Captopril tablets 25 mg blister No. 20

Instructions for use Captopril tablets 25 mg blister No. 20

Composition

active ingredient: captopril;
1 tablet contains captopril, calculated as 100% substance – 25 mg;
Excipients: potato starch; lactose monohydrate; povidone; calcium stearate; colloidal anhydrous silicon dioxide.

Dosage form

Pills.

Main physicochemical properties: white or almost white tablets with a flat surface, with one or two lines, with a bevel.

Pharmacotherapeutic group

Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors, monocomponent.
ATX code C09A A01.

Pharmacological properties

Pharmacodynamics.

The beneficial effects of ACE inhibitors are mainly due to inhibition of the plasma renin-angiotensin-aldosterone system. Renin is an endogenous enzyme synthesized by the kidneys and released into the systemic circulation, where it converts angiotensinogen to angiotensin-I, a relatively inactive decapeptide. Angiotensin-I is then converted by ACE, a peptidyl dipeptidase, to angiotensin-II. Angiotensin-II is a potent vasoconstrictor responsible for constricting arterial vessels and increasing blood pressure, as well as stimulating the adrenal glands to produce aldosterone. Inhibition of ACE results in a decrease in plasma angiotensin-II levels, which reduces vasopressor activity and aldosterone production. Although the decrease in the latter is small, a small increase in serum potassium concentrations may occur, paralleling sodium and fluid loss. The elimination of the negative feedback loop of angiotensin-II with renin production leads to an increase in renin activity in blood plasma.

Another function of the converting enzyme is the degradation of the potent vasodepressant kinin peptide bradykinin to inactive metabolites. Therefore, inhibition of ACE leads to increased activity of the kallikrein-kinin system, which is involved in peripheral vasodilation through activation of the prostaglandin system; this mechanism may be involved in the hypotensive effect of ACE inhibitors and responsible for some of the adverse reactions.

The maximum reduction in blood pressure usually occurs 60–90 minutes after oral administration of an individual dose of captopril. The duration of the effect is dose-dependent. The reduction in blood pressure may be progressive, and several weeks of therapy may be required to achieve the maximum therapeutic effect. The blood pressure-lowering effects of captopril and thiazide diuretics are additive.

With prolonged use, captopril reduces the severity of left ventricular myocardial hypertrophy, prevents the progression of heart failure and slows the development of left ventricular dilatation. Reduces the tone of the efferent arterioles of the renal glomeruli, thereby improving intraglomerular hemodynamics, and prevents the development of diabetic nephropathy.

Pharmacokinetics.

Captopril is an orally active drug that does not require biotransformation to exert its effect. The mean minimum 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%. Protein binding, mainly to albumin, is approximately 25–30%. The apparent half-life of unchanged captopril from the blood is approximately 2 hours. More than 95% of the absorbed dose is excreted in the urine within 24 hours; 40–50% is unchanged drug, the rest is inactive disulfide metabolites (captopril disulfide and captopril cysteine disulfide). Impaired renal function may lead to accumulation of the drug. Therefore, in patients with impaired renal function, the dose should be reduced and/or the dosing intervals should be prolonged (see section 4.2).

Animal studies indicate that captopril does not penetrate the blood-brain barrier to any significant extent.
Breastfeeding. In women who received oral captopril 100 mg 3 times a day, the mean peak level in breast milk was 4.7 mcg/l 3.8 hours after dosing. Based on these data, the maximum daily dose that the infant may receive is less than 0.002% of the maternal daily dose. Captopril can be removed from the general circulation by haemodialysis and peritoneal dialysis. The clearance by haemodialysis is 4.8–7.2 l/h, depending on the filters used. During a 4-hour haemodialysis session, 30–40% of captopril is removed from the blood, while the removal of metabolites is somewhat less.

