Konsilar-D24 (Capsules) Instructions for Use

Marketing Authorization Holder

Vertex, JSC (Russia)

Contact Information

VERTEX JSC (Russia)

ATC Code

C09BA05 (Ramipril and diuretics)

Active Substances

Indapamide (Rec.INN registered by WHO)

Ramipril (Rec.INN registered by WHO)

Dosage Forms

	Konsilar-D24	Capsules 0.625 mg+2.5 mg: 10, 14, 20, 28, 30, 50, 56, 60, 90 or 120 pcs.
		Capsules 1.25 mg+5 mg: 10, 14, 20, 28, 30, 50, 56, 60, 90 or 120 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 3, with a white body and a green cap; capsule contents – powder or compacted mass of white or almost white color, disintegrating when pressed with a glass rod.

	1 cap.
Indapamide	0.625 mg
Ramipril	2.5 mg

Excipients: lactose monohydrate, colloidal silicon dioxide, calcium stearate.

Composition of hard gelatin capsules titanium dioxide, gelatin, dye yellow iron oxide (iron oxide), dye indigo carmine.

7 pcs. – contour cell packs (2) – cardboard packs.
7 pcs. – contour cell packs (4) – cardboard packs.
10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (9) – cardboard packs.
14 pcs. – contour cell packs (1) – cardboard packs.
14 pcs. – contour cell packs (2) – cardboard packs.
14 pcs. – contour cell packs (4) – cardboard packs.
20 pcs. – contour cell packs (1) – cardboard packs.
20 pcs. – contour cell packs (3) – cardboard packs.
20 pcs. – contour cell packs (6) – cardboard packs.

Capsules hard gelatin, size No. 3, with a white body and a white cap; capsule contents – powder or compacted mass of white or almost white color, disintegrating when pressed with a glass rod.

	1 cap.
Indapamide	1.25 mg
Ramipril	5 mg

Excipients: lactose monohydrate, colloidal silicon dioxide, calcium stearate.

Composition of hard gelatin capsules titanium dioxide, gelatin.

Clinical-Pharmacological Group

Antihypertensive combination drug (diuretic + ACE inhibitor)

Pharmacotherapeutic Group

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

Pharmacological Action

Combined antihypertensive drug containing a diuretic from the sulfonamide derivatives group – Indapamide and an ACE inhibitor – Ramipril. The pharmacological action of the combination is due to the combination of individual properties of each of the components, which, in turn, enhance each other’s action. The drug has antihypertensive, diuretic and vasodilating effects.

The antihypertensive effect lasts for 24 hours and does not depend on the patient’s age and body position. Stable BP reduction is achieved within 1 month against the background of Konsilar-D24 use without an increase in heart rate.

Indapamide

Indapamide belongs to sulfonamide derivatives with an indole ring and is close in pharmacological properties to thiazide diuretics, which inhibit the reabsorption of sodium ions in the cortical segment of the nephron loop. This increases the renal excretion of sodium, chloride ions and, to a lesser extent, potassium and magnesium ions, which is accompanied by an increase in diuresis and an antihypertensive effect.

Indapamide reduces the tone of arterial smooth muscles and has a vasodilating effect, reduces total peripheral vascular resistance. These effects are mediated by a decrease in vascular wall reactivity to norepinephrine and angiotensin II; an increase in the synthesis of prostaglandin E2, which has vasodilating activity; inhibition of calcium influx into vascular smooth muscle cells.

Indapamide helps to reduce left ventricular hypertrophy.

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

Thiazide and thiazide-like diuretics at a certain dose reach a plateau of therapeutic effect, while the frequency of side effects continues to increase with a further increase in the drug dose. Therefore, the drug dose should not be increased if the therapeutic effect is not achieved when using the recommended dose.

In short, medium-duration and long-term studies involving patients with arterial hypertension, it was shown that Indapamide

Does not affect lipid metabolism parameters, including the concentration of triglycerides, cholesterol, LDL and HDL;
Does not affect carbohydrate metabolism parameters, including in patients with diabetes mellitus.

Ramipril

The active metabolite of ramipril formed under the influence of liver enzymes – ramiprilat – is a long-acting ACE inhibitor and is a peptidyldipeptidase. ACE in blood plasma and tissues catalyzes the conversion of angiotensin I to angiotensin II, which has a vasoconstrictive effect, and the breakdown of bradykinin, which has a vasodilating effect. Ramipril reduces the formation of angiotensin II and accumulates bradykinin, which leads to vasodilation and a decrease in BP. An increase in the activity of the kallikrein-kinin system in the blood and tissues determines the cardioprotective and endothelial protective action of ramipril due to the activation of the prostaglandin system and, accordingly, an increase in the synthesis of prostaglandins that stimulate the formation of nitric oxide in endothelial cells.

Angiotensin II stimulates the production of aldosterone, so taking ramipril leads to a decrease in aldosterone secretion and an increase in the plasma potassium ion content.

When the concentration of angiotensin II in the blood decreases, its inhibitory effect on renin secretion by the type of negative feedback is eliminated, which leads to an increase in plasma renin activity.

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

In patients with arterial hypertension, taking ramipril leads to a decrease in BP in the supine and standing positions without a compensatory increase in heart rate. Ramipril significantly reduces total peripheral vascular resistance, practically without causing changes in renal blood flow and glomerular filtration rate. The antihypertensive effect begins to appear 1-2 hours after taking a single dose of ramipril, reaching a maximum value in 3-6 hours, and lasts for 24 hours. With a course of administration, the antihypertensive effect may gradually increase, usually stabilizing by the 3-4th week of regular ramipril intake, and then persist 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 down the development and progression of myocardial and vascular wall hypertrophy.

In patients with chronic heart failure, Ramipril reduces total peripheral vascular resistance (reduces cardiac afterload), increases venous capacity and reduces left ventricular filling pressure, which, accordingly, leads to a decrease in cardiac preload. In these patients, when taking ramipril, an increase in cardiac output, ejection fraction and an improvement in exercise tolerance are observed.

In diabetic and non-diabetic nephropathy, taking ramipril slows down the rate of progression of renal failure and the time to onset of end-stage renal failure and, due to this, reduces the need for hemodialysis or kidney transplantation. In the early stages of diabetic or non-diabetic nephropathy, Ramipril reduces the incidence of albuminuria.

In patients at high risk of developing cardiovascular diseases due to vascular lesions (diagnosed coronary artery disease, history of obliterating peripheral arterial diseases, history of stroke) or diabetes mellitus with at least one additional risk factor (microalbuminuria, arterial hypertension, increased total cholesterol concentration, decreased HDL cholesterol concentration, smoking), adding ramipril to standard therapy significantly reduces the incidence of myocardial infarction, stroke and mortality from cardiovascular causes. In addition, Ramipril reduces overall mortality rates, as well as the need for revascularization procedures, and slows down the occurrence or progression of chronic heart failure.

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

In the general patient population, as well as in patients with diabetes mellitus (both with arterial hypertension and with normal BP), Ramipril significantly reduces the risk of developing nephropathy and the occurrence of microalbuminuria.

