Co-Perineva, tablets 1, 25+4 mg 90 pcs

hypotensive combination drug (diuretic + angiotensin-converting enzyme inhibitor)

Indications

Essential hypertension.

Pharmacological effect

antihypertensive combination drug (diuretic + angiotensin-converting enzyme inhibitor)

Special instructions

Systemic connective tissue diseases (including systemic lupus erythematosus (SLE), scleroderma), immunosuppressant therapy (risk of developing neutropenia, agranulocytosis), inhibition of bone marrow hematopoiesis, reduced circulating blood volume (CBV) (taking diuretics, diet with limited salt, vomiting, diarrhea, hemodialysis), coronary heart disease, cerebrovascular diseases, impaired liver and kidney function, renovascular hypertension, diabetes, chronic heart failure (CHF) (IV functional class according to the NYHA classification), hyperuricemia (especially accompanied by gout and urate nephrolithiasis), blood pressure lability, use in elderly patients, blacks, athletes (possible positive reaction during doping control), simultaneous use desensitizing therapy with allergens (for example, hymenoptera venom), the condition after kidney transplantation, stenosis of the aortic and/or mitral valve, hypertrophic obstructive cardiomyopathy (HOCM), atherosclerosis, bilateral renal artery stenosis, the presence of only one functioning kidney, simultaneous therapy with potassium-sparing diuretics, potassium preparations or in patients with increased levels of potassium in the blood plasma, simultaneous use with lithium, gold, non-steroidal anti-inflammatory drugs (NSAIDs), baclofen, corticosteroids, 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. section “Contraindications”).

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

Elderly patients

Before starting to take Co-Perineva®, renal function and potassium levels in the blood plasma should be assessed. The initial dose of Co-Perineva® is selected depending on the degree of blood pressure reduction, especially with a decrease in blood volume and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.

The initial dose is 1 tablet of 0.625 mg + 2 mg of Co-Perineva® 1 time per day. Therapy with the drug should be started under monitoring of renal function and blood pressure.

Patients with impaired renal function

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

Patients with moderately severe renal failure (creatinine clearance 30-60 ml/min) are recommended to begin therapy with the required doses of drugs (in monotherapy) included in the drug Co-Perineva®.

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

Patients with CC³ 60 ml/min do not require dose adjustment. During therapy, it is necessary to regularly monitor the concentration of creatinine and potassium levels in the blood serum.

Patients with liver dysfunction

The drug is contraindicated in patients with severe liver failure (see section “Contraindications”).

For moderately severe liver failure, no dose adjustment is required.

Atherosclerosis

The risk of arterial hypotension exists in all patients, however, special caution should be observed when using Co-Perineva® in patients with coronary heart disease and cerebrovascular 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 a spontaneous increase in potassium levels in the blood plasma), treatment should begin with a low dose of the drug and under close medical supervision.

During the first month of therapy with ACE inhibitors, plasma glucose concentrations should be carefully monitored in patients with diabetes treated with oral hypoglycemic agents or insulin.

Ko-Perineva®

Lithium preparations

The simultaneous use of Co-Perineva® with lithium preparations is not recommended (see section “Interaction with other drugs”).

Renal dysfunction

Therapy with Co-Perineva® is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with arterial hypertension without previous renal impairment, laboratory signs of functional renal failure may appear during therapy with Co-Perineva®. 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.

Such patients require regular monitoring of potassium levels and creatinine concentrations in the blood serum 2 weeks after the start of therapy and every subsequent 2 months of therapy with Co-Perineva®.

Renal failure often develops in patients with severe CHF or underlying renal impairment, including renal artery stenosis.

Arterial hypotension and water-electrolyte imbalance

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 plasma electrolytes, for example, after prolonged diarrhea or vomiting. Such patients require regular monitoring of plasma electrolytes.

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

Transient arterial hypotension is not a contraindication for further continuation of therapy. After restoration of blood volume 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 failure. As with the combined use of other antihypertensive drugs and a diuretic, regular monitoring of potassium levels in the blood plasma is necessary.

