Cardace-AM

Cardace-AM

Amlodipine, Ramipril

Hypertension (patients who are indicated for combination therapy with amlodipine and ramipril in doses, as in combination).

Inside, 1 capsule once a day, at the same time, regardless of the meal.

The dose of the drug AKIpress^® It is selected after previously performed titration of the doses of individual components of the drug: ramipril and amlodipine in patients with hypertension. Drug AKIpress^® with fixed doses of active components, it can not be used for initial therapy. If patients need dose adjustment, it should be carried out only by titrating the doses of active components in monotherapy. Only then is it possible use of the drug AKIpress^® with fixed doses of the active ingredients in the following combinations.

In case of therapeutic necessity, the dose of the drug Aegipres^® It can be changed based on individual titration of the doses of individual components: 5 mg of amlodipine 5 mg of ramipril or 5 mg of amlodipine 10 mg of ramipril or 10 mg of amlodipine 5 mg of ramipril or 10 mg of amlodipine 10 mg of ramipril.

AKIpress^® at a dose of 10 mg of amlodipine, 10 mg of ramipril is the maximum daily dose of the drug, which is not recommended to be exceeded. Dosages of 10 mg of amlodipine 5 mg of ramipril (for amlodipine) and 5 mg of amlodipine 10 mg of ramipril (for ramipril) are the maximum daily doses.

Adult patients

In patients taking diuretics, the drug should be prescribed with caution, due to the risk of a violation of the water-electrolyte balance. In these patients, kidney function and blood potassium levels should be monitored.

Elderly patients and patients with renal insufficiency. The elimination of amlodipine and ramipril and its metabolites in elderly patients and patients with renal insufficiency is slowed. Therefore, in such patients, it is necessary to regularly monitor the content of creatinine and potassium in the blood plasma. AKIpress^® It can be prescribed to patients with a creatinine Cl equal to or greater than 60 ml / min. In patients with creatinine Cl <60 ml/min, as well as in patients with hypertension undergoing hemodialysis, Aegipres^® It is recommended only for patients who received 5 mg of ramipril as the optimal maintenance dose during the titration of the individual dose. There is no need to titrate the individual dose of amlodipine in patients with impaired renal function. AKIpress^® contraindicated in patients with creatinine Cl <20 ml / min/1.73 m². Changes in the concentration of amlodipine in the blood plasma do not correlate with the severity of renal failure.

Patients with hepatic insufficiency. Caution should be exercised in the appointment of Emipres^® patients with hepatic insufficiency due to the lack of recommendations for the dosage of the drug in such patients. AKIpress^® It is recommended only for patients who received 2.5 mg of ramipril as the optimal maintenance dose during the individual dose titration process.

Children and teenagers

AKIpress^® it should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the effectiveness and safety of ramipril and amlodipine in these groups of patients, both in the form of monotherapy and in the form of combination therapy.

Amlodipine

hypersensitivity to amlodipine and other dihydropyridine derivatives,

severe arterial hypotension (sAD less than 90 mmHg), shock (including cardiogenic),

obstructive process that impedes the release of blood from the left ventricle (for example, clinically significant aortic stenosis),

hemodynamically unstable heart failure after myocardial infarction,

pregnancy,

breastfeeding period,

under 18 years of age (safety and efficacy not determined).

Ramipril

hypersensitivity to ramipril, other ACE inhibitors,

a history of angioedema (hereditary or idiopathic, as well as associated with previous therapy with ACE inhibitors),

hemodynamically significant renal artery stenosis (bilateral or unilateral, in the case of a single kidney),

arterial hypotension (sBP less than 90 mm Hg) or conditions with unstable hemodynamic parameters,

hemodynamically significant aortic or mitral valve stenosis or hypertrophic obstructive cardiomyopathy,

primary hyperaldosteronism,

severe renal insufficiency (Creatinine Cl <20 ml / min/1.73 m²),

hemodialysis (clinical experience is insufficient),

nephropathy, which is treated with corticosteroids, NSAIDs, immunomodulators and/or other cytotoxic agents (clinical experience is insufficient),

decompensated chronic heart failure (clinical experience is insufficient),

hemodialysis or hemofiltration using certain types of membranes with a negatively charged surface, such as high-flow polyacrylonitrile membranes (risk of hypersensitivity reactions),

LDL apheresis with dextran sulfate (risk of hypersensitivity reactions),

desensitizing therapy for hypersensitivity reactions to insect poisons-bees, wasps,

acute stage of myocardial infarction in patients with diseases such as severe heart failure (NYHA functional class IV), life-threatening ventricular arrhythmias, pulmonary heart disease,

concomitant use of drugs containing aliskiren in patients with impaired renal function (creatinine Cl less than 60 ml / min) and patients with diabetes mellitus,

pregnancy,

breastfeeding period,

age up to 18 years (experience of clinical use is insufficient).