Pharmacokinetics

The combined use of indapamide and ramipril does not affect their pharmacokinetic parameters compared with the use of these drugs in monotherapy.

Indapamide

Absorption

The bioavailability of indapamide is 93%. The released Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Simultaneous food intake slightly increases the absorption time of indapamide, without affecting the completeness of absorption. C_max in blood plasma is reached 1-2 hours after a single oral dose of 2.5 mg. With repeated doses, fluctuations in the concentration of indapamide in the blood plasma in the interval between doses of the drug are smoothed out. There is individual variability in indapamide absorption parameters.

Distribution

About 75% of indapamide binds to blood plasma proteins and, due to its high affinity for elastin, concentrates in the smooth muscles of vascular walls. It also binds to erythrocyte carbonic anhydrase without inhibiting the activity of this enzyme.

With regular use of the drug, the C_ss of indapamide in blood plasma increases (compared to a single dose). C_ss is reached after 7 days of indapamide use. With repeated use of indapamide, no accumulation is observed.

Metabolism

Indapamide is metabolized in the liver.

Excretion

T_1/2 ranges from 14 to 24 hours (average 18 hours). It is excreted in the form of inactive metabolites, mainly by the kidneys (60-80% of the taken dose) and through the intestines (22%). No more than 5% of indapamide is excreted from the body by the kidneys unchanged.

Ramipril

Absorption

After oral administration, Ramipril is rapidly absorbed from the gastrointestinal tract (50-60%). Simultaneous food intake slows down its absorption but does not affect the completeness of absorption.

Distribution

The bioavailability of ramipril after oral administration ranges from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). The bioavailability of the active metabolite – ramiprilat – after oral administration of 2.5 mg and 5 mg of ramipril is approximately 45% (compared to its bioavailability after intravenous administration in the same doses). After oral administration of ramipril, C_max in plasma of ramipril and ramiprilat is reached after 1 hour and 2-4 hours, respectively.

Metabolism

Ramipril undergoes intensive presystemic metabolism in the liver by hydrolysis, resulting in the formation of its only active metabolite – ramiprilat, whose activity in inhibiting ACE is approximately 6 times higher than the activity of ramipril. In addition, as a result of ramipril metabolism, a pharmacologically inactive diketopiperazine is formed, which is then conjugated with glucuronic acid, ramiprilat is also glucuronidated and metabolized to diketopiperazine acid.

Excretion

The decrease in plasma concentration of ramiprilat occurs in several stages: the distribution and elimination phase with a T_1/2 of ramiprilat of approximately 3 hours, then an intermediate phase with a T_1/2 of ramiprilat of approximately 15 hours, and a final phase with a very low concentration of ramiprilat in plasma and a T_1/2 of ramiprilat of approximately 4-5 days. This final phase is due to the slow release of ramiprilat from a strong bond with ACE receptors. Despite the prolonged final phase with a single daily oral dose of ramipril of 2.5 mg or more, C_ss of ramiprilat is reached approximately 4 days after the start of treatment. With a course prescription of the drug, the “effective” T_1/2 depending on the dose is 13-17 hours.

After oral administration of radiolabeled ramipril (10 mg), 39% of the radioactivity is excreted through the intestines and about 60% through the kidneys. After intravenous administration of ramipril, 50-60% of the dose is found in the urine in the form of ramipril and its metabolites. After intravenous administration of ramiprilat, about 70% of the dose is found in the urine in the form of ramiprilat and its metabolites, in other words, with intravenous administration of ramipril and ramiprilat, a significant part of the dose is excreted through the intestines with bile, bypassing the kidneys (50% and 30%, respectively). After oral administration of 5 mg of ramipril in patients with biliary drainage, almost equal amounts of ramipril and its metabolites are excreted by the kidneys and through the intestines during the first 24 hours after administration.

Approximately 80-90% of metabolites in urine and bile were identified as ramiprilat and ramiprilat metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10-20% of the total, and the content of unmetabolized ramipril in urine is approximately 2%.

Pharmacokinetics in special patient groups

Renal failure. In case of impaired renal function with CrCl < 60 ml/min, the excretion of ramipril and its metabolites slows down in proportion to the decrease in CrCl. This leads to an increase in the plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function.

Hepatic failure. When taking ramipril in high doses (10 mg), impaired liver function leads to a slowdown in the presystemic metabolism of ramipril to active ramiprilat and slower excretion of ramiprilat.

Chronic heart failure.

In patients with chronic heart failure after 2 weeks of treatment with ramipril at a daily dose of 5 mg, a 1.5-1.8-fold increase in C_max and AUC of ramiprilat is noted.

Indications

Mild to moderate arterial hypertension.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
I10	Essential [primary] hypertension

ICD-11 code	Indication
BA00.Z	Essential hypertension, unspecified

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

The drug is taken orally, 1 time/day, preferably in the morning. Capsules should be swallowed whole and washed down with a sufficient amount of water.

The dose is selected depending on the therapeutic effect and the patient’s tolerance of the drug.

Treatment with Konsilar-D24 is usually long-term, the duration in each specific case is determined by the doctor.

The initial dose is 1 cap. (0.625 mg + 2.5 mg) once in the morning. If, when taking Konsilar-D24 at this dose for 2 weeks or more, it is not possible to normalize BP, the dose may be increased to 1 cap. with a dosage of 1.25 mg + 5 mg)/day.

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

The maximum daily dose is 2 caps. (1.25 mg + 5 mg) 1 time/day.

Special patient groups

Elderly patients. Initial dose – 1 cap. (0.625 mg + 2.5 mg)/day. In elderly patients, renal function and plasma potassium levels should be assessed before starting the drug. Konsilar-D24 can only be used with normal renal function or with minor renal impairment. The dose is selected depending on the degree of BP reduction, especially with a decrease in circulating blood volume and loss of electrolytes, as well as with chronic heart failure (NYHA functional class IV). Such measures allow avoiding a sharp decrease in BP.

For patients with impaired renal function with CrCl ≥60 ml/min, no dose adjustment is required. For patients with CrCl 30-60 ml/min, the initial dose is 0.625 mg + 2.5 mg/day, the maximum daily dose is 1.25 mg + 5 mg. Treatment should begin with the selection of doses of indapamide and ramipril in monotherapy. In severe renal failure (CrCl < 30 ml/min), the use of the drug is contraindicated (see section “Contraindications”).

For patients with impaired liver function, the maximum daily dose is 1 cap. (0.625 mg + 2.5 mg). At the beginning of treatment, careful medical supervision is required. In severe hepatic insufficiency, the use of the drug is contraindicated (see section “Contraindications”).

Children. The safety and efficacy of Konsilar-D24 in children aged 0 to 18 years have not been established (see section “Contraindications”).

Adverse Reactions

Classification of the frequency of adverse reactions according to WHO recommendations: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000, including isolated reports); frequency unknown - cannot be estimated from the available data.

