Co-Dalneva, tablets 10 mg+2, 5 mg+8 mg 90 pcs

hypotensive combination therapy (slow calcium channel blocker + diuretic + angiotensin-converting enzyme inhibitor)

Indications

Arterial hypertension (if simultaneous therapy with amlodipine, indapamide and perindopril in doses used in single component monotherapy is necessary).

Active ingredient

Amlodipine, Indapamide, Perindopril

Composition

for 1 tablet 5 mg + 0.625 mg + 2 mg

Active ingredients:

Amlodipinabesylate (amlodipinabesylate) 6.935 mg,equivalent to amlodipine 5.000 mgIndapamide 0.625 mg

Perindoprilairbumin B, substance-granules 10.206 mg

[Active substance of the granule substance: Perindoprilaerbumin 2.000 mg

Auxiliary substances of the granule substance: microcrystalline cellulose, calcium chloride hexahydrate]

Supplementary substances: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium hydrocarbonate, colloidal silicon dioxide, magnesium stearate

for 1 tablet 5 mg + 1.25 mg + 4 mg

Active ingredients:

Amlodipinabesylate (amlodipinabesylate) 6.935 mg, equivalent to amlodipine 5.000 mg Indapamide 1.250 mg

Perindoprilaerbumin B, substance-granules 20.412 mg

[Active substance of the granule substance: Perindoprilaerbumin 4.000 mg

Auxiliary substances of the granule substance: microcrystalline cellulose, calcium chloride hexahydrate]

Supplementary substances: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium hydrocarbonate, colloidal silicon dioxide, magnesium stearate

for 1 tablet 5 mg + 2.5 mg + 8 mg

Active ingredients:

Amlodipinabesylate (amlodipinabesylate) 6.935 mg, equivalent to amlodipine5.000 mg Indapamide 2.500 mg

Perindoprilaerbumin B, substance-granules 40.824 mg

[Active substance of the granule substance: Perindoprilaerbumin 8.000 mg

Auxiliary substances of the granule substance: microcrystalline cellulose, calcium chloride hexahydrate]

Supplementary substances: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium hydrocarbonate, colloidal silicon dioxide, magnesium stearate

for 1 tablet 10 mg + 1.25 mg + 4 mg

Active ingredients:

Amlodipinabesylate (amlodipinabesylate) 13.870 mg,equivalent to amlodipine10,000 mg

Indapamide 1.250 mg

Perindoprilaerbumin B, substance-granules 20.412 mg

[Active substance of the granule substance: Perindoprilaerbumin 4.000 mg

Auxiliary substances of the granule substance: microcrystalline cellulose, calcium chloride hexahydrate]

Supplementary substances: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium hydrocarbonate, colloidal silicon dioxide, magnesium stearate

for 1 tablet 10 mg + 2.5 mg + 8 mg

Active ingredients:

Amlodipinabesylate (amlodipinabesylate) 13.870 mg,equivalent to amlodipine10,000 mg

Indapamide 2.500 mg

Perindoprilaerbumin B, substance-granules 40.824 mg

[Active substance of the granule substance: Perindoprilaerbumin 8.000 mg

Auxiliary substances of the granule substance: microcrystalline cellulose, calcium chloride hexahydrate]

Supplementary substances: cellulose microcrystalline, pregelatinized starch, sodium carboxymethylstarch, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate

How to take, the dosage

Orally, 1 tablet once daily, preferably in the morning, before a meal.

The dose of Co-Dalneva^® is adjusted after previously titrated doses of individual active ingredients of the drug.

The maximum daily dose of Co-Dalnerva^® is 10 mg of igamlodipine + 2.5 mg of indapamide + 8 mg of perindopril.

Patients with elderly and impaired renal function

The drug Co-Dalneva^® is contraindicated in patients with severe renal dysfunction (CK less than 30 ml/min) (see section “Contraindications”). The drug Co-Dalnerva® can be used in patients with moderate renal impairment (CKD 30-60 ml/min). Individual selection of amlodipine, indapamide, perindopril doses is recommended for such patients.

Dose adjustment is not required for patients with impaired renal function (CK is 60 ml/min or more). Amlodipine administered in equivalent doses is equally well tolerated by elderly and younger patients. No change in dosing regimen is required in elderly patients, but dose increases should be made with caution due to age-related changes and prolongation of T_1/2. Changes in plasma amlodipine concentration do not correlate with the severity of renal failure. Amlodipine is not dialyzed.

Excretion of perindoprilat in elderly patients and patients with renal failure is delayed. Therefore, in these patients it is necessary to monitor regularly creatinine concentration and potassium content in blood plasma.

Patients with impaired liver function

The drug Co-Dalneva^® is contraindicated in patients with severe liver failure (see section “Contraindications”).

Caution should be exercised when using the drug in patients with mild to moderate hepatic impairment.

Interaction

Amlodipine

Simultaneous use is not recommended

Dantrolene (intravenous administration)

Fatal ventricular fibrillation and collapse have been reported in laboratory animals against the background of verapamil and intravenous (IV) administration of dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia it is recommended to avoid concomitant use of PBMC (amlodipine) and dantrolene in patients with malignant hyperthermia as well as during treatment of malignant hyperthermia.

