Tritace^® (Tablets) Instructions for Use

ATC Code

C09AA05 (Ramipril)

Active Substance

Ramipril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE inhibitor

Pharmacological Action

Antihypertensive drug, ACE inhibitor.

The active metabolite of ramipril, ramiprilat, formed under the influence of liver enzymes, is a long-acting ACE inhibitor, which is a peptidyldipeptidase. ACE in blood plasma and tissues catalyzes the conversion of angiotensin I to angiotensin II and the breakdown of bradykinin. Therefore, when ramipril is taken orally, the formation of angiotensin II decreases and bradykinin accumulates, which leads to vasodilation and a decrease in blood pressure. The increase in the activity of the kallikrein-kinin system in the blood and tissues determines the cardioprotective and endothelioprotective action of ramipril due to the activation of the prostaglandin system and, accordingly, an increase in the synthesis of prostaglandins that stimulate the formation of nitric oxide (NO) in endothelial cells.

Angiotensin II stimulates the production of aldosterone, so taking ramipril leads to a decrease in aldosterone secretion and an increase in serum potassium ion concentrations.

When the concentration of angiotensin II in the blood decreases, its inhibitory effect on renin secretion via negative feedback is eliminated, which leads to an increase in plasma renin activity.

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

In patients with arterial hypertension, taking ramipril leads to a decrease in blood pressure in the supine and standing positions, without a compensatory increase in heart rate. Ramipril significantly reduces total peripheral vascular resistance, practically without causing changes in renal blood flow and glomerular filtration rate. The hypotensive effect begins to appear 1-2 hours after taking a single dose of the drug, reaches its maximum value after 3-9 hours, and lasts for 24 hours. With course administration, the hypotensive effect may gradually increase, usually stabilizing by the 3-4th week of regular use of the drug and then persisting for a long time. Sudden discontinuation of the drug does not lead to a rapid and significant increase in blood pressure (no withdrawal syndrome).

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

In patients with chronic heart failure, Ramipril reduces total peripheral vascular resistance (reduction of cardiac afterload), increases venous capacity and reduces left ventricular filling pressure, which, accordingly, leads to a reduction in cardiac preload. In these patients, taking ramipril is accompanied by an increase in cardiac output, ejection fraction and improved exercise tolerance.

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

In patients at high risk of developing cardiovascular diseases due to either vascular lesions (diagnosed coronary artery disease, history of obliterating peripheral arterial disease, history of stroke), or diabetes mellitus with at least one additional risk factor (microalbuminuria, arterial hypertension, increased total cholesterol concentrations, decreased HDL cholesterol concentrations, smoking), adding ramipril to standard therapy significantly reduces the incidence of myocardial infarction, 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 chronic heart failure.

In patients with heart failure that developed in the first days of acute myocardial infarction (days 2-9), when taking ramipril, starting from day 3 to day 10 of acute myocardial infarction, the risk of mortality (by 27%), the risk of sudden death (by 30%), the risk of progression of chronic heart failure to severe (NYHA functional class III-IV)/therapy-resistant (by 27%), and the likelihood of subsequent hospitalization due to the development of heart failure (by 26%) are reduced.

In the general patient population, as well as in patients with diabetes mellitus, both with arterial hypertension and with normal blood pressure, Ramipril significantly reduces the risk of developing nephropathy and the occurrence of microalbuminuria.

Pharmacokinetics

Absorption, distribution and metabolism

After oral administration, it is rapidly absorbed from the gastrointestinal tract (50-60%). Food does not affect the completeness of absorption but slows down absorption.

Ramipril undergoes intensive presystemic metabolism/activation (mainly in the liver by hydrolysis), resulting in the formation of its only active metabolite, ramiprilat, whose activity in inhibiting ACE is approximately 6 times greater than that of ramipril. In addition, as a result of ramipril metabolism, a pharmacologically inactive diketopiperazine is formed, which is then conjugated with glucuronic acid; ramiprilat is also glucuronidated and metabolized to diketopiperazine acid.