Amlodipine ramipril

hypersensitivity to the excipients that are part of the drug,

renal insufficiency (Creatinine Cl <20 ml / min/1.73 m²),

pregnancy,

breastfeeding period,

age up to 18 years (experience of clinical use is insufficient).

With caution for the amlodipine ramipril combination: atherosclerotic lesions of the coronary and cerebral arteries (risk of excessive lowering of blood pressure), increased activity of the RAAS, in which, with ACE inhibition, there is a risk of a sharp decrease in blood pressure with deterioration of renal function, pronounced, especially malignant hypertension, CHF, especially severe or for which other drugs with antihypertensive effects are taken, hemodynamically significant unilateral stenosis of the renal artery (in the presence of both kidneys), previous use of diuretics, water-electrolyte balance disorders, decreased blood pressure, BCC (in t.tsch. in patients receiving diuretics, salt-free diet, diarrhoea, vomiting, sweating), concurrent use with drugs containing aliskiren (if dual blockade of RAAS increases the risk of a sharp decline in blood pressure, hyperkalemia and deterioration of renal function), the liver (lack of experience of application: might as strengthening and weakening effects of ramipril in the presence in patients of liver cirrhosis with ascites and edema may be a significant activation of the RAAS), impaired renal function (Cl creatinine of more than 20 ml/min), condition after kidney transplantation, systemic diseases of connective tissue t.tsch. systemic lupus erythematosus, scleroderma, concomitant therapy with drugs that can cause changes in the picture of peripheral blood (in t.tsch.^®).

The following undesirable effects are given in accordance with the following gradations frequency of their occurrence according to the who classification: very often — more than 1/10 (10%), often more than 1/100, but less than 1/10 (more than 1% but less than 10%), infrequently — over 1/1000 but less than 1/100 (more than 0.1% but < 1%), rarely more than 1/10000, but at least 1/1000 (more than 0.01%, but less than 0.1%), very rarely — less than 1/10000 (0.01%).

Amlodipine

From the CCC side: often-peripheral edema (ankles and feet), palpitations, infrequently-excessive decrease in blood pressure, orthostatic hypotension, vasculitis, rarely-development or aggravation of HF, very rarely-cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), MI, chest pain, migraine.

From the musculoskeletal system and connective tissue: infrequently-arthralgia, muscle cramps, myalgia, back pain, arthrosis, rarely-myasthenia gravis.

From the central nervous system and peripheral nervous system: often — a feeling of heat and blood flushes to the skin of the face, increased fatigue, dizziness, headache, drowsiness, infrequently — malaise, fainting, increased sweating, asthenia, hypesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, unusual dreams, nervousness, depression, anxiety, rarely — convulsions, apathy, very rarely — ataxia, amnesia, individual cases have been reported extrapyramidal syndrome.

From the digestive system: often-abdominal pain, nausea, infrequently-vomiting, changes in the mode of defecation (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dryness of the oral mucosa, thirst, rarely-gum hyperplasia, increased appetite, very rarely-gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased activity of hepatic transaminases, hepatitis.

From the blood side: very rarely — thrombocytopenic purpura, thrombocytopenia, leukopenia.

Metabolic disorders: very rarely — hyperglycemia.

From the respiratory system: infrequently-shortness of breath, rhinitis, very rarely — cough.

From the kidneys and urinary tract: infrequently-frequent urination, painful urination, nocturia, impotence, very rarely-dysuria, polyuria.

Allergic reactions: infrequently-skin itching, rash, very rarely-angioedema, erythema multiforme, urticaria.

Other: infrequently — alopecia, tinnitus, gynecomastia, weight gain/loss, visual impairment, diplopia, accommodation disorder, xerophthalmia, conjunctivitis, eye pain, taste perversion, chills, nosebleeds, rarely — dermatitis, very rarely — parosmia, xeroderma, cold sweat, skin pigmentation disorder.

