Rami Sandoz tablets 5 mg blister No. 30

Instructions for Rami Sandoz tablets 5 mg blister No. 30

Composition

active ingredient: ramipril;

1 tablet contains ramipril 2.5 mg or 5 mg or 10 mg;

excipients: microcrystalline cellulose, pregelatinized starch, precipitated silicon dioxide, glycine hydrochloride, glycerol dibehenate, yellow iron oxide (E 172) (for 2.5 mg tablets), red iron oxide (E 172) (for 5 mg tablets).

Dosage form

Pills.

Main physicochemical properties:

2.5 mg tablets: light yellow, slightly spotted, capsule-shaped, with a score on one side;

5 mg tablets: light pink, slightly spotted, capsule-shaped, with a score on one side;

10 mg tablets: white or almost white, capsule-shaped, with a score on one side.

Pharmacotherapeutic group

Angiotensin-converting enzyme (ACE) inhibitors. Monocomponent ACE inhibitors. Ramipril. ATC code C09A A05.

Pharmacological properties

Mechanism of action. Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: ACE; kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to the active vasoconstrictor (vasoconstrictor) angiotensin II, as well as the cleavage of the active vasodilator bradykinin. The reduction in the formation of angiotensin II and the inhibition of the cleavage of bradykinin lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat contributes to the reduction of aldosterone secretion. The response to monotherapy with ACE inhibitors was on average less pronounced in black (Afro-Caribbean) hypertensive patients (a population with a low-renin state in hypertension) than in non-blacks.

Pharmacodynamics

Ramipril administration leads to a significant decrease in peripheral arterial resistance. Usually, there are no significant changes in renal plasma flow or glomerular filtration rate (GFR). Administration of ramipril to patients with arterial hypertension leads to a decrease in blood pressure in both the horizontal and vertical positions of the patient, which is not accompanied by a compensatory increase in heart rate.

In most patients, the antihypertensive effect occurs 1-2 hours after taking a single dose of the drug. The maximum effect of a single dose is usually achieved after 3-6 hours. The antihypertensive effect after taking a single dose is usually maintained for 24 hours.

The maximum antihypertensive effect of long-term treatment with ramipril is generally observed after 3-4 weeks. It has been proven that with long-term therapy the antihypertensive effect is maintained for 2 years.

Abrupt discontinuation of ramipril does not cause a rapid and excessive increase in blood pressure (rebound phenomenon).

Heart failure. Ramipril has been shown to be effective in patients with heart failure of NYHA functional classes II-IV, when used as an adjunct to conventional diuretic therapy and, if necessary, cardiac glycosides. The drug has a beneficial effect on cardiac hemodynamics (reduction of left and right ventricular filling pressures, total peripheral vascular resistance, increase in cardiac output and improvement of cardiac index). It also reduces neuroendocrine activation.

Clinical efficacy and safety.

Prevention of cardiovascular diseases / nephroprotection.

A placebo-controlled preventive study (the HOPE study) was conducted in over 9200 patients who received ramipril in addition to standard therapy. This study included patients at high risk of cardiovascular disease after a history of atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, or peripheral vascular disease) or patients with diabetes mellitus who had at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol, low-density lipoprotein cholesterol, or smoking).

This study demonstrated that ramipril statistically significantly reduced the incidence of myocardial infarction, cardiovascular death, and stroke, both individually and in combination (primary composite endpoint).

HOPE study: main results

The MICRO-HOPE study, which was previously planned as part of the HOPE study, examined the effect of adding ramipril 10 mg to existing treatment compared with placebo in 3,577 patients aged 55 years and older (no upper age limit) with normal or elevated blood pressure, most of whom had type 2 diabetes (and at least one cardiovascular risk factor).

The primary analysis showed that 117 (6.5%) of the study participants receiving ramipril and 149 (8.4%) of the study participants receiving placebo developed significant nephropathy, corresponding to a relative risk reduction of 24%; 95% CI [3-40], p = 0.027.

The REIN study, a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, was conducted to evaluate the effect of ramipril treatment on the rate of decline in GFR in 352 normotensive or hypertensive patients (aged 18–70 years) with mild (mean urinary protein excretion > 1 and < 3 g/day) or severe (mean urinary protein excretion ≥ 3 g/day) proteinuria due to chronic non-diabetic nephropathy. Both subgroups were prospectively stratified.

