Amlodipine + Ramipril - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Calcium channel blockers

ACE Inhibitors

Included in the formulation

Prilar®

capsules inwards

Sandoz d. Slovenia

Egipres®

capsules inwards

Egis Pharmaceutical Plant OJSC Hungary

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

ONLS

АТХ:

C.09.B.B ACE inhibitors in combination with calcium channel blockers

Pharmacodynamics:

Amlodipine is a dihydropyridine derivative. By binding to dihydropyridine receptors, it blocks slow calcium channels, inhibits the transmembrane transition of calcium into the cells of the smooth muscles of the blood vessels and heart (mostly to the smooth muscle cells of the vessels, rather than to the cardiomyocytes). Has antihypertensive and antianginal effects.

Due to the slow start of the action, amlodipine does not cause a sharp decrease in blood pressure.

Ramiprilat, formed with the participation of hepatic enzymes, an active metabolite of ramipril, is a long-acting inhibitor of the enzyme dipeptidylcarboxypeptidase I (synonyms - ACE, kininase II). In plasma and in tissues, this kinase II enzyme catalyzes the conversion of angiotensin I into an active vasoconstrictor substance, 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. The increased activity of the kallikrein-kinin system in the blood and tissues determines the cardioprotective and endothelioprotective action of ramipril due to activation of the prostaglandin system and, accordingly, an increase in the synthesis of PG stimulating the formation of nitric oxide (NO) in endotheliocytes. Angiotensin II stimulates the production of aldosterone, therefore, taking ramipril leads to a decrease in the secretion of aldosterone and an increase in the content of potassium ions in the serum.

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

In patients with CHF ramipril reduces OPSS (decrease the afterload on the heart), increases the capacity of the venous bed and reduces the filling pressure of the left ventricle (LV), which consequently 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 improvement of exercise tolerance.

With diabetic and nondiabetic nephropathy, ramipril slows downprogression of renal failure and the time of the onset of the terminal stage of renal failure and, as a result, reduces the need for hemodialysis or kidney transplantation procedures. At the initial stages of diabetic or nondiabetic nephropathy ramipril reduces the severity of albuminuria.

Pharmacokinetics:

Amlodipine

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

T1 / 2 from the blood plasma is about 35-50 hours, which corresponds to the prescription of the drug 1 time per day. In patients with hepatic insufficiency and severe CHF T1 / 2 increases to 56-60 hours.

The total ground clearance is 0.43 l / h / kg.

During hemodialysis amlodipine not deleted.

Ramipril

After oral administration, it is rapidly absorbed from the digestive tract (50-60%). Eating slows down its absorption, but does not affect the degree of absorption. Ramipril is subjected to intense presystemic metabolism / activation (mainly in the liver, by hydrolysis), which results in the formation of its only active metabolite, ramiprilate, whose activity for inhibition of ACE is about 6 times that of ramipril. In addition, as a result of the metabolism of ramipril, diketopiperazine, which does not possess pharmacological activity, is formed, which is then subjected to conjugation with glucuronic acid. Ramiprilate is also glucuronized and metabolized to diketopiperazic acid. The bioavailability of ramipril after ingestion varies from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). The bioavailability of ramiprilam 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, the time to achieve Cmax of ramipril and ramiprilate is 1 and 2-4 hours, respectively. The decrease in the concentration of ramiprilate in the blood plasma occurs in several stages: the distribution and elimination phase with T1 / 2 ramiprilata, which is approximately 3 hours,then an intermediate phase with T1 / 2 ramiprilata of about 15 hours and a final phase with a very low concentration of ramiprilate in the blood plasma and T1 / 2 ramiprilate of about 4-5 days. This final phase is due to the slow release of ramiprilata from a strong bond with ACE receptors. Despite a prolonged final phase with a single daily ramipril intake of 2.5 mg or more, Css ramiprilata is reached after approximately 4 days of treatment. At the course appointment of the drug effective T1 / 2 (depending on the dose) is 13-17 hours.

Binding to blood plasma proteins approximately makes up 73% for ramipril, and 56% for ramiprilate.

Indications:

Arterial hypertension (patients who are shown combined therapy with amlodipine and ramipril in doses, both in combination).

