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

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:

• antiarrhythmic drugs: Class IA (quinidine, hydroquinidine, disopyramide, procainamide) and Class IC (flecainide);
• antiarrhythmic drugs Class III (amiodarone, sotalol, dofetilide, ibutilide, brettilia tozilate, dronedarone);
• neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazole), benzamides (amisulpride, sulpiride, sultopride, thiapride), butyrophenones (droperidol, haloperidol), pimozide, sertindol;
• antidepressants: tricyclic antidepressants, selective serotonin reuptake inhibitors (citalopram, escitalopram);
• antibacterials: Fluoroquinolones (levofloxacin, moxifloxacin, sparfloxacin, ciprofloxacin), macrolides (IV erythromycin, azithromycin, clarithromycin, roxithromycin, spiramycin), co-trimoxazole;
• antifungal agents of the azole series (voriconazole, itraconazole, ketoconazole, fluconazole);
• antimalarials (quinine, chloroquine, mefloquine, halofantrine, lumefantrine);
• Antineoplastic agents and immunomodulators (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus, anagrelide);
• antiemetics (ondansetron);
• agents affecting gastrointestinal motility (cisapride, domperidone);
• antihistamines (astemisol, terfenadine, misolastin);
• others: pentamidine, difemanil, vincamine when given intravenously, vasopressin, terlipressin, ketanserin, probucol, propofol, sevoflurane, teridylin, cilostazol.

An increased risk of ventricular arrhythmias, especially polymorphic pirouette-type ventricular tachycardia (hypokalemia is a risk factor).

Before administering combined therapy with CONSILAR-D24 and the above drugs, a study should be performed to detect hypokalemia and correction should be made if necessary. It is necessary to control patient’s clinical condition, blood plasma electrolytes content, ECG indexes.

In patients with hypokalemia, drugs that do not cause pirouette-type polymorphic ventricular tachycardia should be used.

– Nonsteroidal anti-inflammatory drugs (when systemically administered), including selective COX-2 inhibitors, high doses of acetylsalicylic acid
(≥3 g/day):

The antihypertensive effect of indapamide may be reduced. In dehydrated patients there is a risk of acute renal failure due to decreased glomerular filtration. Patients need to compensate for fluid loss and renal function should be carefully monitored at the beginning of treatment.

– Angiotensin-converting enzyme inhibitors (ACE)

Administration of ACE inhibitors to patients with initially low blood sodium ion concentrations is accompanied by a risk of sudden arterial hypotension and/or acute renal failure (particularly in patients with renal artery stenosis).

Patients with arterial hypertension and possibly decreased, due to previous diuretic use, plasma sodium ion concentrations are required:

– 3 days before starting treatment with an ACE inhibitor, discontinue diuretics; thereafter, if necessary, noncaliberating diuretics may be resumed;

– or start ACE inhibitor therapy at low doses, with a subsequent gradual increase in dose if necessary.

In all cases, renal function (plasma creatinine concentration) should be monitored in patients during the first weeks of ACE inhibitor therapy.

– Other drugs that may cause hypokalemia: amphotericin B (IV), gluco- and mineralocorticosteroids (when used systemically), tetracosactide, intestinal motility stimulating laxatives:

Increased risk of hypokalemia (additive effect). Continuous monitoring of the content of plasma potassium ions is necessary, and if necessary – its correction. Particular attention should be paid to patients concomitantly receiving cardiac glycosides. It is recommended to use laxatives that do not stimulate intestinal motility.

– Baclofen:

An increased antihypertensive effect has been noted. Patients should compensate for fluid loss and monitor renal function carefully at the beginning of treatment.

– Cardiac glycosides:

Hypokalemia increases the toxic effects of cardiac glycosides. When concomitant use of indapamide and cardiac glycosides, plasma levels of potassium ions and ECG parameters should be monitored and, if necessary, therapy should be adjusted.

Combinations requiring special attention

– Allopurinol:

The co-administration of indapamide may increase the risk of hypersensitivity reactions when treated with allopurinol.

