Captopril

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

Composition:

Active substance: captopril;

1 tablet contains captopril* 25 mg;

Excipients: microcrystalline cellulose; lactose monohydrate; potato starch; magnesium stearate.

* Calculated as 100% substance.

Pharmaceutical form. Tablets.

Main physical and chemical properties: white tablets with a characteristic odor, flat cylindrical shape with beveled edges and a score line.

Pharmacotherapeutic group.
Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors, single-component. ATC code C09AA01.

Pharmacological Properties.

Pharmacodynamics.

Captopril is the first synthetic angiotensin-converting enzyme (ACE) inhibitor to be used in clinical practice. By inhibiting the conversion of angiotensin I to angiotensin II, captopril exerts a vasodilatory effect, thereby reducing total peripheral vascular resistance (afterload), pulmonary capillary wedge pressure (preload), and pulmonary vascular resistance; it increases cardiac output and exercise tolerance. With prolonged use, captopril reduces left ventricular myocardial hypertrophy, prevents progression of heart failure, and slows the development of left ventricular dilation. It reduces the tone of efferent arterioles in renal glomeruli, thus improving intraglomerular hemodynamics and preventing the development of diabetic nephropathy.

The beneficial effects of ACE inhibitors are primarily due to suppression of the plasma renin-angiotensin-aldosterone system (RAAS). Renin is an endogenous enzyme produced by the kidneys and released into systemic circulation, where it converts angiotensinogen into angiotensin-I, a relatively inactive decapeptide. Angiotensin-I is then converted by ACE (a peptidyl dipeptidase) into angiotensin-II. Angiotensin-II is a potent vasoconstrictor responsible for arterial vasoconstriction and increased arterial blood pressure, as well as for stimulating the adrenal glands to produce aldosterone. Inhibition of ACE leads to decreased levels of angiotensin-II in plasma, reducing vasoconstrictor activity and aldosterone production. Although the reduction in aldosterone levels is modest, a slight increase in serum potassium concentration may occur, along with sodium and fluid loss. Blocking the negative feedback of angiotensin-II on renin production results in increased plasma renin activity.

Another function of the converting enzyme is the degradation of the potent vasodilatory kinin peptide, bradykinin, into inactive metabolites. Therefore, ACE inhibition leads to increased activity of the kallikrein-kinin system, which contributes to peripheral vasodilation via activation of the prostaglandin system. This mechanism may be involved in the antihypertensive effect of ACE inhibitors and may account for certain adverse reactions.

Reduction in arterial blood pressure typically occurs within 60–90 minutes after an individual oral dose of captopril. The duration of effect is dose-dependent. The antihypertensive effect may progress gradually, and several weeks of therapy may be required to achieve maximal therapeutic benefit. The antihypertensive effects of captopril and thiazide diuretics are complementary.

Pharmacokinetics.

After oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract (at least 75%). In the presence of food, bioavailability decreases by 30–40%. Maximum plasma concentration is reached within 30–90 minutes. Protein binding, primarily to albumin, is 25–30%. Captopril crosses histohematogenous barriers, except the blood-brain barrier, and penetrates the placenta. It is metabolized in the liver. The elimination half-life is less than 3 hours and increases in renal impairment.

Excretion occurs predominantly via the kidneys, both as metabolites and unchanged drug (up to 50%). Within 24 hours, 95% of the absorbed dose is eliminated. Maximum reduction in arterial blood pressure after oral administration occurs within 60–90 minutes. The duration of the antihypertensive effect is dose-dependent and reaches optimal levels over several weeks.

Lactation period. Data indicate that in women taking captopril orally at a dose of 100 mg three times daily, the average peak level in breast milk was 4.7 mcg/L, measured 3.8 hours after dose administration. Based on these data, the maximum daily dose that an infant may receive is less than 0.002% of the mother's daily dose. Captopril can be removed from systemic circulation by hemodialysis and peritoneal dialysis. Clearance by hemodialysis ranges from 4.8 to 7.2 L/hour, depending on the filters used. During a 4-hour hemodialysis session, 30–40% of captopril is removed from the blood, whereas metabolite elimination is somewhat lower.