Information on excipients

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

Children and teenagers

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

Indapamide

Hepatic encephalopathy

In the presence of liver dysfunction, 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

There are reports of cases of increased photosensitivity while taking thiazide and thiazide-like diuretics. If a photosensitivity reaction develops while taking Co-Perineva®, treatment should be discontinued. If there is a need to resume use of the drug Co-Perineva®, you should protect exposed skin from direct exposure to sunlight and artificial ultraviolet rays.

Water and electrolyte balance

Sodium content in blood plasma

Before starting treatment with Co-Perineva®, it is necessary to determine the sodium content in the blood plasma, and then regularly monitor it while 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 levels is indicated in elderly patients and patients with cirrhosis. Treatment with any diuretics can cause hyponatremia, sometimes leading to serious complications. Hyponatremia accompanied by hypovolemia can lead to dehydration and orthostatic hypotension. A simultaneous decrease in the content of chlorine ions can lead to the development of secondary compensatory metabolic alkalosis: the frequency of its occurrence and severity are insignificant.

Potassium content in blood plasma

Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. It is necessary to avoid hypokalemia (less than 3.4 mmol/l) in the following categories of high-risk patients: elderly patients, malnourished patients (both those receiving and not receiving concomitant drug therapy), patients with liver cirrhosis (with edema and ascites), coronary heart disease, CHF. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of developing arrhythmia.

A high-risk group includes patients with a prolonged QT interval on the ECG, both congenital and drug-induced.

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

Calcium content in blood plasma

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

Plasma glucose concentration

Glucose concentrations should be monitored in patients with diabetes, especially in the presence of hypokalemia.

Uric acid

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

Diuretics and kidney function

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

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

where: age is indicated in years, weight – in kg, creatinine concentration – in µmol/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 failure is not dangerous for patients with unchanged renal function, but its severity may increase in patients with renal failure.

Athletes

Indapamide may 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 quickly as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for the development of an acute attack of angle-closure glaucoma are a history of allergic reactions to sulfonamide derivatives and penicillins.

Perindopril

Double blockade of the RAAS

There is evidence of an increased risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure) with simultaneous use of ACE inhibitors and ARB II or aliskiren. Therefore, double blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended (see sections “Pharmacological properties. Pharmacodynamics” and “Interaction with other drugs”). If a double blockade is necessary, then this should be performed under the strict supervision of a specialist with regular monitoring of kidney function, potassium levels in the blood plasma and blood pressure. Concomitant use with aliskiren or drugs containing aliskiren in patients with diabetes and/or moderate or severe renal impairment (GFR < 60 ml/min/1.73 m2 body surface area) is contraindicated and is not recommended in other patients.

Concomitant use of ACE inhibitors with ARB 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 serum potassium levels remain within normal limits, but hyperkalemia may occur in some patients taking perindopril. Potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels. Caution should also be exercised when using perindopril concomitantly with other drugs that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim + sulfamethoxazole), since trimethoprim is known to act similarly to the potassium-sparing diuretic amiloride. Therefore, simultaneous use of perindopril with the above drugs is not recommended. If simultaneous use is necessary, caution should be exercised and plasma potassium levels should be regularly monitored.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

There are reports of the development of neutropenia/agranulocytosis, thrombocytopenia and anemia during the use of ACE inhibitors. In patients with normal renal function and without concomitant risk factors, neutropenia rarely develops and goes away 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 while 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. If perindopril is prescribed, it is recommended to periodically monitor the number of leukocytes in the blood. The patient should be warned that if any signs of an infectious disease appear (sore throat, fever), consult a doctor immediately.

Hypersensitivity/angioedema

When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may occur. This can happen at any time during therapy. If these symptoms occur, Co-Perineva® should be stopped immediately and the patient should be observed until signs of swelling have completely disappeared. If the swelling affects only the face and lips, it usually goes away on its 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 appear, epinephrine (adrenaline) at a dilution of 1:1000 (0.3 ml or 0.5 ml) should be immediately administered subcutaneously and/or the airway should be secured.

