of creatinine (CC). It leads to increase in plasma concentration of the ramiprilat and their slower decrease unlike patients with normal function of kidneys.
In an abnormal liver function the reception of a ramipril in high doses (10 mg) slows down transformation of a ramipril in ramiprilat, concentration of a ramipril in blood plasma can increase by 3 times, at the same time the maximum concentration in blood plasma of the ramiprilat does not change.
At reception of a ramipril in a dose of 5 mg of 1 times a day by the patients with heart failure and arterial hypertension after 2 weeks of treatment did not observe clinically significant accumulation of a ramipril and the ramiprilat.
At elderly people the drug pharmacokinetics significantly does not change.
Ramipril is excreted with breast milk.
The hydrochlorothiazide after intake is quickly soaked up from gastrointestinal (60-80%). Bioavailability of-70%. The average time of achievement of the maximum concentration in plasma-1.5-4 hours. Linking with proteins of blood plasma about 40-60%. Absorption speed practically does not depend on a dose. Elimination half-life - 6-8 hours. It is not metabolized in a liver, removed mainly by kidneys: 95% - in not changed look and about 4% - in the form of a metabolite. In an hour after intake it is noted in urine and during 24 h about 50-70% of the entered dose are allocated. Removal with bile is insignificant. The hydrochlorothiazide in small amounts is excreted with breast milk.
The renal clearance of a hydrochlorothiazide finds high correlation with clearance of creatinine. At patients at whom the glomerular filtration rate (GFR) less than 10 ml/min. only 10% of the accepted dose are defined in urine.
In a renal failure the excretion of a hydrochlorothiazide decreases and extended elimination half-life.
Significant changes of pharmacokinetics in cirrhosis are not noted.
Regular reception of a combination of a ramipril and hydrochlorothiazide does not influence or slightly affects bioavailability of each of them. Use of the combined tablet of drug Hartil-D 5mg/25mg bioekvivalentno to a concomitant use of its ingredients in separate dosage forms.
The hypotensive effect begins in 1-2 hours after intake of a single dose of drug, the maximum effect develops in 3-6 hours after reception and remains within 24 hours. At daily use the hypotensive activity gradually increases within 3-4 weeks and remains at long-term treatment within 1-2 years. At short-term cancellation the significant increase in arterial blood pressure is not observed (there is no withdrawal).
A pharmacodynamics
Hartil-D - the combined antihypertensive drug which part are AKF inhibitor (ramiprit) also thiazide diuretic (hydrochlorothiazide). Has antihypertensive and diuretic effect.
Ramiprilat, an active metabolite of a ramipril, competitively inhibits activity the angiotensin-the converting enzyme (ACE), reduces the speed of transformation of angiotensin I into angiotensin II. Reduction of concentration of angiotensin II is resulted by secondary increase in activity of renin of plasma due to elimination of negative feedback at release of renin and direct decrease in secretion of Aldosteronum. Reduces degradation of bradykinin and increases synthesis of prostaglandins. Reduction of formation of angiotensin II and increase in activity of bradykinin leads to vasodilatation and makes the contribution to cardioprotective and endotelioprotektivny action of a ramipril. Thanks to the high lipophilicity, ramiprit in comparison with enalapril gets into fabrics better that well influences interaction about angiotensin - the converting system of various fabrics and bodies and also the AKF level in plasma. Drug causes antihypertensive effect both in position of the patient standing, and in a prone position without compensatory increase in heart rate. Thanks to vasodilating action reduces the general peripheric vascular resistance (afterload), pressure in pulmonary capillaries (preloading) and resistance in pulmonary vessels. Causes increase in minute volume of blood and increase in tolerance to loadings. Usually does not cause significant changes in a renal blood-groove (in some cases it raises) and glomerular filtration rate. At long-term treatment contributes to involution of a hypertrophy of a myocardium at patients with arterial hypertension and reduces the frequency of arrhythmias at reperfusion of a myocardium. Improves blood supply of an ischemic myocardium. Reduces aggregation of thrombocytes. Prevents the contractilny changes of an endothelium of vessels caused by a high-cholesteric diet.
