Tenoretic^® (Tablets) Instructions for Use

Marketing Authorization Holder

AstraZeneca UK Limited (United Kingdom)

ATC Code

C07CB03 (Atenolol and other diuretics)

Active Substances

Atenolol (Rec.INN registered by WHO)

Chlorthalidone (USAN adopted for use in the USA)

Dosage Form

Tenoretic®

Film-coated tablets, 100 mg+25 mg: 28 pcs.

Dosage Form, Packaging, and Composition

14 pcs. – blister packs (2) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (beta1-adrenergic blocker + diuretic)

Pharmacological Action

Combined antihypertensive agent. It has a hypotensive effect. The effect is due to the action of two components – a beta-adrenergic blocker (Atenolol) and a diuretic (Chlorthalidone).

The combination of atenolol and chlorthalidone is compatible and, as a rule, more effective than the use of each of these drugs separately.

Atenolol is a cardioselective hydrophilic beta₁-adrenergic blocker. It does not have intrinsic sympathomimetic and membrane-stabilizing activity. It causes an antiadrenergic effect, has antianginal, antiarrhythmic, antihypertensive, and cardioprotective action. Reduces heart rate (negative chronotropic effect); slows AV conduction (negative dromotropic effect); reduces myocardial excitability (negative bathmotropic effect); reduces myocardial contractility (negative inotropic effect); reduces renin activity; reduces blood pressure through the listed mechanisms. Due to the inhibition of beta₂-adrenergic receptors, Atenolol may increase the tone of smooth muscles.

Chlorthalidone – a thiazide-like diuretic – suppresses active sodium reabsorption in the renal tubules (initial part of the distal convoluted tubule of the nephron), increasing the excretion of sodium and chloride and enhancing diuresis; in addition, Chlorthalidone increases the excretion of potassium, magnesium, and bicarbonate, and retains calcium ions and uric acid. The diuretic effect develops 2-3 hours after oral administration and lasts for 2-3 days.

The use of chlorthalidone in high doses is accompanied by increased excretion of bicarbonates, which is associated with inhibition of carbonic anhydrase; this leads to urine alkalinization. With prolonged treatment with chlorthalidone, renal calcium excretion decreases, leading to hypercalcemia. The mechanisms of the antihypertensive action of chlorthalidone include disruption of sodium balance, reduction of extracellular fluid and plasma volume, reduction of renal vascular resistance, and decreased sensitivity to norepinephrine and angiotensin II.

In patients with severe renal failure (creatinine clearance <30 ml/min), Chlorthalidone is ineffective.

Pharmacokinetics

Atenolol

After oral administration, about 50% is absorbed from the gastrointestinal tract. C_max in blood plasma is reached 2-4 hours after oral administration. Bioavailability is 50%. Plasma protein binding is about 3%. It is metabolized very insignificantly. About 90% of the systemically available atenolol is excreted by the kidneys unchanged within 48 hours. T_1/2 is 6-10 hours with normal renal function. In chronic renal failure, T_1/2 can reach 140 hours. The relative V_d is 0.7 l/kg.

Chlorthalidone

It is relatively slowly absorbed from the gastrointestinal tract (time to reach half T_1/2 in blood plasma is about 2.5 hours). Systemic bioavailability is about 64±10% after oral administration. Plasma protein binding is 75%, with 58% bound to albumin. Chlorthalidone is predominantly excreted by the kidneys, mostly unchanged. T_1/2 is about 50 hours. V_d is 4 l/kg.

Indications

Arterial hypertension (when monotherapy with atenolol and chlorthalidone is ineffective).

ICD codes

Dosage Regimen

Initiate therapy with a lower-strength formulation containing 50 mg atenolol and 12.5 mg chlorthalidone taken once daily.

If adequate blood pressure control is not achieved, increase the dose to one Tenoretic tablet (100 mg atenolol / 25 mg chlorthalidone) once daily.

Administer the dose with or without food. Swallow the tablet whole with a glass of water; do not crush or chew.

For patients with renal impairment, dosage adjustment is mandatory. Do not use if creatinine clearance is below 15 mL/min.

In patients with mild to moderate renal impairment (creatinine clearance 15-35 mL/min), use with caution and monitor renal function.

Regularly monitor serum electrolytes, particularly potassium and sodium, especially at the start of therapy, during diuretic dosage adjustments, and in elderly patients.

Monitor for clinical signs of fluid or electrolyte imbalance such as hyponatremia, hypochloremic alkalosis, and hypokalemia.

Assess heart rate and blood pressure regularly. The dose should provide a 24-hour antihypertensive effect.

Do not abruptly discontinue therapy, particularly in patients with coronary artery disease, due to the risk of rebound hypertension and increased angina.