The bioavailability of ramipril after oral administration ranges from 15% (for a 2.5 mg dose) to 28% (for a 5 mg dose). The bioavailability of the active metabolite, ramiprilat, after oral administration of 2.5 mg and 5 mg of ramipril is approximately 45% (compared to its bioavailability after intravenous administration at the same doses).

C_max of ramipril and ramiprilat is reached in plasma after 1 and 2-4 hours, respectively. The binding of ramipril to plasma proteins is 73%, and that of ramiprilat is 56%.

Elimination

The decrease in plasma concentration of ramiprilat occurs in several stages: an initial distribution and elimination phase with a T_1/2 of ramiprilat of approximately 3 hours, then an intermediate phase with a T_1/2 of ramiprilat of approximately 15 hours, and a final phase with a very low plasma concentration of ramiprilat and a T_1/2 of ramiprilat of approximately 4-5 days. This final phase is associated with the slow dissociation of ramiprilat from its binding to ACE receptors. Despite the prolonged final phase, with a single daily dose of ramipril of 2.5 mg or more, the C_ss concentration of ramiprilat in plasma is reached approximately 4 days after the start of treatment.

With course administration of the drug, the T_1/2 is 13-17 hours.

After oral administration of radiolabeled ramipril (10 mg), 39% of the radioactivity is excreted through the intestines and about 60% through the kidneys.

After oral administration of 5 mg of ramipril in patients with biliary drainage, almost equal amounts of ramipril and its metabolites are excreted by the kidneys and through the intestines during the first 24 hours after administration.

Approximately 80-90% of metabolites in urine and bile were identified as ramiprilat and metabolites of ramiprilat. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10-20% of the total, and the content of unmetabolized ramipril in urine is approximately 2%.

Pharmacokinetics in special clinical cases

In case of impaired renal function with a creatinine clearance of less than 60 ml/min, the renal excretion of ramiprilat and its metabolites is slowed down. This leads to an increase in the plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function.

When taking ramipril in high doses (10 mg), impaired liver function leads to a slowdown in the presystemic metabolism of ramipril to active ramiprilat and slower excretion of ramiprilat.

In healthy volunteers and patients with arterial hypertension, after two weeks of treatment with ramipril at a daily dose of 5 mg, no clinically significant accumulation of ramipril and ramiprilat is observed.

In patients with chronic heart failure, after two weeks of treatment with ramipril at a daily dose of 5 mg, a 1.5-1.8-fold increase in plasma concentrations of ramiprilat and AUC is noted.

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

In experimental studies in animals, it was shown that Ramipril is excreted in breast milk.

Indications

• Essential hypertension;
• Chronic heart failure (as part of combination therapy, in particular in combination with diuretics);
• Diabetic or non-diabetic nephropathy preclinical and clinically pronounced stages, including with severe proteinuria, especially when combined with arterial hypertension;
• Reducing the risk of myocardial infarction, stroke or cardiovascular mortality in patients at high cardiovascular risk: in patients with confirmed coronary artery disease, with or without a history of myocardial infarction, including patients who have undergone percutaneous transluminal coronary angioplasty, coronary artery bypass grafting; in patients with a history of stroke; in patients with occlusive lesions of peripheral arteries; in patients with diabetes mellitus with at least one additional risk factor (microalbuminuria, arterial hypertension, increased plasma total cholesterol concentrations, decreased plasma HDL cholesterol concentrations, smoking).
• Heart failure that developed within the first few days (from day 2 to day 9) after acute myocardial infarction.

ICD codes

Dosage Regimen

Tablets

The tablets must be swallowed whole (not chewed) and washed down with a sufficient amount (1/2 glass) of water, regardless of food intake (that is, the tablets can be taken before, during, or after meals). The dose is selected depending on the therapeutic effect and the patient’s tolerance of the drug.

