Ramipril + Felodipine (Ramiprilum + Felodipinum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

ACE Inhibitors

Calcium channel blockers

Included in the formulation
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    Sanofi-Aventis Deutschland GmbH     Germany
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    C.09.B.B   ACE inhibitors in combination with calcium channel blockers

    C.09.B.B.05   Ramipril and felodipine

    Pharmacodynamics:

    Both drugs that make up the combination: a calcium channel blocker - felodipine and an ACE inhibitor - ramipril, reduce blood pressure (BP) due to dilatation of peripheral blood vessels. Calcium channel blockers dilate the arterial bed, while ACE inhibitors expand both the arterial and venous channels. Vasodilatation and, consequently, a decrease in blood pressure can activate the sympathetic nervous system and the renin-angiotensin-aldosterone system. Inhibition of ACE leads to a decrease in plasma concentrations of angiotensin II.

    Felodipine is a blocker of "slow" calcium channels, which reduce blood pressure by decreasing the total peripheral vascular resistance as a result of a direct relaxing effect on the smooth muscles of the vessels. Due to the selective effect on smooth muscle arterioles, therapeutic doses of felodipine do not affect myocardial contractility and conductivity. Felodipine reduces vascular resistance in the kidneys.This does not affect normal glomerular filtration. In case of impaired renal function, glomerular filtration may increase. Felodipine has a weak natriuretic and diuretic effect, fluid retention does not occur in the body.

    Ramipril. Formed by the action of "liver" enzymes active metabolite of ramipril - ramiprilat is a long-acting ACE inhibitor. In the blood plasma and tissues ACE catalyzes the conversion of angiotensin I to angiotensin II (vasoconstrictor active substance) and cleavage of the active vasodilator substances - bradykinin. Therefore, when taking ramipril decreases the formation of angiotensin II and is an accumulation of bradykinin, which results in vasodilatation and lower blood pressure, and also contributes to the cardioprotective effects of ramipril and its endotelioprotektivnoe effect due to induction of nitric oxide (NO) in endothelial cells through activation of prostaglandin and to increase the synthesis of prostaglandins influenced by increasing blood and tissue activity of kallikrein-kinin system.

    Angiotensin II stimulates the release of aldosterone, therefore, taking ramipril leads to a decrease in the secretion of aldosterone and an increase in the serum concentrations of potassium ions. Due to the negative feedback between angiotensin II concentration and renin secretion, a decrease in angiotensin II concentration leads to an increase in renin plasma activity.

    It is also assumed that with the increase in bradykinin activity, some undesirable reactions (dry cough) occur in part.

    Pharmacokinetics:

    The hypotensive effect of a single dose of the drug develops after 1-2 hours. The maximum hypotensive effect is achieved within 2-4 weeks, with prolonged treatment the effect is maintained at a 24-hour dosage interval.

    Felodipine (long-acting dosage form): bioavailability is about 15% and does not depend on food intake.

    The maximum concentration is reached in 3 - 5 hours. The connection with the proteins of the blood plasma is 99%. The volume of distribution in the equilibrium state is 10 l / kg. The half-life of felodipine is approximately 25 hours, the equilibrium state is reached after 5 days.

    With long-term treatment, there is no risk of cumulation. The clearance of felodipine averages 1200 ml / min. In elderly patients, a decrease in clearance leads to an increase in the concentration of felodipine in the blood plasma. Age is only a partial explanation of interindividual differences in the concentration of felodipine in the blood plasma. Felodipine is metabolized in the liver, and all of its known metabolites are devoid of vasodilator action. Approximately 70% of the accepted dose is excreted as metabolites by the kidneys, and about 10% - through the intestine. Less than 0.5% of the dose is excreted unchanged by the kidneys. Impaired renal function does not affect plasma concentrations of felodipine.

    Ramipril: after oral administration ramipril quickly absorbed from the digestive tract (50-60%). The food slows down its absorption, but does not affect the fullness of the intake. Ramipril is subjected to intense presystemic metabolism / activation (mainly in the liver by hydrolysis), which results in its only active metabolite, ramiprilate, whose activity for inhibiting 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,which is then conjugated 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). Bioavailability of the active metabolite - ramiprilata, after ingestion of 2.5 mg and 5 mg ramipril is approximately 45% (compared with intravenous administration of the same dose of ramipril).

