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.
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.
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.
special instructions
If symptoms of angioedema of the larynx and/or vocal folds, lips, tongue, or face appear, the use of Dalneva should be stopped immediately and the patient’s condition should be monitored until signs of edema completely disappear. If necessary (swelling of the tongue or larynx), antihistamine therapy is required, since there is a high risk of airway obstruction and death.
Since intestinal angioedema may develop during the use of ACE inhibitors, this should be taken into account when making a differential diagnosis in patients with abdominal pain and abdominal computed tomography or ultrasound should be used in diagnosis. After discontinuation of the drug, the symptoms disappear.
To prevent the development of anaphylactoid reactions during a desensitizing procedure with hymenoptera venom or low-density lipoprotein apheresis with dextran sulfate, the patient must stop taking the tablets 24 hours before the start of each procedure.
When using high-flow membranes for hemodialysis, the risk of developing anaphylactoid reactions increases, so it is recommended to use a different type of membrane.
It is recommended to accompany the intake of tablets with regular monitoring of the level of leukocytes in the blood plasma.
If a high body temperature, sore throat or other symptoms of an infectious disease appear, the patient should consult a doctor.
In patients with impaired liver function, the activity of liver enzymes should be regularly monitored; if it increases or jaundice develops, immediate discontinuation of the drug is required.
The presence of perindopril in the composition causes a blockade of the renin-aldosterone-angiotensin system, so the use of the drug can contribute to a sharp decrease in blood pressure and/or an increase in the concentration of creatinine in the blood plasma. This usually occurs when you take the first dose or within two weeks of starting therapy.
It is recommended to avoid the simultaneous administration of perindopril and potassium-sparing diuretics, potassium supplements and potassium-containing salt substitutes. If concomitant therapy with potassium-sparing diuretics or potassium preparations is necessary in patients with confirmed hypokalemia, electrocardiographic parameters and the level of potassium in the blood plasma should be regularly monitored.
A dry non-productive cough may occur, associated with the presence of an ACE inhibitor and resolving after discontinuation of the drug.
A necessary condition when treating patients with impaired renal function is regular monitoring of the concentration of creatinine and potassium in the blood plasma.
In patients with chronic heart failure of functional classes III and IV according to the NYHA (New York Heart Association) classification, pulmonary edema may develop while using Dalneva.
During extensive surgery or the use of general anesthesia with a hypotensive effect, a marked decrease in blood pressure may occur in patients taking Dalneva. Therefore, during planned surgery, it is recommended to stop using the drug 24 hours before the start of general anesthesia.
Caution must be exercised when operating vehicles and machinery, as dizziness and other side effects that affect the speed of psychomotor reactions and concentration may occur.
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, 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.
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.
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.
Ko-Dalneva, 30 pcs., 5 mg+0.625 mg+2 mg, tablets
Amlodipine
Concomitant use is not recommended
Dantrolene (intravenous administration).
In laboratory animals, cases of ventricular fibrillation with death and collapse have been reported during the use of verapamil and intravenous administration of dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, it is recommended to avoid the simultaneous use of a CCB (amlodipine) and dantrolene in patients susceptible to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.
Concomitant use requiring special attention
Inducers of the CYP3A4 isoenzyme.
There are no data regarding the effect of inducers of the CYP3A4 isoenzyme on amlodipine. The simultaneous use of inducers of the CYP3A4 isoenzyme (rifampicin, St. John's wort preparations) may lead to a decrease in the concentration of amlodipine in the blood plasma. Caution should be exercised when taking amlodipine simultaneously with inducers of the CYP3A4 isoenzyme.
Inhibitors of the CYP3A4 isoenzyme.
Concomitant use of amlodipine with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungals, macrolides, such as erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients, and therefore monitoring of the clinical condition and dose adjustment may be required.
Concomitant use requiring attention
Amlodipine enhances the antihypertensive effect of drugs for antihypertensive therapy.
Other drug combinations.