Treatment with Tritace^® is usually long-term, and its duration in each specific case is determined by the doctor.

Unless otherwise prescribed, the following dosing regimens are recommended for normal renal and hepatic function.

For essential hypertension

The usual initial dose is 2.5 mg once a day in the morning (in this case, Tritace^® 2.5 mg tablets or 1/2 of a 5 mg tablet with a score line can be used). If blood pressure cannot be normalized with this dose for 3 weeks or more, the dose can be increased to 5 mg/day. If the 5 mg dose is insufficiently effective, after 2-3 weeks it can be doubled again to the maximum recommended daily dose of 10 mg/day.

As an alternative to increasing the dose to 10 mg per day with insufficient antihypertensive efficacy of a daily dose of 5 mg, it is possible to add other antihypertensive agents to the treatment, in particular diuretics or slow calcium channel blockers.

For chronic heart failure

The recommended initial dose is 1.25 mg once a day (in this case, 1/2 of a Tritace^® 2.5 mg tablet with a score line can be used). Depending on the patient’s response to the therapy, the dose can be increased. It is recommended to double the dose at intervals of 1-2 weeks. If a daily dose of 2.5 mg or higher is required, it can be given either once a day or divided into two doses.

The maximum recommended daily dose is 10 mg.

For diabetic or non-diabetic nephropathy

The recommended initial dose is 1.25 mg once a day (in this case, 1/2 of a Tritace^® 2.5 mg tablet with a score line can be used). The dose can be increased to 5 mg once a day. For these conditions, doses above 5 mg once a day have not been sufficiently studied in controlled clinical trials.

To reduce the risk of myocardial infarction, stroke or cardiovascular mortality in patients at high cardiovascular risk

The recommended initial dose is 2.5 mg once a day (in this case, Tritace^® 2.5 mg tablets or 1/2 of a 5 mg tablet with a score line can be used).

Depending on the patient’s tolerance of the drug, the dose can be gradually increased. It is recommended to double the dose after 1 week of treatment, and over the next 3 weeks of treatment, increase it to the usual maintenance dose of 10 mg once a day.

Doses exceeding 10 mg have not been sufficiently studied in controlled clinical trials.

The use of the drug in patients with creatinine clearance less than 0.6 ml/sec has not been sufficiently studied.

For heart failure that developed within the first few days (from day 2 to day 9) after acute myocardial infarction

The recommended initial dose is 5 mg/day, divided into two single doses of 2.5 mg, one taken in the morning and the other in the evening (in this case, Tritace^® 2.5 mg tablets or 1/2 of a 5 mg tablet with a score line can be used). If the patient does not tolerate this initial dose (excessive decrease in blood pressure is observed), then it is recommended to give 1.25 mg twice a day for two days (in this case, 1/2 of a Tritace^® 2.5 mg tablet with a score line can be used).

Then, depending on the patient’s response, the dose can be increased. It is recommended that the dose be doubled at intervals of 1-3 days when increasing it. Later, the total daily dose, which was initially divided into two doses, can be given as a single dose.

The maximum recommended dose is 10 mg.

Currently, experience in treating patients with severe heart failure (NYHA functional class III-IV) that occurred immediately after acute myocardial infarction is insufficient. If a decision is made to treat such patients with Tritace^®, it is recommended that treatment begin with the lowest possible dose of 1.25 mg once a day (in this case, 1/2 of a Tritace^® 2.5 mg tablet with a score line can be used) and special caution should be exercised with each dose increase.

Use in specific patient groups

Patients with impaired renal function

For creatinine clearance from 50 to 20 ml/min, the initial daily dose is usually 1.25 mg (in this case, 1/2 of a Tritace^® 2.5 mg tablet with a score line can be used). The maximum allowable daily dose is 5 mg.

