Capoten (Tablets) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

C09AA01 (Captopril)

Active Substance

Captopril (Rec.INN registered by WHO)

Dosage Form

Capoten

Tablets 25 mg: 28, 40, or 56 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to white with a creamy tint, with a characteristic odor, square with rounded edges, biconvex with a cross-shaped score on one side. Slight “marbling” is allowed.

Excipients: microcrystalline cellulose, corn starch, stearic acid, lactose monohydrate.

10 pcs. – blister packs (4) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (4) – cardboard packs.
20 pcs. – blister packs (2) – cardboard packs.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE inhibitor

Pharmacological Action

Captopril is a first-generation, highly specific competitive ACE inhibitor containing a sulfhydryl group (SH-group). It reduces the activity of the RAAS. By inhibiting ACE, Captopril reduces the conversion of angiotensin I to angiotensin II and eliminates the vasoconstrictor effect of the latter on arterial and venous vessels. As a result of the decrease in angiotensin II concentration, a secondary increase in plasma renin activity occurs (due to the elimination of negative feedback) and a decrease in aldosterone secretion by the adrenal cortex. The antihypertensive effect of captopril does not depend on plasma renin activity. A decrease in blood pressure is noted with normal and even reduced hormone activity, which is due to the effect on the tissue RAAS.

Captopril reduces ACE-mediated degradation of bradykinin and increases its content in body tissues. As a result of ACE inhibition, the activity of the circulating and tissue kallikrein-kinin system increases, which contributes to peripheral vasodilation due to the accumulation of bradykinin (a peptide with a pronounced vasodilating effect) and increased synthesis of prostaglandin E2. This mechanism may contribute to the antihypertensive effect of captopril and is also the cause of some adverse reactions (in particular, dry cough).

In patients with arterial hypertension, Captopril reduces blood pressure without a compensatory increase in heart rate, fluid retention, and sodium ions in the body. After a single oral dose, the maximum antihypertensive effect is observed after 60-90 minutes. The degree of blood pressure reduction is the same in the “standing” and “lying” positions. The duration of the antihypertensive effect depends on the dose of the drug. The antihypertensive effect of captopril may increase over time and reaches optimal values after several weeks of therapy. Orthostatic hypotension rarely develops, mainly in patients with reduced blood volume. Sudden discontinuation of captopril usually does not lead to a “withdrawal” syndrome.

In patients with arterial hypertension, Captopril increases renal blood flow, while GFR usually does not change. With long-term use, it reduces left ventricular myocardial hypertrophy.

With sublingual administration of captopril in patients with uncomplicated hypertensive crisis, the onset of the antihypertensive effect is noted after 10-20 minutes; the maximum antihypertensive effect is observed after 45-60 minutes.

In patients with chronic heart failure (CHF), Captopril significantly reduces systemic vascular resistance and increases venous capacity (thus reducing pre- and afterload on the heart), reduces pressure in the right atrium and pulmonary circulation, increases cardiac output, and improves exercise tolerance.

In placebo-controlled clinical studies in patients with left ventricular dysfunction (left ventricular ejection fraction ≤40%) after myocardial infarction, Captopril increased survival, slowed the development of clinically significant heart failure, and reduced the frequency of hospitalizations for heart failure.

In a clinical study in patients with type 1 diabetes mellitus, diabetic nephropathy, retinopathy, and proteinuria ≥500 mg/day, Captopril reduced proteinuria and slowed the progression of diabetic nephropathy.

The efficacy and safety of captopril in children have not been established.

Pharmacokinetics

Absorption

When taken orally, Captopril is rapidly absorbed from the gastrointestinal tract. C_max of captopril in plasma (C_max – 114 ng/ml) is reached in 30-90 minutes (on average in 1 hour) after oral administration. The minimum bioavailability averages 70-75%. Simultaneous food intake reduces the absorption of captopril by 30-40%. With sublingual administration of captopril in doses of 12.5-25 mg compared to oral administration, a faster achievement of C_max in plasma is noted (T_max 40-45 minutes) with comparable C_max and AUC values.

Distribution

V_d in the terminal phase (2 L/kg) indicates significant penetration of captopril into deep body tissues. Binding to plasma proteins is 25-30%. It insignificantly (less than 1%) penetrates the blood-brain barrier and placental barrier. Less than 0.002% of the administered dose of captopril is excreted in breast milk.

Metabolism

It is metabolized in the liver to form captopril disulfide dimer and captopril-cysteine disulfide. Metabolites are pharmacologically inactive.

