Atenol-n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATELOL-H (ATENOL-H)

Composition:

Active substances: atenolol, chlortalidone;

One film-coated tablet contains atenolol 100 mg, chlortalidone 25 mg;

Excipients: anhydrous lactose (166 mg), corn starch, povidone, sodium lauryl sulfate, talc, magnesium stearate, colloidal anhydrous silicon dioxide;

Film coating: talc, hypromellose, titanium dioxide (E 171), macrogol 400, macrogol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white or almost white, round, biconvex, with a break line on one side.

Pharmacotherapeutic group. Selective β1-adrenoreceptor blockers in combination with other diuretics. Atenolol and other diuretics. ATC code C07CB03.

Pharmacological Properties.

Pharmacodynamics.

This combination antihypertensive agent combines the effects of the cardioselective beta-adrenoblocker atenolol and the diuretic chlorthalidone.

Atenolol is a cardioselective β1-adrenoblocker. It has no intrinsic sympathomimetic or membrane-stabilizing activity. It reduces heart rate, stroke volume, and cardiac output. After oral administration, the maximum effect is achieved within 2–4 hours and lasts up to 24 hours.

Atenolol selectively blocks myocardial beta-adrenergic receptors, thereby reducing the stimulatory effects on the myocardium of the sympathetic nervous system and circulating catecholamines. Due to its cardioselectivity and hydrophilicity, atenolol less frequently induces bronchospasm, disturbances in peripheral circulation, sleep, or emotional status. However, cardioselectivity is lost when high doses are administered. Atenolol reduces the automaticity of the sinoatrial node, heart rate, atrioventricular conduction velocity, myocardial contractility and excitability, myocardial oxygen demand, cardiac output, and systolic and diastolic blood pressure at rest and during exertion. With regular use, it causes a gradual reduction in arterial pressure. Antihypertensive activity of atenolol does not diminish during prolonged treatment.

Chlorthalidone is a thiazide-like diuretic that increases the excretion of sodium, chloride ions, and an equivalent amount of water from the body. The onset of action occurs within 2 hours, with peak effect observed within 2–6 hours. The duration of effect after oral administration lasts from 24 to 72 hours.

Chlorthalidone inhibits the reabsorption of sodium, chloride, and water in the proximal portion of the distal tubules and partially affects the proximal tubules. Under its influence, excretion of potassium, magnesium, and bicarbonate is increased, while excretion of uric acid and calcium ions is reduced. It contributes to lowering elevated arterial pressure by decreasing sodium content in vascular walls and reducing their sensitivity to vasoconstrictive stimuli.

Both components mutually potentiate each other's hypotensive effects and, due to their prolonged pharmacological action, provide a hypotensive effect lasting at least 24 hours after a single daily dose.

Pharmacokinetics.

Absorption. After oral administration, approximately 50% of the atenolol dose is absorbed from the gastrointestinal tract. Food intake does not significantly affect absorption. Maximum plasma concentration is reached within 2–4 hours.

Distribution. Plasma protein binding of atenolol is approximately 6–16%. Chlorthalidone is 90% bound to plasma proteins and erythrocytes.

Metabolism and Elimination. Atenolol is practically not metabolized in the liver. It is primarily excreted by the kidneys (90%). The elimination half-life of atenolol is approximately 6–9 hours. It poorly penetrates the blood-brain barrier but crosses the placenta and is excreted in breast milk. After administration of a 50–100 mg dose, beta-adrenergic blocking and antihypertensive effects last at least 24 hours. Chlorthalidone is excreted in feces and urine. Its elimination half-life ranges from 24 to 55 hours and is prolonged in elderly patients and those with renal insufficiency.

Clinical characteristics.

Indications.

Arterial hypertension.

Contraindications.

