Ramazid N pills 5mg+12.5mg, 100pcs

Composition

Tablets are pink in color, with possible inclusions, flat, oblong, with a risk and engraving “R2” on one side and side risks.

Auxiliary substances:

sodium bicarbonate-5 mg,

calcium sulfate dihydrate-195.9 mg,

pregelatinized corn starch-36.4 mg,

sodium stearyl fumarate-2.6 mg,

reddish-brown dye PB24823-2.6 mg

Pharmacological action

A combined antihypertensive drug that includes the ACE inhibitor ramipril and the thiazide diuretic hydrochlorothiazide. It has antihypertensive and diuretic effects. It has antihypertensive and diuretic effects. The hypotensive effect of both components is almost additive.

Ramipril is an ACE inhibitor. It is a prodrug that is converted in the body to the active metabolite ramiprilate, which has an ACE inhibitory effect. ACE catalyzes the conversion of angiotensin I in tissues to the active vasoconstrictor angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reducing the amount of angiotensin II and inhibiting the breakdown of bradykinin leads to vasodilation. Since angiotensin II also stimulates the release of aldosterone, ramiprilate leads to a decrease in the release of aldosterone. Ramipril reduces OPSS.

Taking ramipril in patients with arterial hypertension reduces blood pressure in the standing and lying positions without compensatory heart rate increase. In most patients, the antihypertensive effect manifests itself 1-2 hours after taking a single dose. The degree of severity of the effect reaches a maximum in 3-6 hours after use. As a rule, the antihypertensive effect after a single dose persists for 24 hours. With prolonged treatment with ramipril, the maximum antihypertensive effect is usually achieved after 2-4 weeks. It is shown that with long-term therapy, the antihypertensive effect can be maintained for 2 years. Abrupt discontinuation of ramipril does not lead to a rapid and excessive increase in blood pressure.

As a rule, there are no significant changes in the rate of renal blood flow and glomerular filtration.

Hydrochlorothiazide is a thiazide diuretic whose diuretic effect is associated with impaired reabsorption of sodium, chlorine, potassium, magnesium, and water ions in the distal nephron; it delays the excretion of calcium and uric acid ions. It has antihypertensive properties; hypotensive effect develops due to the expansion of arterioles. Practically does not affect the normal level of blood pressure.

The elimination of electrolytes and water begins approximately 2 hours after ingestion, the maximum effect is achieved in 3-6 hours and persists for 6-12 hours. The antihypertensive effect is achieved in 3-4 days of treatment and lasts for 1 week after the end of taking the drug. With long-term treatment, a decrease in blood pressure is achieved when using lower doses than necessary for the diuretic effect. A decrease in blood pressure is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance, and plasma renin activity.

Hydrochlorothiazide at a single dose in high doses leads to a decrease in plasma volume, GFR, renal blood flow and average blood pressure. With long-term use in small doses, the blood plasma volume remains reduced, while the minute volume and glomerular filtration rate return to the initial level before the start of treatment. Mean blood pressure and systemic vascular resistance remain reduced. Thiazide diuretics may interfere with breast milk production.

Indications

Arterial hypertension (if necessary, combined therapy with ramipril and hydrochlorothiazide).

Recommendations for use

Take orally 1 time / day daily in the morning.

This combination should be used only after individual selection of doses of each of the components. The dose can be increased at intervals of at least 3 weeks. 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, or 5 mg ramipril and 25 mg hydrochlorothiazide. The recommended maximum daily dose is 5 mg ramipril and 25 mg hydrochlorothiazide.

Contraindications

Angioedema in the anamnesis, including those associated with previous therapy with ACE inhibitors; hereditary/idiopathic angioedema; severe renal dysfunction (creatinine clearance less than 30 ml/min/1.73 m2), anuria; severe liver function disorders and/or cholestasis; primary aldosteronism; arterial hypotension; hemodialysis; condition after kidney transplantation (lack of experience); galactose intolerance, hereditary lactase deficiency or glucose-galactose malabsorption syndrome (due to lactose content in the drug); pregnancy; lactation (breastfeeding); age up to 18 years (efficacy and safety have not been established); hypersensitivity to ramipril and other ACE inhibitors, thiazides or sulfonamide derivatives, as well as to any of the excipients of the drug.

