Symptoms: pronounced 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 administration of activated carbon, restoration of water-electrolyte balance in a hospital setting. With a pronounced decrease in blood pressure, it is necessary to transfer the patient to a lying position on his back with his legs raised upside down, then measures should be taken to increase the BCC (introduction of 0.9% sodium chloride solution in/in). Perindoprilat, the active metabolite of perindopril, it may be removed from the body by dialysis.
hypersensitivity to the active substance, any ACE inhibitor, sulfonamide derivatives, or any excipients of the drug,
angioedema (hereditary, idiopathic, or angioedema) with other ACE inhibitors (in the anamnesis),
severe renal failure,
bilateral renal artery stenosis, stenosis of the artery to a solitary kidney,
refractory hyperkalemia,
lactose intolerance, lactase deficiency, or glucose-galactose malabsorption,
simultaneous administration of drugs that prolong the QT interval on the ECG, simultaneous administration with antiarrhythmic drugs that can cause ventricular tachycardia of the "pirouette" type (see " Interaction»),
severe hepatic insufficiency (including encephalopathy),
pregnancy, breast-feeding, age under 18 (efficacy and safety have not been established),
given the lack of sufficient experience of use, the drug Co-Paxene® it should not be taken in patients on dialysis and in patients with untreated decompensated heart failure.
With caution: systemic diseases of the connective tissue (in t.tsch.
Simultaneous use is not recommended
Lithium preparations. With the simultaneous use of lithium preparations and ACE inhibitors, cases of a reversible increase in the concentration of lithium in the blood serum have been reported. Concomitant administration of thiazide diuretics may contribute to an increase in the concentration of lithium in the blood plasma and the risk of its toxic effect against the background of taking an ACE inhibitor.
The simultaneous use of the drug Co-Paxene® with lithium preparations, it is not recommended. If concomitant use is necessary, serum lithium concentrations should be carefully monitored.
Simultaneous use, requiring special care
Baclofen - potentiation of the hypotensive effect. It is necessary to monitor blood pressure, kidney function and, if necessary, adjust the dose of antihypertensive agents.
NSAIDs, including high doses of acetylsalicylic acid (more than 3 g/day). Concomitant use of ACE inhibitors with NSAIDs (including acetylsalicylic acid in doses that have an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) reduces the hypotensive effect of ACE inhibitors, increases the risk of developing renal impairment, up to the development of acute renal failure, increases the content of potassium in the blood serum, especially in patients with pre-existing renal impairment.
This combination is recommended to be used with caution, 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.
Simultaneous use requiring caution
Tricyclic antidepressants, antipsychotics (neuroleptics). They increase the hypotensive effect and increase the risk of developing orthostatic hypotension (additive effect).
GCS, tetracosactide. Reduction of the hypotensive effect (retention of fluid and sodium ions as a result of the action of GCS).
Other antihypertensive agents: it is possible to increase the hypotensive effect of the drug Co-Paxene®.
Perindopril
Simultaneous use is not recommended
Potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone) and potassium preparations: ACE inhibitors reduce the loss of potassium by the kidneys caused by the diuretic. When used together with ACE inhibitors, it is possible to increase the content of potassium in the blood serum up to a fatal outcome. If the simultaneous use of an ACE inhibitor and the above drugs is necessary (in the case of confirmed hypokalemia), caution should be exercised and regular monitoring of the potassium content in the blood plasma and ECG parameters should be carried out.
Simultaneous use, requiring special care
Hypoglycemic agents for oral administration (sulfonylurea derivatives) and insulin: the use of ACE inhibitors (described for captopril and enalapril) in very rare cases may increase the hypoglycemic effect of sulfonylureas and insulin derivatives in patients with diabetes mellitus, with their simultaneous use, it is possible to increase glucose tolerance and reduce the need for insulin, which may require correction of doses of hypoglycemic agents for oral administration and insulin.
Simultaneous use requiring caution
Allopurinol, cytostatic immunosuppressants, corticosteroids (with systemic use) and procainamide: concomitant use of these drugs with ACE inhibitors may increase the risk of developing leukopenia.
Means for general anesthesia: ACE inhibitors may increase the antihypertensive effect of some general anaesthetic agents.
Diuretics (thiazide and loop): the use of diuretics in high doses can lead to hypovolemia (due to a decrease in BCC), and the addition of perindopril to therapy - to a pronounced decrease in blood pressure.
Indapamide
Simultaneous use, requiring special care
Drugs that can cause ventricular polymorphic tachycardia of the "pirouette" type»: t.to.. Concomitant use with the above drugs should be avoided. 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, to monitor the QT interval on the ECG
Drugs that can cause hypokalemia: amphotericin B with intravenous administration, gluco - and mineralocorticoids (with systemic administration), laxatives that stimulate intestinal motility (laxatives that do not stimulate intestinal motility should be used), tetracosactide — an increase in the risk of hypokalemia (additive effect). It is necessary to control the content of potassium in the blood plasma, if necessary, its correction. Special attention should be paid to patients who are simultaneously receiving cardiac glycosides.