Blood and lymphatic system disorders uncommon – eosinophilia; rare – leukopenia, including neutropenia and agranulocytosis, erythrocytopenia, decreased hemoglobin concentration, thrombocytopenia; very rare – aplastic anemia, hemolytic anemia; frequency unknown – bone marrow depression, pancytopenia.

Immune system disorders frequency unknown – anaphylactic or anaphylactoid reactions (with ACE inhibition, the severity of anaphylactic or anaphylactoid reactions to hymenoptera venoms such as bees, wasps is increased), increased titer of antinuclear antibodies.

Endocrine disorders frequency unknown – syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: common – hyperkalemia; uncommon – anorexia, decreased appetite; very rare – hypercalcemia; frequency unknown – decreased potassium concentration and development of hypokalemia, especially significant for patients at risk, decreased blood sodium content.

Psychiatric disorders uncommon – depressed mood, anxiety, nervousness, psychomotor hyperactivity, sleep disorders, including somnolence; rare – confusion; frequency unknown – attention disturbance.

Nervous system disorders common – headache, dizziness (feeling of “lightheadedness”); uncommon – vertigo, paresthesia, ageusia (loss of taste sensitivity), dysgeusia (disturbance of taste sensitivity); rare – tremor, balance disorder, increased fatigue; frequency unknown – cerebral ischemia, including ischemic stroke and transient ischemic attack, impaired psychomotor reactions, burning sensation, parosmia (impaired perception of smells), syncope.

Eye disorders uncommon – visual disturbances, including blurred vision; rare – conjunctivitis; frequency unknown – myopia, blurred vision, choroidal effusion.

Ear and labyrinth disorders rare – hearing impairment, tinnitus.

Cardiac disorders uncommon – myocardial ischemia, including development of angina pectoris or myocardial infarction, tachycardia, palpitations, peripheral edema; very rare – arrhythmia; frequency unknown – torsades de pointes (potentially fatal).

Vascular disorders: common – excessive decrease in blood pressure, orthostatic hypotension, syncope; uncommon – flushing; rare – occurrence or worsening of circulatory disorders against the background of stenosing vascular lesions, vasculitis; frequency unknown – Raynaud’s syndrome.

Respiratory, thoracic and mediastinal disorders common – dry cough (worsening at night and in a supine position), bronchitis, sinusitis, dyspnea; uncommon – bronchospasm, including worsening of bronchial asthma, nasal congestion.

Gastrointestinal disorders common – inflammatory reactions in the stomach and intestines, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; uncommon – fatal pancreatitis (cases of fatal pancreatitis with ACE inhibitors have been extremely rare), increased activity of pancreatic enzymes in blood plasma, angioedema of the small intestine, pain in the upper abdomen, including associated with gastritis, constipation, dry oral mucosa; rare – glossitis; very rare – pancreatitis; frequency unknown – aphthous stomatitis.

Hepatobiliary disorders uncommon – increased activity of liver enzymes and concentration of conjugated bilirubin in blood plasma; rare – cholestatic jaundice, hepatocellular damage; very rare – impaired liver function; frequency unknown – acute liver failure, cholestatic or cytolytic hepatitis (extremely rare with fatal outcome), possibility of developing hepatic encephalopathy in case of liver failure.

Skin and subcutaneous tissue disorders common – skin rash, in particular maculopapular, hypersensitivity reactions; uncommon – angioedema, including fatal (laryngeal edema can cause airway obstruction leading to death), pruritus, hyperhidrosis (increased sweating), purpura; rare – exfoliative dermatitis, urticaria, onycholysis; very rare – photosensitivity reactions, angioedema, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome; frequency unknown – erythema multiforme, pemphigus, exacerbation of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia, possible exacerbation of pre-existing acute systemic lupus erythematosus, photosensitivity reactions.

Musculoskeletal and connective tissue disorders common – muscle cramps, myalgia; uncommon – arthralgia.

Renal and urinary disorders: uncommon – impaired renal function, including development of acute renal failure, increased urine output, worsening of pre-existing proteinuria, increased plasma urea and creatinine concentration; very rare – renal failure.

Reproductive system and breast disorders uncommon – erectile dysfunction with transient impotence, decreased libido; frequency unknown – gynecomastia.

General disorders and administration site conditions common – chest pain, feeling of tiredness; uncommon – increased body temperature; rare – asthenia.

Investigations frequency unknown – prolongation of the QT interval on ECG, increased blood glucose concentration, increased blood uric acid concentration, increased activity of liver enzymes.

Contraindications

Hypersensitivity to indapamide, ramipril, other ACE inhibitors, sulfonamide derivatives or to any of the excipients of the drug;
History of angioedema (hereditary or idiopathic, as well as associated with previous ACE inhibitor therapy);
Hemodynamically significant renal artery stenosis (bilateral or unilateral, in the case of a single kidney);
Arterial hypotension (systolic BP < 90 mm Hg) or conditions with unstable hemodynamic parameters;
Concomitant use with angiotensin II receptor antagonists in patients with diabetic nephropathy;
Concomitant use with neutral endopeptidase inhibitors (e.g., drugs containing sacubitril) due to the high risk of developing angioedema;
Concomitant use with combined therapy of sacubitril/valsartan (high risk of developing angioedema);
Hemodynamically significant stenosis of the aortic or mitral valve, or hypertrophic obstructive cardiomyopathy;
Primary hyperaldosteronism;
Severe renal failure (GFR < 20 ml/min/1.73 m² body surface area) (insufficient clinical experience);
Hemodialysis (insufficient clinical experience);
Nephropathy treated with corticosteroids, NSAIDs, immunomodulators and/or other cytotoxic drugs (insufficient clinical experience) (see section “Drug Interactions”);
Chronic heart failure in the stage of decompensation (insufficient clinical experience);
Hemodialysis or hemofiltration using certain membranes with a negatively charged surface, such as high-flux polyacrylonitrile membranes (risk of developing severe anaphylactoid reactions) (see sections “Special Precautions”, “Drug Interactions”);
LDL apheresis using dextran sulfate (risk of developing severe anaphylactoid reactions) (see sections “Special Precautions”, “Drug Interactions”);
Desensitization therapy for hypersensitivity reactions to hymenoptera venoms, such as bees, wasps (see section “Special Precautions”);
Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR < 60 ml/min/1.73 m² body surface area);
Acute stage of myocardial infarction in patients with conditions such as:
- Severe chronic heart failure (NYHA functional class IV);
- Unstable angina;
- Life-threatening ventricular arrhythmias;
- Cor pulmonale;
Hepatic encephalopathy or severe liver dysfunction;
Hypokalemia;
Galactose intolerance, lactase deficiency, glucose-galactose malabsorption;
Pregnancy;
Breastfeeding period;
Age under 18 years (efficacy and safety have not been established).

