Co-Perineva, pills 1.25+4mg, 90pcs

Composition

for 1 tablet 0.625 mg + 2 mg/1.25 mg + 4 mg/2.5 mg + 8 mg

Active ingredients:

Indapamide 0.625 mg/1,250 mg/2,500 mg

Perindopril erbumin K, semi-finished granules 37,515 mg / 75,030 mg/150,060 mg

[Active ingredient of semi-finished product-granules:

Perindopril erbumin 2,000 mg / 4,000 mg/8,000 mg

Excipients of semi-finished granules: calcium chloride hexahydrate, lactose monohydrate, crospovidone]

Auxiliary substances: microcrystalline cellulose, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate

Or

per 1 tablet 0.625 mg + 2 mg/1.25 mg + 4 mg/2.5 mg + 8 mg

Active ingredients:

Indapamide 0.625 mg/1,250 mg/2,500 mg

Perindopril erbumin 2,000 mg / 4,000 mg/8,000 mg

Auxiliary substances: calcium chloride hexahydrate, lactose monohydrate, crospovidone, microcrystalline cellulose, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate

Pharmacological action

antihypertensive combined agent (diuretic + angiotensin converting enzyme inhibitor)

Clinical Pharmacology

Pharmacodynamics

Co-Perineva is a combination drug containing an angiotensin-converting enzyme (ACE) inhibitor, perindopril, and a thiazide-like diuretic, indapamide. The drug has antihypertensive, diuretic and vasodilating effects.

The drug Co-Perineva ® has a pronounced dose-dependent antihypertensive effect, independent of the patient’s age and body position and not accompanied by reflex tachycardia. It does not affect the metabolism of lipids (total cholesterol (TC), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), high-density lipoproteins (HDL), triglycerides (TG)) and carbohydrates, including in patients with diabetes mellitus (DM). Reduces the risk of hypokalemia due to diuretic monotherapy.

The antihypertensive effect persists for 24 hours.

A stable reduction in blood pressure (BP) is achieved within 1 month with the use of Co-Perineva® and is not accompanied by tachyphylaxis. Discontinuation of treatment does not lead to the development of “withdrawal”syndrome.

Indapamide

Indapamide is a sulfonamide derivative and is a diuretic. It inhibits the reabsorption of sodium ions in the cortical segment of the Henle loop, increasing the release of sodium and chlorine ions by the kidneys, thus leading to increased diuresis. Increases the excretion of potassium and magnesium ions to a lesser extent. Having the ability to selectively block “slow” calcium channels, indapamide increases the elasticity of arterial walls and reduces total peripheral resistance (OPSS). It has an antihypertensive effect in doses that do not have a pronounced diuretic effect. Increasing the dose of indapamide does not increase the antihypertensive effect, but increases the risk of adverse events.

Indapamide in patients with arterial hypertension does not affect:

· lipid metabolism: TG, LDL and HDL;

· carbohydrate metabolism, including in patients with diabetes and arterial hypertension.

Perindopril

Perindopril is an ACE inhibitor, the mechanism of action of which is associated with inhibition of ACE activity, leading to a decrease in the formation of angiotensin II; eliminates the vasoconstrictor effect of angiotensin II, reduces the secretion of aldosterone. The use of perindopril does not lead to sodium and fluid retention, does not cause reflex tachycardia during long-term treatment. The antihypertensive effect of perindopril develops in patients with low or normal plasma renin activity.

Perindopril acts through its main active metabolite, perindoprilate. Its other metabolites are inactive.

The effect of perindopril leads to:

– expansion of veins (reduced preload on the heart), due to changes in prostaglandin metabolism;

– reduction of OPSS (reduced afterload on the heart).

In patients with heart failure, perindopril contributes to:

– decrease in the filling pressure of the left and right ventricles;

– increase in cardiac output and cardiac index;

– increase in regional blood flow in the muscles.

Perindopril is effective in the treatment of arterial hypertension of any severity: mild, moderate and severe. The maximum antihypertensive effect develops 4-6 hours after a single oral dose and persists for 24 hours. Discontinuation of therapy does not lead to the development of “withdrawal”syndrome.

It has vasodilating properties and restores the elasticity of large arteries.

The addition of a thiazide-like diuretic enhances the antihypertensive (additive) effect of perindopril.

Double blockade of the renin-angiotensin-aldosterone system (RAAS)

There are data from clinical studies of combination therapy with an ACE inhibitor and an angiotensin II receptor antagonist (ARA II).

Clinical studies were conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes accompanied by confirmed damage to the target organ, as well as studies in patients with type 2 diabetes and diabetic nephropathy.

These studies did not show a significant positive effect on the occurrence of renal and/or cardiovascular events and on mortality rates in patients receiving combination therapy, while the risk of hyperkalemia, acute renal failure(AKI) and/or arterial hypotension increased compared to patients receiving monotherapy.

Taking into account the similar intragroup pharmacodynamic properties of the ACE inhibitor and ARA II classes, these results can be expected for the interaction of any other drugs, representatives of the ACE inhibitor and ARA II classes.

Therefore, ACE inhibitors and ARA II inhibitors should not be used simultaneously in patients with diabetic nephropathy. There is evidence from a clinical trial investigating the beneficial effects of adding aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or who have a combination of these diseases. The study was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more frequently in the aliskiren-treated group compared to the placebo group. Also, adverse events and serious adverse events of special interest (hyperkalemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Pharmacokinetics

The combined use of perindopril and indapamide does not change their pharmacokinetic parameters in comparison with separate use of these drugs.

Indapamide

It is rapidly and completely absorbed from the gastrointestinal tract (GIT). Food intake slightly slows down absorption, but does not significantly affect the amount of indapamide absorbed. The maximum concentration (cmax) in blood plasma is reached 1 hour after ingestion of a single dose. Binds to plasma proteins by 79%. The half-life (_half-life) is from 14 to 24 hours (average 18 hours). It doesn’t accumulate.

