Hydrochlorothiazide + Captopril (Tablets) Instructions for Use

Marketing Authorization Holder

Atoll LLC (Russia)

Manufactured By

Ozon, LLC (Russia)

ATC Code

C09BA01 (Captopril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Captopril (Rec.INN registered by WHO)

Dosage Form

Hydrochlorothiazide + Captopril

25 mg+50 mg tablets: 7, 10, 14, 20, 21, 28, 30, 35, 40, 50, 60, 70, 90, 100, 120, 150, or 300 pcs.

Dosage Form, Packaging, and Composition

Tablets white or white with a beige tint, round, flat-cylindrical, with a score and a bevel, with a characteristic odor; slight marbling is allowed.

Excipients: lactose monohydrate (milk sugar) – 169 mg, microcrystalline cellulose (MCC-101 Premium) – 100 mg, corn starch – 40 mg, croscarmellose sodium – 12 mg, magnesium stearate – 4 mg.

7 pcs. – contour cell packaging (1) – cardboard packs.
7 pcs. – contour cell packaging (2) – cardboard packs.
7 pcs. – contour cell packaging (3) – cardboard packs.
7 pcs. – contour cell packaging (4) – cardboard packs.
7 pcs. – contour cell packaging (5) – cardboard packs.
7 pcs. – contour cell packaging (10) – cardboard packs.
10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (2) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (4) – cardboard packs.
10 pcs. – contour cell packaging (5) – cardboard packs.
10 pcs. – contour cell packaging (10) – cardboard packs.
30 pcs. – contour cell packaging (1) – cardboard packs.
30 pcs. – contour cell packaging (2) – cardboard packs.
30 pcs. – contour cell packaging (3) – cardboard packs.
30 pcs. – contour cell packaging (4) – cardboard packs.
30 pcs. – contour cell packaging (5) – cardboard packs.
30 pcs. – contour cell packaging (10) – cardboard packs.
10 pcs. – jars (1) with first opening control – cardboard packs.
20 pcs. – jars (1) with first opening control – cardboard packs.
28 pcs. – jars (1) with first opening control – cardboard packs.
30 pcs. – jars (1) with first opening control – cardboard packs.
40 pcs. – jars (1) with first opening control – cardboard packs.
50 pcs. – jars (1) with first opening control – cardboard packs.
100 pcs. – jars (1) with first opening control – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive agent, combination (diuretic + ACE inhibitor)

Pharmacological Action

A combined medicinal product that has antihypertensive and diuretic effects.

Captopril is an ACE inhibitor. It reduces the formation of angiotensin II from angiotensin I and reduces the secretion of aldosterone. It lowers blood pressure, systemic vascular resistance, afterload, and preload. It dilates arteries to a greater extent than veins. It increases coronary and renal blood flow. With long-term use, it reduces the severity of myocardial hypertrophy and the walls of resistive-type arteries; improves blood supply to the ischemic myocardium; reduces platelet aggregation.

Hydrochlorothiazide is a thiazide diuretic of medium strength, it reduces the reabsorption of sodium ions at the level of the cortical segment of the loop of Henle. It does not affect the acid-base status. It reduces blood pressure by changing the reactivity of the vascular wall, reducing the pressor effect of vasoconstrictor substances (epinephrine, norepinephrine) and enhancing the depressor effect on autonomic ganglia (to a lesser extent, due to a decrease in circulating blood volume). It enhances the antihypertensive effect of captopril.

The diuretic effect is noted after 2 hours and reaches a maximum 4 hours after oral administration. The action lasts for 6-12 hours.

Pharmacokinetics

When taken orally, Captopril is rapidly absorbed from the gastrointestinal tract, C_max in blood plasma is observed approximately 1 hour after administration. The bioavailability of captopril is 60-70%. Simultaneous food intake slows down the absorption of the drug by 30-40%. Plasma protein binding is 25-30%. T_1/2 is 2-3 hours. The drug is excreted from the body mainly by the kidneys, up to 50% unchanged, the rest in the form of metabolites.

When taken orally, Hydrochlorothiazide is relatively rapidly absorbed. T_1/2 in plasma is 2.5 hours when taken on an empty stomach by healthy volunteers. It is excreted by the kidneys, 95% of the dose is unchanged.

Indications

Arterial hypertension (for patients who require combination therapy).

ICD codes

Dosage Regimen

Take orally once daily, typically one tablet containing 50 mg captopril and 25 mg hydrochlorothiazide.