    After taking ramipril inside, the maximum plasma concentrations of ramipril and ramiprilata are reached after 1 and 2-4 hours, respectively. The decrease in plasma concentration of ramiprilata occurs in several stages: the distribution and elimination phase with a half-life of ramiprilata of about 3 hours, then the intermediate phase with half-life ramiprilata, about 15 hours, and a final phase with a very low concentration of ramiprilate in the blood plasma and half-life ramiprilata, which is 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, the equilibrium plasma concentration of ramiprilate is reached after approximately 4 days of treatment. With the course use of the drug "effective" half-life depending on the dose is 13-17 hours.

    The association with blood plasma proteins is about 73% for ramipril, and 56% for ramiprilate.

    After intravenous administration, the volume distribution of ramipril and ramiprilate is approximately 90 liters and 500 liters, respectively.

    Approximately 80-90% of metabolites in urine and bile have been identified as ramiprilata and its metabolites. Ramipril glucuronide and ramipril diketopiperazine constitute approximately 10-20% of the total metabolites in urine, and the urinary urine content of unmetabolized ramipril is approximately 2%.

    With violations of kidney function (creatinine clearance less than 60 ml / min) excretion of ramiprilate and its metabolites by the kidneys slows down. This leads to an increase in the plasma concentration of ramiprilate, which decreases more slowly than in patients with normal renal function.

    Bioequivalence of a fixed combination ( felodipineramipril) and simultaneously taken individual preparations of felodipine and ramipril

    The pharmacokinetics of ramipril, ramiprilate and felodipine does not change significantly compared to that for individual preparations of felodipine and ramipril: long-acting felodipine tablets and ramipril tablets. Felodipine does not affect the inhibition of ACE caused by ramiprilate. Thus, fixed-combination tablets felodipineramipril are bioequivalent to simultaneously taken separate components of this combination (felodipine prolonged action and ramipril).

    Indications:Essential arterial hypertension.
    ICD-10

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

    Contraindications:

    - angioedema in the anamnesis (risk of rapid development of angioneurotic edema);

    - instability of hemodynamics: cardiogenic shock, chronic heart failure in the stage of decompensation, acute myocardial infarction, unstable angina, stroke;

    - atrioventricular blockade of II and III degree;

    - hemodynamics significant stenosis of the aortic or mitral valve or hypertrophic obstructive cardiomyopathy;

    - stenosis of the renal arteries (bilateral or unilateral in the case of a single kidney);

    - condition after kidney transplantation;

    - primary hyperaldosteronism;

    - severe hepatic impairment;

    - severe renal failure (creatinine clearance less than 20 ml / min) or hemodialysis (lack of sufficient clinical experience);

    - Pregnancy;

    - the period of breastfeeding;

    - age under 18 years (effectiveness and safety not established);

    - Extracorporeal types of treatment that lead to blood contact with negatively charged surfaces, such as hemodialysis or hemofiltration with certain highly flowing membranes (polyacrylonitrile membranes) and low density lipoprotein apheresis with dextran sulfate (high risk of severe anaphylactoid reactions);

    - Lactase insufficiency, galactose intolerance or glucose malabsorption syndrome and galactose (due to the content of lactose in the formulation);

    - hypersensitivity to felodipine (or other dihydropyridine derivatives), ramipril, other ACE inhibitors or to any of the excipients of the drug.

    Carefully:

    - conditions in which excessive reduction of blood pressure is especially dangerous (stenosing lesions of coronary and cerebral arteries, expressed ventricular arrhythmias);

    - conditions accompanied by an increase in the activity of the renin-angiotensin-aldosterone system in which, with ACE inhibition, there is a risk of a sharp decrease in blood pressure with impaired renal function (severe arterial hypertension, chronic heart failure of moderate severity, hemodynamically significant unilateral stenosis of the renal artery in the presence of two kidneys, previous intake of diuretics, water-electrolyte balance disorders, diarrhea, vomiting);

    - impaired renal function (creatinine clearance 20-50 ml / min), leading to a risk of hyperkalemia and a decrease in the number of leukocytes;

    - systemic diseases of connective tissue (including systemic lupus erythematosus, scleroderma);

    - concomitant therapy with glucocorticosteroids, immunomodulators, cytostatics, antimetabolites, allopurinol, procainamide and lithium salts, suppression of bone marrow hematopoiesis (risk of immune reactions,neutropenia or agranulocytosis); diabetes mellitus (risk of hyperkalemia); elderly age (risk of more pronounced hypotensive effect); hyperkalemia.