The hydrochlorothiazide suppresses a reabsorption of sodium and chlorine in distal tubules of nephron. The strengthened renal excretion of these ions is followed by the raised uropoiesis (because of osmotic binding of water). Increases removal of potassium ions, magnesium, bicarbonate, delays removal of calcium ions, uric acid. The mechanism of antihypertensive action is definitely not installed and perhaps consists of the next moments: change of sodium balance, reduction of volume of extracellular water and plasma, change of resistance of renal vessels, decrease in reactions to noradrenaline and angiotensin II. At long-term treatment the lowering of arterial pressure is reached at reception of smaller doses, than it is necessary for achievement of diuretic effect. The lowering of arterial pressure is followed by small increase in SKF, vascular resistance of the renal course and activity of renin in plasma. Single dose of high doses of a hydrochlorothiazide leads to reduction of volume of plasma, SKF, renal blood-groove and average arterial blood pressure. At long reception of small doses the volume of plasma remains reduced while the minute volume and SKF return to the initial level preceding an initiation of treatment. Average arterial blood pressure and system vascular resistance remain reduced. Thiazide diuretics can break development of breast milk.
Use of a combination of a ramipril and hydrochlorothiazide leads to more significant decrease in the ABP in comparison with monotherapy by each drug separately and allows to maintain antihypertensive effect of drug at least during 24 h. Antihypertensive effects of both substances supplement each other, and the gipokaliyemichesky effect of a hydrochlorothiazide decreases ramiprily.
Indications
- treatment of arterial hypertension when use
of combination therapy
the Route of administration is required and doses
Is recommended to take the drug on 1-2 tablet a day at the same time, it is preferable in the morning. Tablets can be halved, breaking after risk, washing down with a large amount of liquid, irrespective of meal. The dose of drug and duration of therapy are established individually. Treatment of arterial hypertension should not be begun with use of the fixed combination. Before therapy it is necessary to determine by the drug Hartil-D the corresponding dose of separate components.
The initial recommended dose – tablets 2.5mg/12.5mg. It is possible to increase a dose with an interval not less than 3 weeks. A maintenance dose - tablets 2.5mg/12.5mg or 5mg/25mg. The maximum daily dose - 10 mg of a ramipril and 50 mg of a hydrochlorothiazide.
Patients of advanced age and patients with a renal failure (KK of 30 - 60 ml/min.) Hartil-D should apply only after preliminary selection of doses of each of components. The maintenance dose has to be lower.
To patients with a renal failure (KK of 30-60 ml/min.) an initial dose - 1.25 mg of a ramipril and 6.25 mg of a hydrochlorothiazide. The recommended daily dose - tablets 2.5mg/12.5mg 1 of times a day. The maximum daily dose - tablets 5mg/25mg, divided into 2 receptions (in the morning and in the evening).
Patients with a slight or moderate abnormal liver function Hartil-D should apply only after preliminary selection of a dose of a ramipril.
Side effects
Often of 1 - 9.9% (> 1/100,
- dizziness, fatigue, a headache, weakness
- arterial hypotension (in an initiation of treatment and after increase in a dose)
- bronchitis, the dry cough passing after drug withdrawal
- nausea, vomiting, an abdominal pain, digestion disturbance
- rash on skin and mucous
- a hypopotassemia, a hyperglycemia, increase in level of uric acid, urea and
creatinine in blood
- gout
Infrequently of 0.1 - 0.9% (> 1/1000,
- drowsiness, apathy, nervousness
- a hyperpotassemia, a hyponatremia, a hypomagnesiemia, a hyperchloremia,
a hypercalcemia
- a proteinuria
- conjunctivitis, blepharitis
- a photosensitization
- an itching, urticaria
- peripheral hypostases (in ankle joints)
- spasms in epigastric area, thirst, a loss of appetite, a constipation, diarrhea,
- decrease in potency
is rare 0.01 - 0.09% (> 1/10000,
- uneasiness, confusion of consciousness, a sleep disorder, sonitus, faints,
concern, paresthesias
- disturbance of sense of smell, taste
- balance disturbance
- a disorder of vision, passing short-sightedness
- a thrombembolia
- short wind
- rhinitis, sinusitis, pharyngitis, a glossitis, a bronchospasm (at patients with
hyperexcitability of a tussive reflex), eosinophilic pneumonia
- dryness in a mouth, vomiting, inflammation of mucous membranes of a mouth and language, a sialadenitis