Combinations requiring attention

– Potassium-saving diuretics (amiloride, spironolactone, triamterene):

Combination therapy with indapamide and potassium-saving diuretics is appropriate in some patients, but the possibility of hypokalemia or hyperkalemia (especially in patients with renal impairment or in patients with diabetes) cannot be excluded.

Potassium ion plasma levels and ECG parameters should be monitored and, if necessary, therapy should be adjusted.

– Metformin:

Functional renal failure, which may occur with diuretics, especially loop diuretics, increases the risk of metformin-induced lactic acidosis.

Do not use metformin if creatinine concentrations exceed 15 mg/L (135 μmol/L) in men and 12 mg/L (110 μmol/L) in women.

– Iodine-containing contrast agents:

Iodine contrast agents increase the risk of acute renal failure if the body becomes dehydrated while taking diuretics, especially when using high doses of iodine-containing contrast agents.

Patients should compensate for fluid loss before using iodine-containing contrast agents.

– Tricyclic antidepressants, neuroleptics:

The drugs in these classes increase the antihypertensive effect of indapamide and increase the risk of orthostatic hypotension (additive effect).

– Calcium (salts):

The simultaneous use may result in hypercalcemia due to reduced renal excretion of calcium ions.

– Cyclosporine, tacrolimus:

Possible increase in plasma creatinine concentration without change in circulating cyclosporine concentration, even in the absence of loss of water and sodium ions.

– Corticosteroid drugs, tetracosactide (when used systemically):

Decreased antihypertensive effect (fluid and sodium ion retention due to corticosteroid action).

Ramipril

Contraindicated combinations

Neutral endopeptidase inhibitors: An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor). When concomitant use of ACE inhibitors with drugs containing sacubitril (neprilysin inhibitor), the risk of angioedema increases, therefore concomitant use of these drugs is contraindicated. ACE inhibitors should be administered not earlier than 36 hours after withdrawal of drugs containing Sacubitril. Administration of the drugs containing Sacubitril is contraindicated in patients receiving ACE inhibitors and also within 36 hours after cancellation of ACE inhibitors.

With sacubitril/valvsartan combination therapy

The combined use of ACE inhibitors and combination of APA II and neutral endopeptidase inhibitor (syn.NEP, neprolizine), sacubitril/valvalsartan, is contraindicated because of the risk of angioedema. Treatment with CONSILAR-D24 should not be started until sacubitril and valsartan have been eliminated from the body. If the therapy with CONSILAR-D24 is switched to concomitant therapy with sacubitril/valsartan, the therapy with this combination of drugs should not be started until ramipril is eliminated from the body.

The use of some high-flow membranes with a negative charged surface (e.g., polyacrylonitrile membranes) in hemodialysis or hemofiltration and the use of dextran sulfate in LDL apheresis increases the risk of severe anaphylactic reactions. If the patient needs these procedures, other types of membranes should be used (in case of plasmapheresis and hemofiltration) or the patient should be transferred to hypotensive drugs of other groups.

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

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

Unrecommended combinations

With potassium salts, potassium-saving diuretics (e.g., amiloride, triamterene, spironolactone, eplerenone [spironolactone derivative]), other drugs that can increase serum potassium (including ARA II, tacrolimus, cyclosporine trimethoprim, sulfamethoxazole as part of co-trimoxazole [a combined antibacterial drug containing sulfamethoxazole and trimethoprim]).

There may be an increase in serum potassium, sometimes significantly pronounced (careful monitoring of serum potassium is required with concomitant use).

Combinations to be used with caution

In concomitant use with hypoglycemic agents, such as insulin, hypoglycemic agents for oral administration (sulfonylurea derivatives) due to the reduction of insulin resistance under the influence of ramipril, the hypoglycemic effect of these drugs may be increased up to the development of hypoglycemia. It is recommended to monitor blood glucose concentration particularly carefully at the beginning of combined use of hypoglycemic agents with ACE inhibitors.

In patients taking ACE inhibitors and type IV dipeptidyl peptidase inhibitors (DPP-IV) (glyptins) concomitantly, such as sitagliptin, saxagliptin, vildagliptin, linagliptin, an increase in the rate of angioedema was observed.