It is metabolized in the liver. It is excreted by the kidneys (70%) mainly in the form of metabolites (the fraction of unchanged drug is about 5%) and through the intestine with bile in the form of inactive metabolites (22%). In patients with renal insufficiency, the pharmacokinetic parameters of indapamide do not change significantly.

Perindopril

After oral use, it is rapidly absorbed from the gastrointestinal tract. Bioavailability is 65-70%.

Food intake reduces the conversion of perindopril to perindoprilate. The plasma half-life of perindopril is 1 hour.

_Cmaxin blood plasma is reached 3-4 hours after oral use. Since food intake reduces the conversion of perindopril to perindoprilat and the bioavailability of the drug, perindopril should be taken once a day-in the morning before breakfast. When taking perindopril 1 time a day, the equilibrium concentration is reached within 4 days.

There is a linear relationship between the dose of perindopril and its concentration in blood plasma.

It is metabolized in the liver to form the active metabolite perindoprilate. In addition to the active metabolite of perindoprilate, perindopril forms 5 inactive metabolites. The association of perindoprilat with plasma proteins is dose-dependent and amounts to 20%. Perindoprilat easily passes through histohematic barriers, excluding the blood-brain barrier, a small amount penetrates through the placenta and into breast milk. Excreted by the kidneys, the_half-life of perindoprilat is about 17 hours. It doesn’t accumulate.

In elderly patients, in patients with renal and heart failure, the elimination of perindoprilat is slowed.

In patients with renal insufficiency, it is recommended to reduce the dose of perindopril depending on the severity of renal insufficiency (creatinine clearance (CC)).

The dialysis clearance of perindoprilat is 70 ml / min

. The pharmacokinetics of perindopril are changed in patients with cirrhosis of the liver: hepatic clearance decreases by 2 times.However, the amount of perindoprilate produced does not decrease, so no dose adjustment is required.

Indications

Essential hypertension.

Use during pregnancy and lactation

Pregnancy

Taking Co-Perineva® is contraindicated during pregnancy (see the section “Contraindications”). When planning pregnancy or when it occurs while taking Co-Perineva®, you should immediately stop taking the drug and prescribe another antihypertensive therapy. Do not use Co-Perineva® in the first trimester of pregnancy. No controlled clinical studies have been conducted on the use of ACE inhibitors in pregnant women. Limited data indicate that taking ACE inhibitors in the first trimester did not lead to fetal malformations associated with fetotoxicity, but the fetotoxic effect of ACE inhibitors cannot be completely excluded.

Co-Perineva® is contraindicated in the second and third trimesters of pregnancy. Prolonged use of ACE inhibitors in the second and third trimesters of pregnancy can lead to impaired fetal development (decreased renal function, oligohydramnios, slowing of ossification of the skull bones) and the development of complications in the newborn (renal failure, hypotension, hyperkalemia).

Long-term use of thiazide diuretics in the third trimester of pregnancy can cause hypovolemia in the mother and a decrease in uteroplacental blood flow, which leads to fetoplacental ischemia and fetal development delay. In rare cases, the fetus/newborn may develop hypoglycemia and thrombocytopenia while taking diuretics.

If a woman has taken an ACE inhibitor in the second and third trimesters of pregnancy, an ultrasound examination of the fetal/newborn’s kidneys and skull is recommended.

Newborns whose mothers have been treated with ACE inhibitors may experience hypotension, so newborns should be under close medical supervision.

Breast-feeding period

Co-Perineva® is contraindicated during breastfeeding.

It is not known whether perindopril is excreted in breast milk.

Indapamide is excreted in breast milk. Causes a decrease or suppression of lactation. A newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia, and “nuclear” jaundice. The use of indapamide is contraindicated during breastfeeding.

If the use of Co-Perineva® is necessary, breast-feeding should be discontinued.

Contraindications

• Hypersensitivity to active substances, any ACE inhibitor, sulfonamide derivatives or any excipients of the drug.
• Angioedema (angioedema) in the anamnesis associated with taking an ACE inhibitor(see the section “Special instructions”).
• Hereditary / idiopathic angioedema.
• Hypokalemia.
• Severe renal insufficiency (creatinine clearance less than 30 ml / min).
• Refractory hyperkalemia, concomitant use with potassium-sparing diuretics, potassium and lithium preparations.
• Severe hepatic insufficiency (including encephalopathy).
• Concomitant use of drugs that prolong the QT interval on the ECG, concomitant use with drugs that can cause ventricular tachycardia of the “pirouette” type (see the section “Interaction with other drugs”).
• Concomitant use with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and / or moderate to severe renal impairment (glomerular filtration rate (GFR)
• Concomitant use with ARA II in patients with diabetic nephropathy.
• Concomitant use with neutral endopeptidase inhibitors (for example, with drugs containing sacubitril) due to a high risk of angioedema.
• Extracorporeal therapy methods that cause blood to come into contact with negatively charged surfaces.
• Severe bilateral renal artery stenosis or renal artery stenosis of the only functioning kidney.
• Due to the lack of sufficient clinical experience, Co-Perineva®should not be used in patients undergoing hemodialysis, as well as in patients with untreated heart failure in the decompensation stage.

• Pregnancy and lactation (see the section “Use during pregnancy and lactation”).

• Age up to 18 years (efficacy and safety have not been established).

· Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Side effects

Perindopril has an inhibitory effect on the RAAS and reduces the excretion of potassium ions by the kidneys against the background of taking indapamide. Hypokalemia (potassium content in blood plasma less than 3.4 mmol/l) was observed in 6% of patients treated with the combination of indapamide + perindopril at a dosage of 2.5 mg + 8 mg.