    Pregnancy and lactation:Contraindicated during pregnancy and during breastfeeding.
    Dosing and Administration:

    Tablets should be swallowed whole, regardless of food intake with a sufficient amount of liquid.

    Tablets can not be divided into parts, chew and chew.

    The combination of 2.5 mg + 2.5 mg - 1 tablet per day. The maximum dose is 2 tablets per day.

    The combination of 5 mg + 5 mg - 1 tablet per day. The maximum dose is 1 tablet per day.

    Side effects:

    From the side CNS and sensory organs headache, fatigue, imbalance, conjunctivitis of allergic nature, drowsiness, mood depression, sleep disorders, impotence, decreased libido, confusion, anxiety, irritability, tremor, hearing impairment (eg, ringing in the ears), decreased vision , a violation of taste and smell, a temporary loss of taste sensations, paresthesia.

    From the side of cardio-vascular system - excessive reduction in blood pressure (arterial hypotension, orthostatic reaction), accompanied by symptoms such as dizziness,decreased ability to concentrate, increased sweating, weakness, visual impairment (these phenomena are more often observed at the beginning of treatment and in patients with hyponatremia and hypovolemia, heart failure - especially after acute myocardial infarction, severe arterial hypertension, as well as an increase in the dose of ramipril and (or) diuretics); peripheral edema (in the ankle), loss of consciousness (fainting).

    With a marked decrease in blood pressure, the following adverse reactions may be associated: tachycardia, palpitations, angina pectoris, myocardial infarction, transient ischemic stroke, ischemic stroke; rhythm disturbances (appearance or strengthening), increased circulatory disturbances against the background of stenosing vascular lesions.

    From the side respiratory system - a dry, unproductive cough that often occurs in women and nonsmokers, worse at night and in a horizontal position lying down, bronchospasm, dyspnea, bronchitis, sinusitis, rhinitis, angioedema, involving the larynx, pharynx and / or tongue, more common in patients with Negroid race.

    From the side gastrointestinal tract - nausea, decreased appetite, pain in the epigastric region with increased activity of "liver" enzymes, dyspeptic disorders, vomiting, diarrhea or constipation, inflammation of the mucous membrane of the gastrointestinal tract, including the mucous membrane of the mouth and tongue, dry mouth, thirst, pancreatitis , angioedema of the small intestine, partial or complete intestinal obstruction.

    From the side liver - violations of the liver (including the development of acute liver failure), hepatitis; when taking ACE inhibitors, cases of the onset of liver damage syndrome, which started with cholestatic jaundice and passed into necrosis of the hepatic tissue (sometimes with a lethal outcome), are described.

    From the side skin and mucous membranes: allergic reactions (skin rash, itching, urticaria, angioedema with involvement of the lips, face, and / or extremities), which require the elimination of ramipril, severe skin reactions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), maculopapular exanthema and enanthema, pemphigus, worsening of psoriasis, psoriasis,pemphigoid and lichenoid lesions of the skin and mucous membranes, photosensitization, alopecia, onycholysis, vasculitis and exacerbation or development of Raynaud's syndrome. If a serious skin reaction is suspected, the patient should immediately notify the doctor and stop taking ramipril.

    Some skin reactions may be accompanied by fever, myalgia, arthralgia (or) arthritis, vasculitis, eosinophilia, and / or an increase in the titer of antinuclear antibodies.

    From the side kidneys - impaired renal function or increased already existing renal dysfunction, acute renal failure; proteinuria, sometimes with a decrease in renal function.

    From the side musculoskeletal system - muscle spasms, myalgia, arthralgia, fever.

    From the side pictures of blood and laboratory indicators - Increase in serum concentrations of urea and creatinine (especially in patients with impaired renal function), increased bilirubin concentration and hepatic enzyme activity, decreased hemoglobin concentration, decreased hematocrit, leukopenia, anemia, thrombocytopenia, eosinophilia, increased concentration of potassium ions patientsdiabetes mellitus), decreased concentration of sodium ions, increased activity of pancreatic enzymes, agranulocytosis or pancytopenia (especially in patients with impaired renal function, connective tissue disease or with concomitant treatment with allopurinol, procainamide and some suppresses the immune system), increased antinuclear antibodies, hemolysis / hemolytic anemia, including as a result of insufficiency of glucose-6-phosphate dehydrogenase, proteinuria.

