INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAKLOR® (TAKLOR)

Composition:

Active substance: chlortalidone;

1 tablet contains chlortalidone 25.0 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; povidone; colloidal anhydrous silicon dioxide; magnesium stearate; sodium starch glycolate (Type A).

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets from white or almost white to white with a yellowish tint, round-shaped with a flat surface, bevelled edges.

Pharmacotherapeutic group. Diuretics. Non-thiazide diuretic agents with moderately expressed activity. Simple sulfonamides. Chlortalidone. ATC code C03BA04.

Pharmacological Properties.

Pharmacodynamics.

Chlorthalidone is a long-acting thiazide-like diuretic.

Thiazide and thiazide-like diuretics, including chlorthalidone, act primarily at the level of the distal renal tubules (distal convoluted tubule), inhibiting the reabsorption of Na and Cl, thereby promoting the excretion of approximately 15% of filtered sodium, and enhancing calcium ion reabsorption, which may lead to hypercalcemia. Increased delivery of sodium ions and water to the cortical collecting tubule and increased urinary flow rate result in enhanced secretion and excretion of potassium and hydrogen ions.

High doses of chlorthalidone may increase bicarbonate excretion due to inhibition of carbonic anhydrase, leading to alkaline urine.

Acidosis or alkalosis do not significantly affect the saluretic or diuretic effect of chlorthalidone. During prolonged therapy with chlorthalidone, renal calcium excretion decreases, which may result in hypercalcemia.

The diuretic effect begins 2–3 hours after administration, reaches its peak within 4–24 hours, and may persist for up to 2–3 days.

Diuresis induced by chlorthalidone leads to a reduction in plasma volume, cardiac output, and systemic arterial pressure. In patients with arterial hypertension, chlorthalidone gradually reduces arterial pressure. The antihypertensive effect of chlorthalidone at the beginning of therapy is due to a reduction in extracellular volume, resulting in decreased peripheral resistance. During long-term treatment, extracellular volume normalizes while antihypertensive efficacy persists, which may be due to a later reduction in sodium concentration in vascular walls and, consequently, reduced sensitivity to norepinephrine.

Chlorthalidone exerts an antidiuretic effect in patients with nephrogenic diabetes insipidus. The mechanism of action has not yet been fully elucidated.

Chlorthalidone is ineffective in patients with severe renal insufficiency (creatinine clearance below 30 mL/min and/or serum creatinine above 1.8 mg/100 mL).

Pharmacokinetics.

Absorption

Chlorthalidone is absorbed relatively slowly from the gastrointestinal tract (t₅₀ of absorption is approximately 2.6 hours). The bioavailability of a 50 mg oral dose of chlorthalidone is approximately 64%, with maximum plasma concentration reached 8–12 hours after administration.

Distribution

Plasma protein binding of chlorthalidone is approximately 75%, and the volume of distribution is 4 L/kg. Only a small fraction of free chlorthalidone is detectable in plasma due to extensive accumulation in erythrocytes and high plasma protein binding.

Metabolism and Elimination

Approximately 70% of the administered dose is excreted in urine and feces within 120 hours, predominantly in unchanged form. Hepatic metabolism and biliary excretion represent only a minor elimination pathway. The mean elimination half-life is approximately 50 hours.

Special Patient Populations

Elimination of chlorthalidone is slower in elderly patients compared to healthy young volunteers, although absorption is similar.

Chlorthalidone crosses the placental barrier and is excreted into breast milk.

Clinical characteristics.

Indications.

Treatment

of arterial hypertension;
of cardiac, hepatic, and nephrogenic edema;
of chronic heart failure;
of nephrogenic diabetes insipidus, when other therapeutic measures are excluded.

Contraindications.

Known hypersensitivity to chlorthalidone, other thiazides, or sulfonamide derivatives (possibility of cross-reactions; use with caution in patients with bronchial asthma) or to any of the components of the drug;
anuria (urine output less than 100 mL/day);
severe renal insufficiency (markedly reduced diuresis, creatinine clearance <30 mL/min and/or serum creatinine >1.8 mg/100 mL);
glomerulonephritis;
severe hepatic insufficiency (hepatic precoma and coma);
hypercalcemia;
therapy-resistant hypokalemia or conditions with increased potassium loss;
severe hyponatremia;
symptomatic hyperuricemia.

Interaction with other medicinal products and other forms of interaction.

