Ramazid H (Tablets) Instructions for Use

ATC Code

C09BA05 (Ramipril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Ramipril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

A combined antihypertensive drug containing the ACE inhibitor Ramipril and the thiazide diuretic Hydrochlorothiazide. It has antihypertensive and diuretic effects. The hypotensive effect of both components is practically additive.

Ramipril is an ACE inhibitor. It is a prodrug that is converted in the body into the active metabolite ramiprilat, which exerts an inhibitory effect on ACE. ACE catalyzes the conversion of angiotensin I in tissues into the active vasoconstrictor angiotensin II, as well as the breakdown of the active vasodilator bradykinin. The reduction in the amount of angiotensin II and the suppression of bradykinin breakdown leads to vasodilation. Since angiotensin II also stimulates the release of aldosterone, ramiprilat leads to a decrease in aldosterone release. Ramipril reduces total peripheral vascular resistance.

In patients with arterial hypertension, taking ramipril reduces blood pressure in both standing and lying positions without a compensatory increase in heart rate. In most patients, the antihypertensive effect appears 1-2 hours after taking a single dose. The magnitude of the effect peaks 3-6 hours after administration. Typically, the antihypertensive effect after a single dose lasts for 24 hours. With prolonged treatment with ramipril, the maximum antihypertensive effect is usually achieved after 2-4 weeks. Long-term therapy has been shown to maintain the antihypertensive effect for up to 2 years. Abrupt discontinuation of ramipril does not lead to a rapid and excessive increase in blood pressure.

Significant changes in renal blood flow rate and glomerular filtration rate are generally not observed.

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

The excretion of electrolytes and water begins approximately 2 hours after administration, the maximum effect is reached within 3-6 hours and lasts for 6-12 hours. The antihypertensive effect is achieved within 3-4 days of treatment and lasts for 1 week after discontinuation of the drug. With long-term treatment, blood pressure reduction is achieved with lower doses than those required for a diuretic effect. The decrease in blood pressure is accompanied by a slight increase in the glomerular filtration rate, vascular resistance of the renal bed, and plasma renin activity.

Hydrochlorothiazide, when taken in a single high dose, leads to a decrease in plasma volume, glomerular filtration rate, renal blood flow, and mean arterial pressure. With long-term use in low doses, plasma volume remains reduced, while cardiac output and glomerular filtration rate return to the baseline level prior to the start of treatment. Mean arterial pressure and systemic vascular resistance remain reduced. Thiazide diuretics can interfere with breast milk production.

Pharmacokinetics

Ramipril

After oral administration, Ramipril is rapidly absorbed. Judging by the radioactivity determined in urine after oral administration of labeled ramipril (renal excretion is only one of several pathways), at least 56% of the drug is absorbed. Concurrent food intake does not affect absorption.

Ramipril is a prodrug and undergoes first-pass metabolism in the liver, resulting in the formation (via hydrolysis, mainly in the liver) of the single active metabolite ramiprilat. Besides conversion to the active metabolite ramiprilat, Ramipril is conjugated with glucuronic acid and converted into the diketopiperazine ester of ramipril. Ramiprilat is also conjugated with glucuronic acid and converted into diketopiperazine-ramiprilat (acid). Due to the activation/metabolism of ramipril, its oral bioavailability is approximately 20%.

The C_max of ramipril in plasma is reached within 1 hour after oral administration. The C_max of ramiprilat in plasma is reached within 2-4 hours after oral administration of ramipril.

Plasma protein binding is approximately 73% for ramipril and 56% for ramiprilat.

Experimental studies have established that Ramipril is excreted in breast milk.

The T_1/2 of ramipril is 5.1 hours. The decrease in plasma concentration of ramiprilat is multiphasic. The initial distribution and elimination phase is characterized by a T_1/2 of approximately 3 hours. This is followed by an intermediate phase (T_1/2 approximately 15 hours) and a terminal phase, during which plasma concentrations of ramiprilat are very low (T_1/2 – 4-5 days). This terminal phase is due to the slow dissociation of ramiprilat from tight, but saturated, complexes with ACE. Despite the long elimination phase, C_ss of ramiprilat is reached in approximately 4 days with daily intake of 2.5 mg or more of ramipril. The effective T_1/2 (a parameter relevant to dose selection) is 13-17 hours after multiple doses.