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

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

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience 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 made using computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after stopping ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of developing angioedema of the intestine must be taken into account when making a differential diagnosis.

mTOR inhibitors

In patients concomitantly taking mTOR inhibitors (eg, sirolimus, everolimus, temsirolimus), therapy may be associated with an increased risk of angioedema (eg, swelling of the upper respiratory tract or tongue with or without respiratory distress).

Tissue plasminogen activators: Observational studies have shown an increased incidence of angioedema in patients taking ACE inhibitors following the use of alteplase for thrombolytic therapy of ischemic stroke.

Neutral endopeptidase inhibitors: when ACE inhibitors are used simultaneously with drugs containing sacubitril (neprilysin inhibitor), the risk of developing angioedema increases, and therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. Prescription of drugs containing sacubitril is contraindicated in 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 the development of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (bees, wasps). ACE inhibitors should be used with caution in patients with a history of allergies or those prone to allergic reactions undergoing desensitization procedures. The use of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, the development of anaphylactoid reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the start of the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions have developed in patients receiving ACE inhibitors 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-flux membranes (eg, AN69®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.

Primary aldosteronism

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

Cough

During therapy with an ACE inhibitor, a dry persistent cough may occur, which disappears after discontinuation of drugs from this group. If a dry cough appears, you should be aware of the possible connection of this symptom with taking an ACE inhibitor. If the doctor believes that ACE inhibitor therapy is necessary for the patient, taking Co-Perineva® can be continued.

Risk of arterial hypotension and/or renal failure (in patients with CHF, fluid and electrolyte imbalance, etc.)

In some pathological conditions, significant activation of the RAAS may be observed, especially with severe hypovolemia and a decrease in the content of electrolytes in the blood plasma (due to 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 the blood plasma is possible, indicating the development of functional renal failure, which is more often observed when taking the first dose of Co-Perineva® or during the first two weeks of therapy.

Elderly patients

Before starting to take Co-Perineva®, renal function and potassium levels in the blood plasma should be assessed. The initial dose of Co-Perineva® is selected depending on the degree of blood pressure reduction, especially with a decrease in blood volume and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of arterial hypotension exists in all patients, however, special caution should be observed when using Co-Perineva® in patients with coronary heart disease and cerebrovascular insufficiency. In such patients, treatment should begin with a dose of Co-Perineva® 0.625 mg + 2 mg (initial dose).

Active ingredient

Indapamide, Perindopril

Composition

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 erbumine K, semi-finished granules 37.515 mg/75.030 mg/150.060 mg

[Active ingredient of the semi-finished granule product:

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

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

Excipients: 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 erbumine 2,000 mg/4,000 mg/8,000 mg

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

Pregnancy

Pregnancy

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

The drug Co-Perineva® is contraindicated in the second and third trimesters of pregnancy. Long-term use of ACE inhibitors in the second and third trimesters of pregnancy can lead to impaired fetal development (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial 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 growth retardation. In rare cases, while taking diuretics, hypoglycemia and thrombocytopenia may develop in the fetus/newborn.

If a woman took an ACE inhibitor in the second and third trimesters of pregnancy, it is recommended to conduct an ultrasound examination of the kidneys and skull of the fetus/newborn.

In newborns whose mothers received therapy with ACE inhibitors, arterial hypotension may occur, so newborns should be under close medical supervision.

Breastfeeding period

The drug 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. The newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia and nuclear jaundice. The use of indapamide is contraindicated during breastfeeding.

If it is necessary to use the drug Co-Perineva®, breastfeeding should be stopped.

