Captopril: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CAPTOPRIL (CAPTOPRIL)

Composition:

Active substance: captopril;

1 tablet contains captopril 25 mg (0.025 g);

Excipients: potato starch, lactose monohydrate, microcrystalline cellulose, povidone, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets with a flat surface, a score line and beveled edges, with a specific odor.

Pharmacotherapeutic group.

Angiotensin-converting enzyme (ACE) inhibitors.

ATC code C09A A01.

Pharmacological Properties.

Pharmacodynamics.

Captopril is an angiotensin-converting enzyme (ACE) inhibitor that reduces blood concentrations of angiotensin II and aldosterone, while preventing the inactivation of endogenous vasodilators—bradykinin and prostaglandin E2. As a result, arterial pressure, total peripheral vascular resistance, preload and afterload on the heart, pulmonary circulation pressure, and pulmonary vascular resistance gradually decrease; cardiac output increases without changing heart rate, left ventricular hypertrophy is reduced (with prolonged therapy), and exercise tolerance improves.

The antihypertensive effect begins within 15–60 minutes after oral administration, reaching its maximum within 60–90 minutes, and lasts for 6–12 hours. The duration of the antihypertensive effect depends on the dose and reaches optimal levels over several weeks with continuous use. In patients with mild to moderate arterial hypertension, captopril administered at doses of 25–50 mg twice daily improves quality of life, prolongs life expectancy, and enhances general well-being, sleep, and emotional state. In patients with arterial hypertension associated with diabetes mellitus, it reduces the incidence of cardiovascular complications. Captopril exhibits angioprotective effects on microcirculatory vessels, increases the diameter of large peripheral arteries (from 13% to 21%), and slows the progression of renal failure in diabetic nephropathy.

Pharmacokinetics.

Captopril is rapidly and completely absorbed from the gastrointestinal tract, with a minimum absorption rate of 60–75%. When administered on an empty stomach, maximum plasma concentration is reached within 30–90 minutes. It undergoes biotransformation in the liver. It crosses histohematic barriers, except for the blood-brain barrier, and penetrates through the placenta and into breast milk (reaching concentrations of approximately 1% of maternal plasma levels). The elimination half-life is 2–3 hours; in patients with chronic heart or renal failure, it increases to 3.5–32 hours. Excretion is primarily renal (about 2/3 of the dose is eliminated within 4 hours; more than 95% of the dose is excreted within 24 hours) in the form of metabolites and unchanged drug (40–50%). Captopril accumulates in patients with chronic renal failure.

Clinical characteristics.

Indications.

Arterial hypertension.
Heart failure. Captopril is indicated for the treatment of chronic heart failure with reduced ventricular systolic function, as well as in combination with diuretics and, if necessary, with digitalis and beta-blockers.

‒ Myocardial infarction:

for short-term (4 weeks) treatment, captopril may be administered within 24 hours after acute myocardial infarction in patients with stable clinical condition;
for long-term prevention of symptomatic heart failure, the drug is indicated in clinically stable patients with asymptomatic left ventricular dysfunction (ejection fraction ≤ 40%).
Diabetic nephropathy in patients with type 1 diabetes mellitus, manifested by macroproteinuria.

Contraindications.

Hypersensitivity to captopril or to excipients of the drug, as well as to other ACE inhibitors; history of angioedema associated with the use of ACE inhibitors;
aortic valve stenosis or mitral stenosis, presence of other outflow obstructions from the left ventricle;
hypertrophic cardiomyopathy with low cardiac output;
primary hyperaldosteronism;
hyperkalemia;
severe renal function impairment; bilateral renal artery stenosis or stenosis of the artery of a solitary kidney; status after kidney transplantation;
congenital (idiopathic) angioedema;
porphyria;
pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding");
breastfeeding period (see section "Use in pregnancy or breastfeeding");
concomitant use of captopril with aliskiren-containing products in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

Potassium-sparing diuretics or potassium-containing dietary supplements. ACE inhibitors reduce potassium loss caused by diuretic therapy. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to hyperkalemia. When co-administered, especially in the presence of hypokalemia, they should be used with great caution and with frequent monitoring of serum potassium concentration.

Diuretics (thiazide or loop diuretics). Prior treatment with high-dose diuretics may lead to reduced blood volume and increase the risk of significant hypotension (see section "Special precautions for use"). The hypotensive effect can be minimized by discontinuing the diuretic, increasing salt and fluid intake, or initiating therapy with a low dose of captopril. However, no clinically significant interaction has been observed with hydrochlorothiazide or furosemide.

Other antihypertensive agents. Concomitant use of captopril with other antihypertensive agents (e.g., beta-blockers and long-acting calcium channel blockers) is safe, and their combined use may enhance the antihypertensive effect of captopril. Caution should be exercised when using nitroglycerin, other nitrates, or other vasodilating agents.

Treatment of acute myocardial infarction. In patients with myocardial infarction, captopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers, and/or nitrates.

Lithium. Concomitant use of ACE inhibitors and lithium may cause a transient increase in serum lithium levels and lithium toxicity. Combined use of ACE inhibitors with thiazide diuretics may further increase serum lithium levels and increase the risk of lithium toxicity. Therefore, concomitant use of captopril with lithium is not recommended. If such combination is necessary, careful monitoring of serum lithium levels is required.