Hypokalemia develops in 4% of patients treated with the combination of indapamide + perindopril at a dosage of 1.25 mg + 4 mg and in 2% of patients treated with the combination of indapamide + perindopril at a dosage of 0.625 mg + 2 mg.

The most common side effects are:

for indapamide: hypersensitivity reactions(mainly dermatological) in patients prone to allergic bronchial obstructive reactions and maculopapular rash;

for perindopril: dizziness, headache, paresthesia, dysgeusia (dysgeusia), impaired vision, vertigo, tinnitus, hypotension, cough, shortness of breath, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, pruritus, skin rash, muscle spasms and fatigue.

Classification of the incidence of side effects recommended by the World Health Organization (WHO):

very common ≥1/10

common ≥1/100 to <1/10

uncommon ≥1/1000 to <1/100

rare ≥1/10000 to <1/1000

very rare <1/10000

frequency unknown cannot be estimated based on available data.

In each group, undesirable effects are presented in decreasing order of severity.

MedDRA Organ classes and systems	Undesirable Effects	Frequency
		Indapamide	Perindopril
Infectious and parasitic diseases	Rhinitis	–	Very rare
Disorders of the blood and lymphatic system	Eosinophilia	–	Infrequently*
	Agranulocytosis (see section “Special instructions”)	Very rare	Very rare
	Aplastic anemia	Very rare	–
	Pancytopenia	–	Very rare
	Leukopenia	Very rare	Very rare
	Neutropenia (see section “Special instructions”)	–	Very rare
	Hemolytic anemia	Very rare	Very rare
	Thrombocytopenia (see section “Special instructions”)	Very rare	Very rare
Immune system disorders	Hypersensitivity reactions, mainly dermatological, in patients predisposed to bronchoobstructive and allergic reactions	are common	–
Metabolic and nutritional disorders	Hypoglycemia (see sections “Special instructions” and “Interaction with other medicinal products”)	–	Infrequently*
	Hyperkalemia, often transient (see section “Special instructions”)	–	Infrequently*
	Hyponatremia (see section “Special instructions”)	Frequency unknown	Infrequently*
	Hypercalcemia	Very rare	–
	Hypokalemia, especially significant for patients at risk (see section “Special instructions”)	Frequency unknown	–
Mental disorders	Mood lability	–	Infrequently
	Sleep disturbance	–	Infrequently
	Confusion of consciousness	–	Very rare
Nervous system disorders	Dizziness	–	Often
	Headache	Rarely	Often
	Paresthesia	Rarely	Often
	Dysgeusia	–	Often
	Drowsiness	–	Infrequently*
	Syncope	Frequency unknown	Infrequently*
	Stroke, possibly due to excessive lowering of blood pressure in high-risk patients (see section “Special instructions”)	–	Very rare
	Possible development of hepatic encephalopathy in case of hepatic insufficiency (see sections “Contraindications” and “Special instructions”)	Frequency unknown	–
Visual disturbances	Visual impairment	Frequency unknown	Often
	Myopia (see section “Special instructions”)	Frequency unknown	–
	Blurred vision	Frequency unknown	–
Hearing disorders and labyrinth disorders	Vertigo	Rarely	Often
	Ringing in the ears	–	Often
Cardiac disorders	Palpitation sensation	–	Infrequently*
	Tachycardia	–	Infrequently*
	Angina pectoris (see section “Special instructions”)	–	Very rare
	Cardiac arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation)	Very rare	Very rare
	Myocardial infarction, possibly due to an excessive decrease in blood pressure in high-risk patients (see the section “Special instructions”)	–	Very rare
	Polymorphic ventricular tachycardia of the “pirouette” type (possibly fatal) (see sections “Special instructions” and “Interaction with other drugs”)	Frequency unknown	–
Vascular disorders	Hypotension and related symptoms (see section “Special instructions”)	Very rarely	Often
	Vasculitis	–	Infrequently*
	Raynaud	‘s Syndrome-	Frequency unknown
Respiratory, thoracic and mediastinal disorders	Cough (see section “Special instructions”)	–	Often
	Shortness	of Breath-	Often
	Bronchospasm	–	Infrequently
	Eosinophilic pneumonia	–	Very rare
Disorders of the digestive system	Abdominal Pain	–	Often
	Constipation	Rarely	Often
	Diarrhea	–	Often
	Dyspepsia	–	Often
	Nausea	Rarely	Often
	Vomiting	Infrequently	Often
	Dryness of the oral mucosa	Rarely	Infrequently
	Pancreatitis	Very rare	Very rare
Liver and biliary tract disorders	Hepatitis(see section “Special instructions”)	Frequency unknown	Very rare
	Impaired liver function	Very rare	–
Skin and subcutaneous tissue disorders	Itching	of the skin-	Often
	Skin rash	–	Often

Interaction

Common drug interactions for perindopril and indapamide

Simultaneous use is not recommended

Lithium preparations: with the simultaneous use of lithium preparations and ACE inhibitors, cases of reversible increase in the content of lithium in blood plasma and associated toxic effects have been reported. Concomitant use of thiazide diuretics may further increase the level of lithium in blood plasma and increase the risk of its toxic effect against the background of taking an ACE inhibitor.

Concomitant use of Co-Perineva® with lithium preparations is not recommended. If simultaneous use is necessary, the lithium content in the blood plasma should be carefully monitored (see the section “Special instructions”).

Concomitant use of drugs that require special attention and caution

Baclofen: may increase the antihypertensive effect. It is necessary to monitor blood pressure, renal function and, if necessary, adjust the dose of antihypertensive agents.