Patients with incompletely corrected fluid and electrolyte loss, patients with severe arterial hypertension, as well as patients for whom an excessive decrease in blood pressure poses a certain risk (for example, with severe atherosclerotic lesions of the coronary and cerebral arteries)

The initial dose is reduced to 1.25 mg/day (in this case, 1/2 of a Tritace^® 2.5 mg tablet with a score line can be used).

Patients with prior diuretic therapy

If possible, diuretics should be discontinued 2-3 days (depending on the duration of action of the diuretics) before starting treatment with Tritace^®, or at least the dose of diuretics taken should be reduced. Treatment of such patients should begin with the lowest dose of 1.25 mg of ramipril (in this case, 1/2 of a Tritace^® 2.5 mg tablet with a score line can be used), taken once a day in the morning. After taking the first dose and each time after increasing the dose of ramipril and/or “loop” diuretics, patients should be under medical supervision for at least 8 hours to avoid an uncontrolled hypotensive reaction.

Elderly patients (over 65 years old)

The initial dose is reduced to 1.25 mg/day (in this case, 1/2 of a Tritace^® 2.5 mg tablet with a score line can be used).

Patients with impaired liver function

The blood pressure response to taking Tritace^® may either increase (due to slower excretion of ramiprilat) or decrease (due to slower conversion of the weakly active ramipril to active ramiprilat). Therefore, careful medical supervision is required at the beginning of treatment. The maximum allowable daily dose is 2.5 mg (in this case, Tritace^® 2.5 mg tablets or 1/2 of a 5 mg tablet with a score line can be used).

Adverse Reactions

The adverse effects listed below are given in accordance with the following frequency gradations: very common (≥10%), common (≥1%, but <10%), uncommon (≥0.1%, but <1%), rare (≥0.01%, but <0.1%), very rare (<0.01%, including isolated cases), frequency unknown (cannot be estimated from the available data).

From the cardiovascular system: common – excessive decrease in blood pressure, impaired orthostatic regulation of vascular tone (orthostatic hypotension), syncope; uncommon – myocardial ischemia, including the development of an angina attack or myocardial infarction, tachycardia, arrhythmias (appearance or intensification), palpitations, peripheral edema, flushing of the skin of the face; rare – occurrence or intensification of circulatory disorders against the background of stenosing vascular lesions, vasculitis; frequency unknown – Raynaud’s syndrome.

From the central nervous system common – headache, feeling of “lightheadedness”; uncommon – dizziness, ageusia (loss of taste sensitivity), dysgeusia (impaired taste sensitivity), depressed mood, anxiety, nervousness, restlessness, sleep disorders, including drowsiness; rare – tremor, imbalance, confusion; frequency unknown – cerebral ischemia, including ischemic stroke and transient ischemic attack, impaired psychomotor reactions, paresthesia (burning sensation), parosmia (impaired perception of smells), impaired attention.

Visual organ side effects sometimes – visual disturbances, including blurred vision; rarely – conjunctivitis.

Hearing organ side effects rarely – hearing impairment, tinnitus.

Respiratory system side effects frequently – dry cough (worsening at night and when lying down), bronchitis, sinusitis, dyspnea; sometimes – bronchospasm, including exacerbation of bronchial asthma, nasal congestion.

Digestive system side effects frequently – inflammatory reactions in the stomach and intestines, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; sometimes – pancreatitis, including fatal cases (cases of fatal pancreatitis with ACE inhibitors have been observed very rarely), increased activity of pancreatic enzymes in blood plasma, intestinal angioedema, abdominal pain, gastritis, constipation, dry mouth; rarely – glossitis; frequency unknown – aphthous stomatitis (inflammatory reaction of the oral mucosa).

Hepatobiliary system side effects: sometimes – increased activity of liver enzymes and concentration of conjugated bilirubin in blood plasma; rarely – cholestatic jaundice, hepatocellular damage; frequency unknown – acute liver failure, cholestatic or cytolytic hepatitis (fatal outcome has been observed very rarely).