Simultaneous use,requiring special attention

Isoenzyme inducersCYP3A4

The plasma concentration of amlodipine may be altered when CYP3A4 isoenzyme inducers are used concomitantly. Therefore, it is necessary to monitor blood pressure and adjust the dose both during and after concomitant use, especially with potent inducers of CYP3A4 isoenzyme (e.g., rifampicin, St. John’s Wort preparations).

Isoenzyme inhibitors CYP3A4

Concomitant use of amlodipine with potent to moderate CYP3A4 isoenzyme inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in a significant increase in amlodipine concentration, which increases the risk of arterial hypotension. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. Due to this, clinical condition monitoring and dosage adjustment may be required.

Inhibitors of the mechanistic target for rapamycin in mammals (tTOR)

MTOR inhibitors, such ascaxirolimus, temsirolimus, and everolimus, are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.

Clarithromycin

Clarithromycin is an inhibitor of CYP3A4 isoenzyme. Concomitant use of amlodipine and clarithromycin increases the risk of arterial hypotension. Close medical monitoring of patients receiving amlodipine concomitantly with clarithromycin is recommended.

Tacrolimus

When used concomitantly with amlodipine, there is a risk of increased plasma concentrations of tacrolimus, but the pharmacokinetic mechanism of this interaction is not fully understood. To prevent the toxic effect of tacrolimus concomitantly used with amlodipine, the tacrolimus plasma concentration should be monitored and the tacrolimus dose should be adjusted if necessary.

Cyclosporine

Drug interaction studies using cyclosporine and amlodipine in healthy volunteers or other patient groups have not been performed, except in kidney transplant patients who have had variable minimum concentrations (mean values: 0 %-40 %) of cyclosporine. When concomitant use of amlodipine in patients undergoing renal transplantation, the plasma concentration of cyclosporine should be monitored and the dose should be reduced if necessary.

Simvastatin

The concomitant repeated use of amlodipine at a dose of 10 mg and with imvastatin at a dose of 80 mg increases simvastatin exposure by 77% compared with that of imvastatin monotherapy. In patients receiving amlodipine it is recommended to use simvastatin in dose not more than 20 mg/day.

Single use requiring attention

Amlodipine enhances the antihypertensive effects of hypotensive therapy drugs.

Tasonermin

When used concomitantly, amlodipine may increase the systemic plasma exposure of tasonermin. In such cases, regular monitoring of tasonermin blood concentration and dose adjustment if necessary are necessary.

Other drug combinations

Cimetidine

Cimetidine does not affect the pharmacokinetics of amlodipine.

Aluminum- or magnesium-containing antacids

A single administration of aluminum- or magnesium-containing antacids has no significant effect on the pharmacokinetics of amlodipine.

Sildenafil

A single administration of 100 mg sildenafil in patients with essential hypertension has no effect on amlodipine pharmacokinetic parameters.

In clinical studies of drug interactions amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin, warfarin.

The simultaneous use of amlodipine and grapefruit or grapefruit juice is not recommended because of possible increase of bioavailability of amlodipine in some patients that can increase antihypertensive effect.

Indapamide

Single use,requiring special attention

Drugs thatcan cause polymorphic ventricular tachycardia typea”pirouette“

Given the risk of hypokalemia, caution should be exercised when concomitant use of indapamide with drugs that can cause pirouette-type polymorphic ventricular tachycardia, such as antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylate, sotalol), some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroperazine), benzamides (amisulpride, sulpiride, sultopride, thiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide), other drugs such as bepridil, cisapride, difemanil methyl sulfate, erythromycin w/v, halofantrine, misolastin, moxifloxacin, pentamidine, sparfloxacin, vincamine w/v, methadone, astemizole, terfenadine. It is necessary to avoid concomitant usage with the above mentioned drugs in case of hypokalemia development, its correction should be performed, ECG (QT interval) should be monitored.

Drugs that may cause hypokalemia

Concomitant administration with amphotericinB w/v, systemic glucocorticosteroids and mineralocorticosteroids, tetracosactide, and laxatives that stimulate GI motility increases the risk of hypokalemia (additive effect). Control of plasma potassium is necessary, if necessary – correction of hypokalemia. Special caution should be exercised when concomitant use with cardiac glycosides. Laxatives should be used which do not stimulate gastrointestinal motility.

Heart glycosides

Hypokalemia increases toxic effects of cardiac glycosides. When concomitant use, plasma potassium and ECG should be monitored and if necessary, the decision whether to continue therapy should be made.

Simultaneous use,requiring attention

Metformin

Functional renal insufficiency, which can occur with diuretics, especially loop diuretics, increases the risk of lactoacidosis when metformin is used concomitantly. Metformin should not be used if plasma CK exceeds 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodine-containing contrast agents

Dehydration from diuretics increases the risk of acute renal failure, especially when administering high doses of iodine-containing contrast agents. Before the use of iodine-containing contrast agents it is necessary to compensate hypovolemia.

Calcium salts

The simultaneous use can cause hypercalcemia due to decrease of calcium excretion by kidneys.

