Egipres, 10 mg+10 mg capsules 30 pcs

Pharmacodynamics

Amlodipine

A dihydropyridine derivative. Binds to dihydropyridine receptors, blocks slow calcium channels, inhibits transmembrane calcium transfer in vascular and heart smooth muscle cells (more so in vascular smooth muscle cells than in cardiomyocytes). It has antihypertensive and antianginal effects.

The mechanism of antihypertensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle.

Amlodipine reduces myocardial ischemia in the following two ways:

1. It dilates the peripheral arterioles and thus decreases the RPS (post-load), with little or no change in heart rate, resulting in a decrease in energy consumption and myocardial oxygen demand.

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

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

In patients with angina a single daily dose of the drug increases duration of exercise, delays onset of another angina attack and ST-segment depression (by 1 mm) with exercise, reduces angina attack frequency and decreases nitroglycerin requirement.

The use of amlodipine in patients with CHD. In patients with CHD (including coronary atherosclerosis with lesions from one vessel to stenosis of 3 or more arteries and carotid atherosclerosis, who have had myocardial infarction (MI), percutaneous transluminal angioplasty (PTA) or suffering from angina), use of amlodipine prevents the development of carotid artery intima-media thickening, significantly reduces mortality from cardiovascular causes, MI, stroke, THA, coronary artery bypass grafting, leads to fewer hospitalizations for unstable angina and CHF progression, and reduces the frequency of interventions to restore coronary blood flow.

The use of amlodipine in patients with heart failure (HF). Amlodipine does not increase the risk of death or complications and fatal outcomes in patients with New York Heart Association (NYHA) Class III-IV CHF during treatment with digoxin, diuretics and ACE inhibitors. In patients with CHF class III-IV according to NYHA nonischemic etiology, there is a possibility of pulmonary edema when using amlodipine. Amlodipine does not cause adverse metabolic effects, including its effect on parameters of lipid profile.

Ramipril

The active metabolite of ramipril is a long-acting inhibitor of the enzyme dipeptidylcarboxypeptidase I (synonyms: ACE, kininase II). In blood plasma and tissues, this enzyme kininase II catalyzes the conversion of angiotensin I into the active vasoconstrictor, angiotensin II, and also promotes the breakdown of bradykinin.

The reduction of angiotensin II formation and inhibition of bradykinin breakdown leads to vasodilation and BP reduction. The increase of kallikrein-kinin system activity in blood and tissues causes cardioprotective and endothelioprotective effects of ramipril due to the activation of prostaglandin system and accordingly – increase of PG synthesis, which stimulate nitric oxide (NO) formation in endotheliocytes. Angiotensin II stimulates the production of aldosterone, so taking ramipril leads to a decrease in aldosterone secretion and an increase in serum potassium ions.

When angiotensin II is reduced in blood, its negative feedback inhibitory effect on renin secretion is eliminated, resulting in increased plasma renin activity.

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

In patients with AH, administration of ramipril leads to a decrease in BP in the supine and standing positions, without a compensatory increase in HR. Ramipril significantly reduces RPS with little or no change in renal blood flow and glomerular filtration rate. Antihypertensive effect begins to appear 1-2 hours after oral administration of a single dose of the drug, reaching its greatest value after 3-6 hours, and lasts for 24 hours. When taking a course of the drug, the antihypertensive effect may gradually increase, stabilizing usually by the 3rd-4th week of regular drug intake and then remaining for a long time. Sudden discontinuation of the drug does not lead to a rapid and significant increase in BP (no withdrawal syndrome).

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

In patients with CHF, ramipril decreases PEEP (decreased post-loading on the heart), increases venous system capacity and decreases left ventricular (LV) filling pressure, which leads to a corresponding decrease in cardiac preload. In these patients, taking ramipril increases cardiac output, ejection fraction and improves exercise tolerance.

In diabetic and nondiabetic nephropathy, administration of ramipril slows the rate of progression of renal failure and time to end-stage renal failure and thereby reduces the need for hemodialysis or renal transplantation procedures. In initial stages of diabetic or nondiabetic nephropathy, ramipril reduces the severity of albuminuria.

