Pharmacodynamics and pharmacokinetics
Pharmacodynamics
Antihypertensive drug with a combined composition of active ingredients.
Perindopril is an active ACE inhibitor that transforms angiotensin I into angiotensin II , which has a pronounced vasoconstrictor effect. ACE also has a destructive effect on bradykinin , which has a vasodilating effect. ACE inhibition increases the activity of the kallikrein-kinin system .
The pharmacological effect of Perindopril is determined by its active metabolite, perindoprilate , which has a pronounced therapeutic effect in arterial hypertension of any degree, in any body position, reducing systolic and diastolic pressure. blood flow decreases and peripheral blood flow increases, while heart rate remains unchanged.
The hypotensive effect is maximally manifested 4-6 hours after taking perindopril and persists throughout the day. The decrease in blood occurs quickly, and a pronounced therapeutic effect occurs 3-4 weeks after starting the drug and is not accompanied by tachycardia . withdrawal syndrome . In addition to the vasodilator effect. Perindopril reduces left ventricular hypertrophy and restores the elasticity and structure of blood vessels.
Amlodipine dihydropyridine derivative , and has a pronounced hypotensive and antianginal effect. Having a blocking effect, it reduces the process of transition of calcium ions into the cell. The antianginal effect is caused by the dilation of the blood vessels of the heart muscle and peripheral arteries: it reduces afterload on the myocardium, peripheral vascular resistance , myocardial oxygen demand, and relieves spasm of the coronary arteries. In patients with angina pectoris it reduces the severity of ischemia of the heart muscle , reduces the number of angina attacks, increases exercise tolerance, and reduces the need for nitroglycerin .
It has a pronounced dose-dependent hypotensive effect, which is caused by a vasodilating effect on the vascular muscles. Reduces hypertrophy of the left ventricular muscles, while it does not affect the conductivity and contractility of the myocardium, inhibits platelet , does not cause an increase in heart rate , and has a mild natriuretic effect. It does not affect metabolism and the concentration of lipids in the blood and can be prescribed to patients with diabetes , bronchial asthma , and gout . A pronounced therapeutic effect occurs after 6-10 hours and lasts for an average of about a day.
Pharmacokinetics
Perindopril is rapidly absorbed from the gastrointestinal tract after oral administration, while the bioavailability of perindopril with food is reduced. Cmax in the blood is reached within one hour. Low connection with blood proteins (20%). Pharmacological activity is achieved due to the metabolite - perindoprilate . Excreted in urine. T1/2 of perindopril is about one hour.
Amlodipine is well absorbed from the gastrointestinal tract , absolute bioavailability is 80%, food intake has no effect on bioavailability. Cmax in the blood occurs after 8-10 hours. Metabolized in the liver to form metabolites that do not have activity. It is excreted mainly in the urine.
Co-Dalneva tablets 5 mg+1.25 mg+4 mg 30 pcs.
Co-Dalneva is a combination drug containing perindopril erbumine (angiotensin-converting enzyme (ACE) inhibitor), indapamide (thiazide-like diuretic) and amlodipine besylate (slow calcium channel blocker (SCBC)). Ko-Dalneva combines the properties of each of the active substances, which also have a potentiating effect. Perindopril Perindopril is an angiotensin-converting enzyme inhibitor. ACE, or kininase II, is an exopeptidase that converts angiotensin I into the vasoconstrictor angiotensin II, and also destroys bradykinin, which has vasodilatory properties, into an inactive heptapeptide. As a result, perindopril provides the following effects: reduces the secretion of aldosterone; increases the activity of plasma renin according to the principle of “negative” feedback; with long-term use, it reduces total peripheral vascular resistance (TPVR) - the afterload of the heart, which is mainly due to the effect on the muscular and renal vessels. A decrease in peripheral vascular resistance is not accompanied by sodium and water retention and does not cause reflex tachycardia; A study of hemodynamic parameters in patients with chronic heart failure (CHF) revealed: a decrease in filling pressure in the left and right ventricles of the heart; decrease in OPSS; increased cardiac output and cardiac index; increased peripheral blood flow in the muscles. In addition, an improvement in the results of the exercise test was noted. The action of perindopril is carried out through the active metabolite - perindoprilate. Other metabolites do not have an inhibitory effect on ACE in vitro. Perindopril is effective in the treatment of arterial hypertension (AH) of any severity, reduces both systolic and diastolic blood pressure (BP) in the “lying” and “standing” positions. The antihypertensive effect reaches its maximum 4-6 hours after a single oral dose and persists for 24 hours. The antihypertensive effect 24 hours after a single oral dose is about 87-100% of the maximum antihypertensive effect. Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity. The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Stopping therapy does not cause withdrawal syndrome. Concomitant use with a thiazide diuretic increases the severity of the antihypertensive effect and reduces the risk of developing hypokalemia while taking diuretics. Indapamide. Indapamide is a sulfonamide derivative. Its pharmacological properties are similar to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to increased excretion by the kidneys of sodium and chloride ions, and to a lesser extent, potassium and magnesium ions, thereby increasing diuresis and reducing blood pressure. In monotherapy mode, the antihypertensive effect persists for 24 hours and manifests itself when the drug is used in doses that have a minimal diuretic effect. The antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries and a decrease in peripheral vascular resistance. When taking indapamide, LVH decreases. Indapamide does not affect the concentration of lipids in the blood plasma (triglycerides, total cholesterol, low- and high-density lipoproteins), or carbohydrate metabolism (including in patients with diabetes mellitus (DM)). Amlodipine. Amlodipine is a BMCC, a dihydropyridine derivative. Amlodipine inhibits the transmembrane transition of calcium ions into cardiomyocytes and smooth muscle cells of the vascular wall. The antihypertensive effect of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vascular wall. The mechanism of the antianginal action of amlodipine has not been fully studied, presumably it is associated with the following effects: causes dilation of peripheral arterioles, reducing peripheral vascular resistance - afterload, which leads to a decrease in myocardial oxygen demand; causes dilation of the coronary arteries and arterioles in both intact and ischemic areas of the myocardium, which increases the supply of oxygen to the myocardium, including in patients with Prinzmetal's angina. In patients with hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (in the “lying” and “standing” positions) within 24 hours. The antihypertensive effect develops slowly, and therefore the development of acute arterial hypotension is uncharacteristic. In patients with angina pectoris, taking