Cyclosporine

An increase of CK in plasma is possible without changing cyclosporine concentration, even if water and sodium levels are normal.

Perindopril

Data from clinical trials show that dual RAAS blockade resulting from concomitant administration of ACE inhibitors, ARA II, or aliskiren results in an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and renal function impairment (including ARF) compared with situations in which only one RAAS-acting drug is used (see

Pharmacodynamics, Contraindications, and Precautions

Pharmacodynamics

Pharmacodynamics, Contraindications, and Precautions

.)

Drugs that cause hyperkalemia

Some drugs or classes of drugs may increase the incidence of hyperkalemia: Aliskiren, potassium salts, potassium-saving diuretics, ACE inhibitors, ARA II, NSAIDs, heparin, immunosuppressants such as cyclosporine or tacrolimus, drugs containing trimethoprim.

Simultaneous use with these drugs increases the risk of hyperkalemia.

Simultaneous use is contraindicated

Combined use: justify;”> Aliskiren

In patients with diabetes mellitus or renal insufficiency, there is an increased risk of hyperkalemia, impaired renal function, increased incidence of cardiovascular adverse events, and cardiovascular mortality.

The concomitant use of ACE inhibitors with aliskirenomil or drugs containing aliskiren in patients with diabetes and/or moderate to severe renal function impairment (GFR < 60 ml/min/1.73 m² body surface area) is contraindicated (see “Contraindications”).

Neutral endopeptidase inhibitors

an increased risk of angioedema has been reported with concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor).

The simultaneous use of ACE inhibitors with drugs containing sacubitril (neprolizine inhibitor) increases the risk of angioedema, therefore simultaneous use of these drugs is contraindicated. ACE inhibitors should be administered not earlier than 36 hours after withdrawal of drugs containing Sacubitril. Administration of medicines containing Sacubitril is contraindicated in patients receiving ACE inhibitors and also within 36 hours after cancellation of ACE inhibitors.

Extracorporeal therapy

Extracorporeal therapies that lead to blood contact with negatively charged surfaces, such as hemodialysis using high-flow membranes (such as polyacrylonitrile membranes) and LDL apheresis using dextran sulfate, can lead to an increased risk of severe anaphylactoid reactions (see See section “Contraindications”). Therefore, it is desirable to use another type of membrane or use a hypotensive drug of another pharmacotherapeutic group.

Simultaneous use is not recommended

Aliskiren

In patients without diabetes mellitus or impaired renal function, there may be an increased risk of hyperkalemia, impaired renal function, and increased cardiovascular morbidity and mortality.

Double blockade of the renin-angiotensin-aldosterone system in patients with atherosclerosis, CHF or DM with target organ damage is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia and impaired renal function (including development of ARF) compared to use of one of the above groups. Dual RAAS blockade is possible only in single cases under close control of renal function, potassium and BP.

The simultaneous use of ACE inhibitors with ARA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Estramustine

The concomitant use of ACE inhibitors with estramustine is accompanied by the risk of angioedema.

Lithium

Combined use of lithium and ACE inhibitors may result in a reversible increase in serum lithium and associated toxic effects. The use of perindopril in combination with indapamide and lithium is not recommended, but serum lithium should be carefully monitored if necessary.

The concomitant use of thiazide diuretics may further increase plasma lithium levels and increase the risk of its toxic effects with an ACE inhibitor.

Simultaneous use of the combination of perindopril and indapamide with lithium preparations is not recommended. If simultaneous use is necessary, the lithium content in plasma should be monitored carefully.

Kalice-saving diuretics, potassium preparations and potassium-containing substitutes for dietary salt

To the background of ACE inhibitor therapy, plasma potassium content is usually within normal limits, but hyperkalemia may develop. Concomitant use of potassium-saving diuretics (triamterene, amiloride), potassium preparations and potassium-containing salt substitutes may lead to a significant increase in plasma potassium content. Caution should also be exercised when using perindopril concomitantly with other drugs that increase serum potassium levels, such as trimethoprim and co-trimoxazole (sulfamethoxazole + trimethoprim), since it is known that trimethoprim acts similarly to the potassium-saving diuretic amiloride. If simultaneous use of ACE inhibitor with the above mentioned drugs is necessary (in case of hypokalemia), caution should be exercised and plasma potassium and ECG parameters should be monitored regularly.

MTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)

In patients using an ACE inhibitor and mTOR inhibitor simultaneously, therapy may be accompanied by an increased risk of angioedema.

Simultaneous use,requiring special attention

Non-steroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid (ASA) (more than 3 g/day)

The concomitant use of ACE inhibitors with NSAIDs (including ASA at a dose with anti-inflammatory effects, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) may result in decreased antihypertensive effects as well as worsened renal function, including development of ARF, and increased plasma potassium levels, especially in patients with reduced renal function. Caution should be exercised when using this combination, especially in elderly patients. Patients should compensate fluid loss and perform regular monitoring of renal function both at the beginning of treatment and during treatment.

Hypoglycemic agents (insulin, oral hypoglycemic agents)

Epidemiological studies have shown that concomitant use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may increase the hypoglycemic effect of insulin and oral hypoglycemic agents, up to the development of hypoglycemia. This effect is most likely to be observed during the first weeks of concomitant therapy as well as in patients with impaired renal function.