Excretion

T_1/2 of captopril is 2-3 hours. The drug is excreted from the body mainly by the kidneys, up to 50% unchanged, the rest in the form of metabolites. About 95% of captopril is excreted by the kidneys within the first 24 hours, of which 40-50% is unchanged, the rest is in the form of metabolites. In daily urine, 38% of unchanged captopril and 62% in the form of metabolites are determined.

Pharmacokinetics in special patient groups

Patients with impaired renal function. Captopril accumulates in chronic renal failure. T_1/2 of captopril in renal failure is 3.5-32 hours (increase in T_1/2 correlates with a decrease in creatinine clearance). For non-renal elimination, T_1/2 is 156 hours. Patients with impaired renal function should reduce the dose of captopril and/or increase the interval between doses of the drug.

Indications

For use in adults from 18 years of age

• Arterial hypertension, incl. renovascular (including uncomplicated hypertensive crisis);
• Chronic heart failure (as part of combination therapy);
• Acute myocardial infarction (within the first 24 hours from the moment of infarction in clinically stable condition);
• Left ventricular dysfunction (left ventricular ejection fraction ≤40%) after myocardial infarction in clinically stable condition to reduce the incidence of clinically significant heart failure, increase survival and reduce the frequency of hospitalizations for chronic heart failure;
• Diabetic nephropathy in type 1 diabetes mellitus (with albuminuria more than 30 mg/day).

ICD codes

Dosage Regimen

The drug is taken orally 1 hour before meals. The dosage regimen is set individually.

Arterial hypertension, incl. renovascular

Captopril is prescribed at an initial dose of 12.5 mg 2 times/day. If necessary, the dose is gradually (at intervals of 2-4 weeks) increased until the optimal effect is achieved. For mild and moderate arterial hypertension, the usual maintenance dose of captopril is 25 mg 2 times/day; the maximum dose is 50 mg 2 times/day. For severe arterial hypertension, the initial dose is 12.5 mg 2 times/day. The dose is gradually increased to a maximum daily dose of 150 mg (50 mg 3 times/day).

Captopril can be used as monotherapy or in combination with other antihypertensive drugs (e.g., thiazide diuretics). Captopril should be prescribed to patients receiving diuretics with particular caution under medical supervision.

In case of uncomplicated hypertensive crisis, sublingual administration of the drug Capoten is possible. The initial dose of captopril is 25 mg (1 tab.). The tablet should be placed under the tongue and held there until completely dissolved, without swallowing or drinking water. After taking the drug, blood pressure and heart rate should be carefully monitored. If there is no decrease in blood pressure within 30 minutes after taking the drug, 25 mg (1 tab.) of Capoten can be taken again sublingually. The maximum dose is 50 mg (2 tabs.).

Chronic heart failure (as part of combination therapy)

In patients with chronic heart failure, therapy with captopril should be started under close medical supervision. In most cases, Captopril should be used together with diuretics and (if indicated) cardiac glycosides. If diuretic therapy was carried out before the appointment of captopril, it is necessary to exclude the presence of a pronounced decrease in blood sodium content and/or blood volume.

The initial daily dose of captopril is 6.25 mg 3 times/day (for patients with verified or possible hyponatremia and/or hypovolemia) or 12.5 mg 3 times/day. Subsequently, the dose is increased gradually (at intervals of at least 2 weeks to assess the achieved clinical effect) depending on individual tolerance. The average maintenance dose of captopril is 25 mg 2-3 times/day. The maximum dose of captopril is 150 mg/day in 2-3 doses.

Acute myocardial infarction (within the first 24 hours from the moment of infarction in clinically stable condition)

In acute myocardial infarction, treatment with Capoten should be started as soon as possible when the patient is clinically stable. The drug is prescribed in a test dose of 6.25 mg, after 2 hours in the absence of hemodynamic disturbances, the drug is prescribed at a dose of 12.5 mg, after 12 hours the drug is prescribed at a dose of 25 mg. Starting from the next day, the drug Capoten is prescribed at a dose of 100 mg/day in 2 doses for a period of 4 weeks. After 4 weeks, the patient’s condition and prescribed treatment should be re-evaluated.

Left ventricular dysfunction (left ventricular ejection fraction ≤40%) after myocardial infarction in clinically stable condition

In patients who are clinically stable, the use of captopril can be started as early as 3 days after myocardial infarction. The first dose of captopril is 6.25 mg once/day. Then the dose of captopril is increased to 12.5 mg 3 times/day. Subsequently, the dose of captopril is gradually, over several days to several weeks (depending on tolerance), increased to 75 mg/day (in 2-3 doses) up to a maximum daily dose of 150 mg (50 mg 3 times/day). Increasing the dose of captopril to 75 mg/day is recommended in a hospital setting under close medical supervision.