With caution

Severe lesions of the coronary and cerebral arteries (risk of reduced blood flow due to excessive blood pressure reduction), unstable angina, severe ventricular arrhythmias, stage IV chronic heart failure, decompensated “pulmonary heart”, conditions accompanied by a decrease in BCC (including diarrhea, vomiting), systemic connective tissue diseases, diabetes mellitus, suppression of bone marrow hematopoiesis, with aortic and mitral stenosis, hypertrophic hypertrophy, hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic hypertrophic obstructive cardiomyopathy, bilateral renal artery stenosis or stenosis of the artery of a single kidney, gout, hyperkalemia, hyponatremia (including on the background of taking diuretics and a diet with limited salt intake), hypokalemia, hypercalcemia, CHD, renal and/or liver failure, cirrhosis of the liver; in elderly patients.

Side effects

At the beginning of the course of treatment and after increasing the dose, severe hypotension was observed. This effect is especially characteristic for some risk groups. There may be symptoms such as dizziness, general weakness, blurred vision, sometimes in combination with loss of consciousness (fainting). Isolated cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction, severe arterial hypertension and shock, dynamic cerebrovascular accident, cerebral hemorrhage and ischemic stroke were observed while taking ACE inhibitors against the background of arterial hypotension.

From the hematopoietic system:  rarely-decreased hemoglobin and hematocrit concentrations, leukopenia, thrombocytopenia; very rarely-agranulocytosis, pancytopenia, eosinophilia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.

From the side of the neural system:  often – dizziness, fatigue, headache, weakness; infrequently-apathy, nervousness, drowsiness; rarely-a feeling of fear, confusion, sleep disorders, anxiety, olfactory disorders, balance disorders, paresthesia.

From the side of the visual organ:  infrequently-conjunctivitis, blepharitis; rarely-transient myopia, blurred vision.

From the side of the hearing organ:  rarely-ringing in the ears.

Co-neurons of the cardiovascular system:  marked decrease in blood pressure; infrequently-ankle edema; rarely-syncope, thromboembolic complications; very rarely-angina pectoris, myocardial infarction, arrhythmias, palpitations, tachycardia, dynamic cerebrovascular accident, brain hemorrhage, exacerbation of Raynaud’s disease, vasculitis, venous diseases, thrombosis, embolism.

Respiratory system disorders:  dry cough, bronchitis; rarely – shortness of breath, sinusitis, rhinitis, pharyngitis, glossitis, bronchospasm, allergic interstitial pneumonia; very rarely-angioedema with fatal airway obstruction*, pulmonary edema due to hypersensitivity to hydrochlorothiazide.

From the digestive system:  nausea, abdominal pain, vomiting, dyspepsia; infrequently-epigastric spasms, thirst, constipation, diarrhea, loss of appetite; rarely – dry mouth, vomiting, taste disorders, inflammation of the mucous membranes of the mouth and tongue, sialadenitis, glossitis; very rarely – intestinal obstruction, hemorrhagic pancreatitis.

From the liver:  rarely-increased activity of liver enzymes and / or bilirubin; very rarely – cholestatic jaundice, hepatitis, cholecystitis (against the background of cholelithiasis), liver necrosis.

From the side of the skin:  infrequently-photosensitivity, pruritus, urticaria; rarely-flushes of blood to the skin of the face, increased sweating, peripheral edema; very rarely-erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, skin reactions such as psoriatic or pemphigoid, systemic lupus erythematosus, alopecia, psoriasis exacerbation, onycholysis. It has been reported that taking this combination can lead to a symptom complex consisting of at least one of the following components: fever, vasculitis, myalgia, arthralgia/arthritis, positive reaction to antinuclear antibodies, increased ESR, eosinophilia and leukocytosis, rash, photosensitization (other skin manifestations are also possible).