Concomitant use of ACE inhibitors and mTOR inhibitors (mammalian Target of Rapamycin in mammalian cells), such as temsirolimus, sirolimus, everolimus, showed an increased incidence of angioedema.

In concomitant use with vasopressor sympathomimetics (epinephrine, isoproterenol, dobutamine, dopamine) a decrease of the antihypertensive effect of ramipril is noted, regular BP control is required.

With hypotensive drugs (e.g., diuretics) and other BP-lowering drugs (nitrates, tricyclic antidepressants, agents for general and local anesthesia, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin), potentiation of antihypertensive effect is noted. When combining with diuretics serum sodium content should be monitored regularly.

In concomitant use with hypnotics, narcotic and analgesic drugs it is possible to increase the antihypertensive effect.
Concomitant use with allopurinol, procainamide, cytostatics, immunosuppressants, corticosteroids (glucocorticosteroids and mineralocorticosteroids) and other drugs that may affect hematological parameters, the risk of hematological reactions increases.

With lithium salts: increased serum lithium concentration and increased cardio- and neurotoxic effects of lithium. Therefore, serum lithium content should be monitored.

The simultaneous use of ACE inhibitors with estramustine may increase the risk of angioedema.

Combinations to be considered

With nonsteroidal anti-inflammatory drugs (indomethacin, acetylsalicylic acid): the effect of ramipril may be impaired, the risk of impaired renal function and increased serum potassium may increase.

With heparin: possible increase in serum potassium.

With sodium chloride: weakening of the antihypertensive effect of ramipril.

In concomitant use with ethanol an increase in symptoms of vasodilation is noted. Ramipril may increase the adverse effects of ethanol on the body.

When used concomitantly with estrogens, a decrease in the antihypertensive effect of ramipril (fluid retention) has been noted.

Desensitizing therapy in hypersensitivity to insect venoms: ACE inhibitors increase the likelihood of severe anaphylactic or anaphylactoid reactions to insect venoms. It has been suggested that this effect may also occur with other allergens.

With parenteral gold preparations (sodium aurothiomalate): The following reactions have been reported when concomitant use of ACE inhibitors with parenteral gold preparations (sodium aurothiomalate): flushing, nausea, vomiting and hypotension.

With tissue plasminogen activators: in observational studies, an increased incidence of angioedema has been found in patients taking ACE inhibitors after use of alteplase for thrombolytic therapy of ischemic stroke.

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.

The intravenous administration of antihistamines (H₁– and H₂-histamine receptor antagonists) is also recommended, and if enzyme inactivators
C1-esterase inhibitors, consideration may be given to the need for administration of C1-esterase enzyme inhibitors in addition to epinephrine (adrenaline). The patient should be hospitalized and monitored until symptoms have resolved, but not less than 24 h. Thereafter, such patients should not be used ACE inhibitors. Patients with a history of Quincke’s edema not associated with the use of ACE inhibitors may have an increased risk of developing Quincke’s edema when taking this group of drugs. Concomitant use with other drugs that may cause angioedema increases the risk of angioedema.

In rare cases, intestinal angioedema has developed during therapy with ACE inhibitors. Patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding angioedema of the face and with a normal level of
C-1 esterase. Diagnosis is made by abdominal computed tomography, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema must be considered when making the differential diagnosis.

Anaphylactic and anaphylactoid reactions during desensitization

. There have been isolated reports of long-term life-threatening anaphylactic and anaphylactoid reactions (e.g., decreased BP, dyspnea, vomiting, allergic skin reactions) in patients receiving ACE inhibitors during desensitization therapy with venom of hymenopteran insects (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 desensitization therapy with venom of hymenopteran insects such as bees, wasps. The development of anaphylactic and anaphylactoid reactions can be avoided by temporary withdrawal of ACE inhibitor at least 24 hours before the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

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

Anaphylactoid reactions during gemodialysis or plasma filtration using certain high-flow membranes

. In patients receiving ACE inhibitors, anaphylactoid reactions, sometimes to the point of developing shock, have been noted when hemodialysis is performed using high-flow membranes. Therefore, it is necessary to use a different type of membrane or use a hypotensive drug of a different pharmacotherapeutic group.