Kidney and urinary tract side effects sometimes – impaired renal function, including development of acute renal failure, increased urine output, exacerbation of pre-existing proteinuria, increased blood concentrations of urea and creatinine.

Reproductive system and breast side effects sometimes – transient impotence due to erectile dysfunction, decreased libido; frequency unknown: gynecomastia.

Hematopoietic system side effects sometimes – eosinophilia; rarely – leukopenia, including neutropenia and agranulocytosis, decreased red blood cell count in peripheral blood, decreased hemoglobin concentration, thrombocytopenia; frequency unknown – bone marrow depression, pancytopenia, hemolytic anemia.

Skin and mucous membranes side effects: frequently – skin rash (in particular maculopapular); sometimes – angioedema, including fatal cases (laryngeal edema can cause airway obstruction leading to death), pruritus, hyperhidrosis; rarely – exfoliative dermatitis, urticaria, onycholysis; very rarely – photosensitivity reactions; frequency unknown – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.

Musculoskeletal system side effects frequently – muscle cramps, myalgia; sometimes – arthralgia.

Metabolism, nutrition and laboratory findings side effects frequently – increased blood potassium concentration; sometimes – anorexia, decreased appetite; frequency unknown – decreased blood sodium concentration.

Immune system side effects frequency unknown – anaphylactic or anaphylactoid reactions (with ACE inhibition, the number of anaphylactic or anaphylactoid reactions to insect venoms increases), increased concentration of antinuclear antibodies.

General disorders frequently – chest pain, feeling of fatigue; sometimes – increased body temperature; rarely – asthenia (weakness).

Contraindications

• History of angioedema (hereditary or idiopathic, as well as after taking ACE inhibitors) – risk of rapid development of angioedema;
• Hemodynamically significant renal artery stenosis (bilateral or unilateral in the case of a single kidney);
• Arterial hypotension (systolic BP less than 90 mm Hg) or conditions with unstable hemodynamic parameters;
• Hemodynamically significant stenosis of the aortic or mitral valve or hypertrophic obstructive cardiomyopathy;
• Primary hyperaldosteronism;
• Severe renal failure (CrCl less than 20 ml/min with a body surface area of 1.73 m²) (insufficient clinical experience);
• Hemodialysis (insufficient clinical experience);
• Pregnancy;
• Lactation period;
• Nephropathy treated with corticosteroids, NSAIDs, immunomodulators and/or other cytotoxic agents (insufficient clinical experience);
• Chronic heart failure in the stage of decompensation (insufficient clinical experience);
• Age under 18 years (insufficient clinical experience);
• Hemodialysis or hemofiltration using certain membranes with a negatively charged surface, such as high-flux polyacrylonitrile membranes (risk of hypersensitivity reactions);
• Low-density lipoprotein apheresis using dextran sulfate (risk of hypersensitivity reactions);
• Hyposensitizing therapy for hypersensitivity reactions to insect venoms, such as bees, wasps;
• Hypersensitivity to ramipril, other ACE inhibitors, or to any component of the drug.

Additional contraindications for the use of the drug Tritace^® in the acute phase of myocardial infarction

• Severe heart failure (functional class IV according to NYHA classification);
• Unstable angina;
• Life-threatening ventricular cardiac arrhythmias;
• Cor pulmonale.