The disulfide metabolites of captopril are excreted by the kidneys more slowly than captopril. Since the disulfide metabolites are converted back to captopril in the body, accumulation of captopril can be expected in patients with renal insufficiency. The accumulation of captopril metabolites in patients with renal insufficiency leads to a stronger pharmacodynamic effect and a prolonged effect. Therefore, the dose of captopril should be adjusted according to renal function in such patients.

In patients with heart failure, the elimination of captopril is slowed. Therefore, patients with heart failure should be treated with a lower initial dose of captopril, and the dose should be adjusted according to the achieved therapeutic effect.
The pharmacokinetics of captopril in healthy elderly volunteers are the same as in healthy younger volunteers. Therefore, elderly patients with hypertension and normal renal function can be given the usual daily doses of captopril.

Indication

– Arterial hypertension.

– Heart failure. Captopril is prescribed for the treatment of chronic heart failure with decreased 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 prescribed within 24 hours after myocardial infarction in patients with a 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, manifested by macroproteinuria.

Contraindication

Hypersensitivity to captopril, to any excipient or to other ACE inhibitors;

Quincke's edema (including history, after use of ACE inhibitors, hereditary/idiopathic);

bilateral renal artery stenosis affecting hemodynamics, or stenosis of the artery of a single kidney affecting hemodynamics;

porphyria;

galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;

pregnancy; also contraindicated in women planning to become pregnant (see section "Use during pregnancy or breastfeeding");

breastfeeding period (see section "Use during pregnancy or breastfeeding");

simultaneous use of captopril with drugs containing aliskiren in patients with diabetes mellitus or patients with renal insufficiency (glomerular filtration rate < 60 ml/min/1.73 m2).

Interaction with other medicinal products and other types of interactions

Potassium-sparing diuretics or potassium supplements. ACE inhibitors reduce potassium loss caused by diuretics. Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or salt substitutes containing potassium may lead to hyperkalaemia. They should be used with great caution and with frequent monitoring of serum potassium when co-administered because of pre-existing hypokalaemia.

Diuretics (thiazide or loop diuretics). Previous treatment with high doses of diuretics may result in volume depletion and an increased risk of significant hypotension (see section 4.4). The hypotensive effect can be reduced 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 drugs. The simultaneous use of captopril with other antihypertensive drugs (e.g. beta-blockers and long-acting calcium channel blockers) is safe, and concomitant use of such drugs may increase the hypotensive effect of captopril. Caution should be exercised when treating with nitroglycerin, other nitrates or other drugs.

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

Treatment of acute myocardial infarction. Captopril can be administered concomitantly with acetylsalicylic acid (in cardiological doses), thrombolytics, beta-blockers and/or nitrates in patients with myocardial infarction.

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 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 proves necessary, careful monitoring of serum lithium levels should be performed.

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

Nonsteroidal anti-inflammatory drugs (NSAIDs). ACE inhibitors and NSAIDs have been described to have an additive effect on serum potassium levels, which may lead to renal dysfunction. This effect is usually reversible. Acute renal failure may occur rarely, especially in patients with compromised renal function, such as the elderly or dehydrated. Prolonged administration of NSAIDs may reduce the antihypertensive effect of ACE inhibitors.

Sympathomimetics: May reduce the antihypertensive effect of ACE inhibitors, so the patient's blood pressure should be carefully monitored.

Antidiabetic agents: ACE inhibitors, including captopril, may enhance the antiglycaemic effect of insulin and other oral antidiabetic agents (sulfonylureas) in patients with diabetes mellitus. This effect is very rare, but if it occurs, it may be necessary to reduce the dose of the antidiabetic agent during concomitant treatment with ACE inhibitors.

Features of use. Dual blockade of the RAAS: the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and leads to a decrease in renal function (including acute renal failure). Therefore, dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended.

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

ACE inhibitors and angiotensin-II receptor blockers should not be used simultaneously in patients with diabetic nephropathy.

