Ramazid N, tablets 5 mg+12, 5 mg 100 pcs

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

Ramipril is an ACE inhibitor. It is a prodrug, in the body converts to the active metabolite ramiprilat, which has an inhibitory effect on ACE. 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. Reduction of angiotensin II and suppression of bradykinin breakdown leads to vasodilation. Because angiotensin II also stimulates the release of aldosterone, ramiprilat leads to a decrease in aldosterone release. Ramipril reduces ROS.

The administration of ramipril to patients with arterial hypertension reduces BP in the standing and lying position without a compensatory increase in HR. In most patients the antihypertensive effect is evident in 1-2 hours after a single dose. The severity of the effect reaches its maximum 3-6 hours after dosing. As a rule, the antihypertensive effect after a single dose lasts for 24 hours. During long-term treatment with ramipril maximum antihypertensive effect is usually achieved in 2-4 weeks. It has been 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 BP.

In general, there are no significant changes in renal blood flow rate and glomerular filtration.

Hydrochlorothiazide is a thiazide diuretic whose diuretic effect is associated with disruption of reabsorption of sodium, chloride, potassium, magnesium and water ions in the distal nephron; it delays excretion of calcium and uric acid ions. It has antihypertensive properties; hypotensive effect develops due to dilatation of arterioles. It has practically no effect on normal blood pressure.

The excretion of electrolytes and water begins about 2 hours after intake, the maximum effect is achieved in 3-6 hours and lasts for 6-12 hours. Antihypertensive effect is achieved within 3-4 days of treatment and lasts for 1 week after completion of the drug. With long-term treatment, BP reduction is achieved using smaller doses than those required for the diuretic effect. Decrease in BP is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance and plasma renin activity.

Hydrochlorothiazide at a single high dose leads to a decrease in plasma volume, FFR, renal blood flow and mean BP. With long-term administration at low doses, plasma volume remains reduced, while minute volume and glomerular filtration rate return to baseline levels before the start of treatment. Mean BP and systemic vascular resistance remain reduced. Thiazide diuretics may interfere with breast milk production.

Indications

Active ingredient

Composition

Pills are pink, possibly flecked, flat, oblong, with a groove and “R2” engraved on one side and lateral ribs.

Excipients:

sodium bicarbonate – 5 mg,

calcium sulfate dihydrate – 195.9 mg,

Pregelatinized corn starch – 36.4 mg,

sodium stearyl fumarate – 2.6 mg,

dye reddish brown PB24823 – 2.6 mg.

Interaction

Ramipril

When used concomitantly with diuretics, a summation of the antihypertensive effect is noted. In patients who are already taking diuretics, especially those who have recently been prescribed diuretics, the addition of ramipril may sometimes cause excessive BP reduction. The likelihood of arterial hypotension symptoms under the influence of ramipril is reduced if the diuretic is discontinued before starting ramipril treatment.

The administration of some anesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors may increase arterial hypotension.

Sympathomimetics may decrease the hypotensive effect of ACE inhibitors, so patients require close monitoring.

Epidemiological studies have shown that concomitant use of ACE inhibitors and hypoglycemic agents (insulin and oral hypoglycemic agents) may potentiate the effects of the latter, up to and including hypoglycemia. The probability of these phenomena is particularly high during the first weeks of combined treatment of patients, as well as in case of impaired renal function.

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

Long-term use of NSAIDs may weaken the hypotensive effect of ACE inhibitors. The effects of NSAIDs and ACE inhibitors on the increase in serum potassium levels are summarized, which may lead to impaired renal function. These effects are usually reversible. In rare cases, acute renal failure may be observed, especially in impaired renal function, 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.

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

The 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.

The ramipril+hydrochlorothiazide combination should not be used concomitantly with aliskiren in patients with diabetes mellitus, in patients with moderate to severe renal dysfunction (GFR < 60 ml/min/173 m2), in patients with hyperkalemia (>5 mmol/l), in patients with chronic heart failure with decreased BP.

The ramipril+hydrochlorothiazide combination should not be used concomitantly with angiotensin II receptor antagonists or other ACE inhibitors in patients with diabetes mellitus and terminal target organ damage, in patients with moderate to severe renal function impairment (GFR <60 ml/min/173 m2), in patients with hyperkalemia (>5 mmol/l), in patients with chronic heart failure with decreased BP.

Hydrochlorothiazide

In concomitant use with amphotericin B (parenteral), carbenoxolone, GCS, corticotropin (ACTH) or stimulant laxatives, hydrochlorothiazide may cause electrolyte imbalances, especially hypokalemia.

Concomitant use of calcium salts with thiazide diuretics may cause hypercalcemia (with reduced excretion of calcium ions).

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

Colestyramine and colestipol may reduce or delay absorption of hydrochlorothiazide. Therefore, sulfonamide diuretics should be taken at least 1 h before or 4-6 h after taking these drugs.