Kaliesaving diuretics

Patients taking diuretics, especially fluid-removing and/or salt-removing diuretics, may experience a significant decrease in BP at the start of ACE inhibitor therapy. The risk of hypotensive effect can be reduced by withdrawal of the diuretic, by replenishing fluid or salt loss before therapy with perindopril, and by administration of low dose perindoprilav with its gradual increase.

In arterial hypertension patients with prior diuretic therapy that may have resulted in excessive fluid and/or salt excretion, diuretics should be discontinued before starting ACE inhibitors (with a potassium-saving diuretic later reappointed) or ACE inhibitor treatment at a low dose with a gradual increase in dose.

When using diuretics to treat CHF, the ACE inhibitor should be given at a very low dose, possibly after reducing the dose of a concurrent potassium-sparing diuretic.

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

Kaliesaving diuretics (eplerenone, spironolactone)

The use of eplerenone or spironolactone in doses of 12.5 mg to 50 mg per day and low-dose ACE inhibitors when treating patients with heart failure of functional class II-IV according to NYHA classification with left ventricular ejection fraction < 40% in patients who received ACE inhibitors and “loop” diuretics previously, there is a risk of hyperkalemia (with possible death), especially if the recommendations regarding this drug combination are not followed.

Before using this drug combination, make sure there is no hyperkalemia or renal failure.

Creatinine and plasma potassium concentrations should be monitored regularly weekly in the first month of therapy and monthly thereafter.

Simultaneous use, requiring attention

Allopurinol, cytostatic and immunosuppressive drugs, glucocorticosteroids (when used systemically), and procainamide

Simultaneous use with ACE inhibitors may increase the risk of leukopenia.

General anesthesia drugs

The simultaneous use of ACE inhibitors and general anesthesia drugs may increase the antihypertensive effect.

Gold drugs

In the use of ACE inhibitors, including perindopril, a symptom complex including facial skin hyperemia, nausea, vomiting, and arterial hypotension has been described in patients receiving intravenous gold (sodium aurothiomalate).

Co-trimoxazole (sulfamethoxazole + trimethoprim)

Concurrent use with ACE inhibitors may increase the risk of hyperkalemia.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)

Simultaneous use with ACE inhibitors may increase the risk of angioedema due to suppression of dipeptidyl peptidase IV (DPP-IV) activity by glyptin.

Sympathomimetics

Sympathomimetics may attenuate the antihypertensive effects of ACE inhibitors.

Cyclosporine

Concomitant use with ACE inhibitors may increase the risk of hyperkalemia. It is recommended to monitor serum potassium.

Heparin

Simultaneous use with ACE inhibitors may increase the risk of hyperkalemia. It is recommended to monitor serum potassium.

Tissue plasminogen activators

In observational studies, an increased incidence of angioedema was found in patients taking ACE inhibitors after using alteplase for thrombolytic therapy of ischemic stroke.

Co-Dalneva^®

Single use,requiring special attention

Baclofen

Augmentation of antihypertensive effects is possible. BP and renal function should be monitored and the dose of hypotensive drugs should be adjusted if necessary.

Single use requiring attention

Hypotensive drugs (such as beta-adrenoblockers) and vasodilators

When concomitant use with hypotensive drugs, the antihypertensive effect may be enhanced. Caution should be exercised when concomitant use with nitroglycerin, other nitrates or other vasodilators because an additional decrease of BP is possible.

Corticosteroids (mineral and glucocorticosteroids), tetracosactide (systemic action)

Alpha-adrenoblockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin)

Augmentation of antihypertensive action and increased risk of orthostatic hypotension.

Amifostine

Amlodipine may enhance the antihypertensive effect.

Tricyclic antidepressants/neuroleptics/general anesthetic agents

Augmentation of antihypertensive effects and increased risk of orthostatic hypotension (additive effect).

Special Instructions

mild to moderate hepatic failure, moderate renal failure (CK 30-60 ml/min), systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), bilateral renal artery stenosis, single renal artery stenosis, therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia and agranulocytosis), concomitant use with drugs that can cause pirouette-type polymorphic ventricular tachycardia, concomitant use with potassium-saving diuretics, potassium and lithium preparations, concomitant use of QT interval prolongers, hyperkalemia, bone marrow hematopoiesis inhibition, decreased circulating blood volume (use of diuretics, diet with restriction of table salt, vomiting, diarrhea, hemodialysis), coronary heart disease (CHD), unstable angina (except for Prinzmetal angina), atherosclerosis, cerebrovascular disease, renovascular hypertension, diabetes, CHF (functional class III-IV according to NYHA classification), acute myocardial infarction (within 1 month after the myocardial infarction), sinus node weakness syndrome, disorder of the water-electrolyte balance, use in patients with prolongation of QT interval on electrocardiogram (ECG), hyperuricemia (especially in combination with gout and urate nephrolithiasis), hyperparathyroidism, simultaneous use of dantrolene, estramustine, simultaneous use with CYP3A4 inducers and/or inhibitors, surgical intervention/general anesthesia, BP lability, hemodialysis with high flow membranes (e.g. AN69< strong>^{®)strong>®), prior to low-density lipoprotein (LDL) apheresis with dextran sulfate, concomitant desensitization therapy with allergens (e.g., hymenopteran venom), post kidney transplantation condition, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy (HCMP), congenital glucose-6-phosphate dehydrogenase deficiency, use in elderly patients and in patients of non-human race.}

It is contraindicated in persons under 18 years of age (efficacy and safety have not been established).

