Amprilan^® HD (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

Agents acting on the renin-angiotensin system; angiotensin-converting enzyme (ACE) inhibitors, combinations; ACE inhibitors and diuretics

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 has 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 decrease 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 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 maximum effect is reached 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. It has been shown that during 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, the diuretic effect of which is associated with impaired reabsorption of sodium, chloride, potassium, magnesium ions, and water in the distal nephron; it delays the excretion of calcium ions and uric acid. It has antihypertensive properties; the hypotensive effect develops due to the expansion 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 in 3-6 hours and lasts for 6-12 hours. The antihypertensive effect is achieved in 3-4 days of treatment and lasts for 1 week after discontinuation of the drug. With long-term treatment, a decrease in blood pressure 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, GFR, renal blood flow, and mean arterial pressure. With long-term use in low doses, plasma volume remains reduced, while minute volume 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 may interfere with breast milk production.

Pharmacokinetics

Ramipril

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

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

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

Binding to plasma proteins 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 strong 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 intestines 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 metabolites. The glucuronide and 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 administration, C_max of hydrochlorothiazide is reached within 1-3 hours. Absolute bioavailability, estimated by cumulative renal excretion of hydrochlorothiazide, is about 60%. Binding to plasma proteins 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. There is a difference in plasma concentrations between men and women. 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 CrCl 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

Simultaneous 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 daily in the morning.

This combination should be used only after individual dose selection 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 increasing the dose. This effect is especially characteristic of some risk groups. Symptoms such as dizziness, general weakness, blurred vision, sometimes in combination with loss of consciousness (fainting) may be observed. Isolated cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction, marked arterial hypertension and shock, dynamic cerebrovascular accident, cerebral hemorrhage and ischemic stroke were observed during ACE inhibitor therapy against the background of arterial hypotension.

From the hematopoietic system rarely – decreased hemoglobin and hematocrit, 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 disturbances, 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 – ringing in the ears.

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

From the 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.

From the digestive system nausea, abdominal pain, vomiting, dyspepsia; infrequently – epigastric cramps, thirst, constipation, diarrhea, loss of appetite; rarely – dry mouth, vomiting, taste disturbances, inflammation of the oral mucosa 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 skin: infrequently – photosensitivity, skin itching, urticaria; rarely – flushing of the skin of the face, 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 may lead to the occurrence of 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 – impaired renal function, increased residual 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 persons of the Black race. In a small group of patients, the occurrence of facial and oropharyngeal angioedema was 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 – disturbances 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 mellitus.

Contraindications

History of angioedema, including that associated with previous ACE inhibitor therapy; hereditary/idiopathic angioedema; severe renal impairment (CrCl less than 30 ml/min/1.73 m²), anuria; severe hepatic impairment and/or cholestasis; primary aldosteronism; arterial hypotension; hemodialysis; condition after kidney transplantation (no experience of use); intolerance to galactose, 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 decrease in blood pressure), unstable angina, severe ventricular cardiac 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 hematopoiesis depression, with aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy, bilateral renal artery stenosis or stenosis of the artery of a single 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 during lactation (breastfeeding).

Use in Hepatic Impairment

Contraindication: severe hepatic impairment and/or cholestasis.

Use in Renal Impairment

Contraindication: severe renal impairment (CrCl 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 his 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 is symptomatic, 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., 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 ACE inhibitor use.

There have been 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, during LDL apheresis with dextran sulfate, develop life-threatening anaphylactoid reactions. Such reactions can be avoided by temporarily refraining from taking the ACE inhibitor before each apheresis procedure.

In patients taking ACE inhibitors, during desensitizing therapy (e.g., with hymenoptera venom), prolonged anaphylactoid reactions develop. 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 with a fatal outcome. The mechanism of development of this syndrome is unclear. If patients taking Ramipril develop jaundice or a significant increase in liver enzyme activity, the drug should be discontinued, and the patient should be monitored by a physician until symptoms disappear.