The results of the main analysis of patients with the most severe proteinuria (the subgroup that discontinued early because of proven benefit in the ramipril group) showed that the mean rate of decline in GFR per month was lower with ramipril than with placebo: −0.54 (0.66) vs −0.88 (1.03) mL/min/month, p = 0.038. Thus, the between-group difference was 0.34 [0.03–0.65] mL/min/month and approximately 4 mL/min/year; 23.1% of patients in the ramipril group reached the combined secondary endpoint of doubling of plasma creatinine and/or end-stage renal disease (requiring hemodialysis or kidney transplantation) compared with 45.5% in the placebo group (p = 0.02).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Two large randomized controlled trials [ONTARGET (Telmisartan Monotherapy and Ramipril Combination Outcome Study) and VA NEPHRON-D (Veterans Diabetic Nephropathy Study)] have investigated the combination of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET study was conducted in patients with a history of cardiovascular or cerebrovascular disease or with type 2 diabetes mellitus with concomitant signs of target organ damage. The VA NEPHRON-D study included patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not show a significant benefit of combination therapy with respect to renal and/or cardiovascular outcomes and mortality, while there was an increased risk of hyperkalemia, acute renal failure, and/or hypotension compared with monotherapy. Given the similar pharmacodynamic characteristics of these drugs, these results are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.

Therefore, ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

The ALTITUDE (Aliskiren in Type 2 Diabetes Cardiovascular and Renal Endpoints Trial) evaluated the benefits of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was terminated early due to an increased risk of adverse clinical outcomes. There was a higher incidence of cardiovascular death and stroke in the aliskiren group compared with the placebo group, as well as an increased incidence of serious adverse events of particular interest (hyperkalemia, hypotension, and renal dysfunction).

Paediatric population In a randomised, double-blind, placebo-controlled clinical trial involving 244 paediatric hypertensive patients (73% of whom had primary hypertension) aged 6-16 years, participants were given low, medium or high doses of ramipril to achieve plasma concentrations of ramiprilat corresponding to the adult dose range of 1.25 mg; 5 mg and 20 mg based on body weight. After a 4-week period, ramipril was found to be ineffective on the endpoint of systolic blood pressure reduction, but it did reduce diastolic blood pressure at the highest dose of the range studied. Both medium and high doses of ramipril were shown to reduce systolic and diastolic blood pressure to a statistically significant extent in children with established hypertension.

This effect was not observed in a 4-week, randomized, double-blind, dose-escalation study evaluating the effect of drug withdrawal in 218 pediatric patients aged 6 to 16 years (75% of whom had primary hypertension). In this study, a modest rebound increase in both diastolic and systolic blood pressure was observed after drug withdrawal, but it was not statistically significant for the return to baseline pressure in any dose group of the ramipril dose range studied [low dose (0.625-2.5 mg), medium dose (2.5-10 mg), or high dose (5-20 mg)] based on body weight. Ramipril did not show a linear dose-dependent effect in the pediatric population studied.

Pharmacokinetics

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 1 hour. Based on the amount of substance recovered in the urine, the extent of absorption is at least 56% and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of ramipril at a dose of 2.5 mg and 5 mg is 45%.

Peak plasma concentrations of ramiprilat, the only active metabolite of ramipril, are reached 2-4 hours after administration of ramipril. After the use of usual doses of ramipril once daily, steady-state plasma concentrations of ramiprilat are reached by approximately the 4th day of treatment.

Distribution: The plasma protein binding of ramipril is approximately 73% and that of ramiprilat is approximately 56%.

Metabolism: Ramipril is almost completely metabolized to ramiprilat, diketopiperazine ester, diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.

Elimination. Elimination of metabolites occurs mainly by renal excretion. The decline in plasma concentrations of ramiprilat is multiphasic. Due to the strong saturable binding to ACE and the slow dissociation from the enzyme, ramiprilat has a prolonged terminal elimination phase at very low plasma concentrations.

After repeated doses of ramipril once daily, the effective half-life is 13-17 hours for doses of 5-10 mg and longer for lower doses (1.25-2.5 mg). The difference is due to the saturable capacity of the enzyme to bind ramiprilat.