After oral administration of 10 mg of labeled ramipril, about 40% of the radioactivity is excreted through the intestine and 60% through the kidneys. Within 24 hours after oral administration of 5 mg of ramipril to patients with a catheter draining the bile produced, equal amounts of ramipril and its metabolites were excreted by the kidneys and bile. Approximately 80-90% of the metabolites excreted by the kidneys and bile were represented by ramiprilat and its further metabolism products. The glucuronide and diketopiperazine derivative of ramipril accounted for approximately 10-20%, and unmetabolized Ramipril constituted approximately 2% of the total ramipril.

Hydrochlorothiazide

After oral administration, the C_max of hydrochlorothiazide is reached within 1-3 hours. The absolute bioavailability, estimated by cumulative renal excretion of hydrochlorothiazide, is about 60%. Plasma protein binding is 40-70%. V_d is 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 orally administered dose is excreted within 48 hours. Renal clearance is about 250-300 mL/min. T_1/2 is 10-15 hours. A difference in plasma concentrations between men and women is observed. Women tend to have a clinically significant increase in plasma concentration of hydrochlorothiazide. In patients with impaired renal function, the excretion rate of hydrochlorothiazide is reduced. Studies involving patients with a creatinine clearance of 90 mL/min showed that the T_1/2 of hydrochlorothiazide increases. In patients with reduced renal function, T_1/2 is about 34 hours.

Ramipril and Hydrochlorothiazide

Concomitant administration of ramipril and hydrochlorothiazide does not affect the bioavailability of each component.

Indications

Arterial hypertension (when combination therapy with ramipril and hydrochlorothiazide is necessary).

ICD codes

Dosage Regimen

Tablets

Take orally once a day every morning.

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

Adverse Reactions

Marked arterial hypotension was observed at the beginning of the course of treatment and after dose increase. This effect is especially characteristic of some risk groups. Symptoms such as dizziness, general weakness, blurred vision, sometimes in combination with loss of consciousness ( syncope) may occur. Isolated cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction, marked arterial hypertension and shock, transient ischemic attack, cerebral hemorrhage, and ischemic stroke were observed during ACE inhibitor therapy against a 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 nervous system often – dizziness, fatigue, headache, weakness; infrequently – apathy, nervousness, drowsiness; rarely – feeling of fear, confusion, sleep disorders, anxiety, smell disturbances, balance disorders, paresthesia.

From the organ of vision infrequently – conjunctivitis, blepharitis; rarely – transient myopia, blurred vision.

From the organ of hearing rarely – tinnitus.

From the cardiovascular system marked decrease in blood pressure; infrequently – ankle edema; rarely – syncope, thromboembolic complications; very rarely – angina pectoris, myocardial infarction, arrhythmias, palpitations, tachycardia, transient ischemic attack, cerebral hemorrhage, exacerbation of Raynaud’s disease, vasculitis, venous diseases, thrombosis, embolism.

From the respiratory systemdry cough, bronchitis; rarely – dyspnea, 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 systemnausea, abdominal pain, vomiting, dyspepsia; infrequently – epigastric cramps, thirst, constipation, diarrhea, loss of appetite; rarely – dry mouth, vomiting, taste disturbances, inflammation of the oral and tongue mucous membranes, 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 skin: infrequently – photosensitivity, skin itching, urticaria; rarely – flushing of the facial skin, increased sweating, peripheral edema; very rarely – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriatic or pemphigoid-like skin reactions, systemic lupus erythematosus, alopecia, exacerbation of psoriasis, onycholysis. It has been reported that taking this combination can lead to a symptom complex represented by at least one of the following components: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody test, increased ESR, eosinophilia and leukocytosis, rash, photosensitivity (other skin manifestations are also possible).

From the musculoskeletal system rarely – muscle spasm, myalgia, arthralgia, muscle weakness, arthritis; very rarely – paralysis.

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

From the reproductive system infrequently – decreased libido; rarely – impotence.

Allergic reactions very rarely – anaphylactic reactions, angioedema. Angioedema develops more often in Black individuals. In a small group of patients, the occurrence of facial and oropharyngeal angioedema has been associated with the use of ACE inhibitors.

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

Contraindications

History of angioedema, including that associated with previous ACE inhibitor therapy; hereditary/idiopathic angioedema; severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²), anuria; severe hepatic impairment and/or cholestasis; primary aldosteronism; arterial hypotension; hemodialysis; status after kidney transplantation (no experience of use); galactose intolerance, hereditary lactase deficiency or glucose-galactose malabsorption syndrome (due to the lactose content in the drug); pregnancy; lactation period (breastfeeding); age under 18 years (efficacy and safety not established); hypersensitivity to ramipril and other ACE inhibitors, thiazides or sulfonamide derivatives, as well as to any of the excipients of the drug.