    Adverse effects on the fetus

    Disturbance of fetal kidney development, decrease in fetal and newborn infants, renal dysfunction, hyperkalemia, skull hypoplasia, oligohydramnia, limb contracture, skull bones deformation, lung hypoplasia.

    In connection with the reception of felodipine, the following adverse reactions may develop.

    From the side CNS and sensory organs - Headache, dizziness, paresthesia.

    From the side of cardio-vascular system - "tides" of blood to the skin of the face, peripheral edema, tachycardia, a feeling of intense heartbeat, loss of consciousness (fainting), leukocytoclastic vasculitis, extrasystole, marked decrease in blood pressure.

    From the side GIT and liver - nausea, pain in the epigastric region, vomiting, gingival hyperplasia, tongue mucosa, gingivitis, increased activity of "liver" transaminases.

    From the side skin and mucous membranes: allergic reactions, skin rash, itching, urticaria, angioedema, edema of the lips or tongue, photosensitivity reactions, hypersensitivity reactions.

    From the side kidneys - Frequent urination.

    From the side musculoskeletal system - myalgia, arthralgia.

    Other: fatigue, impotence, sexual dysfunction, fever, hyperglycemia.

    Overdose:

    Overdose can cause excessive peripheral vasodilation with pronounced lowering of blood pressure, bradycardia (sometimes tachycardia), atrioventricular blockade of I-III degree, hypokalemia, ventricular extrasystole, ventricular fibrillation, shock, electrolyte imbalance and kidney failure.

    Primary detoxification with, for example, gastric lavage, the appointment of adsorbents and (or) laxatives (if possible in the first 30 minutes). With a pronounced decrease in blood pressure: in addition to replenishing the volume of circulating blood and salts, the appointment of α1-adrenergic sympathomimetics and angiotensin II may be necessary.With bradycardia, atrioventricular blockade or excessive excitation of the vagus nerve, enter atropine. A specific antidote for felodipine is calcium preparations (an overdose shows a slow intravenous injection of 10% calcium chloride or calcium gluconate, followed by a switch to a long infusion).

    Experiments with regard to the efficacy of forced diuresis, changes in urinary pH, hemofiltration or dialysis for the purpose of accelerated elimination of ramipril or ramiprilate are not available.

    Interaction:

    Combinations not recommended

    Potassium salts, potassium-sparing diuretics (eg, amiloride, triamterene, spironolactone) - a more pronounced increase in the concentration of potassium ions in the blood serum (with the simultaneous application requires careful monitoring of the concentration of potassium ions in the blood serum).

    Felodipine is a substrate of the isoenzyme CYP3A4. Drugs that induce or inhibit the isoenzyme CYP3A4 have a significant effect on the plasma concentration of felodipine.

    To drugs that enhance the metabolism of felodipine due to the induction of the isoenzyme CYP3A4, carbamazepine, phenytoin, phenobarbital and rifampicin, as well as St. John's wort (Hypericum perforatum). When felodipine is administered simultaneously with carbamazepine, phenytoin, phenobarbital AUC (the area under the concentration-time curve) is reduced by 93%, and the maximum concentration by 82%. A similar effect is possible with St. John's wort. Combinations with inducers of the isoenzyme CYP3A4 should be avoided.

    The powerful inhibitors of the isoenzyme CYP3A4 include azole antifungal agents, macrolide antibiotics, telithromycin and HIV protease inhibitors. With the simultaneous use of felodipine with itraconazole, the maximum concentration increases 8-fold, and AUC-6-fold. During the application of felodipine simultaneously with erythromycin, the maximum concentration and AUC values ​​increased almost 2.5-fold. Combinations with potent inhibitors of the CYP3A4 isoenzyme should be avoided.

    Grapefruit juice suppresses the isoenzyme CYP3A4. Simultaneous reception of felodipine with grapefruit juice increases the maximum concentration and AUC of felodipine approximately in 2 times. This combination should be avoided.