Hydrochlorothiazide may increase the effect of nondepolarizing myorelaxants (tubocurarin).

The simultaneous use of hydrochlorothiazide and drugs that cause pirouette-type ventricular tachycardia, such as some antipsychotics, increases the risk of hypokalemia.

Concomitant use with sotalol increases the risk of arrhythmia.

Hydrochlorothiazide may increase the toxic effects of salicylates on the CNS when used in high doses (>3 g/day).

Ramipril/hydrochlorothiazide

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

The risk of hyperkalemia has been associated with a number of factors, including renal insufficiency, diabetes mellitus, and concomitant use of potassium-saving diuretics (such as spironolactone, triamterene, or amiloride) as well as potassium-containing supplements or saline substitutes.Use of potassium-containing food supplements, potassium-saving diuretics or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels, especially in patients with impaired renal function. When ramipril is taken against the background of potassium-containing diuretics, hypokalemia caused by their intake may be attenuated.

The simultaneous use of lithium and ACE inhibitors reversibly increases serum lithium levels and develops toxic effects. The use of thiazide diuretics may increase the risk of lithium intoxication and aggravate lithium intoxication if it is already caused by concomitant use of ACE inhibitors. Use of ramipril concomitantly with lithium is not recommended, but serum lithium levels should be closely monitored when such a combination is necessary.

The use of ACE inhibitors and thiazides concomitantly 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, whereas ramipril potentiates it.

When used concomitantly with sodium chloride, a weakening of the antihypertensive effect of the fixed combination of ramipril and hydrochlorothiazide has been noted.

Directions for use

Take orally once daily in the morning.

This combination should only be used after individual selection of doses of each component. The dose may be increased at intervals of at least 3 weeks. The usual starting dose is 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide. The usual maintenance dose is 2.5 mg of ramipril and 12.5 mg of hydrochlorothiazide or 5 mg of ramipril and 25 mg of hydrochlorothiazide. The recommended maximum daily dose is 5 mg of ramipril and 25 mg of hydrochlorothiazide.

Special Instructions

Ramipril

In case of arterial hypotension, the patient should be placed on his back, his legs elevated and, if necessary, sodium chloride solution should be infused intravenously. Transient hypotensive reaction is not a contraindication for subsequent administration of the drug.

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

As with other ACE inhibitors, ramipril should be prescribed with caution in patients with aortic stenosis or left ventricular ejection difficulties (e.g., aortic stenosis or hypertrophic cardiomyopathy). In individual cases, the hemodynamic picture may make the fixed combination of ramipril and hydrochlorothiazide unacceptable.

In patients with a history of angioedema unrelated to ACE inhibitor administration, there may be an increased risk of developing angioedema in response to ACE inhibitor administration.

There have been reports of anaphylactoid reactions in patients on hemodialysis using high hydraulic permeability membranes (e.g., AN69) when concomitant use of ACE inhibitors. In such cases, a different type of membrane or antihypertensive agents of a different class should be considered.

In rare cases, life-threatening anaphylactoid reactions develop in patients taking an ACE inhibitor against LDL apheresis with dextran sulfate. Such reactions can be avoided by temporarily refraining from taking an ACE inhibitor before each apheresis procedure.

Patients taking ACE inhibitors against a background of desensitizing therapy (e.g., with hymenopteran venom) develop prolonged anaphylactoid reactions. If such patients refrained from taking ACE inhibitors during desensitization, no reactions were observed, but accidental ACE administration provoked an anaphylactoid reaction.

A rare syndrome has been associated with ACE inhibitor administration that begins with cholestatic jaundice or hepatitis and progresses to transient hepatic necrosis, sometimes fatal. The mechanism of this syndrome is not clear. If patients taking ramipril develop jaundice or have significantly increased hepatic enzyme activity, the drug should be withdrawn, leaving the patient under medical supervision until the symptoms disappear.

ACE inhibitors are more likely to cause angioedema in black patients compared to patients of other racial backgrounds. Like other ACE inhibitors, ramipril may be less effective in lowering BP in black patients than in patients of other races, possibly due to the higher incidence of individuals with low renin levels in the black patient population with arterial hypertension.

It has been reported that administration of ACE inhibitors may be accompanied by coughing. Characteristically, the cough is dry and persistent, passing after discontinuation of the drug. The fact that cough is caused by taking an ACE inhibitor should be considered a differential diagnostic feature.

In patients undergoing surgery or general anesthesia with BP-lowering drugs, ramipril may block increased angiotensin II formation 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 blood pressure.

In diabetic patients receiving 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 in patients whose condition requires dialysis, since administration of ACE inhibitors against the background of dialysis using high current membranes is often accompanied by anaphylactoid reactions. This combination is unacceptable.