Not recommended combinations:

Lithium

Concomitant use of chlorthalidone and lithium may enhance the cardiotoxic and neurotoxic effects of lithium due to reduced lithium excretion. If diuretic therapy is essential, careful monitoring of blood lithium levels and dose adjustment are required.

Combinations requiring special precautionary measures:

Medicinal products that may cause torsade de pointes:

Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
Class III antiarrhythmics (e.g., amiodarone, sotalol);
certain antipsychotics: phenothiazines (e.g., chlorpromazine, ciampine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g., amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g., droperidol, haloperidol);
others: bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, intravenous vincaamine.

When these medicinal products are administered concomitantly with chlorthalidone, especially in the presence of hypokalemia, there is an increased risk of ventricular arrhythmia, particularly torsade de pointes. Before administering the above-mentioned medicinal products together with chlorthalidone, serum potassium levels should be determined and corrected. Regular ECG monitoring and plasma electrolyte determinations are required. In the presence of hypokalemia, it is recommended to use medicinal products that do not induce torsade de pointes.

ACE inhibitors (e.g., captopril, enalapril)

Concomitant use of chlorthalidone and ACE inhibitors (e.g., captopril, enalapril) may lead to a significant reduction in arterial pressure and impairment of renal function, especially at the beginning of treatment. Therefore, diuretic therapy should be discontinued 2–3 days before initiating ACE inhibitor treatment to reduce the likelihood of hypotension at the start of therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., indomethacin, acetylsalicylic acid), including COX-2 inhibitors, salicylates

NSAIDs (e.g., indomethacin, acetylsalicylic acid), including COX-2 inhibitors and salicylates, may reduce the antihypertensive and diuretic effects of chlorthalidone. When high doses of salicylates are used, the toxic effects of salicylates on the central nervous system may be enhanced. In patients developing hypovolemia during chlorthalidone therapy, concomitant use of NSAIDs may precipitate acute renal failure.

Potassium-depleting diuretics (e.g., furosemide), glucocorticoids, adrenocorticotropic hormone (ACTH), carbenoxolone, penicillin G, salicylates, stimulant laxatives, intravenous amphotericin B

Concomitant use of chlorthalidone with these medicinal products may lead to electrolyte imbalance, particularly increased potassium loss. This is especially important during concomitant treatment with cardiac glycosides. Plasma potassium levels should be regularly monitored and corrected if necessary.

Other diuretics, other antihypertensive agents (e.g., beta-blockers, calcium channel blockers, ACE inhibitors, vasodilators, methyldopa, guanethidine), nitrates, barbiturates, phenothiazines, tricyclic antidepressants, alcohol

The hypotensive effects of chlorthalidone may be enhanced when these medicinal products are used or alcohol is consumed.

Cardiac glycosides

If hypokalemia and/or hypomagnesemia develop during concomitant use of chlorthalidone and cardiac glycosides, myocardial sensitivity to cardiac glycosides increases, and the effects and adverse reactions of cardiac glycosides are correspondingly enhanced.

Possible interactions with the following medicinal products

Insulin, oral antidiabetic agents, uricosuric agents, sympathomimetics (norepinephrine [noradrenaline], adrenaline [epinephrine])

The effects of these medicinal products may be reduced when used concomitantly with chlorthalidone. Dose adjustments of insulin and oral antidiabetic agents may be required.

Non-depolarizing (curare-like) muscle relaxants (e.g., tubocurarine)

The effect of curare-like muscle relaxants may be potentiated or prolonged by chlorthalidone. If chlorthalidone cannot be discontinued prior to administration of curare-like muscle relaxants, the anesthesiologist should be informed about chlorthalidone therapy.

Antineoplastic agents (e.g., cyclophosphamide, fluorouracil, methotrexate)

Chlorthalidone may reduce the renal excretion of cytostatic agents (e.g., cyclophosphamide, fluorouracil, methotrexate). When cytostatic agents are used concomitantly, increased bone marrow toxicity (particularly development of granulocytopenia) may be expected.

Cholestyramine, colestipol

Concomitant use of cholestyramine or colestipol reduces the absorption of chlorthalidone.

Therefore, Taklor® should be taken at least 1 hour before or 4–6 hours after taking these medicinal products.

Calcium salts, vitamin D

Concomitant use of chlorthalidone with calcium or vitamin D may lead to increased serum calcium levels due to reduced excretion.

