Universal reference book for medicines
Product name: HARTIL ®- D (HARTIL ® -D)

Active substance: hydrochlorothiazide, ramipril

Type: Antihypertensive drug

Manufacturer: EGIS Pharmaceuticals (Hungary) manufactured by ALLPHAMED PHARBIL ARZNEIMITTEL (Germany)
Composition, form of production and packaging
Tablets are
white, oval, with a facet, with a risk on both sides, with engraving on one side of the numbers "2.5" and "12.5" on different sides of the risks.

1 tab.

ramipril 2.5 mg

hydrochlorothiazide 12.5 mg

Excipients: lactose monohydrate, hypromellose, crospovidone, microcrystalline cellulose, sodium stearyl fumarate.

14 pcs.
- blisters (2) - packs of cardboard.
Tablets are white, oval, with a facet, with a risk on both sides, with engraving on one side of the numbers "5" and "25" on opposite sides of the risks.

1 tab.

ramipril 5 mg

hydrochlorothiazide 25 mg

Excipients: lactose monohydrate, hypromellose, crospovidone, microcrystalline cellulose, sodium stearyl fumarate.

14 pcs.
- blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2014.

PHARMACHOLOGIC EFFECT

Antihypertensive drug.
The drug has antihypertensive and diuretic effect. Ramipril and hydrochlorothiazide are used alone or together in the treatment of elevated blood pressure. The antihypertensive effects of both components are complementary, almost additive, and the hypokalemic effect of hydrochlorothiazide is reduced by ramipril.
Ramipril

Ramiprilate, an active metabolite of ramipril, suppresses the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin converting enzyme, kininase II).
This enzyme catalyzes the conversion of angiotensin I by tissues to the active angiotensin II vasoconstrictor, as well as the breakdown of the active bradykinin vasodilator.Reducing the amount of angiotensin II and suppressing the decay of bradykinin leads to vasodilation.
Since angiotensin II also stimulates the release of aldosterone, ramiprilat leads to a decrease in the release of aldosterone.

The use of ramipril leads to a marked decrease in peripheral vascular resistance.
Usually, there are no significant changes in the rate of renal blood flow and glomerular filtration.
Taking ramipril by patients with arterial hypertension lowers blood pressure in a standing and lying position without compensatory increase in heart rate.
In most patients, the antihypertensive effect is manifested 1-2 hours after the administration of a single dose. The degree of severity of the effect reaches a maximum after 3-6 hours after administration. Typically, the antihypertensive effect after a single dose is maintained for 24 hours. With prolonged treatment with ramipril, the maximum antihypertensive effect is usually achieved in 2-4 weeks. It is shown that with long-term therapy, the antihypertensive effect can be maintained for 2 years. A sharp discontinuation of ramipril does not lead to a rapid and excessive increase in blood pressure.
Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic.
Suppresses the reabsorption of sodium and chlorine ions in the distal nephron. Reinforced renal excretion of these ions is accompanied by increased urination (due to osmotic binding of water). The excretion of potassium and magnesium ions increases, and uric acid is delayed. High doses lead to increased elimination of bicarbonate, and long-term intake delays excretion of calcium ions. Possible mechanisms of antihypertensive action include: a change in the sodium balance, a decrease in the volume of extracellular fluid and plasma, a change in the resistance of renal vessels, or a decrease in reactions to noradrenaline and angiotensin II.
Excretion of electrolytes and water begins approximately 2 hours after administration, the maximum effect is achieved in 3-6 hours and persists for 6-12 hours. The antihypertensive effect is achieved in 3-4 days of treatment and lasts for 1 week after completion of the drug.
With long-term treatment, a decrease in blood pressure is achieved by using smaller doses than necessary for a diuretic effect. Decrease in blood pressure is accompanied by a slight increase in the rate of glomerular filtration, vascular resistance of the renal bed and the activity of renin in the blood plasma.
The administration of single high doses of hydrochlorothiazide leads to a decrease in plasma volume, glomerular filtration rate, renal blood flow and mean blood pressure.
With prolonged administration of small doses, the volume of blood plasma remains reduced, while the minute volume and the rate of glomerular filtration return to the initial level preceding the initiation of treatment. Mean arterial pressure and systemic vascular resistance remain reduced. Thiazide diuretics can interfere with the production of breast milk.
PHARMACOKINETICS

