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Amprilan nd instructions for use. Instructions for use Amprilan nd (amprilan hd)

Dosage form

Tablets, 2.5 mg/12.5 mg, 5 mg/25 mg

Compound

One tablet contains

Amprilan® NL:

active substance - ramipril 2.5 mg

hydrochlorothiazide 12.5 mg

Amprilan® ND:

active substance - ramipril 5.0 mg

hydrochlorothiazide 25.0 mg

excipients: sodium bicarbonate, lactose monohydrate, sodium croscarmellose, pregelatinized starch (starch 1500), sodium stearyl fumarate

Description

Capsule-shaped flat tablets, from white to almost white, 4.0 x 8.0 mm in size, scored on one side and marked "12.5" on the other (for a dosage of 2.5 mg / 12.5 mg).

Capsule-shaped flat tablets, white to almost white, 5 x 10 mm in size, scored and marked "25" on one side and scored on the sides (for a dosage of 2.5 mg / 12.5 mg).

Pharmacotherapeutic group

Drugs affecting the renin-angiotensin system. AKF (angiotensin-converting enzyme) inhibitors in combination with diuretics.

Ramipril in combination with diuretics.

ATX code C09BA05

Pharmacological properties

Pharmacokinetics

Ramipril

Suction

After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract, the maximum plasma concentration of ramipril is reached within one hour, the degree of absorption is at least 56%, and the presence of food in the gastrointestinal tract does not significantly affect this. The bioavailability of the active metabolite of ramiprilat after oral administration of 2.5 mg and 5 mg of ramipril is 45%.

The maximum concentration of ramiprilat, the only active metabolite of ramipril, in plasma is reached within 2-4 hours after taking ramipril. Following regular once-daily doses of ramipril, steady-state plasma concentrations of ramiprilat are reached after approximately 4 days of treatment.

Distribution

The binding of ramipril to plasma proteins is approximately 73%, for ramiprilat about 56%.

Metabolism

Ramipril is almost completely metabolized to ramiprilat, converted to ramipril diketopiperazine ester and diketopiperazine acid, ramipril and ramiprilat glucuronides.

breeding

Excretion of metabolites occurs mainly by renal excretion. The decrease in plasma concentrations of ramiprilat is multiphasic. Due to the strong storage binding to the angiotensin-converting enzyme (ACE) and the slow dissociation from the bond with the enzyme, ramiprilat has a prolonged terminal elimination phase at very low plasma concentrations. The effective elimination half-life of ramipril after multiple doses of 5–10 mg ramipril once daily is 13–17 hours and is longer at lower doses (1.25–2.5 mg). The difference is due to the fact that the ability of the enzyme to bind to ramiprilat is saturating. After oral administration of a single dose of ramipril, neither ramipril nor its metabolite was detected in breast milk. However, it is not known what effect occurs with repeated administration.

Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal clearance of ramiprilat is proportional to creatinine clearance. This leads to an increase in the plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function.

In patients with impaired liver function, the metabolism of ramipril to ramiprilat is delayed as a result of a decrease in hepatic esterase activity, and plasma levels of ramipril increase in such patients.

However, the maximum concentrations of ramiprilat in these patients do not differ from the maximum concentrations in patients with normal liver function.

Hydrochlorothiazide
Suction

After oral administration, about 70% of hydrochlorothiazide is absorbed in the gastrointestinal tract. The maximum concentration of hydrochlorothiazide in plasma is reached within 1.5-5 hours.

Distribution.

For hydrochlorothiazide, plasma protein binding is 40%.
Metabolism

Hydrochlorothiazide is metabolized in the liver in very small amounts.
breeding

Hydrochlorothiazide is excreted by the kidneys almost completely (> 95%) unchanged. 50-70% of a single dose is eliminated within 24 hours.

The half-life is 5-6 hours.

Patients with impaired renal function

In patients with impaired renal function, renal excretion of hydrochlorothiazide is reduced, and renal clearance of hydrochlorothiazide is proportional to creatinine clearance. This leads to an increase in the concentration of hydrochlorothiazide in the blood plasma, which decreases more slowly than in individuals with normal renal function.

Patients with impaired liver function

In patients with cirrhosis of the liver, the pharmacokinetics of hydrochlorothiazide does not undergo significant changes. No pharmacokinetic studies of hydrochlorothiazide have been conducted in patients with heart failure.

Ramipril and hydrochlorothiazide

The simultaneous use of ramipril and hydrochlorothiazide does not affect their bioavailability. Fixed combinations of ramipril and hydrochlorothiazide can be considered bioequivalent to similar dosages of ramipril and hydrochlorothiazide alone.

Pharmacodynamics

Amprilan® NL and Amprilan® ND tablets have antihypertensive and diuretic effects. Ramipril and hydrochlorothiazide are used alone and in combination in antihypertensive therapy. The antihypertensive effect of both substances complements each other, and potassium losses caused by hydrochlorothiazide are reduced by ramipril.

Mechanism of action

Ramipril

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme, kininase II). In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to the active vasoconstrictor angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reducing the formation of angiotensin II and inhibition of the breakdown of bradykinin leads to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat leads to a decrease in aldosterone secretion. The mean response to ACE inhibitor monotherapy in black (Afro-Caribbean) patients with arterial hypertension (usually a category of hypertensive population with low renin levels) was lower than in other patients.

Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. Inhibits the reabsorption of sodium and chloride ions in the distal tubule. Increased renal excretion of these ions is accompanied by an increase in urine production (due to osmotic water binding). The excretion of potassium and magnesium also increases, while the excretion of uric acid decreases. Possible mechanisms of the hypotensive effect of hydrochlorothiazide are changes in sodium balance, a decrease in the volume of extracellular fluid and plasma, a change in renal vascular resistance, or a decrease in reactions to norepinephrine and angiotensin II.

Pharmacodynamic effect

Ramipril

The use of ramipril leads to a significant decrease in peripheral arterial resistance. As a rule, there are no significant changes in renal plasma flow or glomerular filtration rate. In patients with arterial hypertension, the administration of ramipril leads to a decrease in blood pressure, both in a horizontal and vertical position, which is not accompanied by a compensatory increase in heart rate.

In most patients, the antihypertensive effect occurs approximately 1-2 hours after oral administration of a single dose of the drug. The maximum effect after oral administration of a single dose usually occurs after 3-6 hours. The antihypertensive effect after taking a single dose usually persists for 24 hours.

With long-term treatment with ramipril, the maximum antihypertensive effect develops after 3-4 weeks. It has been proven that with long-term therapy, the antihypertensive effect persists for 2 years.

Sudden discontinuation of ramipril does not lead to a rapid and excessive increase in blood pressure.

Hydrochlorothiazide

Regarding hydrochlorothiazide, the onset of the diuretic effect occurs after approximately 2 hours and lasts for 6-12 hours, and the maximum effect occurs after 4 hours.

The antihypertensive effect occurs after 3-4 days of treatment and may persist for 1 week after completion of treatment.

The antihypertensive effect is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance and plasma renin activity.

Simultaneous use of ramipril and hydrochlorothiazide.

In clinical studies, the use of this combination resulted in a greater reduction in blood pressure than the use of each of the active substances separately. Probably, by blockade of the renin-angiotensin-aldosterone system, the simultaneous use of ramipril and hydrochlorothiazide contributes to the reversible loss of potassium associated with these diuretics.

The combination of an ACE inhibitor with a thiazide diuretic has a synergistic effect and also reduces the risk of hypokalemia caused by the use of a single diuretic.

Indications for use

Essential hypertension that is not adequately controlled

with monotherapy with ramipril or hydrochlorothiazide

Dosage and administration

For ingestion.

Amprilan® NL and Amprilan® ND tablets can be taken before, after or during a meal, as food intake does not affect its bioavailability. Tablets should be swallowed whole with liquid. It must not be chewed or crushed.

adults

The dose should be selected individually depending on the age of the patient, the profile of the disease and the level of blood pressure. The appointment of a fixed combination of ramipril / hydrochlorothiazide is usually recommended after individual selection of doses of these components separately.

The usual starting dose is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide. The usual maintenance dose is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide in the morning. If necessary, the dose can be gradually increased until the target blood pressure level is reached. The maximum dose is 5 mg ramipril and 25 mg hydrochlorothiazide.

In patients receiving simultaneous treatment with diuretics, caution is advised, since hypotension may occur after the start of treatment. It is necessary to reduce the dose of diuretics, or stop taking diuretics before starting therapy with a fixed combination of ramipril / hydrochlorothiazide.

Patients with renal insufficiency

The use of Amprilan® NL and Amprilan® ND is contraindicated in severe renal failure (creatinine clearance<30 мл / мин) из-за наличия гидрохлоротиазида в составе препарата.

Patients with a creatinine clearance between 30 and 60 ml/min should be treated with the lowest fixed dose combination of ramipril and hydrochlorothiazide after taking ramipril alone.

The maximum allowable doses are 5 mg of ramipril and 25 mg of hydrochlorothiazide per day.

Patients with liver failure

The use of Amprilan® NL and Amprilan® ND is contraindicated in severe liver failure.

In patients with mild to moderate hepatic insufficiency, treatment should only be started under strict medical supervision, where the maximum daily dose is 2.5 mg ramipril and 12.5 mg hydrochlorothiazide.

Elderly patients

Initial doses should be lower and subsequent dose increases should be more gradual due to the high likelihood of side effects, especially in very old and frail patients.

Amprilan® NL and Amprilan® ND are contraindicated for use in children and adolescents under the age of 18 years due to insufficient data on safety and efficacy.