NSAIDs, including high doses of aspirin (3 to 3 g/day): the concurrent use of ACE inhibitors and NSAIDs (including acetylsalicylic acid in doses of anti-inflammatory action, inhibitors of cyclooxygenase-2 (COX-2) and non-selective NSAIDs) may reduce the antihypertensive effect of ACE inhibitors, increases the risk of developing renal dysfunction, including the development of ARF increases the potassium content in the blood serum, especially in patients with initially reduced renal function.

Caution should be exercised when using this combination, especially in elderly patients. Before starting treatment, patients should be compensated for fluid loss, as well as regularly monitor kidney function both at the beginning of therapy and during treatment.

Simultaneous use that requires attention

Tricyclic antidepressants, antipsychotics (neuroleptics):drugs of these classes enhance the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Drug interactions for andndapamide

Simultaneous use that requires special attention and caution

Drugs that can cause polymorphic ventricular tachycardia type “pirouette”: because there is a risk of hypokalemia, indapamide should be used with caution simultaneously with the drugs that can cause ventricular tachycardia type “pirouette”, such as antiarrhythmic agents class IA (quinidine, gedragingen, disopyramide) and class III (amiodarone, dofetilide, ibutilide, bretilia tosylate, sotalol), certain antipsychotic drugs (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide); other drugs, such as bepridil, cisapride, was diphemanil metilsulfate, erythromycin for I/o applications, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine has to/in use, methadone, astemizole, terfenadine. It is necessary to monitor the content of potassium in the blood serum in order to avoid hypokalemia, with the development of which it is necessary to correct it, monitor the QT interval on the ECG.

Medications that can cause hypokalemia: amphotericin B with intravenous use, gluco-and mineralocorticoids (with systemic use), tetracosactide, laxatives that stimulate intestinal motility, contribute to an increased risk of hypokalemia (additive effect). It is necessary to monitor the content of potassium in the blood plasma, if necessary – its correction. Special attention should be paid to patients receiving concomitant cardiac glycosides. Laxatives that do not stimulate intestinal motility should be used.

Cardiac glycosides: hypokalemia increases the toxic effect of cardiac glycosides. With simultaneous use of indapamide and cardiac glycosides, the content of potassium in the blood plasma, ECG indicators should be monitored and, if necessary, the dose of cardiac glycosides should be adjusted.

Simultaneous use that requires attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene): this combination is reasonably used in some patients. Hypokalemia or hyperkalemia may occur (especially in patients with renal insufficiency or DM). If the simultaneous use of indapamide and potassium-sparing diuretics is necessary, monitoring of the potassium content in the blood plasma and ECG parameters should be carried out. If necessary, the treatment regimen can be revised.

Metformin:functional renal failure when taking diuretics, especially “loop” diuretics, when used simultaneously with metformin, the risk of developing lactic acidosis increases. Metformin should not be used if the plasma creatinine concentration exceeds 15 mg / l (135 mmol/l) in men and 12 mg/l (110 mmol/l) for women.

Iodine-containing contrast agents: patients with hypovolemia who are treated with diuretics have an increased risk of developing acute renal failure, especially when using contrast agents containing high doses of iodine. Before using iodine-containing contrast media, the BCC should be filled in.

Preparations containing calcium salts: with simultaneous use, hypercalcemia may develop due to a decrease in the excretion of calcium by the kidneys.

Cyclosporine, tacrolimus: it is possible to increase the concentration of creatinine in blood plasma without changing the concentration of cyclosporine in blood plasma, even in the absence of pronounced loss of sodium ions and dehydration.

Glucocorticosteroids (corticosteroids), tetracosactide (with systemic use): reduced antihypertensive effect (fluid retention and sodium ions as a result of the action of corticosteroids).

Drug interactions for perindopril

Data from clinical studies show that double blockade of the RAAS as a result of simultaneous use of ACE inhibitors, ARA II or aliskiren leads to an increased incidence of adverse events such as hypotension, hyperkalemia and impaired renal function (including acute renal failure), compared with situations when only one drug is used that affects the RAAS (see the sections ” Pharmacological properties. Pharmacodynamics”, “Contraindications” and “Special instructions”).

Medications that cause hyperkalemia

Certain medications or classes of medications may increase the incidence of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, ARA II, NSAIDs, heparins, immunosuppressants (such as cyclosporine or tacrolimus), medications containing trimethoprim, including a fixed combination of trimethoprim and sulfomethoxazole.

The combination of these medications increases the risk of hyperkalemia.

Simultaneous use is contraindicated

Aliskiren and drugs containing aliskiren: concomitant use of ACE inhibitors with aliskiren or drugs containing aliskiren in patients with SDi/or with moderate to severe renal impairment (GFR

The risk of hyperkalemia, deterioration of kidney function, cardiovascular morbidity and mortality increases.

Extracorporeal therapy: extracorporeal therapies that cause blood to come into contact with negatively charged surfaces, such as hemodialysis or hemofiltration using high-flow membranes(for example, polyacrylonitrile membranes) and LDL apheresis using dextran sulfate, are contraindicated due to the increased risk of anaphylactoid reactions. If such treatment is necessary, a different type of membrane should be used or a hypotensive drug of a different pharmacotherapeutic group should be used.

Neutral endopeptidase inhibitors: concomitant use of ACE inhibitors with drugs containing sacubitril (a neprilysin inhibitor) increases the risk of angioedema, and therefore the concomitant use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. It is contraindicated to prescribe drugs containing sacubitril to patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Simultaneous use is not recommended

Aliskiren: in patients without DM or impaired renal function (GFR

Couse of ACE inhibitors and ARA II: according to available literature data, patients with established atherosclerotic disease, heart failure or diabetes with lesions of target organs concomitant use of ACE inhibitors and ARA II leads to an increase in the frequency of hypotension, syncope, hyperkalemia, and renal dysfunction (including OPN), compared to situations in which uses only one drug acting on the RAAS. The use of double blockade of the RAAS (for example, simultaneous use of ACE inhibitors and ARA II) should be limited to isolated cases with strict monitoring of renal function, blood potassium content (see the section “Special instructions”).

