Consilar-D24, capsules 0.625 mg+2, 5 mg 30 pcs.

Pharmacotherapeutic group

Hypertensive combined (diuretic + angiotensin-converting enzyme inhibitor (ACE inhibitor)).

ATX code

C09BA05

Pharmacological properties

Pharmacodynamics

Combined hypotensive drug containing the diuretic from the group of sulfonamide derivatives – indapamide and angiotensin-converting enzyme (ACE) inhibitor – ramipril. The pharmacological effect of the combination is due to the combination of individual properties of each of the components, which in turn reinforce each other’s action. The drug has antihypertensive, diuretic and vasodilatory actions.

Controlar-D24 has expressed dose-dependent antihypertensive effect both on systolic and diastolic blood pressure (BP). Antihypertensive effect does not depend on the age and body position of the patient. It does not affect lipid and carbohydrate metabolism, including in patients with diabetes.

The antihypertensive effect lasts for 24 hours.

A steady lowering of BP is achieved within 1 month of using CONSILAR-D24 without increasing of heart rate (HR). Discontinuation of treatment does not lead to development of “withdrawal” syndrome.

Indapamide

Indapamide belongs to derivatives of sulfonamide with an indole ring and has pharmacological properties similar to thiazide diuretics, which inhibit reabsorption of sodium ions in the cortical segment of the nephron loop. At the same time, renal excretion of sodium ions, chlorine and, to a lesser extent, potassium and magnesium ions increases, which is accompanied by increased diuresis and antihypertensive effect.

Indapamide reduces arterial smooth muscle tone and has a vasodilator effect, decreases total peripheral vascular resistance (TPR). These effects are mediated by the decrease of vascular wall reactivity to noradrenaline and angiotensin II; increase of prostaglandin E2 synthesis with vasodilator activity; inhibition of calcium current in vascular smooth muscle cells.

Indapamide promotes reduction of left ventricular hypertrophy.

Indapamide in monotherapy in doses that do not cause a pronounced diuretic effect has a 24-hour antihypertensive effect. Antihypertensive activity of indapamide is associated with improvement of elastic properties of large arteries, reduction of arteriolar and total peripheral vascular resistance.

The thiazide and thiazide-like diuretics reach a plateau of therapeutic effect at a certain dose, while the incidence of side effects continues to increase with further increase of the drug dose. Therefore, do not increase the dose of the drug if the therapeutic effect is not achieved at the recommended dose.

In short-, medium-, and long-term studies involving patients with arterial hypertension, it has been shown that indapamide:

– has no effect on lipid metabolism, including triglyceride, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) concentrations;

– has no effect on carbohydrate metabolism, including in patients with diabetes.

Ramipril

The active metabolite of ramipril formed by liver enzymes, ramiprilate, is a long-acting ACE inhibitor (synonyms: kininase II, dipeptidylcarboxydipeptidase I), which is a peptidyl dipeptidase. ACE in blood plasma and tissues catalyzes the conversion of angiotensin I into angiotensin II, which has a vasoconstrictor effect, and the breakdown of bradykinin, which has a vasodilator effect. Therefore, oral administration of ramipril reduces angiotensin II formation and bradykinin accumulation, which leads to vasodilation and BP reduction. Increase of activity
of kallikrein-kinin system in blood and tissues causes cardioprotective and endoprotective effects of ramipril due to the activation of prostaglandin system and, correspondingly, increase of synthesis of prostaglandins that stimulate nitric oxide formation in endotheliocytes.

Angiotensin II stimulates production of aldosterone, so taking ramipril results in decreased secretion of aldosterone and increased plasma potassium ions.

When the concentration of angiotensin II in blood decreases, its negative feedback inhibitory effect on renin secretion is eliminated, resulting in increased plasma renin activity.

It is assumed that the development of some adverse reactions (in particular, dry cough) is also associated with increased bradykinin activity.