Administer at least one hour before a meal for optimal absorption.

Initiate therapy only after prior titration of the individual components to ensure tolerability.

For patients with impaired renal function (creatinine clearance 30-60 ml/min), use with caution and monitor renal function closely.

In patients with a risk of excessive hypotension, correct salt and/or volume depletion prior to initiation.

Adjust dosage based on individual patient response and blood pressure control.

Do not exceed the maximum recommended daily dose.

The dosage regimen must be determined and supervised by a physician.

Adverse Reactions

From the cardiovascular system infrequently – tachycardia or tachyarrhythmia, chest pain, angina pectoris, palpitations, myocardial infarction, orthostatic hypotension, syncope, peripheral edema, excessive decrease in blood pressure, Raynaud’s syndrome, flushing; very rarely – cardiac arrest, cardiogenic shock.

From the respiratory system often – dry non-productive cough, shortness of breath; very rarely – bronchospasm, eosinophilic pneumonitis, rhinitis, pulmonary edema.

Allergic reactions often – skin itching, with or without rash, sometimes accompanied by fever and arthralgia, skin rash; infrequently – angioedema of the skin and subcutaneous tissue; rarely – angioneurotic intestinal edema; very rarely – urticaria, Stevens-Johnson syndrome, erythema multiforme, photosensitivity, erythroderma, reversible pemphigoid reactions, bullous pemphigus, exfoliative dermatitis, allergic alveolitis, eosinophilic pneumonia, angioedema of the extremities, face, lips, mucous membranes, tongue, pharynx and larynx (including fatal outcome).

From the central nervous system often – drowsiness, dizziness; rarely – headache, ataxia, paresthesia; very rarely – confusion, depression, cerebrovascular accidents, including stroke and syncope, blurred vision.

From the hematopoietic system very rarely – neutropenia, agranulocytosis, pancytopenia, lymphadenopathy, eosinophilia, thrombocytopenia, anemia (including aplastic and hemolytic forms), increased titers of antinuclear antibodies, autoimmune diseases.

From the digestive system often – nausea, vomiting, irritation of the gastric mucosa, abdominal pain, diarrhea, constipation, taste disturbance, dry oral mucosa; rarely – stomatitis, aphthous stomatitis, anorexia; very rarely – glossitis, gastric ulcer, pancreatitis, gingival hyperplasia, impaired liver function and cholestasis (including jaundice), increased activity of liver enzymes, hepatitis (including necrosis), hyperbilirubinemia.

From the musculoskeletal system very rarely – myalgia, arthralgia, myasthenia.

From the urinary system infrequently – impaired renal function (including renal failure), polyuria, oliguria, frequent urination, nephrotic syndrome.

From the reproductive system and mammary gland very rarely – impotence, gynecomastia.

Other often – alopecia; infrequently – chest pain, increased fatigue, malaise.

Laboratory parameters often – eosinophilia; very rarely – proteinuria, hyperkalemia, hyponatremia (including symptomatic), increased blood urea nitrogen, bilirubin and creatinine, decreased hematocrit, decreased hemoglobin, leukocytes, platelets.

Contraindications

Hereditary or idiopathic angioedema (history of ACE inhibitor use); aortic stenosis; mitral stenosis; hypertrophic obstructive cardiomyopathy; bilateral renal artery stenosis or stenosis of the artery of a single kidney; condition after kidney transplantation; chronic heart failure; cardiogenic shock; arterial hypotension; severe hepatic failure (precomatose state, hepatic coma); severe renal failure (serum creatinine >1.8 mg/dl or creatinine clearance <20-30 ml/min, anuria); primary hyperaldosteronism; simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (GFR <60 ml/min); pregnancy, breastfeeding period; age under 18 years; hypersensitivity to the components of the combination, other ACE inhibitors, thiazide diuretics, sulfonamide derivatives (cross-allergic reactions are possible).

With caution

Impaired liver function, progressive liver diseases; moderate renal failure (creatinine clearance 30-60 ml/min); proteinuria (more than 1 g/day); hypokalemia (not corrected by medications); hyponatremia; hypovolemia; hypercalcemia; gout, hyperuricemia; systemic connective tissue diseases and other autoimmune diseases (including systemic lupus erythematosus, scleroderma, polyarteritis nodosa); elderly age (over 65 years); simultaneous use of drugs that suppress the body’s defense reactions (glucocorticoids, cytostatics, immunosuppressants), allopurinol, procainamide; surgery/general anesthesia; use in patients of the Black race; hemodialysis using high-flux membranes (e.g., AN69^®); simultaneous desensitizing therapy; simultaneous use of potassium-sparing diuretics, potassium preparations, potassium-containing substitutes; simultaneous use of lithium preparations; acute myopia and secondary angle-closure glaucoma.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated in severe hepatic failure (precomatose state, hepatic coma).