amlodipine once a day increases exercise tolerance, the time before the development of an angina attack and until “ischemic” depression of the ST segment, reduces the frequency of angina attacks and the need for taking nitroglycerin (short-acting forms). Amlodipine has no effect on the lipid profile and does not cause changes in lipid-lowering parameters of blood plasma. The drug can be used in patients with bronchial asthma (BA), diabetes and gout. With long-term use of the perindopril/amlodipine combination in patients aged 40 to 79 years with arterial hypertension and at least 3 of the additional risk factors (LVH, type 2 diabetes mellitus, peripheral arterial atherosclerosis, previous stroke or transient ischemic attack, male gender, age 55 years and older, microalbuminuria or proteinuria, smoking, total cholesterol/high-density lipoprotein cholesterol ≥ 6, early development of coronary heart disease in close relatives) the incidence of complications such as coronary revascularization, fatal and non-fatal, was significantly reduced stroke, exacerbation of angina pectoris, development of diabetes mellitus, renal dysfunction and peripheral artery disease, as well as total coronary and cardiovascular events, cardiovascular mortality, compared with the use of the atenolol/bendroflumethiazide combination. Perindopril/Indapamide. The combination of perindopril/indapamide has a dose-dependent antihypertensive effect on both systolic and diastolic blood pressure (in the “standing” and “lying” positions), regardless of the patient’s age. The antihypertensive effect lasts for 24 hours. The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Stopping therapy does not cause withdrawal syndrome. In clinical studies, the simultaneous use of perindopril and indapamide increased the severity of the antihypertensive effect compared with monotherapy with each drug. The combination of perindopril tertbutylamine (perindopril erbumine)/indapamide resulted in a significantly greater reduction in LVH than enalapril monotherapy. The most significant effect on LVH is achieved with the use of perindopril tertbutylamine (perindopril erbumine) 8 mg/indapamide 2.5 mg.
Contraindications
High sensitivity to the drug, age under 18 years, renal failure , pregnancy , lactation.
Use with caution in patients with CHF immunosuppressant therapy , cardiomyopathy , mitral/aortic stenosis , atherosclerosis , cerebrovascular diseases, hemodialysis , diabetes mellitus , when taking potassium-sparing diuretics , estramustine , dantrolene , lithium drugs, with scleroderma , lupus erythematosus , black patients ide race.
Dalneva
Special instructions related to amlodipine and perindopril also apply to Dalneva.
Perindopril
Hypersensitivity/angioedema (Quincke's edema)
When using ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, lips, tongue, vocal folds, and/or larynx may occur. If these symptoms appear, use of the drug should be stopped immediately, and the patient should be observed until signs of edema disappear completely.
If angioedema affects only the face and lips, its symptoms usually resolve on their own, or antihistamines can be used to treat the symptoms. Angioedema, accompanied by swelling of the tongue or larynx, can lead to airway obstruction and death.
If such symptoms appear, you should immediately administer epinephrine (adrenaline) subcutaneously at a dilution of 1:1000 (0.3 or 0.5 ml) and/or ensure airway patency. The patient should be under medical supervision until symptoms disappear completely and permanently.
Patients with a history of angioedema not associated with the use of ACE inhibitors may have an increased risk of developing it when using drugs in this group.
In rare cases, intestinal angioedema (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 levels. The diagnosis is made using computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after stopping the use of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of developing intestinal angioedema must be taken into account when making a differential diagnosis.
Anaphylactoid reactions during desensitization procedures
There are isolated reports of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitization therapy with Hymenoptera venom. ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescription 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 using dextran sulfate
In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each LDL apheresis procedure using high-flux membranes.
Hemodialysis
Anaphylactic reactions have been observed in patients receiving ACE inhibitors during hemodialysis using high-flow membranes. Therefore, it is advisable to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.
Neutropenia/agranulocytosis, thrombocytopenia and anemia
In patients taking ACE inhibitors, cases of neutropenia/agranulocytosis, thrombocytopenia and anemia may develop. In patients with normal renal function in the absence of other complications, neutropenia rarely develops and resolves spontaneously after discontinuation of ACE inhibitors.
Perindopril should be used with great caution in patients with connective tissue diseases and simultaneously receiving immunosuppressive therapy, allopurinol or procainamide, especially with existing renal impairment. Some patients may develop severe infections that do not respond to intensive antibiotic therapy. If perindopril is prescribed, monitoring the number of leukocytes in the blood plasma is recommended. The patient should be warned that if any signs of an infectious disease appear (sore throat, fever), consult a doctor immediately.
Risk of arterial hypotension and/or renal failure (in patients with chronic heart failure, fluid and electrolyte imbalance, etc.)
In liver cirrhosis, accompanied by edema and ascites, arterial hypotension, and CHF, significant activation of the renin-angiotensin-aldosterone system (RAAS) may be observed, especially with severe hypovolemia and a decrease in the content of electrolytes in the blood plasma (against the background of a diet with limited salt or long-term use of diuretics ).
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 acute renal failure, which is more often observed when taking the first dose or during the first two weeks of therapy.
ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic hypotension rarely occurs in patients without underlying medical conditions. The risk of an excessive decrease in blood pressure is increased in patients with reduced blood volume, which can be observed during diuretic therapy, while following a strict diet with limited salt, hemodialysis, with diarrhea or vomiting, or in patients with severe arterial hypertension with high renin activity. In patients at high risk of developing symptomatic hypotension, blood pressure, renal function, and serum potassium levels should be carefully monitored during drug therapy.
The same precautions apply to patients with angina pectoris or cerebrovascular diseases, in whom a pronounced decrease in blood pressure can lead to the development of myocardial infarction or cerebrovascular accident.
If arterial hypotension develops, the patient should be transferred to the supine position with legs elevated. If necessary, replenish the blood volume with intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not a contraindication for further use of the drug. After restoration of blood volume and blood pressure, therapy can be continued.