In patients with diabetes, monitor blood glucose levels closely as hyperglycemia may occur.

The maximum recommended daily dose is one Tenoretic tablet (100 mg/25 mg). Do not exceed this dose.

Adverse Reactions

Definition of categories of frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000) and very rare (<1/10,000); frequency unknown (frequency cannot be estimated from the available data).

From the cardiovascular system common – bradycardia, cold extremities, progression of intermittent claudication in patients with Raynaud’s syndrome; rare – progression of heart failure, orthostatic hypotension, tachycardia, Raynaud’s syndrome; very rare – AV block.

From the nervous system uncommon – sleep disturbance; rare – dizziness, headache, nightmares, increased fatigue, paresthesia, confusion, hallucinations, psychosis, emotional lability.

From the organ of vision rare – dryness of the eye mucosa, visual impairment.

From the digestive system common – dyspeptic disorders (nausea, pain and spasm in the epigastric region, diarrhea, coprostasis); rare – dryness of the oral mucosa, hepatotoxicity with intrahepatic cholestasis, jaundice, pancreatitis; frequency unknown – constipation.

From the hematopoietic system rare – purpura, thrombocytopenia, leukopenia, hemorrhagic rash.

From the skin rare – skin rash, alopecia, psoriasiform skin reactions, exacerbation of psoriasis.

From the genitourinary system rare – impotence.

From the respiratory system rare – syncope, occurrence of bronchospasm in patients with bronchial asthma, or with a history of bronchospasm.

Laboratory parameters common – hyponatremia, hypokalemia, hyperuricemia, hyperglycemia and glucosuria, impaired glucose tolerance; uncommon – increased activity of liver transaminases in blood serum; very rare – increased titer of antinuclear antibodies.

Other there are reports of the following side effects – increased bilirubin content, jaundice (intrahepatic cholestatic jaundice), Peyronie’s disease, sick sinus syndrome, lupus syndrome, anorexia, stomach irritation, vomiting, convulsions, vertigo, xanthopsia, agranulocytosis, aplastic anemia, photosensitivity, Lyell’s syndrome (toxic epidermal necrolysis), necrotizing angiitis (vasculitis, cutaneous vasculitis), muscle spasm, weakness, anxiety.

Contraindications

Refractory heart failure; sick sinus syndrome; severe bradycardia (heart rate less than 45-50 beats/min); AV block II and III degree; severe arterial hypotension; severe peripheral circulatory disorders; cardiogenic shock; severe renal failure (creatinine clearance <15 ml/min); metabolic acidosis; untreated pheochromocytoma (without simultaneous use of alpha-adrenergic blockers); bronchial asthma and severe forms of chronic obstructive bronchitis; refractory water-electrolyte balance disorders (hypokalemia, hyponatremia, hypercalcemia); gout; age under 18 years; anuria; severe liver dysfunction (more than 9 points on the Child-Pugh scale); pregnancy; breastfeeding period; hypersensitivity to atenolol/chlorthalidone and to other sulfonamide derivatives.

With caution:

Chronic heart failure (compensated), bradycardia (heart rate less than 60 beats/min), Prinzmetal’s angina, AV block I degree, coronary artery disease (upon drug withdrawal), thyrotoxicosis, pheochromocytoma (with simultaneous use of alpha-adrenergic blockers), diabetes mellitus, impaired renal function (creatinine clearance 15-35 ml/min), water-electrolyte balance disorders, history of bronchial asthma, COPD, peripheral circulatory disorders, mild and moderate liver dysfunction, hyperuricemia and gout, elderly age, desensitizing therapy.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in hepatic insufficiency.

Use in Renal Impairment

Contraindicated in renal failure. In patients with reduced renal excretory function, control of creatinine clearance is necessary.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Although this combination is contraindicated in decompensated heart failure, use is possible in those patients whose signs of heart failure are controlled, while caution should be exercised in patients with reduced ejection fraction.

In rare cases, a decrease in heart rate may be accompanied by clinical manifestations, which requires a reduction in the dose of the combination.

Atenolol may mask tachycardia caused by hypoglycemia, as well as symptoms of thyrotoxicosis.

The combination should not be abruptly discontinued in patients with coronary artery disease, since abrupt withdrawal of treatment may increase the frequency and severity of angina attacks.

In case of deterioration of bronchial patency, the use of this combination should be discontinued and therapy with bronchodilators (e.g., salbutamol) should be prescribed.

Atenolol may increase sensitivity to allergens and cause anaphylactic reactions, therefore patients undergoing desensitizing therapy should take the drug with great caution.

In patients with a family history of psoriasis, the use of the combination is possible only after careful weighing of the risk-benefit ratio.