. In patients at high risk of CHD due to the presence of vascular lesions (diagnosed CHD, peripheral artery obliterative disease in the past, stroke in the past) or diabetes with at least one additional risk factor (microalbuminuria, AH, increase in total cholesterol, decrease in HDL cholesterol, smoking) addition of ramipril to standard therapy significantly reduces the rate of MI, stroke and mortality from cardiovascular causes.

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

. In patients with CHF developed in first days of acute AMI (days 2-9) taking ramipril, beginning from day 3 to day 10 of AMI, the risk of mortality rate decreases (by 27%), the risk of sudden death (by 30%), the risk of CHF progression to severe – III-IV class NYHA, resistant to therapy (by 27%), the probability of subsequent hospitalization due to CHF development (by 26%). In the general patient population, as well as in diabetic patients with both AH and normal BP, ramipril significantly reduces the risk of nephropathy and microalbuminuria.

Pharmacokinetics

Amlodipine

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

The T1/2 from blood plasma is about 35-50 h, which corresponds to administration of the drug once daily. In patients with hepatic insufficiency and severe CHF the T1/2 is increased to 56-60 h.

The total clearance is 0.43 l/h/kg.

The stable Css (5-15 ng/ml) is reached after 7-8 days of continuous amlodipine administration; 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% are excreted through the intestine. Excretion with breast milk is unknown. Amlodipine is not eliminated during hemodialysis.

Special groups of patients

Renal failure.The T1/2 from plasma in patients with renal failure is increased up to 60 h. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal impairment.

Elderly patients.Times of reaching Cmax and Cmax of amlodipine are almost the same as those of younger patients. In elderly patients with CHF, there is a tendency to decrease clearance of amlodipine, which leads to an increase in AUC and T1/2 up to 65 h.

Ramipril

After oral administration, it is rapidly absorbed from the GI 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), as a result of which its only active metabolite is formed – ramiprilat, which activity with regard to ACE inhibition is approximately 6 times higher than activity of ramipril. In addition, ramipril metabolism produces diketopiperazine, which has no pharmacological activity and then undergoes conjugation with glucuronic acid.

Ramiprilat is also glucuronized 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 ramipril after oral administration of 5 mg ramipril is approximately 45% (compared to its bioavailability after intravenous administration at the same doses).

After oral administration of ramipril, the time to reach Cmax of ramipril and ramiprilate is 1 and 2-4 h, respectively. The decrease in plasma concentration of ramiprilat occurs in several phases: a distribution and excretion phase with a T1/2 of ramiprilat of approximately 3 h, followed by an intermediate phase with a T1/2 of ramiprilat of approximately 15 h, and an end phase with a very low plasma concentration of ramiprilat and a T1/2 of ramiprilat of approximately 4-5 days.

This end phase is due to the slow release of ramiprilat from strong binding to ACE receptors. Despite the prolonged end phase when ramipril is taken once daily at a dose of 2.5 mg or more, the Css of ramiprilat is reached after approximately 4 days of treatment. When the drug is administered in courses, the effective T1/2 (depending on the dose) is 13-17 h.

The plasma protein binding is approximately 73% for ramipril and 56% for ramiprilat.

After intravenous administration, the Vd of ramipril and ramiprilat are approximately 90 and 500 L, respectively.

After intravenous administration of radioactive isotope-labeled 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 as ramipril and its metabolites.

After intravenous administration of ramiprilat – about 70% of the dose is detected in the urine as ramiprilat and its metabolites, in other words, when ramipril and ramiprilat are administered intravenously, a significant portion of the dose is eliminated through the intestine with the bile, bypassing the kidneys (50 and 30% respectively). After oral administration of 5 mg of ramipril in patients with bile duct drainage, almost equal amounts of ramipril and its metabolites are excreted by the kidneys and through the intestine during the first 24 h after administration.

About 80-90% of metabolites in urine and bile have been identified as ramipril and ramiprilate metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10-20% of the total, and the urinary content of unmetabolized ramipril is approximately 2%.