Aortic stenosis/Mitral stenosis/Hypertrophic obstructive cardiomyopathy
ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as in patients with mitral stenosis.
Potassium-sparing diuretics and potassium supplements
The simultaneous use of perindopril and potassium-sparing diuretics, as well as potassium preparations and potassium-containing salt substitutes is not recommended.
Cough
During therapy with an ACE inhibitor, a dry, nonproductive cough may occur, which disappears after discontinuation of drugs in this group. If a dry cough appears, you should be aware of the possible connection of this symptom with the use of an ACE inhibitor.
Children and adolescents under 18 years of age
The drug is contraindicated in children and adolescents under 18 years of age due to the lack of data on the effectiveness and safety of the drug in this age group.
Renal dysfunction
If renal function is impaired (creatinine clearance less than 60 ml/min), individual selection of doses of perindopril and amlodipine is recommended. Regular monitoring of potassium and creatinine levels in the blood plasma is a necessary condition in the treatment of such patients.
In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, taking ACE inhibitors, there was an increase in plasma urea and creatinine concentrations, reversible after discontinuation of therapy. These changes are more likely in patients with renal failure. Patients with renovascular hypertension are at increased risk of severe hypotension and renal failure. In some hypertensive patients without obvious evidence of existing renal disease who took perindopril concomitantly with a diuretic, small and transient increases in serum urea and creatinine concentrations were observed. These changes more often develop in patients with pre-existing renal impairment.
Liver dysfunction
Rarely, the use of ACE inhibitors is accompanied by a syndrome, the development of which begins with cholestatic jaundice and which then progresses to fulminant liver necrosis, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice occurs or liver transaminases increase during use of an ACE inhibitor, the ACE inhibitor should be discontinued immediately and the patient should remain under appropriate medical supervision.
Ethnic characteristics
In patients of the Negroid race, angioedema develops more often than in representatives of other races while using ACE inhibitors. Perindopril, like other ACE inhibitors, may have a less pronounced hypotensive effect in patients of the Black race compared to representatives of other races. Perhaps this difference is due to the fact that patients with arterial hypertension of the Negroid race more often have low plasma renin activity.
Surgery/general anesthesia
The use of ACE inhibitors in patients undergoing major surgery and/or general anesthesia can lead to a significant decrease in blood pressure if general anesthesia agents with a hypotensive effect are used. This is due to blocking the formation of angiotensin II against the background of a compensatory increase in renin activity. If the development of arterial hypotension is associated with the described mechanism, the blood volume should be increased. It is recommended to stop using the drug 24 hours before surgery.
Hyperkalemia
During therapy with ACE inhibitors, including perindopril, plasma potassium levels may increase in some patients. Risk factors for the development of hyperkalemia are renal failure, decreased renal function, old age (over 70 years), diabetes mellitus, intercurrent conditions, in particular dehydration, acute cardiac decompensation, metabolic acidosis, simultaneous use of potassium-sparing diuretics (for example, spironolactone, eplerenone, triamterene or amiloride), potassium-containing drugs or supplements, potassium-containing salt substitutes, or concomitant use of other drugs that increase plasma potassium levels (eg, heparin). Hyperkalemia can cause serious, sometimes life-threatening arrhythmias. If it is necessary to use perindopril and one of the above substances simultaneously, caution should be exercised and the potassium level in the blood plasma should be regularly monitored.
Patients with diabetes mellitus
In patients with diabetes mellitus taking oral hypoglycemic agents and/or insulin, increased monitoring of blood glucose concentrations is necessary during the first few months of therapy with ACE inhibitors.
Amlodipine
Liver dysfunction
In patients with impaired liver function, T1/2 of amlodipine is prolonged. When prescribing the drug to such patients, caution should be exercised and the activity of liver enzymes should be regularly monitored.
Patients with heart failure
In patients with CHF (functional class III and IV according to the NYHA classification), treatment is carried out with caution, due to the possibility of developing pulmonary edema.
Side effects
Local allergic reactions, nausea, dyspepsia , diarrhea , weight change, tinnitus, agranulocytosis, leukopenia/neutropenia, thrombocytopenia, visual disturbances , headache , drowsiness , sleep disturbance , dizziness , insomnia , tremor , mood lability , fainting , palpitations, cough, shortness of breath , abdominal pain, vomiting, constipation , hepatitis , skin rash and itching, alopecia increased sweating , myalgia , photosensitivity , muscle spasms, arthralgia , frequent urination, peripheral edema , impotence , increased fatigue, asthenia , malaise.