Cough

An ACE inhibitor therapy may result in a dry, non-productive, prolonged, persistent cough that disappears after discontinuation of the drugs of this group. If a patient has a dry cough, remember that this symptom may be associated with ACE inhibitor therapy. If a physician thinks that therapy with ACE inhibitor is necessary for the patient, administration of CONSILAR-D24 can be continued.

Risk of arterial hypotension and/or renal failure

. Significant activation of the RAAS may be noted in some pathological states, especially in severe hypovolemia and decrease of plasma electrolytes (due to salt-free diet or long-term use of diuretics), in patients with baseline low BP, with bilateral renal artery stenosis or artery stenosis of the sole kidney, chronic heart failure or liver cirrhosis with edema and ascites. ACE inhibitor use causes RAAS blockade and therefore may be accompanied by a sharp decrease in BP and/or an increase in creatinine concentration, plasma azotemia, 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 two weeks of therapy. Sometimes these conditions develop acutely and in other terms of therapy. In such cases, when resuming therapy, it is recommended to use CONSILAR-D24 at a lower dose and then gradually increase the dose. Caution should be exercised when treating elderly patients, because they may be particularly sensitive to ACE inhibitors, it is recommended to monitor renal function parameters during the initial phase of treatment. In patients for whom BP reduction may pose a certain risk (e.g., patients with atherosclerotic narrowing of coronary or cerebral arteries), treatment should be initiated under close medical supervision. Caution should be exercised during physical activity and/or hot weather because of the risk of increased sweating and dehydration with the development of arterial hypotension, due to decreased circulating blood volume and decreased sodium content in the blood. Transient excessive BP decrease is not a contraindication for continuation of treatment after BP stabilization. In case of repeated development of significant BP decrease, the dose should be reduced or the drug should be discontinued.

In case of cardiac insufficiency, especially in acute myocardial infarction, treatment with CONSILAR-D24 should be started only under hospital conditions.

Continuous use of CONSILAR-D24 preparation with drugs containing aliskiren or with ARA II leading to double RAAS blockade is not recommended due to the risk of excessive decrease of BP, development of hyperkalemia and worsening of renal function in comparison with monotherapy. Simultaneous use of CONSILAR-D24 and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or renal insufficiency of moderate to severe degree
(FFR less than 60 ml/min/1.73 m² of body surface area) and is not recommended in other patients. Concomitant use of APA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Diabetes mellitus

When using CONSILAR-D24 in diabetic patients receiving oral hypoglycemic agents or insulin, blood glucose concentrations should be monitored regularly during the first month of therapy.

Renovascular hypertension

The use of ACE inhibitors has beneficial effects in patients with renovascular hypertension both awaiting surgical intervention and when surgery is not possible. Treatment with CONSILAR-D24 should be started with low dose of the drug in hospital conditions with monitoring of renal function and plasma potassium content. Some patients may develop functional renal failure which disappears quickly after discontinuation of the drug.

Surgical intervention/General anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia may result in a marked decrease in BP, especially with the use of general anesthetics with an antihypertensive effect. It is recommended to discontinue ACE inhibitors 48 hours before the surgical procedure, warning 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 greater the decrease in hemoglobin concentration, the higher the initial concentration. This effect does not seem 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 hemoglobin concentration remains stable and completely recovers after discontinuation of the drug. In these patients the treatment can be continued, but a general blood test 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 GOCMP.

Hepatic impairment

In patients with impaired liver function the response to treatment with CONSILAR-D24 may be enhanced or impaired. Besides, in patients with severe liver cirrhosis with edemas and/or ascites there can be a significant activation of RAAS that is why special caution should be exercised while treating these patients. In rare cases, against the background of ACE inhibitors cholestatic jaundice occurs, the progression of which may cause rapid development of fulminant liver necrosis, sometimes with fatal outcome. If jaundice or significant increase of “hepatic” transaminases activity occurs together with ACE inhibitors administration, the patient should discontinue the drug CONSILAR-D24.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors. The risk factors of hyperkalemia are renal insufficiency, elderly age, diabetes mellitus, some concomitant conditions (decreased BOD, decompensated acute heart failure, metabolic acidosis), concomitant use of potassium-saving diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing salt substitutes and other drugs that increase plasma potassium content (eg, heparin). Hyperkalemia can lead to serious cardiac rhythm disturbances, sometimes fatal. Simultaneous use of the above drugs is contraindicated.