With caution

Severe lesions of the coronary and cerebral arteries (risk of reduced blood flow with excessive blood pressure reduction), unstable angina, severe ventricular arrhythmias, chronic heart failure stage IV, decompensated cor pulmonale, conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), systemic connective tissue diseases, diabetes mellitus, bone marrow depression, with aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy, bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, gout, hyperkalemia, hyponatremia (including against the background of diuretic use and a salt-restricted diet), hypokalemia, hypercalcemia, coronary artery disease, renal and/or hepatic insufficiency, liver cirrhosis; in elderly patients,

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindication: severe hepatic impairment and/or cholestasis.

Use in Renal Impairment

Contraindication: severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²), anuria.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Ramipril

In case of development of arterial hypotension, the patient should be placed on their back, legs raised, and if necessary, an intravenous infusion of sodium chloride solution should be administered. A transient hypotensive reaction is not a contraindication for subsequent administration 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 and therefore is usually not a reason to discontinue treatment. If arterial hypotension manifests with symptoms, it may be necessary to reduce the dose or discontinue treatment.

Like other ACE inhibitors, Ramipril should be prescribed with caution to patients with aortic stenosis or obstruction of left ventricular outflow (e.g., in aortic stenosis or hypertrophic cardiomyopathy). In some cases, the hemodynamic picture may make the use of the fixed combination of ramipril and hydrochlorothiazide unacceptable.

Patients with a history of angioedema not associated with ACE inhibitor use may have an increased risk of developing angioedema in response to an ACE inhibitor.

There are reports of anaphylactoid reactions in patients on hemodialysis using high-flux membranes (e.g., AN69) with concurrent use of ACE inhibitors. In such cases, the possibility of using a different type of membrane or antihypertensive agents of another class should be considered.

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

Patients taking ACE inhibitors have developed prolonged anaphylactoid reactions during desensitizing therapy (e.g., with hymenoptera venom). If such patients refrained from taking ACE inhibitors during desensitization, no reactions were observed, but accidental administration of an ACE inhibitor provoked an anaphylactoid reaction.

The use of ACE inhibitors has been associated with the development of a rare syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant liver necrosis, sometimes fatal. The mechanism of this syndrome is unclear. If patients taking Ramipril develop jaundice or a marked increase in liver enzyme activity, the drug should be discontinued, and the patient should be monitored by a physician until symptoms resolve.

ACE inhibitors cause angioedema more frequently in Black patients compared to patients of other races. Like other ACE inhibitors, Ramipril may be less effective in lowering blood pressure in Black patients compared to individuals of other races, possibly due to a higher frequency of individuals with low renin levels in the Black hypertensive patient population.

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

In patients undergoing surgery or general anesthesia with agents that lower blood pressure, Ramipril may block the increased formation of angiotensin II in response to compensatory renin release. If arterial hypotension is suspected to develop via this mechanism, it can be corrected by increasing the circulating blood volume.

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.

Not indicated for patients whose condition requires dialysis, since the use of ACE inhibitors during dialysis using high-flux membranes is often accompanied by anaphylactoid reactions. This combination is not permissible.

Hydrochlorothiazide

In patients with renal disease, thiazides may cause azotemia. The use of medicinal products in the presence of impaired renal function may lead to cumulative effects. If progressive renal failure, characterized by an increase in non-protein nitrogen, occurs, the necessity of therapy should be carefully assessed and consideration given to discontinuing the diuretic.

Thiazides should be prescribed with caution to patients with impaired or progressive impairment of liver function, as even minor fluctuations in fluid and electrolyte balance can cause hepatic coma.

Thiazide therapy may reduce glucose tolerance. In diabetes mellitus, dosage adjustment of insulin or oral hypoglycemic agents may be required. Thiazide therapy may unmask latent diabetes mellitus. Thiazide diuretic therapy has been associated with increases in cholesterol and triglyceride levels. Some patients receiving thiazide diuretics may experience an increase in 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 the excretion of uric acid, thereby attenuating the degree of increase in uric acid levels caused by hydrochlorothiazide.

Thiazides, including Hydrochlorothiazide, can cause fluid and electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Symptoms of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, myalgia or muscle cramps, muscle fatigue, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Although the use of thiazide diuretics can lead to hypokalemia, concurrent use of ramipril may reduce the severity of diuretic-induced hypokalemia. The likelihood of developing hypokalemia is highest in liver cirrhosis, in patients with increased diuresis, with inadequate oral intake of electrolytes, and during treatment with corticosteroids and ACTH.