Estramustin: concomitant use may lead to an increased risk of side effects, such as angioedema.

Potassium-sparing diuretics (spironolactone, triamterene), potassium preparations or potassium-containing salt substitutes:Usually, the serum potassium level remains within the normal range, but hyperkalemia may occur in some patients taking perindopril. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium preparations, or potassium-containing salt substitutes can cause significant increases in serum potassium. Caution should also be exercised when using perindopril concomitantly with other drugs that increase the content of potassium in the blood serum, such as trimethoprim and co-trimoxazole (trimethoprim + sulfamethoxazole), since trimethoprim is known to act like a potassium – sparing diuretic-amiloride. Therefore, the simultaneous use of perindopril with the above drugs is not recommended. If simultaneous use is necessary due to hypokalemia, caution should be exercised and the serum potassium content and ECG should be regularly monitored.

Co-trimoxazole (trimethoprim + sulfamethoxazole): concomitant use with ACE inhibitors may increase the risk of hyperkalemia.

Simultaneous use that requires special attention

Hypoglycemic agents for oral use (sulfonylurea derivatives) and insulin: epidemiological studies have shown that the combined use of ACE inhibitors and hypoglycemic agents (insulin, hypoglycemic agents for oral use) can increase the hypoglycemic effect of insulin and hypoglycemic agents for oral use up to the development of hypoglycemia. This effect is most likely observed during the first weeks of concomitant therapy, as well as in patients with impaired renal function.

Potassium-sparing diuretics: patients receiving diuretics, especially those with hypovolemia and/or reduced salt concentrations, may experience a marked decrease in blood pressure at the start of ACE inhibitor therapy. The risk of developing hypotension can be reduced by discontinuing the diuretic, replacing fluid or salt loss before starting perindopril therapy, and prescribing perindopril at a low dose with a further gradual increase.

If hypertension occurs in patients with hypovolemia or reduced salt concentrations during diuretic therapy, the diuretic should be discontinued before starting the use of an ACE inhibitor (in this case, a potassium-sparing diuretic may be re-prescribed later), or the ACE inhibitor should be prescribed at a low dose with a further gradual increase.

When using diuretics in patients with CHF, an ACE inhibitor should be prescribed at a very low dose, possibly after reducing the dose of a concomitant potassium-sparing diuretic.

In all cases, monitoring of renal function (plasma creatinine concentrations) is necessary during the first weeks of ACE inhibitor therapy.

Potassium-sparing diuretics (eplerenone, spironolactone):when using eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day and low doses of ACE inhibitors in the treatment of CHF of NYHA functional class II-IV with left ventricular ejection fraction

Before using this combination of medications, it is necessary to make sure that there is no hyperkalemia and impaired renal function.

It is recommended to regularly monitor the concentration of creatinine and potassium in the blood plasma: weekly in the first month of treatment and monthly thereafter.

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

mTOR inhibitors (for example, sirolimus, everolimus, temsirolimus): when used concomitantly with mTOR inhibitors, therapy may be associated with an increased risk of angioedema.

Tissue plasminogen activators: observational studies have revealed an increased incidence of angioedema in patients treated with ACE inhibitors after the use of alteplase for thrombolytic therapy of ischemic stroke.

Simultaneous use that requires attention

Antihypertensive agents and vasodilators: concomitant use of these drugs may increase the antihypertensive effect of perindopril.

Allopurinol, cytostatic and immunosuppressive agents, corticosteroids (with systemic use) and procainamide: concomitant use with ACE inhibitors may increase the risk of leukopenia.

Drugs for general anesthesia: the use of ACE inhibitors can lead to an increase in the hypotensive effect of a number of drugs for general anesthesia.

Gold preparations: with the simultaneous use of ACE inhibitors, including perindopril, and intravenous use of the drug gold (sodium aurothiomalate), a symptom complex is described, including hyperemia of the facial skin, nausea, vomiting and a pronounced decrease in blood pressure.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): when used concomitantly with ACE inhibitors, the risk of angioedema increases due to the suppression of dipeptidyl peptidase-4 (DPP-4) activity by gliptin.

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 potassium content in the blood serum.

Heparin: concomitant use with ACE inhibitors may increase the risk of hyperkalemia. It is recommended to monitor the potassium content in the blood serum.

How to take, course of use and dosage

Inside,1 time a day, preferably in the morning hours before breakfast, with a sufficient amount of liquid.

If possible, the use of Co-Perineva® should begin with the selection of doses of single-component drugs. If clinically necessary, it is possible to prescribe combination therapy with Co-Perineva® immediately after monotherapy with one of the components of the drug (perindopril and indapamide).

Doses are given for the indapamide/perindopril ratio.

The initial dose is 1 tablet of Co-Perineva® (0.625 mg + 2 mg) once a day. If after 1 month of taking the drug it is not possible to achieve adequate blood pressure control, the dose of the drug should be increased to 1 tablet of Co-Perineva® (1.25 mg + 4 mg) once a day.

If necessary, to achieve a more pronounced antihypertensive effect, it is possible to increase the dose of the drug to the maximum daily dose of Co-Perineva® – 1 tablet (2.5 mg + 8 mg) once a day.

Elderly patients

The initial dose is 1 tablet of 0.625 mg + 2 mg of Co-Perineva® once a day. Start therapy with the drug should be under the control of renal function and blood pressure.

Patients with impaired renal function

Ko-Perineva® is contraindicated in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min) (see section “Contraindications”).

