TENORETIC® AstraZeneca Atenolol–Chlorthalidone Antihypertensive Agent
Action and Clinical
Tenoretic combines the antihypertensive activity of 2 agents, a b-adrenergic receptor blocking agent (atenolol) and diuretic (chlorthalidone).
Atenolol is a b 1-selective, b-adrenergic blocking agent, devoid of membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities. It is a racemic mixture and the b 1 properties reside in the S(-) enantiomer. b 1-selectivity decreases with increasing dose.
The mechanism of the antihypertensive effect of atenolol has not been established. Among the factors that may be involved are: competitive ability to antagonize catecholamine-induced tachycardia at the b-receptor sites in the heart, thus decreasing cardiac output; inhibition of renin release by the kidneys; inhibition of the vasomotor centres.
In man atenolol reduces both isoproterenol-and exercise-induced increases in heart rate over the dose range of 50 to 200 mg. At an oral dose of 100 mg the b 1-blocking effects persist for at least 24 hours; the reduction in exercise-induced heart rate increase being about 32% and 13%, 2 and 24 hours after dosing, respectively. The logarithm of the plasma atenolol level correlates with the degree of b 1-blockade but not with the antihypertensive effect.
Chlorthalidone, a monosulfonamyl diuretic, increases excretion of sodium and chloride. Natriuresis is accompanied by some loss of potassium. The mechanism by which chlorthalidone reduces blood pressure is not fully known but may be related to the excretion and redistribution of body sodium. Chlorthalidone usually does not decrease normal blood pressure.
The combination of atenolol with thiazide-like diuretics has been shown to be compatible and generally more effective than either drug used alone as an antihypertensive agent.
Pharmacokinetics: Approximately 40 to 50% of an oral dose of atenolol is absorbed from the gastrointestinal tract, the remainder being excreted unchanged in the feces. Peak plasma concentrations occur 2 to 4 hours after dosing and are subject to a 4-fold variability. The plasma levels are proportional to dose over the range 50 to 400 mg and 6 to 16% of atenolol is bound to plasma proteins. The plasma half-life is approximately 6 to 7 hours.
Approximately 60% of an oral dose of chlorthalidone is absorbed from the gastrointestinal tract and excreted unchanged in the urine. Following a single dose, the peak blood concentration of chlorthalidone occurs after approximately 12 hours and decreases thereafter according to first-order kinetics; the disposition half-life is approximately 50 hours. Approximately 75% of chlorthalidone is bound in plasma.
Indications And Clinical Uses:
This fixed combination is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. It is always better to adjust the dosage of each antihypertensive drug separately, but when the fixed combination corresponds to the optimum drug and dose requirements of the patient, its use may be more convenient in patient management. For further adjustment of dosage, however, it is best to use the individual drugs again. The treatment of hypertension is not static, but must be re-evaluated as conditions in each patient warrant.
Tenoretic is indicated for the maintenance therapy of patients with hypertension who require atenolol and chlorthalidone in the dosage and ratios present in Tenoretic.
Sinus bradycardia, or bradycardia of other origin; second and third degree AV block; sick sinus syndrome; right ventricular failure secondary to pulmonary hypertension; congestive heart failure; cardiogenic shock; hypotension; severe peripheral arterial disorders; anesthesia with agents that produce myocardial depression; pheochromocytoma, in the absence of a-blockade; metabolic acidosis; anuria; hypersensitivity to atenolol, chlorthalidone or to sulfonamide-derived drugs.
Warnings in Clinical States:
Cardiac Failure: Special caution should be exercised when administering Tenoretic to patients with a history of cardiac failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure and inhibition with b-blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure.
In patients without a history of cardiac failure, continued depression of the myocardium with b-blocking agents over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given additional diuretic and the response observed closely.
Atenolol acts selectively without blocking the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effect of atenolol when the two drugs are used concomitantly. The effects of b-blockers and digitalis are additive in depressing AV conduction. If cardiac failure continues, despite adequate digitalization, Tenoretic therapy should be withdrawn immediately and diuretic therapy maintained (see below).