Musculoskeletal disorders:  rarely-muscle spasm, myalgia, arthralgia, muscle weakness, arthritis; very rarely-paralysis.

From the urinary system: infrequently-proteinuria; rarely-deterioration of renal function, increased residual nitrogen and serum creatinine, dehydration; very rarely-acute renal failure, nephrotic syndrome, interstitial nephritis, oliguria.

From the side of the reproductive system: infrequently-decreased libido; rarely-impotence.

Allergic reactions: very rarely – anaphylactic reactions, angioedema. Aangioedema develops more often in people of the black race. In a small group of patients, the occurrence of angioedema of the face and oropharyngeal region is associated with the use of ACE inhibitors.

From the side of laboratory parameters: often – hypokalemia, increased levels of uric acid, urea and creatinine in the blood, hyperglycemia, gout; infrequently – hyperkalemia, hyponatremia, hypomagnesemia, hyperchloremia, hypercalcemia; rarely – impaired water and electrolyte balance (especially in patients with kidney disease), hypochloremia, metabolic alkalosis; very rarely-increased serum trigicerides, hypercholesterolemia, increased blood pressure. serum amylase, decompensation of diabetes mellitus.

Interaction

Ramipril

When used concomitantly with diuretics, the antihypertensive effect is summed up. In patients who are already taking diuretics, especially those who have recently been prescribed diuretics, the addition of ramipril can sometimes cause an excessive decrease in blood pressure. The likelihood of hypotension symptoms under the influence of ramipril is reduced if you stop taking the diuretic before starting ramipril treatment.

Taking certain anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may increase hypotension.

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors, so patients should be closely monitored.

Epidemiological studies have shown that simultaneous use of ACE inhibitors and hypoglycemic agents (insulins and hypoglycemic agents for oral use) can increase the effect of the latter, up to the development of hypoglycemia. The probability of such events is especially high during the first weeks of combined treatment of patients, as well as with impaired renal function.

Concomitant use of nitroglycerin and other organic nitrates or vasodilators may increase the hypotensive effect of ramipril.

Long-term use of NSAIDs may weaken the antihypertensive effect of ACE inhibitors. The effects of NSAIDs and ACE inhibitors on increased serum potassium levels are summed up, which can lead to impaired renal function. These effects are usually reversible. In rare cases, acute renal failure may occur, especially when renal function is impaired, such as in elderly or dehydrated patients.

Concomitant treatment with ACE inhibitors and allopurinol increases the risk of renal failure and may lead to an increased risk of leukopenia.

Concomitant use of ACE inhibitors and cyclosporine increases the risk of renal failure and hyperkalemia.

Concomitant use of ACE inhibitors and lovastatin increases the risk of hyperkalemia.

Concomitant use of procainamide, cytostatics, and immunosuppressants with ACE inhibitors may increase the risk of leukopenia.

You should not use the combination of ramipril+hydrochlorothiazide simultaneously with aliskiren in patients with diabetes, in patients with impaired renal function from moderate to severe (GFR <60 ml/min/1.73 m2), in patients with hyperkalemia (>5 mmol/l) in patients with chronic heart failure with reduced BP.

You should not use the combination of ramipril+hydrochlorothiazide simultaneously with the antagonists of angiotensin II receptors blockers or other ACE inhibitors in patients with diabetes and lesion of target organs in the terminal stage, patients with impaired renal function from moderate to severe (GFR <60 ml/min/1.73 m2), in patients with hyperkalemia (>5 mmol/l) in patients with chronic heart failure with reduced BP.