Patients with moderate renal insufficiency (creatinine clearance 30-60 ml/min) are recommended to start therapy with the necessary doses of drugs (in monotherapy) that are part of the drug Co-Perineva®.

The maximum daily dose of Co-Perineva® is -1.25 mg + 4 mg.

No dose adjustment is required in patients with CC3 of 60 ml / min. During therapy, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood serum.

Patients with impaired liver function

The drug is contraindicated in patients with severe hepatic insufficiency. section “Contraindications”).

No dose adjustment is required for moderate hepatic insufficiency.

Children and teenagers

Ko-Perineva® should not be used in children and adolescents under 18 years of age, as data on efficacy and safety are insufficient (see the section “Contraindications”).

Overdose

Symptoms: marked decrease in blood pressure, nausea, vomiting, muscle cramps, dizziness, drowsiness, confusion, oliguria up to anuria (due to a decrease in BCC), possible violations of the water-electrolyte balance (low content of sodium and potassium in blood plasma).

Treatment: gastric lavage and / or use of activated charcoal, restoration of water and electrolyte balance in a hospital setting. With a pronounced decrease in blood pressure, it is necessary to transfer the patient to the “lying” position on his back with his legs raised up, then measures should be taken to increase the BCC (use of 0.9% sodium chloride solution intravenously (iv)). Perindoprilate, the active metabolite of perindopril, can be eliminated from the body by dialysis.

Description

Tablets 0.625 mg + 2 mg:

Round, biconvex tablets of white or almost white color with a chamfer, a short line is engraved on one side.

Tablets 1.25 mg + 4 mg:

Round, biconvex tablets of white or almost white color, with a risk on one side and a chamfer.

2.5 mg + 8 mg tablets:

Round, biconvex tablets of white or almost white color, with a risk on one side.

Special instructions

Systemic connective tissue diseases (including systemic lupus erythematosus (SLE), scleroderma), immunosuppressant therapy (risk of neutropenia, agranulocytosis), inhibition of bone marrow hematopoiesis, reduced circulating blood volume (BCC) (diuretics, diet with salt restriction, vomiting, diarrhea, hemodialysis), coronary heart disease, cerebrovascular diseases, impaired liver and kidney function, renovascular hypertension, DM, chronic heart failure (CHF) (NYHA functional class IV), hyperuricemia (especially accompanied by gout and urate nephrolithiasis), blood pressure lability, use in elderly patients, black race, athletes (possible positive reaction during doping control), simultaneous desensitizing therapy with allergens (for example, hymenopteran venom), condition after kidney transplantation, stenosis aortic and/or mitral valve disease, hypertrophic obstructive cardiomyopathy (HOCMP), atherosclerosis, bilateral renal artery stenosis, the presence of only one functioning kidney, concomitant therapy with potassium-sparing diuretics, potassium preparations or in patients with increased potassium content in blood plasma, concomitant use with lithium, gold, nonsteroidal anti-inflammatory drugs (NSAIDs), baclofen, corticosteroids, drugs that can be used in combination with other drugs. drugs that can cause prolongation of the QT interval, drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type, except for non-antiarrhythmic drugs (see the section “Contraindications”).

Ko-Perineva® should not be used in children and adolescents under 18 years of age, as data on efficacy and safety are insufficient.

Elderly patients

Renal function and plasma potassium levels should be evaluated before starting Co-Perineva. The initial dose of Co-Perineva® is selected depending on the degree of blood pressure reduction, especially with a decrease in BCC and loss of electrolytes. Such measures can avoid a sharp decrease in blood pressure.

The initial dose is 1 tablet of 0.625 mg + 2 mg of Co-Perineva® once a day. Start therapy with the drug should be under the control of renal function and blood pressure.

Patients with impaired renal function

Ko-Perineva® is contraindicated in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min) (see section “Contraindications”).

Patients with moderate renal insufficiency (creatinine clearance 30-60 ml/min) are recommended to start therapy with the necessary doses of drugs (in monotherapy) that are part of the drug Co-Perineva®.

The maximum daily dose of Co-Perineva® is 1.25 mg + 4 mg.

No dose adjustment is required in patients with CC3 of 60 ml / min. During therapy, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood serum.

Patients with impaired liver function

The drug is contraindicated in patients with severe hepatic insufficiency (see the section “Contraindications”).

No dose adjustment is required for moderate hepatic insufficiency.

Atherosclerosis

The risk of hypotension exists in all patients, but special care should be taken when using Co-Perineva® in patients with coronary heart disease and cerebral circulatory insufficiency. In such patients, treatment should begin with a dose of Co-Perineva ® 0.625 mg + 2 mg (initial dose).

Diabetes mellitus

In patients with type 1 diabetes mellitus (risk of spontaneous increase of potassium content in blood plasma), treatment should be started with a low dose of the drug and under close medical supervision.

During the first month of ACE inhibitor therapy, the plasma glucose concentration should be carefully monitored in patients with DM treated with hypoglycemic drugs for oral use or insulin.

Ko-Perineva®

Lithium preparations

Concomitant use of Co-Perineva® with lithium preparations is not recommended (see section “Interaction with other medicinal products”).

Impaired renal function

Co-Perineva is contraindicated in patients with severe renal insufficiency (creatinine clearance < 30 ml / min). Laboratory signs of functional renal failure may occur in some patients with arterial hypertension without previous renal impairment during Co-Perineva therapy. In this case, treatment with Co-Perineva should be discontinued. In the future, you can resume combination therapy using low doses of Co-Perineva®, or using perindopril and indapamide in monotherapy.

These patients need regular monitoring of serum potassium and creatinine levels 2 weeks after starting therapy and every subsequent 2 months of therapy with Co-Perineva®.

Renal failure is more common in patients with severe CHF or underlying renal dysfunction, including renal artery stenosis.