Dalneva tablets Tablets, box, 90 pcs., 5 + 8 mg + mg, for internal use
Interaction with other drugs
Perindopril Concomitant use is not recommended Potassium-sparing diuretics, potassium preparations or potassium-containing salt substitutes: although serum potassium levels remain within normal limits, hyperkalemia may occur in some patients when using perindopril. Potassium-sparing diuretics (for example, spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes can lead to a significant increase in plasma potassium levels, so their use simultaneously with ACE inhibitors is not recommended. If simultaneous therapy is necessary (in case of confirmed hypokalemia), caution should be exercised and regular monitoring of plasma potassium levels and ECG parameters should be carried out. Lithium preparations: with simultaneous use of lithium preparations and ACE inhibitors, cases of reversible increases in serum lithium concentrations and associated with this there are toxic effects. Simultaneous therapy with perindopril and lithium preparations is not recommended. If such combination therapy is necessary, it should be carried out under regular monitoring of the concentration of lithium in the blood plasma. Estramustine: simultaneous use is accompanied by an increased risk of developing angioedema. Simultaneous use, which requires special caution, NSAIDs, incl. COX-2 inhibitors, acetylsalicylic acid in high doses (more than 3 g/day) and non-selective NSAIDs: the use of NSAIDs can lead to a decrease in the diuretic, natriuretic and hypotensive effects of ACE inhibitors. The simultaneous use of ACE inhibitors and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure and an increase in serum potassium, especially in patients with reduced renal function. Caution should be exercised when using this combination, especially in elderly patients. In this case, patients need to compensate for fluid loss and carefully monitor renal function, both at the beginning and during treatment. Hypoglycemic drugs (hypoglycemic agents for oral administration and/or insulin): the use of ACE inhibitors may enhance the hypoglycemic effect of insulin or sulfonylurea derivatives in patients with diabetes mellitus. The development of episodes of hypoglycemia was observed very rarely (there may be an increase in glucose tolerance, leading to a decrease in the need for insulin). Concomitant use requiring attention Diuretics (thiazide and loop): in patients taking diuretics, especially with excessive fluid excretion and/or electrolytes, a significant decrease in blood pressure may be observed when starting to use ACE inhibitors. The risk of developing arterial hypotension can be reduced by discontinuing the diuretic, increasing fluid and/or sodium intake before starting therapy, starting therapy with low doses of perindopril and then gradually increasing them. Sympathomimetics: sympathomimetics can weaken the hypotensive effect of ACE inhibitors. Gold preparations: in patients receiving simultaneous injection therapy with gold preparations (sodium aurothiomalate) and ACE inhibitors, including perindopril, nitrate-like reactions (“flushes” of blood to the facial skin, nausea, vomiting, decreased blood pressure) are rarely observed. Allopurinol, cytostatic and immunosuppressive agents, GCS (with systemic use ) and procainamide: simultaneous use with ACE inhibitors may be accompanied by an increased risk of leukopenia. Agents for general anesthesia: simultaneous use of ACE inhibitors and agents for general anesthesia may lead to an increased hypotensive effect. Amlodipine Simultaneous use is not recommended Dantrolene (iv administration): in experiments on In animals, after administration of verapamil and dantrolene (iv), cases of fatal ventricular fibrillation and cardiovascular failure associated with hyperkalemia were observed. Considering the risk of developing hyperkalemia, the simultaneous use of amlodipine and dantrolene should be avoided. Concomitant use requiring special caution. CYP3A4 inducers (rifampicin, St. John's wort preparations, anticonvulsants such as carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone): a possible decrease in the plasma concentration of amlodipine due to increased its metabolism in the liver. Caution should be exercised when using amlodipine and inducers of microsomal oxidation simultaneously and, if necessary, adjust the dose of amlodipine. Strong and moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungals (itraconazole and ketoconazole), macrolides such as erythromycin and clarithromycin, verapamil and diltiazem): it is possible to increase the plasma concentration of amlodipine and increase the risk of side effects, especially in elderly patients. Caution should be exercised during simultaneous use and, if necessary, adjust the dose of amlodipine. Simultaneous use that requires attention Simultaneous use of β-blockers (bisoprolol, metoprolol) and the α- and β-blocker carvedilol, used for CHF: increases the risk of developing arterial hypotension and worsening the course CHF in patients with uncontrolled or latent CHF (increased negative inotropic effect). In addition, β-blockers can reduce excessive reflex cardiac sympathetic activation against the background of concomitant CHF. There is no interaction of the following drugs with amlodipine: - with simultaneous use of amlodipine and cimetidine, the pharmacokinetic parameters of amlodipine did not change; - with simultaneous use of amlodipine and sildenafil, no increase in the hypotensive effect was noted each of the drugs. Grapefruit juice: taking 240 ml of grapefruit juice together with a single dose of amlodipine (10 mg orally) did not have a significant effect on the pharmacokinetics of amlodipine. Amlodipine does not affect the pharmacokinetics of the following drugs: - atorvastatin: taking repeated doses of amlodipine 10 mg in combination with atorvastatin at a dose of 80 mg does not lead to a significant change in the equilibrium pharmacokinetic parameters of atorvastatin; - digoxin: simultaneous use of amlodipine and digoxin is not accompanied by changes in the concentration of digoxin in the blood serum and the renal clearance of digoxin in healthy volunteers; - warfarin: in healthy male volunteers who took warfarin, the addition of amlodipine does not have a significant effect on the change in PT due to warfarin; - cyclosporine: amlodipine does not have a significant effect on the pharmacokinetic parameters of cyclosporine. Dalneva® Simultaneous use requiring special attention Baclofen: possible potentiation of the hypotensive effect. Monitoring of blood pressure and renal function is necessary, as well as dose adjustment of amlodipine. Concomitant use that requires attention. Antihypertensive drugs (for example, β-blockers) and vasodilators: the hypotensive effect of perindopril and amlodipine may be enhanced. Caution should be exercised when used concomitantly with nitroglycerin, other nitrates or other vasodilators, as this may further reduce
Dalneva, instructions for use (Method and dosage)
Dalnev tablets are taken orally before meals, preferably before breakfast, 1 tablet once a day.
For patients with stable angina or arterial hypertension, the dose is selected based on the results of dose titration: amlodipine and perindopril . The maximum daily dosage of amlodipine is 10 mg; perindopril - 8 mg.
Dalneva should not be prescribed to patients with CC less than 60 ml/min. The use of Dalnev requires caution in patients with liver failure , since there are no recommendations on the dosage of the drug for such patients. Patients over 60 years of age do not require dose adjustment.
Co-Dalneva® (Co-Dalneva®)
Amlodipine
During treatment with amlodipine, it is necessary to monitor body weight and sodium intake, and prescribe an appropriate diet. It is necessary to maintain dental hygiene and follow-up with a dentist (to prevent pain, bleeding and gum hyperplasia).
Low body weight patients, short patients and patients with severe hepatic impairment may require a lower dose.
CHF
In patients with CHF (functional class III and IV according to the NYHA classification), treatment is carried out with caution, due to the possibility of developing pulmonary edema. BMCCs, including amlodipine, should be used with caution in patients with CHF due to a possible increased risk of adverse events from the cardiovascular system and mortality.
Liver dysfunction
In patients with impaired liver function, T1/2 and AUC of amlodipine increase. Amlodipine should be started with the lowest doses and caution should be exercised both when starting therapy and when increasing the dose of amlodipine. In patients with severe hepatic impairment, the dose should be increased gradually and careful monitoring of the clinical condition is required.