ICD-10

IX.I10-I15.I10 Essential [primary] hypertension

IX.I10-I15.I15 Secondary Hypertension

Contraindications:

Hypersensitivity to the excipients included in the preparation; renal failure (Cl creatinine <20 ml / min / 1.73 m²); pregnancy; the period of breastfeeding; age to 18 years (experience of clinical use is insufficient).With caution Atherosclerotic lesions of the coronary and cerebral arteries (the risk of excessive blood pressure lowering); increased activity of RAAS, in which, with ACE inhibition, there is a risk of a sharp decrease in blood pressure with impaired renal function; expressed, especially malignant hypertension; CHF, especially severe or about which other drugs with antihypertensive action are taken; hemodynamically significant unilateral stenosis of the renal artery (in the presence of both kidneys); previous administration of diuretics; disturbance of water-electrolyte balance, reduction of BCC (including on the background of diuretics, salt-free diets, diarrhea, vomiting, excessive sweating); simultaneous use with preparations containing aliskiren (with a double blockade of RAAS, the risk of a sharp decrease in blood pressure, hyperkalemia and impaired renal function increases); impaired liver function (insufficient experience of application: it is possible both to strengthen and weaken the effects of ramipril, in the presence of cirrhosis of the liver with ascites and edema, a significant activation of RAAS is possible); impaired renal function (Cl creatinine more than 20 ml / min); condition after kidney transplantation; systemic connective tissue diseases, incl.systemic lupus erythematosus, scleroderma, concomitant therapy with drugs that can cause changes in the picture of peripheral blood (incl. allopurinol, procainamide) - possible oppression of bone marrow hematopoiesis, development of neutropenia or agranulocytosis; diabetes mellitus (risk of hyperkalemia); elderly age (risk of increased antihypertensive action); hyperkalemia; hyponatremia; CHF of non-ischemic etiology of III-IV functional class according to NYHA classification; aortic stenosis; syndrome of weakness of the sinus node; mitral stenosis; arterial hypotension; the only functioning kidney; Renovascular hypertension; simultaneous application of dantrolene, estramustine, potassium-sparing diuretics and potassium preparations, potassium-containing substitutes for edible salt, lithium preparations; surgical intervention / general anesthesia; hemodialysis with the use of high-flow membranes.

Carefully:

Atherosclerotic lesions of the coronary and cerebral arteries (danger of excessive reduction HELL); increased activity RAAS, in which, upon inhibition ACE there is a risk of a sharp decline HELL with impaired renal function; expressed, especially malignant hypertension; CHF, especially severe or about which other Drugs with antihypertensive action; hemodynamically significant unilateral stenosis of the renal artery (in the presence of both kidneys); previous administration of diuretics; disturbance of water-electrolyte balance, decrease BCC (in t.ch. on the background of taking diuretics, salt-free diets, diarrhea, vomiting, profuse sweating); simultaneous use with preparations containing aliskiren (with a double blockade RAAS the risk of a sharp decrease HELL, hyperkalemia and impaired renal function); impaired liver function (insufficient experience of application: it is possible both to strengthen and weaken the effects of ramipril, in the presence of patients with cirrhosis of the liver with ascites and edema, significant activation is possible RAAS); impaired renal function (Cl creatinine more than 20 ml / min); condition after kidney transplantation; systemic connective tissue diseases, in t.ch. systemic lupus erythematosus, scleroderma, concomitant therapy with drugs that can cause changes in the picture of peripheral blood (in t.ch. allopurinol, procainamide) - possible oppression of bone marrow hematopoiesis, development of neutropenia or agranulocytosis; diabetes mellitus (risk of hyperkalemia); elderly age (risk of increased antihypertensive action); hyperkalemia; hyponatremia; CHF non-ischemic etiology of III-IV functional class by classification NYHA; aortic stenosis; syndrome of weakness of the sinus node; mitral stenosis; arterial hypotension; the only functioning kidney; Renovascular hypertension; simultaneous application of dantrolene, estramustine, potassium-sparing diuretics and potassium preparations, potassium-containing substitutes for edible salt, lithium preparations; surgical intervention / general anesthesia; hemodialysis with the use of high-flow membranes.

Pregnancy and lactation:

The drug is contraindicated for use, tk. ramipril may have an adverse effect on the fetus: impairment of fetal kidney development, fetal and newborn fetal loss, renal dysfunction, hyperkalemia, skull bones hypoplasia, oligohydramnia, limb contracture, skull bones deformation, and lung hypoplasia.Before starting the drug in women of childbearing age, pregnancy should be excluded.

If a woman is planning a pregnancy, then the drug should be discontinued. In case of pregnancy during treatment with the drug should stop as soon as possible and take the patient to other drugs, in which the risk for the child will be the least.