Hydrochlorothiazide

In patients with renal disease, thiazides may cause azotemia. Taking the medication against a background of impaired renal function may lead to cumulative effects. If renal impairment progresses, characterized by an increase in non-protein nitrogen, the need for therapy should be carefully evaluated and discontinuation of diuretics should be considered.

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

Thiazide therapy may decrease glucose tolerance. In diabetes mellitus, it may be necessary to adjust the dose of insulin or oral hypoglycemic agents. Thiazide therapy may cause manifestation of latent diabetes mellitus. Thiazide diuretics therapy is associated with increased levels of cholesterol and triglycerides. Some patients receiving thiazide diuretics may have increased uric acid levels or manifestations of gout.

In some patients, thiazide therapy may increase uric acid levels and/or cause gout. However, ramipril may enhance uric acid excretion, thus attenuating the degree to which hydrochlorothiazide increases uric acid levels.

The thiazides, including hydrochlorothiazide, may cause disruption of the water-electrolyte balance (hypokalemia, hyponatremia and hypochloremic alkalosis). Symptoms of water-electrolyte imbalance include dry mouth, thirst, weakness, lethargy, sleepiness, restlessness, myalgia or muscle cramps, muscle fatigue, arterial hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.

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

The thiazides may decrease urinary excretion of calcium ions, resulting in a slight intermittent increase in blood calcium levels even in the absence of obvious disorders of calcium metabolism. Apparent hypercalcemia may indicate occult hyperparathyroidism. Thiazides should be discontinued until the results of a parathyroid function study are available.

Thiazides have been shown to increase renal excretion of magnesium, which may result in lower blood magnesium levels.

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

Hydrochlorothiazide may react positively in antidoping controls.

Impact on the ability to drive and operate vehicles

Mild to moderate effect on the ability to drive and operate machinery is possible. Due to differences in individual reactions, in some patients the ability to drive vehicles, operate machinery, as well as perform other types of work requiring increased attention may be impaired. This is especially pronounced at the beginning of treatment and/or after increasing the dosage.

Features

Ramipril

Ramipril is rapidly absorbed after oral administration. Judging by the radioactivity determined in the urine after oral administration of labeled ramipril (excretion by the kidneys is only one of several routes), at least 56% of the drug is absorbed. Concomitant ingestion has no effect on absorption.

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

The Cmax of ramipril in plasma is reached within 1 h after oral administration. Cmax of ramiprilate in plasma is reached within 2-4 h after oral ramipril administration.

The plasma protein binding for ramipril and ramiprilat is approximately 73% and 56%, respectively.

In experimental studies it was found that ramipril is excreted with breast milk.

T1/2 ramipril is 5.1 h. The decrease in plasma concentration of ramiprilat has a multiphase character. The initial distribution and excretion phase is characterized by a T1/2 of approximately 3 h. This is followed by an intermediate phase (T1/2 of approximately 15 h) and a final phase during which plasma concentrations of ramiprilat are very low (T1/2 of 4-5 days). This end phase is due to the slow dissociation of ramiprilat from strong but saturated complexes with ACE. Despite the length of the elimination phase, the Css of ramipril is reached in approximately 4 days with daily administration of 2.5 mg or more of ramipril. The effective T1/2 (a parameter relevant to dose selection) is 13-17 h after multiple doses.

After oral administration of 10 mg of labeled ramipril, about 40% of the radioactivity is excreted through the intestine and 60% by the kidneys. Within 24 h after oral administration of 5 mg of ramipril in patients with catheter-derived bile excretion of ramipril and its metabolites by the kidneys and bile were found to be equal. Approximately 80-90% of the metabolites excreted by the kidneys and bile were represented by ramiprilat and its further metabolized preparations. Glucuronide and the diketopiperazine derivative of ramipril accounted for approximately 10-20%, and unmetabolized ramipril accounted for approximately 2% of total ramipril.

Hydrochlorothiazide

After oral administration, Cmax of hydrochlorothiazide is reached within 1-3 h. Absolute bioavailability is estimated by cumulative renal excretion of hydrochlorothiazide and is about 60%. Binding to plasma proteins is 40-70%. Vd is 0.8±0.3 l/kg. It is not metabolized in human body and excreted practically unchanged in urine. About 60% of the dose taken orally is excreted within 48 hours. Renal clearance is about 250-300 ml/min. T1/2 is 10-15 h. There is a difference in plasma concentrations in men and women. In women there is a tendency for clinically significant increase in plasma concentration of hydrochlorothiazide. In patients with impaired renal function the excretion rate of hydrochlorothiazide is reduced. Studies conducted in patients with a CK of 90 ml/min have shown that the T1/2 of hydrochlorothiazide is increased. In patients with decreased renal function, the T1/2 is about 34 h.

Ramipril and hydrochlorothiazide

The simultaneous administration of ramipril and hydrochlorothiazide does not affect the bioavailability of either component.