Neither ramipril nor its metabolite has been detected in breast milk following a single oral dose. However, the effect of repeated doses is unknown.

Patients with renal impairment (see section 4.2). In patients with renal impairment, renal excretion of ramiprilat is reduced and renal clearance of ramiprilat is proportional to creatinine clearance. This results in increased plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.

Patients with impaired hepatic function (see section 4.2). In patients with impaired hepatic function, the metabolism of ramipril to ramiprilat was slowed down due to a decrease in the activity of hepatic esterases, and the plasma levels of ramipril were increased in these patients. However, the maximum concentration of ramiprilat in these patients did not differ from that in subjects with normal hepatic function.

Patients with heart failure: In patients with heart failure, after 2 weeks of treatment with 5 mg ramipril, a 1.5- to 1.8-fold increase in plasma ramiprilat concentration and an increase in the area under the pharmacokinetic concentration-time curve (AUC) were observed.

Paediatric population. The pharmacokinetic profile of ramipril was studied in 30 paediatric hypertensive patients aged 2-16 years, weighing >10 kg. After doses of 0.05 to 0.2 mg/kg, ramipril was rapidly and extensively metabolised to ramiprilat. Peak plasma concentrations of ramiprilat were reached after 2-3 hours. Ramiprilat clearance was significantly correlated with logarithm of body weight (p<0.01) and dose (p<0.001). Clearance and volume of distribution increased in direct proportion to age in each dose group. Exposure levels were comparable in children at a dose of 0.05 mg/kg to those in adults at a dose of 5 mg ramipril. A dose of 0.2 mg/kg in children resulted in exposure levels that were higher than the maximum recommended dose of 10 mg/day in adults.

Preclinical safety data. When administered orally to animals, ramipril did not cause acute toxic effects. Studies with prolonged oral administration of the drug were conducted in rats, dogs and monkeys. In all three species of animals, changes in electrolyte balance and blood picture were observed. In dogs and monkeys receiving the drug at a dose of 250 mg/kg body weight per day, a significant increase in the juxtaglomerular apparatus was observed, which is a manifestation of the pharmacodynamic activity of ramipril. Rats, dogs and monkeys tolerated daily doses of the drug, which were 2; 2.5 and 8 mg/kg body weight per day, respectively. At the same time, they did not experience undesirable effects.

Reproductive toxicity studies conducted in rats, rabbits and monkeys did not reveal any teratogenic properties of the drug. No adverse effects on fertility were observed in either male or female rats.

Administration of ramipril to female rats during pregnancy and lactation resulted in irreversible renal damage (dilation of the renal pelvis) in the offspring at doses of 50 mg/kg body weight per day and above.

Numerous mutagenicity tests using various test systems have not revealed any mutagenic or genotoxic properties of ramipril.

Indication

Treatment of arterial hypertension.

Prevention of cardiovascular disease: reduction of cardiovascular morbidity and mortality in patients with:

severe cardiovascular disease of atherothrombotic origin (history of ischemic heart disease or stroke or peripheral vascular disease);

diabetes mellitus who have at least one cardiovascular risk factor.

Treatment of kidney disease:

initial glomerular diabetic nephropathy, as evidenced by the presence of microalbuminuria;

severe glomerular diabetic nephropathy, as evidenced by the presence of macroproteinuria, in patients who have at least one cardiovascular risk factor (see section "Pharmacological properties");

severe glomerular non-diabetic nephropathy, as evidenced by the presence of macroproteinuria ≥ 3 g/day.

Treatment of heart failure accompanied by clinical manifestations.

Secondary prevention after acute myocardial infarction: reduction of mortality during the acute phase of myocardial infarction in patients with clinical signs of heart failure, provided that treatment is started more than 48 hours after the onset of acute myocardial infarction.

Contraindication

Hypersensitivity to the active substance, to any other component of the drug or to other ACE inhibitors.

History of angioedema (hereditary, idiopathic or associated with the use of ACE inhibitors or angiotensin II receptor antagonists).

Significant bilateral renal artery stenosis or renal artery stenosis in the presence of a single functioning kidney.

