Captopril

APPROVED Order of the Ministry of Health of Ukraine 11.2016 No 1166 Registration Certificate No UA/4800/01/01 No UA/4800/01/02

No UA/4800/01/03

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

Composition:

Active substance: captopril;

1 tablet contains 12.5 mg or 25 mg or 50 mg of captopril;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

12.5 mg tablets: white, slightly biconvex, round tablets with bevelled edges;

25 mg tablets: white, slightly biconvex, round tablets with bevelled edges and a notch on one side;

50 mg tablets: white, slightly biconvex, round tablets with bevelled edges and a notch on one side.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Monocomponent angiotensin-converting enzyme (ACE) inhibitors. ATC code C09A A01.

Pharmacological Properties.

Pharmacodynamics.

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

Another function of the converting enzyme is the degradation of the potent vasodepressor kinin peptide bradykinin into inactive metabolites. Therefore, ACE inhibition leads to increased activity of both circulating and locally acting kallikrein-kinin systems, which contribute to peripheral vasodilation via activation of the prostaglandin system; this mechanism may contribute to the antihypertensive effect of ACE inhibitors and may be responsible for certain adverse reactions.

Reduction in blood pressure typically occurs within 60–90 minutes after oral administration of an individual dose of captopril. The duration of the effect is dose-dependent. Blood pressure reduction may progress gradually, and maximal therapeutic effect may require several weeks of therapy. The antihypertensive effects of captopril and thiazide diuretics are complementary.

In patients with arterial hypertension, captopril reduces blood pressure in both supine and standing positions without stimulating compensatory increases in heart rate, and without water or sodium retention.

In hemodynamic studies, captopril caused a marked reduction in peripheral arterial resistance. Generally, no clinically significant changes were observed in renal plasma circulation or glomerular filtration rate. In most patients, the antihypertensive effect began approximately 15–30 minutes after oral administration of captopril, with peak effect occurring at 60–90 minutes. The maximal blood pressure reduction from a given dose of captopril was typically evident after 3–4 weeks.

At recommended daily doses, the antihypertensive effect persists during long-term treatment. Temporary discontinuation of captopril does not cause any rapid rebound increase in blood pressure (symptom rebound). Treatment of hypertension with captopril also leads to a reduction in left ventricular hypertrophy.

Hemodynamic studies in patients with heart failure showed that captopril reduced systemic vascular resistance and increased venous volume. This resulted in reduced preload and afterload on the heart (decreased ventricular filling pressure). Additionally, increased cardiac output, stroke work index, and exercise capacity were observed during captopril therapy. In a large placebo-controlled trial involving patients with left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) after myocardial infarction, captopril (initiated between days 3 and 16 post-infarction) prolonged survival and reduced cardiovascular mortality. This was manifested by delayed onset of symptomatic heart failure and reduced need for hospitalization due to heart failure compared to placebo. There was also a reduction in the incidence of recurrent myocardial infarction and cardiovascular procedures, including revascularization, as well as reduced need for additional medications with diuretics and/or digoxin or dose escalation compared to placebo.

A retrospective analysis showed that captopril reduces recurrence of myocardial infarction and revascularization procedures (neither of which were primary endpoints of the study).

A placebo-controlled study in patients with myocardial infarction demonstrated that captopril (administered within 24 hours of the event and continued for 1 month) significantly reduced overall mortality at 5 weeks compared to placebo. The positive effect of captopril on overall mortality remained evident at 1 year. No evidence of a negative effect on early mortality during the first day of treatment was observed.

Cardioprotective effects of captopril are observed independently of patient age or sex, infarct location, and concomitant medications with proven efficacy during the post-infarction period (thrombolytics, beta-blockers, and acetylsalicylic acid).

Diabetic Nephropathy Type I

In a placebo-controlled, multicenter, double-blind clinical trial involving insulin-dependent patients with type I diabetes mellitus and proteinuria, with or without arterial hypertension (concomitant antihypertensive therapy was permitted to control blood pressure), captopril significantly delayed (by 51%) the time to doubling of baseline serum creatinine compared to placebo; the incidence of end-stage renal disease (dialysis, transplantation) or death was also significantly lower with captopril than with placebo (by 51%). In patients with diabetes and microalbuminuria, captopril treatment reduces albumin excretion over 2 years.