Ramipril

Suction

After ingestion, ramipril is rapidly absorbed.
Judging by radioactivity determined in the urine after ingestion of labeled ramipril (excretion by the kidney is only one of several ways), at least 56% of the drug is absorbed. Simultaneous food intake does not affect suction.
Ramipril is a prodrug that undergoes metabolism during "first passage" through the liver, as a result of which the only active metabolite of ramiprilate is formed (due to hydrolysis, mainly in the liver).
In addition to transforming into an active metabolite of ramiprilate, ramipril is conjugated with glucuronic acid and converted to a diketopiperazine ester of ramipril. Ramiprilate is also conjugated with glucuronic acid and converted to diketopiperazine-ramiprilate (acid). Thanks to the activation / metabolism of ramipril, bioavailability after ingestion is approximately 20%.
C max of ramipril in blood plasma is achieved within 1 h after ingestion.
C max ramiprilata in blood plasma is achieved within 2-4 hours after taking ramipril inside.
Distribution

Binding to plasma proteins is approximately 73% and 56%, respectively, for ramipril and ramiprilate.

In experimental studies, it is established that ramipril is excreted in breast milk.

Excretion

T 1/2 ramipril is 5.1 hours. The decrease in the concentration of ramiprilate in blood plasma has a multiphase nature.
The initial distribution and elimination phase is characterized by T 1/2 of about 3 hours. Then, the intermediate phase (T 1/2 approximately 15 hours) and the final phase during which the plasma ramiprilate concentrations are very low (T 1/2 -4 -5 days). This final phase is due to the slow dissociation of ramiprilate from strong, but saturated complexes with ACE. Despite the duration of the elimination phase, C ss of ramipril is reached in about 4 days with a daily intake of 2.5 mg or more of ramipril. The effective T 1/2 (parameter related to dose selection) is 13-17 hours after taking several doses.
After ingestion of 10 mg of labeled ramipril, about 40% of the radioactivity is released through the intestine and 60% - by the kidneys.
Within 24 hours after ingestion of 5 mg of ramipril in patients with a catheter that removes bile, equal amounts of ramipril and its metabolites were excreted by the kidneys and bile. Approximately 80-90% of the metabolites released by the kidneys and bile were represented by ramiprilate and preparations for its further metabolism. The share of glucuronide and diketopiperazine derivative of ramipril accounted for about 10-20%, and unmetabolized ramipril accounted for approximately 2% of the total amount of ramipril.
Pharmacokinetics in special clinical cases

The pharmacokinetics of ramipril and ramiprilate in healthy volunteers depends little on age (no differences between young people and those aged 65 to 75 years).

In patients with impaired renal function, excretion of ramiprilata by the kidneys decreases.
The renal clearance of ramiprilat is proportional to the creatinine clearance and correlates with it. Due to this, the concentration of ramiprilate in the blood plasma is higher, and its elimination is carried out for a longer time than in patients with normal renal function.
If ramipril is administered in high doses (10 mg), a violation of liver function slows the activation of ramipril (transformation into ramiprilate) and leads to an increase in its concentration in the blood plasma.
Elimination of ramiprilate slows down.
In adults with hypertension and chronic heart failure, there is no significant accumulation of ramipril and ramiprilate after ingestion of ramipril (5 mg 1 time / day for 2 weeks).