If treatment with the drug is necessary during breastfeeding, it should be discontinued (there is no data on excretion of amlodipine and ramipril with breast milk of women).

Dosing and Administration:

Inside, 1 caps. 1 time per day, at the same time, regardless of food intake. The dose of the drug is selected after previous titration of the doses of individual components of the drug: ramipril and amlodipine in patients with AH. A drug with fixed doses of active ingredients can not be used for initial therapy. If patients need dose adjustment, then it should be done only by titrating the doses of the active components in monotherapy. Only then is it possible to use the drug with fixed doses of the active ingredients in the following combinations.

When necessary, the therapeutic dose may be changed based on the individual titration doses of the individual components: amlodipine 5 mg + 5 mg ramipril 5 mg or amlodipine 10 mg + 10 mg or ramipril + Amlodipine 5 mg ramipril or amlodipine 10 mg + 10 mg ramipril.

In a dose of 10 mg of amlodipine + 10 mg of ramipril is the maximum daily dose of the drug, which should not be exceeded. Dosages of 10 mg + Amlodipine 5 mg ramipril (as amlodipine) 5 mg amlodipine and 10 mg of ramipril + (ramipril on) are the maximum daily doses.

Older patients and patients with renal insufficiency. Removal 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 creatinine and potassium content in the blood plasma. Can be given to patients with Cl creatinine equal to or greater than 60 mL / min. When Cl creatinine <60 ml / min, and in patients with hypertension, are on hemodialysis, it is recommended only in patients who received 5 mg ramipril as an optimal maintenance dose during titration of an individual dose.There is no need to titrate an individual dose of amlodipine in patients with impaired renal function. Contraindicated in patients with Cl creatinine <20 ml / min / 1.73 m2. The change in the concentration of amlodipine in the blood plasma does not correlate with the degree of renal insufficiency.

Patients with hepatic insufficiency. Caution should be exercised when administering the drug to patients with hepatic impairment because of the lack of recommendations for dosing the drug in such patients. It is recommended only to patients receiving 2.5 mg of ramipril as the optimal maintenance dose during the titration of an individual dose.

Children and teens

Do not administer to children and adolescents under 18 years of age because of the lack of data on the efficacy and safety of ramipril and amlodipine in these patient groups, either as monotherapy or as combination therapy.

Side effects:

From the CCC: often - peripheral edema (ankles and feet), a feeling of palpitations; infrequently - excessive reduction of blood pressure, orthostatic hypotension, vasculitis; rarely - development or exacerbation of heart failure; very rarely - heart rhythm disturbances (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 side of the central nervous system and peripheral nervous system: often - a feeling of heat and tides of blood to the skin of the face, increased fatigue, dizziness, headache, drowsiness; infrequently - malaise, fainting, increased sweating, asthenia, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, unusual dreams, nervousness, depression, anxiety; rarely - cramps, apathy; Very rarely - ataxia, amnesia, individual cases of extrapyramidal syndrome have been reported.

From the side of the digestive system: often - pain in the abdominal cavity, nausea; infrequent - vomiting, changes in the bowel movement (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dryness of the oral mucosa, thirst; rarely - gingival hyperplasia, increased appetite; very rarely - gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased activity of hepatic transaminases, hepatitis.

On the part of the blood: very rarely - thrombocytopenic purpura, thrombocytopenia, leukopenia.

Metabolic disorders: very rarely - hyperglycemia.

From the respiratory system: infrequently - dyspnea, rhinitis; very rarely - cough.

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

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

Other: infrequent alopecia, ringing in the ears, gynecomastia, weight gain / increase, vision impairment, diplopia, accommodation disorder, xerophthalmia, conjunctivitis, eye pain, taste perversion, chills, nosebleeds; rarely - dermatitis; very rarely - parosmia, xeroderma, cold sweat, a violation of skin pigmentation.

Overdose:

Amlodipine

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

Treatment: the appointment of activated charcoal (especially in the first 2 hours after an overdose), gastric lavage, elevating the limbs, active maintenance of CAS functions, monitoring of heart and lung function, control of bcc and diuresis.To restore the tone of blood vessels and blood pressure, if there are no contraindications, it may be useful to use vasoconstrictors. I / O administration of gluconate calcium. Amlodipine is largely associated with serum proteins, so hemodialysis is ineffective.