The beneficial effect of captopril treatment on preservation of renal function is attributed to blood pressure reduction.

In two large randomized controlled trials (ONTARGET [Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [Veterans Affairs Nephropathy in Diabetes]), the use of a combination of an ACE inhibitor with an angiotensin II receptor blocker was evaluated. The ONTARGET trial was conducted in patients with a history of cardiovascular or cerebrovascular disease or type II diabetes with evidence of target organ damage. The VA NEPHRON-D trial was conducted in patients with type II diabetes and diabetic nephropathy. These studies showed no significant benefit on renal function and/or cardiovascular disease and mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic properties, these findings are relevant to other ACE inhibitors and angiotensin II receptor blockers. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. The ALTITUDE trial (Aliskiren Trial in Type II Diabetes Mellitus Patients with Cardiovascular Disease and Kidney Disease) was conducted to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type II diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was terminated prematurely due to an increased risk of adverse reactions. Cardiovascular deaths and stroke occurred more frequently in the aliskiren group than in the placebo group, and adverse reactions and serious adverse reactions (hyperkalemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Pharmacokinetics.

Captopril is an orally active drug that does not require biotransformation to exert its activity. Mean minimal absorption is approximately 75%. Peak plasma concentrations are reached within 60–90 minutes. The presence of food in the gastrointestinal tract reduces absorption by approximately 30–40%. Approximately 25–30% of the circulating drug is bound to plasma proteins.

The apparent elimination half-life of unchanged captopril from blood is approximately 2 hours. More than 95% of the absorbed dose is excreted in urine within 24 hours; 40–50% as unchanged drug and the remainder as inactive disulfide metabolites (captopril disulfide and captopril-cysteine disulfide). Impaired renal function may lead to drug accumulation. Therefore, the dose should be reduced and/or the dosing intervals extended in patients with renal impairment (see section "Dosage and Administration").

Animal studies indicate that captopril does not significantly penetrate the blood-brain barrier.

Lactation. In a report of 12 women taking oral captopril 100 mg three times daily, the average peak concentration in breast milk was 4.7 µg/L, occurring 3.8 hours after dose administration. Based on these data, the maximum daily infant dose would be less than 0.002% of the maternal daily dose. Captopril can be removed from systemic circulation by hemodialysis and peritoneal dialysis. Clearance by hemodialysis ranges from 4.8 L/h to 7.2 L/h, depending on the filters used. During a 4-hour hemodialysis session, 30–40% of captopril is removed from blood, whereas clearance of metabolites is somewhat less efficient.

The disulfide metabolites of captopril are eliminated more slowly by the kidneys than captopril itself. Since these disulfide metabolites are reversibly converted back to captopril in the body, accumulation of captopril can be expected in patients with renal insufficiency. Accumulation of captopril metabolites in patients with renal insufficiency leads to a stronger pharmacodynamic effect and prolonged duration of action. Therefore, captopril doses in such patients should be adjusted according to actual renal function.

In patients with impaired liver function, the renin-angiotensin system functions normally. Since captopril is not a prodrug but an active compound, its effect is comparable to that observed in hypertensive patients without liver dysfunction.

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

Pharmacokinetics of captopril in healthy elderly volunteers is similar to that observed in younger healthy volunteers. Therefore, standard daily doses of captopril can be administered to elderly patients with hypertension and normal renal function.

Clinical characteristics.

Indications.