Side effects

Often (>1/100,<1/10)

Dizziness, headache

Cough, bronchitis

Decompensation of diabetes mellitus, decreased glucose tolerance,

increased blood glucose levels, increased uric acid levels,

exacerbation of gout, increased cholesterol and / or TG due to

action of hydrochlorothiazide

Fatigue, asthenia

Uncommon (>1/1000,<1/100)

Myocardial ischemia, including angina pectoris, tachycardia, arrhythmia,

palpitations, peripheral edema

Decrease in the number of leukocytes, decrease in the number

erythrocytes, decreased hemoglobin levels, hemolytic anemia,

decrease in the number of platelets

Vertigo, paresthesia, tremor, imbalance, burning sensation,

dysgeusia, ageusia

Visual disturbances including blurred vision, conjunctivitis

Tinnitus

Sinusitis, shortness of breath, nasal congestion

Inflammatory manifestations of the gastrointestinal tract, digestive disorders,

abdominal pain, dyspepsia, gastritis, nausea, constipation, gingivitis

impaired renal function, including acute renal failure,

increased diuresis, increased blood urea levels, increased

blood creatinine level

Angioedema (in very exceptional cases,

fatal due to obstruction

respiratory tract)

Psoriatic dermatitis, hyperhidrosis, maculopapular exanthema,

itching, alopecia

Myalgia

Anorexia, decreased appetite, decreased potassium levels, feeling thirsty

Hypotension, decreased orthostatic blood pressure,

syncope, hyperemia

Chest pain, pyrexia

Cholestatic or cytolytic hepatitis (very exceptionally

cases - with a fatal outcome), an increase in the level of hepatic

enzymes and/or bilirubin conjugates, calculous cholecystitis

Transient erectile impotence

Decreased mood, apathy, anxiety, nervousness, sleep disturbance,

including drowsiness

Very rarely (<1/10,000):

Vomiting, aphthous stomatitis, glossitis, diarrhea, pain in the upper abdomen,

dry mouth

Frequency unknown (cannot be calculated from available data):

myocardial infarction

Bone marrow suppression, neutropenia, including

agranulocytosis, pancytopenia, eosinophilia, hemoconcentration at

fluid retention

Cerebral ischemia, including ischemic stroke and transient

ischemic attack, impaired psychomotor function, parosmia

Xanthopsia, decreased tear production

Hearing disorders

Bronchospasm, including exacerbation of bronchial asthma, allergic

alveolitis, non-cardiogenic pulmonary edema

Pancreatitis (in isolated cases, a fatal outcome was reported with

the use of ACE inhibitors), increased levels of enzymes

pancreas, angioedema of the small intestine,

sialadenitis

Worsening of underlying proteinuria, interstitial nephritis

Toxic epidermal necrolysis, Stevens-Johnson syndrome,

erythema multiforme, pemphigus, exacerbation of psoriasis,

exfoliative dermatitis, photosensitivity, onycholysis,

pemphigoid or lichenoid exanthema or enanthema, urticaria,

systemic lupus erythematosus

Arthralgia, muscle spasms, muscle weakness, musculoskeletal

stiffness, tetanic convulsions

Decreased plasma sodium levels, glucosuria, metabolic

alkalosis, hypochloremia, hypomagnesemia, hypercalcemia, dehydration

Thrombosis due to severe depletion of circulating blood volume,

vascular stenosis, hypoperfusion, Raynaud's syndrome, vasculitis.

Anaphylactic or anaphylactoid reactions to ramipril or

anaphylactic reactions to hydrochlorothiazide, increased levels

antinuclear antibodies

Acute liver failure, cholestatic jaundice,

Decreased libido, gynecomastia

Confusion of consciousness, impaired attention

Contraindications

Hypersensitivity to active substances or to any

another ACE inhibitor (angiotensin-converting enzyme),

hydrochlorothiazide, other thiazide diuretics, sulfonamides and

to any of the excipients

Angineurotic edema (hereditary, of unknown origin or

associated with previous angioedema that occurred while taking

ACE inhibitors or angiotensin II receptor antagonists)

Extracorporeal therapy leading to blood contact

with negatively charged surfaces

Bilateral stenosis of the renal arteries, stenosis of the artery of the only

kidneys, condition after kidney transplantation, hemodialysis

Severe renal failure (creatinine clearance< 30 мл/мин)

severe liver failure

Primary hyperaldosteronism

Pregnancy and lactation

Gout

Children and adolescents up to 18 years of age

Drug Interactions

Contraindicated combinations

Extracorporeal therapies that result in blood coming into contact with negatively charged surfaces, such as dialysis or hemofiltration with certain highly hydraulically permeable membranes (eg, polyacrylonitrile membranes), and low-density lipoprotein apheresis with dextran sulfate, due to an increased risk of severe anaphylactic reactions. If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

Carefully

Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim tacrolimus, cyclosporine): may lead to hyperkalemia, therefore careful monitoring of plasma potassium levels is required.

Antihypertensive agents (eg, diuretics) and other substances that may lower blood pressure (eg, nitrates, tricyclic antidepressants, anesthetics, increased alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin) increase the risk of hypotension).

Vasopressor sympathomimetic agents and some other substances (eg, epinephrine) may reduce the antihypertensive effect of ramipril, so it is recommended to control blood pressure.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatic agents, and other substances that can alter blood cell count increase the chance of hematological reactions

Lithium excretion may be reduced by the action of ACE inhibitors, so lithium toxicity may increase. Lithium levels need to be monitored. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and increase the already increased risk of lithium toxicity with ACE inhibitors. Therefore, the combination of ramipril and hydrochlorothiazide with lithium is not recommended.

Antidiabetic agents, including insulin, may cause hypoglycemic reactions. Hydrochlorothiazide may reduce the effect of antidiabetic drugs. Therefore, at the initial stage of joint therapy, particularly careful monitoring of blood glucose levels is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid lead to a decrease in the antihypertensive effect of Amprilan® NL and Amprilan® ND. Moreover, co-treatment with ACE inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) may lead to an increased risk of impaired renal function and hyperkalemia.

Due to the simultaneous use of hydrochlorothiazide, the anticoagulant effect of oral anticoagulants may be reduced.

Corticosteroids, ACTH, amphotericin B, carbenoxolone, large amounts of licorice, laxatives (in case of long-term use) and other kaliuretic diuretics or drugs that lower plasma potassium levels increase the risk of hypokalemia.

Electrolyte imbalance (eg, hypokalemia, hypomagnesemia) increases antiarrhythmic toxicity or reduces the antiarrhythmic effect of digitalis preparations, the active substances of which prolong the QT interval, and antiarrhythmic drugs.

Methyldopa increases the risk of hemolysis.

Colestyramine or other ion-exchange drugs reduce the absorption of hydrochlorothiazide. Sulfa diuretics should be taken 1 hour before

or 4-6 hours after taking the drug.

Amprilan® NL and Amprilan® ND enhance the effect of muscle relaxants

(like curare).

With the simultaneous use of calcium salts and drugs that increase the level of calcium in the blood plasma with hydrochlorothiazide, it leads to an increase in the concentration of calcium in the blood serum, so it is necessary to carefully monitor the level of calcium in the blood plasma.

Carbamazepine increases the risk of hyponatremia due to an additive effect with hydrochlorothiazide.
In case of dehydration caused by diuretics, including hydrochlorothiazide, there is an increased risk of developing acute renal failure, this is especially important when dosing

contrast agents containing iodine.

Hydrochlorothiazide is secreted in the distal tubules and reduces

excretion of penicillin.

Hydrochlorothiazide reduces the excretion of quinine.

special instructions

Patients with a highly activated renin-angiotensin-aldosterone system are at risk of a sharp decrease in blood pressure and deterioration of kidney function as a result of exposure to ACE inhibition, especially when an ACE inhibitor or concomitant diuretic is taken for the first time, or at the first increase in dosage.

The possibility of significant activation of the renin-angiotensin-aldosterone system should be considered, and medical supervision, including monitoring of blood pressure, should be provided, for example, in the following patients:

Patients with severe arterial hypertension

Patients with decompensated chronic heart

insufficiency

Patients with hemodynamically significant difficulty

left ventricular outflow and inflow (eg, aortic stenosis or

mitral valve)

Patients with unilateral renal artery stenosis

functioning kidney

Patients with existing or developing fluid deficiency or

salt (including patients taking diuretics)

Patients with liver cirrhosis and/or ascites

Patients who have undergone major surgery or drug anesthesia,

causing hypotension.

In general, it is recommended to correct dehydration, hypovolemia, or salt deficiency before starting treatment (however, in patients with heart failure, such corrective actions should be carefully weighed and checked for the risk of volumetric fluid overload).

Patients at risk of cardiac or cerebral ischemia in case of acute arterial hypotension

The initial phase of treatment requires special medical supervision.

Primary hyperaldosteronism

The combination of ramipril + hydrochlorothiazide is not the preferred treatment for primary hyperaldosteronism. In the case of the use of a combination of ramipril + hydrochlorothiazide in patients with primary hyperaldosteronism, careful monitoring of the level of potassium in the blood plasma is necessary.

Patients with liver disease

Electrolyte disturbances due to diuretic therapy, including hydrochlorothiazide, may lead to hepatic encephalopathy in patients with liver disease.

Monitoring of kidney function

Before and during treatment with the drug, it is necessary to monitor kidney function and adjust doses, especially in the first weeks of treatment. Particularly careful monitoring is necessary in patients with impaired renal function. There is a risk of impaired renal function, especially in patients with congestive heart failure or a kidney transplant.

kidney failure

In patients with renal insufficiency, the use of thiazides may cause uremia. In patients with impaired renal function, cumulative effects of the active substance may develop. If progressive renal failure develops, characterized by an increase in the level of non-protein nitrogen, treatment should be carefully evaluated and consideration should be given to interrupting diuretic treatment.

Electrolyte imbalance

As in other patients treated with diuretics, periodic determination of electrolytes in blood plasma should be carried out at appropriate intervals. Thiazides, including hydrochlorothiazide, may cause fluid or electrolyte imbalances (hypokalemia, hyponatremia, and hypochloremic alkalosis). Although hypokalemia may develop with the use of thiazide diuretics, concomitant therapy with ramipril may reduce the risk of diuretic-induced hypokalemia. Patients with cirrhosis of the liver, patients with rapid diuresis, patients receiving insufficient electrolytes, and patients receiving concomitant therapy with corticosteroids or ACTH (adrenocorticotropic hormone) are most at risk of hypokalemia. The first measurement of the level of potassium in the blood plasma should be carried out within the first week after the start of treatment. If low levels of potassium are detected, correction is necessary.

Dilutional hyponatremia may occur. Decreased sodium levels may initially be asymptomatic, so checking sodium levels regularly is essential. Most often, it is necessary to monitor in elderly patients and patients with cirrhosis of the liver.

Thiazides have shown increased excretion of magnesium from the body in the urine, which can lead to hypomagnesemia.

Hyperkalemia

Hyperkalemia has been observed in some patients treated with ACE inhibitors, including Amprilan® NL and Amprilan® ND.

Patients at risk of developing hyperkalemia include patients with renal insufficiency, elderly patients (over 70 years of age), patients with uncontrolled diabetes mellitus, or patients taking potassium salts, potassium-sparing diuretics and other active substances that increase plasma potassium levels, or patients with dehydration, acute heart failure and metabolic acidosis. If it is necessary to use the above drugs together, regular monitoring of the level of potassium in the blood plasma is recommended.

Hepatic encephalopathy

Electrolyte disturbances due to diuretic therapy, including hydrochlorothiazide, may lead to hepatic encephalopathy in patients with liver disease. In case of hepatic encephalopathy, treatment should be discontinued immediately.

Hypercalcemia

Hydrochlorothiazide stimulates calcium reabsorption in the kidneys and may lead to hypercalcemia. This can lead to false readings of the parathyroid function test.

Angioedema

There have been cases of angioedema in patients treated with ACE inhibitors, including ramipril.

In the event of angioedema, the use of Amprilan® NL or Amprilan® ND should be discontinued.

Then it is necessary to immediately begin emergency therapy. The patient should be observed for at least 12-24 hours and discharged only after the symptoms have completely disappeared.

There have been cases of angioedema of the intestine in patients treated with ACE inhibitors. Such patients experience abdominal pain (with or without nausea and vomiting).