Elderly patients
In elderly patients, T1/2 may increase and amlodipine clearance may decrease. No dosage adjustment is required, but careful monitoring of patients is necessary.
Indapamide
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 the drug.
Photosensitivity
Cases of photosensitivity reactions have been reported while taking thiazide and thiazide-like diuretics. If a photosensitivity reaction develops, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.
Water and electrolyte balance
Sodium content in blood plasma
Before starting treatment, it is necessary to determine the sodium content in the blood plasma. While taking the drug, this indicator should be regularly monitored. All diuretics can cause hyponatremia, which sometimes leads to serious complications. At the initial stage of therapy, a decrease in sodium levels in the blood plasma may be asymptomatic, so regular laboratory monitoring is necessary. Elderly patients are advised to monitor plasma sodium levels more frequently.
Hyponatremia in combination with hypovolemia can cause dehydration and orthostatic hypotension.
A concomitant decrease in chlorine content in the blood plasma can lead to secondary compensatory metabolic alkalosis (the incidence and severity of this effect 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 patients from high-risk groups: elderly patients, malnourished patients, patients with liver cirrhosis, including edema and ascites, patients with coronary artery disease, CHF. In such patients, hypokalemia enhances the toxic effect of cardiac glycosides and increases the risk of developing arrhythmia.
Patients with a prolonged QT interval, either hereditary or drug-induced, are also at increased risk. Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially polymorphic ventricular tachycardia of the “pirouette” type, which can be fatal. In all the cases described above, regular monitoring of potassium levels in the blood plasma is necessary. It is necessary to determine the potassium content in the blood plasma during the first week after starting therapy. If hypokalemia is detected, appropriate therapy should be provided.
Calcium content in blood plasma
Thiazide and thiazide-like diuretics reduce the excretion of calcium by the kidneys, which may cause a slight temporary increase in calcium levels in the blood plasma. Severe hypercalcemia may be associated with previously undiagnosed hyperparathyroidism. In such cases, it is necessary to conduct a study of the function of the parathyroid glands, having first stopped taking diuretics.
Uric acid
In patients with elevated concentrations of uric acid in the blood plasma, the frequency of gout attacks may increase during therapy.
Renal dysfunction
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, CC is calculated taking into account age, body weight and gender.
In patients with hypovolemia and hyponatremia at the beginning of diuretic therapy, a temporary decrease in GFR and an increase in the concentration of urea and creatinine in the blood plasma may be observed. This transient functional renal failure is not dangerous for patients with unchanged renal function, but its severity may increase in patients with renal failure.
In such patients, potassium levels and plasma creatinine concentrations should be regularly monitored.
Athletes
Indapamide may give a positive reaction during doping control.
Choroidal effusion/acute myopia/acute secondary angle-closure glaucoma
Sulfonamides and their derivatives can cause an idiosyncratic reaction, leading to the development of choroidal effusion with visual field impairment, acute myopia and an acute attack of secondary closed-angle glaucoma. Symptoms include sudden loss of vision or pain in the eye; usually occur within hours or weeks after starting thiazide/thiazide-like diuretic therapy. If left untreated, acute secondary angle-closure glaucoma can lead to irreversible vision loss. If symptoms occur, the thiazide/thiazide-like diuretic should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for the development of angle-closure glaucoma are a history of an allergic reaction to sulfonamide derivatives and/or 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 section “Interaction with other drugs”). If a double blockade is necessary, it should be performed under strict medical supervision with regular monitoring of renal function, plasma potassium levels and blood pressure. Concomitant use of ACE inhibitors with aliskiren or drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) 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.
Neutropenia/agranulocytosis/thrombocytopenia/anemia
While taking ACE inhibitors, neutropenia/agranulocytosis, thrombocytopenia and anemia may occur. In patients with normal renal function in the absence of other risk factors, neutropenia rarely develops. After discontinuation of the ACE inhibitor, neutropenia and agranulocytosis resolve on their own. Perindopril should be used with extreme caution in patients with systemic connective tissue diseases during therapy with immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When using perindopril in such patients, it is recommended to periodically monitor the number of leukocytes in the blood plasma. If any symptoms of infectious diseases appear (for example, sore throat, fever), patients should consult a doctor.
Hypersensitivity/angioedema
While 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. If symptoms appear, you should immediately stop taking the drug and continue to monitor the patient until symptoms are completely relieved. As a rule, swelling of the face and lips does not require treatment, although antihistamines can be used to relieve symptoms.
Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, you should immediately administer a subcutaneous solution of epinephrine (adrenaline) at a dilution of 1:1000 (0.3-0.5 ml) and/or ensure airway patency. 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.
In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients complain of abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with a normal level of C1-esterase. The diagnosis was made using computed tomography, ultrasound examination of the abdominal organs, or during surgery. Symptoms disappear after stopping ACE inhibitors. Therefore, in patients with complaints of abdominal pain taking ACE inhibitors. When carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.
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).
Anaphylactoid reactions during desensitization
There are isolated reports of the development of anaphylactoid reactions in patients taking ACE inhibitors during desensitizing therapy (for example, hymenoptera venom: bees, wasps). The development of such reactions was avoided by temporarily discontinuing ACE inhibitors (at least 24 hours before desensitization); if an ACE inhibitor was accidentally taken, the anaphylactoid reaction occurred again.
Anaphylactoid reactions during LDL apheresis
In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent such reactions, ACE inhibitors should be temporarily discontinued before each apheresis procedure.
Hemodialysis
In rare cases, anaphylactoid reactions have developed in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (for example, AN69®). Therefore, it is recommended to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism are usually refractory to antihypertensive drugs that act by inhibiting the RAAS. Therefore, the use of this drug is not recommended.
Cough
During therapy with ACE inhibitors, a dry cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possibility of its occurrence in connection with taking an ACE inhibitor. If it is necessary to use drugs in this group, taking an ACE inhibitor can be continued.
Aortic and mitral stenosis, HOCM
ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and mitral stenosis.
Diabetes
In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, regular monitoring of blood glucose concentrations is necessary during the first month of treatment with an ACE inhibitor.