Tricyclic antidepressants/neuroleptics. Concomitant use of certain tricyclic antidepressants and neuroleptics with ACE inhibitors may result in additional reduction in blood pressure (see section "Special precautions for use"). Postural hypotension may occur.

Allopurinol, procainamide, cytostatic or immunosuppressive agents. Concomitant use with ACE inhibitors may increase the risk of leukopenia, especially when these agents are used at doses exceeding the recommended ones.

Non-steroidal anti-inflammatory drugs (NSAIDs). It has been reported that ACE inhibitors and NSAIDs may have an additive effect on increasing serum potassium levels, which may impair renal function. This effect is usually reversible. Rarely, acute renal failure may occur, particularly in patients with pre-existing renal impairment, e.g., elderly patients or those suffering from dehydration. Prolonged use of NSAIDs may reduce the antihypertensive effect of ACE inhibitors.

Sympathomimetics. These may reduce the antihypertensive effect of ACE inhibitors; therefore, careful monitoring of blood pressure is required.

Antidiabetic agents. ACE inhibitors, including captopril, may enhance the hypoglycemic effect of insulin and other oral antidiabetic agents (sulfonylureas) in patients with diabetes mellitus. This effect is very rare, but if it occurs, a reduction in the dose of antidiabetic agents may be necessary during concomitant therapy with ACE inhibitors.

Clinical chemical analysis: captopril may cause a false-positive result in urine tests for acetone.

Special precautions for use.

Dual blockade of the RAAS: It is evident that the combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension and hyperkalemia and leads to impaired renal function (including acute kidney injury). Therefore, dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If dual blockade therapy is absolutely necessary, it should be administered under physician supervision with frequent monitoring of renal function, electrolytes, and blood pressure.

ACE inhibitors and angiotensin II receptor blockers must not be used concomitantly in patients with diabetic nephropathy.

Arterial hypotension. Arterial hypotension may rarely occur in patients with arterial hypertension who have reduced blood volume and/or decreased sodium levels due to diuretic therapy, restricted dietary salt intake, diarrhea, vomiting, or hemodialysis. Before initiating ACE inhibitors, circulating blood volume should be corrected, and consideration should be given to starting with the lowest effective dose.

Patients with heart failure are also at risk of symptomatic hypotension when treated with ACE inhibitors. Therefore, these patients should be started on captopril at a lower initial dose. Dose escalation of ACE inhibitors and diuretics should be performed under close medical supervision.

Excessive reduction in blood pressure in patients with cerebrovascular and ischemic heart disease increases the risk of myocardial infarction and stroke. In case of hypotension, the patient should be placed in a supine position (lying flat on the back), and circulating blood volume should be expanded, if necessary, by intravenous administration of 0.9% sodium chloride solution.

Renovascular hypertension. There is an increased risk of hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney when taking ACE inhibitors. In such cases, renal function may cease even with minor changes in serum creatinine. Therefore, these patients should start treatment with low doses of captopril under close medical supervision, with dose titration and continuous monitoring of renal function during treatment.

Renal impairment. Patients with impaired renal function (creatinine clearance ≤40 mL/min) require individual dose adjustment (see section "Dosage and administration"). In such patients, serum potassium and creatinine levels should be monitored regularly during captopril therapy.

Angioedema. Rarely, during treatment with ACE inhibitors, particularly within the first weeks of therapy, angioedema of extremities, face, lips, mucous membranes, tongue, larynx, and/or glottis may develop. However, angioedema may exceptionally develop after prolonged ACE inhibitor therapy. In such cases, treatment must be discontinued immediately. Angioedema of the tongue, glottis, and/or larynx may be fatal; therefore, immediate emergency treatment is required, followed by hospitalization and observation for at least 12–24 hours until complete resolution of symptoms.

Cough. Cases of cough have been reported during ACE inhibitor therapy. The cough is typically persistent, dry, non-productive, and resolves after discontinuation of therapy.

Hepatic impairment. ACE inhibitors have rarely been associated with a syndrome beginning with cholestatic jaundice, progressing to fulminant necrotizing hepatitis, and sometimes resulting in death. The mechanism of this syndrome remains unclear. Therefore, if jaundice or elevated liver enzymes occur during ACE inhibitor therapy, treatment should be discontinued immediately, and the patient should be closely monitored.

Hyperkalemia. The risk of hyperkalemia is increased in patients with renal impairment, diabetes mellitus, or those concurrently receiving potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may cause hyperkalemia (e.g., heparin). If concomitant use of these agents is considered necessary, regular monitoring of serum potassium levels is recommended.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy. ACE inhibitors should be used with caution in patients with aortic or mitral valve stenosis or left ventricular outflow tract obstruction. Captopril should be avoided in cases of cardiogenic shock or significant hemodynamic disturbances.

Lithium. Combination of lithium and captopril is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other complicating factors. Captopril should be used cautiously in patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma), concomitant therapy with antidepressants, allopurinol, or procainamide, or a combination of these factors, especially if renal impairment is already present. Severe infections, sometimes unresponsive to intensive antibiotic therapy, may develop in some of these patients. If captopril is necessary in such patients, monitoring of white blood cell count is recommended, including a complete blood count before treatment initiation, every 2 weeks during the first 3 months of treatment, and periodically thereafter. Patients should be instructed to promptly report any signs of infection (e.g., sore throat, fever) for further blood analysis with differential leukocyte count. Captopril and any concomitant medication (see section "Interaction with other medicinal products and other forms of interaction") should be discontinued immediately if neutropenia (neutrophil count <1000/mm³) is detected or suspected.