With caution

Concomitant use with drugs containing aliskiren, or angiotensin II receptor antagonists (with dual blockade of the RAAS there is an increased risk of a sharp decrease in blood pressure, development of hyperkalemia and deterioration of renal function compared with monotherapy);
Conditions in which an excessive decrease in blood pressure is especially dangerous (with atherosclerotic lesions of the coronary and cerebral arteries);
Conditions accompanied by increased activity of the RAAS, in which ACE inhibition carries a risk of a sharp decrease in blood pressure with deterioration of renal function;
Severe arterial hypertension, especially malignant arterial hypertension;
Chronic heart failure, especially severe, or for which other drugs with antihypertensive action are taken;
Hemodynamically significant unilateral renal artery stenosis (in the presence of both kidneys) – in such patients even a slight increase in plasma creatinine concentration may be a manifestation of unilateral deterioration of renal function;
Prior use of diuretics;
Water-electrolyte imbalance as a result of insufficient intake of fluid and salt, diarrhea, vomiting, profuse sweating;
Liver dysfunction (insufficient clinical experience: both enhancement and weakening of drug effects are possible);
In patients with liver cirrhosis with ascites and edema, significant activation of the RAAS is possible;
Diabetes mellitus (risk of hyperkalemia);
Renal dysfunction (GFR >20 ml/min/1.73 m² body surface area) (risk of hyperkalemia and leukopenia);
Status after kidney transplantation;
Systemic connective tissue diseases (SLE, systemic scleroderma);
Bone marrow depression;
Concomitant therapy with myelotoxic drugs, immunosuppressants capable of causing changes in the peripheral blood picture (bone marrow depression, development of neutropenia or agranulocytosis is possible);
Hyperkalemia;
Use during major surgical interventions or during general anesthesia;
Hyperuricemia and gout;
Hyperparathyroidism;
Prolonged QT interval on ECG;
Use in patients receiving concomitant therapy with drugs that can prolong the QT interval; use with drugs that can cause torsades de pointes; lithium preparations; drugs that can cause hypokalemia; cardiac glycosides (see section “Drug Interactions”);
Use in debilitated patients;
Elderly age (risk of increased antihypertensive effect);
In patients of Black race.

Use in Pregnancy and Lactation

Pregnancy

The use of Konsilar-D24 is contraindicated during pregnancy. Before starting treatment, pregnancy should be excluded. If pregnancy is planned or occurs during treatment, it is necessary to immediately discontinue Konsilar-D24 and prescribe another therapy with an established safety profile for use during pregnancy.

Indapamide

Long-term use of thiazide diuretics in the third trimester of pregnancy can cause hypovolemia in the mother and reduced uteroplacental blood flow, leading to fetoplacental ischemia and fetal growth retardation. In rare cases, with the use of diuretics shortly before delivery, newborns develop hypoglycemia and thrombocytopenia.

Ramipril

ACE inhibitors are able to cross the placental barrier. When using ACE inhibitors during pregnancy, there is a risk of impaired fetal kidney development, decreased blood pressure in the fetus and newborn, impaired renal function, hyperkalemia, skull bone hypoplasia, oligohydramnios, limb contractures, skull deformation, lung hypoplasia. If exposure to ACE inhibitors occurred in the second trimester of pregnancy or later, fetal ultrasound is recommended to monitor kidney function and skull bone condition.

Close monitoring of newborns who were exposed to ACE inhibitors in utero is recommended to detect arterial hypotension, oliguria and hyperkalemia. In case of oliguria, it is necessary to maintain blood pressure and renal perfusion by replenishing circulating blood volume and using vasoconstrictors. Newborns are at risk of oliguria and neurological disorders, possibly due to reduced renal and cerebral blood flow due to the decrease in blood pressure caused by ACE inhibitors (received by pregnant and lactating women).

Breastfeeding period

The use of Konsilar-D24 is contraindicated during breastfeeding. If treatment with Konsilar-D24 is necessary, breastfeeding should be discontinued.

Indapamide

Data on the penetration of indapamide or its metabolites into breast milk are insufficient. Taking thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. The newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia. Therefore, the risk to the newborn/infant cannot be excluded.

Ramipril

Animal studies have shown that Ramipril is excreted in the milk of lactating animals.

Use in Hepatic Impairment

Contraindicated in hepatic encephalopathy or severe liver dysfunction.

The drug should be used with caution in liver dysfunction.

Use in Renal Impairment

Contraindicated in severe renal failure (GFR less than 20 ml/min/1.73 m² body surface area).

The drug should be used with caution in renal dysfunction (GFR more than 20 ml/min/1.73 m² body surface area).

Pediatric Use

The use of the drug is contraindicated under the age of 18 years.

Geriatric Use

The drug should be used with caution in elderly patients.

Special Precautions

Before starting treatment, hyponatremia and hypovolemia must be corrected.

Patients with prior diuretic therapy

If possible, diuretics should be discontinued 2-3 days (depending on the duration of action of the diuretics) before starting treatment with Konsilar-D24 or, at least, the dose of diuretics taken should be reduced. Treatment of such patients should be started with 1 caps. (0.625 mg + 2.5 mg) once/day in the morning. After taking the first dose and after increasing the dose of Konsilar-D24, patients should be under medical supervision for at least 8 hours to avoid an uncontrolled hypotensive reaction.

Coronary artery disease and cerebrovascular insufficiency

The risk of arterial hypotension exists in all patients, however, in patients with coronary artery disease and cerebrovascular insufficiency, special caution should be exercised when treating with Konsilar-D24. Treatment should be started with a daily dose of 0.625 mg + 2.5 mg (initial dose).

Renal dysfunction

Therapy with Konsilar-D24 is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with arterial hypertension without pre-existing renal dysfunction, symptoms of acute renal failure may appear during therapy with Konsilar-D24. In this case, treatment with Konsilar-D24 should be discontinued. Subsequently, combination therapy can be resumed using low doses of Konsilar-D24, or indapamide and ramipril preparations can be used in monotherapy. Such patients require regular monitoring of potassium levels and plasma creatinine concentration every 2 weeks after the start of therapy and every subsequent 2 months of therapy with Konsilar-D24.

Acute renal failure develops more often in patients with severe chronic heart failure or pre-existing renal dysfunction, including bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Arterial hypotension and water-electrolyte imbalance

Before starting treatment with Konsilar-D24, hyponatremia and hypovolemia must be corrected. Hyponatremia is associated with the risk of a sudden decrease in blood pressure (especially in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney). Therefore, during dynamic observation of patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte levels, for example, after prolonged diarrhea or vomiting. Such patients require regular monitoring of plasma electrolyte levels. With a pronounced decrease in blood pressure, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continuing therapy. After restoration of circulating blood volume and blood pressure, therapy with Konsilar-D24 can be resumed using the drug in low doses, or Indapamide and Ramipril can be used in monotherapy.

Potassium content

Combined use of indapamide and ramipril may lead to the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. During treatment with Konsilar-D24, plasma potassium levels should be regularly monitored. The use of Konsilar-D24 is contraindicated in patients with hypokalemia.