The use of the combination in patients undergoing surgery with general anesthesia may lead to the development of arterial hypotension. The use of general anesthetics that reduce myocardial contractility should, if possible, be avoided.

During treatment, systematic monitoring of potassium and sodium levels in the blood is necessary, especially in elderly patients, in patients taking cardiac glycosides, in patients with gastrointestinal dysfunction, and also in patients with an unbalanced diet (low potassium intake). In patients taking cardiac glycosides, hypokalemia can lead to serious cardiac arrhythmias.

In patients with diabetes mellitus, it is necessary to regularly monitor blood and urine glucose concentrations.

In patients with impaired liver function or progressive liver disease, minor water-electrolyte balance disorders can cause hepatic coma.

During the use of this combination, false-positive doping test results are possible.

During the use of this combination, a decrease in tear production is possible, which is important for patients using contact lenses.

In smoking patients, the effectiveness of drugs containing beta-adrenergic blockers is lower.

Effect on ability to drive vehicles and operate machinery

During treatment, dizziness, drowsiness, increased fatigue, and visual impairment are possible, therefore 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

Slow calcium channel blockers (e.g., verapamil, diltiazem) – enhancement of the negative inotropic effect of atenolol, especially in patients with reduced myocardial contractility and/or with sinoatrial or AV conduction disorders. This can lead to the development of severe arterial hypotension, bradycardia, or heart failure. Slow calcium channel blockers should not be administered intravenously within 48 hours after discontinuation of beta-adrenergic blockers.

Class I antiarrhythmic drugs (disopyramide) and amiodarone – possible increase in atrial conduction time and enhancement of the negative inotropic effect of atenolol; the cardiodepressive effect may be additive.

Norepinephrine, epinephrine – possible significant increase in blood pressure.

Cardiac glycosides, reserpine, alpha-methyldopa, guanfacine, or clonidine – due to the possible occurrence of potassium and/or magnesium deficiency associated with the intake of this beta-adrenergic blocker combination, the sensitivity of the heart muscle to cardiac glycosides may increase, and, accordingly, the frequency of their side effects may increase.

Clonidine – abrupt withdrawal of clonidine can lead to an increase in blood pressure, so discontinuation of clonidine should be done gradually and only a few days after discontinuation of beta-adrenergic blockers.

Tricyclic antidepressants, barbiturates, phenothiazines, diuretics, vasodilators and other antihypertensive agents, ethanol – possible enhancement of the antihypertensive effect.

ACE inhibitors (captopril, enalapril) – at the beginning of therapy, a sharp enhancement of the antihypertensive effect of the drug is possible.

Salicylates and other NSAIDs – possible reduction of the antihypertensive action of beta-adrenergic blockers, and with high doses of salicylates – enhancement of the toxic effect of salicylates on the central nervous system. With simultaneous use of this combination with NSAIDs, a weakening of the diuretic and hypotensive action is possible.

Lithium – decreased excretion of lithium and enhancement of the cardio- and neurotoxic effect of lithium.

Curare-like muscle relaxants (tubocurarine) – possible enhancement or weakening of neuromuscular blockade.

Corticosteroids, carbenoxolone, amphotericin B, furosemide – possible enhancement of potassium ion excretion.

Allopurinol – possible increase in the frequency of hypersensitivity reactions to chlorthalidone.

Chlorthalidone may increase the risk of adverse reactions caused by amantadine.

Anticholinergic drugs (e.g., atropine, biperiden) may increase the bioavailability of chlorthalidone by reducing gastrointestinal motility and gastric emptying.

The pharmacological effects of calcium salts and vitamin D may be enhanced to a clinically significant level when used concomitantly with chlorthalidone.

Concomitant use with cyclosporine increases the risk of hyperuricemia and complications such as gout.

Cholestyramine impairs the absorption of chlorthalidone (possible reduction of the pharmacological effect of chlorthalidone).

Concomitant use of chlorthalidone with methotrexate and cyclophosphamide may lead to potentiation of the pharmacological effect of antitumor drugs.

With simultaneous use of this combination with insulin and oral hypoglycemic agents, the effect of the latter may be enhanced. It is necessary to regularly monitor blood glucose concentration, since signs of hypoglycemia (tremor, tachycardia) may be masked or weakened when taking this combination.

With simultaneous use with anesthetics, the antihypertensive effect is enhanced and the negative inotropic effect is additive.

Slow calcium channel blockers, dihydropyridine derivatives (e.g., nifedipine) possible increase in the risk of arterial hypotension, in patients with latent heart failure, signs of circulatory disorders may appear.

Baclofen possible enhancement of the antihypertensive effect.

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.