In most patients, neutrophil count returns rapidly to normal after discontinuation of captopril.

Proteinuria. Proteinuria may occur in patients with impaired renal function or when high doses of ACE inhibitors are used. Total urinary protein exceeding 1 g per day is observed in approximately 0.7% of patients taking captopril. Most of these patients had evidence of pre-existing kidney disease or were receiving relatively high doses of captopril (over 150 mg daily), or both. Nephrotic syndrome occurs in 1 out of 5 patients with proteinuria. In most cases, proteinuria decreases or resolves within 6 months, regardless of continued captopril use. In patients with proteinuria, parameters of renal function such as serum urea and creatinine levels rarely change.

Patients with a history of kidney disease should undergo urine protein testing (dipstick test of first morning urine) before starting treatment and periodically thereafter.

Anaphylactoid reactions during allergen desensitization with insect venom may occur in patients concurrently taking ACE inhibitors, which in rare cases may be life-threatening. These reactions may be avoided by temporarily discontinuing ACE inhibitor therapy before each desensitization session, but reactions may recur upon accidental re-exposure to the antigen. Therefore, ACE inhibitor therapy should be administered with caution in patients undergoing such desensitization procedures.

Cases of anaphylactoid reactions have been reported in patients during dialysis using high-flux membranes or during low-density lipoprotein apheresis with dextrin sulfate. For such patients, consideration should be given to using alternative dialysis methods, membranes, or medications from another drug class.

Surgery/anesthesia. Arterial hypotension may occur in patients undergoing major surgery under anesthesia while receiving ACE inhibitors. If blood pressure decreases, circulating blood volume should be replenished.

Diabetes mellitus. In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first month of concomitant ACE inhibitor therapy.

Ethnic characteristics. Like other ACE inhibitors, captopril is less effective as an antihypertensive agent in patients of Black race, possibly due to a higher prevalence of low-renin essential hypertension.

Use during pregnancy or breastfeeding.

Pregnancy. This medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment, the drug must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive. A small increased risk cannot be excluded. If continued therapy with ACE inhibitors is not considered essential, women planning pregnancy should be switched to alternative antihypertensive treatment with an established safety profile during pregnancy.

It is known that the use of ACE inhibitors during the second and third trimesters of pregnancy may cause fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If ACE inhibitor use occurs during the second trimester of pregnancy, ultrasound assessment of fetal renal and skull development is recommended.

Infants born to mothers who took ACE inhibitors should be closely monitored for arterial hypotension (see also sections "Contraindications" and "Special precautions for use").

Breastfeeding. Captopril is contraindicated during breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

During treatment, caution is required when driving or performing potentially hazardous activities requiring concentration and increased psychomotor reaction speed, as dizziness and somnolence may occur, especially at the beginning of therapy.

Method of Administration and Dosage.

Captopril is taken orally before, during, or after meals. The drug should be taken regularly at the same time each day. If a dose is missed, it should be taken as soon as possible; however, if only a few hours remain before the next scheduled dose, the next dose should be taken according to the schedule, and the missed dose should not be taken. Do not take two doses of captopril simultaneously.

Arterial Hypertension. The recommended initial dose is 25–50 mg daily, divided into two doses per day. After 2–4 weeks of treatment, dose titration may be performed depending on achieved blood pressure, up to 100–150 mg daily, divided into two doses. Captopril may be used alone or in combination with other antihypertensive agents, particularly thiazide diuretics. A once-daily regimen may be used when a concomitant antihypertensive agent such as a thiazide diuretic is added.

For patients with increased activity of the renin-angiotensin-aldosterone system (hypovolemia, renovascular hypertension, decompensated heart failure), therapy should preferably be initiated with a single dose of *6.25 mg* or 12.5 mg. Initial treatment should be started under close medical supervision, followed by administration of the drug twice daily. The dosage may be gradually increased to 50 mg or 100 mg daily in one or two divided doses.

Heart Failure. Initial dose: *6.25 mg* or 12.5 mg two or three times daily. Titration to a maintenance dose (75–150 mg daily) should be based on patient response (objective examination findings and drug tolerability) to treatment. The dose should be increased gradually, with intervals of at least once every 2 weeks, to assess patient response to therapy. The maximum daily dose is 150 mg, divided into two doses.

Myocardial Infarction.

Short-term treatment. Initiate treatment within the first 24 hours after myocardial infarction as follows: initial dose of *6.25 mg*, followed by 12.5 mg after 2 hours, and then 25 mg after 12 hours. Starting the next day, captopril should be administered for 4 weeks at a dose of 100 mg daily, divided into two doses. At the end of the 4-week treatment period, reassess the patient's condition to make a decision regarding post-myocardial infarction phase treatment.

Long-term treatment. If captopril has not been initiated within the first 24 hours of the acute phase of myocardial infarction, treatment should be started between days 3 and 16 after the infarction, once necessary treatment conditions are ensured (stable hemodynamics and management of any residual ischemia). Treatment should be initiated in hospital under strict monitoring (particularly of blood pressure) until the dose of 75 mg daily is reached. The initial dose should be low (see section "Special Warnings and Precautions"), especially if the patient has normal or low blood pressure at the start of therapy. Treatment should begin with a dose of *6.25 mg*, then progress to 12.5 mg three times daily for 2 days, followed by 25 mg three times daily in the absence of adverse hemodynamic reactions. The recommended dose for effective cardioprotection during long-term treatment is 75–150 mg daily, divided into two or three doses. In cases of symptomatic hypotension, as in heart failure, the dose of diuretics and/or other vasodilating agents may be reduced to achieve a stable captopril dose. If necessary, the captopril dose may be adjusted according to the patient's clinical response. Captopril may be used in combination with other treatments for myocardial infarction, such as thrombolytic agents, beta-blockers, and acetylsalicylic acid.