Excipients

It should be taken into account that the excipients of Konsilar-D24 include lactose monohydrate. The use of the drug is contraindicated in patients with lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Indapamide

Liver dysfunction

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

Visual Disorders

When using thiazide and thiazide-like diuretics, there is a risk of developing acute myopia/secondary angle-closure glaucoma. If symptoms of these complications appear, emergency medical care is necessary.

Photosensitivity

Cases of photosensitivity reactions have been reported during the use of thiazide and thiazide-like diuretics. If photosensitivity reactions occur during treatment with Konsilar-D24, therapy should be discontinued. If continuation of therapy with Konsilar-D24 is necessary, it is recommended to protect exposed skin areas from direct exposure to sunlight and artificial UVA rays.

Plasma Sodium Content

Plasma sodium levels must be determined before starting treatment. This parameter should be regularly monitored during drug administration. All diuretic drugs can cause hyponatremia, which sometimes leads to extremely serious consequences. Regular monitoring of sodium levels is necessary because the initial decrease in plasma sodium may not be accompanied by pathological symptoms. The most thorough monitoring of sodium levels is indicated for patients with liver cirrhosis and elderly patients.

Hyponatremia combined with hypovolemia can cause dehydration and orthostatic hypotension.

Concomitant decrease in plasma chloride ion concentration can lead to secondary compensatory metabolic alkalosis; the frequency of occurrence and severity of this effect are insignificant.

Plasma Potassium Content

Therapy with thiazide and thiazide-like diuretics is associated with the risk of developing hypokalemia (plasma potassium level below 3.4 mmol/L) in patients of the following categories: elderly patients, debilitated patients, or those receiving combined drug therapy with other antiarrhythmic drugs and drugs that can prolong the QT interval, patients with liver cirrhosis, peripheral edema or ascites, coronary artery disease, heart failure. Hypokalemia in such patients enhances the toxic effect of cardiac glycosides and increases the risk of arrhythmias.

Furthermore, patients with an increased QT interval on ECG are at increased risk, regardless of whether this increase is due to congenital causes or drug effects.

Hypokalemia, as well as bradycardia, is a condition that promotes the development of severe arrhythmias, and especially torsades de pointes arrhythmias, which can be fatal. In all the cases described above, it is necessary to monitor plasma potassium levels more frequently than usual. The first measurement of plasma potassium should be performed within the first week of starting therapy with Konsilar-D24.

If hypokalemia is detected, appropriate treatment should be prescribed.

Plasma Calcium Content

Thiazide and thiazide-like diuretics reduce renal calcium excretion, leading to a slight and temporary increase in plasma calcium levels. Marked hypercalcemia may be a consequence of latent hyperparathyroidism.

Intake of Konsilar-D24 should be discontinued before testing parathyroid function.

Plasma Glucose Concentration

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

Uric Acid

In patients with hyperuricemia, the risk of gout attacks may increase.

Diuretic Drugs and Renal Function

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

It should be considered that at the beginning of treatment, patients may experience a decrease in GFR due to hypovolemia, which, in turn, is caused by fluid and sodium ion loss during diuretic use. Consequently, the concentration of urea and creatinine in the blood plasma may increase. If renal function is not impaired, such temporary functional renal failure usually resolves without consequences; however, in pre-existing renal failure, the patient’s condition may worsen.

Athletes

Indapamide may give a positive result in doping control.

Ramipril

Neutropenia/Agranulocytosis

Patients taking ACE inhibitors may develop neutropenia/agranulocytosis. 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 and no other complications, neutropenia is rare and resolves on its own after discontinuation of ACE inhibitors. Particular caution is necessary in patients with systemic connective tissue diseases (including SLE, scleroderma), as well as during therapy with immunosuppressants, allopurinol, or procainamide, especially with existing renal impairment. In such patients, severe infection may develop that does not respond to intensive antibiotic therapy. It is recommended to periodically monitor the white blood cell count. The patient should be warned that if any signs of an infectious disease appear (sore throat, fever), they should immediately consult a doctor. If neutropenia is detected (neutrophil count less than 2000/µL), treatment with ACE inhibitors should be discontinued.

Angioedema (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 appear, Konsilar-D24 should be discontinued immediately. The patient’s condition should be monitored until the signs of edema completely disappear. If the edema affects only the face and lips, its manifestations usually resolve without special treatment; however, antihistamines can be used to relieve symptoms faster.

Angioedema involving swelling of the tongue, pharynx, and/or larynx can lead to airway obstruction and death. In such a case, epinephrine (adrenaline) should be administered immediately subcutaneously at a dose of 1:1000 (0.3 to 0.5 ml) or intravenously as a drip at 0.1 mg, and/or airway patency should be ensured followed by the use of corticosteroids (IV, IM, or orally).

Intravenous administration of antihistamines (histamine H₁– and H₂-receptor antagonists) is also recommended, and in case of C1-esterase inhibitor deficiency, the need for additional administration of C1-esterase inhibitors along with epinephrine (adrenaline) can be considered. The patient should be hospitalized and observed until symptoms are completely resolved, but for at least 24 hours. Subsequently, such patients should not use ACE inhibitors. Patients with a history of angioedema not associated with ACE inhibitor use may have an increased risk of developing angioedema when taking drugs of this group. Concurrent use with other drugs that can cause angioedema increases the risk of angioedema.

In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, sometimes without preceding facial angioedema and with normal C1-esterase levels. The diagnosis is established using abdominal CT, ultrasound, or during surgery. Symptoms disappear after discontinuation of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

Anaphylactic and Anaphylactoid Reactions During Desensitization

There are isolated reports of prolonged life-threatening anaphylactic and anaphylactoid reactions (e.g., decreased blood pressure, shortness of breath, vomiting, allergic skin reactions) in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (bees, wasps). During treatment with ACE inhibitors, hypersensitivity reactions to insect venom (such as bees, wasps) develop faster and are more severe. ACE inhibitors are contraindicated in patients receiving desensitizing therapy with hymenoptera venom, such as bees, wasps. Anaphylactic and anaphylactoid reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before starting the desensitization procedure.

Anaphylactoid Reactions During LDL Apheresis

In rare cases, patients receiving ACE inhibitors may develop life-threatening anaphylactoid reactions during LDL apheresis using dextran sulfate. Therefore, this method should not be used in patients receiving ACE inhibitors. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each LDL apheresis procedure using dextran sulfate.

Anaphylactoid Reactions During Hemodialysis or Plasma Filtration Using Certain High-Flux Membranes

Anaphylactoid reactions, sometimes up to shock, have been observed in patients receiving ACE inhibitors during hemodialysis using high-flux membranes. Therefore, it is necessary to use a different type of membrane or use an antihypertensive drug from a different pharmacotherapeutic group.

Cough

During therapy with an ACE inhibitor, a dry, non-productive, prolonged, persistent cough may develop, which disappears after discontinuation of drugs in this group. If a patient develops a dry cough, a possible connection of this symptom with ACE inhibitor use should be considered. If the physician believes that ACE inhibitor therapy is necessary for the patient, Konsilar-D24 intake may be continued.