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens increase with ACE inhibition. Before desensitization, consider temporarily stopping Amprilan® NL and Amprilan® ND.

Neutropenia / agranulocytosis

Cases of neutropenia/agranulocytosis have been observed in rare cases, and cases of bone marrow depression have also been noted. It is recommended to monitor the number of leukocytes to detect possible leukopenia. In the initial stage of treatment, as well as in patients with impaired renal function with associated collagen disease (for example, lupus erythematosus or scleroderma), and patients receiving other medications that can cause changes in the blood picture, it is recommended to monitor more frequently.

Ethnic features

Taking ACE inhibitors causes a higher risk of angioedema in patients of the black race than in others. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients than in others, possibly due to the higher prevalence of arterial hypertension with low renin levels in the black population.

Athletes
Hydrochlorothiazide may give a positive result when carried out

doping control test.

Metabolism and endocrine effects

Thiazide diuretics may lead to decreased glucose tolerance. Patients with diabetes may need to adjust the dose of insulin or oral hypoglycemic drug. During treatment with thiazide diuretics, latent diabetes mellitus can go into an open form.

Thiazide diuretics can also increase cholesterol and triglyceride levels. It is possible to develop hyperuricemia or an acute attack of gout in some patients when using thiazide diuretics.

Coughing has been reported with the use of ACE inhibitors. Usually the cough is non-productive, persistent and stops after treatment is stopped. Cough caused by ACE inhibitors should be considered as part of the differential diagnosis of cough.

Other
A reaction to the drug may occur in patients with or without a history of allergies or bronchial asthma. Information about exacerbation of systemic

lupus erythematosus has not been reported.

Amprilan® NL and Amprilan® ND contain lactose. Patients with rare hereditary problems of galactose intolerance, congenital lactase deficiency and malabsorption of glucose-galactose should not use these drugs

Features of the influence of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

Some side effects (for example, symptoms that occur when blood pressure is lowered, such as dizziness) can impair the patient's ability to concentrate and react, and therefore pose a risk in situations where such abilities of the patient are very important (for example, when operating machinery or driving vehicle). This is especially likely at the beginning of treatment or when switching from other drugs. It is not recommended to drive a vehicle or work with mechanisms within a few hours after the first dose of the drug or a subsequent increase in dosage.

Overdose

Symptoms: excessive peripheral vasodilation (with severe hypotension and shock), bradycardia, electrolyte disturbances, renal failure, cardiac arrhythmias, impaired consciousness, up to coma, cerebral convulsions, paresis and paralytic

intestinal obstruction.

In patients with prostatic hyperplasia, an overdose of hydrochlorothiazide may cause acute urinary retention.

Treatment: Patients should be closely monitored and treatment should be symptomatic and supportive. Suggested interventions include primary detoxification (gastric lavage, administration of absorbents) and measures to restore hemodynamic stability, including alpha-1-adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from the general circulation by hemodialysis.

Shelf life

Do not use after the expiration date

Terms of dispensing from pharmacies

On prescription

Manufacturer

Krka, d.d., Novo mesto, Slovenia

Šmarješka 6, 8501 Novo mesto, Slovenia

Description of the dosage form

The tablets are flat, capsule-shaped, white or almost white in color, scored on one side and marked "25" on the other.

Pharmacodynamics

Ramipril. ACE inhibitor, prevents the conversion of angiotensin I to angiotensin II without a compensatory increase in heart rate. Reduces the production of aldosterone, OPSS, pressure in the pulmonary capillaries, resistance in the pulmonary vessels, does not change the glomerular filtration rate, increases coronary blood flow. With prolonged use of the drug, myocardial hypertrophy decreases in patients with arterial hypertension, the frequency of arrhythmias decreases during myocardial reperfusion; improves blood circulation of the ischemic myocardium. The cardioprotective effect is due to the influence on the synthesis of PG, the induction of the formation of nitric oxide in endotheliocytes. The drug reduces platelet aggregation. The beginning of the hypotensive action is 1.5 hours after ingestion, the maximum effect is after 5–9 hours, the duration of action is 24 hours. Ramipril does not cause a withdrawal syndrome.

Hydrochlorothiazide. Thiazide diuretic, the diuretic effect of which is associated with a violation of the reabsorption of sodium, chlorine, potassium, magnesium, water ions in the distal nephron; delays the excretion of calcium ions, uric acid. Has antihypertensive properties. Virtually no effect on normal blood pressure. The diuretic effect occurs after 1-2 hours, reaches a maximum after 4 hours and lasts 6-12 hours. The antihypertensive effect occurs after 3-4 days, but it may take 3-4 weeks to achieve the optimal therapeutic effect. Ramipril and hydrochlorothiazide have an additive effect. Ramipril reduces the loss of potassium ions caused by hydrochlorothiazide.

Pharmacokinetics

The pharmacokinetics of ramipril and hydrochlorothiazide, when taken simultaneously, does not differ from that when they are administered separately.

Absorption of ramipril averages 50-60%. Eating does not affect the degree of absorption, but reduces its speed, the time to reach Cmax is 2-4 hours.

After oral administration, the absorption of hydrochlorothiazide is 60-80%. C max hydrochlorothiazide in the blood is achieved 1-5 hours after ingestion.

The relationship of ramipril with plasma proteins is 73%, ramiprilat - 56%. Communication with plasma proteins of hydrochlorothiazide - 64%. T 1/2 for ramipril - 5.1 h; in the phase of distribution and elimination, a decrease in the concentration of ramiprilat in the blood serum occurs with a T 1/2 of 4-5 days. T 1/2 increases with renal failure.

The volume of distribution of ramipril is 90 liters, ramiprilat is 500 liters.

The metabolism of ramipril occurs mainly in the liver with the formation of an active metabolite - ramiprilat, which inhibits ACE 6 times more actively than ramipril and an inactive metabolite of diketopiperazine, which are then glucuronized.

The drug is excreted mainly in the form of metabolites, by the kidneys - 60%, by the intestines - 40%. Hydrochlorothiazide is not metabolized and is rapidly excreted through the kidneys. T 1/2 is 5–15 hours.

Amprilan ND: Indications

Arterial hypertension (for patients who are indicated for combination therapy).

Amprilan ND: Contraindications

Ramipril

hypersensitivity to ramipril and any other ingredient of the drug or other ACE inhibitors;

angioedema in history, incl. associated with previous therapy with ACE inhibitors;

hemodynamically significant bilateral stenosis of the renal arteries;

stenosis of the artery of a single kidney;

condition after kidney transplantation;

hemodialysis;

renal failure (Cl creatinine<30 мл/мин);

hemodynamically significant aortic or mitral stenosis (risk of excessive reduction in blood pressure with subsequent impaired renal function);

hypertrophic obstructive cardiomyopathy;

primary hyperaldosteronism;

pregnancy and lactation;

age up to 18 years (efficacy and safety have not been established).

Carefully:

severe lesions of the coronary and cerebral arteries (danger of reducing blood flow with an excessive decrease in blood pressure);

unstable angina;

severe ventricular arrhythmias;

chronic heart failure stage IV;

decompensated "cor pulmonale";

renal and / or liver failure;

hyperkalemia, hyponatremia (including against the background of diuretics and a diet with limited salt intake);

conditions accompanied by a decrease in BCC (including diarrhea, vomiting);

systemic connective tissue diseases, incl. scleroderma and systemic lupus erythematosus;

diseases requiring the appointment of corticosteroids and immunosuppressants (lack of clinical experience);

diabetes;

oppression of bone marrow hematopoiesis;

elderly age.

Hydrochlorothiazide

hypersensitivity to the drug or other sulfonamides in history;

diabetes mellitus (severe forms);

chronic renal failure (Cl creatinine<20–30 мл/мин, анурия);

severe liver failure;

refractory hypokalemia, hypercalcemia, hyponatremia;

pregnancy;

lactation period;

age up to 3 years (solid dosage form).

Carefully:

hypokalemia, hyponatremia, hypercalcemia;

liver failure, cirrhosis;

bronchial asthma in history;

elderly age.

Use during pregnancy and lactation

The drug is contraindicated in pregnancy. If pregnancy occurs, the drug should be discontinued immediately. If necessary, the appointment of the drug during lactation, it is necessary to stop breastfeeding.

Dosage and administration

inside. The dose is selected individually. Daily dose for adults - 1 tab. per day.

In case of impaired renal function of mild or moderate degree (Cl creatinine> 30 ml / min, serum creatinine - approximately 3 mg / dl or 265 μmol / l), the usual dose of the drug is recommended. With Cl creatinine<30 мл/мин препарат применять не рекомендуется.

The duration of therapy is not limited.

Amprilan ND side effects

Ramipril

decrease in blood pressure, orthostatic hypotension, orthostatic collapse, tachycardia, rarely - arrhythmia, palpitations, exacerbation of Raynaud's syndrome. With an excessive decrease in blood pressure, mainly in patients with coronary artery disease and clinically significant vasoconstriction of the brain, myocardial ischemia (angina pectoris myocardial infarction) and cerebral ischemia (possibly with dynamic cerebrovascular accident or stroke) may develop.

development or intensification of symptoms of renal failure, proteinuria, oliguria, interstitial nephritis, nephrotic syndrome, decrease in urine volume, gynecomastia, decreased potency, libido.

From the side of the central nervous system: dizziness, headache, weakness, drowsiness, peripheral neuropathy (paresthesia), nervous irritability, anxiety, tremor, muscle spasm, mood disturbances, apathy, when used in high doses - insomnia, anxiety, depression, ataxia, confusion, fainting.

From the sense organs: vestibular disorders, taste disorders (eg metallic taste), smell, hearing and vision disorders, blepharitis, conjunctival dryness, lacrimation, tinnitus.

nausea, vomiting, diarrhea or constipation, pain in the epigastric region, intestinal obstruction, flatulence, pancreatitis, hepatitis, cholestatic jaundice, cholecystitis (in the presence of cholelithiasis), impaired liver function with the development of liver failure, melena, ileus, dry mouth, thirst, decreased appetite, stomatitis, glossitis, inflammation of the salivary glands.

From the respiratory system:"dry" cough, bronchospasm, shortness of breath, rhinorrhea, rhinitis, sinusitis, pharyngitis, hoarseness, bronchitis, interstitial pneumonia, pulmonary embolism, pulmonary infarction, pulmonary edema.

Allergic reactions: skin rash, itching, urticaria, conjunctivitis, photosensitivity, angioedema of the face, extremities, lips, tongue, pharynx and / or larynx, exfoliative dermatitis, exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (syndrome Lyell), pemphigus, serositis, onycholysis, vasculitis, myositis, muscle weakness, myalgia, arthralgia, arthritis, eosinophilia.

Others: convulsions, alopecia, herpes zoster, hyperthermia, increased sweating.

Laboratory indicators: hypercreatininemia, increased urea nitrogen, increased activity of "liver" enzymes, hyperbilirubinemia, hyperkalemia, hyponatremia, anemia, decreased hemoglobin and hematocrit, neutropenia, thrombocytopenia, agranulocytosis, pancytopenia, hemolytic anemia, the appearance of antinuclear antibodies.