Diabetic Nephropathy in Patients with Type 1 Diabetes Mellitus. Captopril should be administered at a dose of 75–100 mg daily in two divided doses. If necessary, may be combined with other antihypertensive agents.

Renal Impairment. Since captopril is primarily excreted by the kidneys, in patients with impaired renal function, either the dose should be reduced or the dosing interval extended to prevent drug accumulation. If concomitant diuretic therapy is required, loop diuretics (furosemide) should be preferred over thiazide diuretics.

The following captopril dosing regimen is recommended for patients with renal impairment to prevent its accumulation in the body.

Creatinine clearance (ml/min/1.73 m²)	Initial daily dose (mg)	Maximum daily dose (mg)
>40	25–50	150
21–40	25	100
10–20	12.5	75
<10	6.25	37.5

Children. The efficacy and safety of Captopril in children have not been sufficiently studied. Captopril administration in children should be initiated under strict medical supervision. The initial dose of Captopril is 0.3 mg/kg body weight. For special patient groups (children with renal impairment, premature newborns, newborns, and infants due to immaturity of the urinary system), the initial dose should be 0.15 mg/kg body weight. Captopril is usually administered to children three times daily; however, the dosing interval should be individually adjusted depending on the patient's response to the drug.

Elderly patients. As with therapy using other antihypertensive agents, treatment with Captopril should be initiated at a dose of *6.25 mg* twice daily, since elderly patients may have impaired renal function as well as dysfunction of other organs and systems. The dose should be titrated according to the blood pressure response to the drug, aiming to prescribe the lowest effective dose that adequately controls blood pressure.

* – Captopril formulations allowing such dosing should be used.

Children.

The efficacy and safety of Captopril in children have not been sufficiently studied. Captopril administration in children should be conducted under strict medical supervision.

Overdose.

Manifests as profound arterial hypotension with possible development of shock, stupor, bradycardia, electrolyte imbalance, and renal failure.

Treatment: pronounced arterial hypotension requires immediate discontinuation of the drug. The patient should be placed in a supine position, gastric lavage should be performed, and therapy directed toward normalization of arterial blood pressure should be initiated. In cases of severe overdose symptoms, the patient must be urgently hospitalized for intensive detoxification measures, including hemodialysis, and interventions aimed at increasing circulating blood volume and restoring cardiovascular, respiratory, and nervous system functions, as well as renal function. Hemodialysis using high-flux membranes made of polyacrylonitrile-metal sulfate (AN69) and hemofiltration should be avoided due to the risk of anaphylactoid reactions. Peritoneal dialysis is ineffective.

Adverse Reactions.

Cardiovascular system: orthostatic hypotension; tachycardia, tachyarrhythmia, angina pectoris, palpitations, cardiogenic shock, cardiac arrest; arterial hypotension, Raynaud's syndrome, flushing, pallor;

Respiratory system: dry cough, dyspnea, bronchospasm, rhinitis, allergic alveolitis/eosinophilic pneumonia;

Gastrointestinal system: nausea, decreased appetite; abdominal pain, diarrhea, elevated liver transaminase activity, vomiting, gastric irritation, constipation, dry mouth, stomatitis/aphthous ulcers, glossitis, peptic ulcer, pancreatitis;

Hepatobiliary system: impaired liver function; cholestasis, including jaundice; hepatitis, including necrotizing hepatitis; increased levels of liver enzymes and bilirubin;

Central nervous system: dizziness, headache, fatigue, asthenia;

Neurological disorders: taste disturbances, somnolence, paresthesia, cerebrovascular events, ataxia, including stroke and loss of consciousness;

Hematopoietic system: neutropenia, agranulocytosis in patients with autoimmune diseases, leukopenia, pancytopenia (particularly in patients with impaired renal function), anemia (including aplastic and hemolytic), thrombocytopenia, lymphadenopathy, eosinophilia;

Immune system: autoimmune disorders and/or positive antinuclear antibody test;

Metabolic and nutritional disorders: anorexia, acidosis, hypoglycemia;

Psychiatric disorders: sleep disturbances, confusion, depression;

Eye disorders: blurred vision;

Skin and subcutaneous tissue disorders: pruritus, rash, alopecia, urticaria, Stevens-Johnson syndrome, polymorphic erythema, photosensitivity, erythroderma, pemphigoid reactions and exfoliative dermatitis, angioedema of the face, eyelids, tongue, interstitial angioedema;

Musculoskeletal and connective tissue disorders: myalgia, arthralgia;

Renal and urinary disorders: renal failure, impaired kidney function, polyuria, oliguria, and frequent urination, nephrotic syndrome;

Reproductive system and breast disorders: impotence, gynecomastia;

General disorders: chest pain, weakness, malaise;

Laboratory test changes: hyperkalemia, proteinuria, hyponatremia (most commonly observed in patients on a low-salt diet combined with diuretic therapy), elevated blood urea and serum creatinine levels, as well as decreased hemoglobin and hematocrit levels and increased erythrocyte sedimentation rate (ESR), elevated antinuclear antibody titer. Captopril may cause a false-positive result in urine acetone testing.

