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.
Ko-Dalneva, tablets 5 mg+0.625 mg+2 mg, 30 pcs.
In some patients with arterial 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 a combination of perindopril and indapamide in low doses, 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 chronic heart failure or underlying renal impairment, incl. with renal artery stenosis. The drug is not recommended for use in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.
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 2 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.
Before starting to use the combination, it is necessary to assess 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.
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.
Amlodipine
In patients with chronic heart failure (FC III and IV according to the NYHA classification), treatment is carried out with caution, due to the possibility of developing pulmonary edema. Calcium channel blockers, including amlodipine, should be used with caution in patients with chronic heart failure due to the possible increased risk of cardiovascular adverse events and mortality.
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.
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.
Cases of photosensitivity reactions have been reported with the use of 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 UV rays.
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.
Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. Hypokalemia (less than 3.4 mmol/l) should be avoided in the following categories of high-risk patients: elderly patients, malnourished patients, patients with cirrhosis, incl. with edema and ascites, patients with ischemic heart disease, chronic heart failure. 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.
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.
In patients with elevated concentrations of uric acid in the blood plasma, the frequency of gout attacks may increase during therapy.
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.
Indapamide may give a positive reaction during doping control.
Perindopril
Neutropenia/agranulocytosis, thrombocytopenia and anemia may occur during the use of ACE inhibitors. 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.
Against the background of the use of ACE inhibitors, incl. and 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 C-1 esterase. The diagnosis was made using CT scan, abdominal ultrasound, 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.
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.
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.
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.
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 the use of an ACE inhibitor. If it is necessary to use drugs in this group, taking an ACE inhibitor can be continued.
ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and mitral stenosis.
In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, regular monitoring of plasma glucose concentrations is necessary during the first month of treatment with an ACE inhibitor.
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 inhibitors, incl. perindopril, 24 hours before surgery.
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.
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 or the appearance of jaundice while taking ACE inhibitors, you should stop taking the drug and continue to monitor the patient.
Hyperkalemia may develop during the use of an ACE inhibitor. Risk factors for hyperkalemia are renal failure, old age (over 70 years), diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium supplements , potassium-containing substitutes for table salt, as well as other drugs that help increase the content of potassium in the blood plasma (for example, heparin) (especially in patients with reduced renal function). Hyperkalemia can lead to serious, sometimes fatal, heart rhythm disturbances. If necessary, simultaneous use of the drug with the above drugs should be used with caution and regularly monitor the potassium content in the blood plasma.
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 diagnosed or suspected renal artery stenosis, treatment should be initiated with lower doses of the combination. Some patients may develop functional renal failure, which resolves after discontinuation of the drug.
Impact on the ability to drive vehicles and machinery
Due to the possibility of weakness and dizziness during the use of this combination, care must be taken when driving vehicles and working with other technical devices that require increased concentration and speed of psychomotor reactions.
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 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
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®
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.
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, tablets 5 mg+4 mg, 30 pcs.
Perindopril
Concomitant use is not recommended
Potassium-sparing diuretics, potassium supplements 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 toxic effects have been reported. 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 angioedema.
Concomitant use requiring 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 kidney function, both at the beginning and during treatment.
Hypoglycemic drugs (oral hypoglycemic agents and/or insulin): the use of ACE inhibitors may enhance the hypoglycemic effect of insulin or sulfonylureas 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 those with excessive fluid and/or electrolyte excretion, a significant decrease in blood pressure may be observed when starting the use of 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 may reduce the hypotensive effect of ACE inhibitors.
Gold preparations: patients receiving simultaneous injection therapy with gold preparations (sodium aurothiomalate) and ACE inhibitors, including perindopril, rarely experience nitrate-like reactions (“flushes” of blood to the facial skin, nausea, vomiting, decreased blood pressure).
Allopurinol, cytostatic and immunosuppressive drugs, corticosteroids (for 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 enhanced hypotensive effect.
Amlodipine
Concomitant use is not recommended
Dantrolene (IV): In animal experiments, cases of fatal ventricular fibrillation and cardiovascular failure associated with hyperkalemia were observed after administration of verapamil and dantrolene (IV). Given the risk of hyperkalemia, 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 decrease in the plasma concentration of amlodipine is possible due to increased 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): the plasma concentration of amlodipine may increase and the risk of side effects may increase, especially in elderly patients. Caution should be exercised during simultaneous use and, if necessary, the dose of amlodipine should be adjusted.
Concomitant use requiring attention
The 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 of CHF in patients with uncontrolled or latent CHF (increased negative inotropic effect). In addition, β-blockers can reduce excessive reflex cardiac sympathetic activation associated with 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 the simultaneous use of amlodipine and sildenafil, there was no increase in the hypotensive effect of either drug.
Grapefruit juice: Taking 240 ml of grapefruit juice 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 taking 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®
Concomitant use requiring special attention
Baclofen: possible potentiation of hypotensive effect. Monitoring of blood pressure and renal function is necessary, as well as dose adjustment of amlodipine.
Concomitant use requiring attention
Antihypertensives (for example, beta-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, since an additional decrease in blood pressure may occur.
Corticosteroids (mineralocorticosteroids and corticosteroids), tetracosactide: decreased hypotensive effect (retention of fluid and sodium ions as a result of the action of corticosteroids).
α-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): increased hypotensive effect and increased risk of orthostatic hypotension.
Amifostine: may potentiate the hypotensive effect of amlodipine.
Tricyclic antidepressants/antipsychotics/general anesthesia: increased hypotensive effect and increased risk of 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.
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- Dalneva tab. 5mg+ 4mg n30Krka-Rus LLC
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- KO-Dalneva tablets 5mg+1.25mg+4mg 30 pcs. Krka-Rus LLC
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- KO-Dalneva tablets 5mg+2.5mg+8mg 30 pcs. Krka-Rus LLC
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