Hydrochlorothiazide

Suction

Approximately 70% of hydrochlorothiazide is absorbed after ingestion and its bioavailability is also 70%.
After ingestion of hydrochlorothiazide at a dose of 12.5 mg C max is achieved within 1.5-4 hours and is 70 ng / ml; in a dose of 25 mg C max is achieved within 2-5 hours and is 142 ng / ml; in a dose of 50 mg C max is achieved within 2-4 hours and is 260 ng / ml.
Distribution

Approximately 40% of hydrochlorothiazide binds to blood plasma proteins.
Hydrochlorothiazide is excreted in small amounts with breast milk.
Excretion

Almost completely (more than 95%) is excreted by the kidneys unchanged.
Within 24 hours after a single oral intake, 50-70% is output. Hydrochlorothiazide is determined in the urine after 60 minutes after ingestion. T 1/2 hydrochlorothiazide is in the range of 5 to 15 hours.
Pharmacokinetics in special clinical cases

If the renal function is impaired, the excretion decreases and T 1/2 increases.
Renal clearance of hydrochlorothiazide reveals a high correlation with creatinine clearance. In patients with a glomerular filtration rate of less than 10 ml / min, only 10% of the dose is determined in the urine.
According to recent studies, hydrochlorothiazide is partially excreted with bile.
Significant changes in pharmacokinetics in liver cirrhosis are not observed.
Patients with heart failure did not undergo pharmacokinetics.

Ramipril and hydrochlorothiazide

The simultaneous administration of ramipril and hydrochlorothiazide does not affect the bioavailability of each of the components.
It can be considered that a fixed combination of 5 mg of ramipril and 25 mg of hydrochlorothiazide in the form of tablets of the preparation Hartil®-D is biologically equivalent to the combined administration of 5 mg of ramipril and 25 mg of hydrochlorothiazide.
INDICATIONS

- Arterial hypertension (patients who are shown combined therapy).

DOSING MODE

Tablets should be taken 1 time / day daily in the morning, with plenty of fluids.
The drug can be taken regardless of food intake. Tablets are not intended to be divided into parts.
Adult drug Hartil ® -D is recommended to be prescribed only after individual selection of the doses of each of the components.
The dose can be increased with an interval of at least 3 weeks. The usual initial dose is 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide. The usual maintenance dose is 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide or 5 mg of ramipril and 25 mg of hydrochlorothiazide. The recommended maximum daily dose is 5 mg ramipril and 25 mg hydrochlorothiazide.
For elderly patients and patients with QC from 30 to 60 ml / min individual doses of each component (ramipril and hydrochlorothiazide) should be carefully selected before switching to the combined drug Hartil ® -D.

The dose of Hartil ® -D should be as low as possible.
The recommended maximum daily dose is 5 mg ramipril and 25 mg hydrochlorothiazide.
Hartil®-D is contraindicated in patients with severe renal dysfunction (CK <30 mL / min / 1.73 m 2 ).

Before switching to Hartil ® -D, a dose of ramipril should be selected for patients with mild or moderate liver function impairment .

Do not take the drug Hartil ® -D in patients with severe impairment of liver function and / or cholestasis.

Hartil®-D is not recommended for children and adolescents under the age of 18 due to a lack of safety and efficacy data for this age group.

SIDE EFFECT

During the administration of ACE inhibitors, ramipril or hydrochlorothiazide, a number of adverse reactions were noted.

At the beginning of the course of treatment and after increasing the dose, pronounced arterial hypotension was observed.
This effect is especially characteristic for some groups of risk. Symptoms such as dizziness, general weakness, blurred vision, sometimes combined with loss of consciousness (fainting) can be observed.Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction, severe arterial hypertension and shock, dynamic cerebral circulation disorder, cerebral hemorrhage and ischemic stroke were observed during the administration of ACE inhibitors against the background of arterial hypotension.
The incidence of side effects is defined as follows: often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10 000, <1/1000), very rarely (<1/10 000, including in single cases).