Risk of Arterial Hypotension and/or Renal Failure

In some pathological conditions, significant activation of the RAAS may be noted, especially in cases of marked hypovolemia and decreased plasma electrolyte levels (against the background of a salt-free diet or long-term diuretic use), in patients with initially low blood pressure, with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, chronic heart failure, or liver cirrhosis with edema and ascites. The use of an ACE inhibitor causes blockade of the RAAS and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in creatinine concentration, azotemia in the blood plasma, oliguria, indicating the development of acute renal failure. These phenomena are more often observed when taking the first dose of ramipril or during the first 2 weeks of therapy. Sometimes these conditions develop acutely at other times during therapy. In such cases, when resuming therapy, it is recommended to use Konsilar-D24 at a lower dose and then gradually increase the dose.

Caution should be exercised when treating elderly patients, as they may be particularly sensitive to ACE inhibitors; in the initial phase of treatment, monitoring of renal function parameters is recommended. In patients for whom a decrease in blood pressure may pose a certain risk (e.g., patients with atherosclerotic narrowing of the coronary or cerebral arteries), treatment should be initiated under strict medical supervision. Caution should be exercised during physical exertion and/or in hot weather due to the risk of increased sweating and dehydration with the development of arterial hypotension, as a result of decreased blood volume and reduced blood sodium levels. Transient excessive lowering of blood pressure is not a contraindication for continuing treatment after blood pressure stabilizes. In case of repeated marked decrease in blood pressure, the dose should be reduced or the drug discontinued.

In heart failure, especially in the acute phase of myocardial infarction, treatment with Konsilar-D24 should be started only in a hospital setting.

Concomitant use of Konsilar-D24 with drugs containing aliskiren or with ARBs (see section “Drug Interactions”). Concomitant use of Konsilar-D24 and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate to severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients. Concomitant use of ARBs is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section “Contraindications”).

Diabetes Mellitus

When using Konsilar-D24 in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be regularly monitored during the first month of therapy.

Renovascular Hypertension

The use of ACE inhibitors has a beneficial effect in patients with renovascular hypertension, both those awaiting surgery and when surgery is not possible. Treatment with Konsilar-D24 should be started with a low dose of the drug in a hospital setting, monitoring renal function and plasma potassium levels. In some patients, functional renal failure may develop, which quickly disappears upon drug discontinuation.

Surgery/General Anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia may lead to a marked decrease in blood pressure, especially when using general anesthetic agents that have an antihypertensive effect. It is recommended to discontinue ACE inhibitors 48 hours before surgery, informing the anesthesiologist about the use of ACE inhibitors.

Anemia

Anemia may develop in patients who have undergone kidney transplantation or in patients on hemodialysis. The decrease in hemoglobin concentration is greater the higher its initial concentration was. This effect does not appear to be dose-dependent but may be related to the mechanism of action of ACE inhibitors. A slight decrease in hemoglobin concentration occurs during the first 6 months of treatment, then the hemoglobin concentration remains stable and fully recovers after drug discontinuation. In such patients, treatment may be continued, but a complete blood count should be performed regularly.

Aortic Stenosis/Mitral Stenosis/Hypertrophic Obstructive Cardiomyopathy

ACE inhibitors are contraindicated in patients with left ventricular outflow tract obstruction and with aortic and/or mitral stenosis and HOCM.

Hepatic Insufficiency

In patients with impaired liver function, the response to treatment with Konsilar-D24 may be enhanced or weakened. Furthermore, in patients with severe liver cirrhosis with edema and/or ascites, significant activation of the RAAS is possible, so special caution should be exercised when treating these patients. In rare cases, cholestatic jaundice occurs during ACE inhibitor use, which may progress rapidly to fulminant hepatic necrosis, sometimes with a fatal outcome. If jaundice appears or a significant increase in liver transaminase activity occurs during ACE inhibitor use, the patient should discontinue Konsilar-D24.

Hyperkalemia

During treatment with ACE inhibitors, hyperkalemia may develop. Risk factors for hyperkalemia are renal failure, old age, diabetes mellitus, some concomitant conditions (decreased blood volume, acute decompensated heart failure, metabolic acidosis), concurrent use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing salt substitutes and the use of other drugs that contribute to increased plasma potassium levels (e.g., heparin). Hyperkalemia can lead to serious cardiac arrhythmias, sometimes fatal. Concurrent use of the above-mentioned drugs is contraindicated (see section “Contraindications”).

Other Risk Groups

In patients with chronic heart failure (NYHA functional class IV) and patients with type 1 diabetes mellitus (risk of spontaneous increase in potassium levels), treatment should be started with low doses of Konsilar-D24 and conducted under constant medical supervision.

In patients with arterial hypertension and coronary artery disease, beta-blockers should not be discontinued: ACE inhibitors should be used together with beta-blockers.

Elderly Patients

In elderly patients, before starting Konsilar-D24, renal function and plasma potassium levels should be assessed. To prevent the development of arterial hypotension, sequential correction of the initial dose of the drug is carried out according to blood pressure indicators, especially with a decrease in blood volume.

Ethnic Differences

ACE inhibitors have a less pronounced antihypertensive effect in Black patients compared to other races. Konsilar-D24 should be prescribed with caution to Black patients due to a higher risk of developing angioedema.

Patients After Kidney Transplantation

Experience with the use of Konsilar-D24 in patients who have recently undergone kidney transplantation is insufficient.

Monitoring of Laboratory Parameters Before and During Treatment with Konsilar-D24 (up to once a month during the first 3-6 months of treatment)

Monitoring of Renal Function (determination of serum creatinine concentrations)

During treatment with ACE inhibitors, in the first weeks of treatment and subsequently, monitoring of renal function is recommended. Particularly careful monitoring is required for patients with acute and chronic heart failure, impaired renal function, after kidney transplantation, patients with renovascular diseases, including patients with hemodynamically significant unilateral renal artery stenosis in the presence of two kidneys (in such patients, even a slight increase in serum creatinine concentration may be an indicator of decreased renal function).

Monitoring of Electrolyte Levels

Regular monitoring of serum potassium and sodium levels is recommended. Particularly careful monitoring of serum potassium is required for patients with impaired renal function, significant water-electrolyte balance disorders, and chronic heart failure.

Monitoring of Hematological Parameters (hemoglobin, white blood cell count, red blood cell count, platelet count, white blood cell differential)

It is recommended to monitor complete blood count parameters to detect possible leukopenia. More regular monitoring is recommended at the beginning of treatment and in patients with impaired renal function, as well as in patients with connective tissue diseases or in patients concurrently receiving other drugs that can alter the peripheral blood picture. Monitoring the white blood cell count is necessary for early detection of leukopenia, which is especially important in patients at increased risk of its development, as well as at the first signs of infection. If neutropenia is detected (neutrophil count less than 2000/µL), treatment with ACE inhibitors should be discontinued. If symptoms due to leukopenia occur (e.g., fever, swollen lymph nodes, tonsillitis), urgent monitoring of the peripheral blood picture is necessary. In case of signs of bleeding (tiny petechiae, red-brown rashes on the skin and mucous membranes), monitoring of the platelet count in the peripheral blood is also necessary.