Hypersensitivity to any component of the drug. Marked sinus bradycardia, arterial hypotension, metabolic acidosis, severe peripheral circulatory disorders, second- or third-degree atrioventricular block, sinoatrial block, sick sinus syndrome, cardiogenic shock, acute heart failure, decompensated chronic heart failure, untreated pheochromocytoma, anuria, renal and hepatic insufficiency, precoma associated with Addison's disease, hypokalemia, cardiac glycoside intoxication, bronchial asthma, bronchoobstructive syndrome, gout. The drug is contraindicated in patients receiving verapamil within 48 hours. Hyponatremia, hypercalcemia, concomitant use of lithium-containing drugs. Concurrent use of monoamine oxidase inhibitors (except MAO-B inhibitors).

Interaction with other medicinal products and other forms of interaction.

Atenol-N, when used concomitantly, potentiates the effects of other antihypertensive agents. In patients treated with Atenol-N together with catecholamines (e.g., reserpine), arterial hypotension and/or bradycardia have been observed during examinations, which may lead to dizziness, syncope, or orthostatic hypotension.

Concomitant use with dihydropyridines (e.g., nifedipine) may increase the risk of arterial hypotension, particularly in patients with chronic heart failure.

Calcium channel blockers also have an additive effect when used with Atenol-N.

Cardiac glycosides and atenolol slow heart rate and impair atrioventricular conduction. Concomitant use with cardiac glycosides increases effects on the sinoatrial node and intraventricular conduction. Concurrent use with cardiac glycosides intensifies hypokalemia manifestations; therefore, laboratory monitoring is required. Caution should be exercised when prescribing the drug to patients taking cardiac glycosides along with an inadequate diet (not meeting the body’s potassium requirements) or those with gastrointestinal disorders.

Atenol-N enhances the antihypertensive effect of hydralazine and prazosin; using such combinations leads to a greater reduction in arterial blood pressure than administration of either drug alone.

Concomitant use of β1-adrenoblockers with calcium channel blockers that cause negative inotropic effects (e.g., verapamil, diltiazem) may enhance this effect, especially in patients with reduced myocardial contractility and/or sinoatrial or atrioventricular conduction disturbances. This may result in severe arterial hypotension, marked bradycardia, and heart failure. Intravenous administration of "slow" calcium channel blockers should not be used within 48 hours after discontinuation of β1-adrenoblockers.

Concomitant therapy with dihydropyridines (e.g., nifedipine) may increase the risk of arterial hypotension; signs of circulatory impairment may appear in patients with latent heart failure.

β1-adrenoblockers may exacerbate rebound hypertension that may occur after discontinuation of clonidine. When Atenol-N and clonidine are used concomitantly, clonidine should be discontinued only several days after stopping Atenol-N.

Atenolol may mask clinical symptoms (manifestations) of hypoglycemia. When Atenol-N is used concomitantly with insulin or oral antidiabetic agents, their hypoglycemic effect increases. Regular monitoring of blood glucose levels is necessary.

Concomitant use of Atenol-N with antihypertensive agents from different classes, tricyclic antidepressants, barbiturates, ethanol, diuretics, phenothiazines, nitrates, and peripheral vasodilators increases their hypotensive effect.

Concomitant use of Atenol-N with reserpine, methyldopa, clonidine, or verapamil may lead to bradycardia.

β1-adrenoblockers should be prescribed with caution in combination with Class I antiarrhythmic agents (e.g., disopyramide), as the cardiodepressive effects of these drugs may be mutually additive. When used with amiodarone, there is a risk of impaired automaticity, conduction, and myocardial contractility.

The use of inhalational anesthetics (e.g., halothane, methoxyflurane) together with Atenol-N increases the risk of myocardial depression and arterial hypotension; therefore, Atenol-N should be discontinued several days before anesthesia, or an anesthetic with minimal negative inotropic effect should be selected.

Concomitant use of Atenol-N and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, indomethacin), as well as estrogens, reduces the effectiveness of atenolol.

The interaction of atenolol (a component of Atenol-N) with quinolones increases atenolol bioavailability; with adrenaline, it enhances vasoconstrictor action followed by bradycardia; with lidocaine, it increases lidocaine levels; with amiodarone, it increases the risk of sinoatrial or atrioventricular node dysfunction (should not be prescribed); with cimetidine, atenolol clearance decreases, leading to elevated plasma levels and enhanced therapeutic effect. When used concomitantly with ephedrine or theophylline, mutual suppression of therapeutic effects may occur.