In patients with arterial hypertension administration of ramipril leads to a decrease in BP in lying and standing position without a compensatory increase in HR. Ramipril significantly reduces PPS with little or no change in renal blood flow and glomerular filtration rate. Antihypertensive effect begins to appear 1-2 hours after oral administration of a single dose of ramipril, reaching its greatest value after 3-6 hours, and lasts for 24 hours. When administered as a course, the antihypertensive effect may gradually increase, stabilizing usually by 3-4 weeks of regular ramipril administration and then persisting for a long time. Sudden discontinuation of ramipril does not lead to a rapid and significant increase in BP (no “withdrawal” syndrome).

In patients with arterial hypertension ramipril slows the development and progression of myocardial and vascular wall hypertrophy.

In patients with chronic heart failure, ramipril decreases PEEP (decreases afterload on the heart), increases venous capacitance and decreases left ventricular filling pressure, which consequently leads to a decrease in cardiac preload. In these patients, ramipril administration has increased cardiac output, ejection fraction and improved exercise tolerance.

In diabetic and nondiabetic nephropathy, taking ramipril slows the rate of progression of renal failure and time to end-stage renal failure and thus reduces the need for hemodialysis or renal transplantation. In the initial stages of diabetic or nondiabetic nephropathy, ramipril reduces the incidence of albuminuria.

In patients at high risk of cardiovascular disease Due to vascular lesions (diagnosed coronary heart disease (CHD), a history of peripheral arterial obliterative disease, a history of stroke) or diabetes with at least one additional risk factor (microalbuminuria, arterial hypertension, increased concentration of total cholesterol, decreased concentration of HDL cholesterol, smoking) the addition of ramipril to standard therapy significantly reduces the incidence of myocardial infarction, stroke and mortality from cardiovascular causes. In addition, ramipril reduces overall mortality as well as the need for revascularization procedures, and slows the onset or progression of chronic heart failure.

In patients with heart failure with clinical manifestations that developed during the first days of acute myocardial infarction (days 2-9), use of ramipril initiated from day 3 to day 10 of acute myocardial infarction reduced mortality (by 27%), risk of sudden death (by 30%), risk of progression of heart failure to severe (NYHA functional class III-IV)/resistant to therapy (by 23%), and likelihood of subsequent hospitalization due to development of heart failure (by 26%).

In the general patient population as well as in patients with diabetes mellitus (both hypertensive and normal AD, ramipril significantly reduces the risk of nephropathy and microalbuminuria.

Pharmacokinetics

The combined use of indapamide and ramipril has no effect on their pharmacokinetic parameters compared with taking these drugs in monotherapy.

Indapamide

absorption

The bioavailability of indapamide is 93%.

Released indapamide is quickly and completely absorbed in the gastrointestinal tract. Simultaneous intake of food slightly increases the time of absorption of indapamide without affecting the completeness of absorption. Maximum plasma concentration is reached 1-2 hours after a single oral dose of 2.5 mg. In repeated doses, the fluctuations in plasma concentrations of indapamide between doses are smoothed out. There is individual variability in indapamide absorption rates.

Distribution

About 75% of indapamide is bound to plasma proteins and due to its high affinity for elastin is concentrated in the smooth muscle of the vascular walls. It also binds to erythrocyte carboxyhydrazone without inhibiting the activity of this enzyme.

When taking the drug regularly, the equilibrium concentration of indapamide in plasma is increased (compared to a single dose). Equilibrium concentration is reached after 7 days of indapamide administration. No cumulation is observed when indapamide is taken repeatedly.

Metabolism

Indapamide is metabolized in the liver.

Elimation

The elimination half-life (T_1/2) is 14 to 24 h (18 h on average). It is excreted as inactive metabolites, mainly by the kidneys (60-80% of the dose taken) and through the intestine (22%). No more than 5% of indapamide is excreted unchanged by the kidneys.

Pharmacokinetics in special groups of patients

In patients with renal insufficiency pharmacokinetic parameters of indapamide do not change significantly.

Ramipril

absorption

. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract
(50-60%). Concomitant ingestion slows its absorption, but does not affect the completeness of absorption.

Distribution

The bioavailability of ramipril after oral administration ranges from 15% (for 2.5 mg dose) to 28% (for 5 mg dose). The bioavailability of the active metabolite, ramiprilate, after oral administration of 2.5 mg and 5 mg of ramipril is approximately 45% (compared to its bioavailability after intravenous administration at the same doses). After oral administration of ramipril, maximum plasma concentrations of ramipril and ramiprilate are reached after 1 and 2-4 hours, respectively.