Hydrochlorothiazide

When used concomitantly with amphotericin B (parenterally), carbenoxolone, corticotropin (ACTH) or laxatives with stimulating effects, hydrochlorothiazide can cause electrolyte imbalances, especially hypokalemia.

When taking calcium salts with thiazide diuretics at the same time, hypercalcemia may develop (against the background of a decrease in the excretion of calcium ions).

Concomitant use of cardiac glycosides increases the risk of digitalis intoxication and hypokalemia.

Colestyramine and colestipol may reduce or slow the absorption of hydrochlorothiazide. Therefore, sulfonamide diuretics should be taken at least 1 hour before or 4-6 hours after taking these medications.

Hydrochlorothiazide may enhance the effect of non-depolarizing muscle relaxants (tubocurarin).

Concomitant use of hydrochlorothiazide and drugs that cause ventricular tachycardia of the “pirouette” type, for example, some antipsychotics, increases the risk of hypokalemia.

When used concomitantly with sotalol, the risk of arrhythmia increases.

Hydrochlorothiazide may increase the toxic effect of salicylates on the central nervous system, used in high doses (>3 g / day).

Ramipril / hydrochlorothiazide

Although serum potassium levels in clinical trials of ACE inhibitors usually remained within normal limits, some patients still developed hyperkalemia.

The risk of hyperkalemia is associated with a number of factors, including kidney failure, diabetes mellitus, and concomitant use of potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), as well as potassium-containing dietary supplements or salt substitutes. The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes can lead to a significant increase in serum potassium levels, especially in patients with impaired renal function. While taking ramipril on the background of potassium-withdrawing diuretics, hypokalemia caused by their use may be reduced.

Concomitant use of lithium and ACE inhibitors reversibly increases the level of lithium in the blood serum and develops toxic effects. The use of thiazide diuretics may increase the risk of lithium intoxication and increase lithium intoxication if it is already caused by simultaneous use of ACE inhibitors. It is not recommended to use ramipril simultaneously with lithium, but in cases where such a combination is necessary, careful monitoring of serum lithium levels should be carried out.

Taking ACE inhibitors and thiazides simultaneously with trimethoprim increases the risk of hyperkalemia.

Hydrochlorothiazide may attenuate the hypoglycemic effect of oral hypoglycemic agents (e. g., sulfonylureas and biguanides such as metformin) and insulin, while ramipril potentiates it.

When used concomitantly with sodium chloride, the antihypertensive effect of a fixed combination of ramipril and hydrochlorothiazide is weakened.

Functional features

Ramipril

After oral use, ramipril is rapidly absorbed. Based on the radioactivity detected in the urine after ingestion of labeled ramipril (renal excretion is only one of several routes), at least 56% of the drug is absorbed. Simultaneous food intake does not affect absorption.

Ramipril is a prodrug that undergoes metabolism during the” first pass ” through the liver, resulting in the formation (due to hydrolysis, mainly in the liver) of the only active metabolite ramiprilate. In addition to being converted to the active metabolite ramiprilate, ramipril is conjugated to glucuronic acid and converted to the diketopiperazine ester of ramipril. Ramiprilate also undergoes conjugation with glucuronic acid and is converted to diketopiperazine-ramiprilate (acid). Due to ramipril activation / metabolism, bioavailability after oral use is approximately 20%.

_Cmax of ramipril in blood plasma is reached within 1 h after oral use. _{Cmax of}ramiprilate in blood plasma is reached within 2-4 hours after oral use of ramipril.

Plasma protein binding is approximately 73% and 56% for ramipril and ramiprilate, respectively.

Experimental studies have shown that ramipril is excreted in breast milk.

T_1/2 of ramipril is 5.1 h. The decrease in the concentration of ramiprilate in blood plasma is multiphase. The initial distribution and elimination phase is characterized by a T_1/2of approximately 3 hours, followed by an intermediate phase (T_1/2 of approximately 15 hours) and a final phase during which ramiprilate plasma concentrations are very low (T_1/2 – 4-5 days). This final phase is caused by the slow dissociation of ramiprilate from strong but saturated complexes with ACE. Despite the duration of the elimination phase, the C_ssof ramipril is reached in about 4 days with a daily intake of 2.5 mg or more of ramipril. The effective T_1/2 (a parameter relevant to the choice of dose) is 13-17 hours after taking several doses.