Concomitant use of diuretics (chlorthalidone, a component of Atenol-N) with lithium-containing drugs reduces renal lithium clearance.

Concomitant use with glucocorticoids, amphotericin, and furosemide promotes increased potassium excretion.

Smoking cessation enhances the therapeutic effect of atenolol due to reduced metabolism and increased blood levels of the drug.

Cimetidine may increase the drug concentration in blood.

Alcohol potentiates the effect of the drug.

Propafenone enhances the effect of atenolol, a component of the drug.

MAO inhibitors enhance the effect of chlorthalidone, a component of the drug.

Cholestyramine reduces the effect of chlorthalidone, a component of the drug.

Use of Atenol-N with potassium-containing preparations reduces the effect of the latter.

When Atenol-N is used concomitantly with:

• central nervous system depressants, an enhanced sedative effect is observed;
• lithium – enhanced effect of the latter;
• narcotic analgesics – enhanced narcotic effect, potentially dangerous depression;
• oral hypoglycemic agents, insulin – enhanced effect of the latter;
• anticholinesterase agents, angiotensin-converting enzyme inhibitors (captopril, enalapril, lisinopril) – increased blood potassium levels.

Special precautions for use.

Treatment with the drug should be carried out under medical supervision.

The drug is not intended for the treatment of angina attacks.

Use with caution in patients with first-degree AV block, pulmonary emphysema, fluid and electrolyte imbalances, gastrointestinal disorders, or hypoglycemia.

In patients with a history of bronchial asthma who are receiving thiazides, hypersensitivity reactions may occur. There have been reports of systemic lupus erythematosus exacerbation. The antihypertensive effects of thiazides may be enhanced in patients after sympathectomy.

Heart failure. In chronic heart failure, sympathetic nervous system stimulation is necessary to maintain circulatory function. β1-receptor blockade poses a potential risk of further depressing myocardial contractility and may lead to more severe heart failure. Atenol-N should be used with caution in patients with chronic heart failure controlled with digitalis and/or diuretics. Digitalis preparations and atenolol both slow atrioventricular conduction.

In patients without a history of heart failure, prolonged myocardial depression by β1-blockers may in some cases lead to heart failure. If early signs of worsening heart failure occur, the drug should be discontinued and medical advice sought. If heart failure progresses despite appropriate therapy, Atenol-N should be withdrawn.

Renal and hepatic impairment. Since atenolol is excreted by the kidneys, the drug should not be used in severe renal dysfunction.

In patients with impaired liver and/or kidney function, the functional status should be monitored regularly. In patients with renal insufficiency, the drug may provoke azotemia. Because cumulative effects may develop with reduced renal function, and if renal function continues to deteriorate, treatment with Atenol-N should be discontinued.

In patients with impaired liver function or progressive liver disease, even minor disturbances in fluid and electrolyte balance may precipitate hepatic coma. Therefore, Atenol-N should be prescribed with caution in such patients. Serum creatinine levels should be monitored periodically in patients with renal impairment.

Ischemic heart disease. Abrupt discontinuation of some β1-blockers in patients with ischemic heart disease may provoke angina, and in some cases myocardial infarction. Therefore, discontinuation of therapy with this drug in such patients should be done cautiously and only under medical supervision.

Even in the absence of angina, patients undergoing planned discontinuation of Atenol-N should remain under medical supervision and minimize physical exertion. Treatment with Atenol-N should be resumed if withdrawal symptoms occur.

Since ischemic heart disease is common and may be unrecognized, abrupt discontinuation of Atenol-N should be avoided even in patients treated for arterial hypertension.