Arterial hypotension and impaired water-electrolyte balance

In the case of initial hyponatremia, there is a risk of a sudden decrease in blood pressure (especially in patients with renal artery stenosis). Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and a decrease in the content of electrolytes in the blood plasma, for example, after prolonged diarrhea or vomiting. Such patients need regular monitoring of electrolytes in the blood plasma.

With a pronounced decrease in blood pressure, an intravenous injection of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for further continuation of therapy. After recovery of BCC and blood pressure, you can resume therapy with Co-Perineva®, using low doses of the drug, or using perindopril and indapamide in monotherapy.

Potassium content

The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes or renal insufficiency. As with the combined use of other antihypertensive agents and a diuretic, regular monitoring of the potassium content in the blood plasma is necessary.

Information on excipients

It should be taken into account that the excipients of Co-Perineva®include lactose monohydrate, so the drug is contraindicated in patients with lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome (see the section “Contraindications”).

Children and teenagers

The use of Co-Perineva in children and adolescents under 18 years of age is contraindicated due to the lack of data on the efficacy and safety of perindopril and indapamide, both in monotherapy and combined use in patients of this age group.

Indapamide

Hepatic encephalopathy

In the presence of impaired liver function, taking thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, you should immediately stop taking Co-Perineva®.

Photosensitivity

Increased photosensitivity has been reported with thiazide and thiazide-like diuretics. If a photosensitivity reaction develops while taking Co-Perineva®, treatment should be discontinued. If it is necessary to resume the use of Co-Perineva®, it is necessary to protect exposed areas of the skin from direct exposure to sunlight and artificial ultraviolet rays.

Water-electrolyte balance

Blood plasma sodium content

Before starting treatment with Co-Perineva®, it is necessary to determine the sodium content in the blood plasma, and then regularly monitor it against the background of taking the drug. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium content is indicated in elderly patients and patients with cirrhosis of the liver. Treatment with any diuretics can cause hyponatremia, sometimes leading to serious complications. Hyponatremia, accompanied by hypovolemia, can lead to the development of dehydration and orthostatic hypotension. A simultaneous decrease in the content of chlorine ions can lead to the development of secondary compensatory metabolic alkalosis: its frequency and severity are insignificant.

Potassium content in blood plasma

Therapy with thiazide and thiazide-like diuretics is associated with the risk of hypokalemia. Hypokalemia (less than 3.4 mmol) should be avoided. /k) in the following categories of high-risk patients: elderly patients, emaciated patients (both receiving and not receiving concomitant drug therapy), patients with cirrhosis of the liver (with edema and ascites), coronary heart disease, CHF. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of arrhythmia.

The increased risk group includes patients with an extended QT interval on the ECG, both congenital and caused by the action of drugs.

Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially pirouette-type arrhythmias, which can be fatal. In all these cases, regular monitoring of the potassium content in the blood plasma is necessary. The first determination of the potassium content in the blood plasma should be carried out within the first week after the start of therapy with Co-Perineva®.

Blood plasma calcium content

Thiazide and thiazide-like diuretics can reduce the excretion of calcium by the kidneys, leading to a slight and temporary increase in the content of calcium in the blood plasma. Severe hypercalcemia may be a consequence of latent hyperparathyroidism. Before studying the function of the parathyroid glands, you should stop taking diuretics.

Concentration of glucose in blood plasma

Glucose concentration should be monitored in patients with DM, especially in the presence of hypokalemia.

Uric acid

In patients with elevated uric acid concentrations in the blood plasma, the frequency of gout attacks may increase during therapy.

Diuretics and renal function

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine concentrations in adult patients below 25 mg / l or 220 mmol/l). In elderly patients, the standard indicator of creatinine concentration in blood plasma should be adjusted for age, weight and gender, in accordance with the Cockcroft formula:

KK = (140 – age) x weight/0.814 x plasma creatinine concentration,

where: age is indicated in years, weight – in kg, creatinine concentration – in mmol/l.

For women, this formula should be adjusted by multiplying the result by a factor of 0.85.

At the beginning of treatment with diuretics, patients may experience a temporary decrease in GFR and an increase in plasma creatinine and urea concentrations due to hypovolemia and hyponatremia. This transient functional renal insufficiency is not dangerous for patients with unchanged renal function, but its severity may increase in patients with renal insufficiency.

Athletes

Indapamide can give a positive reaction during doping control.

Acute myopia and secondary acute angle-closure glaucoma

Sulfonamides and their derivatives can cause an idiosyncratic reaction, leading to the development of acute transient myopia and an acute attack of angle-closure glaucoma. If left untreated, an acute attack of angle-closure glaucoma can lead to permanent vision loss. First of all, it is necessary to stop taking the drug as soon as possible. If intraocular pressure remains uncontrolled, urgent medical treatment or surgery may be required. Risk factors for developing an acute attack of angle-closure glaucoma include a history of allergic reactions to sulfonamide derivatives and penicillins.

Perindopril

Double blockade of the RAAS

There is evidence of an increased risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure) with concomitant use of ACE inhibitors and ARA II or aliskiren. Therefore, double blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended (see the sections ” Pharmacological properties. Pharmacodynamics” and “Interaction with other drugs”). If a double blockade is necessary, it should be performed under the strict supervision of a specialist with regular monitoring of kidney function, blood plasma potassium and blood pressure. Concomitant use with aliskiren or drugs containing aliskiren in patients with DM and / or moderate to severe renal impairment (GFR

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

Potassium-sparing diuretics, potassium supplements, and potassium-containing salt substitutes

Usually, the serum potassium level remains within the normal range, but hyperkalemia may occur in some patients taking perindopril. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium preparations, or potassium-containing salt substitutes can cause significant increases in serum potassium. Caution should also be exercised when using perindopril concomitantly with other drugs that increase the content of potassium in the blood serum, such as trimethoprim and co-trimoxazole (trimethoprim + sulfamethoxazole), since trimethoprim is known to act like a potassium– sparing diuretic-amiloride. Therefore, the simultaneous use of perindopril with the above drugs is not recommended. If concomitant use is necessary, caution should be exercised and the potassium content in the blood plasma should be regularly monitored.