Elderly patients and patients with impaired renal function

The drug Co-Dalneva^® is contraindicated in patients with severe impaired renal function (CK less than 30 ml/min) (see section “Contraindications”). The drug Co-Dalnerva® can be used in patients with moderate renal impairment (CKD 30-60 ml/min). Individual selection of amlodipine, indapamide, perindopril doses is recommended for such patients.

Dose adjustment is not required for patients with impaired renal function (CK is 60 ml/min or more). Amlodipine administered in equivalent doses is equally well tolerated by elderly and younger patients. No change in dosing regimen is required in elderly patients, but dose increases should be made with caution due to age-related changes and prolongation of T_1/2. Changes in plasma amlodipine concentration do not correlate with the severity of renal failure. Amlodipine is not dialyzed.

Excretion of perindoprilat in elderly patients and patients with renal failure is delayed. Therefore, in these patients it is necessary to monitor regularly creatinine concentration and potassium content in blood plasma.

Patients with impaired liver function

The drug Co-Dalneva^® is contraindicated in patients with severe liver failure (see section “Contraindications”).

Caution should be exercised when using the drug in patients with mild to moderate hepatic impairment.

Co-Dalneva^®

Kidney function impairment

The drug Co-Dalneva^® is contraindicated in patients with severe renal dysfunction (CK less than 30 ml/min).

The drug Co-Dalneva^® may be used in patients with moderate renal impairment (CKD 30-60 ml/min). Individual selection of amlodipine, indapamide, perindopril doses is recommended for such patients.

In some patients with AH without previous obvious renal dysfunction during therapy, laboratory signs of functional renal insufficiency may appear. In this case, treatment with the drug should be stopped. In the future, the combined therapy can be resumed using low-dose combination of perindopril and indapamide, or these drugs can be used separately. Such patients should have regular monitoring of potassium and creatinine in serum two weeks after the start of therapy and every 2 months thereafter.

Patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney may have elevated serum urea and creatinine during therapy with ACE inhibitors but this usually subsides with discontinuation of therapy.

The development of renal failure occurs more frequently in patients with severe CHF or initial renal dysfunction, including renal artery stenosis.

Arterial hypotension and water-electrolyte imbalance

Patients with hyponatremia (especially those with renal artery stenosis, including bilateral stenosis) have the risk of sudden development of arterial hypotension. Therefore, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte content, e.g., after diarrhea or vomiting. The use of ACE inhibitors causes RAAS blockade, and therefore may be accompanied by a sharp decrease in BP and/or an increase in plasma creatinine concentration, which indicates the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy and sometimes develop acutely. Such patients require regular monitoring of blood plasma electrolytes content. In severe arterial hypotension, intravenous injection of 0.9% sodium chloride solution may be required. Transient arterial hypotension is not a contraindication for continuation of therapy. After the circulating blood volume (RBC) and BP are restored, the treatment can be resumed with low doses of perindopril and indapamide or used separately.

Elderly patients

Before starting Co-Dalneva^®, renal functional activity and plasma potassium content should be evaluated. At the beginning of the therapy, the dose of the drug should be chosen taking into account the degree of BP decrease, especially in case of decrease of the circulatory blood volume and electrolytes loss to avoid a sharp decrease of BP.

Atherosclerosis

The risk of arterial hypotension exists in all patients, but special care should be taken in patients with CHD and cerebrovascular disease. In such patients, treatment should be started with low doses of the drug.

Children

The drug Co-Dalneva^® is contraindicated for use in children under 18 years of age due to lack of efficacy and safety data in this age group.

Amlodipine

During treatment with amlodipine, body weight and sodium intake should be controlled and an appropriate diet prescribed. It is necessary to maintain dental hygiene and see a dentist (to prevent soreness, bleeding, and gum hyperplasia).

Patients with low body weight, short stature, and patients with severe liver dysfunction may require a lower dose.

CSN

In patients with CHF (NYHA functional class III and IV), treatment is given with caution due to the possibility of pulmonary edema. PBMCs including amlodipine should be used with caution in patients with CHF due to the possible increase of risk of cardiovascular adverse events and mortality.

Liver function impairment

The T_1/2 and AUC of amlodipine are increased in patients with impaired liver function. Amlodipine should be started with the lowest dose and caution should be exercised both at the beginning of therapy and when increasing the dose of amlodipine. In patients with severe hepatic impairment the dose should be increased gradually, the clinical condition should be closely monitored.

Elderly patients

In elderly patients the T_1/2 may increase and the clearance of amlodipine may decrease. No dose adjustment is required, but close monitoring of patients is necessary.

Indapamide

In the presence of hepatic dysfunction, taking thiazide and thiazide-like diuretics may lead to the development of hepatic encephalopathy. In this case the drug should be immediately discontinued.