Disulfide metabolites of captopril are excreted more slowly by the kidneys than captopril itself. Since these disulfide metabolites are reversibly converted back to captopril in the body, accumulation of captopril may occur in patients with renal impairment. Accumulation of captopril metabolites in patients with renal failure leads to a stronger pharmacodynamic effect and prolonged action. Therefore, captopril dosage should be adjusted according to renal function in such patients.

In patients with hepatic dysfunction, the renin-angiotensin-aldosterone system (RAAS) functions normally. Since captopril is an active drug and not a prodrug, its effect is comparable to that observed in patients with arterial hypertension without hepatic dysfunction.

In patients with heart failure, elimination of captopril is slowed. Therefore, patients with heart failure should be started on a lower initial dose of captopril, and doses should be adjusted according to the therapeutic response.

The pharmacokinetics of captopril in healthy elderly volunteers are similar to those in younger healthy volunteers. Therefore, standard daily doses of captopril may be administered to elderly patients with arterial hypertension and normal renal function.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to captopril or to excipients of the drug, as well as to other ACE inhibitors;
• Angioedema (including history of angioedema after ACE inhibitors, hereditary/idopathic angioedema);
• Aortic valve stenosis or mitral valve 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 single kidney; post-renal transplantation state;
• Congenital (hereditary) angioneurotic edema;
• Porphyria;
• Galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• Pregnancy; also contraindicated in women planning to become pregnant (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 in patients with renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interactions.

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 concentration.

Diuretics (thiazide or loop diuretics). Prior treatment with high-dose diuretics may lead to reduced blood volume and increased 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 starting 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., β-blockers and long-acting calcium channel blockers) is safe, and concomitant use may enhance the antihypertensive effect of captopril. Caution should be exercised when using nitrates, other nitrates, or similar agents.

Clinical trial data have shown that dual blockade of the RAAS pathway by combining ACE inhibitors, angiotensin-II receptor blockers, or aliskiren is associated with a higher incidence of adverse reactions such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy with agents acting on the RAAS.

Treatment of acute myocardial infarction. Captopril may be used concomitantly with acetylsalicylic acid (in cardiologic doses), thrombolytics, β-blockers, and/or nitrates in patients with myocardial infarction.

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 increase the risk of lithium toxicity. Therefore, concomitant use of captopril with lithium is not recommended. If such a 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 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 increases the risk of leukopenia, especially when the latter are used at doses exceeding the recommended ones.

Non-steroidal anti-inflammatory drugs (NSAIDs). 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 impaired renal function, such as elderly or dehydrated patients. Prolonged use of NSAIDs 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, a reduction in the dose of antidiabetic agents may be necessary during concomitant therapy with ACE inhibitors.

mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus). Patients receiving mTOR inhibitors concomitantly may have an increased risk of developing angioedema (see section "Special precautions for use").

Special precautions for use.

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 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, 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 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 receiving ACE inhibitors. Therefore, these patients should be started on a lower initial dose of captopril. Dose escalation of ACE inhibitors and diuretics should be performed under close 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 supine position, 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 of a single kidney when taking ACE inhibitors. In such cases, renal function may cease with only minor fluctuations in serum creatinine levels. Therefore, treatment of such patients should be initiated with low doses of captopril under close medical supervision, with careful dose titration and continuous monitoring of renal function during therapy.

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

Angioedema. Rarely, during treatment with ACE inhibitors, particularly within the first weeks of therapy, angioedema of the extremities, face, lips, mucous membranes, tongue, larynx, and/or glottis may develop. Extremely rarely, angioedema may occur after prolonged ACE inhibitor therapy. In such cases, treatment must be discontinued immediately. Angioedema of the tongue, glottis, and/or larynx can be life-threatening; therefore, immediate intervention is required, including hospitalization, with observation for at least 12–24 hours until complete symptom resolution.

Cough. Cases of cough have been reported during ACE inhibitor therapy. The cough is typically described as persistent, dry, and non-productive, resolving 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. During treatment with ACE inhibitors, including captopril, serum potassium levels may increase in some patients. 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 and 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 vascular involvement in collagenoses (e.g., systemic lupus erythematosus, scleroderma), especially when concomitantly treated with antidepressants, allopurinol, or procainamide, particularly if renal function is impaired. Serious infections, sometimes unresponsive to intensive antibiotic therapy, may develop in some of these patients.