Diabetic nephropathy in type 1 diabetes mellitus (with albuminuria more than 30 mg/day)

Captopril is prescribed at a daily dose of 75-100 mg, divided into 2-3 doses.

In patients with type 1 diabetes mellitus, normal blood pressure and microalbuminuria (albumin excretion 30-300 mg/day), the effective dose of captopril is 50 mg 2 times/day. In patients with type 1 diabetes mellitus, normal blood pressure and severe proteinuria (urinary protein excretion more than 500 mg/day), the effective dose of captopril is 25 mg 3 times/day.

Special patient groups

Patients with impaired renal function not due to diabetic nephropathy

Since Captopril is excreted primarily by the kidneys, its excretion is impaired in renal failure. Patients with impaired renal function should increase the dose of the drug with particular caution, using lower doses and/or observing longer (at least 1-2 weeks) intervals between dose increases. After achieving the desired therapeutic effect, the maintenance dose of captopril should be reduced and/or the interval between doses of the drug should be increased.

If additional diuretic therapy is necessary in patients with severe renal impairment, the use of “loop” diuretics (e.g., furosemide) is preferable, rather than thiazide diuretics.

In mild to moderate renal impairment (GFR more than 40 ml/min/1.73 m²), Capoten can be prescribed at a dose of 75-150 mg/day (no dose adjustment is required). In severe renal failure, to prevent accumulation of captopril, the following dosage regimen is recommended

Patients with impaired renal function due to diabetic nephropathy

In mild to moderate renal impairment (GFR more than 30 ml/min/1.73 m²), no dose adjustment of captopril is required. There is no experience with the use of captopril in patients with diabetic nephropathy and severe renal failure (GFR less than 30 ml/min/1.73 m²). In such patients, it is recommended to use Captopril with particular caution, in lower doses and/or observing longer (at least 1-2 weeks) intervals between dose increases.

Elderly patients

In elderly patients, the use of captopril is recommended to start at a dose of 6.25 mg 2 times/day. Subsequently, the dose of captopril is gradually increased. Constant dose adjustment depending on the therapeutic response and the use of the lowest doses of captopril that provide adequate blood pressure control is recommended.

Adverse Reactions

Definition of adverse reaction frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated reports; frequency not known (frequency cannot be estimated from the available data).

From the blood and lymphatic system very rare – neutropenia, agranulocytosis, pancytopenia, lymphadenopathy, eosinophilia, thrombocytopenia, anemia (including aplastic, hemolytic), autoimmune diseases.

From metabolism and nutrition rare – anorexia; very rare – hyperkalemia, hypoglycemia.

Psychiatric disorders common – sleep disorders; very rare – confusion, depression.

From the heart uncommon – tachycardia or tachyarrhythmia, palpitations, orthostatic hypotension, pronounced decrease in blood pressure, angina pectoris; very rare – cardiac arrest, cardiogenic shock.

From the vasculature: uncommon – Raynaud’s syndrome, facial flushing, pallor, peripheral edema.

From the respiratory system common – cough (dry non-productive), dyspnea; very rare – bronchospasm, rhinitis, allergic alveolitis, eosinophilic pneumonia, eosinophilic pneumonitis, pulmonary edema.

From the nervous system common – dizziness, drowsiness; uncommon – headache, paresthesia; rare – ataxia; very rare – cerebrovascular accident, including stroke and syncope.

From the organ of vision very rare – blurred vision.

From the gastrointestinal tract common – gastric mucosa irritation, taste disturbance, dry oral mucosa, dyspepsia, nausea, vomiting, abdominal pain, diarrhea, constipation; rare – stomatitis, aphthous stomatitis, intestinal angioedema; very rare – glossitis, gastric ulcer, pancreatitis, gingival hyperplasia.

From the liver and biliary tract very rare – impaired liver function, cholestasis, jaundice, hepatitis (including rare cases of hepatonecrosis), increased activity of liver enzymes.

From the skin and subcutaneous tissues common – pruritus with and without rash, skin rash, alopecia; uncommon – angioedema of the extremities, face, lips, mucous membranes, tongue, pharynx and larynx; very rare – urticaria, Stevens-Johnson syndrome, erythema multiforme, photosensitivity, erythroderma, exfoliative dermatitis, pemphigoid reactions.

From the musculoskeletal system and connective tissue very rare – myalgia, arthralgia.