On the part of the hemopoietic system: rarely - a decrease in the concentration of hemoglobin and hematocrit, leukopenia, thrombocytopenia;
very rarely - agranulocytosis, pancytopenia, eosinophilia, hemolytic anemia in patients with deficiency of glucose-6-phosphate dehydrogenase.
On the part of laboratory indicators: often - hypokalemia, increased levels of uric acid, urea and creatinine in the blood, hyperglycemia, gout;
infrequently - hyperkalemia, hyponatremia, hypomagnesemia, hyperchloremia, hypercalcemia; rarely - violations of water-electrolyte balance (especially in patients with kidney disease), hypochloremia, metabolic alkalosis; very rarely - an increase in serum triglyceride levels, hypercholesterolemia, increased serum amylase, and decompensation of diabetes mellitus.
From the side of the central nervous system: often - dizziness, fatigue, headache, weakness;
infrequently - apathy, nervousness, drowsiness; rarely - a sense of fear, confusion, sleep disorders, anxiety, impaired sense of smell, imbalance, paresthesia.
From the side of the organ of vision: infrequently - conjunctivitis, blepharitis;
rarely - transient myopia, blurred vision.
From the side of the organ of hearing: rarely - ringing in the ears.

From the cardiovascular system: a marked decrease in blood pressure;
infrequently - swelling of the ankles; rarely - fainting, thromboembolic complications; very rarely - angina pectoris, myocardial infarction, arrhythmias, palpitations, tachycardia, cerebral circulatory dysfunction, cerebral hemorrhage, exacerbation of Raynaud's disease, vasculitis, venous disease, thrombosis, embolism.
On the part of the respiratory system: dry cough, bronchitis;
rarely - shortness of breath, sinusitis, rhinitis, pharyngitis, glossitis, bronchospasm, allergic interstitial pneumonia; very rarely - angioedema with lethal airway obstruction *, pulmonary edema due to hypersensitivity to hydrochlorothiazide.
On the part of the digestive system: nausea, abdominal pain, vomiting, indigestion;
infrequently - spasms in the epigastric region, thirst, constipation, diarrhea, loss of appetite; rarely - dry mouth, vomiting, taste disorders, inflammation of the mucous membranes of the mouth and tongue, sialadenitis, glossitis; very rarely - intestinal obstruction, hemorrhagic pancreatitis.
From the liver: rarely - increased activity of liver enzymes and / or bilirubin **;
very rarely - cholestatic jaundice **, hepatitis, cholecystitis (against cholelithiasis), liver necrosis.
Dermatological reactions: infrequently - photosensitivity, skin itching, urticaria;
rarely - flushes of blood to the skin of the face, increased sweating, peripheral edema;very rarely erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, skin reactions like psoriatic or pemphigoid, systemic lupus erythematosus, alopecia, exacerbation of psoriasis, onycholysis.
If skin reactions are pronounced, urgent medical consultation is needed.
It has been reported that taking this medication can lead to the development of a symptom complex, which is represented by at least one of the following components: fever, vasculitis, myalgia, arthralgia / arthritis, positive reaction to antinuclear antibodies, increased ESR, eosinophilia and leukocytosis, rash, photosensitivity (other skin manifestations are also possible).
From the musculoskeletal system: rarely - muscle spasm, myalgia, arthralgia, muscle weakness, arthritis;
very rarely - paralysis.
From the urinary system: infrequently - proteinuria;
rarely - impaired renal function, increased residual nitrogen and serum creatinine, dehydration; very rarely - acute renal failure, nephrotic syndrome, interstitial nephritis, oliguria.
On the part of the reproductive system: infrequently - decreased libido;
rarely - impotence.
Allergic reactions: very rarely - anaphylactic reactions, angioedema.

* angioedema often develops in the Negroid race.
In a small group of patients, the onset of angioedema and the oropharyngeal area is associated with the administration of ACE inhibitors.
** in the case of jaundice or an increase in the activity of the liver enzymes of the patient, it is necessary to observe.

CONTRAINDICATIONS

- angioedema in the anamnesis, incl.
associated with previous therapy with ACE inhibitors;
- hereditary / idiopathic angioedema;

- severe renal dysfunction (CC less than 30 ml / min / 1.73 m 2 ), anuria;

- marked violations of the liver and / or cholestasis;

- primary aldosteronism;

- arterial hypotension;

- hemodialysis;

- condition after kidney transplantation (no experience of application);

- galactose intolerance, hereditary lactase deficiency or glucose-galactose absorption disorder (due to the content of lactose in the preparation);

- Pregnancy;

- the period of lactation (breastfeeding);

- age under 18 years (effectiveness and safety not established);

- Hypersensitivity to ramipril and other ACE inhibitors, thiazides or sulfonamide derivatives, as well as to any of the excipients of the drug.