The drug should be prescribed with caution in case of impaired liver function, progressive liver diseases.

Use in Renal Impairment

Contraindicated in severe renal failure (serum creatinine >1.8 mg/dl or creatinine clearance <20-30 ml/min, anuria).

The drug should be prescribed with caution in moderate renal failure (creatinine clearance 30-60 ml/min).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

At the beginning of treatment, an excessive decrease in blood pressure may be observed, especially in patients with chronic heart failure, severe arterial hypertension (including of renal origin) and/or renal failure. Before starting treatment, it is necessary to compensate for the sodium ion deficiency and normalize the circulating blood volume (reduce the dose of previously prescribed diuretics or, in some cases, completely cancel them), and also determine the indicators of renal function.

Regular monitoring of the concentration of potassium and calcium in the blood serum (especially in patients receiving treatment with cardiac glycosides, glucocorticoids, frequently using laxatives, as well as in elderly patients), glucose, uric acid, lipids (cholesterol and triglycerides), urea and creatinine, and the activity of liver enzymes is necessary.

Regular monitoring of blood pressure and laboratory parameters is especially necessary in the following cases: in patients with renal failure; patients with severe arterial hypertension (including of renal origin); in elderly patients (over 65 years); in patients with water-electrolyte imbalance and decompensated chronic renal failure; and also those receiving simultaneously allopurinol, lithium salts, procainamide and drugs that reduce immunity.

When using ACE inhibitors, a characteristic non-productive cough is noted, which stops after discontinuation of ACE inhibitor therapy.

In some patients with kidney disease, especially with severe renal artery stenosis, an increase in serum urea nitrogen and creatinine concentrations is observed after a decrease in blood pressure. This phenomenon is usually reversible; a decrease in serum urea nitrogen and creatinine concentrations is noted after discontinuation of the drug containing this combination.

In some cases, an increase in the concentration of potassium in the blood serum is observed during the use of ACE inhibitors. The risk of developing hyperkalemia when using ACE inhibitors is increased in patients with renal failure and diabetes mellitus, as well as those taking potassium-sparing diuretics, potassium preparations or other drugs that cause an increase in the concentration of potassium in the blood (for example, heparin). Simultaneous use of potassium-sparing diuretics and potassium preparations should be avoided. In addition, when using ACE inhibitors simultaneously with thiazide diuretics, the risk of developing hypokalemia is not excluded, therefore, in such cases, regular monitoring of the concentration of potassium in the blood should be carried out during therapy.

When performing hemodialysis in patients receiving ACE inhibitors, the use of dialysis membranes with high permeability (for example, AN69) should be avoided, as in such cases the risk of developing anaphylactoid reactions increases. Anaphylactoid reactions have also been observed in patients undergoing LDL apheresis with dextran sulfate. The use of either antihypertensive drugs of another class or another type of dialysis membrane should be considered.

In case of angioedema development, the drug containing this combination should be discontinued and careful medical observation should be carried out until the symptoms completely disappear. Laryngeal angioedema can be fatal. If the edema is localized on the face, special treatment is usually not required (antihistamines can be prescribed to reduce the severity of symptoms); if the edema spreads to the tongue, pharynx or larynx and there is a threat of airway obstruction, emergency therapy is required.

Caution should be exercised when performing desensitization in patients taking ACE inhibitors.

In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be carefully monitored, especially during the first month of ACE inhibitor therapy.

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

During extensive surgical interventions or during therapy with anesthetics in patients taking ACE inhibitors, an excessive decrease in blood pressure may be noted. In these cases, measures aimed at increasing the circulating blood volume are carried out.

In rare cases, when taking ACE inhibitors, a syndrome is noted that begins with the appearance of cholestatic jaundice, turning into fulminant hepatonecrosis, sometimes with a fatal outcome. The mechanism of development of this syndrome is unknown. If a patient receiving ACE inhibitor therapy develops jaundice or a marked increase in liver enzyme activity is noted, ACE inhibitor treatment should be discontinued and the patient should be monitored.