From the kidneys and urinary tract rare – impaired renal function (including renal failure), polyuria, oliguria, increased frequency of urination; very rare – nephrotic syndrome.

From the reproductive system and breast very rare – impotence, gynecomastia.

General disorders uncommon – chest pain, increased fatigue, asthenia, general malaise; very rare – hyperthermia.

From laboratory and instrumental data very rare – proteinuria, eosinophilia, hyponatremia, increased plasma urea nitrogen concentration, acidosis, increased serum creatinine and bilirubin concentration, decreased hemoglobin and hematocrit, decreased white blood cell and platelet count, increased titer of antinuclear antibodies, increased ESR.

Contraindications

• Hypersensitivity to captopril, any other component of the drug and other ACE inhibitors;
• History of angioedema associated with the use of ACE inhibitors;
• Hereditary/idiopathic angioedema;
• Severe renal impairment;
• Severe hepatic impairment;
• Refractory hyperkalemia;
• Bilateral renal artery stenosis or stenosis of the artery of a single kidney with progressive azotemia;
• Condition after kidney transplantation;
• Aortic stenosis and similar obstructive changes that impede the outflow of blood from the left ventricle;
• Simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with angiotensin II receptor antagonists (ARAs II) in patients with diabetic nephropathy;
• Concomitant use with neutral endopeptidase inhibitors (e.g., drugs containing sacubitril) due to the high risk of angioedema;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Lactose intolerance, lactase deficiency, and glucose-galactose malabsorption syndrome.

Use with caution

• Arterial hypotension;
• Chronic heart failure;
• Coronary artery disease or cerebrovascular diseases;
• Primary hyperaldosteronism;
• Hepatic impairment;
• Systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), bone marrow depression, immunosuppressive therapy, concomitant use of allopurinol or procainamide, or a combination of these complicating factors (risk of neutropenia and agranulocytosis);
• Renal impairment;
• Patients on hemodialysis;
• Hyperkalemia;
• Diabetes mellitus;
• Burdened allergic history or history of angioedema;
• Concurrent desensitization with hymenoptera venom allergen;
• Concurrent LDL apheresis procedure using dextran sulfate;
• Hemodialysis using high-flux membranes (e.g., AN69^®);
• Conditions accompanied by reduced blood volume (including during diuretic therapy, salt-restricted diet, diarrhea, or vomiting);
• Use during major surgical interventions or general anesthesia;
• Concomitant use of potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes;
• Concomitant use with lithium preparations;
• Use in patients of Black race;
• Use in elderly patients (over 65 years of age).

Use in Pregnancy and Lactation

Pregnancy

The use of the drug Capoten is contraindicated during pregnancy.

Captopril should not be used in the first trimester of pregnancy. Appropriate controlled studies on the use of ACE inhibitors in pregnant women have not been conducted. The available limited data on the drug’s effects in the first trimester of pregnancy indicate that the use of ACE inhibitors does not lead to fetal malformations associated with fetotoxicity. Epidemiological data indicating a risk of teratogenicity after exposure to ACE inhibitors in the first trimester of pregnancy were not conclusive, but some increase in risk cannot be excluded.

Long-term use of ACE inhibitors in the second and third trimesters of pregnancy may lead to impaired fetal development (decreased renal function, oligohydramnios, delayed skull ossification), fetal death, and the development of complications in the newborn (neonatal renal failure, arterial hypotension, hyperkalemia).

If pregnancy occurs during the use of captopril, the drug should be discontinued as soon as possible and regular monitoring of fetal development should be carried out. If the patient received Captopril during the second and third trimesters of pregnancy, an ultrasound is recommended to assess the fetal skull bones and renal function. Newborns whose mothers took Captopril during pregnancy should be thoroughly examined for arterial hypotension, oliguria, and hyperkalemia.

Women planning pregnancy should not use ACE inhibitors (including Captopril).

Women of childbearing potential should be informed about the potential risks of using ACE inhibitors (including Captopril) during pregnancy. If the use of an ACE inhibitor is considered necessary, patients planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile for use during pregnancy.

Breastfeeding

Approximately 1% of the administered dose of captopril is found in breast milk. Due to the risk of serious adverse reactions in the child, breastfeeding should be discontinued or therapy with the drug Capoten should be discontinued for the mother during breastfeeding.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment.

The drug should be prescribed with caution in cases of hepatic impairment.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal impairment.

The drug should be prescribed with caution in cases of renal impairment, as well as in patients on hemodialysis.

