Tenoric

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TЕNORIC™ (TENORIC™)

Composition:

Active substances: atenolol, chlortalidone;

One tablet contains 50 mg of atenolol and 12.5 mg of chlortalidone or 100 mg of atenolol and 25 mg of chlortalidone;

Excipients: anhydrous lactose, maize starch, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, povidone, talc, magnesium stearate, hypromellose, titanium dioxide (E 171), light mineral oil, polyethylene glycol, carnauba wax;

Coating: isopropyl alcohol, dichloromethane, hydroxypropylmethylcellulose, purified talc, titanium dioxide (E 171), light mineral oil, macrogol.

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group.

Selective beta-adrenoreceptor blockers in combination with diuretics.

ATC code C07C B03.

Pharmacological properties.

Pharmacodynamics.

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

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

Pharmacokinetics.

Absorption. After oral administration, 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 excreted predominantly by the kidneys (90%). Elimination half-life ranges from 6 to 9 hours. Chlorthalidone is excreted in feces and urine. Elimination half-life ranges from 24 to 55 hours and is prolonged in elderly patients and in 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, intoxication with cardiac glycosides, bronchial asthma, bronchoobstructive syndrome. The drug is contraindicated in patients receiving verapamil within 48 hours. Hyponatremia, hypercalcemia, concomitant use of lithium preparations, gout.

Interaction with other medicinal products and other types of interactions.

Tenoric™ enhances the effect of other antihypertensive agents when used concomitantly. In patients treated with Tenoric™ together with catecholamines (e.g., reserpine), arterial hypotension and/or bradycardia have been observed during studies, which may lead to dizziness, syncope, or orthostatic hypotension.

When used concomitantly with dihydropyridines (e.g., nifedipine), the risk of arterial hypotension and heart failure may increase, particularly in patients with chronic heart failure.

Calcium channel blockers also have an additive effect when used with Tenoric™.

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

Tenoric™ enhances the antihypertensive effect of hydralazine and prazosin; their combination leads to a greater reduction in blood pressure than when either drug is used alone.

The use of β-adrenoblockers together with calcium channel blockers ("slow calcium channel blockers") causing negative inotropic effects, such as verapamil or diltiazem, may potentiate this effect, especially in patients with reduced myocardial contractility and/or impaired sinoatrial or atrioventricular conduction. 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 β-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.

β-adrenoblockers may exacerbate rebound hypertension that may occur after discontinuation of clonidine.

If Tenoric™ and clonidine are used simultaneously, clonidine should only be discontinued several days after stopping Tenoric™.

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

When used concomitantly with antihypertensive agents of different classes, tricyclic antidepressants, barbiturates, ethanol, diuretics, phenothiazines, nitrates, and peripheral vasodilators, their hypotensive effect increases.

Concomitant use of Tenoric™ with reserpine, methyldopa, clonidine, or verapamil may lead to bradycardia.

β-adrenoblockers should be prescribed with caution in combination with Class I antiarrhythmic agents (e.g., disopyramide), as the cardiodepressant effect may be additive. When used with amiodarone, there is a risk of impaired automaticity, conduction, and contractility of the heart.

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

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

The interaction of atenolol (a component of Tenoric™) with quinolones increases atenolol bioavailability; with adrenaline, it enhances the vasopressor effect followed by bradycardia; with lidocaine, it increases lidocaine levels; with amiodarone, it increases the risk of dysfunction of the sinus or atrioventricular node (should not be prescribed); with cimetidine, atenolol clearance decreases, leading to increased plasma levels and enhanced therapeutic effect. When used concomitantly with ephedrine or theophylline, mutual inhibition of therapeutic effects may occur.

Concomitant use of diuretics (chlorthalidone) with lithium preparations reduces renal lithium clearance. Concomitant use with glucocorticoids, amphotericin, or furosemide promotes increased potassium excretion.

Cessation of smoking increases the therapeutic effect of atenolol due to reduced metabolism and increased blood levels of the drug.

Cimetidine may increase the blood level of the drug.

Alcohol potentiates the effect of the drug.