Ramipril

From the heart: infrequently-myocardial ischemia, including the development of an attack of angina or MI, tachycardia, arrhythmias (appearance or increase), palpitations, peripheral edema.

From the side of the vessels: often-excessive decrease in blood pressure, violation of orthostatic regulation of vascular tone (orthostatic hypotension), syncopal states, infrequently-flushes of blood to the skin of the face, rarely-the occurrence or increase of circulatory disorders against the background of stenotic vascular lesions, vasculitis, the frequency is unknown-Raynaud's syndrome.

From the central nervous system: often-headache, a feeling of lightness in the head, infrequently-dizziness, ageusia (loss of taste sensitivity), dysgeusia (violation of taste sensitivity), paresthesia (burning sensation), rarely-tremor, balance disorder, frequency unknown-cerebral ischemia, including ischemic stroke and transient cerebrovascular accident, psychomotor disorders, parosmia (violation of smell perception).

On the part of the visual organ: infrequently-visual disturbances, including blurred visual perception, rarely-conjunctivitis.

On the part of the hearing organ: rarely — hearing disorders, ringing in the ears.

From the side of the psyche: infrequently-depressed mood, anxiety, nervousness, motor restlessness, sleep disorders, including drowsiness, rarely-confusion, frequency unknown-impaired concentration.

From the respiratory system: often-dry cough (increasing at night and in a lying position), bronchitis, sinusitis, shortness of breath, infrequently — bronchospasm, including the aggravation of the course of bronchial asthma, nasal congestion.

From the digestive system: often — inflammatory reactions in the stomach and intestines, digestive disorders, a feeling of discomfort in the abdomen, dyspepsia, diarrhea, nausea, vomiting, infrequently — pancreatitis, including with a fatal outcome (cases of pancreatitis with a fatal outcome when taking ACE inhibitors were extremely rare), increased activity of pancreatic enzymes in blood plasma, intestinal angioedema, abdominal pain, gastritis, constipation, dryness of the oral mucosa, rarely — glossitis, the frequency is unknown — aphthous stomatitis (inflammatory reaction of the oral mucosa).

From the side of the hepatobiliary system: infrequently-an increase in the activity of liver enzymes and the content of conjugated bilirubin in blood plasma, rarely-cholestatic jaundice, hepatocellular lesions, the frequency is unknown-acute liver failure, cholestatic or cytolytic hepatitis (fatal outcome was extremely rare).

From the kidneys and urinary tract: infrequently-impaired renal function, including the development of acute renal failure, increased urinary excretion, increased pre-existing proteinuria, increased concentration of urea and creatinine in the blood.

On the part of the reproductive system and mammary glands: infrequently-transient impotence due to erectile dysfunction, decreased libido, frequency unknown-gynecomastia.

From the blood and lymphatic system: infrequently-eosinophilia, rarely-leukopenia, including neutropenia and agranulocytosis, a decrease in the number of red blood cells in the peripheral blood, a decrease in hemoglobin, thrombocytopenia, the frequency is unknown — suppression of bone marrow hematopoiesis, pancytopenia, hemolytic anemia.

From the skin and mucous membranes: often — skin rash, in particular maculopapular, infrequently — angioedema, including with a fatal outcome (laryngeal edema can cause airway obstruction, leading to a fatal outcome), itching, hyperhidrosis (increased sweating), rarely — exfoliative dermatitis, urticaria, onycholysis, very rarely — photosensitization reactions, frequency unknown — toxic epidermal necrolysis, syndrome Stevens-Johnson, erythema multiforme, pemphigus, aggravation of the course of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid (lichen) exanthema or enanthema, alopecia.

From the musculoskeletal system and connective tissue: often-muscle cramps, myalgia, infrequently-arthralgia.

From the side of metabolism, nutrition and laboratory parameters: often-an increase in the content of potassium in the blood, infrequently-anorexia, decreased appetite, the frequency is unknown-a decrease in the concentration of sodium in the blood, the syndrome of inadequate ADH secretion.

On the part of the immune system: the frequency is unknown — anaphylactic or anaphylactoid reactions (with ACE inhibition, the number of anaphylactic or anaphylactoid reactions to insect poisons increases), an increase in the titer of antinuclear antibodies.

General violations: often-chest pain, fatigue, infrequently-fever, rarely-asthenia (weakness).

Information on overdose of the drug AKIpress^® absent.

Amlodipine

Symptoms: a marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation (there is a possibility of severe and persistent arterial hypotension, including with the development of shock and death).