Pediatric Use

The use of the drug is contraindicated in patients under 18 years of age (efficacy and safety not established).

Geriatric Use

The drug should be prescribed with caution in elderly patients (over 65 years of age).

Special Precautions

Arterial hypotension

In patients with arterial hypertension, marked arterial hypotension is observed only rarely with the use of captopril. The likelihood of this condition increases with increased fluid loss and hyponatremia (e.g., after intensive diuretic therapy, salt intake restriction, in patients on dialysis, and in patients with diarrhea or vomiting).

Captopril should be prescribed with caution to patients on a low-salt or salt-free diet. Blood volume and serum sodium levels should be corrected before prescribing captopril. The possibility of a sharp decrease in blood pressure can be minimized by prior withdrawal (4-7 days before) of the diuretic or by increasing sodium chloride intake (approximately one week before starting), or by prescribing low doses of captopril (6.25-12.5 mg/day) at the beginning of treatment. Renal function should be monitored regularly before starting and during treatment with captopril. Excessive reduction in blood pressure due to antihypertensive drugs may increase the risk of myocardial infarction or stroke in patients with coronary artery disease or cerebrovascular diseases. If arterial hypotension develops, the patient should assume a supine position with legs elevated. Intravenous administration of 0.9% sodium chloride solution may be required.

In patients with CHF, a transient decrease in blood pressure of more than 20% from baseline is noted in approximately half of the cases. The degree of blood pressure reduction is maximal in the early stages of treatment (after the first few doses of captopril) and stabilizes within 1-2 weeks from the start of treatment. Blood pressure usually returns to baseline levels without a reduction in therapeutic efficacy within 2 months. In patients with CHF, treatment should be started with low doses of captopril (6.25-12.5 mg/day) under medical supervision. Increasing the dose of captopril should be done with particular caution. Transient arterial hypotension itself is not a reason to discontinue treatment. In cases where arterial hypotension becomes persistent, the dose should be reduced and/or the use of the diuretic and/or captopril should be discontinued.

Aortic or mitral stenosis/hypertrophic obstructive cardiomyopathy

Like all drugs with vasodilating effects, ACE inhibitors should be used with particular caution in patients with obstruction of the left ventricular outflow tract. In the case of hemodynamically significant obstruction, the use of captopril is not recommended.

Renal impairment

In some patients with kidney disease, especially with severe renal artery stenosis, an increase in serum urea nitrogen and creatinine concentrations is observed after blood pressure reduction. This increase is usually reversible upon discontinuation of captopril therapy. In these cases, a reduction in the dose of captopril and/or discontinuation of the diuretic may be required.

During long-term use of captopril, approximately 20% of patients experience an increase in serum urea and creatinine concentrations by more than 20% compared to the norm or baseline value.

In less than 5% of patients, especially with severe nephropathies, treatment discontinuation is required due to an increase in creatinine concentration.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, there is an increased risk of arterial hypotension and renal failure when using ACE inhibitors. Renal failure may initially manifest only as minor changes in plasma creatinine levels. The use of captopril in such patients is not recommended.

Kidney transplantation

Experience with the use of captopril in patients who have recently undergone kidney transplantation is lacking. Therefore, the use of captopril in such patients is not recommended.

Proteinuria

With the use of captopril, proteinuria of more than 1000 mg/day was noted in 0.7% of patients. In 90% of cases, proteinuria occurred in patients with impaired renal function, as well as with the use of high doses of captopril (more than 150 mg/day). Approximately 20% of patients with proteinuria developed nephrotic syndrome. In most cases, proteinuria with captopril intake disappeared or its severity decreased within 6 months, regardless of whether the drug was discontinued or not. Renal function parameters (blood urea nitrogen and creatinine concentrations) in patients with proteinuria were almost always within normal limits. In patients with kidney disease, urine protein content should be determined before starting treatment and periodically during the course of therapy.

Hepatic impairment

In rare cases, the use of ACE inhibitors has been accompanied by the development of a syndrome starting with the appearance of cholestatic jaundice or hepatitis and progressing to fulminant liver necrosis, sometimes with a fatal outcome. The mechanism of development of this syndrome is unknown. If a patient receiving ACE inhibitor therapy develops jaundice or a significant increase in liver enzyme activity, captopril treatment should be discontinued and appropriate supportive therapy should be prescribed. The patient should be under appropriate observation.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been observed in patients taking ACE inhibitors. In patients with normal renal function and in the absence of other disorders, neutropenia is rare. In renal failure, concomitant use of captopril and allopurinol has led to neutropenia.