Other risk groups

In patients with chronic heart failure (functional class IV by NYHA classification) and in patients with diabetes mellitus type 1 (danger of spontaneous increase of potassium content) the treatment should be started with low doses of CONSILAR-D24 and under constant medical control.

In patients with arterial hypertension and CHD, the
beta-adrenoblockers should not be discontinued: ACE inhibitors should be used together with
beta-adrenoblockers.

Elderly patients

In elderly patients before starting the drug CONSILAR-D24 renal function and plasma potassium content should be evaluated. In order to prevent arterial hypotension the initial dose of the drug should be adjusted consistently in accordance with the blood pressure readings, especially in case of decrease of the blood circulatory volume.

Ethnic differences

The ACE inhibitors have less pronounced antihypertensive effect in patients of Negro race compared to other races. CONSILAR-D24 should be used with caution in patients of non-hispanic race because of higher risk of angioedema.

Patients after renal transplantation

There is little experience with CONSILAR-D24 in patients who have recently had a renal transplantation.

Control of laboratory values before and during treatment with the drug
CONSILAR-D24 (up to once a month during the first 3-6 months of treatment)

Monitoring of laboratory parameters before and during treatment with the drug
ConSILAR-D24 (up to once a month during the first 3-6 months of treatment).Renal function monitoring (determination of serum creatinine concentrations)

When treated with ACE inhibitors, in the first weeks of treatment and thereafter, renal function monitoring is recommended. Especially close monitoring is required in patients with acute and chronic heart failure, impaired renal function, after renal transplantation, patients with renovascular disease, including patients with hemodynamically significant unilateral renal artery stenosis in two kidneys (in these patients even a slight increase of serum creatinine concentration may be an indication of reduced renal function).

Electrolyte monitoring

The regular monitoring of serum potassium and sodium is recommended. Particularly close monitoring of serum potassium is required in patients with impaired renal function, significant water-electrolyte balance disorders, and chronic heart failure.

Monitoring of hematologic parameters (hemoglobin, number of leukocytes, erythrocytes, platelets, leukocytic formula)

Control of general blood counts is recommended 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 concomitantly receiving other drugs which may alter peripheral blood count. Control of leukocyte count is necessary for early detection of leukopenia, which is especially important in patients at high risk of its development, as well as at the first signs of infection. If neutropenia is detected (neutrophil count less than 2000/μl), discontinuation of ACE inhibitor treatment is required. If symptoms associated with leukopenia (e.g., fever, enlarged lymph nodes, tonsillitis) are detected, peripheral blood counts should be urgently monitored. If there are signs of bleeding (tiny petechiae, reddish-brown rashes on skin and mucous membranes), peripheral blood platelet counts should also be monitored.

Determination of liver enzymes activity, bilirubin concentration in blood

If jaundice or significant increase of liver enzymes activity occurs, CONSILAR-D24 treatment should be stopped and the patient should be under medical supervision.

Influence on the ability to drive vehicles, mechanisms

Influence on the ability to drive During the period of KONSILAR-D24 treatment it is necessary to refrain from potentially dangerous activities requiring high concentration and quick psychomotor reactions including driving vehicles as dizziness and slow psychomotor reactions and slow attention especially after the first dose may appear during the use of the drug KONSILAR-D24.