    Combinations that require caution

    - antihypertensives (especially diuretics) and other drugs that reduce blood pressure (nitrates, tricyclic antidepressants) - potentiation of hypotensive effects;

    - hypnotics, narcotics and anesthetics - can cause a more pronounced decrease in blood pressure;

    - vasopressor adrenomimetics (epinephrine) may cause a decrease in the action of ramipril;

    - allopurinol, procainamide, cytostatics, immunosuppressants, systemic glucocorticosteroids and other drugs that can affect hematologic indices - joint use increases the risk of developing leukopenia;

    - lithium - increased serum lithium concentration and increased cardio-and neurotoxic effect of lithium;

    - hypoglycemic agents for oral administration (derivatives of sulfonylureas, biguanides), insulin - in connection with a decrease under the influence of ramipril insulin resistance, an increase in the hypoglycemic effect of these agents is possible up to the development of hypoglycemia;

    - non-steroidal anti-inflammatory drugs (indomethacin, acetylsalicylic acid) - it is possible to weaken the action of ramipril, increase the risk of impaired renal function and increase the concentration of potassium ions in the blood serum;

    - heparin - a possible increase in the concentration of potassium ions in the blood serum;

    - sodium chloride - weakening of the hypotensive effect of ramipril and less effective treatment of symptoms of heart failure;

    - ethanol - strengthening vasodilation;

    - estrogens - weakening of the hypotensive effect of ramipril (delay

    liquid);

    - theophylline - simultaneous treatment with felodipine and theophylline for oral administration reduces the absorption of theophylline, approximately, by 20%. This phenomenon probably has little clinical significance;

    - tacrolimus - felodipine can increase the concentration of tacrolimus. With simultaneous application it is necessary to monitor the concentration of tacrolimus in the serum, a dose correction of tacrolimus may be required.

    Special instructions:

    If there is edema, for example, a person (lips, eyelids) or tongue, or a violation of swallowing or breathing, the patient should immediately stop taking the drug. Angioedema of the tongue, throat or larynx (possible symptoms: swallowing or breathing disorder) can be life threatening and requires emergency care (immediate subcutaneous injection of epinephrine (adrenaline) 1: 1000 (0.3-0.5 ml) or slow intravenous injection of 1 mg / ml epinephrine (note the instructions for breeding) under the control of ECG and blood pressure.The patient is hospitalized and observed for at least 12-24 hours until the symptoms are completely resolved.

    The intestinal form of angioedema was recorded in patients treated with ACE inhibitors. Such patients had abdominal pain (with or without nausea and vomiting); in some cases without prior edema of the face and with normal activity of chloroasterase. This condition was diagnosed during CT or ultrasound examination of the abdominal cavity or during surgery; symptoms were resolved after the withdrawal of the ACE inhibitor. In patients taking an ACE inhibitor and having abdominal pain, an intestinal form of angioedema must be included in the differential diagnosis.

    In the treatment of ACE inhibitors, angioedema is more often reported in patients of the Negroid race than in Europeans.

    It is necessary to observe the function of the kidneys, especially during the first weeks of treatment and especially careful in patients with concomitant circulatory insufficiency, renal vascular disease (for example,with stenosis of the renal arteries still clinically insignificant, or with unilateral hemodynamically significant stenosis of the renal artery, since in this case even a slight increase in the serum creatinine concentration may indicate a one-sided decrease in kidney function) in cases of a previously existing renal dysfunction.

    In some patients treated with ACE inhibitors, including ramipril, an increase in the serum potassium concentration was observed. The risk group for hyperkalemia includes patients with renal insufficiency, diabetes mellitus, or patients who simultaneously use potassium-sparing diuretics, potassium supplements or potassium-containing salts, as well as patients taking other drugs whose use is accompanied by an increase in the serum potassium concentration (eg, heparin). If the simultaneous use of these medicines is necessary, the serum potassium concentrations should be monitored regularly.

    The likelihood of developing proteinuria is higher in patients with renal failure or at relatively high doses of ACE inhibitors.

    There is an increased risk of developing severe arterial hypotension and renal failure if a patient with renovascular hypertension and established bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney are treated with ACE inhibitors. In patients with unilateral renal artery stenosis (in the presence of two kidneys), the decrease in renal function can occur only with small changes in serum creatinine concentration.