With cautionuse in patients with severe coronary and cerebral arteries (risk reduction of blood flow in the excessive reduction in blood pressure), unstable angina, severe ventricular arrhythmias, congestive heart failure IV stage decompensated "cor pulmonale", conditions involving reduction of the bcc (m. h. diarrhea, vomiting), systemic connective tissue diseases, diabetes, suppression of medullary hemopoiesis, in elderly patients with aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy, bilateral renal artery stenosis or artery stenosis single kidney, gout, hyperkalemia, hyponatremia (including in patients receiving diuretics and diet restriction of salt intake), hypokalemia, hypercalcemia, ischemic heart disease,kidney and / or liver failure, liver cirrhosis.
PREGNANCY AND LACTATION

I do not take Hart ® -D I trimester of pregnancy. In the event of planned or confirmed pregnancy as soon as possible to switch to another therapy. Controlled studies of ACE inhibitor during pregnancy was performed.
Hart ® -A contraindicated in II and III trimester of pregnancy. Long-term use in trimesters II and III can cause toxic symptoms in the fetus (depression of renal function, oligohydramnios, delay of ossification of the skull) and newborn (neonatal kidney failure, hypotension, hyperkalaemia).
Long-term use of hydrochlorothiazide in the III trimester of pregnancy can cause fetal and placental ischemia, risk of growth retardation. Moreover, in some cases, the reception shortly before delivery may cause hypoglycemia and thrombocytopenia in neonates. Hydrochlorothiazide can reduce plasma volume and to reduce the fetoplacental circulation.
Women taking Hart ® -A pregnancy (starting with II trimester) need to pass ultrasound to verify the status of the kidneys and the skull of the fetus.
Hart ®D'contraindicated during breast-feeding. Ramipril and hydrochlorothiazide are excreted in breast milk. Reduce and eliminate the release of milk associated with the receiving thiazides during breastfeeding. hypersensitivity reactions may occur drug sulfonamides group, hyperkalemia and kernicterus. Because of the possibility of serious side effects in infants it is necessary to consider the termination of breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER

Patients with kidney failure require correction dosing regimen. At moderate renal impairment (creatinine clearance of 20 to 50 ml / min per 1.73 m 2 of body surface) an initial dose is typically 1.25 mg 1 time / day (1 tab. 1.25 mg / day). The maximum daily dose should not exceed 5 mg.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

When hepatic dysfunction may occur equally frequently increased or decreased drug effect Hart ® , therefore, for early treatment of these patients require close medical supervision. The maximum daily dose in such cases should not exceed 2.5 mg.
APPLICATION FOR CHILDREN

Hart ® -D is not recommended for children and adolescents (under 18 years) due to a lack of data on safety and efficacy in this age group.
APPLICATION IN ELDERLY PATIENTS

For elderly patients and patients with CC from 30 to 60 ml / min individual doses of each component (Ramipril and hydrochlorothiazide) should be carefully selected to go to a combined preparation Hart ® -A.
SPECIAL INSTRUCTIONS