• Arterial hypertension;
• Heart failure:

Chronic heart failure with reduced left ventricular systolic function (in combination with diuretics, and if indicated, with digoxin and beta-blockers);

• Myocardial infarction:

Short-term (4 weeks) treatment of any clinically stable patient within the first 24 hours following myocardial infarction;

• Long-term prevention of symptomatic heart failure in clinically stable patients with asymptomatic left ventricular dysfunction (ejection fraction ≤ 40%);
• Type I diabetic nephropathy:

Macroproteinuric diabetic nephropathy in patients with type I diabetes mellitus.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of this medicinal product or to any other angiotensin-converting enzyme (ACE) inhibitors;
• History of angioedema during therapy with other ACE inhibitors;
• Hereditary or idiopathic angioedema;
• Hemodynamically significant bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney;
• Porphyria;
• Pregnancy or planned pregnancy (see section "Use in pregnancy or lactation");
• Breastfeeding (see section "Use in pregnancy or lactation");
• 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);
• Concomitant use with sacubitril/valsartan. Captopril therapy must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Potassium-sparing diuretics, potassium-containing dietary supplements or potassium-containing salt substitutes: Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving captopril. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium concentration. Caution is also advised when captopril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of captopril with the above-mentioned agents is not recommended. If co-administration is required due to evident hypokalemia, it should be done with great caution and frequent monitoring of serum potassium concentrations (see section "Special precautions for use").

Diuretics (thiazide or loop diuretics): Prior treatment with high-dose diuretics may lead to reduced intravascular 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, in specific interaction studies, no clinically significant interaction was observed with hydrochlorothiazide or furosemide.

Other antihypertensive agents: Captopril can generally be safely co-administered with other antihypertensive agents (e.g., beta-blockers and long-acting calcium channel blockers). Concomitant use of such agents may enhance the antihypertensive effects of captopril. Caution should be exercised when combining with nitroglycerin, other nitrates, or other vasodilating agents, and consideration should be given to using a lower dose.

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

Agents affecting sympathetic nervous system activity: Agents affecting sympathetic nervous system activity (such as ganglionic blockers or adrenergic neuron blockers) should be used with caution, as they may potentiate the antihypertensive effect of captopril.

Alpha-blockers: Concomitant use of alpha-blockers may enhance the antihypertensive effect of captopril, increasing the risk of orthostatic hypotension.

Agents acting via renin release: The antihypertensive effect of captopril is enhanced by agents acting via renin release. For example, diuretics (including thiazides) may activate the renin-angiotensin-aldosterone system.

Treatment of acute myocardial infarction: Captopril may be co-administered with acetylsalicylic acid (in cardiologic doses), thrombolytics, beta-blockers, and/or nitrates.

Lithium: Concomitant use of ACE inhibitors and lithium may lead to a transient increase in serum lithium levels and lithium toxicity. Concomitant use of ACE inhibitors with thiazide diuretics may further increase serum lithium levels and increase the risk of lithium toxicity. Concomitant use of captopril with lithium is not recommended. If such combination is necessary for a patient, careful monitoring of serum lithium levels is required (see section "Special precautions for use").

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 for use"). Postural hypotension may occur.

Allopurinol, procainamide, cytostatic or immunosuppressive agents: Concomitant administration with ACE inhibitors may increase the risk of leukopenia, particularly when the latter are used at doses exceeding current recommendations.

Non-steroidal anti-inflammatory drugs (NSAIDs): Long-term concomitant use of non-steroidal anti-inflammatory drugs (i.e., selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs) with ACE inhibitors may reduce the antihypertensive effect of the ACE inhibitor.

It has been reported that NSAIDs and ACE inhibitors have an additive effect on increasing serum potassium levels, while renal function may deteriorate. These effects are mainly reversible. Concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening renal function, and rarely may lead to acute renal failure, particularly in patients with pre-existing renal impairment, such as elderly patients or those with dehydration.

This combination should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter.

Indomethacin has also been reported to reduce the antihypertensive effect of captopril, particularly in cases of low-renin hypertension.

Sympathomimetics: May reduce the antihypertensive effects of ACE inhibitors; therefore, close monitoring of patients is required.

Antidiabetic agents: Pharmacological studies indicate that concomitant use of ACE inhibitors, including captopril, may enhance the glucose-lowering effects of insulin and oral antidiabetic agents (sulfonylureas) in patients with diabetes mellitus. In the rare event of such interaction, dose reduction of the antidiabetic agent may be necessary during concomitant therapy with ACE inhibitors.

Medicinal products increasing the risk of angioedema: Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").

The risk of angioedema is increased in patients receiving ACE inhibitors concomitantly with rac-cadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin (see section "Special precautions for use").

Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly have an increased risk of developing hyperkalemia (see section "Special precautions for use").

Cyclosporine: Hyperkalemia may occur during concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin: Hyperkalemia may occur during concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium levels is recommended.

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

Gold: In rare cases, patients receiving ACE inhibitors concomitantly with injectable gold preparations (sodium aurothiomalate) have experienced nitritoid reactions characterized by flushing, dizziness, nausea, vomiting, and hypotension up to circulatory collapse.

Special precautions for use.

Dual blockade of the RAAS: It is evident that combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and leads to impaired kidney 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 kidney function, electrolytes, and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is not allowed in patients with diabetic nephropathy.

Arterial hypotension: Symptomatic hypotension is more likely to occur in hypertensive patients who have reduced blood volume and/or low sodium levels, for example, due to diuretic therapy, dietary salt restriction, diarrhea, vomiting, or hemodialysis. Before initiating ACE inhibitor therapy, blood volume and/or sodium levels should be corrected, and consideration should be given to starting with a lower initial dose.

Potential hypotensive effects at the beginning of captopril therapy can be minimized by discontinuing diuretic therapy or increasing salt intake approximately one week before starting captopril, or by initiating therapy with lower doses (6.25 mg or 12.5 mg). Additionally, patients should be monitored for at least one hour after administration of the initial dose. Transient hypotensive response is not a contraindication for subsequent doses, which can be administered without difficulty after blood pressure has increased. Arterial hypotension itself is not a reason to discontinue captopril therapy. Blood pressure reduction is greater at the beginning of therapy; this effect stabilizes within one to two weeks and typically returns to baseline levels within two months without loss of therapeutic effect.

Symptomatic hypotension may occur in patients with heart failure receiving angiotensin-converting enzyme inhibitors — a lower initial dose is recommended. Approximately half of patients with heart failure who had normal or low blood pressure experienced transient blood pressure reductions exceeding 20%. Such transient hypotension is usually most likely after the first dose and is generally well tolerated, either asymptomatic or with only mild dizziness. Dose escalation of captopril or diuretics should be performed cautiously in patients with heart failure.

As with any antihypertensive agent, excessive blood pressure reduction in patients with ischemic cardiovascular or cerebrovascular disease may increase the risk of myocardial infarction or stroke. If hypotension develops, the patient should be placed in a supine position. If necessary, plasma volume should be expanded using 0.9% sodium chloride solution.

Infants, especially newborns, may be more sensitive to the adverse hemodynamic effects of captopril. Excessive, prolonged, and unpredictable blood pressure reduction and associated complications, including oliguria and seizures, have been reported.

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 functioning kidney who are taking ACE inhibitors. Loss of kidney function may occur with minimal changes in serum creatinine levels. Such patients should start therapy under physician supervision with low doses; careful dose titration and monitoring of kidney function are required during treatment.

Following blood pressure reduction with captopril, some patients with kidney disease, especially those with severe renal artery stenosis, may experience increases in blood urea nitrogen and serum creatinine levels. These parameters usually return to baseline after discontinuation of therapy. Dose reduction of captopril and/or discontinuation of diuretics may be required.

Impaired kidney function: Patients with impaired kidney function (creatinine clearance ≤ 40 mL/min) require dose adjustment according to creatinine clearance (see section "Dosage and administration"), followed by adjustment based on the patient's response to therapy. In such patients, serum creatinine and potassium levels should be regularly monitored, which is part of standard medical practice.

Hypersensitivity/angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported in patients receiving ACE inhibitors, particularly captopril. Angioedema may occur at any time during treatment. In such cases, captopril should be discontinued immediately, and appropriate monitoring should be conducted to ensure complete resolution of symptoms before patient discharge. In cases where swelling is limited to the face and lips, the condition usually stabilizes without treatment, although antihistamines may be helpful in relieving symptoms. Angioedema involving the larynx may be fatal. If the tongue, glottis, or larynx is involved and airway obstruction is possible, immediate appropriate therapy should be initiated, for example, subcutaneous administration of 1:1000 adrenaline solution (0.3–0.5 mL) and/or measures to secure the airway. The patient should be hospitalized and observed for at least 12 to 24 hours and not discharged until symptoms have completely resolved.