In impaired renal function with a creatinine Cl less than 60 mL/min, excretion of ramiprilat and its metabolites by the kidneys is delayed. This leads to increased plasma concentrations of ramiprilat, which decrease more slowly than in patients with normal renal function.

When taking ramipril at high doses (10 mg), impaired liver function leads to slower presystemic metabolism of ramipril to active ramiprilate and slower excretion of ramiprilate. No clinically significant accumulation of ramipril and ramiprilate was observed in healthy volunteers and patients with AH after 2 weeks of treatment with ramipril at a daily dose of 5 mg. In patients with CHF after 2 weeks of treatment with ramipril at a daily dose of 5 mg there was a 1.5-1.8-fold increase in plasma concentrations of ramiprilat and AUC.

In healthy elderly volunteers (65-76 years), the pharmacokinetics of ramipril and ramiprilat are not significantly different from those of young healthy volunteers.

Indications

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

Active ingredient

Composition

1 capsule contains:

acting ingredients:

amlodipine besylate 13.9 mg (corresponding to amlodipine 10 mg),

ramipril 10 mg;

excipients:

crospovidone – 20/40/40/40 mg;

Hypromellose – 1.18/2.36/2.36/2.36 mg;

MCC – 114.82/229.64/229.64/229.64 mg;

Glyceryl dibegenate – 2.05/4.1/4.1/4.1 mg;

Capsules, 10 mg+5 mg; hard gelatin capsule (CONI-SNAP 0), color code for cap and base – 33007/37350: lid – titanium dioxide; azorubin dye (E122); indigo carmine (E132); gelatin; base – titanium dioxide; iron oxide red dye (E172); gelatin.

How to take, the dosage

Overly, 1 capsule once daily, at the same time, regardless of meals.

The dose of Egipres is adjusted after previously titrated doses of the individual components of the drug: ramipril and amlodipine in patients with AH. Egipres with fixed doses of the active components should not be used for initial therapy. If patients require dose adjustment, it should be performed only with titration of doses of active components in monotherapy. Only after that can Egipres with fixed doses of the active ingredients be used in the combinations listed below.

In case of therapeutic necessity the dose of Egipres may be changed on the basis of individual dose titration of individual components: 5 mg amlodipine + 5 mg ramipril or 5 mg amlodipine + 10 mg ramipril or 10 mg amlodipine + 5 mg ramipril or 10 mg amlodipine + 10 mg ramipril.

Egipres at a dose of 10 mg amlodipine + 10 mg ramipril is the maximum daily dose of the drug, which should not be exceeded. The doses of 10 mg amlodipine + 5 mg ramipril (for amlodipine) and 5 mg amlodipine + 10 mg ramipril (for ramipril) are the maximum daily doses.

Adult patients

In patients taking diuretics, the drug should be administered with caution due to the risk of electrolyte-water imbalance. Renal function and blood potassium levels should be monitored in these patients.

Patients of advanced age and patients with renal insufficiency. Excretion of amlodipine and ramipril and its metabolites is delayed in elderly patients and patients with renal failure. Therefore, plasma creatinine and potassium should be regularly monitored in such patients. Egipres may be administered to patients with creatinine Cl equal to or greater than 60 ml/min.

When creatinine Cl is less than 60 mL/min and in patients with AH on hemodialysis, Egipres is recommended only in patients receiving 5 mg of ramipril as the optimal maintenance dose during individual dose titration. There is no need for individual dose titration of amlodipine in patients with impaired renal function. Egipres is contraindicated in patients with creatinine Cl less than 20 ml/min/1.73 m2. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment.

Patients with hepatic impairment. Caution should be exercised when prescribing Egipres in patients with hepatic impairment due to the lack of dosing recommendations for such patients. Egipres is recommended only for patients who received 2.5 mg of ramipril as the optimal maintenance dose during individual dose titration.

Children and adolescents

Egipres should not be administered to children and adolescents less than 18 years of age due to lack of data on efficacy and safety of ramipril and amlodipine in these patient groups both as monotherapy and as combination therapy.