Surgery/general anesthesia
The use of ACE inhibitors in patients undergoing surgery under general anesthesia can lead to a significant decrease in blood pressure, especially when using general anesthetic agents that have antihypertensive effects. It is recommended to stop taking long-acting ACE inhibitors, including perindopril, 24 hours before surgery.
Ethnic differences
In patients of the Negroid race, angioedema develops more often than in representatives of other races while using ACE inhibitors. Perindopril, like other ACE inhibitors, apparently has a less pronounced antihypertensive effect in patients of the Black race compared to representatives of other races. Perhaps this difference is due to the fact that black patients with arterial hypertension more often have low plasma renin activity.
Liver failure
In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. If there is a significant increase in the activity of liver enzymes in the blood plasma or the appearance of jaundice while taking ACE inhibitors, you should stop taking perindopril and continue to monitor the patient.
Hyperkalemia
The use of ACE inhibitors may cause hyperkalemia due to inhibition of aldosterone release, which is usually mild in patients with normal renal function. Risk factors for hyperkalemia are renal failure, old age (over 70 years), diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of CHF, metabolic acidosis), simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing table salt substitutes, as well as other drugs that help increase potassium levels in the blood plasma (for example, heparin, trimethoprim or co-trimoxazole (sulfamethoxazole + trimethoprim) and especially aldosterone antagonists or ARA II, ASA ≥ 3 g / day, COX-inhibitors 2 and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus (especially in patients with reduced renal function)). Hyperkalemia can lead to serious, sometimes fatal, heart rhythm disturbances. Caution should be exercised during the simultaneous use of ACE inhibitors and potassium-sparing diuretics and ARA II; renal function and serum potassium levels must be monitored.
Kidney transplant
There is no experience with the use of perindopril in patients with recent kidney transplantation.
Renovascular hypertension
The treatment method for renovascular hypertension is revascularization. However, the use of ACE inhibitors may be effective in patients with renovascular hypertension, both awaiting surgery and those who cannot undergo surgery.
In patients with bilateral renal artery stenosis or renal artery stenosis of a single functioning kidney during therapy with ACE inhibitors, there may be an increase in serum urea and creatinine concentrations (usually resolving when therapy is discontinued), and the risk of developing arterial hypotension and renal failure also increases. Taking diuretics may be an additional risk factor. Deterioration of renal function can be observed with even a slight change in plasma creatinine concentration, even in patients with unilateral renal artery stenosis.
Ko-Dalneva®
Renal dysfunction
Co-Dalneva® is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).
The drug Co-Dalneva® can be used in patients with moderate renal dysfunction (creatinine clearance 30-60 ml/min). For such patients, individual selection of doses of amlodipine, indapamide, and perindopril is recommended.
In some patients with hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment with the drug should be stopped. In the future, combination therapy can be resumed using low doses of a combination of perindopril and indapamide, or these drugs can be used separately. Such patients require regular monitoring of potassium levels and creatinine concentrations in the blood serum 2 weeks after the start of therapy and every 2 months thereafter. The development of renal failure more often occurs in patients with severe CHF or underlying renal impairment, including renal artery stenosis.
In patients with diagnosed or suspected renal artery stenosis, treatment should begin with lower doses of Co-Dalneva®. Some patients may develop functional renal failure, which resolves after discontinuation of the drug.
Arterial hypotension and water-electrolyte imbalance
Patients with hyponatremia (especially with renal artery stenosis, including bilateral) are at risk of sudden development of arterial hypotension. Therefore, you should pay attention to possible symptoms of dehydration and decreased electrolyte levels in the blood plasma, for example, after diarrhea or vomiting. The use of ACE inhibitors causes blockade of the RAAS, and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in the concentration of creatinine in the blood plasma, which indicates the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy and sometimes develop acutely. Such patients require regular monitoring of blood plasma electrolyte levels.
In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required. Transient arterial hypotension is not a contraindication for continued therapy. After restoration of blood volume and blood pressure, treatment can be resumed using low doses of perindopril and indapamide, or used separately.
Elderly patients
Before starting to take Co-Dalneva®, it is necessary to evaluate the functional activity of the kidneys and the potassium content in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of decrease in blood pressure, especially in the case of a decrease in blood volume and loss of electrolytes, which helps to avoid a sharp decrease in blood pressure.
Atherosclerosis
The risk of developing arterial hypotension exists in all patients, but special caution should be observed in patients with coronary artery disease and cerebrovascular diseases. In such patients, treatment begins with low doses of the drug.
Children
The drug Co-Dalneva® is contraindicated for use in children under 18 years of age due to the lack of data on effectiveness and safety in this age group.
Interaction
When taking Dalneva together with Baclofen , there is a risk of increasing the hypotensive effect of the drug. With simultaneous use of the drug with drugs with a hypotensive effect, α-blockers ( Tamsulosin , alfuzosin , Prazosin , Terazosin , Doxazosin ), neuroleptics , general anesthesia, tricyclic antidepressants , an increase in the hypotensive effect and the development of orthostatic hypotension . Corticosteroids and tetracosactide reduce the hypotensive effect of Dalnev.
Dalneva®
Amlodipine
Not recommended drug combinations
Dantrolene (intravenous administration)
In laboratory animals, cases of ventricular fibrillation with death and collapse have been reported during the use of verapamil and intravenous dantrolene, accompanied by hyperkalemia. Due to the risk of developing hyperkalemia, concomitant use of BMCCs, including amlodipine, should be avoided in patients susceptible to malignant hyperthermia, as well as during the treatment of malignant hyperthermia.
Combinations of drugs requiring special attention
Inducers of the CYP3A4 isoenzyme
: when used
, the concentration of amlodipine in the blood plasma may change.
Therefore, it is necessary to monitor blood pressure and adjust the dose both during and after their simultaneous use, especially when used with strong inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John's wort preparations).
Inhibitors of the CYP3A4 isoenzyme
: simultaneous use
of amlodipine and strong or moderate inhibitors of the CYP3A4 isoenzyme
( protease inhibitors, azole antifungals, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem)
can lead to a significant increase in the concentration of amlodipine in the blood plasma. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. In this regard, monitoring of the clinical condition and dose adjustment may be required.