Effect on the fetus: dysfunction in the fetus, decreased blood pressure in the fetus and newborn, impaired renal function, hyperkalemia, hypoplasia of the bones of the skull, oligohydramnios, contracture of the limbs, deformation of the bones of the skull, hypoplasia of the lungs.

Hydrochlorothiazide

From the side of water-electrolyte and acid-base balance: possible development of hypokalemia and hypochloremic alkalosis (dry mouth, increased thirst, heart rhythm disturbances, mood and mental changes, cramps or muscle pain, nausea, vomiting, weakness; with hypochloremic alkalosis, hepatic encephalopathy or hepatic coma may develop), hyponatremia (confusion consciousness, convulsions, apathy, slowing down of the thinking process, fatigue, irritability), hypomagnesemia (arrhythmias).

From the hematopoietic system: agranulocytosis, thrombocytopenia, hemolytic and aplastic anemia, leukocytopenia, eosinophilia, neutropenia, pancytopenia.

From the side of the cardiovascular system: arrhythmia, orthostatic hypotension, tachycardia.

From the digestive system: cholecystitis, pancreatitis, jaundice, diarrhea, sialadenitis, constipation, anorexia, epigastric pain.

From the side of metabolism: hypercholesterolemia, hypertriglyceridemia, hyperglycemia, glucosuria, hyperuricemia, hypercalcemia, exacerbation of gout.

From the side of the central nervous system: depression, sleep disturbance, anxiety, paresthesia, confusion, dizziness.

From the sense organs: xanthopsia, visual impairment.

From the genitourinary system: impaired renal function, reduced potency, interstitial nephritis.

Allergic reactions: skin rash, urticaria, purpura, necrotizing vasculitis, Stevens-Johnson syndrome, respiratory distress syndrome (pneumonitis, non-cardiogenic pulmonary edema), toxic epidermal necrolysis, photosensitivity; anaphylactic reactions (up to life-threatening anaphylactic shock).

Others: hyperthermia, weakness.

Overdose

Ramipril

Symptoms: pronounced decrease in blood pressure, bradycardia, shock, impaired water and electrolyte balance, acute renal failure, stupor, dry mouth, weakness, drowsiness.

Treatment: give the patient a horizontal position with raised legs, in mild cases of overdose - gastric lavage, the introduction of adsorbents and sodium sulfate (it is advisable to take measures within the first 30 minutes after taking the drug). With a decrease in blood pressure - in / in the introduction of catecholamines, angiotensin II; with bradycardia - the use of a pacemaker. The drug is not excreted during hemodialysis.

Hydrochlorothiazide

Symptoms: hypokalemia (adynamia, paralysis, constipation, arrhythmias), drowsiness, decreased blood pressure.

Treatment: infusion of electrolyte solutions; compensation for K + deficiency (prescription of potassium preparations and potassium-sparing diuretics).

Interaction

Ramipril

Enhances the inhibitory effect of ethanol on the central nervous system.

Salt intake with food may reduce the hypotensive effect of ramipril.

The simultaneous use of ramipril and other drugs that reduce blood pressure (for example, diuretics, nitrates, tricyclic antidepressants, agents for general anesthesia) leads to an increase in the hypotensive effect of ramipril.

The simultaneous appointment of ramipril and potassium preparations or potassium-sparing diuretics can cause hyperkalemia.

Vasopressor sympathomimetics (epinephrine, norepinephrine) may reduce the hypotensive effect of ramipril. In this regard, with simultaneous treatment, blood pressure levels should be carefully monitored.

The simultaneous appointment of ramipril and allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics increases the likelihood of changes in the peripheral blood picture (risk of developing leukopenia).

The simultaneous appointment of ramipril and lithium preparations leads to a decrease in the excretion of lithium, so it is necessary to control the concentration of lithium in the blood serum - the risk of toxic effects.

ACE inhibitors may enhance the effect of hypoglycemic agents (eg insulin or sulfonylurea derivatives), which in some cases may cause hypoglycemia. In this regard, blood sugar levels should be carefully monitored, especially at the beginning of joint use.

Simultaneous use of ramipril and NSAIDs (for example, acetylsalicylic acid and indomethacin) may weaken the hypotensive effect of ramipril. In addition, simultaneous use can cause hyperkalemia and increase the risk of impaired renal function.

Simultaneous use of ramipril with estrogens may weaken the hypotensive effect.

The simultaneous use of heparin and ramipril can cause hyperkalemia.

Anaphylactic and anaphylactoid reactions to stinging insect venom (possibly to other allergens) are more pronounced during treatment with ACE inhibitors.

Hydrochlorothiazide

With the simultaneous use of digitalis glycosides with thiazide diuretics, the likelihood of toxic effects of glycosides (including increased excitability of the ventricles) increases due to the likely development of hypokalemia and hypomagnesemia.

Drugs that are intensively bound to blood proteins (indirect anticoagulants, clofibrate, NSAIDs) increase the diuretic effect of hydrochlorothiazide.

The hypotensive effect of hydrochlorothiazide is enhanced by vasodilators, beta-blockers, barbiturates, phenothiazines, tricyclic antidepressants, ethanol.

Hydrochlorothiazide enhances the neurotoxicity of salicylates, weakens the effect of oral hypoglycemic agents, norepinephrine, epinephrine and anti-gout drugs, enhances the cardiotoxic and neurotoxic effects of lithium preparations, the effect of peripheral muscle relaxants, and reduces the excretion of quinidine.

With the simultaneous administration of methyldopa, the development of hemolysis is possible.

Colestyramine reduces the absorption of hydrochlorothiazide.

Hydrochlorothiazide reduces the effect of oral contraceptives.

special instructions

Ramipril

At the beginning of treatment, it is necessary to evaluate renal function. It is necessary to carefully monitor renal function during treatment with ramipril, especially in patients with impaired renal function, with damage to the renal vessels (for example, clinically insignificant stenosis of the renal arteries or hemodynamically significant stenosis of the artery of a single kidney); heart failure.

The risk of hypersensitivity and allergic-like (anaphylactoid) reactions is increased in patients who are simultaneously taking ACE inhibitors and undergoing hemodialysis procedures using AN69 dialysis membranes. Similar reactions have been reported with low-density lipoprotein apheresis with dextran sulfate, so this method should be avoided during treatment with ACE inhibitors.

During treatment with ramipril in patients with impaired renal function, especially with simultaneous treatment with diuretics, the level of urea and creatinine in the blood serum may increase. In this case, treatment should be continued with smaller doses of ramipril or the drug should be discontinued. In patients with impaired renal function, the risk of hyperkalemia is increased.

In patients with impaired hepatic function, due to a decrease in the activity of "liver" enzymes, the metabolism of ramipril and the formation of the active metabolite may be slowed down. In this regard, the treatment of such patients should be started only under strict medical supervision.

Care must be taken when prescribing ramipril to patients on a low-salt or salt-free diet (increased risk of arterial hypotension). In patients with reduced BCC (as a result of diuretic therapy), during dialysis, with diarrhea and vomiting, symptomatic hypotension may develop.

Transient arterial hypotension is not a contraindication for continuing treatment after stabilization of blood pressure. In case of recurrence of severe arterial hypotension, the dose should be reduced or the drug should be discontinued. In patients undergoing major surgery or receiving other agents that cause arterial hypotension during general anesthesia, ramipril can cause blockade of the formation of angiotensin II with compensatory renin release. If the physician associates the development of arterial hypotension with the mechanism mentioned above, arterial hypotension can be corrected by increasing the volume of blood plasma.

In rare cases, agranulocytosis, erythrocytopenia, thrombocytopenia, hemoglobinemia, or bone marrow depression have been observed during treatment with ACE inhibitors. At the beginning and during treatment, it is necessary to monitor the number of white blood cells to detect possible neutropenia / agranulocytosis. More frequent monitoring is recommended in patients with renal insufficiency, with connective tissue diseases (for example, systemic lupus erythematosus or scleroderma) and in patients who simultaneously take drugs that affect hematopoiesis (see "Interactions"). The count of blood cells should also be carried out in the event of clinical signs of neutropenia / agranulocytosis and increased bleeding.

In patients with arterial hypertension during treatment with ramipril, an increase in the level of potassium in the blood serum is rarely observed. The risk of hyperkalemia increases with chronic heart failure, simultaneous treatment with potassium-sparing diuretics (spironolactone, amiloride, triamterene) and the appointment of potassium preparations.

When using ACE inhibitors during desensitization therapy to aspen or bee venom, anaphylactoid reactions (eg, arterial hypotension, shortness of breath, vomiting, skin rash) may occur, which can be life-threatening. Hypersensitivity reactions may occur with insect stings (eg bees or wasps). If it is necessary to carry out desensitizing treatment with bee or wasp venom, it is necessary to cancel ACE inhibitors and continue treatment with suitable drugs from other groups.

Hydrochlorothiazide

To prevent potassium and magnesium deficiency, a diet with a high content of them, potassium-sparing diuretics, potassium and magnesium salts are prescribed. Regular monitoring of plasma potassium, glucose, uric acid, lipids and creatinine is necessary.

Influence on the ability to drive a car and mechanisms. During the period of treatment, care must be taken when driving vehicles, as well as during classes of potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.

Instructions for the medical use of the drug

Description of the pharmacological action

Antihypertensive combination drug.

Indications for use

Arterial hypertension (for patients who are indicated for combination therapy).

Release form

tablets 5 mg + 25 mg; blister 7, cardboard pack 2,4,8,12,14.
tablets 5 mg + 25 mg; blister 10, cardboard pack 3,6,9.

Pharmacodynamics

Ramipril. ACE inhibitor, prevents the conversion of angiotensin I to angiotensin II without a compensatory increase in heart rate. Reduces the production of aldosterone, OPSS, pressure in the pulmonary capillaries, resistance in the pulmonary vessels, does not change the glomerular filtration rate, increases coronary blood flow. With prolonged use of the drug, myocardial hypertrophy decreases in patients with arterial hypertension, the frequency of arrhythmias decreases during myocardial reperfusion; improves blood circulation of the ischemic myocardium. The cardioprotective effect is due to the influence on the synthesis of PG, the induction of the formation of nitric oxide in endotheliocytes. The drug reduces platelet aggregation. The beginning of the hypotensive action is 1.5 hours after ingestion, the maximum effect is after 5–9 hours, the duration of action is 24 hours. Ramipril does not cause a withdrawal syndrome.

Hydrochlorothiazide. Thiazide diuretic, the diuretic effect of which is associated with a violation of the reabsorption of sodium, chlorine, potassium, magnesium, water ions in the distal nephron; delays the excretion of calcium ions, uric acid. Has antihypertensive properties. Virtually no effect on normal blood pressure. The diuretic effect occurs after 1-2 hours, reaches a maximum after 4 hours and lasts 6-12 hours. The antihypertensive effect occurs after 3-4 days, but it may take 3-4 weeks to achieve the optimal therapeutic effect. Ramipril and hydrochlorothiazide have an additive effect. Ramipril reduces the loss of potassium ions caused by hydrochlorothiazide.