It is known that angioedema occurs more frequently in patients of African descent receiving ACE inhibitors than in others.

Patients with a history of angioedema unrelated to ACE inhibitor use have an increased risk of developing angioedema during ACE inhibitor therapy (see sections "Contraindications").

Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior history of facial angioedema and C1 esterase levels were normal. Intestinal angioedema was diagnosed using procedures including abdominal CT scan or ultrasound examination of the abdomen, or during surgical intervention. Symptoms resolved after discontinuation of ACE inhibitors. Intestinal angioedema should be included in the differential diagnosis for patients receiving ACE inhibitors who present with abdominal pain (see section "Adverse reactions").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Therapy with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of captopril. Captopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin increases the risk of angioedema (e.g., airway or tongue swelling with or without breathing difficulty) (see section "Interaction with other medicinal products and other forms of interaction"). Therapy with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin should be initiated cautiously in patients already receiving ACE inhibitors.

Cough: Cough has been reported during treatment with angiotensin-converting enzyme inhibitors. The cough is characterized as persistent, dry, non-productive, and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Hepatic impairment: ACE inhibitors have rarely been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant necrotic hepatitis, sometimes resulting in fatal outcomes. The mechanism of this syndrome is unclear. If jaundice or marked elevation of liver enzymes occurs during ACE inhibitor therapy, treatment should be discontinued immediately, and the patient should be closely monitored.

Hyperkalemia: ACE inhibitors may cause hyperkalemia because they suppress aldosterone release. The effect is usually mild in patients with normal kidney function. The risk of hyperkalemia is increased in patients with renal impairment, diabetes mellitus, those concurrently receiving potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other agents that may cause hyperkalemia (e.g., heparin, co-trimoxazole [trimethoprim/sulfamethoxazole], and especially aldosterone antagonists or angiotensin receptor blockers). Potassium-sparing diuretics and angiotensin receptor blockers should be used cautiously in patients receiving ACE inhibitors, and serum potassium levels and kidney function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Lithium: The combination of lithium and captopril is not recommended due to increased lithium toxicity (see section "Interaction with other medicinal products and other forms of interaction").

Aortic or mitral valve stenosis / hypertrophic cardiomyopathy / cardiogenic shock: ACE inhibitors should be administered very cautiously to patients with left ventricular outflow tract obstruction or outflow tract obstruction and should be avoided in cases of cardiogenic shock and hemodynamically significant obstruction.

Heart failure: During long-term captopril therapy, approximately 20% of patients experienced sustained increases in blood urea nitrogen (BUN) and serum creatinine levels exceeding 20% above normal. Less than 5% of patients, typically those with severe kidney disease, had to discontinue therapy due to progressive increases in creatinine levels. Further outcomes depended on the severity of renal impairment.

Neutropenia/agranulocytosis: Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving angiotensin-converting enzyme inhibitors, including captopril. Neutropenia is rare in patients with normal kidney function and no other complications. Neutropenia is usually detected about 3 months after starting captopril therapy.

In clinical studies of patients with any degree of renal impairment (serum creatinine ≥ 1.6 mg/dL) but without collagen vascular diseases, the risk of neutropenia was about 0.2%; in patients with renal impairment, concomitant use of allopurinol with captopril was associated with neutropenia. Among patients with collagen vascular diseases (such as systemic lupus erythematosus or scleroderma) and impaired kidney function, neutropenia was observed in 3.7% of patients.

Captopril should be used with extreme caution 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 kidney function is already impaired. In some of these patients, serious infections may develop, which sometimes do not respond to intensive antibiotic therapy.

If captopril is administered to such patients, leukocyte count and complete blood count should be performed before treatment, every 2 weeks during the first 3 months of captopril therapy, and periodically thereafter. Patients should be instructed to immediately report any signs of infection (e.g., sore throat, fever), after which a complete leukocyte count should be performed. Captopril and any concomitant medication (see section "Interaction with other medicinal products and other forms of interaction") should be discontinued if neutropenia (neutrophil count less than 1000/mm³) is detected or suspected; careful monitoring of the patient is recommended.