The drug should not be used in patients with arterial hypotension or hemodynamically unstable conditions.

Concomitant use with sacubitril/valsartan (see sections “Interaction with other medicinal products and other types of interactions” and “Special warnings and precautions for use”).

Pregnancy and planning pregnancy (see section "Use during pregnancy or breastfeeding").

Do not use with aliskiren-containing products in patients with diabetes mellitus or moderate or severe renal impairment (GFR < 60 ml/min/1.73 m2) (see section “Interaction with other medicinal products and other types of interactions”).

The concomitant use of ACE inhibitors and extracorporeal therapies that result in contact of blood with negatively charged surfaces should be avoided (see section 4.5).

Interaction with other medicinal products and other types of interactions

Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with an increased incidence of adverse events such as hypotension, hyperkalemia and worsening renal function (including acute renal failure) compared with the use of a single agent affecting the RAAS (see sections 5.1, 5.3 and 5.4).

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections 4.3 and 4.4). Ramipril treatment should only be initiated 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan treatment should only be initiated 36 hours after the last dose of ramipril.

Extracorporeal therapies that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high flux membranes (e.g. polyacrylonitrile membranes) and low density lipoprotein apheresis using dextran sulfate, due to the increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is necessary, consideration should be given to using a different dialysis membrane or a different class of antihypertensive medicinal product.

Combinations requiring precautions.

Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim and its fixed combinations with sulfamethoxazole, tacrolimus, ciclosporin). Hyperkalaemia may occur, therefore careful monitoring of plasma potassium levels is necessary.

Antihypertensive drugs (e.g. diuretics) and other substances that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). An increased risk of arterial hypotension should be expected (see section "Special warnings and precautions for use" for diuretics).

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of Rami Sandoz®. Close monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may cause changes in the blood picture. Increased likelihood of hematological reactions (see section "Special instructions").

Lithium salts: ACE inhibitors may reduce lithium excretion, which may lead to increased lithium toxicity. Lithium levels should be carefully monitored.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Close monitoring of blood glucose levels is recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. The antihypertensive effect of Rami Sandoz® is expected to be reduced. Furthermore, the concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of worsening of renal function and an increase in blood potassium levels.

Salt. Excessive salt consumption may weaken the hypotensive effect of the drug.

Specific hyposensitization. ACE inhibition increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom. It is believed that this effect may also be observed for other allergens.

Mammalian target of rapamycin (mTOR) inhibitors or vildagliptin: There may be an increased risk of angioedema in patients receiving concomitant treatment with mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin. Such therapy should be initiated with caution (see section 4.4).

Racecadotril: A potential increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and a neutral endopeptidase (NEP) inhibitor, such as racecadotril (see section 4.4).

Sacubitril/valsartan: Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema.

Application features

Special categories of patients.

Pregnancy: Treatment with ACE inhibitors such as ramipril or angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).

Patients at particular risk of hypotension.

Patients with significantly increased RAAS activity. The risk of a sudden marked decrease in blood pressure with deterioration of renal function due to ACE inhibition is increased in patients with marked activation of the PAAC, especially when an ACE inhibitor or concomitant diuretic is administered for the first time or at the first dose increase.

A significant increase in PAAC activity, requiring medical supervision, including constant blood pressure monitoring, can be expected, for example, in patients:

with decompensated congestive heart failure;

with hemodynamically significant obstruction to the inflow or outflow of blood from the left ventricle (for example, with aortic or mitral valve stenosis);

with unilateral renal artery stenosis in the presence of a second functioning kidney;

who have or may develop fluid or electrolyte depletion (including those receiving diuretics);

with liver cirrhosis and/or ascites;

who perform extensive surgical interventions or during anesthesia with the use of drugs that cause arterial hypotension.

It is usually recommended to correct dehydration, hypovolemia, or electrolyte depletion before initiating treatment (however, in patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

Transient or persistent heart failure after myocardial infarction.

Patients at risk of cardiac or cerebral ischemia in the event of acute arterial hypotension. Special medical supervision is required in the initial phase of treatment.

Double blockade of RAAS.

Concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren has been shown to increase the risk of hypotension, hyperkalaemia and deterioration of renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see sections 5.1 and 5.5).