Neutropenia/agranulocytosis, thrombocytopenia and anemia have been noted in patients taking ACE inhibitors. In patients with normal renal function and in the absence of other disorders, neutropenia is rare.

In patients with autoimmune connective tissue diseases, in patients taking immunosuppressants, allopurinol and procainamide, especially in the presence of pre-existing renal impairment. Since most fatal cases of neutropenia during the use of ACE inhibitors developed in such patients, the number of leukocytes should be monitored in them before starting treatment, in the first 3 months – every 2 weeks, then – every 2 months.

In all patients, the number of leukocytes in the blood should be monitored monthly for the first 3 months after the start of therapy, then – every 2 months. If the number of leukocytes is below 4000/µl, a complete blood count should be repeated; if below 1000/µl, the drug should be discontinued, continuing to monitor the patient. Usually, the number of neutrophils recovers within 2 weeks after discontinuation of captopril. In 13% of cases of neutropenia, a fatal outcome was noted. In almost all cases, a fatal outcome of neutropenia was noted in patients with connective tissue diseases, renal or heart failure, while taking immunosuppressants, or a combination of these factors.

When using ACE inhibitors, proteinuria may be noted, mainly in patients with impaired renal function, as well as when using drugs in high doses. In most cases, proteinuria when taking captopril disappeared or its severity decreased within 6 months, regardless of whether the drug was discontinued or not. Renal function indicators (blood urea nitrogen and creatinine concentrations) in patients with proteinuria were almost always within normal limits. In patients with kidney disease, the concentration of protein in the urine should be determined before starting treatment and periodically during the course of therapy.

Sulfonamide derivatives (including Hydrochlorothiazide) can cause transient myopia and acute angle-closure glaucoma, risk factors are a history of allergy to sulfonylurea drugs or penicillin. Symptoms (sudden decrease in visual acuity, pain in the eyeball) are usually observed from several hours to several weeks after the start of treatment. If symptoms appear, this combination should be discontinued immediately; if necessary, drugs to correct intraocular pressure should be prescribed.

In all patients taking thiazide diuretics, clinical signs of water-electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia) should be identified. It is especially important to determine the content of electrolytes in the blood serum and urine in case of excessive prolonged vomiting or when administering infusion solutions. Signs of water-electrolyte imbalance may be dry mouth, thirst, weakness, lethargy, confusion, restlessness, muscle pain or cramps, muscle weakness, excessive decrease in blood pressure, oliguria, tachycardia, nausea, vomiting.

Hypokalemia can provoke or enhance the cardiotoxic effect of cardiac glycosides.

The deficiency of chloride ions is usually mild and does not require correction.

In patients with edema during hot weather, hyponatremia caused by an increase in blood volume may be observed. Fluid intake should be restricted. In cases of life-threatening hyponatremia, a sodium chloride solution is prescribed.

During therapy with thiazide diuretics, hyperuricemia or gout attacks may occur; latent diabetes mellitus may also become manifest.

Thiazide derivatives can cause a decrease in the concentration of protein-bound iodine in the blood serum without signs of thyroid dysfunction.

During the administration of thiazide diuretics, the degree of calcium excretion decreases; cases of pathological changes in the parathyroid glands accompanied by hypercalcemia and hypophosphatemia have been reported. Thiazide diuretic administration should be discontinued before testing parathyroid function.

During the administration of thiazide diuretics, an increase in the degree of magnesium excretion has been noted, which can lead to hypomagnesemia.

If fever, enlarged lymph nodes, and/or signs of laryngitis and/or pharyngitis appear, the white blood cell count should be determined immediately.

The use of thiazide diuretics may cause a positive result in doping control.

Effect on the ability to drive vehicles and mechanisms

During treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

Captopril

In patients taking diuretics, especially at the start of therapy, as well as in combination with strict sodium restriction (salt-free diets) or hemodialysis, excessive blood pressure reduction may sometimes be observed, which usually occurs within the first hour after taking the first dose of this combination. Transient excessive blood pressure reduction is not a contraindication to further therapy, which can be continued after normalization of blood pressure by increasing the blood volume.

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

Caution should be exercised when using this combination concomitantly with drugs that affect the sympathetic nervous system (e.g., ganglion blockers, alpha-adrenergic blockers).