Contraindications

Hypersensitivity to the active substances, any ACE inhibitor, sulfonamide derivatives or any excipients of the drug.
History of angioedema (Quincke’s edema) associated with taking an ACE inhibitor (see section “Special instructions”).
Hereditary/idiopathic angioedema.
Hypokalemia.
Severe renal failure (creatinine clearance less than 30 ml/min).
Refractory hyperkalemia, simultaneous use with potassium-sparing diuretics, potassium and lithium preparations.
Severe liver failure (including encephalopathy).
Simultaneous use of drugs that prolong the QT interval on the ECG, simultaneous use with drugs that can cause ventricular tachycardia of the “pirouette” type (see section “Interaction with other drugs”).
Concomitant use with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and/or with moderate or severe renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2 body surface area). Concomitant use with ARA II in patients with diabetic nephropathy. Concomitant use with neutral endopeptidase inhibitors (for example, with drugs containing sacubitril) due to the high risk of developing angioedema. Extracorporeal therapy methods that bring blood into contact with negatively charged surfaces. Severe bilateral renal artery stenosis or renal artery stenosis of a single functioning kidney. Due to the lack of sufficient clinical experience, Co-Perineva® should not be used in patients on hemodialysis, as well as in patients with untreated heart failure in the stage of decompensation. Pregnancy and breastfeeding (see section “Use during pregnancy and breastfeeding”). 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 while taking indapamide. In 6% of patients using the combination of indapamide + perindopril at a dosage of 2.5 mg + 8 mg, the development of hypokalemia (potassium content in blood plasma less than 3.4 mmol/l) was noted.

Hypokalemia develops in 4% of patients when using the combination of indapamide + perindopril at a dosage of 1.25 mg + 4 mg and in 2% of patients when using 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 predisposed to allergic, broncho-obstructive reactions and maculopapular rash;

– for perindopril: dizziness, headache, paresthesia, dysgeusia (taste perversion), blurred vision, vertigo, ringing in the ears, arterial hypotension, cough, shortness of breath, abdominal pain, constipation, dyspepsia, diarrhea, nausea, vomiting, itching, skin rash, muscle spasms and asthenia.

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

very often ≥1/10

often ≥1/100 to <1/10

uncommon ≥1/1000 to <1/100

rarely from ≥1/10000 to <1/1000

very rare <1/10000

frequency unknown cannot be estimated from available data.

Within each group, adverse effects are presented in order of decreasing severity.

MedDRA

Classes and organ systems

Undesirable effects

Frequency

Indapamide

Perindopril

Infectious and parasitic diseases

Rhinitis

–

Very rarely

Blood and lymphatic system disorders

Eosinophilia

–

Uncommon*

Agranulocytosis (see section “Special instructions”)

Very rarely

Very rarely

Aplastic anemia

Very rarely

–

Pancytopenia

–

Very rarely

Leukopenia

Very rarely

Very rarely

Neutropenia (see section “Special instructions”)

–

Very rarely

Hemolytic anemia

Very rarely

Very rarely

Thrombocytopenia (see section “Special instructions”)

Very rarely

Very rarely

Immune system disorders

Hypersensitivity reactions, mainly dermatological, in patients predisposed to broncho-obstructive and allergic reactions

Often

–

Metabolic and nutritional disorders

Hypoglycemia (see sections “Special instructions” and “Interaction with other drugs”)

–

Uncommon*

Hyperkalemia, often transient (see section “Special instructions”)

–

Uncommon*

Hyponatremia (see section “Special instructions”)

Frequency unknown

Uncommon*

Hypercalcemia

Very rarely

–

Hypokalemia, especially significant for patients at risk (see section “Special instructions”)

Frequency unknown

–

Mental disorders

Mood lability

–

Uncommon

Sleep disturbance

–

Uncommon

Confusion

–

Very rarely

Nervous system disorders

Dizziness

–

Often

Headache

Rarely

Often

Paresthesia

Rarely

Often

Dysgeusia

–

Often

Drowsiness

–

Uncommon*

Fainting

Frequency unknown

Uncommon*

Stroke, possibly due to an excessive decrease in blood pressure in high-risk patients (see section “Special instructions”)

–

Very rarely

Possible development of hepatic encephalopathy in case of liver failure (see sections “Contraindications” and “Special instructions”)

Frequency unknown

–

Visual disorders

Visual impairment

Frequency unknown

Often

Myopia (see section “Special instructions”)

Frequency unknown

–

Blurred vision

Frequency unknown

–

Hearing and labyrinth disorders

Vertigo

Rarely

Often

Tinnitus

–

Often

Heart disorders

Feeling of heartbeat

–

Uncommon*

Tachycardia

–

Uncommon*

Angina (see section “Special instructions”)

–

Very rarely

Heart rhythm disturbances (including bradycardia, ventricular tachycardia, and atrial fibrillation)