Ramipril

Symptoms: excessive peripheral vasodilation with the development of pronounced decrease in blood pressure, shock; bradycardia or reflex tachycardia, water-electrolyte disorders, acute renal failure, stupor.lechenie: washing the stomach, the appointment of adsorbents, sodium sulfate (if possible for the first 30 minutes). In the case of a pronounced reduction in blood pressure, the patient should be laid, legs elevated, actively support CAS functions; to therapy for replenishment of BCC and restoration of electrolyte balance, addition of alpha 1-adrenergic agonists (norepinephrine, dopamine) and angiotensinamide. In the case of refractory to medical treatment of bradycardia, it may be necessary to install a temporary artificial pacemaker. In case of an overdose it is necessary to monitor the content of creatinine and electrolytes in the blood serum. Ramiprilate is poorly excreted from the blood by hemodialysis.

Interaction:

Amlodipine

It can be expected that inhibitors of microsomal liver oxidase enzymes (erythromycin - in 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 inductors of microsomal liver oxidase enzymes - reduce. With the simultaneous use of amlodipine with cimetidine, the pharmacokinetics of amlodipine does 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 CCBs, there was no clinically significant interaction of amlodipine (III generation of CCB) when combined with NSAIDs, especially indomethacin.

It is possible to enhance the anti-anginal and antihypertensive action of CCB when combined with thiazide and loop diuretics, verapamil, ACE inhibitors, beta-blockers and nitrates, as well as increase their antihypertensive effect when combined with alpha1-blockers, antipsychotics. Although in the study of amlodipine a negative inotropic effect was not usually observed, nevertheless,some CCBs can 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 CCBs with lithium preparations (there is no data for amlodipine), the manifestation of their neurotoxicity may be enhanced (nausea, vomiting, diarrhea, ataxia, tremor, and tinnitus).

Amlodipine does not influence in vitro the degree of binding to blood proteins of digoxin, phenytoin, warfarin and indomethacin.

A single intake 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 parameters of amlodipine.

The repeated use of amlodipine in 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 serum digoxin content and its renal clearance do not change. At a single and repeated application in a dose of 10 mg amlodipine does not have a significant effect on 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.

Unrecommended combinations

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

Ramipril

Contraindicated combinations

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

Unrecommended combinations

With potassium salts, potassium-sparing diuretics (for example, amiloride, triamterene, spironolactone) and other drugs, incl. with angiotensin II receptor antagonists (APA II), trimethoprim, tacrolimus,cyclosporine - it is possible to develop hyperkalemia (with simultaneous use requires regular monitoring of potassium content in blood serum).

Combinations that should be used with caution

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

With hypnotics, narcotics and other anesthetics - perhaps a more pronounced decrease in blood pressure.

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

With allopurinol, procainamide, cytostatics, immunosuppressants, systemic GCS, and other agents that may affect hematologic indices, joint use increases the risk of developing leukopenia.

With lithium salts, an increase in the lithium content in serum and an increase in the cardio- and neurotoxic effects of lithium.

With hypoglycemic agents for oral administration (derivatives of sulfonylureas, biguanides), insulin - in connection with a 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 (Cl creatinine less than 60 ml / min), as well as with vildagliptin - in connection with an increased incidence of angioedema and simultaneous use with ACE inhibitors.

Combinations that should be taken 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 potassium content in the blood serum.

With heparin - it is possible to increase the potassium content 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 can enhance the adverse effects of ethanol on the body.

With estrogens, weakening of the antihypertensive action of ramipril (fluid retention).

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

Special instructions:

Amlodipine

In the treatment of hypertension amlodipine can be combined with the use of thiazide diuretics, alpha and beta-adrenoblockers, ACE inhibitors, prolonged-action nitrates, sublingual nitroglycerin, NSAIDs, antibiotics and hypoglycemic agents for oral administration.

In the treatment of angina pectoris amlodipine can be prescribed in combination with other anti-anginal drugs, incl. patients who are refractory to treatment with nitrates and / or beta-adrenoblockers in adequate doses.

Amlodipine does not have any adverse effect on the metabolism and lipids of blood plasma and can be used in the treatment of patients with bronchial asthma, diabetes and gout.

Amlodipine can be used in cases where the patient is prone to vasospasm / vasoconstriction.

Patients with low body weight, low growth and patients with severe impairment of liver function may require a lower dosage.

During treatment, it is necessary to control body weight and monitor the dentist (to prevent soreness, bleeding and gingival hyperplasia).

