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

Co-Dalneva^® is a combination drug containing perindoprilairbumin (angiotensin-converting enzyme (ACE) inhibitor), indapamide (thiazide-like diuretic) and amlodipine (slow calcium channel blocker (CCB).

The drug Co-Dalneva^® combines the properties of each of the active ingredients while having potentiating effects.

Pharmacodynamics

Amlodipine

Amlodipine is a BMCC, a dihydropyridine derivative. Amlodipine inhibits transmembrane transition of calcium ions in cardiomyocytes and smooth muscle cells of the vascular wall. The antihypertensive effect of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vascular wall. The mechanism of antianginal action of amlodipine is not fully understood, presumably it is related to the following effects:

• causes dilation of peripheral arterioles, reducing total peripheral vascular resistance (PPR)-postload, which leads to a reduction in myocardial oxygen demand;

causes dilation of coronary arteries and arterioles in both intact and ischemic areas of the myocardium, which increases oxygen supply to the myocardium, including in patients with Prinzmetal angina.

In patients with arterial hypertension (AH), administration of amlodipine once daily provides clinically significant reduction of blood pressure (BP) (in lying and standing position) for 24 hours. Antihypertensive effect develops slowly, so the development of acute arterial hypotension is uncommon.

In patients with stenocardia once daily administration of amlodipine increases exercise tolerance, time to angina attack and to “coronary” ST-segment depression, decreases angina attacks frequency and necessity of taking nitroglycerin (short-acting forms). Amlodipine has no effect on lipid profile parameters and does not cause changes in blood plasma hypolipidemic parameters. The drug may be used in patients with bronchial asthma (BA), diabetes mellitus (DM) and gout.

Indapamide

Indapamide is a sulfonamide derivative. In terms of pharmacological properties, it is close to thiazide diuretics. Indapamide inhibits reabsorption of sodium ions in the cortical segment of the loop of Genle, which leads to increased renal excretion of sodium and chlorine ions and, to a lesser extent, potassium and magnesium ions, thereby increasing diuresis and reducing BP.

In monotherapy the antihypertensive effect is maintained for 24 hours and is seen when the drug is used in doses that have minimal diuretic effect. Antihypertensive effect of indapamide is associated with improvement of elastic properties of large arteries, reduction of PPS. Against the background of taking indapamide, left ventricular hypertrophy (LVH) decreases.

Indapamide does not influence plasma concentration of lipids (triglycerides, total cholesterol, low-density and high-density lipoproteins), indices of carbohydrate metabolism (including in patients with diabetes).

Perindopril

Perindopril is an angiotensin-converting enzyme inhibitor. ACE, or kininase II, is an exopeptidase that converts angiotensin I into the vasoconstrictor, angiotensin II, and also degrades bradykinin, which has vasodilatory properties, into an inactive heptapeptide.

As a result, perindopril provides the following effects:

– reduces the secretion of aldosterone;

– increases the activity of blood renin-plasma by the principle of “negative” feedback;

– with long-term use it reduces the OPPS – post-load of the heart, which is mainly due to the action on the muscular and renal vessels. Reduction of OPPS is not accompanied with retention of sodium and water and does not cause reflex tachycardia.

The study of hemodynamic parameters in patients with chronic heart failure (CHF) revealed:

– decreased filling pressures in the left and right ventricles of the heart;

– decreased PPSS;

– increased cardiac output and cardiac index;

– increased peripheral blood flow in the muscles.

In addition, there was an improvement in the results of the exercise test.

The action of perindopril is through the active metabolite, perindoprilat. Other metabolites have no inhibitory effect on ACE under in-vitro conditions.

Perindopril is effective in the treatment of AH of any severity, reduces both systolic and diastolic BP in lying and standing position.

The antihypertensive effect peaks 4-6 hours after a single oral dose and lasts for 24 hours.

The antihypertensive effect 24 hours after a single oral dose is about 87-100% of the maximum antihypertensive effect.

Perindopril has antihypertensive effect in patients with both low and normal plasma renin activity.

Therapeutic effect occurs in less than 1 month from the beginning of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause “withdrawal” syndrome.

Perindoprilobin has vasodilator properties and promotes restoration of elasticity of large arteries, structure of vascular wall of small arteries, and also reduces VFD.

The concomitant use with thiazide diuretic increases the severity of antihypertensive effect and reduces the risk of hypokalemia with diuretic.