Hypotension. Hypotension may occur rarely in hypertensive patients who are volume and/or sodium depleted by diuretic therapy, dietary salt restriction, diarrhea, vomiting, or hemodialysis. Before prescribing ACE inhibitors, volume expansion should be corrected and the lowest effective dose should be considered.

Patients with heart failure are also at risk of symptomatic hypotension when using ACE inhibitors.

Therefore, it is recommended that such patients be given a lower initial dose of captopril. Increasing the dose of ACE inhibitors and diuretics should be done under close medical supervision.

Excessive decrease 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 (on his back), and if necessary, increase the BCC by administering 0.9% sodium chloride solution.

Renovascular hypertension. There is an increased risk of hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with ACE inhibitors. In such cases, renal function may decline with little change in serum creatinine, and it is recommended that these patients be started on low doses of captopril under close medical supervision, and that the dose be titrated and renal function monitored.

Renal impairment: Patients with renal impairment (creatinine clearance ≤ 40 ml/min) require dosage adjustment according to creatinine clearance (see section 4.2). Serum potassium and creatinine levels should be monitored regularly while taking captopril in such patients.

Angioedema. Rarely, during treatment with ACE inhibitors, especially during the first weeks of treatment, angioedema of the extremities, face, lips, mucous membranes, tongue, larynx and/or glottis may develop. However, extremely rarely, angioedema may develop as a result of prolonged treatment with ACE inhibitors. In such cases, treatment should be discontinued immediately. Angioedema of the tongue, glottis and/or larynx can be fatal, therefore such reactions should be stopped immediately, the patient should be hospitalized and observed for at least 12-24 hours until the symptoms have completely disappeared.

Cough: Cough has been reported during treatment with ACE inhibitors. The cough has been described as persistent, dry, non-productive and resolved after discontinuation of therapy.

Hyperkalemia. During treatment with ACE inhibitors, including captopril, some patients may develop increased serum potassium levels. The risk of hyperkalemia is increased in patients with renal insufficiency, diabetes mellitus, or those taking concomitant potassium-sparing diuretics, potassium supplements or salt substitutes containing potassium, or other drugs that may cause hyperkalemia (e.g. heparin). If concomitant use of the above drugs is considered necessary, regular monitoring of serum potassium is recommended.

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

Lithium: The combination of lithium and captopril is not recommended (see section 4.5).

Neutropenia/agranulocytosis: 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 with caution in patients with vascular disease in collagen diseases (e.g. systemic lupus erythematosus, scleroderma), in patients receiving concomitant antidepressants, allopurinol or procainamide, or a combination of these factors, especially if there is pre-existing renal impairment. Some of these patients may develop serious infections, which sometimes do not respond to intensive antibiotic therapy.

If captopril is used in such patients, it is recommended to monitor the white blood cell count and complete blood count before starting treatment, 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) to their physician and to have a complete blood count. Captopril and any concomitant medication (see section 4.5) should be discontinued immediately if neutropenia (neutrophils < 1000/mm3) is detected or suspected.

In most patients, the neutrophil count quickly returns to normal after stopping captopril.

Proteinuria: Proteinuria may occur in patients with impaired renal function or when taking high doses of ACE inhibitors.
Total protein in the urine of more than 1 g per day was observed in approximately 0.7% of patients taking captopril. Most of these patients had kidney disease or were taking relatively high doses of captopril (more than 150 mg per day), or both. Nephrotic syndrome occurs in 1/5 of patients with proteinuria. In most cases, proteinuria decreases or disappears within 6 months regardless of taking captopril. In patients with proteinuria, parameters of renal function such as serum urea and creatinine rarely change.

In patients with a history of kidney disease, urine protein levels should be determined (dipstick analysis of first morning urine) before starting treatment and periodically thereafter.

Anaphylactoid reactions during desensitization with hymenoptera venom may occur in patients receiving concomitant ACE inhibitors, which in rare cases can be life-threatening. Such reactions can be avoided by temporarily stopping ACE inhibitor therapy before each desensitization, but reactions may recur upon accidental re-challenge with the drug. Therefore, caution is recommended when administering ACE inhibitors to patients undergoing such desensitization procedures.