Ramipril

Before starting treatment with ramipril, it is necessary to eliminate hyponatremia and hypovolemia. Patients who had previously taken diuretics should cancel them, or at least reduce their dose 2-3 days before the start of ramipril (in this case, the status of patients with CHF should be monitored regularly due to the possibility of developing their decompensation with increasing OCT).

After taking the first dose of the drug, as well as increasing its dose and / or dose of diuretics (especially loop doses), it is necessary to provide regular medical supervision of the patient for at least 8 hours for timely taking appropriate measures in case of excessive blood pressure lowering.

If ramipril is used for the first time or in a high dose in patients with increased activity of RAAS, then they should regularly monitor blood pressure, especially at the beginning of treatment, t.these patients have an increased risk of excessive blood pressure lowering. In malignant hypertension and HF, especially in the acute stage of MI, treatment with ramipril should be started only in a hospital.

In patients with CHF, taking the drug may lead to a marked decrease in blood pressure, which in some cases is accompanied by oliguria or azotemia and rarely - the development of acute renal failure.

Care should be taken when treating elderly patients. they may be particularly sensitive to ACE inhibitors; it is recommended to monitor the renal function in the initial phase of treatment.

In patients for whom a reduction in blood pressure may pose a certain risk (for example, patients with atherosclerotic narrowing of the coronary or cerebral arteries), treatment should begin under strict medical supervision.

Care should be taken with physical activity and / or hot weather because of the risk of increased sweating and dehydration with the development of arterial hypotension due to a decrease in BCC and a decrease in the sodium content in the blood.

During treatment, it is not recommended to drink alcohol.

Transient arterial hypotension is not a contraindication for continuing treatment after stabilizing blood pressure. In the case of repeated occurrence of severe arterial hypotension, the dose should be reduced or the drug should be withdrawn. Patients treated ingibitoramiAPF, there have been cases of angioedema the face, extremities, lips, tongue, throat or larynx. If there is swelling in the face (lips, eyelids) or tongue, or violation of swallowing or breathing, the patient should immediately stop taking the drug. Angioedema is localized in the tongue, pharynx or larynx (possible symptoms: impaired swallowing or breathing) may be life threatening and requires urgent measures for its relief of: p / or administering 0.3-0.5 mg / in drip administration of 0.1 mg epinephrine (under the control of blood pressure, heart rate and ECG) followed by the use of GCS (iv, IM orally); also recommended / introduction antihistamines (antagonists N1- and H2-histamine receptors), and in case of failure of enzyme inactivators C1-esterase can consider the need for administration in addition to epinephrine enzyme inhibitor C1-esterase.The patient should be hospitalized and monitored until the symptoms come to a complete relief, but not less than 24 hours.

In patients receiving ACE inhibitors, there were cases of intestinal angioedema, which manifested itself with abdominal pain with or without nausea and vomiting; in some cases, angioedema has also been observed. When a patient appears on the background of treatment with ACE inhibitors of the above-described symptoms, it is necessary to consider the possibility of developing an intestinal angioedema in the course of a differential diagnosis.

Treatment aimed at desensitization to insect venoms (bees, wasps), and simultaneous administration of ACE inhibitors can initiate anaphylactic and anaphylactoid reactions (eg, lowering blood pressure, dyspnoea, vomiting, allergic skin reactions), which can sometimes be life threatening. Against the background of treatment with ACE inhibitors, hypersensitivity reactions to insect venom (eg, bees, wasps) develop more rapidly and take more severe course. If it is necessary to conduct desensitization to insect venom, the ACE inhibitor must be temporarily replaced by a corresponding drug of another class.

With the use of ACE inhibitors, life-threatening, rapidly developing anaphylactoid reactions have been described, sometimes up to the development of shock during hemodialysis or plasma filtration using certain high-flow membranes (eg polyacrylonitrile membranes) (see also membrane manufacturers instructions). It is necessary to avoid the joint use of ramipril and such membranes (for example for urgent hemodialysis or hemofiltration). In this case, it is preferable to use other membranes or to exclude the use of an ACE inhibitor. Similar reactions were observed in the apheresis of LDL with the use of dextran sulfate. Therefore, this method should not be used in patients receiving an ACE inhibitor. In patients with impaired hepatic function, the response to Ramipril therapy may be either increased or decreased. In addition, in patients with severe cirrhosis of the liver with edema and / or ascites, significant activation of RAAS is possible, therefore, special care must be taken in the treatment of these patients.