Ramipril
symptoms of hypotension
In patients with uncomplicated hypertension symptoms of hypotension are rare. In hypertensive patients receiving ramipril, the likelihood of arterial hypotension increases with a decrease in the bcc (eg, as a result of treatment with diuretics, salt intake restriction with food, dialysis, diarrhea or vomiting), as well as severe renin-dependent hypertension. Symptoms of hypotension have been observed in patients with heart failure, regardless of whether it is combined with renal insufficiency. It is most commonly seen in patients with more severe heart failure who are forced to take high doses of "loop" diuretics, who observed hyponatremia or functional renal impairment.Patients with an increased risk of arterial hypotension need close monitoring in the initial period of treatment and dose selection. This also applies to patients with ischemic heart disease or cerebral vascular disease, in which a significant drop in blood pressure can lead to myocardial infarction or cerebral circulation.
In the case of arterial hypotension of the patient must be put on the back, legs and make the lift / in infusion of sodium chloride solution if needed. Transient hypotensive response is not a contraindication to a subsequent dose.
Some patients with heart failure who have normal or low blood pressure, ramipril may cause further reduction in systolic blood pressure. This effect can be anticipated, so it is usually not a reason for discontinuation of treatment. If hypotension manifested symptoms, it may be necessary to reduce the dose or stop treatment.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy
Like other ACE inhibitors, ramipril should be used with caution in patients with aortic stenosis, or obstruction of left ventricular ejection (e.g., aortic stenosis and hypertrophic cardiomyopathy). In some cases, hemodynamic picture can make unacceptable reception fixed combination of ramipril and hydrochlorothiazide.
Primary aldosteronism (Conn's disease)
Using a fixed combination of ramipril and hydrochlorothiazide contraindicated because patients with primary aldosteronism is not sensitive to antihypertensives, the action of which is based on inhibition of the renin-angiotensin system.
Impaired renal function