Interaction

Amlodipine

It can be expected that enzyme inhibitors of microsomal liver oxidation (erythromycin in the young, diltiazem in the elderly, ketoconazole, itraconazole, ritonavir) will increase the plasma concentration of amlodipine, increasing the risk of side effects, while enzyme inducers of microsomal liver oxidation will decrease. Concomitant use of amlodipine with cimetidine does not change the pharmacokinetics of amlodipine.

Concomitant administration of 240 ml of grapefruit juice and 10 mg of oral amlodipine is not accompanied by significant changes in amlodipine pharmacokinetics. Unlike other BCAAs, no clinically significant interaction of amlodipine (III generation BCAAs) has been found when co-administered with NSAIDs, especially indomethacin.

The antianginal and antihypertensive effects of BCA may be enhanced with thiazide and loop diuretics, verapamil, ACE inhibitors, beta-adrenoblockers and nitrates, and their antihypertensive effects may be increased with alpha 1-adrenoblockers and neuroleptics. Although in studies of amlodipine a negative inotropic effect has not usually been observed, however, some BCAAs may increase the severity of the negative inotropic effect of antiarrhythmic drugs that cause QT interval prolongation (e.g., amiodarone and quinidine).

In coadministration of BCAA with lithium preparations (no data available for amlodipine) there may be increased neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

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

A single administration of aluminum/magnesium-containing antacids has no significant effect on the pharmacokinetics of amlodipine.

Single administration of 100 mg sildenafil in patients with essential hypertension has no effect on amlodipine pharmacokinetic parameters.

The repeated use of amlodipine 10 mg and atorvastatin 80 mg dose is not associated with significant changes in pharmacokinetic parameters of atorvastatin. When concomitant use of amlodipine with digoxin in healthy volunteers, serum digoxin content and renal clearance do not change. Amlodipine has no significant effect on the pharmacokinetics of ethanol when administered in a single and repeated dose of 10 mg.

Amlodipine has no effect on the change in PV caused by warfarin. Amlodipine does not cause significant changes in the pharmacokinetics of cyclosporine.

Unrecommended combinations

. Concomitant use of dantrolene (IV), CYP3A4 cytochrome isoenzyme inducers (e.g., rifampicin, St. John’s wort) and CYP3A4 cytochrome isoenzyme inhibitors (protease inhibitors, azole antifungals, macrolides (such as erythromycin or clarithromycin), verapamil or diltiazem).

Ramipril

Contraindicated combinations

The use of certain high-flow membranes with a negatively charged surface (e.g. polyacrylonitrile membranes) when performing hemodialysis or hemofiltration; use of dextran sulfate in LDL apheresis – risk of severe anaphylactic reactions.

Unrecommended combinations

With potassium salts, potassium-saving diuretics (e.g., amiloride, triamterene, spironolactone) and other drugs, including with angiotensin II receptor antagonists (ARA II), trimethoprim, tacrolimus, cyclosporine – possible development of hyperkalemia (with simultaneous use, regular monitoring of serum potassium is required).

Combinations to be used with caution

With antihypertensive agents (especially diuretics) and other drugs that reduce BP (nitrates, tricyclic antidepressants, means for general and local anesthesia, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin) – potentiation of antihypertensive effect. When combining with diuretics serum sodium content should be monitored.

With sleeping pills, narcotics and other analgesics – possible more pronounced BP reduction.

With vasopressor sympathomimetics (epinephrine, isoproterenol, dobutamine, dopamine) – reduction of the antihypertensive effect of ramipril, regular BP control is required.

With allopurinol, procainamide, cytostatics, immunosuppressants, systemic GCS and other drugs that may affect hematological parameters – combined use increases the risk of 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 of insulin resistance under the influence of ramipril, the hypoglycemic effect of these drugs may increase, up to the development of hypoglycemia.

The concomitant use of the 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 the increased incidence of angioedema when used simultaneously with ACE inhibitors.

Combinations to be considered

With NSAIDs (indomethacin, acetylsalicylic acid) – the effect of ramipril may be impaired, the risk of increased renal function and increased serum potassium may increase.

With heparin – possible increase in serum potassium.

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

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

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

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

Special Instructions

The information regarding ramipril and amlodipine applies to Egipres.