Metabolism

. Ramipril undergoes extensive presystemic metabolism/activation (mainly in the liver by hydrolysis), which produces its only active metabolite, ramiprilate, which has approximately 6 times the activity of ramipril with respect to ACE inhibition. In addition, ramipril metabolism produces diketopiperazine, which has no pharmacological activity and then undergoes conjugation with glucuronic acid; ramiprilat is also glucuronized and metabolized to diketopiperazine acid.

Elimation

The decrease in plasma concentration of ramiprilat occurs in several phases: A distribution and excretion phase with a half-life (T_1/2) of ramiprilat of approximately 3 h, followed by an intermediate phase with T_1/2 of ramiprilat, which is approximately 15 h, and an end phase with very low plasma concentration of ramiprilat and T_1/2 ramiprilat, which is approximately 4-5 days. This end phase is due to the slow release of ramiprilat from its strong binding to ACE receptors. Despite the prolonged terminal phase when ramipril is administered orally at a single daily dose of 2.5 mg or more, the equilibrium plasma concentration of ramiprilat is reached after approximately 4 days of treatment. When the drug is administered in courses, the “effective” T_1/2 depending on the dose is
13-17 h.

After oral administration of radioactive isotope-labeled ramipril (10 mg), 39% of radioactivity is excreted through the intestine and about 60% by the kidneys. After intravenous administration of ramipril, 50-60% of the dose is detected in the urine as ramipril and its metabolites. After intravenous administration of ramiprilat about 70% of the dose is detected in the urine as ramiprilat and its metabolites, in other words, when ramipril and ramiprilat are administered intravenously, a significant part of the dose is excreted through the intestine with the bile, bypassing the kidneys (50% and 30%, respectively). After oral administration of 5 mg of ramipril in patients with bile duct drainage, almost equal amounts of ramipril and its metabolites are excreted by the kidneys and through the intestine during the first 24 h after administration.

About 80-90% of metabolites in urine and bile have been identified as ramipril and ramiprilate metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10-20% of the total, and the urinary content of unmetabolized ramipril is approximately 2%.

In animal studies, ramipril has been shown to be excreted in maternal milk.

Pharmacokinetics in special patient groups

The pharmacokinetics of ramipril and ramiprilate are not significantly different in healthy elderly volunteers (65-76 years) than in young healthy volunteers.

In impaired renal function with creatinine clearance (CK) less than 60 mL/min, excretion of ramipril and its metabolites is delayed in proportion to the decrease in creatinine clearance (CK). This leads to an increase in plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function.

When ramipril is taken at high doses (10 mg), impaired liver function leads to slower presystemic metabolism of ramipril to active ramiprilate and slower excretion of ramiprilate.

In patients with chronic heart failure, a 1.5-1.8-fold increase in plasma concentrations of ramiprilat and area under the pharmacokinetic curve “concentration-time” (AUC) was observed after two weeks of treatment with ramipril at a daily dose of 5 mg.

In healthy volunteers and in patients with arterial hypertension after two weeks of treatment with ramipril at a daily dose of 5 mg, there is no clinically significant accumulation of ramipril and ramiprilat.

Indications

Active ingredient

Composition

Dosage 0.625 mg + 2.5 mg

acting ingredients: indapamide, 0.625 mg; ramipril, 2.500 mg;

excipients: lactose monohydrate, 143.875 mg; colloidal silica, 1.500 mg; calcium stearate, 1.500 mg;

solid gelatin capsules: body: titanium dioxide – 2.0%, gelatin – up to 100%; lid: titanium dioxide – 1.0%, iron oxide yellow dye (iron oxide) – 1.7143%, indigo carmine dye – 0.3%, gelatin – up to 100%.

How to take, the dosage

One time per day, preferably in the morning.

The capsules should be swallowed whole and with plenty of water.

The dose is adjusted according to the therapeutic effect and patient tolerability.

The treatment with the drug CONSILAR-D24 is usually prolonged and its duration is determined by the physician in each individual case.