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

Approximately 13% of neutropenia cases were fatal, but these occurred in patients with serious conditions, including collagen vascular diseases, renal or cardiac failure, or receiving immunosuppressive therapy, or with multiple such factors.

Proteinuria: Proteinuria may occur in patients with pre-existing kidney dysfunction or those receiving relatively high doses of ACE inhibitors.

Total urinary protein exceeding 1 g per day was observed in approximately 0.7% of patients receiving captopril. Most patients had evidence of prior kidney disease or were receiving relatively high doses of captopril (over 150 mg/day), or both. Nephrotic syndrome occurred in approximately 1/5 of patients with proteinuria. In most cases, proteinuria decreases or resolves within 6 months, regardless of whether captopril therapy is continued. Changes in kidney function parameters such as blood urea nitrogen and creatinine are rarely observed in patients with proteinuria.

Patients with a history of kidney disease should have urine protein analysis (dipstick test of first morning urine) performed before starting therapy and periodically thereafter.

In a double-blind, placebo-controlled, multicenter study involving 207 patients with diabetic nephropathy and proteinuria (≥ 500 mg/day) who received 75 mg/day of captopril for an average of 3 years, a sustained reduction in proteinuria was observed. It is unknown whether short-term therapy in patients with other types of kidney disease may have similar effects.

Pseudoallergic reactions during desensitization: In patients receiving ACE inhibitors during desensitization to hymenoptera venom, rare life-threatening reactions resembling allergic (pseudoallergic) reactions may occur. These reactions may be avoided by temporarily discontinuing ACE inhibitor therapy before each desensitization session, but they recur after accidental antigen stimulation. Therefore, ACE inhibitor therapy should be administered cautiously in patients undergoing such desensitization procedures.

Anaphylactoid reactions during dialysis with high-flux membranes / low-density lipoprotein apheresis: Reports have been made of pseudoallergic reactions in patients undergoing hemodialysis sessions using high-flux membranes or low-density lipoprotein apheresis with dextran sulfate. For such patients, consideration should be given to using a different type of dialysis, membrane, or class of medication.

Surgery/anesthesia: Arterial hypotension may occur in patients after major surgical procedures or during treatment with anesthetics known to reduce blood pressure, as captopril blocks the formation of secondary angiotensin II induced by compensatory renin release. If hypotension occurs and is considered related to this mechanism, it can be corrected by volume expansion.

Diabetes mellitus: In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, blood glucose levels should be carefully monitored during the first several months of concomitant ACE inhibitor therapy. ACE inhibitors and angiotensin receptor blockers should not be used concomitantly in patients with diabetic neuropathy.

Hypokalemia risk: The combination of an ACE inhibitor with a thiazide diuretic does not exclude the possibility of hypokalemia. Regular monitoring of potassium levels is required.

Ethnic considerations: As with all ACE inhibitors, captopril is less effective as an antihypertensive agent in patients of African descent compared to other patients, possibly due to the higher prevalence of low renin levels among hypertensive patients of African descent.

Pregnancy: ACE inhibitors are contraindicated in pregnant women or women planning to become pregnant (see sections "Contraindications", "Use during pregnancy or breastfeeding").

Pediatric population: Captopril is used for the treatment of hypertension in newborns and children. Clinical experience has shown that recommended doses for newborns and children, based on body weight, are comparable to those used in adult patients. The efficacy and safety of captopril in children have not been sufficiently studied; therefore, captopril should be prescribed to newborns and children only if treatment with other antihypertensive agents has been insufficiently effective.

Use during pregnancy or breastfeeding.

Pregnancy.

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

Epidemiological conclusions regarding the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are not definitive. A small increased risk cannot be excluded. If continuation of ACE inhibitor therapy is not considered necessary, patients 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 kidney 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 kidney and skull development is recommended.