- feeling of rush of blood with feeling of heat on certain sites of skin,
the strengthened sweating, swelled
- muscular spasms, muscle weakness, myalgias, arthralgias
- arthritis
- a renal failure
- decrease in level of hemoglobin and a hematocrit, a leukopenia, thrombocytopenia
- increase in residual nitrogen and serumal creatinine, increase
in activity of liver enzymes, a hyperbilirubinemia, disturbances of water
electrolytic balance (especially at patients with a renal failure),
a hypochloraemia, a metabolic alkalosis
- disturbance of potency
is Very rare
- arrhythmias, heart consciousness, tachycardia, in the profound
lowering of arterial pressure, generally at patients with coronary heart disease
and clinically significant vasoconstriction of a brain,
myocardium ischemia (stenocardia, a myocardial infarction) and brain ischemia
(passing disturbance of cerebral circulation, an ischemic stroke)
- Reynaud's syndrome, a vasculitis, thrombosis, a thrombembolia
- anaphylactic reactions, a Quincke's disease, a fluid lungs owing to
hypersensitivity to a hydrochlorothiazide
- intestinal impassability, hemorrhagic pancreatitis, cholestatic
jaundice, hepatitis, acute cholecystitis (against the background of cholelithiasis),
liver necrosis
- a multiformny erythema, Stephens-Johnson's syndrome, a toxic
epidermal necrolysis, psoriazopodobny or pemfigoidny skin reactions,
a system lupus erythematosus, an alopecia, exacerbation of psoriasis, an onycholysis
- paralysis
- an oliguria, an acute renal failure, a nephrotic syndrome,
interstitial nephrite
- an agranulocytosis, a pancytopenia, an eosinophilia, hemolytic anemia against the background of
deficiency of glyukozo-6-phosphate-dehydrogenase
- a gipertriglitseridemiya, a hypercholesterolemia, increase in serumal amylase
of the Contraindication
- hypersensitivity to a ramipril or to other components of drug
and also to other AKF inhibitors, tiazida or derivatives of sulfonamide
- the Quincke's disease in the anamnesis connected with use before
AKF inhibitors
- a hereditary or idiopathic Quincke's disease
- the profound renal failures (KK less 30ml/min/1.73m2
body surface areas) or an anury
- the profound abnormal liver functions and/or a cholestasia
- hemodynamically significant bilateral (or unilateral at patients with
one kidney) a renal artery stenosis
- arterial hypotension or instability of a hemodynamics
- the emergency hemodialysis or haemo filtration with use
of high-permeability dialysis membranes
- aferez LDL dextran sulfate
- a concomitant use Hartil-D with the desensibilizing therapy by poison
of Hymenoptera
- pregnancy and the period of a lactation
- children's and teenage can develop the age up to 18 years (due to the lack of data on
safety and efficiency of use)
Medicinal interactions
of Hartil® - D reduces lithium excretion by kidneys and increase risk of development litiye-
howl intoxications. The increase in level of lithium developing as a result of it
in serum increase risk it kardio- and nephrotoxicity. Lithium drugs
are not appointed, as a rule, along with diuretics or AKF inhibitors.
In need of purpose of such combination of drugs, it is necessary to carry out
regular control of level of lithium in serum.
Simultaneous use of Hartila® - D with Trimethoprimum increases risk of a hyperpotassemia.
The hydrochlorothiazide weakens hypoglycemic effect of oral anti-diabetic means and insulin while ramiprit exponentiates it, up to development of a hypoglycemia. Risk of development of such phenomena is especially high within the first weeks of simultaneous use of these drugs with AKF inhibitors and also at patients with a renal failure.
At simultaneous use with sodium chloride the easing of antihypertensive effect of Hartila® - is possible.
Simultaneous long administration of drug with non-steroidal anti-inflammatory drugs (NPVS), including acetylsalicylic acid in high doses (to 3g/days), can weaken hypotensive effect of AKF inhibitors, and the hydrochlorothiazide can enhance neurotoxicity of salicylates. Effects of NPVS and AKF inhibitors on increase in level of potassium in serum are summarized that can lead to a renal failure. These effects are usually reversible. In rare instances, mainly at elderly patients or in dehydration, the acute renal failure can be observed. Хартил®-Д it is possible to apply against the background of intake of acetylsalicylic acid in cardiological doses, trombolitik, beta-blockers and/or nitrates.
The concomitant use of kaliysberegayushchy diuretics (Spironolactonum, Triamterenum or amiloride) or other drugs promoting increase in potassium concentration in blood plasma (heparin) with Hartilom® - D can lead to a hyperpotassemia.