Very rarely

Very rarely

Myocardial infarction, possibly due to an excessive decrease in blood pressure in high-risk patients (see section “Special instructions”)

–

Very rarely

Polymorphic ventricular tachycardia of the “pirouette” type (possibly fatal) (see sections “Special instructions” and “Interaction with other drugs”)

Frequency unknown

–

Vascular disorders

Arterial hypotension and symptoms associated with it (see section “Special instructions”)

Very rarely

Often

Vasculitis

–

Uncommon*

Raynaud’s syndrome

–

Frequency unknown

Respiratory, thoracic and mediastinal disorders

Cough (see section “Special instructions”)

–

Often

Dyspnea

–

Often

Bronchospasm

–

Uncommon

Eosinophilic pneumonia

–

Very rarely

Digestive system disorders

Abdominal pain

–

Often

Constipation

Rarely

Often

Diarrhea

–

Often

Dyspepsia

–

Often

Nausea

Rarely

Often

Vomit

Uncommon

Often

Dryness of the oral mucosa

Rarely

Uncommon

Pancreatitis

Very rarely

Very rarely

Disorders of the liver and biliary tract

Hepatitis (see section “Special instructions”)

Frequency unknown

Very rarely

Liver dysfunction

Very rarely

–

Skin and subcutaneous tissue disorders

Itchy skin

–

Often

Skin rash

–

Often

Interaction

Common drug interactions for perindopril and indapamide

Concomitant use is not recommended

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

The simultaneous use of Co-Perineva® with lithium preparations is not recommended. If simultaneous use is necessary, it is necessary to carefully monitor the lithium content in the blood plasma (see section “Special Instructions”).

Concomitant use of drugs requiring special attention and caution

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

NSAIDs, incl. high doses of acetylsalicylic acid (³ 3 g/day): simultaneous use of ACE inhibitors and NSAIDs (including acetylsalicylic acid in doses that have an anti-inflammatory effect, cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs) can lead to a decrease in the antihypertensive effect of ACE inhibitors, increases the risk of developing renal dysfunction, including the development of acute renal failure, increases potassium levels in 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 need to compensate for fluid loss, as well as regularly monitor kidney function both at the beginning of therapy and during treatment.

Concomitant use requiring attention

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

Drug interactions for indapamide

Concomitant use requiring special attention and caution

Drugs that can cause torsades de pointes: Since there is a risk of hypokalemia, indapamide should be used with caution concomitantly with drugs that can cause torsades de pointes, such as class IA (quinidine, hydroquinidine, disopyramide) and class III antiarrhythmics (amiodarone, dofetilide, ibutilide, bretylium). tosylate, sotalol), some antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other antipsychotics (pimozide); other drugs such as bepridil, cisapride, difemanil methyl sulfate, erythromycin for IV use, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine for IV use, methadone, astemizole, terfenadine. It is necessary to monitor the potassium content in the blood serum to avoid hypokalemia, the development of which requires its correction, and to monitor the QT interval on the ECG.

Drugs that can cause hypokalemia: amphotericin B when administered intravenously, gluco- and mineralocorticoids (when administered systemically), tetracosactide, laxatives that stimulate intestinal motility, increase the risk of developing hypokalemia (additive effect). It is necessary to monitor the potassium content in the blood plasma and, if necessary, correct it. Particular attention should be paid to patients concomitantly receiving cardiac glycosides. Laxatives that do not stimulate intestinal motility should be used.

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

Concomitant use requiring attention

Potassium-sparing diuretics (amiloride, spironolactone, triamterene): this combination is justifiably used in some patients. In this case, hypokalemia or hyperkalemia may occur (especially in patients with renal failure or diabetes). If simultaneous use of indapamide and potassium-sparing diuretics is necessary, the potassium content in the blood plasma and ECG parameters should be monitored. If necessary, the treatment regimen can be revised.

Metformin: functional renal failure while 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 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Iodinated contrast media: Patients with hypovolemia during diuretic therapy have an increased risk of developing AKI, especially when using contrast media containing high doses of iodine. Before using iodine-containing contrast agents, the blood volume should be replenished.