If captopril is prescribed to 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 therapy, and periodically thereafter. Patients should be instructed to immediately report any signs of infection (e.g., sore throat, fever) and undergo complete blood count testing. Captopril and any concomitant medication (see section "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 levels exceeding 1 g per day were observed in approximately 0.7% of patients receiving captopril. Most of these patients had pre-existing kidney disease or were receiving relatively high doses of captopril (over 150 mg daily), or both factors were present. Nephrotic syndrome occurred 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 significantly.

In patients with a history of kidney disease, urine protein levels (dipstick test of first morning urine) should be assessed 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 can be avoided by temporarily discontinuing ACE inhibitor therapy before each desensitization session, but may recur upon accidental re-exposure to antigen. Therefore, ACE inhibitor therapy should be administered cautiously in patients undergoing such desensitization procedures.

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

Hypersensitivity/angioedema. Patients concurrently taking mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) may have an increased risk of developing angioedema (e.g., swelling of the airways or tongue, with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction").

Surgery/anesthesia. Arterial hypotension may occur in patients undergoing major surgery under anesthesia. 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 with this drug, therapy 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. Women planning pregnancy should be switched to alternative antihypertensive therapy 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, arterial hypotension, hyperkalemia).

If an ACE inhibitor is used during the second trimester of pregnancy, ultrasound assessment of renal and skull development is recommended.

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

Breastfeeding period.

Captopril is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Caution is required when driving or performing other tasks requiring heightened attention, as reaction speed may be reduced, particularly at the beginning of treatment, when dosage is changed, or when alcohol is consumed concurrently. These effects are individual and depend on patient-specific factors.

Method of Administration and Dosage.

Dosage should be adjusted according to the patient's condition.

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 there are only a few hours remaining before the next scheduled dose, the next dose should be taken according to the schedule, and the missed dose should not be taken. Two doses of captopril should not be taken simultaneously.

If captopril administration at a dose of 6.25 mg is required, the drug should be used in the appropriate dosage strength or in another pharmaceutical form.

Arterial Hypertension.

The recommended initial dose is 25–50 mg daily in two divided doses. After 2–4 weeks of treatment, the dose may be titrated according to the achieved blood pressure 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 adding a concomitant antihypertensive agent such as a thiazide diuretic.

In patients with increased RAAS activity (hypovolemia, renovascular hypertension, decompensated heart failure), therapy should preferably be initiated with a single dose of 6.25 mg or 12.5 mg. Initiation of such therapy should be performed under close medical supervision, followed by twice-daily administration of the drug. The dose may be gradually increased up to 50 mg or 100 mg daily in one or two divided doses.

Heart Failure.

Initial dose: 6.25–12.5 mg two or three times daily. Titration to the maintenance dose (75–150 mg daily) should be based on the patient's response to treatment (clinical evaluation and drug tolerability). The dose should be increased gradually, with intervals of at least 2 weeks, to assess the patient's response to therapy. The maximum daily dose is 150 mg in two divided doses.

Myocardial Infarction.

Short-term treatment. Administration of the drug within the first 24 hours after myocardial infarction should follow this regimen: initial dose of 6.25 mg, followed by 12.5 mg after 2 hours, and then 25 mg of captopril after 12 hours. From the next day, captopril should be administered for 4 weeks at a dose of 100 mg daily in two divided doses. At the end of the 4-week treatment period, the patient's condition should be re-evaluated to make a decision regarding post-infarction phase management.

Long-term treatment. If captopril administration was not initiated within the first 24 hours of acute myocardial infarction, treatment should be started between day 3 and day 16 after the infarction, once appropriate treatment conditions are ensured (stable hemodynamics and management of any residual ischemia). Therapy should be initiated in a hospital setting 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 Instructions"), especially if the patient has normal or low blood pressure at the start of therapy. Treatment should be initiated 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 in two or three divided 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, β-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 and, if necessary, combined with other antihypertensive agents.

Renal Function 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 should be prolonged 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 impaired renal function to prevent its accumulation in the body.

Children.