Anaphylactoid reactions have been reported in patients undergoing dialysis with high-flux membranes/LDL apheresis with dextrin sulfate. A decision should be made to use a different type of dialysis, membrane, or drug class for these patients.

Surgery/anesthesia: In the case of major surgery, patients may experience hypotension during anesthesia. If blood pressure decreases, volume replacement is recommended.

Diabetes mellitus: In diabetic patients taking oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first month of concomitant use of ACE inhibitors.

Ethnic characteristics: Like other ACE inhibitors, captopril is a less effective antihypertensive drug in patients of the black race, possibly due to a higher prevalence of low-renin essential hypertension.

Use during pregnancy or breastfeeding

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy is inconclusive. A slight increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

It is known that the use of angiotensin-converting enzyme inhibitors during the 2nd and 3rd trimesters of pregnancy may cause fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If exposure to an ACE inhibitor has occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see also sections "Contraindications" and "Special Instructions").

Breastfeeding. Captopril is contraindicated during breastfeeding.

Ability to influence reaction speed when driving vehicles or other mechanisms

Caution is required when driving vehicles or performing other work that requires increased attention, as a decrease in reaction speed is possible, especially at the beginning of treatment or when changing the dosage of the drug, as well as with simultaneous use of alcohol. These effects manifest themselves individually and depend on the characteristics of the patient's body.

Method of administration and doses

The dosage should be adjusted depending on the nature of the patient's disease (see section "Special instructions for use") and the blood pressure response to treatment.

Arterial hypertension

The recommended initial dose of captopril is 25-50 mg/day in 2 divided doses. After 2-4 weeks of treatment, the dose can be titrated, depending on the blood pressure achieved, to 100-150 mg/day in 2 divided doses. Captopril can be used alone or with other antihypertensive drugs, especially thiazide diuretics. A once-daily dosing regimen can be used when a concomitant antihypertensive drug such as a thiazide diuretic is added.

In patients with increased activity of the renin-angiotensin-aldosterone system (hypovolemia, renovascular hypertension, decompensated heart failure), therapy should preferably be started with a single dose of 6.25 mg or 12.5 mg. In the case of prescribing captopril in a dose of less than 12.5 mg, other captopril preparations with the possibility of such a dosage should be used.

The initiation of such treatment should be carried out under close medical supervision, with subsequent administration of the drug 2 times a day. The dose can be gradually increased to 50 mg or 100 mg per day in 1 or 2 doses.

Heart failure

Treatment of heart failure with captopril should be initiated under close medical supervision. The initial dose is 6.25–12.5 mg 2 or 3 times a day. Titration to a maintenance dose (75–150 mg/day) should be based on the patient's response to treatment, clinical status, and tolerability, up to a maximum dose of 150 mg/day in 2 divided doses. The dose should be increased gradually, at intervals of at least 2 weeks, to assess the patient's response to treatment.

Myocardial infarction

Diabetic nephropathy in patients with type 1 diabetes: captopril is used at a dose of 75–100 mg per day in 2 divided doses.

If necessary, combine with other antihypertensive drugs.

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

For patients with impaired renal function, the following daily doses are recommended to avoid accumulation of captopril 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

Elderly patients: as with other antihypertensive agents, captopril therapy should be initiated at a dose of 6.25 mg twice daily, since elderly patients may have impaired renal function as well as the function of other organs and systems.
The dose should be titrated based on the blood pressure response to the drug, with the lowest dose required to adequately control blood pressure.

Children: The efficacy and safety of captopril in children have not been sufficiently studied. The use of captopril in children should be initiated under close medical supervision. The recommended initial dose is 0.3 mg/kg body weight. For patients requiring special care (children with renal insufficiency, premature infants, newborns and infants due to immaturity of the urinary system), the initial dose should be only 0.15 mg/kg body weight. Usually, captopril is administered to children 3 times a day, but the interval between administrations should be selected individually, depending on the response to the drug.