At simultaneous use of Hartila® - D with diuretics strengthening of antihypertensive effect is possible. Reception of Hartila® - D can sometimes cause arterial hypotension in patients who already accept diuretics.
Intake of other antihypertensive drugs, vazodilatator, nitroglycerine and other nitrates exponentiates hypotensive effect of Hartila®-.
Tricyclic antidepressants, antipsychotic means, anesthetics can enhance hypotensive effect of Hartila®-.
Sympathomimetics can weaken hypotensive effect of AKF inhibitors therefore patients in such cases need careful observation.
At simultaneous use of Hartila® - D with Allopyrinolum or cyclosporine the risk of developing a renal failure and a leukopenia increases.
Simultaneous use of Hartila® - D with lovastatiny increases risk of a hyperpotassemia.
Simultaneous use of Hartila® - D with procaineamide, cytostatics and immunodepressants increases risk of a leukopenia.
Хартил® - D at its appointment together with Amphotericinum B (parenterally), karbenoksolony, GKS, AKTG, depletive increases risk of development of a hypopotassemia.
At simultaneous use with cardiac glycosides the risk of developing glikozidny intoxication and a thiazide hypopotassemia increases.
At simultaneous use of Hartila® - D with the drugs extending QT interval (some antipsychotic means, quinidine, Amiodaronum, sotalol and other drugs) the hypopotassemia and development of ventricular arrhythmia like 'pirouette' is possible.
Thiazide diuretics reduce calcium excretion therefore their concomitant use can increase calcium level in serum.
Colestyraminum and kolestipol reduce absorption of Hartila®-. Therefore sulphonamide diuretics should be accepted, at least, in 1 hour prior to or in 4-6 hours after intake of the anion-exchange pitches.
Хартил® - D can strengthen action of not depolarizing muscle relaxants.
Special instructions
during the Hartil-D drug treatment the regular medical control is necessary that is caused by clinical effects of both active components of drug. Periodically it is necessary to control the level of arterial blood pressure, function of kidneys, the content of hemoglobin, creatinine, urea, level of electrolytes and activity of liver enzymes in blood plasma. Prior to administration of drug it is necessary to correct dehydration, a hypovolemia, decrease in number of erythrocytes.
Symptomatic arterial hypotension seldom occurs at treatment of Hartilom® - D in patients with uncomplicated arterial hypertension, however it can develop as a result of therapy by AKF inhibitors at patients with a reduced volume of the circulating blood (for example, against the background of therapy by diuretics, at restriction of consumption of liquid and salt with food, when carrying out dialysis, at insufficient completion of losses of liquid and salts in diarrhea, vomiting or the increased sweating) and also at severe forms renin - dependent hypertensia.
In the beginning treatments and at selection (increase) of a dose the careful medical observation of a state is required from patients with high risk of developing hypotension and also from patients with coronary heart disease or cerebrovascular insufficiency at which the profound arterial hypotension can lead to a myocardial infarction or disturbance of cerebral circulation.
In case of an excessive lowering of arterial pressure the patient should give horizontal position with sublime position of legs, if necessary to correct the volume of the circulating blood by intravenous infusion of normal saline solution and other measures.
At patients with chronic heart failure, with the normal or low level of arterial blood pressure, ramiprit can cause an additional lowering of arterial pressure. This predictable effect, usually is not the basis for the treatment termination. In long and clinically apparent hypotension the reduction of a dose or cancellation of administration of drug can be required. At patients with chronic heart failure the frequency of development of hypotension does not depend on existence or absence of the accompanying renal failure. More often hypotension is observed at patients with heavy chronic heart failure, as a result of reception of high doses of diuretics, against the background of a hyponatremia or in a functional renal failure.
At patients with chronic heart failure in an initiation of treatment AKF inhibitors deterioration in function of kidneys is possible. Development cases in such situations of an acute renal failure, usually passing are described.
It is required to be careful when assigning a ramipril, to patients with an aortal and mitral stenosis or difficulty of emission of blood from a left ventricle, for example, at a hypertrophic cardiomyopathy. In some cases hemodynamic disturbances can make inadmissible a concomitant use of a ramipril and a hydrochlorothiazide.