Photosensitivity

Cases of photosensitivity reaction have been reported against the background of thiazide and thiazide-like diuretics. In case of photosensitivity reaction, the treatment should be discontinued. If it is necessary to continue diuretics therapy, it is recommended to protect the skin from sunlight or artificial ultraviolet rays.

Water-electrolyte balance

Plasma sodium content

Prior to treatment, plasma sodium content should be determined. This value should be monitored regularly during the treatment. All diuretics may cause hyponatremia, which sometimes leads to serious complications. At the initial stage of therapy, plasma sodium reduction may be asymptomatic, so regular laboratory monitoring is necessary. Elderly patients require more frequent monitoring of sodium content in plasma.

Hyponatremia combined with hypovolemia can cause dehydration and orthostatic hypotension.

Concomitant decrease of plasma chlorine content may cause a secondary compensatory metabolic alkalosis (frequency of development and degree of severity of this effect are insignificant).

Plasma potassium

Therapy with thiazide and thiazide-like diuretics is connected with risk of hypokalemia development. Hypokalemia (less than 3.4 mmol/l) should be avoided in the following categories of patients from high-risk groups: elderly patients, emaciated patients, patients with cirrhosis, including those with edema and ascites, patients with CHD, CHF. In these patients hypokalemia increases toxic effects of cardiac glycosides and increases the risk of arrhythmia.

Patients with prolonged QT interval, either hereditary or drug-induced, are also at increased risk. Hypokalemia, like bradycardia, contributes to severe heart rhythm disorders, especially pirouette-type polymorphic ventricular tachycardia, which can be fatal.In all the cases described above, regular monitoring of plasma potassium is necessary. It is necessary to determine plasma potassium content during the first week after the start of therapy. If hypokalemia is detected, an appropriate therapy should be conducted.

Calcium content in plasma

Thiazide and thiazide-like diuretics decrease renal calcium excretion that may cause a slight temporary increase in plasma calcium. Severe hypercalcemia may be associated with previously undiagnosed hyperparathyroidism. In such cases it is necessary to investigate the parathyroid gland function after discontinuing diuretics.

Ric acid

Patients with elevated plasma uric acid concentrations during therapy may have an increased incidence of gout attacks.

Kidney function impairment

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

Transient decrease in GFR and increase in plasma urea and creatinine may be observed in patients with hypovolemia and hyponatremia at the beginning of diuretic therapy. This transient functional renal failure is not dangerous for patients with unchanged renal function, however in patients with renal insufficiency its severity can increase.

Potassium and plasma creatinine concentration should be regularly monitored in such patients.

Athletes

Indapamide may produce a positive reaction in doping control.

Acute myopia and secondary acute closed-angle glaucoma

Sulfonamides and their derivatives can cause an idiosyncratic reaction, leading to the development of acute transient myopia and an acute attack of closed-angle glaucoma. Left untreated, an acute attack of closed angle glaucoma can lead to permanent vision loss. The first step is to discontinue the drug as soon as possible. If the intraocular pressure remains uncontrolled, emergency medication or surgery may be necessary. A history of allergic reactions to sulfonamide derivatives and penicillins are risk factors for an acute attack of closed angle glaucoma.

Perindopril

Double RAAS blockade

There is evidence of an increased risk of arterial hypotension, hyperkalemia, and renal dysfunction (including ARF) when using ACE inhibitors and ARA II or aliskiren simultaneously. Therefore, dual blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended (see section “Interaction with other medicinal products”). If dual blockade is necessary, it should be performed under close supervision of a specialist with regular monitoring of renal function, plasma potassium and BP.

The concomitant use of ACE inhibitors with aliskirenomil or drugs containing aliskiren is contraindicated in patients with DM and/or moderate to severe renal function impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Simultaneous use of ACE inhibitors with ARA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Neutropenia/ Agranulocytosis/Trombocytopenia/Anemia

Neutropenia/granulocytosis, thrombocytopenia, and anemia may occur while taking ACE inhibitors. In patients with normal renal function in the absence of other risk factors, neutropenia is rare. After withdrawal of ACE inhibitor, neutropenia and agranulocytosis disappear on their own. Perindopril should be used with special caution in patients with systemic connective tissue diseases against the background of therapy with immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When using perindopril in such patients, it is recommended to periodically monitor the plasma leukocyte count. If any symptoms of infectious diseases appear (e.g., sore throat, fever) patients should consult a physician.

Ensensitivity/angioedema

The development of angioedema of the face, extremities, lips, tongue, vocal folds, and/or larynx may occur in rare cases while taking ACE inhibitors, including perindopril. If symptoms occur, the drug should be discontinued immediately and the patient should continue to be monitored until the symptoms have resolved. Swelling of the face and lips usually does not require treatment, although antihistamines may be used to control symptoms.

Angioedema with laryngeal edema may be fatal. Swelling of the tongue, vocal folds or larynx may cause airway obstruction. If these symptoms occur, epinephrine (adrenaline) solution 1:1000 (0.3-0.5 ml) should be administered immediately by subcutaneous injection and/or airway patency should be secured. Patients with a history of angioedema, not associated with the use of ACE inhibitors, may be at increased risk of its development when taking this group of drugs.