Cardiac glycosides: hypokalemia increases the toxic effect of cardiac glycosides. With the 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 requiring caution
Metformin: functional renal failure on the background of taking diuretics, especially loop, when used simultaneously with metformin increases the risk of lactic acidosis. Do not use metformin if the concentration of creatinine in the blood plasma exceeds 15 mg/l (135 mmol/l) - in men and 12 mg / l (110 mmol/l) - women.
Iodine-containing contrast agents: in patients with hypovolemia on the background of the use of diuretics, there is an increased risk of acute renal failure, especially when using contrast agents containing high doses of iodine. Before using iodine-containing contrast agents, the BCC should be replenished.
Preparations containing calcium salts: with simultaneous use, hypercalcemia may develop due to a decrease in the excretion of calcium by the kidneys.
Cyclosporine: 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.
Perindopril has an inhibitory effect on the RAAS and reduces the excretion of potassium ions by the kidneys while taking indapamide. The risk of hypokalemia (potassium level in the blood serum of less than 3.4 mmol/l) in patients on the background of the use of the drug Co-Paxene® the daily dose of 0.625 mg/2 mg is 2%, 1.25 mg/4 mg-4% and 2.5 mg/8 mg-6%.
WHO classification of the frequency of side effects: very often - ≥1/10, often-from ≥1/100 to <1/10, infrequently-from ≥1/1000 to <1/100, rarely-from ≥1/10000 to <1/1000, very rarely - from <1/10000, the frequency is unknown-cannot be estimated based on available data. In each group, undesirable effects are presented in order of decreasing severity.
From the side of the hematopoietic organs: very rarely — thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (there are reports of the use of ACE inhibitors). In certain clinical situations (conditions after kidney transplantation or in patients undergoing hemodialysis or peritoneal dialysis), ACE inhibitors can cause anemia.
From the central and peripheral nervous system: often-paresthesia, headache, dizziness, vertigo, infrequently-mood lability, sleep disorders, very rarely-confusion.
On the part of the senses: often-visual disturbances, tinnitus.
From the cardiovascular system: often marked reduction in blood pressure, including orthostatic hypotension, rarely — arrhythmia including bradycardia, ventricular tachycardia, atrial fibrillation, and angina, myocardial infarction, secondary, due to blood pressure lowering in patients at high risk, the frequency is unknown — ventricular tachycardia type "pirouette" (possibly fatal).
From the respiratory system: often-dry, long-lasting against the background of the use of ACE inhibitors and disappearing after their withdrawal cough, shortness of breath, infrequently — bronchospasm, very rarely — eosinophilic pneumonia, rhinitis.
From the digestive system: often-constipation, dryness of the oral mucosa, decreased appetite, nausea, epigastric pain, abdominal pain, impaired taste perception, vomiting, dyspepsia, diarrhea, very rarely-pancreatitis, angioedema of the intestine, jaundice, the frequency is not established — in the case of liver failure, there is a possibility of developing hepatic encephalopathy.
From the skin and subcutaneous fat: often — skin itching, skin rash, maculopapular rashes, infrequently — angioedema of the face, limbs, lips, oral mucosa, tongue, vocal folds and/or larynx, urticaria, hypersensitivity reactions, mainly dermatological, in patients with a burdened allergic history, worsening of SLE, very rarely — erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, isolated cases of photosensitivity reactions.
From the musculoskeletal system: often-muscle spasms.
From the urinary system: infrequently-renal failure, very rarely-acute renal failure.
On the part of the reproductive system: infrequently-impotence.
Other: often-asthenia, infrequently-increased sweating.
Laboratory parameters:
According to clinical studies, the side effects correspond to the previously established safety profile of the combination of perindopril and indapamide. In rare cases, the following serious adverse events have developed: hyperkalemia, acute renal failure, hypotension and cough, possibly the development of angioedema.
Essential hypertension.
Co-Paxene® - a combination drug containing an ACE inhibitor-perindopril and a thiazide-like diuretic-indapamide. The drug has antihypertensive, diuretic and vasodilating effects.
Co-Paxene® It has a pronounced dose-dependent antihypertensive effect, which does not depend on the age and body position of the patient and is not accompanied by reflex tachycardia. It does not affect the metabolism of lipids (total cholesterol, LDL, VLDL, HDL, triglycerides (TG) and carbohydrates), including in patients with diabetes mellitus. Reduces the risk of hypokalemia due to diuretic monotherapy.
The antihypertensive effect persists for 24 hours.
A stable decrease in blood pressure is achieved within 1 month on the background of the use of the drug Co-Paxene® without increasing the heart rate. Discontinuation of treatment does not lead to the development of the "withdrawal"syndrome.
Perindopril-an ACE inhibitor, the mechanism of action of which is associated with the 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 with 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 the drug Co-Paxene® results in:
- venous dilation (reduction of preload on the heart), due to changes in the metabolism of PG,
- reduction of OPSS (reduction of afterload on the heart).
In patients with heart failure, perindopril promotes:
- reducing the filling pressure of the left and right ventricles,
- increased cardiac output and cardiac index,
- increased regional blood flow in the muscles.