Determination of liver enzyme activity, blood bilirubin concentration

If jaundice or a significant increase in liver enzyme activity occurs, treatment with Konsilar-D24 should be discontinued and medical supervision of the patient should be provided.

Excipients

The drug Konsilar-D24 contains lactose monohydrate. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Effect on the ability to drive vehicles and machinery

During treatment with the drug, it is necessary to refrain from engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, including driving vehicles, because while taking Konsilar-D24, dizziness, decreased speed of psychomotor reactions and attention may occur, especially after taking the first dose.

Overdose

Symptoms pronounced decrease in BP, bradycardia, nausea, vomiting, convulsions, dizziness, drowsiness, confusion, stupor, water-electrolyte balance disorders (hyponatremia, hypokalemia), oliguria up to anuria (due to hypovolemia), acute renal failure.

Treatment in mild cases of overdose – gastric lavage, intake of adsorbents (activated charcoal), sodium sulfate (preferably within 30 minutes) followed by restoration of water-electrolyte balance. Vital organ function should be monitored. In more severe cases, additional measures aimed at stabilizing BP are carried out: intravenous administration of 0.9% sodium chloride solution, plasma substitutes, installation of a temporary artificial pacemaker for bradycardia resistant to drug therapy. In case of a pronounced decrease in BP, the administration of alpha-adrenomimetics (norepinephrine, dopamine) may be added to the therapy for replenishing circulating blood volume and restoring water-electrolyte balance. In case of bradycardia, the administration of atropine or installation of a temporary artificial pacemaker is recommended. It is necessary to carefully monitor BP, kidney function and plasma electrolyte levels.

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

Drug Interactions

Konsilar-D24

Concomitant use is contraindicated

Lithium preparations

With simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in plasma lithium concentration and an increase in the cardio- and neurotoxic effects of lithium are possible. Additional use of thiazide diuretics may contribute to a further increase in lithium concentration due to reduced excretion and increase the risk of toxic reactions.

Potassium preparations, potassium-sparing diuretics and other drugs that can increase plasma potassium levels

Simultaneous use with potassium preparations, potassium-sparing diuretics (amiloride, spironolactone, eplerenone, triamterene), other drugs that can increase plasma potassium levels (including trimethoprim, tacrolimus, cyclosporine, heparin), increases the risk of hyperkalemia (especially in patients with diabetes and patients with renal failure).

Special caution is required during concomitant use

Baclofen

Baclofen potentiates the antihypertensive effect of indapamide and ramipril, control of BP, kidney function and, if necessary, dose adjustment of Konsilar-D24 is required.

NSAIDs

Acetylsalicylic acid in doses that have an anti-inflammatory effect (more than 3 g/day), reduces the antihypertensive effect of indapamide and ramipril; increases the risk of impaired renal function, up to the development of acute renal failure; increases plasma potassium levels in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. Patients need to compensate for circulating blood volume, and also monitor renal function before and after starting treatment with Konsilar-D24.

Caution is required during concomitant use

Tricyclic antidepressants, antipsychotic agents (neuroleptics)

With simultaneous use, the antihypertensive effect is enhanced and the risk of orthostatic hypotension increases (additive effect).

Glucocorticosteroids, tetracosactide

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

Antihypertensive agents

When used concomitantly with other antihypertensive agents, the antihypertensive effect of Konsilar-D24 may be enhanced.

Indapamide

Combinations not recommended for use

Lithium preparations

With simultaneous use of indapamide and lithium preparations, as well as with a salt-free diet, an increase in plasma lithium concentration may be observed due to reduced excretion, accompanied by signs of overdose. If necessary, diuretic drugs can be used in combination with lithium preparations, while plasma lithium concentration should be carefully monitored and the drug dose should be adjusted accordingly.

Combinations requiring precautions

Drugs that can cause polymorphic ventricular tachycardia of the "torsades de pointes" type

Antiarrhythmic drugs: class IA (quinidine, hydroquinidine, disopyramide, procainamide) and class IC (flecainide);
Class III antiarrhythmic drugs (amiodarone, sotalol, dofetilide, ibutilide, bretylium tosilate, dronedarone);
Antipsychotics – phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazole), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), pimozide, sertindole;
Antidepressants – tricyclic antidepressants, selective serotonin reuptake inhibitors (citalopram, escitalopram);
Antibacterial agents: fluoroquinolones (levofloxacin, moxifloxacin, sparfloxacin, ciprofloxacin), macrolides (erythromycin with intravenous administration, azithromycin, clarithromycin, roxithromycin, spiramycin), co-trimoxazole;
Azole antifungal agents (voriconazole, itraconazole, ketoconazole, fluconazole);
Antimalarial agents (quinine, chloroquine, mefloquine, halofantrine, lumefantrine);
Antianginal agents (ranolazine, bepridil);
Antineoplastic drugs and immunomodulators (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus, anagrelide);
Antiemetic agents (ondansetron);
Agents affecting gastrointestinal motility (cisapride, domperidone);
Antihistamines (astemizole, terfenadine, mizolastine);
Others – pentamidine, diphemanil, vincamine with intravenous administration, vasopressin, terlipressin, ketanserin, probucol, propofol, sevoflurane, terodiline, cilostazol.

Increased risk of ventricular arrhythmias, especially polymorphic ventricular tachycardia of the "torsades de pointes" type (risk factor – hypokalemia). Before prescribing combined therapy with Konsilar-D24 and the above drugs, a study should be conducted to detect hypokalemia and, if necessary, correction should be carried out. Clinical monitoring of the patient, monitoring of plasma electrolyte levels, and ECG parameters are necessary. In patients with hypokalemia, drugs that do not cause polymorphic ventricular tachycardia of the "torsades de pointes" type should be used.

NSAIDs (with systemic use), including selective COX-2 inhibitors, high doses of acetylsalicylic acid (≥3 g/day)

A decrease in the antihypertensive effect of indapamide is possible. In dehydrated patients, there is a risk of acute renal failure due to decreased glomerular filtration. Patients need to compensate for fluid loss and at the beginning of treatment it is necessary to carefully monitor renal function.

ACE inhibitors

Prescribing ACE inhibitors to patients with initially reduced blood sodium ion concentration is accompanied by the risk of sudden arterial hypotension and/or acute renal failure (in particular, patients with renal artery stenosis).

Other drugs that can cause hypokalemia: amphotericin B (intravenous), gluco- and mineralocorticosteroids (with systemic use), tetracosactide, laxatives that stimulate intestinal motility

Increased risk of hypokalemia (additive effect). Constant monitoring of plasma potassium ion levels is necessary, and if necessary, its correction. Particular attention should be paid to patients simultaneously receiving cardiac glycosides. It is recommended to use laxatives that do not stimulate intestinal motility.

Baclofen

Enhancement of the antihypertensive effect is noted. Patients need to compensate for fluid loss and at the beginning of treatment carefully monitor renal function.