Patients with primary aldosteronism (Kronn's disease) are not sensitive to antihypertensive drugs which effect is based on suppression system renin-angiotenzinovoy. Therefore use of the fixed combinations of a ramipril and a hydrochlorothiazide is not shown.
At some patients with arterial hypertension without pathology of vessels of kidneys the reception of a ramipril in combination with diuretic, usually causes slight and passing increase of level of urea in blood and creatinine in serum. Probability of their emergence is higher at patients, with the available renal failure. In such cases the dose decline and/or the termination of reception of each of components separately can be required.
At some patients with defeat of vessels of kidneys (narrowing of both renal arteries or a stenosis of an artery of the only kidney) the intake of AKF inhibitors can lead to a renal failure and an acute renal failure, increase in level of urea in blood and creatinine in serum. Usually these changes take place after the termination of administration of drugs. Probability of it is especially high at the existing renal failure.
In the presence of renovascular hypertensia the risk of developing heavy hypotension and renal failure increases. At such patients the treatment should be begun with low doses under careful medical observation.
The patients who recently transferred transplantation of a kidney are not recommended to apply ramiprit, due to the lack of experience of its use for such patients.
In rare instances during reception of a ramipril there can be a Quincke's disease of the face, lips, language, phonatory bands and/or throats, extremities. Hypostasis can arise at any stage of therapy. In this case reception of a ramipril should be stopped immediately, to carry out the corresponding treatment and to establish observation of a state by the patient. Even when hypostasis extends only to language, and signs of disturbance of breath are absent, patients need rather long observation as out-patient treatment by antihistaminic drugs and corticosteroids can be insufficient. There are rare messages about a lethal outcome in connection with a Quincke's disease of a throat or language.
If the Quincke's disease extends to area of language, a glottis and/or throat and accepts life-threatening character, it is necessary to take urgent measures: monitoring of the ECG and arterial blood pressure to provide passability of airways and adequate ventilation of the lungs, immediate hypodermic introduction 0.3-0.5ml adrenaline or slow intravenous administration of adrenaline, intravenous or intramuscular administration of glucocorticoids, parenteral administration of antihistaminic drugs. The patient has to be under careful medical observation before total and permanent disappearance of symptomatology.
At the instruction in the anamnesis on the Quincke's disease which is not connected with intake of AKF inhibitors the risk of developing a Quincke's disease against the background of therapy by AKF inhibitors increases.
At the patients of negroid race accepting AKF inhibitors a Quincke's disease more often develops, than at other patients. Ramipril can render smaller hypotensive effect at patients of negroid race, in comparison with persons of other race, perhaps owing to higher frequency of persons with the low level of renin in population of patients of negroid race, with arterial hypertension.
It was reported about several cases of development of an acute liver failure with cholestatic jaundice, necrosis of a liver and a lethal outcome during treatment by AKF inhibitors. The reason of these syndromes is completely not clear. During the developing of jaundice and increase in activity of liver enzymes the treatment has to be immediately stopped, and patients have to be under observation.
At extensive surgical interventions or during the general anesthesia with use of the drugs reducing arterial blood pressure ramiprit, blocks the formation of angiotensin II caused by compensatory release of renin. If at the same time the profound arterial hypotension explained with the similar mechanism it develops it is possible to correct increase in volume of the circulating blood.
At some patients accepting ramiprit, increase in level of potassium in serum is possible. Patients, with a renal failure or diabetes, the accepting kaliysberegayushchy diuretics (Spironolactonum, Triamterenum or amiloride) or kaliysoderzhashchy drugs and also the patients taking other drugs increasing potassium level in blood serum (heparin) treat risk group of development of a hyperpotassemia. Use of potassium additives, kaliysberegayushchy diuretics or kaliysoderzhashchy salts can lead to substantial increase of level of potassium in serum, especially at patients with a renal failure. If reception above the listed drugs along with AKF inhibitor is necessary, regular control of level of potassium in serum is recommended.
At the patients with diabetes taking the oral antidiabetic drugs or insulin it is regularly necessary to control glycemia level during treatment by AKF inhibitor.
There are messages about life-threatening anaphylactic reactions, sometimes up to development of shock, for patients during a hemodialysis with use of certain high-flowing membranes (for example, polyacrylonitrile) at simultaneous use of AKF inhibitors. Similar reactions were observed at a LDL afereza using dextran sulfate.