With caution

• Conditions in which an excessive decrease in BP is particularly dangerous (with atherosclerotic lesions of the coronary and cerebral arteries);
• Conditions accompanied by increased activity of the renin-angiotensin-aldosterone system (RAAS), in which ACE inhibition carries a risk of a sharp decrease in BP with deterioration of renal function (severe arterial hypertension, especially malignant arterial hypertension; chronic heart failure, especially severe or for which other antihypertensive drugs are taken; hemodynamically significant unilateral renal artery stenosis (in the presence of both kidneys); prior use of diuretics; water-electrolyte imbalance due to insufficient intake of fluid and salt, diarrhea, vomiting, profuse sweating);
• Impaired liver function (insufficient experience of use: both enhancement and weakening of ramipril effects are possible;
• In patients with liver cirrhosis with ascites and edema, significant activation of RAAS is possible, see above Conditions accompanied by increased RAAS activity);
• Impaired renal function (CrCl greater than 20 ml/min with a body surface area of 1.73 m²) due to the risk of hyperkalemia and leukopenia);
• Status after kidney transplantation;
• Systemic connective tissue diseases, including systemic lupus erythematosus, scleroderma, concomitant therapy with drugs that can cause changes in the peripheral blood picture (bone marrow depression, development of neutropenia or agranulocytosis is possible);
• Diabetes mellitus (risk of hyperkalemia);
• Elderly age (risk of increased hypotensive effect);
• Hyperkalemia.

Use in Pregnancy and Lactation

Ramipril is contraindicated during pregnancy, as it may have an adverse effect on the fetus: impaired fetal kidney development, decreased BP in the fetus and newborns, impaired renal function, hyperkalemia, skull bone hypoplasia, oligohydramnios, limb contractures, skull bone deformities, lung hypoplasia.

Therefore, before starting the drug in women of childbearing potential, pregnancy should be excluded.

If a woman is planning a pregnancy, treatment with ACE inhibitors should be discontinued.

If pregnancy occurs during treatment with Tritace^®, it should be discontinued as soon as possible and the patient should be switched to other drugs with the lowest risk to the child.

If treatment with Tritace^® is necessary during breastfeeding, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in severe liver dysfunction.

Use in Renal Impairment

Use with caution in severe renal dysfunction.

The drug is contraindicated in severe renal failure (CrCl less than 20 ml/min with a body surface area of 1.73 m²), in hemodialysis.

Pediatric Use

Contraindication: age under 18 years (insufficient clinical experience).

Geriatric Use

Elderly patients (over 65 years) – initial dose should be reduced to 1.25 mg/day (in this case, 1/2 tablet of Tritace^® 2.5 mg with a score line can be used).

Special Precautions

Before starting treatment with Tritace^®, hyponatremia and hypovolemia must be corrected. In patients previously taking diuretics, they should be discontinued or at least their dose reduced 2-3 days before starting Tritace^® (in this case, patients with chronic heart failure should be carefully monitored due to the possibility of decompensation associated with increased blood volume).

After taking the first dose of the drug, as well as when increasing its dose and/or the dose of diuretics (especially “loop” diuretics), careful medical supervision of the patient for at least 8 hours is necessary to take appropriate measures in case of excessive BP reduction.

If Tritace^® is used for the first time or in a high dose in patients with increased RAAS activity, their BP should be carefully monitored, especially at the beginning of treatment, as these patients have an increased risk of excessive BP reduction.

In malignant arterial hypertension and heart failure, especially in the acute phase of myocardial infarction, treatment with Tritace^® should be started only in a hospital setting.

In patients with chronic heart failure, taking the drug may lead to the development of a pronounced decrease in BP, which in some cases is accompanied by oliguria or azotemia and rarely – the development of acute renal failure.

Caution should be exercised when treating elderly patients, as they may be particularly sensitive to ACE inhibitors; in the initial phase of treatment, monitoring of renal function parameters is recommended.

In patients for whom a decrease in BP may pose a certain risk (e.g., patients with atherosclerotic narrowing of the coronary or cerebral arteries), treatment should be initiated under strict medical supervision.

Caution should be exercised during physical exertion and/or in hot weather due to the risk of increased sweating and dehydration with the development of arterial hypotension, as a result of decreased blood volume and decreased blood sodium concentration.

During treatment with Tritace^®, alcohol consumption is not recommended.

Transient arterial hypotension is not a contraindication for continuing treatment after BP stabilization. In case of recurrent severe arterial hypotension, the dose should be reduced or the drug discontinued.