In clinical drug interaction studies, amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporine. Concomitant use of amlodipine and consumption of grapefruits or grapefruit juice is not recommended due to the possible increase in the bioavailability of amlodipine in some patients, which may lead to an enhanced antihypertensive effect.
Indapamide
Concomitant use requiring special attention
Drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type.
Given the risk of developing hypokalemia, caution should be exercised when using indapamide simultaneously with drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type, for example, antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylium tosylate, sotalol), some antipsychotics ( chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other antipsychotics (pimozide), other drugs such as bepridil, cisapride, difemanil methyl sulfate, erythromycin IV c, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine IV, methadone, astemizole, terfenadine. Simultaneous use with the above drugs should be avoided; if hypokalemia develops, correct it and monitor the ECG (QT interval).
Drugs that can cause hypokalemia.
Concomitant use with intravenous amphotericin B, systemic corticosteroids and mineralocorticosteroids, tetracosactide, laxatives that stimulate gastrointestinal motility increases the risk of hypokalemia (additive effect). It is necessary to monitor the potassium content in the blood plasma and, if necessary, correct hypokalemia. Particular caution should be observed when used simultaneously with cardiac glycosides. Laxatives that do not stimulate gastrointestinal motility should be used.
Cardiac glycosides.
Hypokalemia enhances the toxic effect of cardiac glycosides. With simultaneous use, you should monitor the potassium content in the blood plasma and ECG indicators and, if necessary, decide on the advisability of continuing therapy.
Concomitant use requiring attention
Metformin.
Functional renal failure, which can occur while taking diuretics, especially loop diuretics, with simultaneous use of metformin increases the risk of developing lactic acidosis. Metformin should not be used if plasma creatinine Cl exceeds 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.
Iodinated contrast agents.
Dehydration while taking diuretics increases the risk of developing acute renal failure, especially when high doses of iodinated contrast agents are administered. Before using iodinated contrast agents, it is necessary to compensate for hypovolemia.
Calcium salts.
With simultaneous use, the development of hypercalcemia may occur due to a decrease in calcium excretion by the kidneys.
Cyclosporine.
It is possible to increase Cl creatinine in blood plasma without changing the concentration of cyclosporine, even with normal water and sodium content.
Perindopril
Concomitant use is not recommended
Aliskiren.
Concomitant use of perindopril with aliskiren is contraindicated in patients with diabetes or moderate to severe renal impairment (creatinine clearance less than 60 ml/min).
Potassium-sparing diuretics, potassium supplements and potassium-containing table salt substitutes.
During therapy with ACE inhibitors, the potassium content in the blood plasma, as a rule, remains within normal limits, but hyperkalemia may develop. Concomitant use of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium supplements and potassium-containing table salt substitutes can lead to a significant increase in potassium levels in the blood plasma. If it is necessary to take an ACE inhibitor simultaneously with the above drugs (in case of hypokalemia), caution should be exercised and regular monitoring of potassium levels in the blood plasma and ECG parameters should be carried out.
Estramustine.
The simultaneous use of ACE inhibitors with estramustine is accompanied by a risk of developing angioedema.
Concomitant use requiring special attention
Double blockade of the RAAS in patients with atherosclerosis, CHF or diabetes mellitus accompanied by target organ damage is associated with a higher incidence of arterial hypotension, fainting, hyperkalemia and renal dysfunction (including the development of acute renal failure) compared with the use of the drug one of the listed groups. Double blockade of the RAAS is possible only in selected cases under careful monitoring of renal function.
NSAIDs, including high doses of acetylsalicylic acid (ASA) (more than 3 g/day).
The simultaneous use of ACE inhibitors with NSAIDs (including ASA at a dose that has an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) can lead to a decrease in the antihypertensive effect, as well as to a deterioration in renal function, including the development of acute renal failure, and an increase in plasma potassium levels blood, especially in patients with reduced renal function. Caution should be exercised when using this combination, especially in elderly patients. Patients need to compensate for fluid loss and regularly monitor kidney function, both at the beginning of treatment and during treatment.