Concomitant use of calcium channel blockers. Bradycardia, atrioventricular block (including potentially fatal left ventricular effects), and increased diastolic pressure may occur when β1-blockers are used concomitantly with verapamil or diltiazem. Patients with pre-existing disturbances in intraventricular conduction or left ventricular dysfunction are particularly sensitive to this effect.

Bronchial obstructive syndrome. β1-blockers should not be used in patients with bronchial obstructive syndrome.

Since Atenol-N is a relatively selective β1-adrenoblocker, it may be used cautiously in patients with bronchial obstructive syndrome who do not respond to or cannot tolerate other medications or antihypertensive therapies. Because selective β1-adrenoblockers are not absolutely selective, Atenol-N should be used at the lowest possible doses, and β2-adrenergic agonists should be available. If dose escalation is necessary, the dose should be fractionated to achieve lower peak plasma levels.

β1-blockers should not be used in patients with bronchial diseases. However, due to its relative selectivity, Atenol-N may be cautiously used when necessary in patients with bronchospastic disorders.

Anesthesia and major surgery. As with other β1-receptor blockers, discontinuation of the drug may be required before surgical procedures. In such cases, at least 48 hours should elapse between the last dose and anesthesia. If treatment continues, caution should be exercised when using anesthetic agents. If vagal dominance occurs, it may be counteracted with atropine (1–2 mg intravenously).

β1-blockers are competitive inhibitors of β1-receptor agonists, and their cardiac effects may be completely reversed by agents such as dobutamine or isoproterenol.

Analgesics should be prescribed with caution together with Atenol-N.

The anesthesiologist should carefully select analgesics with minimal negative inotropic activity, if possible. Concomitant use of β-adrenergic blockers with anesthetic agents may blunt tachycardia and increase the risk of arterial hypotension.

Analgesics that cause myocardial depression should be avoided.

Metabolism and endocrine disorders. Atenol-N should be used with caution in patients with diabetes mellitus. β1-blockers may mask tachycardia associated with hypoglycemia or other symptoms such as dizziness and sweating.

At recommended doses, atenolol does not potentiate insulin-dependent hypoglycemia and, unlike non-selective β1-blockers, does not delay the restoration of normal blood glucose levels.

Insulin requirements in diabetic patients may be increased, decreased, or unchanged.

Latent diabetes mellitus may manifest during treatment with chlorthalidone.

β1-adrenergic blockers may mask certain clinical symptoms of hyperthyroidism (e.g., tachycardia). Abrupt discontinuation of β-blocker therapy may provoke exacerbation of thyroid disease; therefore, in patients suspected of developing thyrotoxicosis, the decision to discontinue Atenol-N or to implement close monitoring should be considered.

Since thiazides reduce calcium excretion, Atenol-N should be discontinued before parathyroid function tests. Pathological changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed in patients on long-term thiazide therapy; however, typical complications of hyperparathyroidism such as nephrolithiasis, bone atrophy, and peptic ulcer have not been reported.

Hyperuricemia or acute gout may occur in some patients receiving thiazide therapy.

Untreated pheochromocytoma. Atenol-N should not be used in patients with untreated pheochromocytoma. When prescribing the drug to patients with pheochromocytoma, α-adrenergic blockers must be administered first (to prevent hypertensive crisis).

Fluid and electrolyte balance. Periodic monitoring of electrolyte levels to detect possible imbalances should be performed at appropriate intervals.

Patients should be monitored for clinical signs of fluid and electrolyte imbalance, such as hyponatremia, hypochloremic alkalosis, and hypokalemia, and creatinine levels should be monitored.

Electrolyte measurement in urine is particularly important in patients with excessive vomiting or receiving parenteral fluids.

Warning signs or symptoms of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Monitoring potassium levels is advisable, especially in elderly patients, patients receiving digitalis for heart failure, patients with unbalanced diets, or those with gastrointestinal complaints.

Hypokalemia may develop during rapid diuresis, in severe cirrhosis, or during concomitant use of corticosteroids or ACTH (adrenocorticotropic hormone).