Perindopril/indapamide

The perindopril/indapamide combination has dose-dependent antihypertensive effects on both systolic and diastolic BP (standing and lying) regardless of patient age. Antihypertensive effect lasts for 24 hours. Therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause “withdrawal” syndrome.

In clinical studies, concomitant use of perindopril and indapamide increased the severity of antihypertensive effect compared to monotherapy with each drug. The perindoprilatetbutylamine (perindopril erbumin)/indapamide combination resulted in a significantly more pronounced reduction in VLDL than did enalapril monotherapy. The most significant effect on VFD was achieved with perindoprilatetbutylamine (perindopril erbumin) 8 mg/indapamide 2.5 mg.

Pharmacokinetics

Amlodipine

Intake, distribution

After oral administration, amlodipine is slowly absorbed from the gastrointestinal tract (GIT). Food intake has no effect on the bioavailability of amlodipine. Maximum concentration (C_max) of amlodipine in plasma is achieved 6-12 hours after oral administration. Absolute bioavailability is approximately 64-80%. The volume of distribution (Vd) is approximately 21 l/kg. In xin vitro studies the degree of binding of amlodipine to plasma proteins was about 97.5%.

Metabolism, excretion

The final half-life (T_1/2) from blood plasma is about 35-50 hours, which allows taking amlodipine once daily. Amlodipine is metabolized in the liver to form inactive metabolites, with 10% of the ingested dose of amlodipine excreted unchanged, about 60% – by the kidneys as metabolites. Amlodipine is not excreted from the body by hemodialysis.

The time to reach C_max amlodipine does not differ in elderly and younger patients. Amlodipine clearance is decreased in elderly patients, resulting in increased area under the concentration-time curve (AUC) and T_1/2. Dose adjustment in elderly patients is not required, but the dose of amlodipine should be increased with caution. The increase in AUC and T_1/2 in patients with CHF is as expected for this age group.

In patients with impaired renal function, changes in plasma amlodipine concentrations do not correlate with the degree of renal failure. There may be a slight prolongation of T_1/2.

In patients with impaired hepatic function, there are limited data on the use of amlodipine and a decrease in clearance of amlodipine, resulting in an increase in T_1/2 and AUC of approximately 40-60%.

Indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract. C_max in blood plasma is reached approximately 1 hour after oral administration. The degree of binding to plasma proteins is 79%.

Metabolism, excretion

T_1/2 is 14-24 hours (average 18 hours). Repeated administration of indapamide does not result in its cumulation. It is eliminated mainly by the kidneys (70% of the oral dose) and through the intestine (22%) in the form of inactive metabolites.

Pharmacokinetics of indapamide does not change in patients with renal insufficiency.

Perindopril

Intake, metabolism

Perindopril is rapidly absorbed when taken orally. C_max in plasma is reached 1 hour after oral administration.

Perindopril is a prodrug, which means it has no pharmacological activity. About 27% of the oral dose of perindopril enters the bloodstream as the active metabolite – perindoprilate. In addition to the active metabolite – perindoprilat, 5 other metabolites are formed that have no pharmacological activity. C_max perindoprilat in blood plasma is reached 3-4 hours after oral administration.

Eating slows the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, perindopril should be taken once daily, in the morning, before meals.

There is a linear dependence of plasma concentration of perindopril on the dose taken orally.

Distribution

The Vdc of free perindoprilat is approximately 0.2 L/kg. The degree of binding of perindoprilat to plasma proteins (mainly ACE) is about 20% and is dose-dependent.

T_1/2perindoprilat from blood plasma is 1 hour. Perindoprilat is eliminated from the body by the kidneys. The final T_1/2 free fraction is about 17 hours, the equilibrium state is reached within 4 days.

The excretion of perindoprilat is delayed in elderly patients as well as in patients with cardiac and renal insufficiency. Dose adjustment in patients with renal insufficiency is carried out taking into account the degree of renal impairment (creatinine clearance (CK)). Dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril changes in patients with cirrhosis: hepatic clearance decreases by half. However, the amount of perindoprilat produced is not decreased, therefore no dose adjustment is required (see sections “Dosage and administration” and “Precautions”).

Indications

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

Active ingredient

Composition

For 1 tablet, 5 mg + 2.5 mg + 8 mg

The active ingredients:

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

Perindoprilaerbumin B, pellet substance 40.824 mg

[Active ingredient of pellet substance: Perindoprilaerbumin 8,000 mg

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

Auxiliary substances: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium hydrocarbonate, 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 T1/2. 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

Combined use is not recommended

Dantrolene (intravenous)

Intravenous administration. There have been cases of fatal ventricular fibrillation and collapse in laboratory animals when using verapamil and intravenous (IV) 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 and in the treatment of malignant hyperthermia.