Captopril should be used with particular caution in patients with systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), those taking immunosuppressants, allopurinol, or procainamide, or with a combination of these complicating factors, especially if there are pre-existing renal function impairments.

In 13% of cases, neutropenia was fatal. In almost all cases, death occurred in patients with connective tissue diseases, renal or heart failure, while taking immunosuppressants, or with a combination of both of these factors.

Since most fatal cases of neutropenia with ACE inhibitors occurred in such patients, their white blood cell count should be monitored before starting treatment, every 2 weeks for the first 3 months, then every 2 months. In all patients, the white blood cell count should be monitored monthly for the first 3 months after starting captopril therapy, then every 2 months. If the white blood cell count is below 4000/µL, a complete blood count should be repeated; if below 1000/µL, the drug should be discontinued, and the patient should continue to be monitored. Usually, neutrophil count recovery occurs within 2 weeks after discontinuation of captopril.

Some patients developed serious infectious diseases, which in some cases did not respond to intensive antibiotic therapy. When using captopril in patients at high risk of neutropenia/agranulocytosis, regular monitoring of the white blood cell count is recommended. Patients should be warned to consult a doctor immediately if any signs of an infectious disease appear (e.g., fever, sore throat).

Hypersensitivity reactions/angioedema

Rare cases of angioedema of the face, extremities, lips, tongue, vocal folds, and/or larynx have been observed with the use of ACE inhibitors, including Captopril. Angioedema can occur at any time during treatment.

In case of angioedema development, captopril should be discontinued immediately and the patient’s condition should be carefully monitored until symptoms completely resolve.

If the edema is localized on the face, specific treatment is usually not required (antihistamines may be used to reduce symptom severity). Even in cases where only tongue swelling is observed without the development of respiratory distress syndrome, patients may require prolonged observation, as therapy with antihistamines and corticosteroids may be insufficient.

Angioedema associated with swelling of the larynx and tongue can, in very rare cases, be fatal. If the edema spreads to the tongue, pharynx, or larynx and there is a threat of airway obstruction, 0.3-0.5 ml of 0.1% epinephrine (adrenaline) solution should be administered subcutaneously immediately and/or airway patency should be ensured (intubation or tracheostomy).

In rare cases, intestinal edema (angioedema of the intestine) developed during therapy with ACE inhibitors, manifested by abdominal pain with or without nausea and vomiting, sometimes without preceding facial angioedema and with normal C1-esterase levels. The diagnosis is established by abdominal CT, ultrasound, or during surgery. Symptoms disappeared after discontinuation of ACE inhibitors. The possibility of intestinal edema should be considered in the differential diagnosis of abdominal pain in patients taking ACE inhibitors.

Patients with a history of angioedema not associated with ACE inhibitor use may be at greater risk of developing angioedema during ACE inhibitor therapy.

In Black patients, cases of angioedema with the use of ACE inhibitors have been reported more frequently compared to other races.

An increased risk of angioedema has been observed in patients simultaneously taking ACE inhibitors and drugs such as mTOR inhibitors (temsirolimus, sirolimus, everolimus), DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, linagliptin), estramustine, neutral endopeptidase inhibitors (racecadotril, sacubitril), and tissue plasminogen activators.

Anaphylactoid reactions during desensitization with hymenoptera venom allergen

In rare cases, life-threatening anaphylactoid reactions have been observed in patients undergoing desensitization with hymenoptera venom allergen while on ACE inhibitor therapy. In such patients, these reactions were prevented by temporarily discontinuing ACE inhibitor therapy before starting desensitization. The use of captopril should be avoided in patients receiving immunotherapy with bee venom.

Anaphylactoid reactions during LDL apheresis

In patients taking ACE inhibitors during LDL apheresis using dextran sulfate, life-threatening anaphylactoid reactions have rarely been observed. The development of these reactions can be prevented by temporarily discontinuing the ACE inhibitor before each LDL apheresis procedure.

Hemodialysis using high-flux membranes

When performing hemodialysis in patients receiving ACE inhibitors, the use of high-flux polyacrylonitrile dialysis membranes (e.g., AN69^®) should be avoided, as this increases the risk of anaphylactoid reactions. In such cases, dialysis membranes of a different type should be used or antihypertensive agents of other classes should be used.

Diabetes mellitus

In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be monitored regularly when ACE inhibitors are used concomitantly.

Patients taking oral hypoglycemic agents or insulin should be informed before starting ACE inhibitors about the need for regular monitoring of blood glucose concentration (hypoglycemia), especially during the first month of concomitant use of these drugs.