Contraindications

• high sensitivity to indapamide, ramipril, other ACE inhibitors, sulfonamide derivatives and excipients contained in the drug;
• An history of angioedema (hereditary or idiopathic as well as due to previous therapy with ACE inhibitors);
• hemodynamically significant renal artery stenosis (bilateral or unilateral, in case of a single kidney);
• arterial hypotension (systolic BP less than 90 mmHg.systolic BP less than 90 mmHg.
• current use with angiotensin II receptor antagonists in patients with diabetic nephropathy;
• current use with angiotensin II receptor antagonists in patients with diabetic nephropathyconcomitant use with neutral endopeptidase inhibitors (e.g., drugs containing sacubitril) due to the high risk of angioedema;
• concomitant use with sacubitril/valsartan combination therapy (high risk of angioedema), see
• See “Interaction with other medicinal products”, “Cautions”.
• hemodynamically significant aortic or mitral valve stenosis, or hypertrophic obstructive cardiomyopathy (HCMP);
• severe renal insufficiency (FFR less than 20 mL/min-1.73 m² body surface area) (insufficient clinical experience);
• hemodialysis (insufficient clinical experience);
• nephropathy treated with glucocorticosteroids, nonsteroidal anti-inflammatory drugs, immunomodulators and/or other cytotoxic drugs (insufficient clinical experience, see “Interaction of clinical use.
• Chronic heart failure in decompensation (insufficient clinical experience);
• hemodialysis or hemofiltration using some negatively charged membranes such as polyacrylonitrile high flow membranes (risk of severe anaphylactoid reactions).
• LDL apheresis with dextran sulfate (risk of severe anaphylactoid reactions) (see Sections Interaction with Other Drugs and Precautions).
• Desensitization therapy for hypersensitivity reactions to venoms of hymenopteran insects such as bees, wasps (see “Cautions and Precautions”).
• concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes and/or moderate to severe renal impairment (glomerular filtration rate (GFR) less than 60 mL/min/1.73 m
• ^{supplementary therapysup>2} body surface area);
• acute myocardial infarction in patients with conditions such as:
  • severe chronic heart failure (NYHA functional class IV);
  • unstable angina;
  • life-threatening ventricular arrhythmias;
  • “pulmonary” heart;
• hypokalemia;
• Galactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• pregnancy, breastfeeding period;
• age under 18 years (efficacy and safety not established).

Cautions

• concomitant use with drugs containing aliskiren or angiotensin II receptor antagonists (with double blockade
  of the renin-angiotensin-aldosterone system (RAAS), there is an increased risk of a sharp decrease in BP, development of hyperkalemia and worsening of renal function compared to monotherapy) (see “Cautionary Instructions.
• States where an excessive decrease in BP is especially dangerous (atherosclerotic lesions of coronary and cerebral arteries);
• Developed arterial hypertension, especially malignant arterial hypertension;
• Chronic heart failure, especially severe, or for which other hypotensive medications are taken;
• hemodynamically significant unilateral renal artery stenosis (if both kidneys are present) – in such patients, even a slight increase in serum creatinine concentration may be a manifestation of unilateral impairment of renal function;
previous use of diuretics;
• disorders of water-electrolyte balance due to insufficient fluid and table salt intake, diarrhea, vomiting, profuse sweating;
• disorders of liver function (insufficient experience in clinical use: both enhancement and attenuation of the drug’s effects are possible;
• If patients have cirrhosis with ascites and edema, significant activation of the RAAS is possible, see. Therapeutic use of the drug should be performed in patients with liver cirrhosis (ascites, edema, significant activation of the RAAS is possible; see “Conditions associated with increase in RAAS activity” above);
• diabetes mellitus (risk of hyperkalemia);
• renal function disorders (GFR over 20 ml/min/1.73 m

  ).sup>2 body surface area) (risk of hyperkalemia and leukopenia);

• disorders after kidney transplantation;
• oppression of medullary hematopoiesis;
• concomitant therapy with myelotoxic drugs, immunosuppressants, which may cause changes in the peripheral blood pattern (suppression of medullary hematopoiesis, development of neutropenia or agranulocytosis is possible) (see “Interaction with other drugs”).
• Hyperkalemia;
• Application during major surgery or general anesthesia (see section “Interaction with other medicinal products.
• hyperuricemia and gout;
• hyperparathyroidism;
• increased QT interval on ECG;
• use in patients receiving concomitant therapy with drugs that may prolong the QT interval; use with drugs that may cause pirouette-type polymorphic ventricular tachycardia; lithium preparations; drugs that may cause hypokalemia; cardiac glycosides (see “Interaction with Other Drugs”).
• Application in malnourished patients;
• Elderly age (risk of increasing antihypertensive effect);
• In non-human race patients (see
• Specific directions

.

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.