Before surgery (including dental surgery), the surgeon / anesthesiologist should be alerted to the use of an ACE inhibitor.

The use of an ACE inhibitor in patients undergoing extensive surgery and / or general anesthesia can lead to a marked decrease in blood pressure if general anesthetics with hypotensive action are used. This is due to the blocking of the formation of angiotensin II against a background of compensatory enhancement of renin activity. In this case, the volume of the circulating fluid should be increased. It is recommended to stop taking an ACE inhibitor 24 hours before surgery. Based the results of epidemiological studies suggest that the simultaneous administration of ACE inhibitors and insulin, as well as hypoglycemic agents for oral administration may lead to the development of hypoglycemia. The greatest risk of development is observed during the first weeks of combination therapy, as well as in patients with impaired renal function.

Patients with diabetes require regular monitoring of glycemia, especially during the first month of therapy with ACE inhibitors.

It is recommended to closely monitor newborns who have been exposed to intrauterine exposure to ACE inhibitors for the detection of arterial hypotension, oliguria and hyperkalemia.

In oliguria it is necessary to maintain BP and renal perfusion by introducing appropriate fluids and vasoconstrictors.

In such newborns, there is a risk of developing oliguria and neurological disorders, possibly due to a reduction in renal and cerebral blood flow due to a reduction in blood pressure caused by ACE inhibitors.

Against the background of therapy with ACE inhibitors, dry cough may occur. Cough persists for a long time against the background of taking this group's drugs and disappears after their withdrawal. When a patient has a dry cough, remember the possible iatrogenic nature of this symptom.

In patients of the Negroid race, angioneurotic edema develops more often than in representatives of other races against the background of the administration of ACE inhibitors. Ramipril, as well as other ACE inhibitors, may have a less pronounced antihypertensive effect in patients of the Negroid race compared with representatives of other races. Perhaps this difference is due to the fact that patients with Negroid races with hypertension often have a low renin activity.

Monitoring of laboratory parameters before and during treatment with ramipril (up to 1 time per month for the first 3-6 months of treatment) includes:

- control of kidney function (determination of creatinine content in serum). In the treatment of ACE inhibitors in the first weeks of treatment and in the following it is recommended to monitor the function of the kidneys. Particularly careful monitoring is required for patients with heart failure, renal dysfunction, after kidney transplantation, patients with renovascular disease, including patients with hemodynamically significant unilateral renal artery stenosis in the presence of two kidneys (in such patients, even a slight increase in serum creatinine may be indicative of a decrease in renal function ).

- control of the content of electrolytes. Regular monitoring of potassium content in serum is recommended. Particularly careful monitoring of potassium in the blood serum is required for patients with impaired renal function, significant disturbances in the water-electrolyte balance, CHF.

- control of hematological parameters (hemoglobin content, leukocyte count, erythrocytes, platelets, leukocyte formula). It is recommended to monitor the parameters of a general blood test to detect possible leukopenia.More regular monitoring is recommended at the beginning of treatment and in patients with impaired renal function, and also in patients with connective tissue diseases or in patients receiving concomitantly other drugs capable of altering the pattern of peripheral blood.

Controlling the number of leukocytes is necessary for the early detection of leukopenia, which is especially important in patients with an increased risk of developing it, and also at the first signs of infection. If neutropenia is detected (neutrophil count is less than 2000 / μL), discontinuation of ramipril treatment is required. When symptoms appear due to leukopenia (eg fever, lymphadenopathy, tonsillitis), urgent monitoring of the peripheral blood pattern is necessary. In the case of signs of bleeding (petit petechia, red-brown rashes on the skin and mucous membranes), it is also necessary to control the number of platelets in the peripheral blood.

- determination of hepatic enzyme activity, bilirubin concentration in the blood. If jaundice or a significant increase in activity of hepatic enzymes occurs, the treatment with ramipril should be stopped and medical supervision of the patient should be ensured.

During drug treatment, it is recommended to refrain from driving and other potentially dangerous activities requiring increased concentration of attention and speed of psychomotor reactions (possibly dizziness, especially at the beginning of treatment, and in patients taking diuretic drugs - reduced concentration of attention). After the first dose, and after a significant increase in the dose of the drug is not recommended to drive vehicles and work with technical equipment in the flow s to several hours.

Instructions

Amlodipine + Ramipril (Amlodipinum + Ramiprilum)