In rare cases angioedema of the bowel develops during therapy with ACE inhibitors. Patients complain of abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding angioedema of the face and with normal C1-esterase levels. The diagnosis was established by computed tomography, abdominal ultrasound or during surgical intervention. Symptoms disappear after discontinuation of ACE inhibitors. Therefore, in patients with complaints of abdominal pain taking ACE inhibitors, the possibility of development of angioedema of the bowel should be considered when making the differential diagnosis.

MTOR inhibitors

In patients simultaneously taking mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), therapy may be accompanied by an increased risk of angioedema (e.g., upper respiratory or tongue edema with/without respiratory impairment).

Anaphylactoid reactions whendesensitization

There have been isolated reports of anaphylactoid reactions in patients taking ACE inhibitors during desensitization therapy (e.g., by venom of hymenopteran insects: bees, wasps). The development of such reactions was avoided by temporary cancellation of ACE inhibitors (at least 24 hours prior to desensitization), anaphylactoid reactions occurred again if an ACE inhibitor was taken accidentally.

Anaphylactoid reactions during LDL apheresis

In rare cases, patients receiving ACE inhibitors may develop life-threatening anaphylactoid reactions when performing LDL apheresis with dextran sulfate. To prevent such reactions, ACE inhibitors should be temporarily discontinued before each apheresis procedure.

Hemodialysis

In rare cases, patients receiving ACE inhibitors have developed anaphylactoid reactions when performing hemodialysis using high-flow membranes (e.g., AN69^®). Therefore, it is recommended to use another type of membrane or use a hypotensive drug of another pharmacotherapeutic group.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are generally immune to hypotensive drugs whose action is based on inhibiting the RAAS. Therefore the use of this drug is not recommended.

Cough

Dry cough may occur during ACE inhibitor therapy. Cough is prolonged with this group of drugs and disappears after cough discontinuation. If it is necessary to use this group of drugs, ACE inhibitor use may be continued.

Aortic and mitral stenosis, GOCMP

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and mitral stenosis.

Csugardiabetes

In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, regular monitoring of plasma glucose concentrations is necessary during the first month of ACE inhibitor treatment.

Surgery/general anesthesia

The use of ACE inhibitors in patients undergoing surgery involving general anesthesia may result in a marked decrease in BP, especially when using general anesthetic agents with an antihypertensive effect. It is recommended to discontinue long-acting ACE inhibitors, including perindopril, 24 hours prior to surgical intervention.

Ethnic differences

Patients of the Negro race are more likely than other races to develop angioedema when using ACE inhibitors. Perindopril, like other ACE inhibitors, appears to have less pronounced antihypertensive effects in black race patients compared to other races. It is possible that this difference is due to the fact that patients with arterial hypertension of the Negro race are more likely to have low plasma renin activity.

Hepatic failure

In rare cases cholestatic jaundice occurs against ACE inhibitors. With the progression of this syndrome, fulminant necrosis of the liver develops, sometimes with a fatal outcome. The mechanism of this syndrome is unclear. If there is a significant increase in liver enzymes activity or jaundice when taking ACE inhibitors, the drug should be stopped and the patient should be monitored further.

Hyperkalemia

use of ACE inhibitors may cause hyperkalemia due to inhibition of aldosterone release usually mild in patients with normal renal function. Risk factors of hyperkalemia are renal insufficiency, old age (over 70 years), diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), simultaneous use of potassium-saving diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes as well as other drugs that contribute to increased plasma potassium levels (e.g., heparin, trimethoprim or co-trimoxazole (sulfamethoxazole + trimethoprim) and especially aldosterone antagonists or ARA II, ASA ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus (especially in patients with reduced renal function). Hyperkalemia may lead to serious, sometimes fatal cardiac arrhythmias. Caution should be exercised when concomitant use of ACE inhibitors and potassium-saving diuretics and ARA II, renal function and serum potassium content should be monitored.

Kidney transplantation

There is no experience with perindopril in patients with a recent kidney transplant.

Renovascular hypertension

The treatment of renovascular hypertension is revascularization. However, the use of ACE inhibitors can be effective in patients with renovascular hypertension, both awaiting surgical intervention and when it is not possible.

Patients with bilateral renal artery stenosis or renal artery stenosis of the only functioning kidney have an increased risk of arterial hypotension and renal failure with ACE inhibitors therapy. Taking diuretics may be an additional risk factor. Even in patients with unilateral renal artery stenosis, worsening of renal function may be observed even with a small change in creatinine concentration in plasma.

In patients with diagnosed or suspected renal artery stenosis, treatment should be started with lower doses of Co-Dalnerva^®. Some patients may develop functional renal failure, which resolves after discontinuation of the drug.

Because of the possibility of weakness and dizziness on using the drug Ko-Dalneva^® one should use caution while driving vehicles and operating other technical devices requiring high concentration and quick psychomotor reactions.

Synopsis

Tablets 5 mg + 0.625 mg + 2 mg:

Oval, biconvex tablets, white or almost white, with a rib on one side.