Shelf life. 2 years.

Storage conditions.

Store in a dry, light-protected place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

No. 20 (10×2) in blister packs.

Prescription status. Prescription only.

Manufacturer/Marketing Authorization Holder.

LLC "Ternopharm".

Manufacturer's address and location of business activity / Marketing Authorization Holder's address.

46010, Ternopil, Fabrychna St., 4, Ukraine.

Tel./fax: (0352) 521-444, www.ternopharm.com.ua.

INSTRUCTIONS

for medical use of the medicinal product

CAPTOPRIL

(CAPTOPRIL)

Composition:

Active ingredient: captopril;

1 tablet contains captopril 25 mg (0.025 g);

Excipients: potato starch, lactose monohydrate, microcrystalline cellulose, povidone, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets with a flat surface, a score line, beveled edges, and a specific odor.

Pharmacotherapeutic group.

Angiotensin-converting enzyme (ACE) inhibitors.

ATC code C09AA01.

Pharmacological properties.

Pharmacodynamics.

Captopril is an angiotensin-converting enzyme (ACE) inhibitor that reduces blood concentrations of angiotensin II and aldosterone and prevents the inactivation of endogenous vasodilators—bradykinin and prostaglandin E2. As a result, arterial blood pressure, total peripheral vascular resistance, post- and preload on the heart, pulmonary artery pressure, and pulmonary vascular resistance gradually decrease, while cardiac output increases without altering heart rate. Left ventricular hypertrophy is reduced (with long-term therapy), and exercise tolerance improves.

The antihypertensive effect begins within 15–60 minutes after oral administration, reaches its maximum within 60–90 minutes, and lasts 6–12 hours. The duration of the antihypertensive effect depends on the dose and reaches optimal levels over several weeks with continuous use. In patients with moderate arterial hypertension, captopril administered at doses of 25–50 mg twice daily improves quality and length of life, enhances general well-being, sleep, and emotional state. In patients with arterial hypertension combined with diabetes mellitus, it reduces the frequency of cardiovascular complications. It exhibits angioprotective effects on microcirculatory vessels, increases the diameter of large peripheral arteries (by 13% to 21%), and slows the progression of renal failure in diabetic nephropathy.

Pharmacokinetics.

Captopril is rapidly and completely absorbed from the gastrointestinal tract, with a minimum absorption of 60–75%. When taken on an empty stomach, maximum blood concentration is reached within 30–90 minutes. It undergoes biotransformation in the liver. It crosses histohematogenous barriers, except the blood-brain barrier, and penetrates through the placenta and into breast milk (reaching concentrations of approximately 1% of maternal blood levels). The elimination half-life is 2–3 hours; in patients with chronic heart or renal failure, it increases to 3.5–32 hours. It is primarily excreted by the kidneys (2/3 of the dose is eliminated within 4 hours, more than 95% within 24 hours) as metabolites and unchanged (40–50%). It accumulates in chronic renal failure.

Clinical characteristics.

Indications.

Arterial hypertension.
Heart failure. Captopril is indicated for the treatment of chronic heart failure with reduced ventricular systolic function, and may be used in combination with diuretics and, if necessary, digitalis and beta-blockers.
Myocardial infarction:
- for short-term (4 weeks) treatment, captopril may be initiated within 24 hours after myocardial infarction in patients with stable condition;
- for long-term prevention of symptomatic heart failure, the drug is indicated in clinically stable patients with asymptomatic left ventricular dysfunction (ejection fraction ≤ 40%).
Diabetic nephropathy in patients with type 1 diabetes mellitus, characterized by macroproteinuria.

Contraindications.

Hypersensitivity to captopril or any of the excipients, or to other ACE inhibitors; history of angioedema during previous ACE inhibitor therapy;
aortic or mitral valve stenosis, or other conditions causing obstruction of blood outflow from the left ventricle;
hypertrophic cardiomyopathy with low cardiac output;
primary hyperaldosteronism;
hyperkalemia;
severe renal impairment; bilateral renal artery stenosis or stenosis of the artery of a solitary kidney; post-renal transplantation state;
hereditary (idiopathic) angioedema;
porphyria;
pregnancy or planned pregnancy (see section "Use during pregnancy or breastfeeding");
breastfeeding period (see section "Use during pregnancy or breastfeeding");
concomitant use of captopril with aliskiren-containing products in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

Potassium-sparing diuretics or potassium-containing dietary supplements. ACE inhibitors reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to hyperkalemia. When used concomitantly, especially in the presence of hypokalemia, they should be used with great caution and with frequent monitoring of serum potassium levels.

Diuretics (thiazide or loop diuretics). Prior treatment with high-dose diuretics may lead to reduced circulating blood volume and increased risk of significant hypotension (see "Special precautions"). The hypotensive effect can be minimized by discontinuing the diuretic, increasing salt and fluid intake, or initiating therapy with a low dose of captopril. However, no clinically significant interactions have been observed with hydrochlorothiazide or furosemide.

Other antihypertensive agents. Concomitant use of captopril with other antihypertensive agents (e.g., beta-blockers and long-acting calcium channel blockers) is safe, and combination therapy may enhance the antihypertensive effect of captopril. Caution is advised when using nitroglycerin, other nitrates, or other vasoconstrictive agents.