After oral use of 10 mg of labeled ramipril, about 40% of the radioactivity is released through the intestines and 60% – by the kidneys.Within 24 hours after ingestion of 5 mg of ramipril by patients with a catheter that removes the resulting bile, equal amounts of excretion of ramipril and its metabolites by the kidneys and bile were found. Approximately 80-90% of the metabolites excreted by the kidneys and bile were represented by ramiprilate and drugs for its further metabolism. Glucuronide and the diketopiperazine derivative of ramipril accounted for approximately 10-20%, and unmetabolized ramipril accounted for approximately 2% of the total amount of ramipril.

Hydrochlorothiazide

After oral use, cmax of hydrochlorothiazide is reached within 1-3 hours. Absolute bioavailability is estimated by cumulative renal excretion of hydrochlorothiazide and is about 60%. Binding to plasma proteins is 40-70%. V_d – 0.8±0.3 l / kg. It is not metabolized in the human body and is excreted in the urine almost unchanged. About 60% of the oral dose is eliminated within 48 hours. Renal clearance is about 250-300 ml / min. T_1/2 – 10-15 h. There is a difference in plasma concentrations in men and women. In women, there is a tendency for a clinically significant increase in the concentration of hydrochlorothiazide in blood plasma. In patients with impaired renal function, the rate of elimination of hydrochlorothiazide is reduced. Studies conducted in patients with creatinine clearance of 90 ml / min showed that T_1/2of hydrochlorothiazide increases. In patients with reduced renal function, T_1/2is about 34 hours.

Ramipril and hydrochlorothiazide

Simultaneous use of ramipril and hydrochlorothiazide does not affect the bioavailability of each of the components.

Special instructions

Ramipril

If arterial hypotension develops, the patient should be placed on his back, his legs raised and, if necessary, an intravenous infusion of sodium chloride solution should be made. A transient hypotensive reaction is not a contraindication for subsequent use of the drug.

In some patients with heart failure who have normal or low blood pressure, ramipril may cause an additional decrease in systolic blood pressure. This effect can be anticipated, so it is usually not a reason to stop treatment. If hypotension is symptomatic, it may be necessary to reduce the dose or discontinue treatment.

Like other ACE inhibitors, ramipril should be administered with caution in patients with aortic stenosis or difficulty ejecting from the left ventricle (for example, with aortic stenosis or hypertrophic cardiomyopathy). In some cases, the hemodynamic picture may make it unacceptable to take a fixed combination of ramipril and hydrochlorothiazide.

Patients with a history of angioedema that is not associated with ACE inhibitor use may be at increased risk of developing angioedema in response to ACE inhibitor use.

Anaphylactoid reactions have been reported in patients on hemodialysis using membranes with high hydraulic permeability (for example, AN69) with simultaneous use of ACE inhibitors. In such cases, consideration should be given to using a different type of membrane or a different class of antihypertensive agents.

In rare cases, patients taking an ACE inhibitor who undergo LDL apheresis with dextran sulfate develop life-threatening anaphylactoid reactions. Such reactions can be avoided if you temporarily refrain from taking an ACE inhibitor before each apheresis procedure.

Long-term anaphylactoid reactions occur in patients taking ACE inhibitors on the background of desensitizing therapy (for example, hymenopteran venom). If such patients refrained from taking ACE inhibitors during desensitization, no reactions were observed, but accidental use of ACE provoked an anaphylactoid reaction.