In rare instances at the patients accepting AKF inhibitors at the desensibilizing therapy for the purpose of prevention or treatment of allergic reaction to a sting of insects (for example, bees and wasps) heavy, life-threatening anaphylactic reactions (falling of arterial blood pressure, breath disturbance, vomiting, skin reactions) developed.
Intake of AKF inhibitors can be followed by dry cough with continuous increase in a tussive reflex. Cough amplifies at night and in a prone position more often, to a thicket is observed at women and not smokers. The cough caused by intake of AKF inhibitor should be considered differential diagnostic character. Cough can stops after drug withdrawal or at conversion of the patient to other AKF inhibitor.
With renal failures thiazide diuretics can cause an azotemia in patients. At such patients cumulative effects of tiazid can be shown. In case of progressing of the renal failure which is characterized by increase in nonprotein nitrogen it is necessary to estimate carefully need of therapy and to consider the possibility of the termination of intake of diuretics.
Drug is appointed with care at patients with the moderated or progressing abnormal liver function as Hydrochlorthiazidum can cause a hepatic coma even at insignificant disturbances of water and electrolytic balance.
The hydrochlorothiazide can reduce tolerance to glucose that Therapy of a tiazidama can demand dose adjustment of hypoglycemic means at treatment of diabetes can cause manifestation of latent diabetes.
Thiazide diuretics connect increase in levels of cholesterol and triglycerides with therapy.
Constant reception of a hydrochlorothiazide reduces excretion of uric acid and can contribute to the development of gout in some patients. However ramiprit can strengthen excretion of uric acid and by that to weaken giperurikemichesky effect of a hydrochlorothiazide. Therefore at a concomitant use of these drugs the attacks of gout do not arise.
Intake of thiazide diuretics, including a hydrochlorothiazide, can cause disturbance of water and electrolytic balance (hypopotassemia, a hyponatremia and a gipokhloremichesky alkalosis). At the patients accepting diuretics it is necessary to reveal signs of disturbance of water or electrolytic balance, such as dryness in a mouth, thirst, weakness, a lethargy, drowsiness, concern, myalgia or muscular spasms, fatigue of muscles, hypotension, an oliguria, tachycardia and disorders from digestive tract, nausea, vomiting.
Potassium loss which is caused by diuretics of a tiazidovy row, as a rule, decreases under the influence of a ramipril. Risk of development of a hypopotassemia increases in cirrhosis, at patients with the raised diuresis, at inadequate oral administration of electrolytes, against the background of therapy of GKS and AKTG.
The hyponatremia can develop in hot weather at patients with peripheral hypostases.
Reception of tiazid increases renal excretion of magnesium that can lead to a hypomagnesiemia.
The deficiency of chlorides connected with therapy by thiazide diuretic is usually mild and does not demand special treatment.
Reception of tiazid can reduce excretion of calcium with urine and also cause an insignificant and passing hypercalcemia, even in the absence of obvious disturbances of calcic metabolism. At development of a hypercalcemia it is necessary to exclude the latent hyperparathyreosis. Reception of tiazid should be stopped before carrying out researches of function of epithelial bodies.
It is necessary to stop reception of a combination of the fixed doses of a ramipril and a hydrochlorothiazide in case of emergence or suspicion on emergence of a neutropenia (quantity of neutrophils less than 1000/mm3).
The hydrochlorothiazide gives positive reaction when conducting doping control.
During drug treatment, hypersensitivity reactions at patients without the previous allergy or bronchial asthma can be noted.
There are messages about cases of aggravation of a system lupus erythematosus.
If skin reactions are pronounced, urgent consultation of the doctor is necessary.
In inherited disorders of tolerance to a galactose and a lactose intolerance it is necessary to consider its contents in each tablet: Hartil-D of 2.5 mg/12.5 mg – 25 mg of lactose, Hartil-D 5mg/25mg – 50 mg of lactose.
Pregnancy and the period of a lactation
Hartil-D is contraindicated at pregnancy therefore before his reception it is necessary to be convinced of lack of pregnancy. If reception Hartil-D is absolutely necessary, it is necessary to avoid pregnancy. If the patient is going to have the child, she should stop intake of AKF inhibitors and a hydrochlorothiazide and to replace them with other antihypertensive drugs. At pregnancy approach administration of drug Hartil-D follows as soon as possible (before termination I of a trimester) to replace with the drug which is not cont
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