Neutropenia/agranulocytosis / thrombocytopenia/anemia

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported with ACE inhibitors. In patients with normal renal function and without concomitant risk factors, neutropenia rarely develops and resolves on its own after discontinuation of ACE inhibitors. Perindopril should be used with extreme caution in patients with systemic connective tissue diseases (including SLE, scleroderma), as well as when taking immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function. These patients may develop severe infections that do not respond to intensive antibiotic therapy. In the case of prescribing perindopril, it is recommended to periodically monitor the number of white blood cells in the blood. The patient should be warned that if there are any signs of an infectious disease (sore throat, fever), it is necessary to immediately consult a doctor.

Hypersensitivity/angioedema

When taking ACE inhibitors, including perindopril, in rare cases, angioedema of the face, limbs, lips, tongue, vocal folds and/or larynx may develop. This can happen during any period of therapy. If these symptoms occur, Co-Perineva should be discontinued immediately and the patient should be monitored until the signs of edema disappear completely. If the swelling affects only the face and lips, then its manifestations usually go away on their own or antihistamines can be used to treat its symptoms. Angioedema, accompanied by swelling of the tongue or larynx, can lead to airway obstruction and death. If such symptoms occur, epinephrine (epinephrine) should be immediately administered subcutaneously in a 1:1000 dilution (0.3 ml or 0.5 ml) and / or airway patency should be ensured.

A higher risk of angioedema has been reported in black patients.

Patients who have a history of angioedema that is not associated with ACE inhibitors may have an increased risk of developing angioedema when taking drugs in this group (see the section “Contraindications”).

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. At the same time, patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal C-1 esterase activity. The diagnosis is established by computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. In patients with abdominal pain treated with ACE inhibitors, the differential diagnosis should take into account the possibility of developing angioedema of the intestine.

mTOR inhibitors

In patients taking concomitant mTOR inhibitors (e. g., sirolimus, everolimus, temsirolimus), therapy may be associated with an increased risk of angioedema (e. g., upper respiratory tract or tongue edema with / without respiratory disorders).

Tissue plasminogen activators: observational studies have revealed an increased incidence of angioedema in patients treated with ACE inhibitors after the use of alteplase for thrombolytic therapy of ischemic stroke.

Neutral endopeptidase inhibitors: concomitant use of ACE inhibitors with drugs containing sacubitril (a neprilysin inhibitor) increases the risk of angioedema, and therefore the concomitant use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. It is contraindicated to prescribe drugs containing sacubitril to patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Anaphylactoid reactions during desensitization procedures

There are isolated reports of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenopteran venom (bees, wasps). ACE inhibitors should be used with caution in patients with a severe allergic history or prone to allergic reactions, undergoing desensitization procedures. The use of an ACE inhibitor should be avoided in patients receiving hymenopteran venom immunotherapy. However, the development of anaphylactoid reactions can be avoided by temporarily stopping the ACE inhibitor at least 24 hours before the start of the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

In rare cases, patients receiving ACE inhibitors have experienced life-threatening anaphylactoid reactions during LDL apheresis using dextran sulfate.To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each apheresis procedure.

Hemodialysis

Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flow membranes (for example, AN69®). Therefore, it is advisable to use a different type of membrane or use a hypotensive drug of a different pharmacotherapeutic group.

Primary aldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that inhibit RAAS, so the use of perindopril is not recommended.

Cough

Against the background of therapy with an ACE inhibitor, a dry persistent cough may occur, which disappears after the withdrawal of drugs of this group. If a dry cough occurs, you should be aware of the possible association of this symptom with taking an ACE inhibitor. If the doctor considers that ACE inhibitor therapy is necessary for the patient, Co-Perineva may be continued.

Risk of arterial hypotension and / or renal failure (in patients with CHF, impaired water-electrolyte balance, etc. )

In some pathological conditions, significant activation of the RAAS may occur, especially with severe hypovolemia and a decrease in the content of electrolytes in blood plasma (against the background of a salt-free diet or long-term use of diuretics), arterial hypotension, renal artery stenosis, CHF, or cirrhosis of the liver with edema and ascites.

The use of an ACE inhibitor causes blockade of the RAAS, and therefore a sharp decrease in blood pressure and/or an increase in the concentration of creatinine in blood plasma is possible, indicating the development of functional renal failure, which is more often observed with the first dose of Co-Perineva® or during the first two weeks of therapy.

Elderly patients

Renal function and plasma potassium levels should be evaluated before starting Co-Perineva. The initial dose of Co-Perineva® is selected depending on the degree of blood pressure reduction, especially with a decrease in BCC and loss of electrolytes. Such measures can avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of hypotension exists in all patients, but special care should be taken when using Co-Perineva® in patients with coronary heart disease and cerebral circulatory insufficiency. In such patients, treatment should begin with a dose of Co-Perineva ® 0.625 mg + 2 mg (initial dose).

Form of production

Care should be taken when driving vehicles and other technical devices that require increased attention and speed of psychomotor reactions.

Storage conditions

At a temperature not exceeding 25 °C, in the original contour cell packaging.

Keep out of reach of children.

Shelf

life is 3 years.

Do not use the drug after the expiration date.

Active ingredient

Indapamide, Perindopril

Conditions of release from pharmacies

By prescription

Dosage form

Tablets