Treatment: administration of activated charcoal (especially in the first 2 hours after overdose), gastric lavage, elevation of the limbs, active maintenance of CCC functions, monitoring of heart and lung performance, control of BCC and diuresis. To restore vascular tone and blood pressure, if there are no contraindications, it may be useful to use vasoconstrictors. Use the intravenous administration of calcium gluconate. Amlodipine is largely bound to serum proteins, so hemodialysis is ineffective.

Ramipril

Symptoms: excessive peripheral vasodilation with the development of a pronounced decrease in blood pressure, shock, bradycardia or reflex tachycardia, water-electrolyte disorders, acute renal failure, stupor.

Treatment: gastric lavage, administration of adsorbents, sodium sulfate (if possible during the first 30 minutes). In the case of a pronounced decrease in blood pressure, the patient should be laid down, the legs should be raised, the CCC functions should be actively maintained, alpha administration can be added to therapy to replenish the BCC and restore the electrolyte balance₁- adrenergic agonists (norepinephrine, dopamine) and angiotensinamide. In the case of drug-resistant bradycardia, it may be necessary to install a temporary artificial pacemaker. In case of overdose, it is necessary to monitor the content of creatinine and electrolytes in the blood serum. Ramiprilat is poorly excreted from the blood by hemodialysis.

Amlodipine

A derivative of dihydropyridine. Binding to dihydropyridine receptors, it blocks slow calcium channels, inhibits the transmembrane transfer of calcium into the cells of vascular smooth muscles and the heart (to a greater extent - into vascular smooth muscle cells than into cardiomyocytes). It has antihypertensive and antianginal effects.

The mechanism of antihypertensive action of amlodipine is due to the direct relaxing effect on the smooth muscles of the vessels.

Amlodipine reduces myocardial ischemia in the following two ways:

1. Expands the peripheral arterioles and thus reduces the heart rate (afterload), while the heart rate practically does not change, which leads to a decrease in energy consumption and myocardial oxygen demand.

2. Dilates the coronary and peripheral arteries and arterioles in both normal and ischemic areas of the myocardium, which increases the oxygen supply to the myocardium in patients with vasospastic angina (Prinzmetal angina) and prevents the development of coronary spasm caused by smoking.

In patients with arterial hypertension (AH), the daily dose of amlodipine provides a decrease in blood pressure for 24 hours (both in the supine and standing position). Due to the slow onset of action, amlodipine does not cause a sharp decrease in blood pressure.

In patients with angina pectoris, a single daily dose of the drug increases the duration of physical activity, delays the development of another attack of angina pectoris and ST-segment depression (by 1 mm) against the background of physical activity, reduces the frequency of angina attacks and the need for nitroglycerin.

The use of amlodipine in patients with CHD.

The use of amlodipine in patients with heart failure (HF). Amlodipine does not increase the risk of death or the development of complications and deaths in patients with CHF of functional class III–IV (FC) according to the classification of the New York Heart Association (NYHA) on the background of therapy with digoxin, diuretics and ACE inhibitors. In patients with CHF III-IV FC according to NYHA of non-ischemic etiology, when using amlodipine, there is a possibility of pulmonary edema. Amlodipine does not cause adverse metabolic effects, including it does not affect the parameters of the lipid profile.

Ramipril

Ramiprilate, formed with the participation of liver enzymes, the active metabolite of ramipril, is a long-acting inhibitor of the enzyme dipeptidyl carboxypeptidase I (synonyms-ACE, kininase II). In blood plasma and in tissues, this enzyme kininase II catalyzes the conversion of angiotensin I to the active vasoconstrictor-angiotensin II, and also promotes the breakdown of bradykinin. Reducing the formation of angiotensin II and inhibiting the breakdown of bradykinin leads to vasodilation and a decrease in blood pressure. An increase in the activity of the kallikrein-kinin system in blood and tissues causes the cardioprotective and endothelioprotective effects of ramipril due to the activation of the PG system and, accordingly, an increase in the synthesis of PG that stimulate the formation of nitric oxide (NO) in endotheliocytes. Angiotensin II stimulates the production of aldosterone, so taking ramipril leads to a decrease in the secretion of aldosterone and an increase in the content of potassium ions in the serum

With a decrease in the content of angiotensin II in the blood, its inhibitory effect on renin secretion is eliminated by the type of negative feedback, which leads to an increase in the activity of plasma renin.