Allopurinol

Taklor® may enhance hypersensitivity reactions to allopurinol.

Amantadine

Chlorthalidone may increase the risk of adverse effects of amantadine.

Beta-adrenergic blockers, diazoxide

There is an increased risk of hyperglycemia when Taklor is used concomitantly with beta-blockers or diazoxide.

Cyclosporine

Concomitant use of cyclosporine may increase the risk of hyperuricemia and gout-related complications.

Anticholinergic agents (e.g., atropine, biperiden)

Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide diuretics, probably due to reduced gastrointestinal motility and delayed gastric emptying.

Special precautions.

Renal impairment

Taklor® should be used with caution in patients with kidney disease.

In patients with mild to moderate renal impairment (creatinine clearance of 30–60 mL/min and/or serum creatinine of 1.1–1.8 mg/100 mL), dosage adjustment should be made according to therapeutic requirements and tolerability (see section "Dosage and administration").

In patients with severe renal impairment (creatinine clearance below 30 mL/min and/or serum creatinine above 1.8 mg/100 mL), thiazide diuretics and thiazide-like agents, including chlorthalidone, lose their diuretic effect (see section "Contraindications").

Thiazide and thiazide-like diuretics, including chlorthalidone, may cause azotemia in patients with kidney disease. Cumulative drug effects may occur in patients with impaired renal function. If renal insufficiency progresses, as indicated by increasing blood nitrogen levels without protein nitrogen, a decision on the appropriateness of continuing treatment should be made. Discontinuation of diuretic therapy should be considered.

Chronic diuretic abuse may lead to a pseudohyperaldosteronism syndrome (Bartter-like syndrome), accompanied by edema development. Edema is a manifestation of increased renin levels, leading to secondary hyperaldosteronism.

The antihypertensive effect of ACE inhibitors is enhanced by agents that increase plasma renin activity (diuretics). Therefore, diuretic therapy should be discontinued 2–3 days before initiating ACE inhibitor treatment to reduce the risk of hypotension at the beginning of therapy.

Hepatic impairment

Taklor® should be used with caution in patients with impaired liver function or progressive liver disease, as even minor disturbances in fluid and electrolyte balance caused by thiazide diuretics, especially in patients with hepatic cirrhosis, may precipitate hepatic coma (see section "Contraindications").

Metabolic and endocrine disorders

Patients with diabetes mellitus or gout require special attention.

Therapy with thiazide and thiazide-like diuretics, including chlorthalidone, may affect glucose tolerance. In patients with diabetes mellitus, metabolic disturbances may occur, possibly requiring adjustment of insulin or oral hypoglycemic agent dosage. Latent diabetes mellitus may be unmasked during chlorthalidone therapy.

Serum uric acid levels may increase during chlorthalidone treatment, although gout attacks are rarely observed during long-term therapy.

Mild and partially reversible increases in total cholesterol, low-density lipoprotein (LDL), or plasma triglycerides have been observed in patients receiving prolonged treatment with thiazide and thiazide-like diuretics.

Electrolyte disturbances

Serum electrolytes (especially potassium, sodium, calcium) should be monitored at regular intervals during diuretic therapy.

Regular monitoring of serum electrolytes is particularly important in elderly patients, patients with ascites due to liver cirrhosis, and patients with nephrogenic edema. Under these conditions, Taklor® should be used only under close supervision and only in patients whose serum potassium levels are within normal limits and who show no signs of dehydration.

Thiazide and thiazide-like diuretics, including chlorthalidone, may cause disturbances in fluid and electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Early signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle weakness, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may also increase myocardial sensitivity to the toxic effects of cardiac glycosides.

The highest risk of hypokalemia occurs in patients with liver cirrhosis, those with high diuresis, those with insufficient electrolyte intake, and those receiving corticosteroids, ACTH, cardiac glycosides, or laxatives (see section "Interaction with other medicinal products and other forms of interaction"). Such patients require careful monitoring.

As with all thiazide and thiazide-like diuretics, chlorthalidone-induced kaliuresis is dose-dependent, and its extent varies individually. With a daily dose of 25 mg, serum potassium concentration decreases on average by 0.5 mmol/L. During long-term treatment, serum potassium levels should be measured at the beginning of therapy and then after 3–4 weeks. Thereafter, in the absence of other factors affecting potassium levels (e.g., vomiting, diarrhea, changes in renal function), serum potassium can be monitored every 4–6 months.