Concurrent use requiring special attention

CYP3A4 isoenzyme inducers

The plasma concentrations of amlodipine may change with concomitant use of CYP3A4 isoenzyme inducers. 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, preparations of St. John’s Wort).

CYP3A4 isoenzyme inhibitors

. Concomitant use of amlodipine with potent or moderate inhibitors of CYP3A4 isoenzyme (protease inhibitors, antifungal drugs of azole group, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may cause significant increase in amlodipine concentration, which increases the risk of hypotension. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required.

Inhibitors of mammalian mechanistic target for rapamycin (tTOR)

MTOR inhibitors, such as caxirolimus, 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

In concomitant use 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 toxic effects of tacrolimus when used concomitantly with amlodipine, plasma concentrations of tacrolimus should be monitored and the dose of tacrolimus should be adjusted if necessary.

Cyclosporine

There have been no studies of drug interaction with cyclosporine and amlodipine in healthy volunteers or other patient groups, except for kidney transplant patients, in whom variable minimum concentrations (mean values: 0%-40%) of cyclosporine were observed. When concomitant use of amlodipine in patients undergoing renal transplantation, plasma concentrations of cyclosporine should be monitored and the dose should be reduced if necessary.

Simvastatin

Concomitant use of amlodipine in dose of 10 mg and with imvastatin in dose of 80 mg increases exposure to simvastatin by 77% compared to that of imvastatin monotherapy. Patients receiving amlodipine are recommended to use simvastatin in a dose not exceeding 20 mg/day.

Concomitant use requiring attention

Amlodipine enhances the antihypertensive effect of drugs for hypotensive therapy.

Tasonermin

Concomitant use of amlodipine may increase the systemic plasma exposure of tasonermin. In such cases, regular monitoring of tasonermine blood concentrations and dosage 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 consumption of grapefruit or grapefruit juice is not recommended due to the possible increase in bioavailability of amlodipine in some patients, which may increase the antihypertensive effect.

Indapamide

Concomitant use requiring special attention

Drugs that can cause pirouette-type polymorphic ventricular tachycardia

. Because of the risk of hypokalemia, caution should be exercised when concomitant use of indapamide with drugs capable of causing pirouette-type polymorphic ventricular tachycardia, such as antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylate, sotalol), certain 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 use with the above mentioned drugs in case of hypokalemia development, to carry out its correction, monitor ECG (QT interval).

Drugs that may cause hypokalemia

Simultaneous use with IV amphotericinB, systemic glucocorticosteroids and mineralocorticosteroids, tetracosactide, laxatives that stimulate gastrointestinal 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 which do not stimulate gastrointestinal motility should be used.

Cardiac glycosides

Hypokalemia increases toxic effects of cardiac glycosides. With concomitant use, plasma potassium and ECG parameters should be monitored and, if necessary, it is necessary to decide whether continuation of therapy is advisable.

Simultaneous use requiring attention

Metformin

Functional renal failure, which can occur with diuretics, especially loop diuretics, increases the risk of lactoacidosis with concomitant use of metformin. 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. Hypovolemia should be compensated before the use of iodine-containing contrast agents.

Calcium salts

The concomitant use can lead to hypercalcemia due to reduced renal calcium excretion.

Cyclosporine

Possible increase of CK in plasma without change in cyclosporine concentration, even with normal water and sodium levels.

Perindopril

. Data from clinical studies demonstrate that dual RAAS blockade resulting from concomitant use of ACE inhibitors, ARA II or aliskiren leads to increased rates of adverse events such as arterial hypotension, hyperkalemia and renal dysfunction (including ARF) compared with situations in which only one RAAS-acting medication is used (see “Pharmacodynamics” sections). (see the sections on Pharmacodynamics and Contraindications and Precautions).

Drugs that cause hyperkalemia

Some drugs or classes of drugs can 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 medications increases the risk of hyperkalemia.

The concomitant use is contraindicated

Aliskiren

In patients with diabetes 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 mellitus and/or moderate to severe renal function impairment (GFR < 60 ml/min/1.73 m2 body surface area) is contraindicated (see “Contraindications” section).

Neutral endopeptidase inhibitors

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

The simultaneous use of ACE inhibitors with drugs containing sacubitril (neprilysin 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 drugs containing Sacubitril is contraindicated in patients receiving ACE inhibitors, and also within 36 hours after cancellation of ACE inhibitors.