Oral electrolyte intake may also promote hypokalemia. Hypokalemia may increase myocardial sensitivity or enhance the toxic effects of digitalis preparations (e.g., increased ventricular irritability). Hypokalemia can be reduced or corrected by potassium-containing supplements or potassium-rich foods.

Any chloride deficit during thiazide therapy is usually mild and does not require specific treatment, except in exceptional circumstances (e.g., liver or kidney disease).

Dilutional hyponatremia may occur in edematous patients during hot weather; appropriate management involves primarily fluid restriction rather than salt restriction, except in rare cases where hyponatremia is life-threatening.

In cases of excessive salt depletion, the drug may be an alternative treatment of choice.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Drugs containing sulfonamide or sulfonamide derivatives may cause idiosyncratic reactions leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute decrease in visual acuity or eye pain and typically occur within hours to weeks after starting the drug.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, medical, pharmacological, or surgical interventions may be required. Risk factors for developing acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

General disorders.

Atenol-N may worsen peripheral arterial circulation.

Treatment with atenolol may alter results of certain laboratory tests: increased levels of lipoproteins, cholesterol, and potassium in blood serum, and increased levels of catecholamines and their metabolites in urine and blood.

Although a causal link between atenolol use and depression has not been established, the drug should be used cautiously in such patients.

Atenolol should be prescribed in lower doses to elderly patients, especially those with renal impairment. Alcohol consumption should be avoided during atenolol therapy.

The drug should be used cautiously during prolonged fasting and intense physical exertion (risk of severe hypoglycemia).

Excipients

The medicinal product contains lactose. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicine.

Use during pregnancy or breastfeeding.

The drug is contraindicated in women during pregnancy or breastfeeding, as atenolol crosses the placenta and is excreted in breast milk.

Ability to affect reaction speed when driving or operating machinery.

Due to the possibility of dizziness during treatment, patients should refrain from driving vehicles or performing tasks requiring high attention.

Dosage and Administration.

Atenol-N is intended for treatment of adult patients. The tablets should be taken orally before meals, without chewing, with water. It is advisable to take the medication at the same time every day.

Dosage and duration of treatment are determined individually by a physician, depending on the therapeutic response achieved.

Atenol-N is not intended for initial therapy of arterial hypertension. The drug is prescribed when monotherapy has proven ineffective.

The usual initial dose is 50 mg/12.5 mg once daily. If the therapeutic effect is insufficient, Atenol-N 100 mg/25 mg one tablet once daily may be prescribed. In most patients with arterial hypertension, administration of one tablet of Atenol-N (atenolol 100 mg and chlorthalidone 25 mg) once daily provides adequate therapeutic effect. Further dose increases generally do not result in additional blood pressure reduction or produce only minimal additional benefit; however, if necessary, another antihypertensive agent may be added.

Maximum therapeutic effect is usually achieved within 1–2 weeks of treatment initiation. Discontinuation of the drug should be carried out gradually. Abrupt withdrawal may lead to withdrawal syndrome.

Elderly patients may require lower doses of the drug (with regard to atenolol), as determined by the physician.

In patients with impaired renal function, dosage regimen depends on the degree of glomerular filtration rate reduction and creatinine clearance values (see table).

Creatinine clearance (mL/min)	Maximum dose
15–35	50 mg daily or 100 mg every other day
< 15	50 mg every other day
hemodialysis	50 mg daily immediately after dialysis

Children.

Safety and efficacy of the drug in children have not been established. Do not use in children.

Overdose.

Symptoms: bradycardia, second–third degree atrioventricular block, acute heart failure, arterial hypotension, respiratory depression, arrhythmias, loss of consciousness, hypoglycemia, bronchospasm, seizures, increased drowsiness, dizziness, nausea, hypovolemia, electrolyte disturbances with cardiac arrhythmias and muscle spasms.