In patients with heart failure at the beginning of treatment with ACE inhibitors may be a deterioration in renal function. In such situations, cases of acute renal failure are described, usually transitory.
Some patients with both renal arteries narrowing or stenosis of the artery to a solitary kidney, ACE inhibitors increase levels of blood urea and serum creatinine; These changes usually tested after discontinuation of medication. The probability of this is particularly high in patients with renal insufficiency. In the presence of renovascular hypertension is high risk of severe hypotension and renal insufficiency. In these patients, treatment should start under close medical supervision with low doses, which must be precisely matched. Because diuretics can contribute to the above-described clinical dynamics, during the first weeks of treatment with ramipril their intake should be discontinued and renal function requires careful monitoring.
Some hypertensive patients without apparent renal vascular disease ramipril, especially against the background of a diuretic, causing an increase in blood urea and serum creatinine; These changes tend to be minor and transient. The probability of their occurrence is higher in patients already suffering from renal impairment. In such cases it may be necessary to decrease the dose and / or discontinuation of diuretics and / or ramipril.
Condition after kidney transplantation
Due to the lack of experience with ramipril in patients who have recently had a kidney transplant, ramipril is not recommended in these patients.
Hypersensitivity / angioedema
Angioedema face, extremities, lips, tongue, vocal cords and / or larynx rarely develop in patients receiving ACE inhibitors, including ramipril. During treatment, angioedema can develop at any time. In this case, ramipril should be discontinued immediately, hold the appropriate treatment and to establish observation of the patient; before releasing the patient, make sure that all symptoms of edema eliminated. Even in cases where the swelling is limited only by the language and signs of respiratory failure are not available, patients may require prolonged observation since treatment angistaminnymi means and corticosteroids may not be sufficient. In rare cases, patients recorded death due to angioedema of the throat or tongue.
If the swelling extends to the tongue, vocal cords and larynx are very likely to overlap the respiratory tract, particularly in patients who previously underwent surgery on the organs of respiration. In such cases it is necessary to take measures of emergency treatment (administration of epinephrine / adrenaline / and / or maintain the airway). The patient should be under close medical supervision until complete and persistent disappearance of symptoms.
In patients with a history of angioedema unrelated to ACE inhibitors, the risk of angioedema in response to receiving an ACE inhibitor can be increased.
Anaphylactoid reactions in patients on hemodialysis
There are reports of anaphylactoid reactions in patients on hemodialysis using membranes with high hydraulic permeability (e.g., AN69) while the use of ACE inhibitors. In such cases, you should consider using another type of membranes or other antihypertensive drugs class.
Anaphylactoid reactions during LDL apheresis
Rarely, patients receiving ACE inhibitor, against LDL apheresis using dextran sulphate develop life-threatening anaphylactoid reactions. Such reactions can be avoided by temporarily refrain from receiving ACE inhibitor before each apheresis procedure.
desensitization
Patients taking ACE inhibitors, amid desensitizing therapy (eg, poison Hymenoptera), developing long-term anaphylactoid reactions. If such patients have refrained from taking ACE inhibitors during desensitization reactions were observed, but the introduction of random ACE provoked anaphylactoid reaction.
Liver failure
With ACE inhibitors bind development rare syndrome that starts with cholestatic jaundice or hepatitis and proceeds to fulminant hepatic necrosis, sometimes with fatal consequences. The mechanism of this syndrome is not clear. If patients taking ramipril, jaundice or significantly increases the activity of hepatic enzymes, the drug should be abolished, leaving the patient under medical supervision until symptoms disappear.
Neutropenia / agranulocytosis
It has been reported that in patients treated with ACE inhibitors may develop neutropenia / agranulocytosis, thrombocytopenia and anemia. In normal renal function, and in the absence of neutropenia complications is rare. Neutropenia and agranulocytosis are reversible and disappear after discontinuation of the ACE inhibitor. It is necessary to exercise extreme caution in the appointment of ramipril to patients suffering from connective tissue diseases with vascular manifestations undergoing treatment with antidepressants taking allopurinol or procainamide, as well as the combination of these factors, especially against the background of renal dysfunction. Some of these patients developed serious infections, which do not always lend themselves to intensive antibiotic therapy. When treating such patients using ramipril, to periodically check the number of leukocytes,and patients should be warned of the need to report any sign of infection.
Race
ACE inhibitors often cause angioneurotic edema in patients blacks compared with patients of other race.
Like other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients compared with those of other races, possibly because of the higher frequency individuals with low renin population black patients with hypertension.
Cough
has been reported that ACE inhibitors may be associated with cough. Characteristically, the cough is dry and permanent passes after discontinuation of the drug. Something that the cough is caused by taking an ACE inhibitor, should be considered its differential diagnostic feature.
Surgery / general anesthesia
In patients undergoing surgery or general anesthesia drugs to lower blood pressure, ramipril may block the formation of angiotensin II increase under the influence of compensatory renin release. If it is assumed that developing hypotension by this mechanism, it can be adjusted to increase BCC.
hyperkalemia
Some patients receiving ACE inhibitors, including ramipril, there is an increase in serum potassium levels. The group of hyperkalemia risk include patients with renal insufficiency or diabetes receiving potassium-sparing diuretics or kalisodergaszczye solezameniteli, as well as those patients who are taking other medications that increase the serum potassium level (e.g., heparin). If reception of the above preparations during the treatment with the ACE inhibitor is considered necessary, it is recommended regular monitoring of the level of potassium in serum.
Diabetics
Diabetic patients taking hypoglycemic agents for oral or insulin, necessary to carefully monitor blood glucose levels during the first month of treatment with an ACE inhibitor.
Lithium
is generally not recommended to combine intake of lithium and ramipril.
Hydrochlorothiazide

Impaired renal function

In patients with renal disease, thiazides may cause azotemia. Receiving drugs on the background of the kidney function may result in additive effects. If progressive renal failure, characterized by an increase in non-protein nitrogen, should carefully evaluate the need for therapy and consider discontinuation of diuretics.
Impaired liver function

Patients with impaired hepatic function or progressive violation of thiazides should be used with caution, because even small variations of water and electrolyte balance may precipitate hepatic coma.
Metabolic and endocrine effects
Treatment thiazides may decrease glucose tolerance. In diabetes may be necessary to dose adjustment of insulin or oral hypoglycemic agents. Thiazide therapy may cause the manifestation of latent diabetes mellitus. With thiazide diuretic therapy associated increase in cholesterol and triglyceride levels. In some patients receiving thiazide diuretics, may experience increased levels of uric acid or gout symptoms.
Gout
Some patients thiazide therapy may increase the level of uric acid and / or cause gout. However, ramipril may increase excretion of uric acid, thereby weakening the degree of increase of uric acid level
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