It is assumed that the development of some adverse reactions (in particular, dry cough) is associated with an increase in the activity of bradykinin.

In patients with hypertension taking ramipril leads to a decrease in blood pressure in the supine and standing positions, without a compensatory increase in heart rate. Ramipril significantly reduces OPSS, almost without causing changes in renal blood flow and glomerular filtration rate. The antihypertensive effect begins to manifest itself in 1-2 hours after ingestion of a single dose of the drug, reaching the highest value in 3-6 hours, and persists for 24 hours. With a course of administration, the antihypertensive effect can gradually increase, usually stabilizing by the 3rd-4th week of regular administration of the drug and then remaining for a long time. Sudden discontinuation of the drug does not lead to a rapid and significant increase in blood pressure (no withdrawal syndrome)

In patients with hypertension, ramipril slows the development and progression of myocardial hypertrophy and vascular wall.

In patients with CHF ramipril reduces OPSS (reduction of afterload on the heart), increases the capacity of the venous bed and reduces the filling pressure of the left ventricle( LV), which accordingly leads to a decrease in preload on the heart. In these patients, when taking ramipril, there is an increase in cardiac output, ejection fraction, and improved exercise tolerance.

In diabetic and non-diabetic nephropathy taking ramipril slows down the rate of progression of renal failure and the time of onset of end-stage renal failure and thus reduces the need for hemodialysis or kidney transplantation procedures. In the initial stages of diabetic or non-diabetic nephropathy, ramipril reduces the severity of albuminuria.

In patients at high risk of developing CVD diseases due to the presence of vascular lesions (diagnosed CHD, a history of peripheral artery obliteration, a history of stroke) or diabetes mellitus with at least one additional risk factor (microalbuminuria, hypertension, increased total cholesterol, decreased HDL cholesterol, smoking), the addition of ramipril to standard therapy significantly reduces the incidence of MI, stroke, and mortality from cardiovascular causes.

In addition, ramipril reduces the overall mortality rate, as well as the need for revascularization procedures, slows the occurrence or progression of CHF.

In patients with HF that developed in the first days of acute MI (AMI) (Day 2-9), when taking ramipril, starting from day 3 to day 10 of AMI, the risk of mortality is reduced (by 27%), the risk of sudden death (by 30%), the risk of progression of CHF to severe — III–IV FC NYHA, resistant to therapy (by 27%), the probability of subsequent hospitalization due to the development of HF (by 26%). In the general population of patients, as well as in patients with diabetes mellitus, both with hypertension and with normal blood pressure, ramipril significantly reduces the risk of developing nephropathy and the occurrence of microalbuminuria.

Amlodipine

After oral administration in therapeutic doses, amlodipine is well absorbed, the time to reach C_max in the blood plasma with oral administration is 6-12 hours. The absolute bioavailability is 64-80%. V_d it is approximately 21 l/kg. The binding to plasma proteins is approximately 97.5%. Food intake does not affect the absorption of amlodipine. The drug penetrates through the BBB.

T_1/2 from the blood plasma is about 35-50 hours, which corresponds to the appointment of the drug 1 time per day. In patients with hepatic insufficiency and severe CHF T_1/2 increases to 56-60 hours.

The total clearance is 0.43 l / h / kg.

Stable C_ss (5-15 ng / ml) is achieved after 7-8 days of continuous intake of amlodipine, it is metabolized in the liver to form inactive metabolites. 10% of the original drug and 60% of the metabolites are excreted by the kidneys, and 20% - through the intestine. Excretion in breast milk is unknown. During hemodialysis, amlodipine is not removed.

Special patient groups

Kidney failure. T_1/2 from the blood plasma in patients with renal insufficiency increases to 60 hours. Changes in the concentration of amlodipine in the blood plasma do not correlate with the degree of impaired renal function.

Elderly patients. Time to reach S_max and with_max amlodipine is virtually indistinguishable from those in younger patients. In elderly patients suffering from CHF, there is a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and T_1/2 up to 65 hours.