If necessary, chlorthalidone may be combined with oral potassium supplements or potassium-sparing diuretics (e.g., triamterene). In combined therapy, serum potassium levels should be checked. If hypokalemia is accompanied by clinical symptoms (e.g., muscle weakness, paralysis, ECG changes), chlorthalidone therapy should be discontinued.

The combination of chlorthalidone with potassium supplements or potassium-sparing diuretics should not be used in patients concurrently receiving ACE inhibitors, unless such combination is life-saving.

In hot weather, dilutional hyponatremia may occur in patients with edema. Chloride deficiency is usually mild and does not require treatment.

Thiazide and thiazide-like diuretics, including chlorthalidone, may reduce urinary calcium excretion and cause transient, mild increases in serum calcium without known disturbances in calcium metabolism. Marked hypercalcemia may indicate occult hyperparathyroidism. Chlorthalidone should be discontinued before assessing parathyroid gland function.

Thiazide and thiazide-like diuretics have been shown to enhance urinary magnesium excretion, which may lead to hypomagnesemia.

Heart failure

In patients with severe heart failure, chlorthalidone absorption may be reduced.

Others

Hypersensitivity reactions may occur in patients with a history of allergy or bronchial asthma, as well as in those without a history of allergic conditions.

Special precautions

During chlorthalidone therapy, serum electrolytes (especially potassium, sodium, calcium ions), creatinine and urea, serum lipids (cholesterol and triglycerides), uric acid, and blood glucose should be monitored regularly.

Adequate fluid intake should be ensured during chlorthalidone therapy, and a diet rich in potassium (bananas, vegetables, nuts) should be consumed due to increased potassium loss.

Treatment of high blood pressure with Taklor requires regular medical check-ups.

Taklor therapy should be discontinued in case of:

Persistent electrolyte imbalances unresponsive to treatment;
Hypersensitivity reactions;
Severe gastrointestinal complaints;
Disorders of the central nervous system;
Pancreatitis;
Blood disorders (anemia, leukopenia, thrombocytopenia);
Acute cholecystitis;
Development of vasculitis;
Worsening of pre-existing myopia;
Serum creatinine levels above 1.8 mg/100 mL or creatinine clearance below 30 mL/min.

Use for illicit purposes

Chlorthalidone use may lead to positive doping test results. Negative health consequences and serious health risks associated with using chlorthalidone as a doping agent cannot be ruled out.

Excipients

If intolerance to certain sugars is known, consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

Chlorthalidone should not be used during pregnancy and lactation.

Chlorthalidone, like other diuretics, may reduce placental blood flow. Thiazides and thiazide analogs also reach the fetal circulation and may cause electrolyte imbalance. Cases of thrombocytopenia in newborns associated with thiazide diuretic use have been reported.

Breastfeeding period

Chlorthalidone passes into breast milk. Women who are breastfeeding should not take chlorthalidone or should refrain from breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Due to the occurrence of various individually determined reactions, reaction speed may be impaired, potentially leading to inability to actively participate in traffic, operate machinery, or work without stable support. This is particularly pronounced at the beginning of treatment, when increasing the dose, when combined with other antihypertensive agents, when switching medications, and when taken concomitantly with alcohol.

Method of Administration and Dosage.

Dosage depends on the clinical condition and the patient's response to therapy. The lowest effective dose is recommended. Gradual dose titration is recommended for patients with ischemic heart disease or cerebral atherosclerosis, as well as after a myocardial infarction or hemorrhagic stroke. Chlorthalidone should be taken orally with sufficient fluid (1 glass of water). If a single daily dose is prescribed, it should be taken in the morning with breakfast; for twice-daily administration, doses should be taken in the morning and evening. If necessary, the dose may be increased no sooner than after 2–3 weeks.

The duration of treatment is determined by the physician. Discontinuation of therapy should be carried out by gradually reducing the dose.

Use in adult patients:

Arterial hypertension

Initial dose: 12.5*–50 mg once daily. Maintenance dose: 25–50 mg of chlorthalidone every other day.

Edema of specific origin and heart failure

Recommended initial dose: 50–100 mg once daily. Maximum daily dose: 200 mg. Maintenance dose: 25–50 mg of chlorthalidone daily.