Cases of angioedema of the face, extremities, lips, tongue, pharynx, or larynx have been observed in patients treated with ACE inhibitors. If swelling occurs in the face area (lips, eyelids) or tongue, or difficulty swallowing or breathing, the patient should immediately discontinue the drug. Angioedema localized in the tongue, pharynx, or larynx (possible symptoms: difficulty swallowing or breathing) can be life-threatening and requires emergency measures for its relief: s.c. injection of 0.3-0.5 mg or i.v. drip infusion of 0.1 mg epinephrine (under BP, heart rate and ECG control) followed by corticosteroids (i.v., i.m. or orally); i.v. administration of antihistamines (histamine H₁– and H₂-receptor antagonists) is also recommended, and in case of C₁-esterase inactivator deficiency, the need for additional administration of C₁-esterase enzyme inhibitors along with epinephrine can be considered. The patient should be hospitalized and observed until symptoms completely resolve, but for at least 24 hours.

Cases of intestinal angioedema have been observed in patients receiving ACE inhibitors, which manifested as abdominal pain with or without nausea and vomiting; in some cases, facial angioedema was also observed simultaneously. If a patient develops the above symptoms during treatment with ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

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

Life-threatening, rapidly developing anaphylactoid reactions, sometimes up to shock, have been described with the use of ACE inhibitors during hemodialysis or plasma filtration using certain high-flux membranes (e.g., polyacrylonitrile membranes) (see also manufacturers’ instructions for membranes). The combined use of Tritace^® and such membranes, for example, for urgent hemodialysis or hemofiltration, should be avoided. In this case, the use of other membranes or discontinuation of ACE inhibitors is preferable. Similar reactions have been observed with low-density lipoprotein apheresis using dextran sulfate. Therefore, this method should not be used in patients receiving ACE inhibitors.

In patients with impaired liver function, the response to treatment with Tritace^® may be either enhanced or weakened. In addition, in patients with severe liver cirrhosis with edema and/or ascites, significant activation of RAAS is possible, so special caution should be exercised when treating these patients.

Before surgery (including dental), the surgeon/anesthesiologist must be informed about the use of ACE inhibitors.

Careful observation of newborns who have been exposed to ACE inhibitors in utero is recommended to detect arterial hypotension, oliguria, and hyperkalemia. In case of oliguria, BP and renal perfusion should be maintained by administering appropriate fluids and vasoconstrictors. In newborns, there is a risk of oliguria and neurological disorders, possibly due to decreased renal and cerebral blood flow due to the BP-lowering effect of ACE inhibitors.

Monitoring of laboratory parameters before and during treatment with Tritace^® (up to once a month during the first 3-6 months of treatment)

Monitoring of renal function (determination of serum creatinine concentrations)

During treatment with ACE inhibitors, monitoring of renal function is recommended in the first weeks of treatment and subsequently. Particularly careful monitoring is required for patients with acute and chronic heart failure, impaired renal function, after kidney transplantation, patients with renovascular diseases, 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 concentration may be an indicator of decreased renal function).

Monitoring of electrolyte concentrations

Regular monitoring of serum potassium concentration is recommended. Particularly careful monitoring of serum potassium concentration is required for patients with impaired renal function, significant water-electrolyte balance disorders, and chronic heart failure.

Monitoring of hematological parameters (hemoglobin concentration, white blood cell count, red blood cell count, platelet count, leukocyte formula)

Monitoring of complete blood count parameters is recommended to detect possible leukopenia. More regular monitoring is recommended at the beginning of treatment and in patients with impaired renal function, as well as in patients with connective tissue diseases or patients simultaneously receiving other drugs that can alter the peripheral blood picture (see section Drug Interactions). Monitoring of white blood cell count is necessary for early detection of leukopenia, which is especially important in patients at increased risk of its development, as well as at the first signs of infection. If neutropenia is detected (neutrophil count less than 2000/µl), treatment with ACE inhibitors should be discontinued.