Pharmacokinetics

The pharmacokinetics of ramipril and hydrochlorothiazide, when taken simultaneously, does not differ from that when they are administered separately.

Absorption of ramipril averages 50-60%. Eating does not affect the degree of absorption, but reduces its speed, the time to reach Cmax is 2-4 hours.

After oral administration, the absorption of hydrochlorothiazide is 60-80%. Cmax of hydrochlorothiazide in the blood is achieved 1-5 hours after ingestion.

The relationship of ramipril with plasma proteins is 73%, ramiprilat - 56%. Communication with plasma proteins of hydrochlorothiazide - 64%. T1 / 2 for ramipril - 5.1 h; in the phase of distribution and elimination, a decrease in the concentration of ramiprilat in the blood serum occurs with a T1 / 2 of 4-5 days. T1 / 2 increases with renal failure.

The volume of distribution of ramipril is 90 liters, ramiprilat is 500 liters.

Use during pregnancy

Contraindications for use

Ramipril

Hypersensitivity to ramipril and any other ingredient of the drug or other ACE inhibitors;

Angioedema in history, incl. associated with previous therapy with ACE inhibitors;

Hemodynamically significant bilateral stenosis of the renal arteries;

Stenosis of the artery of a single kidney;

Condition after kidney transplantation;

Hemodialysis;

Renal failure (Cl creatinine
hemodynamically significant aortic or mitral stenosis (risk of excessive reduction in blood pressure with subsequent impaired renal function);

Hypertrophic obstructive cardiomyopathy;

Primary hyperaldosteronism;

Pregnancy and lactation;

Age up to 18 years (efficacy and safety not established).

Carefully:

Severe lesions of the coronary and cerebral arteries (danger of reducing blood flow with an excessive decrease in blood pressure);

Unstable angina;

Severe ventricular arrhythmias;

Chronic heart failure stage IV;

Decompensated "cor pulmonale";

Renal and / or liver failure;

Hyperkalemia, hyponatremia (including against the background of diuretics and a diet with limited salt intake);

Conditions accompanied by a decrease in BCC (including diarrhea, vomiting);

Systemic connective tissue diseases, incl. scleroderma and systemic lupus erythematosus;

Diseases requiring the appointment of corticosteroids and immunosuppressants (lack of clinical experience);

Diabetes;

Inhibition of bone marrow hematopoiesis;

Elderly age.

Hydrochlorothiazide

Hypersensitivity to the drug or other sulfonamides in history;

Gout;

Diabetes mellitus (severe forms);

Chronic renal failure (Cl creatinine
severe liver failure;

Refractory hypokalemia, hypercalcemia, hyponatremia;

Pregnancy;

lactation period;

Age up to 3 years (solid dosage form).

Carefully:

Hypokalemia, hyponatremia, hypercalcemia;

Liver failure, cirrhosis;

Bronchial asthma in history;

Elderly age.

Side effects

Ramipril

From the side of the cardiovascular system: decreased blood pressure, orthostatic hypotension, orthostatic collapse, tachycardia, rarely - arrhythmia, palpitations, exacerbation of Raynaud's syndrome. With an excessive decrease in blood pressure, mainly in patients with coronary artery disease and clinically significant vasoconstriction of the brain, myocardial ischemia (angina pectoris myocardial infarction) and cerebral ischemia (possibly with dynamic cerebrovascular accident or stroke) may develop.

From the genitourinary system: development or intensification of symptoms of renal failure, proteinuria, oliguria, interstitial nephritis, nephrotic syndrome, decrease in urine volume, gynecomastia, decreased potency, libido.

From the side of the central nervous system: dizziness, headache, weakness, drowsiness, peripheral neuropathy (paresthesia), nervous irritability, anxiety, tremor, muscle spasm, mood disturbances, apathy, when used in high doses - insomnia, anxiety, depression, ataxia, confusion , fainting.

On the part of the senses: vestibular disorders, taste disturbances (for example, a metallic taste), smell, hearing and vision, blepharitis, conjunctival dryness, lacrimation, tinnitus.

From the digestive system: nausea, vomiting, diarrhea or constipation, pain in the epigastric region, intestinal obstruction, flatulence, pancreatitis, hepatitis, cholestatic jaundice, cholecystitis (in the presence of cholelithiasis), abnormal liver function with the development of liver failure, melena, ileus, dryness in the mouth, thirst, loss of appetite, stomatitis, glossitis, inflammation of the salivary glands.

From the respiratory system: "dry" cough, bronchospasm, shortness of breath, rhinorrhea, rhinitis, sinusitis, pharyngitis, hoarseness, bronchitis, interstitial pneumonia, pulmonary embolism, pulmonary infarction, pulmonary edema.

Allergic reactions: skin rash, itching, urticaria, conjunctivitis, photosensitivity, angioedema of the face, extremities, lips, tongue, pharynx and / or larynx, exfoliative dermatitis, exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), pemphigus, serositis, onycholysis, vasculitis, myositis, muscle weakness, myalgia, arthralgia, arthritis, eosinophilia.

Other: convulsions, alopecia, herpes zoster, hyperthermia, increased sweating.

Laboratory indicators: hypercreatininemia, increased urea nitrogen, increased activity of "liver" enzymes, hyperbilirubinemia, hyperkalemia, hyponatremia, anemia, decreased hemoglobin and hematocrit, neutropenia, thrombocytopenia, agranulocytosis, pancytopenia, hemolytic anemia, the appearance of antinuclear antibodies.

Effect on the fetus: impaired function in the fetus, decreased blood pressure in the fetus and newborn, impaired renal function, hyperkalemia, hypoplasia of the bones of the skull, oligohydramnios, contracture of the limbs, deformity of the bones of the skull, hypoplasia of the lungs.

Hydrochlorothiazide

On the part of the water-electrolyte and acid-base balance: hypokalemia and hypochloremic alkalosis may develop (dry mouth, increased thirst, heart rhythm disturbances, mood and mental changes, muscle cramps or pain, nausea, vomiting, weakness; with hypochloremic alkalosis it is possible development of hepatic encephalopathy or hepatic coma), hyponatremia (confusion, convulsions, apathy, slowing of the thinking process, fatigue, irritability), hypomagnesemia (arrhythmias).

From the hemopoietic system: agranulocytosis, thrombocytopenia, hemolytic and aplastic anemia, leukocytopenia, eosinophilia, neutropenia, pancytopenia.

From the side of the cardiovascular system: arrhythmia, orthostatic hypotension, tachycardia.

From the digestive system: cholecystitis, pancreatitis, jaundice, diarrhea, sialadenitis, constipation, anorexia, epigastric pain.

From the side of metabolism: hypercholesterolemia, hypertriglyceridemia, hyperglycemia, glucosuria, hyperuricemia, hypercalcemia, exacerbation of gout.

From the side of the central nervous system: depression, sleep disturbance, anxiety, paresthesia, confusion, dizziness.

From the sensory organs: xanthopsia, visual impairment.

From the genitourinary system: impaired renal function, decreased potency, interstitial nephritis.

Allergic reactions: skin rash, urticaria, purpura, necrotizing vasculitis, Stevens-Johnson syndrome, respiratory distress syndrome (pneumonitis, non-cardiogenic pulmonary edema), toxic epidermal necrolysis, photosensitivity; anaphylactic reactions (up to life-threatening anaphylactic shock).

Others: hyperthermia, weakness.

Dosage and administration

inside. The dose is selected individually. Daily dose for adults - 1 tab. per day.

Overdose

Ramipril

Symptoms: pronounced decrease in blood pressure, bradycardia, shock, impaired water and electrolyte balance, acute renal failure, stupor, dry mouth, weakness, drowsiness.

Treatment: give the patient a horizontal position with raised legs, in mild cases of overdose - gastric lavage, the introduction of adsorbents and sodium sulfate (it is advisable to take measures within the first 30 minutes after taking the drug). With a decrease in blood pressure - in / in the introduction of catecholamines, angiotensin II; with bradycardia - the use of a pacemaker. The drug is not excreted during hemodialysis.

Hydrochlorothiazide

Symptoms: hypokalemia (adynamia, paralysis, constipation, arrhythmias), drowsiness, decreased blood pressure.

Treatment: infusion of electrolyte solutions; compensation for K + deficiency (prescription of potassium preparations and potassium-sparing diuretics).

Interactions with other drugs

Ramipril

Enhances the inhibitory effect of ethanol on the central nervous system.

Salt intake with food may reduce the hypotensive effect of ramipril.

The simultaneous appointment of ramipril and potassium preparations or potassium-sparing diuretics can cause hyperkalemia.

Simultaneous use of ramipril with estrogens may weaken the hypotensive effect.

The simultaneous use of heparin and ramipril can cause hyperkalemia.

Anaphylactic and anaphylactoid reactions to stinging insect venom (possibly to other allergens) are more pronounced during treatment with ACE inhibitors.

Hydrochlorothiazide

Drugs that are intensively bound to blood proteins (indirect anticoagulants, clofibrate, NSAIDs) increase the diuretic effect of hydrochlorothiazide.

The hypotensive effect of hydrochlorothiazide is enhanced by vasodilators, beta-blockers, barbiturates, phenothiazines, tricyclic antidepressants, ethanol.

With the simultaneous administration of methyldopa, the development of hemolysis is possible.

Colestyramine reduces the absorption of hydrochlorothiazide.

Hydrochlorothiazide reduces the effect of oral contraceptives.

Special instructions for admission

Hydrochlorothiazide

Influence on the ability to drive a car and mechanisms. During the period of treatment, care must be taken when driving vehicles, as well as during classes of potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.

Storage conditions

At a temperature not higher than 25 °C.

Best before date

Belonging to ATX-classification:

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Amprilan® ND is a combination of two active substances, ramipril and hydrochlorothiazide.
Ramipril belongs to a group of drugs called ACE inhibitors (angiotensin-converting enzyme inhibitors) and has the following effects:
- suppresses the production in your body of substances that increase blood pressure;
- relaxes and dilates blood vessels;
- facilitates the work of the heart to promote blood throughout the body.
Hydrochlorothiazide belongs to a group of drugs called thiazide diuretics, or diuretic tablets. It stimulates the body to produce more fluid (urine), which lowers your blood pressure.
Amprilan® ND is used to treat high blood pressure. The combination has a more pronounced antihypertensive effect and is used in cases where the components of the drug taken separately are not effective enough.