Perindopril is effective for hypertension of any severity: mild, moderate and severe. The maximum antihypertensive effect develops in 4-6 hours after a single oral administration and persists for a day. Discontinuation of therapy does not lead to the development of the "withdrawal"syndrome.
It has vasodilating properties and restores the elasticity of large arteries. The addition of a thiazide-like diuretic enhances the antihypertensive effect of perindopril.
Indapamide belongs to the derivatives of sulfonamide, is a diuretic. It inhibits the reabsorption of sodium in the cortical segment of the renal tubules, increasing the excretion of sodium and chlorine by the kidneys, thus leading to increased diuresis. To a lesser extent, it increases the excretion of potassium and magnesium. Having the ability to selectively block "slow" calcium channels, indapamide increases the elasticity of the arterial walls and reduces OPSS. It has a hypotensive 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 the metabolism of lipids: TG, LDL and HDL and carbohydrate metabolism, even in patients with diabetes mellitus and arterial hypertension.
The combined use of perindopril and indapamide does not change their pharmacokinetic parameters in comparison with the separate administration of these drugs.
Perindopril after oral administration, it is rapidly absorbed from the gastrointestinal tract. Bioavailability of about 65-70%. Food intake reduces the conversion of perindopril to perindoprilate. T1/2 perindopril from the blood plasma is 1 h.
Cmax in the blood plasma, it is reached in 3-4 hours after oral administration. Since food intake reduces the conversion of perindopril to perindoprilate and the bioavailability of the drug, perindopril should be taken 1 time a day in the morning, before breakfast. Taking perindopril 1 time a day, the equilibrium concentration is reached within 4 days.
In the liver metabolized with the formation of the active metabolite of perindoprilat. In addition to the active metabolite of perindoprilat, perindopril forms 5 more inactive metabolites. The binding to plasma proteins of perindoprilat is dose-dependent and is 20%. Perindoprilat easily passes through the histohematic barriers, excluding BBB, a small amount penetrates through the placenta and into breast milk. Excreted by the kidneys, T1/2 of perindoprilat is about 17 h It does not accumulate.
In elderly patients, in patients with renal and heart failure, the elimination of perindoprilat is slowed down.
In case of renal insufficiency, it is recommended to reduce the dose of perindopril depending on the severity of renal insufficiency (creatinine clearance). The dialysis Cl of perindoprilate is 70 ml/min.
The kinetics of perindopril is changed in patients with cirrhosis of the liver: hepatic clearance is reduced by half. However, the quantity of perindoprilat formed is not reduced, which does not require dose adjustment.
Indapamide. It is quickly and almost completely absorbed into the gastrointestinal tract. Food intake slows down the absorption somewhat, but does not significantly affect the amount of absorbed indapamide. Cmax in the blood plasma, it is reached 1 h after ingestion of a single dose. Is associated with blood plasma proteins is 79%. T1/2 it is from 14 to 24 hours (on average-18 hours). It does not accumulate.
It is 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 by the intestine with bile in the form of inactive metabolites (22%). In patients with renal insufficiency, the pharmacokinetic parameters of indapamide do not significantly change.
Co-Paxene
Indapamid, Perindopril
Inside, 1 time a day, preferably in the morning before breakfast, with a sufficient amount of liquid.
If possible, the drug should be started with the selection of doses of single-component drugs. In case of clinical necessity, it is possible to prescribe combination therapy with Co-Paxene® immediately after monotherapy.
Doses are given for the indapamide/perindopril ratio.
The initial dose is 1 tablet of Co-Paxene.® (0.625 mg/2 mg) 1 time per day. If after 1 month of taking the drug it is not possible to achieve adequate control of blood pressure, the dose of the drug should be increased to 1 table of the drug Co-Paxene® (1.25 mg/4 mg) 1 time per 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-Paxene® — 1 tablet (2.5 mg/8 mg) 1 time per day.
Elderly patients. The initial dose is 1 tab. of the drug Co-Paxene® 0.625 mg/2 mg once a day. It is necessary to prescribe treatment with the drug after monitoring kidney function and blood pressure.
Patients with impaired renal function. Co-Paxene preparation® in patients with severe renal insufficiency, it is contraindicated (creatinine Cl less than 30 ml / min) (see "Contraindications").
Patients with moderate renal insufficiency (creatinine Cl 30-60 ml/min) are recommended to start therapy with the necessary doses of drugs (in monotherapy) that are part of the drug Co-Paxene®, the maximum daily dose of Co-Paxene® - 1.25 mg/4 mg.
In patients with a creatinine Cl equal to or greater than 60 ml/min, no dose adjustment is required. During therapy, it is necessary to regularly monitor the concentration of creatinine and the content of potassium in the blood serum.
Patients with impaired liver function. The drug is contraindicated in patients with severe hepatic insufficiency (see "Contraindications"). In moderate hepatic insufficiency, dose adjustment is not required.
Children and teenagers. Co-Paxene preparation® it should not be used in children and adolescents under 18 years of age, because data on efficacy and safety are insufficient.