Amlodipine may be combined with thiazide diuretics, alpha- and beta-adrenoblockers, ACE inhibitors, sustained release nitrates, sublingual nitroglycerin, NSAIDs, antibiotics and oral hypoglycemic agents in the treatment of AH.

In the treatment of angina pectoris, amlodipine may be administered in combination with other antianginal agents, including patients refractory to treatment with nitrates and/or beta-adrenoblockers in adequate doses.

Amlodipine has no adverse effect on metabolism and plasma lipids and may be used in the treatment of patients with bronchial asthma, diabetes mellitus and gout.

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

Patients of low body weight, short stature, and patients with significant hepatic impairment may require a lower dosage.

Weights should be monitored and a dentist should be seen during treatment (to prevent soreness, bleeding, and gum hyperplasia).

Ramipril

Hyponatremia and hypovolemia should be corrected before starting ramipril treatment. Patients who have previously taken diuretics should discontinue them or at least decrease their dose 2-3 days prior to starting ramipril (in this case the patients with CHF should be monitored regularly due to possibility of decompensation with increase in RBC).

After the first dose of the drug, as well as when increasing the dose and/or dose of diuretics (especially loop diuretics), the patient should be monitored regularly for at least 8 hours to take appropriate measures in case of excessive BP decrease.

If ramipril is used for the first time or at a high dose in patients with increased RAAS activity, their BP should be monitored regularly, especially at the beginning of treatment, since these patients have an increased risk of excessive BP reduction. In malignant AH and CH, especially in acute MI, treatment with ramipril should be started only in hospital.

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

Perhaps caution should be exercised when treating elderly patients as they may be particularly sensitive to ACE inhibitors; renal function tests should be monitored during the initial phase of treatment.

In patients in whom decreased BP may pose some risk (e.g., patients with atherosclerotic narrowing of coronary or cerebral arteries), treatment should be initiated under close medical supervision.

Cautions should be taken during physical activity and/or hot weather because of the risk of increased sweating and dehydration with the development of arterial hypotension due to decreased RBC and lower sodium levels in the blood.

Alcohol consumption is not recommended during treatment.

Transient arterial hypotension is not a contraindication to continue treatment after BP stabilization. If severe arterial hypotension occurs again, the dose should be reduced or the drug should be discontinued. There have been cases of angioedema of the face, limbs, lips, tongue, pharynx or larynx in patients treated with ACE inhibitors. If swelling of the face (lips, eyelids) or tongue, or impaired swallowing or breathing occurs, the patient should stop taking the drug immediately.

The angioedema localized to the tongue, pharynx or larynx (possible symptoms: impaired swallowing or breathing) may be life-threatening and requires urgent measures to control it: p/c injection of 0.3-0.5 mg or intravenous drip injection of 0.1 mg of epinephrine (under control of BP, HR and ECG) followed by administration of GCS (intravenous, intramural or oral); also recommended is intravenous administration of antihistamines (H1- and H2-histamine receptor antagonists), and if C1-esterase enzyme inactivators are insufficient, the need for C1-esterase enzyme inhibitors in addition to epinephrine may be considered.

The patient should be hospitalized and monitored until symptoms have resolved, but not less than 24 hours.

Patients receiving ACE inhibitors have had cases of intestinal angioedema manifested by abdominal pain with or without nausea and vomiting; in some cases, simultaneous angioedema of the face has also been observed. If patients present with these symptoms after treatment with ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

Treatment with desensitization to insect venom (bees, wasps) and simultaneous administration of ACE inhibitors can initiate anaphylactic and anaphylactoid reactions (e.g., BP decrease, dyspnea, vomiting, allergic skin reactions), which may sometimes be life-threatening. During treatment with ACE inhibitors hypersensitivity reactions to insect venom (e.g. bees, wasps) develop more quickly and are more severe. If desensitization to insect venom is necessary, the ACE inhibitor should be temporarily replaced by the appropriate drug of another class.