ACE inhibitors cause angioedema more often 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 persons of other races, possibly due to a higher frequency of individuals with low renin levels in the population of black patients with arterial hypertension.

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

In patients undergoing surgery or general anesthesia with drugs that lower blood pressure, Ramipril may block the increase in angiotensin II formation under the influence of compensatory renin release. If it is assumed that arterial hypotension develops according to this mechanism, it can be corrected by increasing the circulating blood volume.

In patients with diabetes mellitus taking hypoglycemic agents for oral administration or insulin, it is necessary to carefully monitor blood glucose levels during the first month of treatment with an ACE inhibitor.

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

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 necessity of therapy should be carefully assessed and the possibility of discontinuing diuretics should be considered.

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

Thiazide therapy may reduce glucose tolerance. In diabetes mellitus, it may be necessary to adjust the dose of insulin or oral hypoglycemic agents. Thiazide therapy can unmask latent diabetes mellitus. Thiazide diuretic therapy is associated with increased levels of cholesterol and triglycerides. 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, thus attenuating the degree of increase in uric acid levels caused by hydrochlorothiazide.

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

Although the use of thiazide diuretics can lead to the development of hypokalemia, the simultaneous administration 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, as well as during treatment with corticosteroids and ACTH.

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

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

The fixed-dose combination of ramipril and hydrochlorothiazide should be discontinued in case of occurrence or suspicion of occurrence of neutropenia (neutrophil count less than 1000/µl).

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

Effect on the ability to drive vehicles and operate machinery

There may be a mild or moderate effect on the ability to drive a car and operate machinery. Due to differences in individual reactions, some patients may experience impaired ability to drive a car, operate machinery, and perform other activities requiring increased attention. This is especially pronounced at the beginning of treatment and/or after a dosage increase.

Drug Interactions

Ramipril

With simultaneous use with diuretics, an additive antihypertensive effect is noted. In patients 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.

The use of some anesthetics, tricyclic antidepressants, and antipsychotic agents against the background of 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 phenomena is especially high during the first weeks of combined treatment in patients, as well as in case of impaired renal function.

Simultaneous 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 can lead to impaired renal function. These effects are usually reversible. In rare cases, acute renal failure may be observed, especially in case 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.

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

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

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

The combination Ramipril+Hydrochlorothiazide should not be used simultaneously 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), in patients with chronic heart failure with low blood pressure.

The combination Ramipril+Hydrochlorothiazide should not be used simultaneously with angiotensin II receptor antagonists or other ACE inhibitors in patients with diabetes mellitus 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), in patients with chronic heart failure with low blood pressure.

Hydrochlorothiazide

With simultaneous use with amphotericin B (parenterally), carbenoxolone, glucocorticosteroids, corticotropin (ACTH) or stimulant laxatives, Hydrochlorothiazide may cause electrolyte imbalance, especially hypokalemia.

Simultaneous intake of calcium salts with thiazide diuretics may lead to hypercalcemia (against the background of reduced excretion of calcium ions).

With simultaneous use of cardiac glycosides, the risk of digitalis intoxication and hypokalemia increases.

Cholestyramine and colestipol may reduce or slow down 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).

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

With simultaneous use with sotalol, the risk of developing arrhythmia increases.

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 simultaneous 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 the administration of ramipril against the background of potassium-excreting diuretics, the hypokalemia caused by their intake may be attenuated.

With simultaneous intake of lithium and ACE inhibitors, serum lithium levels increase reversibly and toxic effects develop. The use of thiazide diuretics may increase the risk of lithium intoxication and enhance lithium intoxication if it is already caused by the simultaneous use of ACE inhibitors. The use of Ramipril simultaneously with lithium is not recommended, but in cases where such a combination is necessary, careful monitoring of serum lithium levels should be carried out.

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

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

With simultaneous use with sodium chloride, a weakening of the antihypertensive effect of the fixed combination of ramipril and hydrochlorothiazide is noted.

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.