Nephrogenic diabetes insipidus

Initial dose: 100 mg twice daily. During continued therapy, the daily maintenance dose may be reduced to 50 mg daily.

Elderly patients and patients with impaired renal function

For elderly patients and patients with mild renal impairment, the minimal effective dose of chlorthalidone is recommended.

In elderly patients and/or patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min and/or serum creatinine 1.1–1.8 mg/100 mL), dosage should be adjusted according to therapeutic requirements and tolerability. Thiazide and thiazide-like diuretics and thiazide analogs, including chlorthalidone, lose their diuretic effect when creatinine clearance is <30 mL/min and/or serum creatinine exceeds 1.8 mg/100 mL (see section "Contraindications").

Patients with impaired liver function

The dose of chlorthalidone should be appropriately titrated in patients with impaired liver function (see section "Special Warnings and Precautions for Use"). Taklor® should not be used in patients with severe hepatic impairment (see section "Contraindications").

Patients with heart failure

In patients with decompensated heart failure, chlorthalidone is poorly absorbed.

*Chlorthalidone-containing preparations in corresponding dosages should be used.

Children

Experience with the use of this medicinal product in the pediatric population is limited; therefore, chlorthalidone should not be used in children.

Overdose.

Symptoms of overdose

The clinical picture of acute or chronic overdose depends on the degree of fluid and electrolyte loss.

Possible symptoms include:

Dizziness and weakness, nausea, drowsiness, muscle pain and muscle cramps (e.g., calf muscle cramps), headache, tachycardia, hypotension, orthostatic symptoms, and electrolyte disturbances (hypokalemia and/or hyponatremia).

Dehydration and hypovolemia may lead to hemoconcentration, seizures, drowsiness, lethargy, confusion, collapse, and acute kidney injury.

Hypokalemia may cause fatigue, muscle weakness, paresthesia, paralysis, apathy, flatulence, constipation, or cardiac arrhythmias. Severe potassium loss may result in paralytic ileus or loss of consciousness up to hypokalemic coma.

Treatment. If signs of overdose are present, treatment should be discontinued immediately. In addition to general supportive measures, vital parameters should be monitored and corrected as necessary in an intensive care setting. There is no specific antidote for chlorthalidone. If the patient is conscious, gastric lavage should be performed and sorbents administered to reduce absorption. Intravenous administration of fluids and electrolytes, monitoring of blood pressure, fluid and electrolyte balance, and metabolic functions may be required based on clinical indications.

Adverse Reactions

Adverse reactions have been classified by system organ class and frequency of occurrence.

The frequency of adverse reactions is defined as follows:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Rare: thrombocytopenia, leukopenia, agranulocytosis, and eosinophilia.

Metabolism and nutrition disorders

Very common: hypokalemia, hyperuricemia (which may lead to gout flare-ups), increased blood cholesterol and triglyceride levels – primarily during administration of high doses.

Common: hyponatremia, hypomagnesemia, hyperglycemia and glucosuria, worsening of condition in patients with diabetes mellitus, manifestation of latent diabetes mellitus, increased blood urea and creatinine levels (especially at the beginning of treatment).

Rare: hypercalcemia.

Very rare: hypochloremic alkalosis.

Nervous system disorders

Common: headache, dizziness, and weakness.

Rare: paresthesia.

Eye disorders

Rare: visual disturbances, decreased tear production.

Cardiac and vascular disorders

Common: hypotension, orthostatic hypotension, palpitations.

Rare: cardiac arrhythmias.

Respiratory, thoracic and mediastinal disorders

Very rare: idiopathic (allergic) pulmonary edema, dyspnea.

Gastrointestinal disorders

Common: loss of appetite, dry mouth, mild gastrointestinal disturbances, nausea, vomiting, upper abdominal pain and cramps, constipation, and diarrhea.

Very rare: pancreatitis.

Hepatobiliary disorders

Rare: intrahepatic cholestasis or jaundice.

Skin and subcutaneous tissue disorders

Common: urticaria and other forms of skin rash, pruritus.

Rare: photosensitization, allergic vasculitis.

Musculoskeletal and connective tissue disorders

Common: muscle hypotonia, muscle cramps.

Renal and urinary disorders

Very rare: allergic interstitial nephritis.

Reproductive system and breast disorders

Common: impotence

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 4 years.

Storage conditions.

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

Packaging. 10 tablets per blister, 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of operations.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.

Tacloor