With propafenone – enhanced effect of atenolol (component of the drug);

with nicotine – enhanced effect of atenolol due to reduced metabolism and increased blood levels of the drug;

with MAO inhibitors – enhanced effect of chlorthalidone (component of the drug);

with cholestyramine – reduced effect of chlorthalidone (component of the drug);

with potassium-containing preparations – reduced effect of the latter;

with central nervous system (CNS) depressants – enhanced sedative effect;

with lithium – enhanced effect of the latter;

with narcotic analgesics – enhanced narcotic effect; dangerous CNS depression;

with oral hypoglycemic agents, insulin – enhanced effect of the latter;

with anticholinesterase agents, angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril, lisinopril) – increased serum potassium levels.

Special precautions for use.

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

Heart failure. Maintenance of circulatory function in chronic heart failure requires stimulation of the sympathetic nervous system. β-receptor blockade poses a potential risk of further depression of myocardial contractility and may lead to more severe heart failure. In patients with chronic heart failure controlled by digitalis preparations and/or diuretics, Tenoric™ should be used with caution. Digitalis preparations and atenolol both slow atrioventricular conduction.

In patients without a history of heart failure, prolonged myocardial depression due to β-blockers over a long period may in some cases lead to the development of heart failure. At the first signs of worsening heart failure, the drug should be discontinued and medical advice sought. If heart failure progresses despite appropriate therapy, Tenoric™ should be discontinued.

Renal or hepatic impairment: Since atenolol is excreted by the kidneys, the dose should be reduced in severe renal impairment. In patients with hepatic and/or renal dysfunction, functional status should be monitored. In patients with renal impairment, the drug may precipitate azotemia. Given that cumulative effects may develop with reduced renal function, and if worsening renal function persists, treatment with Tenoric™ should be discontinued.

In patients with impaired liver function or progressive liver disease, even minor disturbances in fluid and electrolyte balance may lead to the development of hepatic coma. Therefore, Tenoric™ should be administered with caution in such patients.

Ischemic heart disease. Abrupt discontinuation of therapy with some β-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 existing angina, when discontinuation of Tenoric™ is planned, the patient should remain under medical supervision and minimize physical exertion. Treatment with Tenoric™ should be resumed if withdrawal syndrome occurs.

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

Concomitant use of calcium channel blockers. Bradycardia, atrioventricular block, and left ventricular failure may occur, and diastolic pressure may increase when β-blockers are used concomitantly with verapamil or diltiazem. Patients with pre-existing disturbances in intraventricular conduction or left ventricular dysfunction are particularly sensitive to the drug's effects.

Bronchoobstructive syndrome. β-blockers should not be used in patients with bronchoobstructive syndrome.

Since Tenoric™ is a relatively selective β1-adrenoblocker, it may be used with caution in patients with bronchoobstructive syndrome who do not respond to other treatments or cannot tolerate alternative antihypertensive therapy. Since selective β-adrenoblockers are not absolutely selective, Tenoric™ should be used at the lowest possible doses, and β2-adrenergic stimulants should be available. If dose escalation is required, the dose should be fractionated to achieve lower peak blood levels.

Anesthesia and major surgery. As with other β-receptor blockers, discontinuation of the drug may be necessary prior to 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).

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

Analgesics should be prescribed with caution concomitantly with Tenoric™.

The anesthesiologist should carefully select an analgesic agent with minimal negative inotropic activity, if possible. Concomitant use of β-adrenergic blockers and anesthetic agents may attenuate tachycardia and increase the risk of arterial hypotension. Analgesics that cause myocardial depression should be avoided.

Metabolism and endocrine disorders. Tenoric™ should be prescribed with caution in patients with diabetes mellitus. β-blockers may mask tachycardia associated with hypoglycemia, as well as other symptoms such as dizziness and sweating.

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

The insulin requirement in diabetic patients may be increased, decreased, or unchanged. Latent diabetes mellitus may manifest during treatment with chlorthalidone.

β-adrenergic blockers may mask certain clinical symptoms (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of β-blocker therapy may provoke an exacerbation of thyroid function; therefore, in patients suspected of developing thyrotoxicosis, the decision to discontinue Tenoric™ therapy or to implement careful monitoring should be considered.

Since thiazides reduce calcium excretion, treatment with Tenoric™ should be discontinued prior to parathyroid function testing. 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: Tenoric™ must not be used in patients with untreated pheochromocytoma.

General disorders: Tenoric™ may worsen peripheral arterial circulation.

Fluid and electrolyte balance. Periodic determination of electrolyte levels to detect possible electrolyte imbalance 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.