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

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

Glucocorticosteroids (GCS), tetracosactide (when used systemically): decreased antihypertensive effect (retention of fluid and sodium ions as a result of the action of GCS).

Drug interactions for perindopril

Data from clinical studies show that dual blockade of the RAAS as a result of concomitant use of ACE inhibitors, ARB II or aliskiren leads to an increased incidence of adverse events such as arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure), compared with situations where only one drug acting on the RAAS is used (see sections “Pharmacological properties. Pharmacodynamics”, “Contraindications” and “Special instructions”).

Drugs that cause hyperkalemia

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

The combination of these drugs increases the risk of developing hyperkalemia.

Concomitant use is contraindicated

Aliskiren and medicinal products containing aliskiren: Concomitant use of ACE inhibitors with aliskiren or medicinal products containing aliskiren in patients with diabetes or moderate or severe renal impairment (GFR < 60 ml/min/1.73 m2 body surface area) is contraindicated (see section "Contraindications").

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

Extracorporeal therapy: Extracorporeal therapies that expose blood to negatively charged surfaces, such as hemodialysis or hemofiltration using high-flux membranes (eg, 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 an antihypertensive drug of a different pharmacotherapeutic group should be used.

Neutral endopeptidase inhibitors: when ACE inhibitors are used simultaneously with drugs containing sacubitril (neprilysin inhibitor), the risk of developing angioedema increases, and therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. Prescription of drugs containing sacubitril is contraindicated in patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Concomitant use is not recommended

Aliskiren: In patients without diabetes or renal impairment (GFR < 60 ml/min/1.73 m2 body surface area), the risk of hyperkalemia, deterioration of renal function and increased incidence of cardiovascular morbidity and mortality increases (see section "Special Instructions").

Concomitant use of ACE inhibitors and ARB II: according to the available literature, in patients with established atherosclerotic disease, heart failure or diabetes with target organ damage, the simultaneous use of ACE inhibitors and ARB II leads to an increased incidence of arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure), compared with situations where only one drug acting on the RAAS is used. 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 and potassium levels in the blood plasma (see section “Special Instructions”).

Estramustine: Concomitant use may result in an increased risk of adverse effects such as angioedema.

Potassium-sparing diuretics (spironolactone, triamterene), potassium supplements or potassium-containing salt substitutes: Serum potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients taking perindopril. Potassium-sparing diuretics (eg, spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels. Caution should also be exercised when using perindopril concomitantly with other drugs that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim + sulfamethoxazole), since trimethoprim is known to act similarly to the potassium-sparing diuretic amiloride. Therefore, simultaneous use of perindopril with the above drugs is not recommended. If simultaneous use is necessary due to hypokalemia, caution should be exercised and serum potassium levels and ECGs should be regularly monitored.

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

Concomitant use requiring special attention

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

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

In case of arterial hypertension in patients with hypovolemia or reduced salt concentration during diuretic therapy, it is necessary to stop taking the diuretic before starting the ACE inhibitor (in this case, a potassium-sparing diuretic can be re-prescribed later), or the ACE inhibitor should be prescribed at a low dose and then gradually increase it.

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 concomitantly used potassium-sparing diuretic.

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

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 II-IV functional class according to the NYHA classification with a left ventricular ejection fraction <40% and previously used ACE inhibitors and loop diuretics, there is a risk of developing hyperkalemia (possibly fatal), especially if recommendations regarding the use of this combination of drugs are not followed.

Before using this combination of drugs, you must ensure that there is no hyperkalemia or impaired renal function.

It is recommended to regularly monitor the concentration of creatinine and potassium levels 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 accompanied by an increased risk of angioedema.

Tissue plasminogen activators: Observational studies have shown an increased incidence of angioedema in patients taking ACE inhibitors following the use of alteplase for thrombolytic therapy of ischemic stroke.

Concomitant use requiring attention

Antihypertensives and vasodilators: the simultaneous use of these drugs may enhance the antihypertensive effect of perindopril. When administered simultaneously with nitroglycerin, other nitrates or other vasodilators, an additional reduction in blood pressure is possible.