Treatment of acute myocardial infarction. In patients with myocardial infarction, captopril may be used concomitantly with acetylsalicylic acid (in cardiologic doses), antiplatelet agents, beta-blockers, and/or nitrates.

Lithium. Concomitant use of ACE inhibitors and lithium may cause a transient increase in serum lithium levels and lithium toxicity. Concomitant use of ACE inhibitors and thiazide diuretics may further increase serum lithium levels and raise the risk of lithium toxicity. Therefore, concomitant use of captopril and lithium is not recommended. If such combination is necessary, careful monitoring of serum lithium levels is required.

Tricyclic antidepressants/neuroleptics. Concomitant use of certain tricyclic antidepressants and neuroleptics with ACE inhibitors may lead to additional blood pressure reduction (see section "Special precautions"). Postural hypotension may occur.

Nonsteroidal anti-inflammatory drugs (NSAIDs). It has been reported that ACE inhibitors and NSAIDs may have additive effects on increasing serum potassium levels, potentially leading to impaired renal function. This effect is usually reversible. Rarely, acute renal failure may occur, particularly in patients with pre-existing renal impairment, such as elderly patients or those with dehydration. Long-term NSAID use may reduce the antihypertensive effect of ACE inhibitors.

Sympathomimetics. May reduce the antihypertensive effect of ACE inhibitors; therefore, careful monitoring of blood pressure is required.

Antidiabetic agents. ACE inhibitors, including captopril, may enhance the antihyperglycemic effect of insulin and other oral antidiabetic agents (sulfonylureas) in patients with diabetes mellitus. This effect is very rare, but if it occurs, dosage reduction of antidiabetic agents may be necessary during concomitant therapy with ACE inhibitors.

Clinical chemistry: captopril may lead to a false-positive result in urine acetone testing.

Special precautions.

Dual blockade of the RAAS: Combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If dual blockade therapy is absolutely necessary, it should be conducted under physician supervision with frequent monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

Arterial hypotension. Arterial hypotension may rarely occur in patients with arterial hypertension who have reduced blood volume and/or sodium levels due to diuretic therapy, restricted salt intake, diarrhea, vomiting, or hemodialysis. Before initiating ACE inhibitor therapy, circulating blood volume (CBV) should be corrected, and the lowest effective optimal dose should be considered.

Patients with heart failure are also at risk of symptomatic hypotension when using ACE inhibitors. Therefore, captopril should be initiated at a low starting dose in these patients. Dose escalation of ACE inhibitors and diuretics should be performed under physician supervision.

Excessive reduction in blood pressure in patients with cerebrovascular and ischemic heart disease increases the risk of myocardial infarction and stroke. In case of hypotension, the patient should be placed in a horizontal position (supine), and if necessary, CBV should be increased by administering 0.9% sodium chloride solution.

Renovascular hypertension. Patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney have an increased risk of hypotension and renal failure when taking ACE inhibitors. In such cases, renal function may cease with minor fluctuations in serum creatinine levels; therefore, treatment should be initiated with low doses of captopril under close physician supervision, with dose titration and continuous monitoring of renal function.

Renal impairment. Patients with impaired renal function (creatinine clearance ≤ 40 mL/min) require individual dose adjustment (see "Dosage and administration"). Serum potassium and creatinine levels should be continuously monitored during captopril therapy in these patients.

Angioedema. Rarely, angioedema of the extremities, face, lips, mucous membranes, tongue, larynx, and/or vocal cords may develop during ACE inhibitor therapy, particularly within the first weeks of treatment. However, angioedema may exceptionally develop after prolonged ACE inhibitor therapy. In such cases, treatment should be discontinued immediately. Angioedema of the tongue, glottis, and/or larynx may be fatal; therefore, immediate emergency treatment is required, followed by hospitalization and observation for at least 12–24 hours until symptoms completely resolve.

Cough. Cases of cough have been reported during ACE inhibitor therapy. The cough is typically persistent, dry, and non-productive, and resolves after discontinuation of therapy.

Hepatic impairment. ACE inhibitors have rarely been associated with a syndrome beginning with cholestatic jaundice, progressing to sudden necrotizing hepatitis, and occasionally leading to death. The mechanism of this syndrome remains unclear. Therefore, if jaundice or elevated liver enzymes occur during ACE inhibitor therapy, treatment should be discontinued immediately, and the patient should be closely monitored.

Hyperkalemia. The risk of hyperkalemia is increased in patients with renal impairment, diabetes mellitus, those concurrently using potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other agents that may cause hyperkalemia (e.g., heparin). If concomitant use of these agents is considered necessary, regular monitoring of serum potassium levels is recommended.

Lithium. Combination of lithium and captopril is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients taking ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other risk factors. Captopril should be used cautiously in patients with vascular involvement in collagenoses (e.g., systemic lupus erythematosus, scleroderma), those receiving concomitant therapy with antidepressants, allopurinol, or procainamide, or a combination of these factors, especially if renal function is already impaired. Some of these patients may develop severe infections that sometimes do not respond to intensive antibiotic therapy. If captopril is necessary in such patients, monitoring of white blood cell count and complete blood count is recommended before treatment initiation, every 2 weeks during the first 3 months of treatment, and periodically thereafter. Patients should be instructed to immediately report any signs of infection (e.g., sore throat, fever) and undergo complete blood count with differential. Captopril and any concomitant medication (see "Interaction with other medicinal products and other forms of interaction") should be discontinued immediately if neutropenia (neutrophils < 1000/mm³) is detected or suspected.