Unless otherwise prescribed, the following dosing regimens are recommended when renal and hepatic function is normal.

The initial dose is 1 capsule of 0.625 mg + 2.5 mg, once in the morning. If normalization of BP is not achieved after taking CONSILAR-D24 in this dose for 2 weeks or more, the dose can be increased to 1 capsule with the dosage of 1.25 mg + 5 mg of CONSILAR-D24 daily.

If the antihypertensive effect of the daily dose of 1.25 mg + 5 mg is insufficient, a new therapy regimen should be chosen.

The maximum daily dose is 2 capsules of 1.25 mg + 5 mg once daily.

Application of the drug CONSILAR.-D24 in special patient groups/em>

Patients with impaired renal function

Dose adjustment is not required for CKD 60 ml/min or more.

For patients with CKD 30-60 ml/min, the starting dose is 0.625 mg + 2.5 mg per day, the maximum daily dose is 1.25 mg + 5 mg. Treatment should be started with a selection of doses of indapamide and ramipril in monotherapy.

In severe renal failure (CKR less than 30 ml/min), use of CONSILAR-D24 is contraindicated.

Patients with hepatic dysfunction

For patients with hepatic dysfunction, the maximum daily dose is 1 capsule of 0.625 mg + 2.5 mg. Close medical supervision is required at the beginning of treatment.

In severe hepatic insufficiency the use of the drug CONSILAR-D24 is contraindicated.

Elderly patients

In elderly patients renal function and plasma potassium content should be assessed before starting the drug CONSILAR-D24. CONSILAR-D24 preparation can be used only when renal function is normal or in case of insignificant renal dysfunction. The dose should be adjusted to the degree of BP decrease, especially in case of decreased BCC and electrolyte loss, as well as in chronic heart failure (functional class IV according to NYHA classification). Such measures help to avoid a sharp decrease in BP.

The starting dose is 1 capsule of 0.625 mg + 2.5 mg per day.

Interaction

CONSILAR-D24

Combined use is contraindicated

. Concomitant use of lithium preparations and ACE inhibitors may reversibly increase plasma lithium concentrations and increase the cardio- and neurotoxic effects of lithium. Additional use of thiazide diuretics can promote further increase of lithium concentration due to decrease of its excretion and increase the risk of manifestation of toxic reactions. Synchronous use of CONSILAR-D24 with lithium preparations is contraindicated.

. Concomitant use with drugs of potassium, potassium-saving diuretics (amiloride, spironolactone, eplerenone, triamterene), other drugs which can increase the content of potassium in plasma (including trimethoprim, tacrolimus, cyclosporine, heparin) increases the risk of hyperkalemia (especially in patients with diabetes and patients with renal insufficiency).

Continuous use requires special caution

Baclofen potentiates the antihypertensive effect of indapamide and ramipril (BP and renal function control and, if necessary, correction of the dose of CONSILAR-D24 are required).

Concomitant use with non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors and non-selective NSAIDs such as acetylsalicylic acid in doses having anti-inflammatory effect (more than 3 g per day) reduces antihypertensive effect of indapamide and ramipril; increases the risk of renal dysfunction, up to and including acute renal failure; increases plasma potassium in patients with pre-existing renal dysfunction. This combination is recommended with caution, especially in elderly patients. Patients should compensate their blood circulatory capacity and monitor their renal function before and after starting the treatment with CONSILAR-D24.

Cautious use is required for concomitant use

Tricyclic antidepressants, antipsychotics (neuroleptics) increase antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Glucocorticosteroids, tetracosactide reduce the antihypertensive effect (fluid retention).

In concomitant use with other hypotensive agents it is possible to increase the antihypertensive effect of the drug CONSILAR-D24.

Indapamide

Combinations not recommended for use

– Lithium preparations:

The concomitant use of indapamide and lithium preparations, as well as the maintenance of a salt-free diet, may result in increased plasma lithium concentrations due to decreased excretion, accompanied by signs of overdose. If necessary, diuretics may be used in combination with lithium preparations, and plasma lithium concentration should be carefully monitored and the dose of the drug adjusted accordingly.