The use of ACE inhibitors is associated with the development of a rare syndrome that begins with cholestatic jaundice or hepatitis and turns into transient liver necrosis, sometimes with a fatal outcome. The mechanism of development of this syndrome is not clear. If patients taking ramipril develop jaundice or significantly increase the activity of liver enzymes, the drug should be discontinued, leaving the patient under medical supervision until symptoms disappear.

ACE inhibitors are more likely to cause angioedema in patients of the black race compared to patients of other races. Similar to other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients compared to individuals of other races, possibly due to the higher frequency of individuals with low renin levels in the population of black patients with arterial hypertension.

It has been reported that taking ACE inhibitors may be accompanied by a cough. It is characteristic that the cough is dry and constant, passes after discontinuation of the drug. The fact that cough is caused by taking an ACE inhibitor should be considered a differential diagnostic sign.

In patients undergoing surgery or general anesthesia with blood pressure-lowering drugs, ramipril can block the increase in angiotensin II production under the influence of compensatory renin release. If it is assumed that arterial hypotension develops by this mechanism, it can be corrected by increasing the BCC.

In diabetic patients taking oral hypoglycemic agents or insulin, blood glucose levels should be carefully monitored during the first month of treatment with an ACE inhibitor.

It is not indicated for patients whose condition requires dialysis, since taking ACE inhibitors on the background of dialysis using membranes that provide high current intensity is often accompanied by anaphylactoid reactions. This combination is not allowed.

Hydrochlorothiazide

In patients with kidney disease, thiazides can cause azotemia. Taking medications against the background of impaired renal function can lead to cumulative effects. If renal failure progresses, characterized by an increase in non-protein nitrogen, the need for therapy should be carefully evaluated and the possibility of discontinuing diuretics should be considered.

Patients with impaired or progressive liver function should be prescribed thiazides with caution, as even minor fluctuations in the water-electrolyte balance can cause hepatic coma.

Thiazide therapy may reduce glucose tolerance. With diabetes mellitus, it may be necessary to select the dose of insulin or oral hypoglycemic agents. Thiazide therapy may cause latent diabetes mellitus. Increased cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Some patients receiving thiazide diuretics may experience elevated uric acid levels or gout symptoms.

In some patients, thiazide therapy may increase uric acid levels and / or cause gout. However, ramipril can increase uric acid excretion, thus reducing the degree of increase in uric acid levels under the influence of hydrochlorothiazide.

Thiazides, including hydrochlorothiazide, can cause a violation of the water-electrolyte balance (hypokalemia, hyponatremia and hypochloremic alkalosis). Symptoms of water-electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, myalgia or muscle spasms, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea and vomiting.

Although the use of thiazide diuretics may lead to hypokalemia, concomitant use of ramipril may reduce the severity of hypokalemia caused by diuretics. The likelihood of hypokalemia is highest in patients with cirrhosis of the liver, in patients with increased diuresis, with inadequate oral intake of electrolytes, as well as against the background of treatment with corticosteroids and ACTH.

Thiazides can reduce the excretion of calcium ions in the urine, leading to a slight periodic increase in the level of calcium in the blood, even in the absence of obvious violations of calcium metabolism. Overt hypercalcemia may indicate latent hyperparathyroidism. Thiazides should be discontinued until the results of a parathyroid function study are available.

Thiazides have been shown to increase the renal excretion of magnesium, which can lead to a decrease in blood magnesium levels.

The combination of fixed doses of ramipril and hydrochlorothiazide should be discontinued if neutropenia occurs or is suspected (neutrophil count less than 1000 / µl).

Hydrochlorothiazide may give a positive reaction under anti-doping control.

Influence on the ability to drive vehicles and mechanisms

There may be a slight or moderate impact on the ability to drive a car and work with mechanisms. Due to differences in individual reactions, some patients may have impaired ability to drive a car, work with mechanisms, and perform other types of work that require increased attention. This is especially pronounced at the beginning of treatment and/or after increasing the dosage.

Active ingredient

Ramipril, Hydrochlorothiazide

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Hypertension