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

Lactation

Captopril is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

During treatment, caution is required when driving or engaging in potentially hazardous activities requiring concentration and increased psychomotor reaction speed due to the possibility of their reduction, especially at the beginning of therapy, when dosage changes occur, or when used in combination with alcohol; however, these effects depend on individual patient sensitivity.

Administration and Dosage

Dosage should be adjusted according to the patient's condition (see section "Special Instructions") and blood pressure response to treatment. The recommended maximum daily dose is 150 mg.

Arterial Hypertension

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

Patients with highly active renin-angiotensin-aldosterone system (hypovolemia, renovascular hypertension, heart failure) should start with a single dose of 6.25 mg or 12.5 mg. Initial treatment should preferably be initiated under close medical supervision. After initiation, Captopril should be taken twice daily. Dosage may be gradually increased up to 50 mg daily in one or two doses and, if necessary, up to 100 mg daily in one or two doses.

Myocardial Infarction

• Short-term treatment: Captopril treatment should be initiated in hospital as early as possible after onset of symptoms in patients with stable hemodynamics. A test dose of 6.25 mg should be administered, followed by a dose of 12.5 mg after 2 hours, and then a dose of 25 mg after 12 hours. Starting from the next day, Captopril should be administered at a dose of 100 mg/day in two divided doses for 4 weeks, provided no adverse hemodynamic reactions occur. At the end of the 4-week treatment period, the patient's condition should be re-evaluated to make a decision regarding post-myocardial infarction phase treatment.

• Continuous treatment: If captopril treatment has not been initiated within the first 24 hours of acute myocardial infarction, it is recommended to start treatment between days 3 and 16 after infarction, once appropriate 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/day is reached. Initial dose should be low (see section "Special Instructions"), especially in patients with normal or low blood pressure at the beginning of therapy. Treatment should start with a dose of 6.25 mg, followed by 12.5 mg three times daily for 2 days, then 25 mg three times daily, provided no adverse hemodynamic reactions occur. The recommended dose for effective cardioprotection during long-term treatment is 75–150 mg daily in two or three divided doses. In case of symptomatic hypotension, as in heart failure, doses of diuretics and/or other concomitant vasodilating agents may be reduced to achieve a stable captopril dose. If necessary, captopril dose should 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.

Heart Failure

Treatment of heart failure with captopril should be initiated under close medical supervision. The usual initial dose is 6.25–12.5 mg of captopril two to three times daily. Titration to a maintenance dose (75–150 mg daily) should be based on the patient's response to treatment, clinical status, and tolerability, up to a maximum of 150 mg daily in two divided doses. The dose should be increased gradually, with intervals of at least 2 weeks, to assess the patient's response to treatment.

Type I Diabetic Nephropathy: For patients with type I diabetic nephropathy, the recommended daily dose of captopril is 75–100 mg in two divided doses. If additional blood pressure reduction is desired, other antihypertensive agents may be added.

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. For patients with severe renal impairment requiring concomitant diuretic therapy, a loop diuretic (e.g., furosemide) is preferred over a thiazide diuretic.

The following daily doses may be recommended for patients with renal impairment to avoid accumulation of captopril in the body.

Creatinine clearance (ml/min/1.73 m²)	Daily initial dose (mg)	Daily maximum dose (mg)
> 40	25-50	150
21-40	25	100
10-20	12.5	75
< 10	6.25	37.5

Elderly patients: As with other antihypertensive agents, treatment should be initiated with a lower starting dose (6.25 mg) in elderly patients, who may have reduced renal function and may have organ impairments (see above and section "Special precautions").

The dose should be titrated according to the blood pressure response. The lowest effective dose that adequately controls blood pressure should be used.

Children and adolescents: The efficacy and safety of captopril 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 patients requiring special caution (children with impaired renal function, preterm infants, newborns, and infants, since their renal function differs from that in older children and adults), the initial dose should be only 0.15 mg captopril/kg body weight. Captopril is generally administered to children three times daily; however, the dose and dosing interval must be individually adjusted according to the patient's response to treatment.

Administration method

Captopril may be taken 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 missed dose should be skipped and the next dose taken according to the regular schedule. Two doses of captopril should not be taken simultaneously.

Children.