Life-threatening, rapidly developing anaphylactoid reactions, sometimes to the point of shock, have been described when using ACE inhibitors during hemodialysis or plasmafiltration using certain high-flow membranes (e.g. polyacrylonitrile membranes) (see also instructions of membrane manufacturers).

The combined use of ramipril and these types of membranes (e.g. for emergency hemodialysis or hemofiltration) should be avoided. In this case, the use of other membranes or exclusion of ACE inhibitor administration is preferable. Similar reactions have been observed in LDL apheresis with dextran sulfate. Therefore, this method should not be used in patients receiving an ACE inhibitor. In patients with liver dysfunction, the response to treatment with ramipril may be either enhanced or impaired. Besides, in patients with severe liver cirrhosis with edemas and/or ascites, significant activation of RAAS is possible, therefore special caution should be exercised when treating these patients.

Before a surgical procedure (including dental), the surgeon/anesthesiologist should be warned about the use of an ACE inhibitor.

The use of an ACE inhibitor in patients undergoing extensive surgery and/or general anesthesia may result in a marked decrease in BP if general anesthesia agents with hypotensive effects are used. This is due to the blocking of angiotensin II formation against the background of a compensatory increase in renin activity.

In such case, the volume of circulating fluid should be increased. It is recommended to stop ACE inhibitor administration 24 h before surgical intervention. On the basis of the results of epidemiological studies it is suggested that simultaneous use of ACE inhibitors and insulin as well as hypoglycemic agents for oral administration may lead to hypoglycemia. The highest risk of development is observed during the first weeks of combined therapy, as well as in patients with impaired renal function.

In patients with diabetes mellitus, regular monitoring of glycemia is required, especially during the first month of therapy with ACE inhibitors.

The close monitoring of neonates who have been intrauterine exposed to ACE inhibitors is recommended for the detection of arterial hypotension, oliguria, and hyperkalemia.

In oliguria, BP and renal perfusion should be maintained by administration of appropriate fluids and vasoconstrictors.

These infants are at risk of oliguria and neurologic disorders, possibly due to decreased renal and cerebral blood flow due to the decrease in BP caused by ACE inhibitors.

Dry cough may occur during therapy with ACE inhibitors. Cough persists for a long time while taking this group of drugs and disappears after their withdrawal. If a patient has a dry cough, we should keep in mind the possible iatrogenic nature of this symptom.

Patients of the Negro race are more likely than those of other races to develop angioedema while taking ACE inhibitors. Ramipril, like other ACE inhibitors, may have less pronounced antihypertensive effects in black race patients compared to other races. It is possible that this difference is due to the fact that non-Hispanic patients with AH are more likely to have low renin activity.

The monitoring of laboratory parameters before and during treatment with ramipril (up to once a month for the first 3-6 months of treatment) includes:

– monitoring of renal function (determination of serum creatinine). During treatment with ACE inhibitors in the first weeks of treatment and thereafter, it is recommended to monitor renal function. Especially close monitoring is required for patients with CH, impaired renal function, after renal transplantation, patients with renovascular diseases, including patients with hemodynamically significant unilateral renal artery stenosis in presence of two kidneys (in such patients even a slight increase of serum creatinine level may be an indicator of reduced renal function).

– control of electrolytes. Regular monitoring of serum potassium is recommended. Particularly close monitoring of serum potassium is required in patients with impaired renal function, significant electrolyte-water balance disorders, CHF.

Hematological parameters control (hemoglobin, leukocyte, erythrocyte, platelet count, leukocytic formula). It is recommended to monitor general blood counts to detect possible leukopenia. More regular monitoring is recommended at the beginning of treatment and in patients with renal dysfunction, as well as in patients with connective tissue diseases or in patients concomitantly receiving other drugs which may change peripheral blood count.

Contraindications

Amlodipine

Side effects

The adverse effects listed below are given according to the following WHO gradations of frequency of occurrence: very frequently, more than 1/10 (more than 10%); frequently, more than 1/100, but less than 1/10 (more than 1%, but less than 10%); infrequently, more than 1/1000, but less than 1/100 (more than 0.1%, but less than 1%); rarely, more than 1/10000, but less than 1/1000 (more than 0.01%, but less than 0.1%); very rarely, less than 1/10000 (less than 0.01%).