In patients taking amlodipine concomitantly with clarithromycin,
increased risk of developing arterial hypotension.
Patients receiving perindopril concomitantly with clarithromycin should be closely monitored .
Drug combinations requiring attention
Amlodipine enhances the antihypertensive effect of antihypertensive drugs.
Tacrolimus:
There is a risk of increased serum concentrations of tacrolimus when used concomitantly with amlodipine. To avoid the development of toxic effects of tacrolimus during simultaneous use of these drugs, monitoring of serum concentrations of tacrolimus and adjustment of its dose if necessary is required.
Cyclosporine:
No studies have been conducted to study the interaction of cyclosporine with amlodipine in healthy volunteers or other populations, with the exception of patients who have undergone kidney transplantation, in which variability in the increase in trough concentrations of cyclosporine in plasma was observed (average from 0% to 40%). The possibility of monitoring serum concentrations of cyclosporine in patients after kidney transplantation when used concomitantly with amlodipine should be considered. If necessary, the dose of cyclosporine should be reduced.
Simvastatin:
with simultaneous use of several doses of amlodipine 10 mg and simvastatin 80 mg, an increase in simvastatin exposure by 77% was noted compared with simvastatin alone. In patients taking Dalneva® at a dosage of 10 mg + 4 mg or 10 mg + 8 mg, simvastatin should be limited to 20 mg per day.
Concomitant use of amlodipine and grapefruit
or
grapefruit juice
is not recommended due to the possible increase in the bioavailability of amlodipine in some patients, which in turn may lead to increased blood pressure lowering effects.
mTOR inhibitors ( Mammalian Target of Rapamycin ):
mTOR inhibitors, such as sirolimus, temsirolimus and everolimus, are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.
Clarithromycin:
Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. There is an increased risk of developing arterial hypotension in patients concomitantly using clarithromycin with amlodipine. Careful monitoring of patients is recommended during concomitant use of amlodipine with clarithromycin.
Simultaneous use of beta-blockers (bisoprolol, metoprolol) and the alpha- and beta-blocker carvedilol for CHF:
increases the risk of developing arterial hypotension and worsening the course of CHF in patients with uncontrolled or latent CHF (increased inotropic effect). In addition, beta-blockers can reduce excessive reflex cardiac sympathetic activation associated with concomitant CHF.
When used concomitantly, amlodipine may increase the systemic exposure of tasonermin
in blood plasma.
In such cases, regular monitoring of the concentration of tasonermin
in the blood plasma and dose adjustment if necessary is necessary.
Other drug combinations
Calcium preparations
may reduce the effect of BMCC.
With simultaneous use of BMCC with lithium preparations
(no data available for amlodipine) their neurotoxicity may increase (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).
In clinical drug interaction studies, amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Single dose of 100 mg sildenafil
in patients with essential hypertension does not affect the pharmacokinetic parameters of amlodipine.
Perindopril
Clinical trial data show that dual blockade of the RAAS resulting from concomitant use of ACE inhibitors, ARB II or aliskiren
leads to an increase in the incidence of adverse events such as arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure), compared with situations where only one drug that affects the RAAS is used (see sections “Pharmacological properties. Pharmacodynamics”, “Contraindications”, “Special instructions”).
Drugs that cause hyperkalemia
Some drugs may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, ARB II, nonsteroidal anti-inflammatory drugs (NSAIDs), heparin, immunosuppressants,
such as
cyclosporine
or
tacrolimus, trimethoprim,
including a fixed combination
of trimethoprim and sulfamethoxazole (co-trimoxazole).
The combination of these drugs increases the risk of developing hyperkalemia.
Cyclosporine:
with simultaneous use of ACE inhibitors with cyclosporine, hyperkalemia may develop. It is recommended to monitor serum potassium levels.
Heparin:
possible increase in serum potassium levels. It is recommended to monitor serum potassium levels.
Concomitant use is contraindicated
Aliskiren and medicinal products containing aliskiren
Concomitant use of ACE inhibitors with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients ( see section "Contraindications"). The risk of hyperkalemia, deterioration of renal function, cardiovascular morbidity and mortality increases.
Extracorporeal therapy
Extracorporeal treatments that expose blood to negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (eg, polyacrylonitrile), or LDL apheresis using dextran sulfate, are contraindicated due to the increased risk of severe anaphylactoid reactions (see section 4.4). section "Contraindications"). If the patient requires extracorporeal therapy, the use of a different type of dialysis membrane or a different class of antihypertensive drugs should be considered.
Neutral endopeptidase inhibitors
When using ACE inhibitors 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.
The use of drugs containing
sacubitril
in patients receiving ACE inhibitors. and also within 36 hours after discontinuation of ACE inhibitors.
Not recommended drug combinations
Aliskiren and medicinal products containing aliskiren
In patients without diabetes mellitus or renal impairment, there may be an increased risk of hyperkalemia, worsening renal function, and increased incidence of cardiovascular morbidity and mortality.
Simultaneous administration of ACE inhibitors and ARA II
According to the available literature, in patients with an established diagnosis of atherosclerosis, heart failure or diabetes mellitus with target organ damage, simultaneous use of ACE inhibitors and ARB II leads to an increased incidence of arterial hypotension, fainting, hyperkalemia and deterioration of renal function (including acute renal failure) compared to 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, potassium levels in the blood plasma and blood pressure (see section "Special Instructions").
Estramustine
The simultaneous use of estramustine with ACE inhibitors is accompanied by an increased risk of developing angioedema.
Co-trimoxazole (trimethoprim + sulfamethoxazole)
When used simultaneously with co-trimoxazole (trimethoprim + sulfamethoxazole), the risk of developing hyperkalemia may increase (see section "Special instructions").