During therapy with drugs containing Captopril, potassium-sparing diuretics (e.g., triamterene, spironolactone, amiloride), potassium preparations, potassium supplements, salt substitutes (contain significant amounts of potassium ions) should be prescribed only for proven hypokalemia, as their use increases the risk of hyperkalemia.

This combination increases the plasma concentration of digoxin by 15-20% and increases the bioavailability of propranolol.

The risk of an immunosuppressive effect increases with the combined use with procainamide, as well as with drugs that block tubular secretion (decrease in the number of leukocytes and granulocytes).

It increases the neurotoxicity of salicylates, enhances the effect of competitive non-depolarizing muscle relaxants, and ethanol.

It decreases the excretion of quinidine, reduces the effect of oral hypoglycemic drugs, norepinephrine, epinephrine, and anti-gout drugs.

It enhances the side effects of cardiac glycosides, especially when used concomitantly with drugs that increase the excretion of potassium and magnesium ions and/or delay calcium ions (e.g., diuretics, adrenal cortex hormones, laxatives, amphotericin B, carbenoxolone, penicillin G, salicylates).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) caused by the simultaneous use of ACE inhibitors and angiotensin II receptor blockers or aliskiren and aliskiren-containing drugs was associated with an increased incidence of adverse effects such as arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure).

Cimetidine, by slowing down the metabolism of captopril in the liver, increases its plasma concentration.

Hydrochlorothiazide

Indomethacin and other NSAIDs, including COX-2 inhibitors, as well as table salt, may reduce the antihypertensive effect of the drug, especially in arterial hypertension accompanied by low renin activity, and also reduce the absorption of hydrochlorothiazide. In patients with risk factors (old age, hypovolemia, use of diuretics, impaired renal function), the simultaneous use of NSAIDs (including COX-2 inhibitors) and ACE inhibitors (including Captopril) may lead to deterioration of renal function, up to acute renal failure. Renal function impairment in such cases is usually reversible.

Hydrochlorothiazide may enhance the effect of non-depolarizing muscle relaxants, and general anesthetics used in surgery (e.g., tubocurarine chloride and gallamine triethiodide), so dose adjustment of these drugs may be required. Monitoring and, if possible, correction of water and electrolyte balance before surgery is recommended.

Hydrochlorothiazide reduces the effect of therapeutically used pressor amines (e.g., norepinephrine) on the arteries but does not completely prevent it.

Anesthetics and premedication agents should be used in the lowest possible doses. If possible, Hydrochlorothiazide should be discontinued one week before surgery.

Combination with nitrates, thiazide diuretics, verapamil, beta-blockers and other antihypertensive drugs, MAO inhibitors, ganglion blockers, as well as tricyclic antidepressants, hypnotics, and ethanol enhances the severity of the hypotensive effect.

With the simultaneous use of ACE inhibitors with lithium preparations, a delay in the excretion of lithium ions, an increase in the serum lithium concentration, and, as a consequence, an enhancement of its damaging effect on the heart and central nervous system may occur. Furthermore, Hydrochlorothiazide also increases the risk of lithium toxicity. When using such combination therapy, regular monitoring of serum lithium concentration should be performed.

Drugs that are highly protein-bound enhance the diuretic effect. Dose adjustment of indirect anticoagulants, probenecid, and sulfinpyrazone may be required since Hydrochlorothiazide may suppress their action.

Hydrochlorothiazide has a hyperuricemic effect, so adjustment of anti-uricosuretic drugs may be required with simultaneous use.

Diazoxide enhances the hyperglycemic, hyperuricemic, and antihypertensive effects of thiazide diuretics, so serum uric acid and glucose concentrations should be monitored.

With the simultaneous use of oral hypoglycemic agents and insulin, an increase in their doses may be required because Hydrochlorothiazide increases blood glucose concentration.

With the simultaneous use of methyldopa, hemolysis of erythrocytes may develop.

Cholestyramine and colestipol hydrochloride may delay or reduce the absorption of hydrochlorothiazide.

Potassium salts, potassium-sparing diuretics (triamterene, amiloride, and spironolactone), and heparin contribute to the development of hyperkalemia.

Methenamine may reduce the effect of hydrochlorothiazide due to an increase in urine pH.

Carbamazepine increases the risk of symptomatic hyponatremia when used concomitantly with hydrochlorothiazide.

With the combined use of calcium salts and thiazide diuretics, the serum calcium concentration may increase due to slowed excretion. Control of serum calcium concentration and, if necessary, dose adjustment is required.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.