Method of application

Captopril is taken orally before, during, and after meals.

You should take the medicine regularly at the same time each day. If you miss a dose, take it as soon as possible; however, if it is only a few hours before your next dose, take your next dose as scheduled and skip the missed dose. You should not take two doses of captopril at the same time.

Children. The effectiveness and safety of captopril in children have not been sufficiently studied. Captopril should be used in children under close medical supervision.

Overdose

Manifested by severe hypotension with possible development of shock, stupor, bradycardia, electrolyte imbalance and renal failure.

Treatment. To prevent the absorption of a large dose of captopril, it is necessary to wash the stomach as soon as possible, use sorbents and sodium sulfate within 30 minutes after taking captopril. In case of symptoms of arterial hypotension, the patient should be placed in a horizontal position and immediately correct the plasma volume and salt balance.

Angiotensin II may be used. Bradycardia or excessive general reactions should be treated with atropine. Pacemaker use should be considered. Effective hemodialysis.

Adverse reactions

Cardiovascular system: tachycardia, tachyarrhythmia, angina pectoris, hypotension, Raynaud's syndrome, hot flashes, facial pallor, cardiac arrest, cardiogenic shock.

Respiratory, thoracic and mediastinal disorders: dry, irritating (non-productive) cough and shortness of breath. Dry cough usually resolves within a few weeks after discontinuation of captopril. Bronchospasm, rhinitis, allergic alveolitis/eosinophilic pneumonia may also occur.

Hepatobiliary disorders: liver dysfunction, cholestasis, including jaundice, hepatitis, including necrotizing hepatitis, increased liver enzymes and bilirubin. Liver dysfunction usually resolves after discontinuation of captopril.

Neurological disorders: taste disturbance, dizziness, drowsiness, headache, paresthesia, cerebrovascular manifestations, ataxia, including stroke and loss of consciousness.

From the blood and lymphatic system: leukopenia, neutropenia/agranulocytosis, pancytopenia (especially in patients with impaired renal function), anemia (including aplastic and hemolytic), thrombocytopenia, lymphadenopathy, eosinophilia.

Immune system: autoimmune diseases and/or positive test for antinuclear antibodies.

Metabolic and digestive disorders: anorexia, acidosis, hypoglycemia.

Mental disorders: sleep disorders, confusion, depression.

On the part of the organs of vision: blurred vision.

Skin and subcutaneous tissue disorders: pruritus, rash, alopecia, angioedema (see section "Special warnings and precautions for use"), urticaria, Stevens-Johnson syndrome, erythema multiforme, photosensitivity, erythroderma, pemphigoid reactions and exfoliative dermatitis.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Urinary tract disorders: renal dysfunction, including renal failure, polyuria, oliguria and frequent urination, nephrotic syndrome.

From the reproductive system and mammary glands: impotence, gynecomastia.

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

From the laboratory parameters: proteinuria, hyperkalemia, hyponatremia (most often observed when following a salt-free diet with simultaneous use of diuretics), increased levels of urea, creatinine and bilirubin in the blood serum, as well as a decrease in hemoglobin, hematocrit and an increase in erythrocyte sedimentation rate, leukopenia, thrombocytopenia, eosinophilia, increased titer of antinuclear antibodies. Captopril may cause a false-positive result of urine analysis for acetone.

Angioedema of the face, eyelids, tongue, and peripheral edema occurred in approximately one in 1,000 patients.
Interstitial angioedema has been observed in patients treated with ACE inhibitors.

Expiration date

3 years.

Storage conditions

Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Packaging

10 tablets in a blister, 2 blisters in a pack.

Vacation category

According to the recipe.

Producer

PJSC "Kyivmedpreparat".

Location of the manufacturer and address of its place of business.

01032, Ukraine, Kyiv, Saksaganskoho St., 139.