Combinations requiring caution

Drugs capable of causing pirouette-type polymorphic ventricular tachycardia:

Special Instructions

Hyponatremia and hypovolemia should be corrected before starting treatment.

Patients with previous therapy with diuretics

If possible, diuretics should be stopped 2-3 days before starting treatment with CONSILAR-D24 (depending on the duration of diuretics) or at least the dose of diuretics taken should be reduced. Treatment of such patients should be started with 1 capsule of 0.625 mg + 2.5 mg once a day in the morning. After the first dose and after increasing the dosage of CONSILAR-D24, patients should be under medical supervision for at least 8 hours to avoid uncontrolled hypotensive reaction. Ischemic heart disease and insufficiency of cerebral circulation

The risk of arterial hypotension exists in all patients, but in patients with CHD and insufficiency of cerebral circulation special care should be taken when treating with CONSILAR-D24. Treatment should be started with a daily dose of 0.625 mg + 2.5 mg (initial dose).

Kidney function disorders

The therapy with CONSILAR-D24 is contraindicated in patients with severe renal failure (CKR less than 30 ml/min). Some patients with arterial hypertension without previous renal dysfunction during the course of CONSILAR-D24 therapy may have symptoms of acute renal failure. In this case, treatment with CONSILAR-D24 should be stopped. Afterwards, combined therapy can be resumed using low doses of CONSILAR-D24 or indapamide and ramipril can be used in monotherapy. Such patients should have regular monitoring of potassium content and creatinine concentration in plasma every 2 weeks after therapy start and every 2 months after that with CONSILAR-D24.

Acute renal failure develops more frequently in patients with severe chronic heart failure or underlying renal dysfunction, including bilateral renal artery stenosis or artery stenosis of the only functioning kidney. CONSILAR-D24 is contraindicated in patients with bilateral stenosis of the renal arteries or stenosis of the artery of the only functioning kidney.

Arterial hypotension and disruptions of water-electrolyte balance

Hyponatremia and hypovolemia should be eliminated before starting the drug CONSILAR-D24 treatment. Hyponatremia is associated with the risk of sudden BP decrease (especially in patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney). Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte content, e.g., after prolonged diarrhea or vomiting. Such patients need regular monitoring of plasma electrolytes. In marked BP decrease, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continuation of therapy. After the RBC and BP recovery the therapy with CONSILAR-D24 can be resumed using low doses of the drug or the drugs indapamide and ramipril can be used in monotherapy.

Potassium content

Combined use of indapamide and ramipril may lead to hypokalemia, especially in patients with diabetes or renal insufficiency. During administration of CONSILAR-D24, plasma potassium content should be regularly monitored. In patients with hypokalemia the drug CONSILAR-D24 is contraindicated.

Auxiliary substances

We should take into account that excipients of the preparation CONSILAR-D24 contain lactose monohydrate. The use of the drug CONSILAR-D24 is contraindicated in patients with lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Indapamide

Hepatic disorders

. When using thiazide and thiazide-like diuretics in patients with hepatic dysfunction, hepatic encephalopathy may develop, especially in cases of water-electrolyte imbalance, which may progress to hepatic coma. In this case the drug CONSILAR-D24 should be stopped immediately.

VIight organ disorders

When using thiazide and thiazide-like diuretics there is a risk of acute myopia/secondary closed-angle glaucoma. If symptoms of these complications occur, immediate medical attention is required.

Photosensitivity

Photosensitivity reactions have been reported with thiazide and thiazide-like diuretics. In case of photosensitivity reactions when taking CONSILAR-D24 the drug should be discontinued. If it is necessary to continue the therapy with CONSILAR-D24, it is recommended to protect exposed skin from direct sunlight and artificial ultraviolet rays of type A.

Sodium content in plasma

Before starting the treatment it is necessary to determine the sodium content in plasma. This should be monitored regularly while the drug is being taken. All diuretics may cause hyponatremia, with sometimes dire consequences. Regular control of sodium content is necessary, since initially decrease of sodium content in blood plasma may not be accompanied by the appearance of pathological symptoms. The most careful control of sodium content is recommended for patients with liver cirrhosis and elderly patients. Hyponatremia in combination with hypovolemia may be the cause of dehydration and orthostatic hypotension.