Allopurinol, cytostatic and immunosuppressive drugs, corticosteroids (for systemic use) and procainamide: simultaneous use with ACE inhibitors may increase the risk of developing leukopenia.

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

Gold preparations: with the simultaneous use of ACE inhibitors, including perindopril, and intravenous administration of the gold preparation (sodium aurothiomalate), a symptom complex has been described, including facial flushing, nausea, vomiting and a pronounced decrease in blood pressure.

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

Sympathomimetics: may weaken the antihypertensive effect of ACE inhibitors.

Cyclosporine: simultaneous use with ACE inhibitors may increase the risk of developing hyperkalemia. It is recommended to monitor serum potassium levels.

Heparin: simultaneous use with ACE inhibitors may increase the risk of hyperkalemia. It is recommended to monitor serum potassium levels.

Overdose

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

Treatment: gastric lavage and/or administration of activated carbon, restoration of water and electrolyte balance in a hospital setting. If there is 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 aimed at increasing the blood volume (administration of 0.9% sodium chloride solution intravenously (i.v.)). Perindoprilat, the active metabolite of perindopril, can be removed from the body by dialysis.

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. Does not affect the metabolism of lipids (total cholesterol (TC), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), triglycerides (TG)) and carbohydrates, including in patients with diabetes mellitus (DM). Reduces the risk of hypokalemia caused by diuretic monotherapy.

The antihypertensive effect lasts for 24 hours.

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

Indapamide

Indapamide is a sulfonamide derivative and is a diuretic. Inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, increasing the excretion of sodium and chlorine ions by the kidneys, thus leading to increased diuresis. To a lesser extent increases the excretion of potassium and magnesium ions. Having the ability to selectively block “slow” calcium channels, indapamide increases the elasticity of arterial walls and reduces total peripheral resistance (TPR). 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 has no effect on:

· 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 and 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 action of perindopril leads to:

– dilatation of veins (reduction of preload on the heart), caused by changes in prostaglandin metabolism;

– reduction of peripheral vascular resistance (reduction of afterload on the heart).

In patients with heart failure, perindopril helps:

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

– increase in cardiac output and cardiac index;

-increasing 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. Termination of therapy does not lead to the development of withdrawal syndrome.

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 using an ACE inhibitor with 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 target organ damage, as well as studies in patients with type 2 diabetes and diabetic nephropathy.

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

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

Therefore, ACE inhibitors and ARB II should not be used simultaneously in patients with diabetic nephropathy. There is clinical trial data examining the beneficial effects of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin-converting enzyme II inhibitor in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or a combination of these diseases. The study was stopped early due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more frequently in the aliskiren 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 compared to taking these drugs separately.

Indapamide

Quickly and completely absorbed from the gastrointestinal tract (GIT). Eating slightly slows down absorption, but does not significantly affect the amount of indapamide absorbed. The maximum concentration (Cmax) in blood plasma is achieved 1 hour after oral administration of a single dose. Binds to plasma proteins by 79%. The half-life (T½) ranges from 14 to 24 hours (average 18 hours). Does not cumulate.

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

Perindopril

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

Eating reduces the conversion of perindopril to perindoprilat. T½ of perindopril from blood plasma is 1 hour.

Cmax in blood plasma is achieved 3-4 hours after oral administration. Since taking with food 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 once a day, equilibrium concentration is achieved within 4 days.

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

It is metabolized in the liver to form the active metabolite perindoprilate. In addition to the active metabolite perindoprilate, perindopril forms 5 more inactive metabolites. The association of perindoprilate with plasma proteins is dose-dependent and amounts to 20%. Perindoprilat easily passes through histohematic barriers, excluding the blood-brain barrier, and a small amount penetrates the placenta and into breast milk. Excreted by the kidneys, T½ of perindoprilate is about 17 hours. Does not cumulate.

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

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

Dialysis clearance of perindoprilate is 70 ml/min.

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

Storage conditions

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

Keep out of the reach of children.

Shelf life

3 years.

Do not use the drug after the expiration date.

Manufacturer

KRKA-RUS, Russia