Do not take Amprilan® ND if you have

Allergy to ramipril, hydrochlorothiazide or any other auxiliary ingredient of the drug (see section "Composition");
- allergy (hypersensitivity) to drugs similar to Amprilan® ND (other ACE inhibitors or sulfonamide derivatives);
Symptoms of an allergic reaction may include a rash, difficulty swallowing or breathing, swelling of the lips, face, throat, or tongue.
- have ever had a serious allergic reaction called angioedema. Its signs include itching, hives, red spots on the arms, legs and throat, swelling of the throat and tongue, swelling around the eyes and lips, difficulty breathing and swallowing;
- you are undergoing dialysis or any other type of blood filtration. Depending on the equipment used, Amprilan® ND may not be suitable for your treatment;
- severe liver dysfunction;
- the level of some salts (calcium, potassium, sodium) is disturbed in the blood;
- kidney disease, in which the blood supply to the kidneys is disturbed (renal artery stenosis);
- during the last 6 months of pregnancy (see section "Pregnancy and breastfeeding");
- you are breastfeeding (see section "Pregnancy and breastfeeding");
- if you have diabetes or impaired kidney function and are taking blood pressure medicines containing aliskiren.
Do not take Amprilan® ND if any of the above apply to you. If you are not sure, check with your doctor before taking Amprilan® ND.

Special instructions and precautions

Consult with your doctor before taking Amprilan® ND:
- if you have impaired heart, liver or kidney function;
- if you have had significant fluid or salt loss (due to vomiting, diarrhoea, excessive sweating, following a low-salt diet, long-term use of diuretics (diuretics) or dialysis treatment);
- if you are going to be treated to reduce an allergic reaction to bee or wasp stings (desensitization);
- if you are scheduled for anesthesia, which may be necessary for surgery or any dental procedures. You may need to stop taking Amprilan® ND the day before your scheduled intervention. Consult with your doctor!
- if you have an elevated level of potassium in your blood (according to the results of a blood test);
- if you are taking medications or have conditions that cause low sodium levels in your blood. Your doctor may order blood tests at regular intervals to check your sodium levels in your blood, especially if you are an older person;
- if you are taking drugs called mTOR inhibitors (eg temsirolimus, everolimus, sirolimus) or vildagliptin, as these may increase your risk of angioedema, a severe allergic reaction;
- if you experience vision loss or eye pain, especially if you are at risk of developing glaucoma or are allergic to medicines containing penicillin or sulfonamides;
- if you have a collagen disease, such as scleroderma or systemic lupus erythematosus;
- if you are taking any of the following medicines used to treat high blood pressure:
an angiotensin II receptor blocker (ARB) (also known as sartans - for example, valsartan, telmisartan, irbesartan), particularly if you have kidney disease associated with diabetes;
aliskiren.
Your doctor may regularly check your kidney function, blood pressure, and the amount of electrolytes (such as potassium) in your blood.
See also the information under the heading "Do not take Amprilan® ND".
- The active ingredient hydrochlorothiazide may cause an unusual reaction resulting in reduced visual acuity and eye pain. These may be symptoms of increased pressure in the eyes, which can occur within hours or weeks after taking Amprilan® ND. Without treatment, this condition can lead to visual impairment.
You must tell your doctor if you think you are pregnant (or if you are likely to be pregnant). Amprilan® ND is not recommended during the first 3 months of pregnancy and may cause serious harm to your baby after 3 months of pregnancy (see section "Pregnancy and breast-feeding").

Children and teenagers
Amprilan® ND is not recommended for children and adolescents under 18 years of age. This is due to the lack of clinical experience in these age groups.

Other drugs and Amprilan® ND

Tell your doctor if you are taking, have recently taken or may take any other medicines, including over-the-counter medicines (including herbal medicines), as Amprilan® ND may affect the effect of some other medicines, and other medicines may affect the effect Amprilan® ND.
Tell your doctor if you are taking any of the following medicines. They can worsen the effect of Amprilan® ND:
- drugs used to relieve pain and reduce inflammation (for example, non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or indomethacin and aspirin).
- drugs to treat low blood pressure, shock, heart failure, asthma or allergies, such as ephedrine, norepinephrine or epinephrine. Your doctor will monitor your blood pressure.
Tell your doctor if you are taking any of the following medicines. They can increase the likelihood of adverse reactions when used together with Amprilan® ND:
- drugs used to relieve pain and reduce inflammation (for example, non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or indomethacin and aspirin);
- drugs that lower the level of potassium in the blood. These include drugs for constipation, diuretics, amphotericin B (used to treat fungal infections) and ACTH (used to test the effectiveness of adrenal function);
- anticancer drugs (chemotherapy);
- medicines for the treatment of cardiac dysfunction, including heart rhythm disturbances;
- drugs that prevent organ rejection after transplantation, such as cyclosporine;
- diuretics, such as furosemide;
- drugs that increase the level of potassium in the blood, such as spironolactone, triamterene, amiloride, potassium salts and heparin (used to thin the blood);
- anti-inflammatory steroids such as prednisolone;
- drugs to compensate for the lack of calcium;
- allopurinol (used to lower the level of uric acid in the blood);
- procainamide (for the treatment of heart rhythm disturbances);
- cholestyramine (to reduce the amount of lipids in the blood);
- carbamazepine (to treat epilepsy);
- trimethoprim and co-trimoxazole (to treat infections caused by bacteria);
- mTOR inhibitors (eg temsirolimus, everolimus, sirolimus) or vildagliptin (to treat diabetes), as they may increase the risk of angioedema, a severe allergic reaction.
Tell your doctor if you are taking any of the following medicines. Amprilan® ND may affect the effectiveness of these drugs:
- drugs for the treatment of diabetes, lowering blood sugar levels, intended for oral administration, and insulin. Amprilan® ND may lower blood sugar levels. Check your blood sugar regularly while taking Amprilan® ND;
- lithium (for the treatment of psychiatric diseases). Amprilan® ND may increase the level of lithium in the blood. The attending physician should regularly determine the level of lithium in the blood;
- medicines to relax the muscles;
- quinine (to treat malaria);
- medicines containing iodine (can be used for X-ray studies and other imaging methods in a hospital);
- penicillin (to treat infections);
- Oral blood thinners (oral anticoagulants), such as warfarin.
Your doctor may change your dose and/or take other precautions if you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the headings "Do not take Amprilan® ND" and "Special instructions and precautions").
If any of the above applies to you (or you are not sure), check with your doctor before taking Amprilan® ND.
Research results
Talk to your doctor before taking this medicine:
- If you are scheduled to have a parathyroid function test. Amprilan® ND may affect test results.
- If you are an athlete and are planning to take an anti-doping test. Amprilan® ND may give a false positive result.

Amprilan® ND with food, drink and alcohol
The use of alcohol in conjunction with the drug Amprilan® ND may cause dizziness or a state of mental disorder. If you are not sure how much alcohol you can drink while you are taking Amprilan® ND, talk to your doctor about this. drugs used to lower blood pressure and alcohol may enhance each other's effects.
- Amprilan® ND can be taken with or without food.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you are pregnant or have the possibility of pregnancy.
The use of the drug Amprilan® ND is not recommended in the first 12 weeks of pregnancy, and after the 13th week the drug should not be taken, as it can cause severe fetal developmental disorders.
If you become pregnant while being treated with Amprilan® ND, tell your doctor immediately. When a planned pregnancy is recommended to choose alternative methods of treatment.
You should not take Amprilan® ND while breastfeeding.
Consult with your doctor before taking any medications.

Driving vehicles and working with mechanisms

Do not drive or operate machinery until you have determined how Amprilan® ND affects you. You may feel dizzy while taking Amprilan® ND. The occurrence of this effect is most likely at the beginning of treatment or when the dose is increased. If this occurs, do not drive or operate machinery.

Important information about some ingredients

Amprilan® ND contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Application of the drug

Always take Amprilan® ND exactly as directed by your doctor. Check with your doctor if you are unsure.
Mode of application
- Take the drug by mouth at the same time each day, usually in the morning.
- Swallow the tablets whole, without crushing or chewing, with liquid.
How many tablets to take
Treatment of high blood pressure
Your doctor may adjust the dose of the drug to achieve the appropriate pressure.
Elderly patients
Your doctor will start treatment at the lowest dose and will gradually adjust your treatment.
If you have taken more Amprilan® ND than you should
Notify your doctor immediately or go to the nearest emergency room. Do not drive, ask to be driven or call an ambulance. Take the package of the drug with you so that the doctor knows exactly what you have taken.
If you forget to take Amprilan® ND
Do not take a double dose to make up for a missed one.
If you forget to take your medicine at the correct time, follow your regular dosing schedule by taking your next dose at the scheduled time.
If you have any further questions on the use of this drug, ask your doctor.