Ramipril

After oral administration, it is rapidly absorbed from the gastrointestinal tract (50-60%). Food intake slows its absorption, but does not affect the degree of absorption. Ramipril undergoes intensive presystemic metabolism/activation (mainly in the liver, by hydrolysis), resulting in the formation of its only active metabolite — ramiprilat, whose activity for ACE inhibition is approximately 6 times higher than that of ramipril. In addition, as a result of the metabolism of ramipril, diketopiperazine, which does not have pharmacological activity, is formed, which then undergoes conjugation with glucuronic acid. Ramiprilat also glucuronides and metabolized to diketopiperazine acid. The bioavailability of ramipril after oral administration ranges from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). The bioavailability of ramiprilate after oral administration of 5 mg of ramipril is approximately 45% (compared to its bioavailability after intravenous administration at the same doses)

After taking ramipril inside, the time to reach C_max ramipril and ramiprilate are 1 and 2-4 hours, respectively. The decrease in the concentration of ramiprilate in the blood plasma occurs in several stages: the phase of distribution and elimination with T_1/2 ramiprilate, which is approximately 3 h, followed by an intermediate phase with T_1/2 ramiprilate, which is approximately 15 h, and the final phase with a very low concentration of ramiprilate in the blood plasma and T_1/2 ramiprilate, which is approximately 4-5 days. This final phase is due to the slow release of ramiprilate from its strong binding to ACE receptors. Despite the prolonged final phase, with a single oral dose of ramipril at a dose of 2.5 mg or more, C_ss ramiprilat is achieved after approximately 4 days of treatment. In case of course administration of the drug effective T_1/2 (depending on the dose) is 13-17 hours.

The binding to plasma proteins is approximately 73% for ramipril and 56% for ramiprilate.

After I / V introduction V_d ramipril and ramiprilate are approximately 90 and 500 liters, respectively.

After ingestion of the labeled radioactive isotope ramipril (10 mg), 39% of the radioactivity is excreted through the intestine and about 60% - by the kidneys. After intravenous administration of ramipril, 50-60% of the dose is detected in the urine in the form of ramipril and its metabolites. After intravenous administration of ramiprilat-about 70% of the dose is detected in the urine in the form of ramiprilat and its metabolites, in other words, with intravenous administration of ramipril and ramiprilat, a significant part of the dose is excreted through the intestine with bile, bypassing the kidneys (50 and 30%, respectively). After oral administration of 5 mg of ramipril in patients with bile duct drainage, almost the same amounts of ramipril and its metabolites are excreted by the kidneys and through the intestine during the first 24 hours after administration

Approximately 80-90% of the metabolites in the urine and bile were identified as ramiprilate and ramiprilate metabolites. Ramipril glucuronide and ramipril diketopiperazine make up approximately 10-20% of the total amount, and the content of non-metabolized ramipril in the urine is approximately 2%.

With impaired renal function with a creatinine Cl of less than 60 ml / min, the excretion of ramiprilate and its metabolites by the kidneys slows down. This leads to an increase in the concentration of ramiprilate in the blood plasma, which decreases more slowly than in patients with normal renal function. When taking ramipril in high doses (10 mg), impaired liver function leads to a slowdown in the presystemic metabolism of ramipril to active ramiprilate and a slower elimination of ramiprilate. In healthy volunteers and patients with hypertension after 2 weeks of treatment with ramipril at a daily dose of 5 mg, there is no clinically significant accumulation of ramipril and ramiprilate. In patients with CHF, after 2 weeks of treatment with ramipril at a daily dose of 5 mg, there is an increase of 1.5–1.8 times in the concentrations of ramiprilate in blood plasma and AUC

In healthy elderly volunteers (65-76 years), the pharmacokinetics of ramipril and ramiprilate do not differ significantly from those in young healthy volunteers.

• Antihypertensive agent combined (angiotensin converting enzyme inhibitor blocker of "slow" calcium channels) [ACE inhibitors in combinations]
• Antihypertensive agent combined (angiotensin converting enzyme inhibitor blocker of "slow" calcium channels) [Calcium channel blockers in combinations]

Amlodipine

It can be expected that inhibitors of enzymes of microsomal liver oxidation (erythromycin-in the young, diltiazem-in the elderly, ketoconazole, itraconazole, ritonavir) will increase the concentration of amlodipine in the blood plasma, increasing the risk of side effects, and inducers of enzymes of microsomal liver oxidation — reduce. When amlodipine is co-administered with cimetidine, the pharmacokinetics of amlodipine do not change.

Simultaneous single intake of 240 ml of grapefruit juice and 10 mg of amlodipine inside is not accompanied by a significant change in the pharmacokinetics of amlodipine. Unlike other BCCs, there was no clinically significant interaction of amlodipine (generation III BCCs) when co-administered with NSAIDs, especially indomethacin.