In most patients, neutrophil count returns to normal rapidly after discontinuation of captopril.

Proteinuria. Proteinuria may occur in patients with impaired renal function or those receiving high doses of ACE inhibitors. Total urinary protein exceeding 1 g per day occurs in approximately 0.7% of patients taking captopril. Most of these patients had evidence of prior kidney disease or were receiving relatively high doses of captopril (more than 150 mg daily), or both factors. Nephrotic syndrome occurs in 1/5 of patients with proteinuria. In most cases, proteinuria decreases or resolves within 6 months, regardless of captopril continuation. Renal function parameters such as blood urea and creatinine levels rarely change in patients with proteinuria.

Patients with prior kidney disease should undergo urine protein testing (dipstick test of first morning urine) before treatment initiation and periodically thereafter.

Anaphylactoid reactions during allergen desensitization with insect venom may occur in patients receiving concomitant ACE inhibitor therapy, which in rare cases may be life-threatening. Such reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each desensitization session, but reactions may recur upon accidental re-exposure to the antigen. Therefore, ACE inhibitor therapy should be administered cautiously in patients undergoing such desensitization procedures.

Cases of anaphylactoid reactions have been reported during dialysis with high-permeability membranes or LDL apheresis with dextran sulfate. For such patients, consideration should be given to using a different type of dialysis, membrane, or medication from another class.

Surgery/anesthesia. Arterial hypotension may occur in patients undergoing major surgery under anesthesia. In case of reduced blood pressure, circulating blood volume should be replenished.

Ethnic characteristics. Like other ACE inhibitors, captopril is less effective as an antihypertensive agent in patients of African descent, possibly due to a higher prevalence of low-renin essential hypertension.

Use during pregnancy or breastfeeding.

Pregnancy. The medicinal product is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment, the drug should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive. A slight increase in risk cannot be excluded. If continued therapy with ACE inhibitors is not considered necessary, women planning pregnancy should be switched to alternative antihypertensive treatment with an established safety profile during pregnancy.

It is known that use of ACE inhibitors during the second and third trimesters of pregnancy may cause fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If ACE inhibitor use occurs during the second trimester of pregnancy, ultrasound assessment of renal and skull function is recommended.

Infants whose mothers received ACE inhibitors should be closely monitored for arterial hypotension (also see sections "Contraindications" and "Special precautions").

Breastfeeding period. Captopril is contraindicated during breastfeeding.

Effect on ability to drive and use machines.

Dosage and administration.

Captopril should be taken orally before, during, or after meals. The drug should be taken regularly at the same time each day. If a dose is missed, it should be taken as soon as possible; however, if the next dose is due within a few hours, the next dose should be taken according to schedule, and the missed dose should not be taken. Two doses of captopril should not be taken simultaneously.

Arterial hypertension. The recommended initial dose is 25–50 mg daily in two divided doses. After 2–4 weeks of treatment, dose titration may be performed based on achieved blood pressure, up to 100–150 mg daily in two divided doses. Captopril may be used alone or in combination with other antihypertensive agents, particularly thiazide diuretics. A once-daily dosing regimen may be used when combined with a concomitant antihypertensive agent such as a thiazide diuretic.

In patients with increased renin-angiotensin-aldosterone system activity (hypovolemia, renovascular hypertension, decompensated heart failure), therapy should preferably be initiated with a single dose of *6.25 mg* or 12.5 mg. Such initiation should be performed under strict medical supervision, followed by twice-daily administration. The dose may be gradually increased to 50 mg or 100 mg daily in one or two divided doses.

Heart failure. Initial dose – *6.25 mg* or 12.5 mg two or three times daily. Titration to maintenance dose (75–150 mg daily) should be based on patient response (objective examination findings and drug tolerability). The dose should be increased gradually, with intervals of at least once every 2 weeks to assess patient response. The maximum daily dose is 150 mg, divided into two doses.

Myocardial infarction.

Short-term treatment. Initiate therapy within the first 24 hours after myocardial infarction as follows: initial dose *6.25 mg*, followed by 12.5 mg after 2 hours, and another 25 mg after 12 hours. From the next day, captopril should be taken at a dose of 100 mg daily in two divided doses for 4 weeks. At the end of the 4-week treatment, the patient's condition should be re-evaluated to determine further post-infarction therapy.

Long-term treatment. If captopril therapy was not initiated within the first 24 hours of acute myocardial infarction, treatment should be started between days 3 and 16 after infarction, once appropriate treatment conditions are ensured (stable hemodynamics and management of residual ischemia). Therapy should be initiated in hospital under strict monitoring (particularly of blood pressure) until a dose of 75 mg daily is reached. The initial dose should be low (see "Special precautions"), especially if the patient has normal or low blood pressure at the start of therapy. Treatment should begin with a dose of *6.25 mg*, then increased to 12.5 mg three times daily for 2 days, followed by 25 mg three times daily in the absence of adverse hemodynamic reactions. The recommended dose for effective cardioprotection during long-term treatment is 75–150 mg daily, divided into two or three doses. In case of symptomatic hypotension, as in heart failure, the dose of diuretics and/or other vasodilating agents may be reduced to achieve a stable captopril dose. If necessary, the captopril dose may be adjusted based on clinical response. Captopril may be used in combination with other treatments for myocardial infarction, such as thrombolytics, beta-blockers, and acetylsalicylic acid.