Potassium-sparing diuretics (eg, triamterene, amiloride) and potassium salts
Plasma potassium levels usually remain within normal limits, although hyperkalemia may develop in some patients receiving ACE inhibitors. The use of potassium-sparing diuretics (for example, spironolactone, triamterene, eplerenone or amiloride), potassium-containing salt substitutes, and other drugs that increase the level of potassium in the blood plasma can lead to a significant increase in the level of potassium in the blood serum. Caution should also be exercised when co-prescribing perindopril with other drugs that can increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim + sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic, such as amiloride. Therefore, simultaneous use of perindopril with the above drugs is not recommended. If, however, simultaneous use is indicated, use with precautions and regular monitoring of serum potassium levels.
Lithium preparations
With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the content of lithium in the blood plasma and associated toxic effects (severe neurotoxic effects) may occur. The simultaneous use of perindopril and lithium preparations is not recommended. If such therapy is necessary, regular monitoring of the lithium content in the blood plasma is necessary (see section “Special Instructions”).
Combinations of drugs requiring special attention
Hypoglycemic agents (insulin, sulfonylurea derivatives)
According to data obtained from epidemiological studies, ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylureas with a risk of developing hypoglycemia. This effect is most likely to be observed in the first weeks of simultaneous use and in patients with impaired renal function.
Potassium-sparing diuretics
In patients receiving diuretics, especially in patients with hypovolemia and/or reduced salt concentrations, a marked decrease in blood pressure may be observed when perindopril therapy is initiated. the risk of which 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.
With hypertension
In patients with hypovolemia or low salt levels during diuretic therapy, diuretics should either be discontinued before starting the ACE inhibitor (in this case, a potassium-sparing diuretic can be reintroduced later), or the ACE inhibitor should be prescribed at a low dose and then gradually increase it.
When using diuretics in case of CHF
An ACE inhibitor should be prescribed at a very low dose, possibly after reducing the dose of a concomitantly used potassium-sparing diuretic.
In all cases, renal function (plasma creatinine concentration) should be monitored in the first weeks of using ACE inhibitors.
Potassium-sparing diuretics (use of eplerenone, spironolactone in doses from 12.5 mg to 50 mg per day and low doses of ACE inhibitors)
When treating CHF II-IV functional class according to the NYHA classification with a left ventricular ejection fraction <40% in patients who have previously received ACE inhibitors and loop diuretics, there is a risk of developing hyperkalemia (with possible death), especially if recommendations regarding this are not followed combinations of drugs.
Before starting to use 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.
(enkephalinase inhibitor).
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.
mTOR inhibitors (for example, sirolimus, everolimus, temsirolimus)
In patients receiving concomitant therapy with mTOR inhibitors, the risk of developing angioedema increases (see section "Special Instructions").
NSAIDs, including high doses of acetylsalicylic acid (≥ 3 g/day)
Concomitant use of ACE inhibitors with NSAIDs (acetylsalicylic acid at a dose that has an anti-inflammatory effect, cyclooxygenase-2 [COX-2] inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure, and an increase in serum potassium, especially in patients with reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients need to compensate for fluid loss and carefully monitor renal function both at the beginning of treatment and during treatment.
Drug combinations requiring attention
Dipeptidyl peptidase IV (DPP - IV ) inhibitors (gliptins), for example, linagliptin, saxagliptin, sitagliptin, vildagliptin
Concomitant use with ACE inhibitors may increase the risk of developing angioedema due to the suppression of DPP-IV activity by gliptin.
Sympathomimetics
May weaken the antihypertensive effect of ACE inhibitors.
Gold preparations
When using ACE inhibitors, including perindopril, in patients receiving intravenous gold (sodium aurothiomalate), nitrite reactions were described, with a frequency of occurrence of “rare” (a symptom complex including facial flushing, nausea, vomiting, arterial hypotension) .
Allopurinol, immunosuppressives, corticosteroids (if used systemically) and procainamide
Concomitant use with ACE inhibitors may be accompanied by an increased risk of developing leukopenia, especially in patients with existing renal impairment.
General anesthesia products
The simultaneous use of ACE inhibitors and general anesthesia may lead to an antihypertensive effect.
Dalneva®
Combinations of drugs requiring special attention
Baclofen
The antihypertensive effect may be enhanced. Blood pressure and renal function should be monitored and the dose of amlodipine adjusted if necessary.
Combination of drugs requiring attention
Antihypertensives (eg, beta-blockers) and vasodilators
The antihypertensive effect of perindopril and amlodipine may be enhanced. Caution should be exercised when used concomitantly with nitroglycerin, other nitrates or other vasodilators, since an additional decrease in blood pressure may occur.
Corticosteroids (mineral and glucocorticosteroids), tetracosactide
Decreased antihypertensive effect (retention of fluid and sodium ions as a result of the action of corticosteroids).
Alpha blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin)
Strengthening the antihypertensive effect and increasing the risk of developing orthostatic hypotension.
Amifostin
The antihypertensive effect of amlodipine may be enhanced.
Tricyclic antidepressants/neuroleptics/general anesthetics
Strengthening the antihypertensive effect and increasing the risk of developing orthostatic hypotension.
Analogues of Dalnev
Level 4 ATX code matches:
Tarka
Prestance
Drugs with similar therapeutic effects include: Amzaar , Amlodipine , Amlong , Vamloset , Duplekor , Kalchek , Lisinopril , Lizacard , Iruzid , Prestance , Liten , Rasilam , Tenliza , Equacard and others.
Dalneva price, where to buy
The price of Dalnev tablets 5 mg + 4 mg No. 30 varies between 385 - 590 rubles per pack. You can buy Dalnev without difficulty in most pharmacies in Moscow and other cities.
- Online pharmacies in RussiaRussia
ZdravCity
- Dalneva tab.
5mg+ 8mg n30Krka-Rus LLC 557 RUR order - KO-Dalneva tablets 5mg+1.25mg+4mg 30 pcs. Krka-Rus LLC
RUR 543 order
- Dalneva tablets 5mg+8mg 90 pcs. Krka-Rus LLC
RUB 1,049 order
- KO-Dalneva tablets 10mg+2.5mg+8mg 90 pcs. Krka-Rus LLC
RUB 1,311 order
- KO-Dalneva tablets 5mg+0.625mg+2mg 30 pcs. Krka-Rus LLC
RUB 334 order