Hypoglycemic agents (sulfonylureas and insulin)
ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylureas in patients with diabetes mellitus. The development of hypoglycemia is very rare (probably due to increased glucose tolerance and decreased insulin requirements).
Concomitant use requiring attention
Diuretics (thiazide and loop).
In patients receiving diuretics, especially those with excessive fluid and/or electrolyte excretion, a significant decrease in blood pressure may be observed when initiating ACE inhibitor therapy. The risk of developing arterial hypotension can be reduced by discontinuing the diuretic, correcting hypovolemia and electrolyte balance, as well as prescribing perindopril in a low dose (2 mg/day), gradually increasing it.
Allopurinol, cytostatic and immunosuppressive drugs, GCS (for systemic use) and procainamide.
Concomitant use with ACE inhibitors may increase the risk of developing leukopenia.
Preparations for general anesthesia.
The simultaneous use of ACE inhibitors and general anesthesia may lead to increased antihypertensive effect.
Gold preparations.
When using ACE inhibitors, incl. perindopril, in patients receiving intravenous gold (sodium aurothiomalate), a symptom complex was described, including facial flushing, nausea, vomiting, and arterial hypotension.
Sympathomimetics.
May weaken the antihypertensive effect of ACE inhibitors.
Gliptins (linagliptin, saxagliptin, sitagliptin, vitagliptin).
Concomitant use with ACE inhibitors may increase the risk of developing angioedema due to the inhibition of dipeptidyl peptidase IV (DPP-IV) activity by gliptin.
Ko-Dalneva®
Concomitant use is not recommended
Lithium preparations.
With the simultaneous use of ACE inhibitors with lithium preparations, a reversible increase in the concentration of lithium in the blood plasma may occur with the development of intoxication. Concomitant use with thiazide diuretics may further increase lithium concentrations and increase the risk of intoxication. The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. In the case of this therapy, regular monitoring of the concentration of lithium in the blood plasma is necessary.
Concomitant use requiring special attention
Baclofen.
The antihypertensive effect may be enhanced. Blood pressure and renal function should be monitored and, if necessary, the dose of antihypertensive drugs should be adjusted.
Concomitant use requiring attention
Antihypertensives (eg beta-blockers) and vasodilators.
When used simultaneously with antihypertensive drugs, the antihypertensive effect 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 (fluid and sodium retention 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.
Amifostine.
The antihypertensive effect of amlodipine may be enhanced.
Tricyclic antidepressants/neuroleptics/general anesthesia.
Strengthening the antihypertensive effect and increasing the risk of developing orthostatic hypotension (additive effect).
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
- KO-Dalneva tablets 5mg+1.25mg+4mg 30 pcs. Krka-Rus LLC
544 rub. order - Dalneva tab. 10mg+ 8mg n30Krka-Rus LLC
RUR 555 order
- Dalneva tab. 5mg+ 8mg n30Krka-Rus LLC
RUR 564 order
- Dalneva tab. 5mg+ 4mg n30Krka-Rus LLC
RUB 421 order
- KO-Dalneva tablets 5mg+2.5mg+8mg 30 pcs. Krka-Rus LLC
RUR 623 order
Release form and composition
Dalneva is available in the form of almost white or white tablets: 5 mg + 4 mg – slightly biconvex round, with a chamfer; 10 mg + 4 mg – biconvex capsule-shaped, on one side there is a dividing line; 5 mg + 8 mg – round biconvex shape, with a chamfer; 10 mg + 8 mg – round, biconvex shape, with a chamfer and a dividing line on one side (10 pcs. in a blister pack, 3 or 9 packs in a cardboard box).
1 tablet contains:
- active ingredients: amlodipine besylate + perindopril erbumine A (in the form of granules) – 6.935 mg + 21 mg, 13.87 mg + 21 mg, 6.935 mg + 42 mg or 13.87 mg + 42 mg, which is equivalent to the content of 5 mg + 4 mg, 10 mg + 4 mg, 5 mg + 8 mg or 10 mg amlodipine + 8 mg perindopril erbumine;
- auxiliary components: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate.