Amlodipine

Systemic and cardiovascular disorders: frequent – peripheral edema (ankles and feet), palpitations; infrequent – excessive BP decrease, orthostatic hypotension, vasculitis; rare – development or aggravation of CH; very rare – cardiac rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation), MI, chest pain, migraine.

Musculoskeletal and connective tissue disorders: infrequent – arthralgia, muscle cramps, myalgia, back pain, arthrosis; rarely – myasthenia.

CNS and peripheral nervous system disorders: frequent – sensation of fever and blood rush to the face, increased fatigue, dizziness, headache, drowsiness; infrequent – malaise, fainting, increased sweating, asthenia, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, unusual dreams, nervousness, depression, anxiety; Rarely – seizures, apathy; very rarely – ataxia, amnesia, single cases of extrapyramidal syndrome have been registered.

Digestive system disorders: frequent – abdominal pain, nausea; infrequent – vomiting, changes in defecation mode (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dry oral mucosa, thirst; rare – gum hyperplasia, increased appetite; very rare – gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased activity of liver transaminases, hepatitis.

Blood: very rarely – thrombocytopenic purpura, thrombocytopenia, leukopenia.

Metabolic disorders: very rarely – hyperglycemia.

Respiratory system disorders: infrequent dyspnea and rhinitis; very rare – cough.

Kidney and urinary tract: infrequent – frequent urination, painful urination, nicturia, impotence; very rare – dysuria, polyuria.

Allergic reactions: infrequent – skin itching, rash; very rare – angioedema, erythema multiforme, urticaria.

Others: infrequent – alopecia, tinnitus, gynecomastia, weight gain/decrease, visual disturbances, diplopia, accommodation disturbances, xerophthalmia, conjunctivitis, eye pain, perversion of taste, chills, nose bleeds; rarely – dermatitis; very rare – parosmia, xeroderma, cold sweats, impaired skin pigmentation.

Ramipril

Cardiac disorders: infrequent – myocardial ischemia, including development of angina attack or MI, tachycardia, arrhythmias (occurrence or increase), palpitations, peripheral edema.

Vascular disorders: often – excessive decrease of BP, impaired orthostatic regulation of vascular tone (orthostatic hypotension), syncopal conditions; infrequently – flushes of blood to the face; rarely – occurrence or increase of circulatory disorders against stenotic vascular lesions, vasculitis; frequency is unknown – Raynaud’s syndrome.

CNS disorders: frequent – headache, sensation of lightness in the head; infrequent – dizziness, agueusia (loss of taste sensitivity), dysgeusia (disruption of taste sensitivity), paresthesias (burning sensation); rare – tremor, balance disorder; infrequent unknown – cerebral ischemia, including ischemic stroke and transient cerebral circulation disorder, impaired psychomotor reactions, parosmia (disruption of smell perception).

An organ of vision: infrequent visual disturbances, including blurred vision; rarely – conjunctivitis.

Hearing organ: rare – hearing disorders, tinnitus.

Psychiatric disorders: infrequent – depressed mood, anxiety, nervousness, motor restlessness, sleep disorders, including drowsiness; rare – confusion; frequency unknown – impaired concentration.

The respiratory system: often – dry cough (increasing at night and when lying down), bronchitis, sinusitis, shortness of breath; infrequently – bronchospasm, including aggravation of bronchial asthma, nasal congestion.

The digestive system: frequently – inflammatory reactions in the stomach and intestines, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; infrequently – pancreatitis, including lethal. lethal (cases of pancreatitis with lethal outcome while taking ACE inhibitors were extremely rarely observed), increased pancreatic enzyme activity in blood plasma, intestinal angioneurotic edema, abdominal pain, gastritis, constipation, dry oral mucosa; rarely – glossitis; frequency unknown – aphthous stomatitis (inflammatory reaction of the oral mucosa).

Hepatobiliary system disorders: infrequent – increase of liver enzymes activity and content of conjugated bilirubin in blood plasma; rare – cholestatic jaundice, hepatocellular lesions; frequency unknown – acute liver failure, cholestatic or citolytic hepatitis (lethal outcome was observed extremely rarely).