The accompanying decrease in the concentration of chlorine ions in plasma may lead to a secondary compensatory metabolic alkalosis: the frequency of development and the degree of severity of this effect are small.

Plasma potassium

The therapy with thiazide and thiazide-like diuretics is associated with the risk of hypokalemia (plasma potassium below 3.4 mmol/l) in the following categories of patients Elderly patients, those who are impaired or receiving concomitant drug therapy with other antiarrhythmic drugs and drugs that may prolong the QT interval, patients with cirrhosis, peripheral edema or ascites, CHD, and heart failure. Hypokalemia in these patients increases the toxic effects of cardiac glycosides and increases the risk of arrhythmias.

In addition, patients with an increased QT interval on ECG are also at increased risk, regardless of whether the increase is due to congenital causes or to medications.

Hypokalemia, like bradycardia, is a contributing condition for severe arrhythmias, particularly pirouette arrhythmias, which can be fatal. In all cases described above, plasma potassium should be monitored regularly and more frequently than usual. The first measurement of plasma potassium content should be done during the first week of the therapy with CONSILAR-D24.

If hypokalemia is detected, appropriate treatment should be prescribed.

Plasma calcium content

Thiazide and thiazide-like diuretics decrease renal calcium excretion, leading to a slight and temporary increase in plasma calcium content. Severe hypercalcemia may be a consequence of hidden hyperparathyroidism.

The administration of CONSILAR-D24 should be stopped before parathyroid function study.

Plasma glucose concentrations

Plasma glucose concentrations should be monitored in patients with diabetes, especially in the presence of hypokalemia.

Moic acid

Patients with hyperuricemia may have an increased risk of gout attacks.

Diuretics and renal function

Tiazide and thiazide-like diuretics are only fully effective in patients with normal or mildly impaired renal function (plasma creatinine concentration in adults below 25 mg/L or 220 µmol/L). In elderly patients the normal plasma creatinine concentration is calculated taking into account age, body weight and sex.

It should be taken into account that at the beginning of treatment patients may have decreased glomerular filtration rate due to hypovolemia, which in turn is caused by loss of fluid and sodium ions due to diuretic therapy. As a consequence, plasma concentrations of urea and creatinine may increase. If renal function is not impaired, such temporary functional renal failure usually goes without consequences, but if renal failure is already present, the patient’s condition may worsen.

Athletes

Indapamide may test positive in doping controls.

Ramipril

Neutropenia/agranulocytosis

. In patients taking ACE inhibitors, there may be cases of neutropenia/granulocytosis. The risk of neutropenia is dose-dependent and depends on the drug taken and the presence of concomitant diseases. In patients with normal renal function in the absence of other complications, neutropenia is rare and resolves on its own after withdrawal of ACE inhibitors. Particular caution should be exercised at the beginning of treatment and in patients with systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as during therapy with immunosuppressants, allopurinol or procainamide, especially in existing renal function disorders. These patients may develop a severe infection that is not amenable to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended. The patient should be warned that in case of any signs of infectious disease (sore throat, fever) it is necessary to immediately contact the doctor. If neutropenia is detected (neutrophil count is less than 2000/μl), discontinuation of treatment with ACE inhibitors is required.

Angeoneurotic edema (Quincke’s edema)

In rare cases, angioedema of the face, extremities, lips, tongue, uvula, pharynx and/or larynx may develop during therapy with ACE inhibitors. If these symptoms occur, CONSILAR-D24 should be stopped immediately. The patient’s condition should be monitored until the signs of oedema have completely disappeared. If the swelling only affects the face and lips, it usually resolves without special treatment, but antihistamines can be used to relieve the symptoms more quickly.

Contraindications

Side effects

Classification of the frequency of side effects according to the recommendations of the World Health Organization (WHO):

very often ³ 1/10;

often from ³ 1/100 to < 1/10;

infrequently from ³ 1/1000 to < 1/100;

rarely from ³ 1/10000 to < 1/1000;

very rarely < 1/10000, including individual reports;

frequency is unknown – it is not possible to determine the frequency of occurrence from the available data.