If such dual blockade therapy is considered absolutely necessary, it should only be used under specialist supervision and with frequent and careful monitoring of renal function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Elderly patients: See section "Method of administration and dosage".

Surgery: It is recommended to discontinue treatment with ACE inhibitors such as ramipril, if possible, 1 day before surgery.

Monitoring of renal function. Renal function should be assessed before and during treatment and the dose adjusted, especially in the first weeks of treatment. In the presence of renal impairment, particularly close monitoring is required (see section 4.2). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation, and in patients with renal vascular disease, including patients with hemodynamically significant unilateral renal artery stenosis.

Angioedema: Isolated cases of angioedema have been reported in patients receiving ACE inhibitors, including ramipril (see section 4.8).

The combination of ramipril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Ramipril treatment should only be initiated 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).

The risk of angioedema may be increased in patients receiving concomitant medicinal products such as mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, everolimus, sirolimus), vildagliptin or racecadotril (signs may include, for example, swelling of the airways or tongue with or without respiratory distress (see section 4.8). Therefore, caution should be exercised when administering mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus), vildagliptin or racecadotril to patients already receiving ACE inhibitors.

In case of angioedema, the drug should be discontinued and emergency treatment should be initiated immediately. Patients should be observed for at least 12-24 hours until symptoms resolve.

Cases of intestinal angioedema have been reported with ACE inhibitors (see section 4.8). These patients presented with abdominal pain (with or without nausea/vomiting). Symptoms of intestinal angioedema resolved after discontinuation of ramipril.

Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased when taking ACE inhibitors. Temporary discontinuation of ramipril should be considered before desensitization.

Electrolyte monitoring. Hyponatremia. Syndrome of inappropriate antidiuretic hormone secretion with subsequent hyponatremia has been observed in some patients treated with ramipril. Regular monitoring of serum sodium levels is recommended in the elderly and in other patients at risk of hyponatremia.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia have been observed rarely. Bone marrow depression has also been reported. Monitoring of the white blood cell count in the blood plasma is recommended to detect possible leukopenia. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagen disease (e.g. systemic lupus erythematosus or scleroderma) or those taking other medicinal products that may cause changes in the blood picture (see sections “Interaction with other medicinal products and other forms of interaction” and “Adverse reactions”).

Ethnic differences. ACE inhibitors are more likely to cause angioedema in black patients than in whites. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients. This may be because black patients with hypertension are more likely to have low-renin hypertension.

Cough. Cough has been reported with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of therapy. The possibility of cough due to ACE inhibitors should be considered in the differential diagnosis of cough.

Use during pregnancy or breastfeeding

Pregnancy. The drug is contraindicated for use in pregnant women or women planning to become pregnant. If pregnancy is detected during therapy, the drug should be discontinued immediately and, if necessary, replaced with another drug approved for use in pregnant women (see section "Contraindications").

Breastfeeding. Due to the lack of information regarding the use of ramipril during breastfeeding (see section "Pharmacological properties"), this drug is not recommended for use in breast-feeding women and alternative treatments with better established safety profiles during lactation are preferable, especially while breastfeeding a newborn or preterm infant.

Ability to influence reaction speed when driving vehicles or other mechanisms

Some side effects (for example, symptoms of low blood pressure, such as dizziness) may impair the patient's ability to concentrate and reduce the speed of their reactions, which is risky in situations where these qualities are particularly important (for example, when driving vehicles or other mechanisms).

This is usually possible at the beginning of treatment or when switching from other drugs to ramipril. After taking the first dose or a subsequent increase in dose, it is advisable not to drive or operate machinery for several hours.

Method of administration and doses

The drug is administered orally.

Ramipril is recommended to be taken at the same time each day. The drug can be taken regardless of food intake, as food intake does not affect the bioavailability of the drug. The 2.5 mg, 5 mg and 10 mg tablets are intended to be divided in half to obtain doses of 1.25 mg, 2.5 mg and 5 mg, respectively. They should not be chewed or crushed.

Adults.

Patients taking diuretics. Hypotension may occur at the beginning of treatment with the drug, the development of which is more likely in patients who are simultaneously receiving diuretics. In such cases, caution is recommended, since in these patients a decrease in circulating blood volume and/or the number of