The extracorporeal therapy

. Extracorporeal therapies leading to blood contact with negatively charged surfaces, such as hemodialysis using high-flow membranes (e.g., polyacrylonitrile membranes) and LDL apheresis using dextran sulfate, may lead to an increased risk of severe anaphylactoid reactions (see See section “Contraindications”). Therefore, it is advisable to use a different type of membrane or to use a hypotensive drug of a different 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 incidence of 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 ARF) compared to one of these groups. Dual RAAS blockade is possible only in individual cases under close control of renal function, potassium and BP.

The concomitant use of ACE inhibitors with APA 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 a risk of angioedema.

Lithium

Concomitant use of lithium preparations and ACE inhibitors may cause a reversible increase in serum lithium levels and associated toxic effects. Concomitant use of perindopril with indapamide and lithium is not recommended, but serum lithium levels should be monitored closely if necessary.

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

The concomitant use of the combination of perindopril and indapamide with lithium preparations is not recommended. If concomitant use is necessary, plasma lithium levels should be monitored carefully.

Potassium-saving diuretics, potassium preparations, and potassium-containing salt substitutes

In therapy with ACE inhibitors, plasma potassium levels are usually within normal limits, but hyperkalemia may occur. Concomitant use of potassium-saving diuretics (triamterene, amiloride), potassium preparations and potassium-containing table 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 ACE inhibitor and mTOR inhibitor concomitantly, therapy may be associated with an increased risk of angioedema.

Concomitant use requiring special attention

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

Concomitant use Concomitant use of ACE inhibitors with NSAIDs (including ASCs in dose with anti-inflammatory activity, cyclooxygenase-2 inhibitors (COX-2) and non-selective NSAIDs) may lead to decreased antihypertensive effect, and worsened renal function, including development of ARF, and increased plasma potassium, 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 and oral hypoglycemic agents) may increase the hypoglycemic effect of insulin and oral hypoglycemic agents, up to and including 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.

Potassium-bearing diuretics

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

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

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

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

Caliberating diuretics (eplerenone, spironolactone)

The use of eplerenone or spironolactone in doses of 12.5 mg to 50 mg daily and low-dose ACE inhibitors: In therapy of heart failure NYHA functional class II-IV with left ventricular ejection fraction < 40% in patients previously treated with ACE inhibitors and “loop” diuretics, there is a risk of hyperkalemia (with possible death), especially if recommendations for this drug combination are not followed.

Be sure that there is no hyperkalemia or renal impairment before using this drug combination.

Physical creatinine and plasma potassium concentrations must be monitored regularly every week for 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.

The drugs for general anesthesia

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

Gold preparations

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

Co-trimoxazole (sulfamethoxazole + trimethoprim)

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

Glyptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)

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

Sympathomimetics

Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.

Cyclosporine

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

Heparin

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

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-Dalnerva®

Simultaneous use requiring special attention

Baclofen

Possible increase in antihypertensive effect. BP and renal function should be monitored; if necessary, the dose of hypotensive drugs should be adjusted.

Simultaneous use requiring attention

Hypotensive drugs (e.g., beta-adrenoblockers) and vasodilators

Simultaneous use with hypotensive drugs may increase the antihypertensive effect. Caution should be exercised when concomitant use with nitroglycerin, other nitrates, or other vasodilators because additional BP reduction is possible.

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

Decrease antihypertensive effect (fluid and sodium retention as a result of corticosteroid action).

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

Augment the antihypertensive effect and increase the risk of orthostatic hypotension.

Amifostine

May increase the antihypertensive effect of amlodipine.

Tricyclic antidepressants/neuroleptics/general anesthesia 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>®), 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 T1/2. 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 T1/2 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 T1/2 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

Overdose

Symptoms

Pregnancy use

Pregnancy

The drug Co-Dalneva® is contraindicated in pregnancy (see See section “Contraindications”).

If pregnancy is planned or occurs while taking Co-Dalnerva® , immediately discontinue and prescribe an 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 the signs of reproductive toxicity were observed when using high doses of amlodipine.

A reversible decrease in sperm motility was observed in some patients treated with BMCC therapy. Clinical data regarding the potential effect of amlodipine on fertility 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 the II and III trimesters of pregnancy the ACE inhibitors effects on the fetus may result in abnormal fetal development (decreased renal function, oligohydramnios, delayed cranial ossification) and development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

If ACE inhibitor was 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, as 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