Cough

A characteristic cough is often noted when taking ACE inhibitors. Typically, the cough is non-productive, persistent, and ceases after discontinuation of the drug. Cough associated with the use of ACE inhibitors should be considered in the differential diagnosis of dry cough.

Surgical interventions/general anesthesia

During major surgical operations, as well as when using agents for general anesthesia that have an antihypertensive effect, excessive reduction in blood pressure may be noted in patients taking ACE inhibitors (because Captopril blocks the formation of angiotensin II induced by compensatory renin release). In such cases, measures aimed at increasing blood volume are used to correct the reduced blood pressure.

Hyperkalemia

In some cases, an increase in serum potassium levels is observed with the use of ACE inhibitors, including captopril.

Risk factors for the development of hyperkalemia are renal failure, old age (over 65 years), diabetes mellitus, some concomitant conditions (reduced blood volume, acute decompensated heart failure, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, or amiloride), as well as potassium preparations, potassium-containing salt substitutes, and other drugs that contribute to an increase in plasma potassium levels (such as heparin, tacrolimus, cyclosporine; drugs containing co-trimoxazole).

The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, can lead to a significant increase in serum potassium levels. Hyperkalemia can lead to serious cardiac arrhythmias, sometimes fatal. Concomitant use of potassium-sparing diuretics and potassium preparations is recommended to be avoided. If concomitant use of captopril and the aforementioned potassium-containing or potassium-elevating drugs is necessary, caution should be exercised and serum potassium levels should be monitored regularly.

Hypokalemia

When using ACE inhibitors concomitantly with thiazide diuretics, there is a risk of hypokalemia. Therefore, in such cases, regular monitoring of blood potassium levels should be performed during therapy.

Dual blockade of the RAAS

Concomitant use of drugs from different groups affecting the RAAS (dual blockade of the RAAS) is not recommended, as it has been associated with an increased incidence of adverse effects such as arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with ARB II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

In cases where the simultaneous administration of two drugs affecting the RAAS is necessary, their use should be carried out under medical supervision with particular caution and with regular monitoring of renal function, blood pressure parameters, and plasma electrolyte levels.

Lithium preparations

Concomitant use of captopril and drugs containing lithium is not recommended due to the risk of increased toxicity of the latter.

Ethnic differences

ACE inhibitors are less effective in Black patients than in Caucasian patients, which may be associated with a higher prevalence of low renin activity in Black patients.

Other

A false-positive urine test for acetone may be observed when taking captopril.

Effect on the ability to drive vehicles and mechanisms

During treatment, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, as dizziness is possible, especially after taking the initial dose.

Overdose

Symptoms sharp decrease in blood pressure, shock, stupor, bradycardia, water-electrolyte imbalance, renal failure.

Treatment gastric lavage, administration of adsorbents and sodium sulfate within 30 minutes after drug intake, administration of 0.9% sodium chloride solution or other plasma-substituting drugs (the patient should first be placed in a horizontal position with a low headboard, then measures to replenish the circulating blood volume should be carried out), hemodialysis. For bradycardia or pronounced vagal reactions – administration of atropine. The use of a pacemaker may be considered. Peritoneal dialysis is not effective for removing captopril from the body.

Drug Interactions

Dual blockade of the RAAS

Dual blockade of the RAAS using ARB II, ACE inhibitors, or aliskiren (a renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure). Regular monitoring of blood pressure, renal function, and blood electrolyte levels is necessary in patients taking Captopril simultaneously with other drugs affecting the RAAS.

Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with ARB II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes, and other drugs that can increase serum potassium levels

Concomitant use of captopril with potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes, and other drugs that can increase serum potassium levels (including ARB II, heparin, tacrolimus, cyclosporine; drugs containing co-trimoxazole [trimethoprim + sulfamethoxazole]) may lead to a significant increase in plasma potassium levels. During therapy with captopril, potassium-sparing diuretics (e.g., triamterene, spironolactone, amiloride, eplerenone), potassium preparations, potassium-containing salt substitutes (contain significant amounts of potassium ions) should be prescribed only for proven hypokalemia, as their use increases the risk of hyperkalemia.

Non-potassium-sparing (thiazide and “loop”) diuretics

In patients taking diuretics, Captopril may potentiate the antihypertensive effect. A similar effect is also exerted by restriction of salt intake (salt-free diets), hemodialysis. Excessive decrease in blood pressure usually occurs within the 1st hour after taking the first prescribed dose of captopril.