Cardiac glycosides

Hypokalemia enhances the toxic effect of cardiac glycosides. With simultaneous use of indapamide and cardiac glycosides, plasma potassium ion levels and ECG parameters should be monitored, and therapy should be adjusted if necessary.

Combinations requiring special attention

Allopurinol

Concomitant use with indapamide may increase the risk of hypersensitivity reactions during allopurinol treatment.

Combinations requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

Combined therapy with indapamide and potassium-sparing diuretics is appropriate in some patients, but the possibility of hypokalemia or hyperkalemia is not excluded (especially in patients with renal failure or patients with diabetes).

It is necessary to monitor plasma potassium ion levels, ECG parameters and, if necessary, adjust therapy.

Metformin

Functional renal failure, which can occur while taking diuretics, especially "loop" diuretics, increases the risk of metformin-induced lactic acidosis. Metformin should not be used if the creatinine concentration exceeds 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Iodine-containing contrast agents

In case of dehydration while taking diuretic drugs, it increases the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents. Before using iodine-containing contrast agents, patients need to compensate for fluid loss.

Tricyclic antidepressants, antipsychotics

Drugs of these classes enhance the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect).

Calcium (salts)

With simultaneous use, hypercalcemia may develop due to reduced excretion of calcium ions by the kidneys.

Cyclosporine, tacrolimus

An increase in plasma creatinine concentration is possible without changing the concentration of circulating cyclosporine, even in the absence of water and sodium ion loss.

Corticosteroid drugs, tetracosactide (with systemic use)

Reduction of antihypertensive action (fluid and sodium ion retention as a result of the action of corticosteroids).

Ramipril

Contraindicated combinations

Neutral endopeptidase inhibitors

An increased risk of angioedema has been reported with the simultaneous use of ACE inhibitors and racecadotril (an enkephalinase inhibitor). With simultaneous use of ACE inhibitors with drugs containing sacubitril (a neprilysin inhibitor), the risk of angioedema increases, therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. Prescribing drugs containing sacubitril to patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors, is contraindicated.

With combined therapy sacubitril/valsartan

Concomitant use of ACE inhibitors and the combination of ARB II and neutral endopeptidase inhibitor – sacubitril/valsartan – is contraindicated due to the risk of angioedema. Treatment with Konsilar-D24 should not be started until sacubitril and valsartan are eliminated from the body. In case of switching from therapy with Konsilar-D24 to combined therapy with sacubitril/valsartan, therapy with this combination of drugs should not be started until Ramipril is eliminated from the body. The use of some high-flux membranes with a negatively charged surface (for example, polyacrylonitrile membranes) during hemodialysis or hemofiltration and the use of dextran sulfate during LDL apheresis increases the risk of severe anaphylactic reactions. If the patient needs to undergo these procedures, other types of membranes should be used (in the case of plasmapheresis and hemofiltration) or the patient should be switched to antihypertensive drugs of other groups.

Angiotensin II receptor antagonists

Simultaneous use of ramipril with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Drugs containing aliskiren

Simultaneous use of ramipril with drugs containing aliskiren is contraindicated in patients with diabetes and/or with moderate or severe renal failure (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Not recommended combinations

With potassium salts, potassium-sparing diuretics (e.g., amiloride, triamterene, spironolactone, eplerenone [a spironolactone derivative]), other drugs that can increase serum potassium levels (including ARB II, tacrolimus, cyclosporine; trimethoprim, sulfamethoxazole, which are part of co-trimoxazole.

An increase in serum potassium levels is possible, sometimes significantly pronounced (with simultaneous use, careful monitoring of serum potassium levels is required).

Combinations that should be used with caution

Hypoglycemic agents

When used concomitantly with hypoglycemic agents , for example, insulins, oral hypoglycemic agents (sulfonylurea derivatives) due to a decrease in insulin resistance under the influence of ramipril, the hypoglycemic effect of these drugs may be enhanced up to the development of hypoglycemia. Particularly careful monitoring of blood glucose concentration is recommended at the beginning of the combined use of hypoglycemic agents with ACE inhibitors.

Dipeptidyl peptidase type IV inhibitors (gliptins)

When used concomitantly with drugs such as sitagliptin, saxagliptin, vildagliptin, linagliptin, an increased frequency of angioedema was observed.

mTOR inhibitors (mammalian target of rapamycin)

When used concomitantly with drugs such as temsirolimus, sirolimus, everolimus, an increased frequency of angioedema was observed.

Vasopressor sympathomimetics

When used concomitantly with epinephrine, isoproterenol, dobutamine, dopamine, a decrease in the antihypertensive effect of ramipril is noted, regular BP monitoring is required.

Other blood pressure-lowering drugs

When used concomitantly with diuretics, nitrates, tricyclic antidepressants, agents for general and local anesthesia, baclofen, alfuzosin, doxazosin, promazine, tamsulosin, terazosin, potentiation of the antihypertensive effect is noted.

When combined with diuretics, serum sodium levels should be regularly monitored.

Hypnotics, narcotic and analgesic drugs

With simultaneous use, the antihypertensive effect may be enhanced.

Drugs affecting hematological parameters

With simultaneous use with allopurinol, procainamide, cytostatics, immunosuppressants, corticosteroids (glucocorticosteroids and mineralocorticosteroids), the risk of developing hematological reactions increases.

Lithium salts

With simultaneous use, an increase in lithium concentration and an increase in the cardio- and neurotoxic effects of lithium are possible. Therefore, serum lithium levels should be monitored.

Estramustine

Simultaneous use may lead to an increased risk of angioedema.

Combinations that should be taken into account

Nonsteroidal anti-inflammatory drugs

When used concomitantly with indomethacin or acetylsalicylic acid, a weakening of the effect of ramipril, an increased risk of impaired renal function and an increase in serum potassium levels are possible.

Heparin

With simultaneous use, an increase in serum potassium levels is possible.

Sodium chloride

With simultaneous use, a weakening of the antihypertensive effect of ramipril is possible.

Ethanol

With simultaneous use, an increase in the symptoms of vasodilation is noted. Ramipril may enhance the adverse effects of ethanol on the body.

Estrogens

With simultaneous use, a weakening of the antihypertensive effect of ramipril is noted (fluid retention).

Desensitizing therapy for hypersensitivity to insect venoms

ACE inhibitors increase the likelihood of developing severe anaphylactic or anaphylactoid reactions to insect venoms. It is assumed that this effect may also occur when using other allergens.

Drugs containing gold for parenteral administration (sodium aurothiomalate)

With simultaneous use, the development of the following reactions has been reported: flushing of the scalp, nausea, vomiting and hypotension.

Tissue plasminogen activators

Observational studies have revealed an increased frequency of angioedema in patients taking ACE inhibitors after using alteplase for thrombolytic therapy of ischemic stroke.

Storage Conditions

The drug should be stored in the original packaging in a place inaccessible to children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.

Medical Disclaimer

Medixlife (Author)

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