Tablets 5 mg + 1.25 mg + 4 mg:

Circular, slightly biconvex tablets white or nearly white, with a bevel on both sides.

Tablets 5 mg + 2.5 mg + 8 mg:

Circular, biconvex tablets, white or nearly white, beveled on both sides.

Tablets 10 mg + 1.25 mg + 4 mg:

Oval, biconvex tablets white or nearly white, with a ridge on one side.

Tablets 10 mg + 2.5 mg + 8 mg:

Circular, biconvex tablets, white or nearly white in color, with a bevel on both sides and a rib on one side.

Contraindications

• High sensitivity to amlodipine and other dihydropyridine derivatives, indapamide and other sulfonamide derivatives, perindopril and other ACE inhibitors, and the excipients in the drug.
• Angioneurotic edema (Quincke’s edema) in history associated with ACE inhibitor use.
• Hereditary/idiopathic angioedema.
• Severe arterial hypotension (systolic BP <90 mm Hg).
• Shock, including cardiogenic shock.
• Obstruction of the left ventricular exit tract (eg, clinically significant aortic stenosis).
• Hemodynamically unstable heart failure after acute myocardial infarction.
• Severe renal failure (CK less than 30 ml/min).
• Severe liver failure, including liver encephalopathy.
• Refractory hypokalemia.
• Simultaneous use with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and/or moderate to severe renal function impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m² body surface area).
• Simultaneous use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy.
• Simultaneous use with neutral endopeptidase inhibitors (such as those containing sacubitril) due to high risk of angioedema (see section “Interaction with other medicinal products”).

corporal therapies using certain negatively charged membranes.
• Developed bilateral renal artery stenosis or renal artery stenosis of the only functioning kidney.
• Pregnancy and breastfeeding (see “Administration during pregnancy and breastfeeding”). Use in pregnancy and breastfeeding).
• Age under 18 years of age (effectiveness and safety not established).

Given the lack of sufficient clinical experience, should not be used in patients on hemodialysis or in patients with untreated decompensated heart failure.

Overdose

Symptoms

Treatment

Emergency measures are aimed at removing the drug from the gastrointestinal tract: gastric lavage and/or intake of activated charcoal followed by restoration of water-electrolyte balance. In a pronounced BP decrease, the patient should be laid with elevated position of the lower extremities, and if necessary, the correction of hypovolemia (e.g., intravenous infusion of 0.9% sodium chloride solution) should be performed.

Perindoprilat, the active metabolite of perindopril, is removed by hemodialysis. Amlodipine binds closely to plasma proteins, so hemodialysis is ineffective.

Indapamide is not removed by hemodialysis.

Pregnancy use

Pregnancy

Motherhood: justify; mso-pagination: none;”>The drug Co-Dalneva^®is contraindicated in pregnancy (see Contraindications).

If pregnancy is planned or occurs while taking Co-Dalnerva^® , immediately discontinue and prescribe alternative hypotensive therapy with a proven safety profile.

The safety of amlodipine in pregnancy has not been established. The limited data available on the use of amlodipine and other DMARDs in pregnancy suggest no adverse effects on the fetus. In animal experiments, signs of reproductive toxicity have been observed with high doses of amlodipine. A reversible decrease in sperm motility was observed in some patients treated with DMARDs. Clinical data regarding the potential effect of amlodipine on reproductive function are scarce.

There are no or limited data on the use of indapamide in pregnant women (less than 300 cases). Prolonged use of thiazide diuretics in the third trimester of pregnancy may cause hypovolemia in the mother and decrease uterine-placental blood flow, which leads to fetoplacental ischemia and fetal retardation. In rare cases, the newborns develop hypoglycemia and thrombocytopenia when taking diuretics shortly before delivery.

Animal studies have shown no direct or indirect toxic effects on reproduction.

As a precautionary measure, the use of indapamide during pregnancy should be avoided.

The available data about teratogenicity of ACE inhibitors in the first trimester of pregnancy are not conclusive, but this risk cannot be completely excluded. In II and III trimesters of pregnancy, exposure of the fetus to ACE inhibitors may lead to abnormal development (decreased renal function, oligohydramnios, delayed cranial ossification) and complications in the newborn (renal failure, arterial hypotension, hyperkalemia). If an ACE inhibitor has been used in the second or third trimester of pregnancy, an ultrasound examination of the fetal kidneys and skull bones is recommended. Newborns whose mothers received ACE inhibitors during pregnancy need close medical monitoring, since there is a risk of arterial hypotension.

Breastfeeding period

Amlodipine is excreted with breast milk. The fraction of the maternal dose received by the infant was estimated to be between 3% and 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. The decision to extend/terminate breastfeeding or to continue/terminate amlodipine therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of amlodipine use for the mother.

There is currently no reliable information about excretion of indapamide or its metabolites with breast milk.

Tiazide diuretics administration causes decrease or suppression of maternal lactation, the newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia and “nuclear” jaundice.

Indapamide is contraindicated during breastfeeding.

It is unknown whether perindopril is excreted with breast milk.

The drug Co-Dalneva^® is contraindicated during breastfeeding. If it is necessary to use the drug Co-Dalnerva^® during lactation, breastfeeding should be stopped.

Similarities

Triplixam