The efficacy and safety of captopril in children have not been sufficiently established. Captopril therapy in children should be initiated under close medical supervision.

Overdose.

Symptoms: severe arterial hypotension, shock, stupor, bradycardia, electrolyte imbalance, and renal failure.

Treatment: If poisoning has occurred recently, measures should be taken to prevent absorption (e.g., gastric lavage, administration of adsorbents and sodium sulfate within 30 minutes of ingestion) and to accelerate elimination. If signs of hypotension occur, the patient should be placed in a supine position and plasma volume and electrolyte balance should be promptly corrected. Treatment with angiotensin II should be considered. Bradycardia or excessive vagal reactions should be treated by administration of atropine. The use of a cardiac pacemaker should be considered. Captopril is removed from the circulation by hemodialysis, but it cannot be adequately removed by peritoneal dialysis.

Side effects

Side effects are listed by frequency: very common (≥ 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

• Very rare: neutropenia/agranulocytosis, pancytopenia (particularly in patients with impaired renal function), anemia (including aplastic or hemolytic), thrombocytopenia, lymphadenopathy, eosinophilia, autoimmune diseases and/or positive antinuclear antibody test.

Metabolism and nutrition disorders:

• Rare: anorexia;
• Very rare: hyperkalemia, hyponatremia, hypoglycemia.

Psychiatric disorders:

• Common: sleep disorders;
• Very rare: confusion, depression.

Nervous system disorders:

• Common: taste disturbances, dizziness;
• Rare: somnolence, headache, and paresthesia;
• Very rare: cerebrovascular events, ataxia, including stroke and loss of consciousness.

Eye disorders:

• Very rare: blurred vision.

Cardiac disorders:

• Uncommon: tachycardia, tachyarrhythmia, angina pectoris, palpitations;
• Very rare: cardiac arrest, cardiogenic shock.

Vascular disorders:

• Uncommon: arterial hypotension, Raynaud's syndrome, flushing, pallor of the face, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders:

• Common: dry, irritating (non-productive) cough and dyspnea; dry cough usually resolves within several weeks after discontinuation of captopril therapy;
• Very rare: bronchospasm, rhinitis, allergic alveolitis / eosinophilic pneumonia.

Gastrointestinal disorders:

• Common: nausea, vomiting, gastric irritation, abdominal pain, diarrhea, constipation, dry mouth, peptic ulcer, dyspepsia;
• Rare: stomatitis / appearance of aphthous ulcers, intestinal angioedema (see section "Special precautions");
• Very rare: glossitis, pancreatitis.

Hepatobiliary disorders:

• Very rare: hepatic function abnormalities; cholestasis, including jaundice; hepatitis, including necrosis; increased levels of liver enzymes (transaminases and alkaline phosphatase) and elevated bilirubin levels. Liver function abnormalities usually resolve after discontinuation of captopril therapy.

Skin and subcutaneous tissue disorders:

• Common: pruritus with or without rash, alopecia;
• Uncommon: angioedema (see section "Special precautions");
• Very rare: urticaria, Stevens-Johnson syndrome, polymorphic erythema, photoallergic erythroderma, pemphigoid reactions, and exfoliative dermatitis.

Musculoskeletal and connective tissue disorders:

• Very rare: myalgia, arthralgia.

Renal and urinary disorders:

• Rare: renal function impairment, including renal failure, polyuria, oliguria, and increased frequency of urination;
• Very rare: nephrotic syndrome.

Reproductive system and breast disorders:

• Very rare: impotence, gynecomastia.

General disorders:

• Uncommon: chest pain, increased fatigue, weakness, malaise;
• Very rare: collapse.

Laboratory findings:

• Very rare: proteinuria, eosinophilia, hyperkalemia, hyponatremia, increased serum urea, creatinine and bilirubin levels, decreased hemoglobin levels, decreased hematocrit, leukopenia, thrombocytopenia, increased antinuclear antibody titer, elevated erythrocyte sedimentation rate.

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx, and peripheral edema have been reported in approximately 1 in 1000 patients.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging to protect from light and moisture.

Keep out of reach of children.

Packaging. 10 tablets in a blister, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

Date of last review.