Cardiac disorders:

infrequent – myocardial ischemia, including the development of an attack of angina or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema;

very rare – arrhythmia;

frequency unknown – polymorphic pirouette-type ventricular tachycardia (potentially fatal).

Vascular disorders:

often – excessive decrease in BP, orthostatic hypotension, syncopal states;

infrequently – “rushes” of blood to the skin of the face;

infrequent – occurrence or exacerbation of circulatory disorders against a background of stenotic vascular lesions, vasculitis;

frequency unknown – Raynaud’s syndrome.

Nervous system disorders:

often – headache, dizziness (feeling of “lightness” in the head);

infrequent – vertigo, paresthesia, agueusia (loss of taste sensitivity), dysgeusia (impairment of taste sensitivity);

rarely – tremor, impaired balance, increased fatigue;

frequency unknown – cerebral ischemia, including ischemic stroke and transient impairment of cerebral circulation, impaired psychomotor reactions, burning sensation, parosmia (impaired smell perception), fainting.

Visual disorders:

infrequent – visual disturbances, including blurred vision;

rarely – conjunctivitis;

frequency unknown – myopia, blurred vision, chorioidal effusion.

Hearing and labyrinth disorders:

rarely – hearing disorders, tinnitus.

Psychiatric disorders:

infrequent – depressed mood, anxiety, nervousness, motor restlessness, sleep disturbances, including drowsiness;

rarely – confusion;

frequency unknown – impaired attention.

Disorders of the respiratory system, chest and mediastinum:

often – “dry” cough (increasing at night and in the “lying” position), bronchitis, sinusitis, shortness of breath;

infrequently – bronchospasm, including aggravation of the course of bronchial asthma, nasal congestion.

Gastrointestinal disorders:

often – inflammatory reactions in the stomach and intestines, digestive disorders, feeling of abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting;

infrequent – fatal pancreatitis (cases of fatal pancreatitis while taking ACE inhibitors have been extremely rare), increased plasma pancreatic enzyme activity, angioedema of the small intestine, upper abdominal pain, including that associated with gastritis, constipation, dry oral mucosa;

rarely – glossitis;

very rarely – pancreatitis;

frequency unknown – aphthous stomatitis (inflammatory reactions of the oral mucosa).

Disorders of the liver and biliary tract:

infrequent – increased activity of “hepatic” enzymes and concentration of conjugated bilirubin in blood plasma;

rare – cholestatic jaundice, hepatocellular lesions;

very rare – disorders of liver function;

frequency unknown – acute hepatic failure, cholestatic or cytolytic hepatitis (extremely rare with fatal outcome), the possibility of hepatic encephalopathy in case of hepatic failure.

Renal and urinary tract disorders:

infrequent – impaired renal function, including development of acute renal failure, increased urine excretion, increased pre-existing proteinuria, increased plasma urea and creatinine concentrations;

very rarely – renal failure;

Reproductive system and mammary gland disorders:

infrequent – erectile dysfunction with transient impotence, decreased libido;

frequency unknown – gynecomastia.

Disorders of the blood and lymphatic system:

infrequent – eosinophilia;

rare – leukopenia, including neutropenia and agranulocytosis, erythrocytopenia, decreased hemoglobin concentration, thrombocytopenia;

very rarely – aplastic anemia, hemolytic anemia;

frequency unknown – suppression of medullary hematopoiesis, pancytopenia.

Skin and subcutaneous tissue disorders:

often – skin rash, particularly maculopapular, hypersensitivity reactions;

infrequent – angioedema, including fatal (laryngeal edema can cause airway obstruction, leading to death), skin itching, hyperhidrosis (increased sweating), purpura;

rarely – exfoliative dermatitis, urticaria, onycholysis;

Very rare – photosensitization reactions, angioneurotic edema, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome;

frequency unknown – erythema multiforme, pemphigus, worsening of the course of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia, possible exacerbation of already existing acute systemic lupus erythematosus, photosensitivity reactions.

Muscle, skeletal and connective tissue disorders:

often – muscle cramps, myalgia;

infrequently – arthralgia.

Endocrine disorders:

frequency unknown – syndrome of inadequate secretion of antidiuretic hormone.