Treatment: discontinue the drug. Monitor and correct vital functions. In addition to gastric lavage and administration of adsorbents, the following measures are recommended when necessary: excessive bradycardia may be treated by intravenous administration of 1–2 mg atropine and/or pacemaker insertion. If necessary, an intravenous bolus of 10 mg glucagon may be administered. This procedure may be repeated or followed by intravenous infusion of glucagon at a rate of 1–10 mg/hour, depending on the response obtained. If there is no response to glucagon or if glucagon is unavailable, intravenous administration of the adrenomimetic agent dobutamine at a dose of 5–10 mcg/kg/min may be used. Due to its positive inotropic effect, dobutamine may also be used to treat arterial hypotension and acute heart failure. The indicated doses may be insufficient to counteract cardiac symptoms related to β1-adrenergic blockade in cases of significant overdose. Therefore, if necessary, the dose of dobutamine may be increased until the desired response is achieved, according to the patient's clinical condition.

Maintain normal fluid and electrolyte balance. In case of arterial hypotension, administer plasma or plasma substitutes.

Bronchospasm should be controlled using bronchodilators.

In case of significant diuresis, administer fluids and electrolytes.

Adverse Reactions.

Cardiovascular system: bradycardia, cold extremities, orthostatic hypotension which may be associated with syncope, atrioventricular conduction disturbances, signs of heart failure, palpitations, in patients with angina pectoris may experience increased attacks, arterial hypotension with intermittent claudication and may worsen in patients with Raynaud's syndrome, necrotizing vasculitis, sinoatrial node weakness syndrome, arrhythmia.

Blood and lymphatic system: purpura, thrombocytopenia, leukopenia, agranulocytosis, eosinophilia, aplastic anemia, neutropenia, pancytopenia.

Psychiatric disorders: mood changes, nightmares, confusion, loss of consciousness, agitation, aggression, psychosis, disorientation, hallucinations, depression, sleep disturbances, impaired concentration.

Nervous system: dizziness, paresthesia, headache, fatigue, lethargy, somnolence, muscle cramps, weakness, transient memory loss.

Eye disorders: decreased tear secretion, conjunctivitis, dry eyes, visual disturbances; frequency unknown – choroidal effusion.

Respiratory system: bronchospasm in patients with bronchial asthma or patients predisposed to bronchial obstruction, dyspnea, cough, stridor.

Gastrointestinal tract: dyspepsia, nausea, vomiting, constipation, diarrhea, dry mouth, anorexia, gastric irritation, spasms, mesenteric arterial thrombosis, ischemic colitis, abdominal pain.

Hepatobiliary system: hepatotoxicity, intrahepatic cholestasis, liver function abnormalities, cholestatic jaundice, pancreatitis, elevated liver enzymes.

Endocrine system: possible development of hypoglycemia, especially in patients with diabetes mellitus receiving hypoglycemic therapy.

Skin and subcutaneous tissue: pruritus, alopecia, psoriasiform eruptions, exacerbation of psoriasis, skin rashes, erythema, photosensitivity, toxic epidermal necrolysis, purpura, urticaria, necrotic vasculitis, Stevens-Johnson syndrome, erythematous rashes, lupus erythematosus.

Allergic reactions: fever associated with sore throat and inflammation.

Renal and urinary system: interstitial nephritis.

Immune system: hypersensitivity reactions including urticaria and angioneurotic edema, skin hyperemia.

Reproductive system and mammary glands: impotence, Peyronie's disease, gynecomastia.

Other: fatigue, muscle weakness, general weakness, tiredness, muscle spasms, gout, increased sweating, alopecia.

Laboratory findings: hyperuricemia, hyponatremia, hypokalemia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, hyperglycemia, glucosuria, impaired glucose tolerance, increased serum transaminase and bilirubin levels, increased ANA (antinuclear antibodies), hypercholesterolemia, hypertriglyceridemia.

Shelf life. 3 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25°C, in a place inaccessible to children.

Packaging.

10 tablets per strip; 1 strip per cardboard sachet; 10 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Genome Biotech Pvt. Ltd.

Manufacturer's address and location of business activity.

Plot No. D-121,122,123, MIDC Malegaon, Tal. Sinnar, Nashik 422103, Maharashtra State, India.