Renal and urinary tract disorders: infrequent – renal dysfunction, including development of acute renal failure, increased urine excretion, increased pre-existing proteinuria, increased concentration of urea and creatinine in blood.

Reproductive system and mammary glands: infrequent – transient impotence due to erectile dysfunction, decreased libido; frequency unknown – gynecomastia.

The blood and lymphatic system: infrequent eosinophilia; rarely – leukopenia, including neutropenia and agranulocytosis, decrease of erythrocytes in peripheral blood, decrease of hemoglobin, thrombocytopenia; frequency of unknown – suppression of medullar hemopoiesis, pancytopenia, hemolytic anemia.

Skin and mucous membranes: frequently – skin rash, particularly maculopapular; infrequently – angioedema, including angioedema with lethal outcome (FAR). and with fatal outcome (laryngeal edema can cause airway obstruction, leading to death), skin itching, hyperhidrosis (increased sweating); rarely – exfoliative dermatitis, urticaria, onycholysis; very rare – photosensitization reactions; frequency unknown – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, worsening of the course of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid (licheniform) exanthema or enanthema, alopecia.

Musculoskeletal and connective tissue disorders: frequently – muscle cramps, myalgia; infrequently – arthralgia.

Metabolism, nutrition and laboratory parameters: frequent – increase of potassium content in blood; infrequent – anorexia, decreased appetite; frequency unknown – decrease of sodium concentration in blood, ADH inadequate secretion syndrome.

Immune system disorders: frequency unknown – anaphylactic or anaphylactoid reactions (when ACE inhibiting increases the number of anaphylactic or anaphylactoid reactions to insect venoms), increased titer of antinuclear antibodies.

General disorders: often – chest pain, feeling of fatigue; infrequently – increase in body temperature; rarely – asthenia (weakness).

Overdose

There is no information about overdose of Egipres.

Amlodipine

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

The treatment: administration of activated charcoal (especially during the first 2 hours after overdose), gastric lavage, elevation of the limbs, active support of cardiac function, monitoring of cardiac and lung function parameters, control of blood circulation and diuresis. To restore vascular tone and BP, if there are no contraindications, the use of vasoconstrictors may be useful. IV administration of calcium gluconate is used. Amlodipine is largely bound to serum proteins, therefore hemodialysis is ineffective.

Ramipril

Symptoms: excessive peripheral vasodilation with development of marked BP decrease, shock; bradycardia or reflex tachycardia, water-electrolyte disorders, acute renal failure, stupor.

The treatment: gastric lavage, prescription of adsorbents, sodium sulfate (if possible during the first 30 minutes). If BP is significantly decreased, the patient should be laid down, legs elevated, CSS functions actively maintained; administration of alpha1-adrenergic agonists (norepinephrine, dopamine) and angiotensinamide may be added to the therapy for refilling the blood circulation and restoration of electrolyte balance.

In cases of bradycardia refractory to drug treatment, a temporary artificial pacemaker may be required. In overdose, serum creatinine and electrolytes should be monitored. Ramiprilat is poorly excreted from the blood by hemodialysis.

Pregnancy use

The drug Egipres is contraindicated for use because ramipril may have adverse effects on the fetus: impaired fetal renal development, decreased fetal and neonatal BP, impaired renal function, hyperkalemia, skull bone hypoplasia, oligohydramnios, limb contracture, skull bone deformation, lung hypoplasia. Pregnancy should be excluded before starting the drug in women of childbearing age.

If a woman plans to become pregnant, treatment with the drug should be discontinued. If a woman becomes pregnant during treatment with the drug, the drug should be discontinued as soon as possible and the patient should be switched to another drug with the lowest risk to the baby.

If treatment with the drug is necessary during breastfeeding, it should be discontinued (data on excretion of amlodipine and ramipril with the breast milk of women are not available).

Fertility

Amlodipine. Reversible biochemical changes in sperm heads have been observed in some patients receiving BCA. Clinical data are insufficient to assess the potential effect of amlodipine on fertility.