The efficacy and safety of captopril use in children have not been sufficiently studied. Captopril therapy in children should be initiated under close medical supervision. The initial dose of captopril is 0.3 mg/kg body weight. For special patient groups (children with renal impairment or immature 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 based on the patient's response to the drug.

Geriatric patients.

As with therapy using other antihypertensive agents, captopril treatment 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 medication, prescribing the lowest effective dose that adequately controls blood pressure.

Children.

The efficacy and safety of captopril use in children have not been sufficiently studied.

Captopril should be administered to children only when absolutely necessary and under strict medical supervision.

Overdose.

Symptoms: marked arterial hypotension, possible development of shock, stupor, bradycardia, electrolyte imbalance, and renal failure.

Treatment: To prevent absorption of a large dose of captopril, gastric lavage, administration of sorbents, and sodium sulfate should be performed as soon as possible, within 30 minutes after captopril ingestion. If symptoms of arterial hypotension occur, the patient should be placed in a horizontal position and immediate correction of plasma volume and electrolyte balance 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 normalizing the functions of the cardiovascular, respiratory, and nervous systems, as well as restoring kidney function. Hemodialysis using high-flux membranes made of polyacrylonitrile-metallized sulfate (AN69) and hemofiltration should be avoided due to the risk of anaphylactoid reactions. Peritoneal dialysis is ineffective.

Angiotensin-II may be used. Bradycardia or excessive systemic reactions should be treated with atropine administration. Consideration should be given to the use of a cardiac pacemaker. Hemodialysis is effective.

Side effects.

Cardiovascular system: tachycardia, tachyarrhythmia, angina pectoris, arterial hypotension, Raynaud's syndrome, flushing, pallor of the face, cardiac arrest, cardiogenic shock, orthostatic hypotension, rapid heartbeat.

Respiratory system: dry, irritating (non-productive) cough and dyspnea. Dry cough usually resolves within several weeks after discontinuation of captopril therapy. Bronchospasm, rhinitis, allergic alveolitis/eosinophilic pneumonia may also occur.

Gastrointestinal tract: nausea, vomiting, gastric irritation, abdominal pain, diarrhea, constipation, dry mouth, stomatitis/aphthous ulcers, glossitis, peptic ulcer, pancreatitis.

Hepatobiliary system: liver function abnormalities, cholestasis including jaundice, hepatitis (including necrotizing hepatitis), elevated levels of liver enzymes and bilirubin. Liver function disturbances usually resolve after discontinuation of captopril therapy.

Nervous system: dizziness, headache, fatigue, asthenia, taste disturbances, somnolence, paresthesia, cerebrovascular events; ataxia, including stroke and loss of consciousness.

Blood 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 disorders: anorexia, acidosis, hypoglycemia.

Psychiatric disorders: sleep disturbances, confusion, depression.

Eye disorders: blurred vision.

Skin reactions: pruritus, rash, alopecia, angioedema (see section "Special precautions"), urticaria, Stevens-Johnson syndrome, polymorphic erythema, photosensitivity, erythroderma, pemphigoid reactions, and exfoliative dermatitis.

Musculoskeletal system: myalgia, arthralgia.

Urinary system: renal function impairment, including renal failure, polyuria, oliguria, frequent urination, nephrotic syndrome.

Reproductive system: impotence, gynecomastia.

General disorders: chest pain, fatigue, weakness, fever.

Laboratory findings: proteinuria, hyperkalemia, hyponatremia (most commonly observed during salt-free diet combined with diuretic therapy), increased serum levels of urea, creatinine and bilirubin, decreased hemoglobin and hematocrit levels, increased erythrocyte sedimentation rate, leukopenia, thrombocytopenia, eosinophilia, elevated antinuclear antibody titer. Captopril may cause false-positive urine test results for acetone.

Angioedema of the face, eyelids, tongue, peripheral edema occurred in approximately one out of 1000 patients.

Interstitial angioedema has been observed in patients treated with ACE inhibitors.

Shelf life. 3 years.

Storage conditions.

Store in original packaging at temperature not exceeding 25 ºC.

Keep out of reach of children.

Packaging.

10 tablets per blister; 2 or 6 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and location of business activity.

6, Kyivska St., Vyshneve, Kyiv-Sviatoshyn district, Kyiv region, 08132, Ukraine.