If symptoms due to leukopenia occur (e.g., fever, swollen lymph nodes, tonsillitis), urgent peripheral blood count control is necessary. If signs of bleeding appear (tiny petechiae, red-brown rashes on the skin and mucous membranes), platelet count in peripheral blood should also be monitored.

Determination of liver enzyme activity, blood bilirubin concentration

If jaundice or a significant increase in liver enzyme activity occurs, treatment with Tritace^® should be discontinued and medical supervision of the patient should be ensured.

Effect on ability to drive vehicles and operate machinery

During treatment with Tritace^®, it is necessary to refrain from engaging in potentially hazardous activities, including driving, that require increased concentration and speed of psychomotor reactions, because dizziness, decreased speed of psychomotor reactions, and attention may occur, especially after taking the first dose,

Overdose

Symptoms: excessive peripheral vasodilation with the development of a pronounced decrease in BP, shock; bradycardia, water-electrolyte disorders, acute renal failure, stupor.

Treatment gastric lavage, intake of adsorbents, sodium sulfate (if possible within the first 30 minutes). In case of a pronounced decrease in BP, administration of alpha₁-adrenergic agonists (norepinephrine, dopamine) and angiotensin II (angiotensinamide) may be added to therapy aimed at replenishing blood volume and restoring electrolyte balance. In case of bradycardia refractory to drug treatment, placement of a temporary artificial pacemaker may be required. In case of overdose, serum creatinine and electrolyte concentrations should be monitored.

Drug Interactions

Contraindicated combinations

The use of certain high-flux membranes with a negatively charged surface (e.g., polyacrylonitrile membranes) during hemodialysis or hemofiltration and the use of dextran sulfate during low-density lipoprotein apheresis increase the risk of severe anaphylactic reactions.

Not Recommended Combinations

With potassium salts, potassium-sparing diuretics (for example, amiloride, triamterene, spironolactone) a more pronounced increase in serum potassium concentration is possible (with simultaneous use, careful monitoring of serum potassium concentration is required).

Combinations to be Used with Caution

With antihypertensive agents (especially diuretics) and other drugs that lower blood pressure (nitrates, tricyclic antidepressants) potentiation of the hypotensive effect is noted; when combined with diuretics, serum sodium levels should be monitored.

With hypnotics, narcotics, and analgesics, a more pronounced decrease in blood pressure is possible.

With vasopressor sympathomimetics (epinephrine) a reduction in the hypotensive effect of ramipril is noted, careful blood pressure monitoring is required.

With allopurinol, procainamide, cytostatics, immunosuppressants, systemic glucocorticoids and other agents that may affect hematological parameters, the risk of leukopenia increases.

With lithium salts, an increase in serum lithium concentration and an enhancement of the cardio- and neurotoxic effects of lithium are noted.

With oral hypoglycemic agents (sulfonylurea derivatives, biguanides), insulin: due to the decrease in insulin resistance under the influence of ramipril, an enhancement of the hypoglycemic effect of these drugs up to the development of hypoglycemia is possible.

Combinations to be Considered

With NSAIDs (indomethacin, acetylsalicylic acid) a weakening of the effect of ramipril, an increased risk of impaired renal function and an increase in serum potassium concentration are possible.

With heparin, an increase in serum potassium concentration is possible.

With sodium chloride, a weakening of the hypotensive effect of ramipril and less effective treatment of symptoms of chronic heart failure are possible.

With ethanol, an enhancement of vasodilation is noted. Ramipril may enhance the adverse effects of ethanol on the body.

With estrogens, a weakening of the hypotensive effect of ramipril is noted (fluid retention).

When performing desensitizing therapy for hypersensitivity to insect venoms, ACE inhibitors, including Ramipril, increase the likelihood of developing severe anaphylactic or anaphylactoid reactions to insect venoms.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 5 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.