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, somnolence, nervousness, 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 preparations for heart failure, patients with unbalanced diets, or those complaining of gastrointestinal disturbances.

Hypokalemia may develop, particularly with rapid diuresis, in severe cirrhosis, or during concomitant use of corticosteroids or ACTH.

Oral electrolyte intake may also contribute to the development of hypokalemia. Hypokalemia may increase cardiac sensitivity or enhance the toxic effects of digitalis preparations (e.g., increased ventricular irritability). Hypokalemia can be corrected or treated with potassium-containing supplements or foods rich in potassium.

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

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

In cases of excessive salt loss, this drug may be the treatment of choice.

Due to the presence of lactose in the excipients, the drug should be used with caution in patients with hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption, or diabetes mellitus.

This medicinal product contains sodium lauryl sulfate. Caution is advised when administering to patients on a sodium-controlled diet.

β-blockers should not be used in patients with bronchial diseases. However, due to its relative selectivity, Tenoric™ may be cautiously used, if necessary, in patients with bronchospastic disorders.

When prescribing the drug to patients with pheochromocytoma, α-adrenoreceptor blockers should be administered beforehand (to prevent hypertensive crisis).

Treatment with the drug should be under medical supervision. The drug is not indicated for the treatment of acute angina attacks.

In patients with a history of bronchial asthma who are receiving thiazides, hypersensitivity reactions may occur.

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

The drug should not be used prior to parathyroid function testing, as thiazides reduce calcium excretion.

Serum creatinine levels should be periodically monitored in patients with impaired renal function.

Use during pregnancy or breastfeeding.

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

Effect on ability to drive vehicles or operate machinery.

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

Dosage and Administration

Tenoric™ tablets should be administered orally to adults without chewing, with water, before meals, preferably at the same time each day.

The dosage and duration of treatment must be individually determined based on the therapeutic response achieved.

Tenoric™ is not intended for initial therapy of arterial hypertension. The drug should be prescribed when monotherapy has proven ineffective.

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

Elderly patients require a lower dose of the atenolol component, as prescribed by the physician.

Caution is required when treating patients with severe renal impairment. In patients with creatinine clearance below 35 mL/min/1.73 m² (normal range 100–150 mL/min/1.73 m²), the drug may be used only after adjusting the doses of the individual components.

Children.

Do not use in children.

Overdose.

Symptoms: bradycardia, II-III 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 by pacemaker insertion. If necessary, intravenous bolus injection of 10 mg glucagon may be administered. This procedure may be repeated if needed, or followed by continuous intravenous infusion of glucagon at a rate of 1–10 mg/hour depending on the response obtained. In the absence of response to glucagon or if glucagon is unavailable, intravenous administration of the β1-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. These doses may be insufficient to counteract cardiac symptoms related to β-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 blood plasma or plasma substitutes. Treat bronchospasm with bronchodilators.

In case of significant diuresis, administer fluids and electrolytes.

Side effects.

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 dysfunction, lupus erythematosus, arrhythmia.

Blood system: purpura, thrombocytopenia, leukopenia, agranulocytosis, eosinophilia, aplastic anemia, neutropenia, pancytopenia, worsening of diabetes mellitus.

Psychiatric disorders: mood changes, nightmares, confusion, loss of consciousness, excitement, 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.

Respiratory system: bronchospasm in patients with bronchial asthma or in 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 on hypoglycemic therapy.

Skin and subcutaneous tissue: pruritus, alopecia, psoriasiform rashes, exacerbation of psoriasis, skin rashes, erythema, photosensitivity, toxic epidermal necrolysis, purpura, urticaria, necrotic vasculitis, Lyell's syndrome, erythematous eruptions.

Allergic reactions: fever associated with sore throat and inflammation.

Urinary system: interstitial nephritis.

Immune system: hypersensitivity reactions, including urticaria and angioedema.

Reproductive system: impotence, Peyronie's disease.

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 transaminases, bilirubin, increased ANA (antinuclear antibodies), hypercholesterolemia, hypertriglyceridemia.

Shelf life. 3 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

14 tablets per blister pack; 2 blisters per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Ipkal Laboratories Limited.

Ipkal Laboratories Ltd.

Manufacturer's address and place of business.

Plot No. 255/1, Village – Atal, U.T. Dadra and Nagar Haveli, 396230 Silvassa, India.

P.O. Segwada, District Ratlam – 457002 (M.P.), India.