Possible adverse reactions

Like all medicines, Amprilan® ND can cause side effects, although not everyone gets them.
Stop taking Amprilan® ND and contact your doctor immediately if you notice any of the following serious side effects: you may need urgent medical attention:
- swelling of the face, lips or throat that makes it difficult to swallow or breathe, as well as itching and rashes. This may be a sign of a serious allergic reaction to Amprilan® ND.
- severe skin reactions, including rash, mouth ulcers, worsening of existing skin disease, redness, blistering or peeling of the skin (so-called Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme).
Tell your doctor right away if you have any of the following conditions:
- fast heart rate, irregular or fast heartbeat (palpitations), chest pain, tightness in the chest, or more serious problems, including heart attack and stroke.
- shortness of breath, cough lasting 2-3 days, loss of appetite. These may be signs of impaired lung function, including inflammation;
- easy bruising, prolonged bleeding or any signs of bleeding (such as bleeding gums), purple spots on the skin that develop more often than usual, infections, sore throat, fever, tiredness, weakness, dizziness or pale skin. These may be signs of impaired hematopoiesis or bone marrow function;
- Severe pain in the stomach, radiating to the back. This may be a sign of pancreatitis (inflammation of the pancreas);
- fever, chills, fatigue, loss of appetite, stomach pain, nausea, yellowing of the skin or eyes (jaundice). These may be signs of liver disease, such as hepatitis (inflammation of the liver) or damage to the liver.
Other side effects
Please tell your doctor if any of the following conditions become severe or last more than a few days.
Common (may affect up to 1 in 10 people):
- headache, feeling of weakness, fatigue;
- feeling of dizziness. The occurrence of this effect is more likely at the beginning of treatment or with an increase in the dose of Amprilan® ND;
- dry irritating cough or bronchitis;
- A blood test shows an increase in the amount of sugar in the blood. If you have diabetes, it may get worse;
- a blood test shows an increase in the level of uric acid or lipids in your blood;
Painful, reddened or swollen joints.
Uncommon (may affect up to 1 in 100 people):
- skin rashes, protruding or not protruding above the surface of the skin;
- redness of the skin of the face, weakness, hypotension (abnormally low blood pressure), especially if you get up or sit down quickly;
- imbalance (vertigo);
- itching and unusual sensations on the skin such as numbness, tingling, burning sensation or goosebumps on the skin (paresthesia);
- loss or change in taste sensations;
- sleep disturbance;
- a state of depression, anxiety, feeling unusually nervous or anxious;
- nasal congestion, inflammation of the sinuses (sinusitis), shortness of breath;
- inflammation of the gums (gingivitis), swelling of the mouth;
- redness, itching, swelling or tearing of the eyes;
- ringing in the ears;
- blurred vision;
- hair loss;
- chest pain;
- muscle pain;
- constipation, pain in the stomach or intestines;
- indigestion or nausea;
- increased fluid intake and increased frequency of urination during the day;
- increased sweating or feeling thirsty;
- loss or decrease in appetite (anorexia), reduced feeling of hunger;
- fast or irregular heartbeat;
- swelling of the hands and feet. This may be a sign of fluid retention in the body;
- fever;
- violation of sexual function in men;
- blood tests showing a decrease in the number of red blood cells, white blood cells, platelets or hemoglobin;
- blood tests showing abnormal liver, pancreas or kidney function;
- blood tests that show a decrease in the level of potassium in the blood.
Very rare (may affect up to 1 in 10,000 people):
- nausea, beginning diarrhea or heartburn;
- reddened swollen tongue or dry mouth;
- blood tests that show an increase in the level of potassium in the blood.
Frequency not known (frequency cannot be estimated from the available data):
- concentrated urine (dark color), sensitivity or disease state, muscle cramps, confusion and seizures, which may be caused by inadequate secretion of ADH (antidiuretic hormone). If you experience these symptoms, contact your doctor as soon as possible.
Other side effects:
Please tell your doctor if any of the following side effects get severe or last longer than a few days.
- impaired concentration, a feeling of anxiety or confusion;
- fingers and toes change color in the cold, tingling or soreness when warmed. It could be Raynaud's syndrome;
- an increase in the mammary glands in men;
- thickening of the blood;
- hearing impairment;
- dry eyes;
- visual perception of objects in yellow color;
- deterioration of vision and pain in the eyes (possible signs of acute myopia or angle-closure glaucoma);
- dehydration;
- swelling, pain and redness in the neck (inflammation of the salivary gland);
- swelling in the intestines, called "angioneurotic edema of the intestines", with symptoms such as abdominal pain, vomiting and diarrhea;
- increased photosensitivity;
- severe skin peeling, itching, pustular rash or other skin reactions such as a red rash on the skin of the face or forehead;
- skin rashes or hemorrhages;
- spots on the skin and cold extremities;
- changes in the nails (for example, softening or detachment of the nail);
- musculoskeletal stiffness or inability to move the jaw (tetany);
- muscle weakness or cramps;
- decreased sexual libido in men or women;
- blood in the urine. This may be a sign of kidney disease (interstitial nephritis);
- increased sugar levels in the urine;
- an increase in the level of certain white blood cells (eosinophilia) found during a blood test;
- a blood test indicates a decrease in the amount of formed elements in your blood (pancytopenia);
- a blood test showing changes in the levels of salts such as sodium, calcium, magnesium and chlorides in the blood.
- slowing down or impaired reactions;
- change in sense of smell;
- Difficulty breathing or exacerbation of asthma.
- severe eye pain, blurred or haloed vision, headache, increased tearing, nausea and vomiting, which may indicate a condition called glaucoma.
Reporting adverse reactions
If you experience any adverse reactions, please consult your physician. This recommendation applies to any possible adverse reactions, including those not listed in this package insert. By reporting adverse reactions, you help to get more information about the safety of the drug.

Store at a temperature not exceeding 25°C. Keep out of the reach of children.

Expiry date from date of manufacture

Product description

Tablets are white or almost white, flat, capsule-shaped, scored on one side and marked "25" on the other side.

pharmachologic effect

Ramipril.
An angiotensin-converting enzyme (ACE) inhibitor prevents the conversion of angiotensin I to angiotensin II without a compensatory increase in heart rate (HR). Reduces aldosterone production, total peripheral vascular resistance, pressure in the pulmonary capillaries, resistance in the pulmonary vessels, does not change the glomerular filtration rate, increases coronary blood flow. With prolonged use of the drug, myocardial hypertrophy decreases in patients with arterial hypertension, the frequency of arrhythmias decreases during myocardial reperfusion; improves blood circulation of the ischemic myocardium. The cardioprotective effect is due to the influence on the synthesis of prostaglandins, the induction of the formation of nitric oxide in endotheliocytes. The drug reduces platelet aggregation. The beginning of the hypotensive action is 1.5 hours after ingestion, the maximum effect is 5-9 hours, the duration of action is 24 hours. The drug has no withdrawal syndrome.
Hydrochlorothiazide.
Thiazide diuretic, the diuretic effect of which is associated with a violation of the reabsorption of sodium, chlorine, potassium, magnesium, water ions in the distal nephron; delays the excretion of calcium ions, uric acid. Has antihypertensive properties; hypotensive effect develops due to the expansion of arterioles. Virtually no effect on normal blood pressure (BP). The diuretic effect occurs after 1-2 hours, reaches a maximum after 4 hours and lasts 6-12 hours. The antihypertensive effect occurs after 3-4 days, but it may take 3-4 weeks to achieve the optimal therapeutic effect. Ramipril and hydrochlorothiazide have an additive effect. Ramipril reduces the loss of potassium ions caused by hydrochlorothiazide.

Pharmacokinetics

The pharmacokinetics of ramipril and hydrochlorothiazide, when taken simultaneously, does not differ from that when they are administered separately.
Absorption of ramipril averages 50-60%. Eating does not affect the degree of absorption, but reduces its speed, the time to reach the maximum concentration is 2-4 hours.
After oral administration, the absorption of hydrochlorothiazide is 60-80%. Cmax of hydrochlorothiazide in the blood is achieved 1-5 hours after ingestion. The relationship of ramipril with plasma proteins is 73%, ramiprilat - 56%. Communication with plasma proteins of hydrochlorothiazide - 64%. T1 / 2 for ramipril -5.1 h; in the phase of distribution and elimination, a decrease in the concentration of ramiprilat in the blood serum occurs from T1 / 2 - 4-5 days. T1 / 2 increases with renal failure. The volume of distribution of Ramipril is 90 liters, ramiprilat is 500 liters.
The metabolism of ramipril occurs mainly in the liver with the formation of the active metabolite ramiprilat, which inhibits ACE 6 times more actively than ramipril and the inactive metabolite diketopiperazine, which are then glucuronized. The drug is excreted mainly in the form of metabolites, by the kidneys - 60%, by the intestines - 40%. Hydrochlorothiazide is not metabolized and is rapidly excreted through the kidneys. T1 / 2 is 5-15 hours.

Indications for use

Arterial hypertension (for patients who are indicated for combination therapy).

Use during pregnancy and lactation

special instructions

Ramipril
At the beginning of treatment, it is necessary to evaluate renal function. It is necessary to carefully monitor renal function during treatment with ramipril, especially in patients with impaired renal function, with damage to the renal vessels (for example, clinically insignificant stenosis of the renal arteries or hemodynamically significant stenosis of the artery of a single kidney); heart failure.
The risk of hypersensitivity and allergic-like (anaphylactoid) reactions is increased in patients who are simultaneously taking ACE inhibitors and undergoing hemodialysis procedures using AN69 dialysis membranes. Similar reactions have been observed with low-density lipoprotein apheresis with dextran sulfate, so this method should be avoided during treatment with ACE inhibitors.
During treatment with ramipril in patients with impaired renal function, especially with simultaneous treatment with diuretics, the level of urea and creatinine in the blood serum may increase. In this case, treatment should be continued with smaller doses of ramipril or the drug should be discontinued. In patients with impaired renal function, the risk of hyperkalemia is increased.
In patients with impaired hepatic function, due to a decrease in the activity of "liver" enzymes, the metabolism of ramipril and the formation of the active metabolite may be slowed down. In this regard, the treatment of such patients should be started only under strict medical supervision.
Care must be taken when prescribing ramipril to patients on a low-salt or salt-free diet (increased risk of arterial hypotension). In patients with a reduced volume of circulating blood (as a result of diuretic therapy), during dialysis, with diarrhea and vomiting, symptomatic hypotension may develop.
Transient arterial hypotension is not a contraindication for continuing treatment after stabilization of blood pressure. In case of recurrence of severe arterial hypotension, the dose should be reduced or the drug should be discontinued. In patients undergoing major surgery or receiving other agents that cause arterial hypotension during general anesthesia, ramipril may cause blockade of angiotensin II formation due to compensatory renin release. If the physician associates the development of arterial hypotension with the mechanism mentioned above, arterial hypotension can be corrected by increasing the volume of blood plasma.
In rare cases, agranulocytosis, erythrocytopenia, thrombocytopenia, hemoglobinemia, or bone marrow depression have been observed during treatment with ACE inhibitors. At the beginning and during treatment, it is necessary to monitor the number of white blood cells to detect possible neutropenia / agranulocytosis. More frequent monitoring is recommended for
patients with renal insufficiency, with connective tissue diseases (eg, systemic lupus erythematosus or scleroderma) and in patients who simultaneously take drugs that affect hematopoiesis (see Interactions with other drugs). The count of blood cells should also be carried out in the event of clinical signs of neutropenia / agranulocytosis and increased bleeding.
In patients with arterial hypertension during treatment with ramipril, an increase in the level of potassium in the blood serum is rarely observed. The risk of hyperkalemia increases with chronic heart failure, simultaneous treatment with potassium-sparing diuretics (spironolactone, amiloride, triamterene) and the appointment of potassium preparations. When using ACE inhibitors during desensitization therapy to wasp or bee venom, anaphylactoid reactions (eg, arterial hypotension, shortness of breath, vomiting, skin rash) may occur, which can be life-threatening. Hypersensitivity reactions can occur with insect stings (for example, bees or wasps). If it is necessary to carry out desensitizing treatment with bee or wasp venom, it is necessary to cancel ACE inhibitors and continue treatment with suitable drugs from other groups.
Hydrochlorothiazide
To prevent K+ and Mg2+ deficiency, a diet with a high content of these salts, potassium-sparing diuretics, K+ and Mg2+ salts are prescribed. Regular monitoring of plasma potassium, glucose, uric acid, lipids and creatinine is necessary.
Influence on the ability to drive a car and mechanisms
During the period of treatment, care must be taken when driving vehicles, as well as during classes of potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.

With caution (Precautions)

With caution: severe lesions of the coronary and cerebral arteries (danger of reducing blood flow with an excessive decrease in blood pressure), unstable angina pectoris, severe ventricular arrhythmias, stage IV chronic heart failure, decompensated cor pulmonale, renal and / or liver failure, hyperkalemia, hyponatremia ( including against the background of diuretics and a diet with limited salt intake), conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), systemic connective tissue diseases, including scleroderma and systemic lupus erythematosus, diseases requiring the appointment of GCS ( glucocorticosteroids) and immunosuppressants (lack of clinical experience), diabetes mellitus, depression of bone marrow hematopoiesis, old age; With caution: hypokalemia, hyponatremia, hypercalcemia, coronary heart disease, liver failure, cirrhosis, history of bronchial asthma, old age.