It is possible to increase the antianginal and antihypertensive effects of BCC when used together with thiazide and loop diuretics, verapamil, ACE inhibitors, beta-blockers and nitrates, as well as to increase their antihypertensive effect when used together with alpha₁- adrenoblockers, neuroleptics. Although a negative inotropic effect was not usually observed in the study of amlodipine, however, some BCC may increase the severity of the negative inotropic effect of antiarrhythmic drugs that cause prolongation of the QT interval (for example, amiodarone and quinidine).

With the combined use of BCC with lithium preparations (no data are available for amlodipine), their neurotoxicity may increase (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Amlodipine has no effect in vitro the degree of binding to plasma proteins of digoxin, phenytoin, warfarin and indomethacin.

A single dose of aluminum / magnesium-containing antacids does not significantly affect the pharmacokinetics of amlodipine.

A single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the pharmacokinetics of amlodipine.

Repeated use of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin. With the simultaneous use of amlodipine with digoxin in healthy volunteers, the content of digoxin in the serum and its renal clearance do not change. With a single and repeated use at a dose of 10 mg, amlodipine does not significantly affect the pharmacokinetics of ethanol.

Amlodipine does not affect the change in PV caused by warfarin. Amlodipine does not cause significant changes in the pharmacokinetics of cyclosporine.

Not recommended combinations

Simultaneous use of dantrolene (intravenous administration), inducers of cytochrome CYP3A4 isoenzymes (for example, rifampicin, St. John's wort preparations) and inhibitors of cytochrome CYP3A4 isoenzymes (protease inhibitors, antifungal drugs of the azole group, macrolides (for example, erythromycin or clarithromycin), verapamil or diltiazem).

Ramipril

Contraindicated combinations

Application of some high-flow membranes with a negatively charged surface (for example, polyacrylonitrile membranes) during hemodialysis or hemofiltration, the use of dextran sulfate in LDL apheresis is a risk of severe anaphylactic reactions.

Not recommended combinations

With potassium salts, potassium-sparing diuretics (for example, amiloride, triamterene, spironolactone) and other drugs, including angiotensin II receptor antagonists (ARA II), trimethoprim, tacrolimus, cyclosporine - possible development of hyperkalemia (with simultaneous use, regular monitoring of the content of potassium in the blood serum is required).

Combinations that should be used with caution

With antihypertensive agents (especially diuretics) and other drugs that reduce blood pressure (nitrates, tricyclic antidepressants, agents for general and local anesthesia, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin),- potentiation of the antihypertensive effect. When combined with diuretics, the sodium content in the blood serum should be monitored.

With sleeping pills, narcotic drugs and other painkillers - a more pronounced decrease in blood pressure is possible.

With vasopressor sympathomimetics (epinephrine, isoproterenol, dobutamine, dopamine) - reducing the antihypertensive effect of ramipril, regular blood pressure monitoring is required.

With allopurinol, procainamide, cytostatics, immunosuppressants, systemic corticosteroids and other agents that may affect hematological parameters,- co-administration increases the risk of developing leukopenia.

With lithium salts - increased serum lithium content and increased cardio - and neurotoxic effects of lithium.

With hypoglycemic agents for oral administration (sulfonylurea derivatives, biguanides), insulin — due to the decrease in insulin resistance under the influence of ramipril, it is possible to increase the hypoglycemic effect of these drugs, up to the development of hypoglycemia.

Simultaneous use of drugs containing aliskiren, in patients with diabetes mellitus and renal insufficiency (creatinine Cl less than 60 ml / min), as well as with vildagliptin — due to an increase in the frequency of angioedema when used concomitantly with ACE inhibitors.

Combinations to take into account

With NSAIDs (indomethacin, acetylsalicylic acid) - it is possible to weaken the action of ramipril, increase the risk of impaired renal function and increase the content of potassium in the blood serum.

With heparin - it is possible to increase the content of potassium in the blood serum.

With sodium chloride - weakening of the antihypertensive effect of ramipril and less effective treatment of CHF symptoms.

With ethanol - increased symptoms of vasodilation. Ramipril may increase the adverse effects of ethanol on the body.

With estrogens - weakening of the antihypertensive effect of ramipril (fluid retention).

Desensitizing therapy for hypersensitivity to insect poisons - ACE inhibitors, including ramipril, increase the likelihood of severe anaphylactic or anaphylactoid reactions to insect poisons.