Diabetic nephropathy in patients with type 1 diabetes mellitus. Captopril should be administered at a dose of 75–100 mg daily in two divided doses. Combination with other antihypertensive agents may be necessary.

Renal impairment. Since captopril is primarily excreted by the kidneys, the dose should be reduced or the dosing interval increased in patients with impaired renal function. If concomitant diuretic therapy is required, loop diuretics (furosemide) are preferred over thiazide diuretics.

The following dosing regimen for captopril is recommended in patients with impaired renal function to prevent drug accumulation.

Creatinine clearance (mL/min/1.73 m²)	Initial daily dose (mg)	Maximum daily dose (mg)
>40	25–50	150
21–40	25	100
10–20	12.5	75
<10	6.25	37.5

Children. The efficacy and safety of Captopril in children have not been sufficiently studied. Captopril administration in children should be initiated under strict medical supervision. The initial dose of Captopril is 0.3 mg/kg body weight. For special patient groups (children with renal insufficiency, premature newborns, newborns, and infants due to immaturity of the urinary system), the initial dose should be 0.15 mg/kg body weight. Captopril is usually administered to children three times daily; however, the dosing interval should be individually adjusted according to the patient's response to the drug.

Geriatric patients. As with therapy using other antihypertensive agents, treatment with Captopril should be initiated at a dose of *6.25 mg* twice daily, since elderly patients may have impaired renal function as well as dysfunction of other organs and systems. The dose should be titrated according to the blood pressure response, prescribing the lowest dose that adequately controls blood pressure.

* - Captopril preparations allowing such dosing should be used.

Children.

The efficacy and safety of Captopril in children have not been sufficiently studied. Captopril administration in children should be conducted under strict medical supervision.

Overdose.

Manifests as pronounced arterial hypotension with possible development of shock, stupor, bradycardia, electrolyte imbalance, and renal failure.

Treatment: pronounced arterial hypotension requires immediate discontinuation of the drug. The patient should be placed in a horizontal position, gastric lavage should be performed, and therapy aimed at restoring normal arterial pressure should be initiated. In cases of severe overdose symptoms, the patient must be urgently hospitalized for intensive detoxification measures, including hemodialysis, and interventions to increase circulating blood volume and normalize cardiovascular, respiratory, and nervous system functions, as well as restore kidney function. Hemodialysis using highly permeable polyacrylonitrile membranes (AN69) and hemofiltration should be avoided due to the risk of anaphylactoid reactions. Peritoneal dialysis is ineffective.

Adverse reactions.

Cardiovascular system: orthostatic hypotension, tachycardia, tachyarrhythmia, angina pectoris, palpitations, cardiogenic shock, cardiac arrest; arterial hypotension, Raynaud's syndrome, flushing, pallor;

Respiratory system: dry cough, dyspnea, bronchospasm, rhinitis, allergic alveolitis/eosinophilic pneumonia;

Gastrointestinal system: nausea, decreased appetite, abdominal pain, diarrhea, increased liver transaminase activity, vomiting, gastric irritation, constipation, dry mouth, stomatitis/aphthous ulcers, glossitis, ulcer, pancreatitis;

Hepatobiliary system: liver function disorders; cholestasis, including jaundice; hepatitis, including necrotizing hepatitis; elevated liver enzymes and bilirubin levels;

Central nervous system: dizziness, headache, fatigue, asthenia;

Neurological disorders: taste disturbances, somnolence, paresthesia, cerebrovascular events, ataxia, including stroke and loss of consciousness;

Hematopoietic system: neutropenia; agranulocytosis in patients with autoimmune diseases, leukopenia, pancytopenia (particularly in patients with impaired renal function), anemia (including aplastic and hemolytic), thrombocytopenia, lymphadenopathy, eosinophilia;

Immune system: autoimmune disorders and/or positive antinuclear antibody test;

Metabolic and nutritional disorders: anorexia, acidosis, hypoglycemia;

Psychiatric disorders: sleep disturbances, confusion, depression;

Eye disorders: blurred vision;

Skin and subcutaneous tissue disorders: pruritus, rash, alopecia, urticaria, Stevens-Johnson syndrome, polymorphic erythema, photosensitivity, erythroderma, pemphigoid reactions, exfoliative dermatitis, angioedema of the face, eyelids, tongue, interstitial angioedema;

Musculoskeletal and connective tissue disorders: myalgia, arthralgia;

Urinary system: renal failure, impaired kidney function, polyuria, oliguria, frequent urination, nephrotic syndrome;

Reproductive system and mammary glands: impotence, gynecomastia;

General disorders: chest pain, weakness, fever;

Laboratory test abnormalities: hyperkalemia, proteinuria, hyponatremia (most commonly observed during salt-free diet combined with diuretic use), elevated serum urea and creatinine levels, decreased hemoglobin and hematocrit, increased ESR, elevated antinuclear antibody titer. Captopril may cause a false-positive urine test for acetone.

Shelf life. 2 years.

Storage conditions.

Store in a dry, light-protected place at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

No. 20 (10×2) in blister packs.

Prescription status. By prescription only.

Manufacturer/Applicant.

LLC "Ternopharm".

Manufacturer's address and location of operations/Applicant's address.

46010, 4 Fabrychna St., Ternopil, Ukraine.

Tel./fax: (0352) 521-444, www.ternopharm.com.ua.