    In rare cases, the use of ACE inhibitors is accompanied by a syndrome that begins with cholestatic jaundice, then progresses to fulminant liver necrosis (sometimes fatal). The mechanism of this syndrome is unknown. If you develop jaundice or a marked increase in the activity of "liver" transaminases, you should abolish the ACE inhibitor and provide appropriate medical care.

    During large surgical operations or in the treatment with anesthetics that can reduce blood pressure, it is possible to develop arterial hypotension, which can be corrected by increasing the volume of circulating blood.

    ACE inhibitors should be used with caution in patients with significant hemodynamic impairment of left ventricular function (eg, stenosis of the aorta or mitral valve, obstructive cardiomyopathy). In the initial stage of treatment, careful medical supervision is necessary.

    In some patients, mainly in patients with chronic heart failure (as well as with kidney failure and without it) who took high doses of looped diuretics, in the case of hyponatremia or with a decrease in renal function after the first dose of the drug, the development of symptomatic arterial hypotension. Thus, the appointment of such patients should be done only after further analysis of the condition and proper titration of the doses of individual components. The drug can be administered only with stable hemodynamics. In patients suffering from hypertension without cardiac or renal insufficiency, it is possible to develop arterial hypotension, mainly in the case of reduced blood volume due to diuretic therapy, limited salt content in the diet, diarrhea or vomiting.

    Patients, for whom a decrease in blood pressure presents a particular danger (for example, patients with coronary or cerebrovascular insufficiency), it is necessary to begin to treat and select the necessary doses of this combination with the help of separate preparations of felodipine and ramipril. If it is possible to achieve a satisfactory level and stable blood pressure with the help of doses of ramipril and felodipine equal to the doses contained in the combined preparation, the patient can be transferred to receive a fixed combination. In some cases felodipine can cause arterial hypotension with tachycardia, which can provoke an exacerbation of the course of angina pectoris.

    The drug can cause agranulocytosis and neutropenia. These adverse reactions have been demonstrated with other ACE inhibitors: less frequent in patients without complications, and more often in patients with renal insufficiency, especially when the latter is accompanied by a systemic connective tissue disease (eg, systemic lupus erythematosus or scleroderma) while treated with immunosuppressive agents. It is necessary to ensure control of the number of leukocytes in patients with systemic connective tissue diseases (collagenoses), especially if the disease is accompanied by impaired renal function.After the abolition of the ACE inhibitor, neutropenia and agranulocytosis are reversible.

    If symptoms such as fever, enlarged lymph nodes and / or sore throat develop during treatment, you should consult your doctor and check the number of white blood cells immediately.

    During treatment with an ACE inhibitor, a "dry" cough may appear, which disappears after the drug is withdrawn.

    Simultaneous treatment with ACE inhibitors and hypoglycemic agents (insulin and hypoglycemic agents for oral administration) may lead to an increase in hypoglycemic action with a risk of hypoglycemia. This effect is most pronounced at the beginning of treatment and in patients with impaired renal function.

    Metabolism of felodipine is carried out with the help of the isoenzyme CYP3A4. Therefore, combinations with drugs - potent inhibitors or inductors of the CYP3A4 isoenzyme should be avoided. For the same reason, simultaneous intake of grapefruit juice should be avoided.

    It is not recommended to combine lithium preparations with an ACE inhibitor.

    In patients with hemodialysis using certain high-density membranes (for example, polyacrylonitrile membranes) against the background of the administration of ACE inhibitors (see.as well as the instructions of membrane manufacturers), life-threatening, rapidly developing, allergic-like (anaphylactoid) hypersensitivity reactions were described, sometimes up to the development of shock.

    It is necessary to avoid joint application with 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 ACE inhibitors.

    Similar reactions were observed in the apheresis of low-density lipoproteins using dextran sulfate. Therefore, this method should not be used for patients treated with ACE inhibitors.

    Similar to other ACE inhibitors, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom increases during desensitization (for example, with bee and ostal bites).

    Impact on the ability to drive vehicles and manage mechanisms

    Some side effects (eg, lowering blood pressure, dizziness) can impair the ability to concentrate and slow down the psychomotor reactions, which can increase the risk in situations where it is of particular importance, for example when driving or working with machinery.

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