Thiazides can reduce the urinary excretion of calcium ions, leading to slight and intermittent increases in blood calcium levels even in the absence of obvious disorders of calcium metabolism. Overt hypercalcemia may indicate latent hyperparathyroidism. Thiazide use should be discontinued until the results of parathyroid function tests are obtained.

Thiazides have been shown to increase renal magnesium excretion, which may lead to decreased blood magnesium levels.

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

Hydrochlorothiazide may yield a positive reaction in anti-doping control.

Effect on the ability to drive vehicles and operate machinery

There may be a slight or moderate effect on the ability to drive a car and operate machinery. Due to individual response variations, some patients may experience impaired ability to drive a car, operate machinery, and perform other activities requiring increased attention. This is particularly pronounced at the start of treatment and/or after a dosage increase.

Drug Interactions

Ramipril

Concomitant use with diuretics results in summation of the antihypertensive effect. In patients who are already taking diuretics, especially those recently started on diuretics, the addition of ramipril may sometimes cause an excessive decrease in blood pressure. The likelihood of symptoms of arterial hypotension under the influence of ramipril is reduced if the diuretic is discontinued before starting treatment with ramipril.

Concomitant use of some anesthetics, tricyclic antidepressants, and antipsychotic agents with ACE inhibitors may enhance arterial hypotension.

Sympathomimetics may weaken the hypotensive effect of ACE inhibitors, so patients require careful monitoring.

Epidemiological studies have shown that the simultaneous use of ACE inhibitors and hypoglycemic agents (insulins and oral hypoglycemic agents) may enhance the effect of the latter, up to the development of hypoglycemia. The likelihood of such events is especially high during the first weeks of combination therapy in patients, as well as in cases of impaired renal function.

Concomitant use of nitroglycerin and other organic nitrates or vasodilators may enhance 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 increasing serum potassium levels are additive, which may lead to impaired renal function. These effects are usually reversible. In rare cases, acute renal failure may be observed, especially in cases of impaired renal function, for example, 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 simultaneously with ACE inhibitors may increase the risk of leukopenia.

The combination Ramipril+Hydrochlorothiazide should not be used concomitantly with aliskiren in patients with diabetes mellitus, in patients with moderate to severe renal impairment (GFR <60 ml/min/1.73 m²), in patients with hyperkalemia (>5 mmol/L), and in patients with chronic heart failure with low blood pressure.

The combination Ramipril+Hydrochlorothiazide should not be used concomitantly with angiotensin II receptor antagonists or other ACE inhibitors in patients with diabetes and end-stage target organ damage, in patients with moderate to severe renal impairment (GFR <60 ml/min/1.73 m²), in patients with hyperkalemia (>5 mmol/L), and in patients with chronic heart failure with low blood pressure.

Hydrochlorothiazide

Concomitant use with amphotericin B (parenterally), carbenoxolone, glucocorticoids, corticotropin (ACTH) or stimulant laxatives may cause electrolyte imbalance, especially hypokalemia.

Concomitant intake of calcium salts with thiazide diuretics may lead to hypercalcemia (due to reduced excretion of calcium ions).

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

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

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

Concomitant intake of hydrochlorothiazide and drugs that cause torsades de pointes ventricular tachycardia, for example, some antipsychotic agents, increases the risk of hypokalemia.

Concomitant use with sotalol increases the risk of arrhythmia.

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

Ramipril/Hydrochlorothiazide

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

The risk of hyperkalemia is associated with a number of factors, which include renal failure, diabetes mellitus, and the concomitant use of potassium-sparing diuretics (e.g., 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. During administration of ramipril against the background of potassium-excreting diuretics, the hypokalemia caused by their use may be attenuated.

Concomitant intake of lithium and ACE inhibitors reversibly increases serum lithium levels and leads to toxic effects. The use of thiazide diuretics may increase the risk of lithium intoxication and enhance lithium intoxication if it is already caused by the concomitant use of ACE inhibitors. The use of Ramipril concomitantly with lithium is not recommended, but in cases where such a combination is necessary, careful monitoring of serum lithium levels should be performed.

Concomitant use of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkalemia.

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

Concomitant use with sodium chloride results in a weakening of the antihypertensive effect of the fixed combination of ramipril and hydrochlorothiazide.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.