Contraindications

An history of angioedema, including that associated with prior therapy with ACE inhibitors; hereditary/idiopathic angioedema; severe renal impairment (CK less than 30 ml/min/1.73 m2), anuria; severe hepatic dysfunction and/or cholestasis; primary aldosteronism; arterial hypotension; hemodialysis; conditions after renal transplantation (no experience of use); galactose intolerance, hereditary lactase deficiency or glucose-galactose absorption disorder (because of the lactose content in the drug); pregnancy; lactation (breast-feeding); age under 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 drug excipients.

With caution

Severe coronary and cerebral artery disease (risk of decreased blood flow with excessive lowering of BP), unstable angina pectoris, severe ventricular arrhythmias, chronic heart failure stage IV, decompensated “pulmonary heart”, conditions accompanied by a decrease in the blood circulation (including diarrhea, vomiting), systemic connective tissue diseases, diabetes mellitus, suppression of medullary hematopoiesis, aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy, bilateral renal artery stenosis or stenosis of the artery of a single kidney, gout, hyperkalemia, hyponatremia (including during diuretic therapy).including against the background of diuretics and salt restricted diet), hypokalemia, hypercalcemia, CHD, renal and/or hepatic insufficiency, cirrhosis; in elderly patients.

Side effects

A pronounced arterial hypotension was observed at the beginning of treatment and after increasing the dose. This effect is especially characteristic of some risk groups. Symptoms such as dizziness, general weakness, blurred vision, sometimes combined with loss of consciousness (fainting) may be observed. Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction, severe arterial hypertension and shock, cerebral hemorrhage and ischemic stroke have been observed while taking ACE inhibitors with arterial hypotension.

Hematopoietic system: rarely – decrease of hemoglobin concentration and hematocrit, leukopenia, thrombocytopenia; very rarely – agranulocytosis, pancytopenia, eosinophilia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency.

Nervous system disorders: frequently – dizziness, fatigue, headache, weakness; infrequently – apathy, nervousness, somnolence; rarely – anxiety, confusion, sleep disorders, restlessness, olfactory disorders, balance disorders, paresthesias.

An organ of vision: infrequent – conjunctivitis, blepharitis; rare – transient myopia, blurred vision.

Hearing organ: rare – tinnitus.

Cardiovascular system disorders: pronounced BP decrease; infrequent – ankle edema; rare – syncope, thromboembolic complications; very rare – angina, myocardial infarction, arrhythmias, palpitations, tachycardia, dynamic cerebral circulatory disorders, brain hemorrhage, worsening of Raynaud’s disease course, vasculitis, vein disease, thrombosis, embolism.

Respiratory system: 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.

Digestive system disorders: Nausea, abdominal pain, vomiting, dyspepsia; infrequent – epigastric spasms, thirst, constipation, diarrhea, loss of appetite; rare – dry mouth, vomiting, taste disorders, inflammation of mucous membranes of the mouth and tongue, sialadenitis, glossitis; very rare – bowel obstruction, hemorrhagic pancreatitis.

Hepatic disorders: rare – increased activity of liver enzymes and/or bilirubin; very rare – cholestatic jaundice, hepatitis, cholecystitis (with gallstone disease), liver necrosis.

Skin disorders: infrequent – photosensitization, skin itching, urticaria; rare – flushes to the skin of the face, increased sweating, peripheral edema; very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriatic or pemphigoid type skin reactions, systemic lupus erythematosus, alopecia, psoriasis exacerbation, onycholysis. It has been reported that administration of this combination may result in a symptom complex of at least one of the following: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody reaction, elevated sedimentation, eosinophilia and leukocytosis, rash, photosensitization (other skin manifestations are also possible).

Muscular system disorders: rare – muscle spasm, myalgia, arthralgia, muscle weakness, arthritis; very rare – paralysis.

As to the urinary system: infrequent – proteinuria; rare – deterioration of renal function, increased residual nitrogen and serum creatinine, dehydration; very rare – acute renal failure, nephrotic syndrome, interstitial nephritis, oliguria.

With the sexual system: infrequent – decreased libido; rarely – impotence.

Allergic reactions: very rare – anaphylactic reactions, angioedema. Angioneurotic edema develops more often in persons of non-human race. In a small group of patients angioedema of the face and oropharyngeal area is associated with ACE inhibitors administration.

Laboratory findings: frequent – hypokalemia, elevated blood levels of uric acid, urea and creatinine, hyperglycemia, gout; infrequent – hyperkalemia, hyponatremia, hypomagnesemia, hyperchloremia, hypercalcemia; rarely – disorders of water-electrolyte balance (especially in patients with kidney disease), hypochloremia, metabolic alkalosis; very rarely – increased serum triglyceride levels, hypercholesterolemia, increased serum amylase, decompensation of diabetes.

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