Other antihypertensive drugs

An additive effect may be observed with the simultaneous use of captopril and other antihypertensive therapy.

Captopril can be safely used in combination with other antihypertensive drugs (such as beta-blockers or long-acting slow calcium channel blockers). Caution should be exercised when co-administering captopril (with or without a diuretic) and drugs that affect the sympathetic nervous system (e.g., ganglion blockers, alpha-blockers).

Vasodilators

Vasodilators (e.g., nitroglycerin) in combination with captopril should be used at the lowest effective doses due to the risk of excessive blood pressure reduction.

Tricyclic antidepressants/antipsychotics

Enhancement of the antihypertensive effect of ACE inhibitors (further decrease in blood pressure with simultaneous use) and an increased risk of orthostatic hypotension are possible.

Alpha- and beta-adrenergic agonists

Alpha- and beta-adrenergic agonists (sympathomimetics), such as epinephrine (adrenaline), isoproterenol, dobutamine, dopamine, may reduce the antihypertensive effect of ACE inhibitors.

Lithium preparations

With the simultaneous use of ACE inhibitors (especially in combination with diuretics) and lithium preparations, an increase in serum lithium levels and, consequently, an enhancement of the cardiotoxic and neurotoxic effects of lithium preparations is possible. If simultaneous use of drugs containing lithium and ACE inhibitors is necessary, serum lithium levels should be periodically determined.

NSAIDs, including selective COX-2 inhibitors and high doses of acetylsalicylic acid (≥3 g/day)

NSAIDs, including selective COX-2 inhibitors and acetylsalicylic acid in doses from 3 g/day and above, may reduce the antihypertensive effect of diuretics and other antihypertensive agents. With the combined use of captopril and indomethacin (and possibly other NSAIDs, for example, acetylsalicylic acid), a decrease in the antihypertensive effect may be noted, especially in arterial hypertension accompanied by low renin activity. In patients with risk factors (old age, hypovolemia, simultaneous use of diuretics, impaired renal function), simultaneous use of NSAIDs (including COX-2 inhibitors) and ACE inhibitors (including Captopril) may lead to deterioration of renal function, up to acute renal failure. Usually, renal function impairments in such cases are reversible. Renal function should be periodically monitored in patients taking Captopril and NSAIDs.

The use of captopril in combination with acetylsalicylic acid as an antiplatelet agent is not contraindicated.

Hypoglycemic drugs

ACE inhibitors, including Captopril, may potentiate the hypoglycemic effect of insulin and oral hypoglycemic agents (such as sulfonylurea derivatives). In patients with diabetes mellitus taking oral hypoglycemic drugs or insulin, blood glucose concentration should be regularly monitored, especially during the first month of simultaneous use with captopril, and if necessary, the dose of the hypoglycemic drug should be adjusted.

Allopurinol, procainamide, cytostatics, immunosuppressants, corticosteroids (with systemic use)

The use of captopril in patients taking allopurinol or procainamide increases the risk of developing neutropenia/agranulocytosis and/or Stevens-Johnson syndrome. The use of captopril in patients taking immunosuppressants (e.g., cyclophosphamide or azathioprine) increases the risk of developing hematological disorders.

Gold preparations

With simultaneous use of parenteral gold preparations (sodium aurothiomalate) and ACE inhibitors, including Captopril, a symptom complex (nitrate-like reactions) has been described, including facial flushing, nausea, vomiting, and arterial hypotension.

mTOR inhibitors (mammalian Target of Rapamycin) (e.g., temsirolimus, sirolimus, everolimus)

In patients taking ACE inhibitors and mTOR inhibitors (temsirolimus, sirolimus, everolimus) simultaneously, an increased frequency of angioedema has been observed.

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins), e.g., sitagliptin, saxagliptin, vildagliptin, linagliptin

In patients taking ACE inhibitors and DPP-4 inhibitors (gliptins) simultaneously, an increased frequency of angioedema has been observed.

Estramustine

Increased frequency of angioedema when used concomitantly with ACE inhibitors.

Neutral endopeptidase (NEP) inhibitors

An increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor).

With the simultaneous use of ACE inhibitors with drugs containing sacubitril (a neprilysin inhibitor), the risk of developing angioedema increases, therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. The administration of drugs containing sacubitril is contraindicated in patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Tissue plasminogen activators

Observational studies have revealed an increased frequency of angioedema in patients taking ACE inhibitors after using alteplase for thrombolytic therapy of ischemic stroke.

Storage Conditions

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

Shelf Life

The shelf life is 5 years. Do not use after the expiration date.

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.