Contraindications

Ramipril: a history of angioedema, including those associated with previous therapy with ACE inhibitors; hemodynamically significant bilateral stenosis of the renal arteries; stenosis of the artery of a single kidney; condition after kidney transplantation; hemodialysis; renal failure (creatinine clearance less than 30 ml / min.); hemodynamically significant aortic or mitral stenosis (risk of excessive reduction in blood pressure with subsequent impaired renal function); hypertrophic obstructive cardiomyopathy; primary hyperaldosteronism; pregnancy and lactation; age up to 18 years (efficacy and safety have not been established); hypersensitivity to ramipril and any other ingredient of the drug or other ACE inhibitors.
With caution: severe lesions of the coronary and cerebral arteries (danger of reducing blood flow with an excessive decrease in blood pressure), unstable angina pectoris, severe ventricular arrhythmias, stage IV chronic heart failure, decompensated cor pulmonale, renal and / or liver failure, hyperkalemia, hyponatremia ( including against the background of diuretics and a diet with limited salt intake), conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), systemic connective tissue diseases, including scleroderma and systemic lupus erythematosus, diseases requiring the appointment of GCS ( glucocorticosteroids) and immunosuppressants (lack of clinical experience), diabetes mellitus, depression of bone marrow hematopoiesis, old age.
Hydrochlorothiazide: gout; diabetes mellitus (severe forms); chronic renal failure (creatinine clearance less than 20-30 ml / min, anuria); severe liver failure; refractory hypokalemia, hypercalcemia, hyponatremia; pregnancy, lactation; age up to 3 years (solid dosage form); hypersensitivity to the drug or other sulfonamides in history.
With caution: hypokalemia, hyponatremia, hypercalcemia, coronary heart disease, liver failure, cirrhosis, history of bronchial asthma, old age.

Dosage and administration

inside. The dose is selected individually. The daily dose for adults is 1 tablet of Amprilan ND per day.
In case of impaired renal function of mild or moderate degree (creatinine clearance more than 30 ml / min., serum creatinine approximately 3 mg / dl or 265 μmol / l), the usual dose of the drug is recommended. With creatinine clearance less than 30 ml / min. the drug is not recommended.
The duration of therapy is not limited.

Overdose

Ramipril
Symptoms: pronounced decrease in blood pressure, bradycardia, shock, impaired water and electrolyte balance, acute renal failure, stupor, dry mouth, weakness, drowsiness.
Treatment: give the patient a horizontal position with raised legs, in mild cases of overdose - gastric lavage, the introduction of adsorbents and sodium sulfate (it is advisable to take measures within the first 30 minutes after taking the drug). With a decrease in blood pressure (BP) - intravenous administration of catecholamines, angiotensin II; with bradycardia - the use of Pacemaker. The drug is not excreted during hemodialysis.
Hydrochlorothiazide
Symptoms: hypokalemia (adynamia, paralysis, constipation, arrhythmias), drowsiness, decreased blood pressure.
Treatment: infusion of electrolyte solutions; compensation for K+ deficiency (prescription of K+ drugs and potassium-sparing diuretics).

Side effect

Ramipril
From the side of the cardiovascular system: decreased blood pressure, orthostatic hypotension, orthostatic collapse, tachycardia, rarely - arrhythmia, palpitations, exacerbation of Raynaud's syndrome. With an excessive decrease in blood pressure, mainly in patients with coronary heart disease and clinically significant vasoconstriction of the brain, myocardial ischemia (angina pectoris myocardial infarction) and cerebral ischemia (possibly with a dynamic violation of cerebral circulation or stroke) may develop.
From the genitourinary system: development or intensification of symptoms of renal failure, proteinuria, oliguria, interstitial nephritis, nephrotic syndrome, decrease in urine volume, gynecomastia, decreased potency, libido.
From the side of the central nervous system: dizziness, headache, weakness, drowsiness, peripheral neuropathy (paresthesia), nervous irritability, anxiety, tremor, muscle spasm, mood disturbances, apathy, when used in high doses - insomnia, anxiety, depression, ataxia, confusion, fainting.
From the senses: vestibular disorders, taste disorders (eg, metallic taste), smell, hearing and vision, blepharitis, conjunctival dryness, lacrimation, tinnitus.
From the digestive system: nausea, vomiting, diarrhea or constipation, pain in the epigastric region, intestinal obstruction, flatulence, pancreatitis, hepatitis, cholestatic jaundice, cholecystitis (in the presence of cholelithiasis), impaired liver function with the development of liver failure, melena, ileus, dryness in the mouth, thirst, loss of appetite, stomatitis, glossitis, inflammation of the salivary glands.
From the respiratory system: "dry" cough, bronchospasm, shortness of breath, rhinorrhea, rhinitis, sinusitis, pharyngitis, hoarseness, bronchitis, interstitial pneumonia, pulmonary embolism, pulmonary infarction, pulmonary edema.
Allergic reactions: skin rash, itching, urticaria, conjunctivitis, photosensitivity, angioedema of the face, extremities, lips, tongue, pharynx and / or larynx, exfoliative dermatitis, exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis ( Lyell's syndrome), pemphigus, serositis, onycholysis, vasculitis, myositis, muscle weakness, myalgia, arthralgia, arthritis, eosinophilia.
Other: convulsions, alopecia, herpes zoster, hyperthermia, increased sweating.
Laboratory indicators: hypercreatininemia, increased urea nitrogen, increased activity of "liver" enzymes, hyperbilirubinemia, hyperkalemia, hyponatremia, anemia, decreased hemoglobin and hematocrit, neutropenia, thrombocytopenia, agronulocytosis, pancytopenia, hemolytic anemia, the appearance of antinuclear antibodies.
Impact on the fetus: impaired fetal function, decreased blood pressure (BP) of the fetus and newborns, impaired renal function, hyperkalemia, hypoplasia of the skull bones, oligohydramnios, contracture of the limbs, deformity of the skull bones, pulmonary hypoplasia
Hydrochlorothiazide
On the part of the water-electrolyte and acid-base balance: hypokalemia and hypochloremic alkalosis may develop (dry mouth, increased thirst, heart rhythm disturbances, mood and mental changes, muscle cramps or pain, nausea, vomiting, weakness; with hypochloremic alkalosis it is possible development of hepatic encephalopathy or hepatic coma), hyponatremia (confusion, convulsions, apathy, slowing of the thinking process, fatigue, irritability), hypomagnesemia (arrhythmias).
From the hemopoietic system: agranulocytosis, thrombocytopenia, hemolytic and aplastic anemia, leukocytopenia, eosinophilia, neutropenia, pancytopenia.
From the side of the cardiovascular system: arrhythmia, orthostatic hypotension, tachycardia.
From the digestive system: cholecystitis, pancreatitis, jaundice, diarrhea, sialadenitis, constipation, anorexia, epigastric pain.
From the side of metabolism: hypercholesterolemia, hypertriglyceridemia, hyperglycemia, glucosuria, hyperuricemia, hypercalcemia, exacerbation of gout.
From the side of the central nervous system: depression, sleep disturbance, anxiety, paresthesia, confusion, dizziness.
From the sensory organs: xanthopsia, visual impairment.
From the genitourinary system: impaired renal function, decreased potency, interstitial nephritis.
Allergic reactions: skin rash, urticaria, purpura, necrotizing vasculitis, Stevens-Johnson syndrome, respiratory distress syndrome (pneumonitis, non-cardiogenic pulmonary edema), toxic epidermal necrolysis, photosensitivity; anaphylactic reactions (up to life-threatening anaphylactic shock).
Others: hyperthermia, weakness.

Compound

Active substance: ramipril 5 mg; hydrochlorothiazide 25 mg;
Excipients: sodium bicarbonate, lactose monohydrate, sodium croscarmellose, pregelatinized starch (starch 1500), sodium stearyl fumarate.

Interaction with other drugs

Ramipril
Enhances the inhibitory effect of ethanol on the central nervous system. Salt intake with food may reduce the hypotensive effect of ramipril.
With the simultaneous use of ramipril and other drugs that reduce blood pressure (for example, diuretics, nitrates, tricyclic antidepressants, agents for general anesthesia), it leads to an increase in the hypotensive effect of ramipril.
The simultaneous appointment of ramipril and potassium preparations or potassium-sparing diuretics can cause hyperkalemia.
Vasopressor sympathomimetics (epinephrine, norepinephrine) may reduce the hypotensive effect of ramipril. In this regard, with simultaneous treatment, blood pressure levels should be carefully monitored.
The simultaneous appointment of ramipril and allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics increases the likelihood of changes in the peripheral blood picture (risk of developing leukopenia).
The simultaneous appointment of ramipril and lithium preparations leads to a decrease in the excretion of lithium, it is necessary to control the concentration of lithium in the blood serum - the risk of toxic effects.
ACE inhibitors may enhance the effect of hypoglycemic agents (eg, insulin or sulfonylurea derivatives), which in some cases may cause hypoglycemia. In this regard, blood sugar levels should be carefully monitored, especially at the beginning of joint use.
The simultaneous use of ramipril and non-steroidal anti-inflammatory drugs (NSAIDs) (for example, acetylsalicylic acid and indomethacin) may weaken the hypotensive effect of ramipril. Additionally, simultaneous use may cause hyperkalemia and increase the risk of impaired renal function. Simultaneous use of ramipril with estrogens may weaken the hypotensive effect.
The simultaneous use of heparin and ramipril can cause hyperkalemia. Anaphylactic and anaphylactoid reactions to the venom of stinging insects (possibly to other allergens) are more pronounced during treatment with ACE inhibitors).
Hydrochlorothiazide
With the simultaneous use of digitalis glycosides with thiazide diuretics, the likelihood of toxic effects of glycosides (including increased excitability of the ventricles) increases due to the likely development of hypokalemia and hypomagnesemia.
Drugs that bind extensively to blood proteins (indirect anticoagulants, clofibrate, NSAIDs) increase the diuretic effect of hydrochlorothiazide. The hypotensive effect of hydrochlorothiazide is enhanced by vasodilators, beta-blockers, barbiturates, phenothiazines, tricyclic antidepressants, ethanol. Hydrochlorothiazide enhances the neurotoxicity of salicylates, weakens the effect of oral hypoglycemic agents, norepinephrine, epinephrine and anti-gout drugs, enhances the cardiotoxic and neurotoxic effects of lithium preparations, the effect of peripheral muscle relaxants, and reduces the excretion of quinidine. With the simultaneous administration of methyldopa, the development of hemolysis is possible. Colestyramine reduces the absorption of hydrochlorothiazide. Hydrochlorothiazide reduces the effect of oral contraceptives.

Release form

Tablets are white or almost white, flat, capsule-shaped, scored on one side and marked "25" on the other side.
1 tab. Active substance: ramipril 5 mg; hydrochlorothiazide 25 mg;
Excipients: sodium bicarbonate, lactose monohydrate, sodium croscarmellose, pregelatinized starch (starch 1500), sodium stearyl fumarate.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
7 pcs. - blisters (12) - packs of cardboard.
7 pcs. - blisters (14) - packs of cardboard.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (9) - packs of cardboard.