Metabolic and nutritional disorders:

often – hyperkalemia;

infrequent – anorexia, decreased appetite;

very rare – hypercalcemia;

frequency unknown – decrease in potassium concentration and development of hypokalemia, especially significant in patients at risk, decrease in blood sodium.

Disorders of the immune system:

frequency unknown – anaphylactic or anaphylactoid reactions (ACE inhibition increases the severity of anaphylactic or anaphylactoid reactions to venoms of hymenopteran insects such as bees, wasps), increased antinuclear antibody titer.

General disorders and reactions at the site of administration:

often – chest pain, feeling of fatigue;

infrequently – increased body temperature;

rarely – asthenia (weakness).

Laboratory and instrumental data:

Prevalence unknown: prolongation of QT interval on ECG, increased blood glucose concentration, increased blood uric acid concentration, increased liver enzyme activity.

Overdose

Symptoms

. Marked BP decrease, shock, bradycardia, nausea, vomiting, seizures, dizziness, somnolence, confusion, stupor, electrolyte-water balance disorders (hyponatremia, hypokalemia), polyuria or oliguria up to anuria (due to hypovolemia), acute renal failure.

Treatment

In mild cases of overdose – gastric lavage, adsorbents (activated charcoal), sodium sulfate (preferably within 30 minutes) followed by restoration of water-electrolyte balance. The function of vital organs should be monitored.

In more severe cases, additional measures are taken aimed at stabilizing the BP: intravenous administration of 0.9% sodium chloride solution, plasma substitutes, installation of a temporary artificial pacer if bradycardia is resistant to drug therapy. In case of marked BP decrease, administration of alpha-adrenergic agonists (norepinephrine, dopamine) may be added to therapy to replenish the blood circulation and restore the water-electrolyte balance. In case of bradycardia the administration of atropine or installation of temporary artificial pacemaker is recommended. Blood pressure, renal function and plasma electrolyte content should be monitored closely.

There is no experience of using forced diuresis, change of urine pH, hemofiltration or hemodialysis. Hemodialysis is indicated in cases of renal failure.

Pregnancy use

Pregnancy use

The use of CONSILAR-D24 is contraindicated in pregnancy. Before starting treatment it is necessary to make sure that there is no pregnancy. If pregnancy is planned or occurs during treatment, CONSILAR-D24 should be immediately discontinued and other therapy with the established safety profile of use in pregnancy should be prescribed.

Indapamide

Long-term use of thiazide diuretics in the third trimester of pregnancy may cause hypovolemia in the mother and decrease uteroplacental blood flow, which leads to fetoplacental ischemia and delayed fetal development. In rare cases hypoglycemia and thrombocytopenia develop in newborns against the background of diuretics shortly before delivery.

Ramipril

ACE inhibitors are able to cross the placental barrier. If ACE inhibitors are used during pregnancy, there is a risk of fetal renal impairment, decreased fetal and neonatal BP, impaired renal function, hyperkalemia, skull bone hypoplasia, oligohydramnios, limb contractures, skull deformity, lung hypoplasia.

If exposure to ACE inhibitors has occurred in the second trimester of pregnancy or later, fetal ultrasound is recommended to monitor renal function and cranial bone health.

The close monitoring of newborns who have had intrauterine exposure to ACE inhibitors is recommended for the detection of arterial hypotension, oliguria, and hyperkalemia. In oliguria, BP and renal perfusion should be maintained by filling the RBC and using vasoconstrictors. In newborns there is a risk of oliguria and neurological disorders, possibly due to decreased renal and cerebral blood flow due to BP decrease caused by ACE inhibitors (received by pregnant and lactating women).

Application during breastfeeding

The use of the drug CONSILAR-D24 is contraindicated during breastfeeding. If treatment with the drug CONSILAR-D24 is necessary, breastfeeding should be stopped.

Indapamide

There are insufficient data on penetration of indapamide or its metabolites into breast milk. Administration of thiazide diuretics causes decrease in the amount of breast milk or suppression of lactation. In this case, the newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia. Therefore, the risk to the newborn/infant cannot be ruled out.

Ramipril

In animal studies, ramipril has been shown to be excreted with the milk of lactating animals.