Abrupt Cessation of Therapy: Patients with angina should be warned against abrupt discontinuation of Tenoretic. There have been reports of severe exacerbation of angina and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of b-blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of Tenoretic is planned in patients with angina pectoris, the drug should be stopped and immediately replaced with atenolol and a diuretic given separately, so that the dose of atenolol may be gradually reduced over a period of about 2Â weeks while the dose of diuretic is maintained. The same frequency of administration of both drugs should be maintained. The patient should be carefully observed.
In situations of greater urgency, Tenoretic should be discontinued stepwise over a shorter time and under closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with Tenoretic be reinstituted promptly, at least temporarily.
Since ischemic heart disease may be unrecognized, the above advice should be followed in patients considered to be at risk of having asymptomatic ischemic heart disease.
Oculomucocutaneous Syndrome: Various skin rashes and conjunctival xerosis have been reported with b-blockers, including atenolol. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one b-adrenergic blocking agent (practolol). This syndrome has not been observed with atenolol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment with Tenoretic in the event that they occur.
Prinzmetal’s Angina: Atenolol may increase the number and duration of angina attacks in patients with Prinzmetal’s angina due to unopposed a-receptor mediated coronary artery vasoconstriction. Tenoretic, therefore, should only be used in these patients with the utmost care.
Sinus Bradycardia: Severe sinus bradycardia may occur with the use of atenolol from unopposed vagal activity remaining after blockade of b 1-adrenergic receptors; in such cases, the dose should be reduced.
Thyrotoxicosis: In patients with thyrotoxicosis, possible deleterious effects from long-term use of atenolol have not been adequately appraised. b-blockade may mask the clinical signs of continuing hyperthyroidism or its complications and give a false impression of improvement. Therefore, abrupt withdrawal of atenolol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm. Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Impaired Renal Function: Tenoretic should be used with caution since chlorthalidone may precipitate or increase azotemia. Cumulative effects may develop since both components of Tenoretic are excreted by the kidney. If progressive renal impairment becomes evident, Tenoretic should be discontinued.
When renal function is impaired, clearance of atenolol is closely related to the glomerular filtration rate. However, significant accumulation does not occur until the creatinine clearance falls below 35 mL/min/1.73m
Impaired Hepatic Function: In patients with impaired hepatic function or progressive liver disease, even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Hepatic encephalopathy, manifested by tremors, confusion and coma, has been reported in association with diuretic therapy, including chlorthalidone.
Hypersensitivity Reactions: In patients receiving chlorthalidone, sensitivity reactions may occur with or without a history of allergy or bronchial asthma.
Systemic Lupus Erythematosus: Possible exacerbation of systemic lupus erythematosus has been reported with thiazide-like diuretics.
Bronchospastic Disorders: Patients with bronchospastic diseases should, in general, not receive b-blockers. Due to the relative b 1-selectivity of atenolol, atenolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since b 1-selectivity is not absolute, a b 2-stimulating agent should be administered concomitantly and the lowest possible dose of atenolol should be used. Despite these precautions, the respiratory status of some patients may worsen, and, in such cases, Tenoretic should be withdrawn.
First Degree Heart Block: Due to atenolol’s negative effect on AV conduction time, Tenoretic should be used with caution in patients with first degree block.
Peripheral Arterial Circulatory Disorders: Tenoretic may aggravate less severe peripheral arterial circulatory disorders (see Contraindications).
Anaphylaxis-Epinephrine and b-blockers: There may be increased difficulty in treating an allergic type reaction in patients on b-blockers. In these patients, the reaction may be more severe due to pharmacological effects of b-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive a-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart-block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of b-agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.
Diabetes and Patients Subject to Hypoglycemia: Tenoretic should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. b-adrenergic receptor blocking agents may mask the premonitory signs (e.g., tachycardia) and symptoms of acute hypoglycemia. Insulin requirements in diabetic patients may be increased, decreased, or unchanged by chlorthalidone. Diabetes mellitus which has been latent may become manifest during chlorthalidone administration.
Elective or Emergency Surgery: It is not advisable to withdraw b-adrenoceptor blocking drugs prior to surgery in the majority of patients. However, care should be taken when using Tenoretic with anesthetic agents such as those which may depress the myocardium. Vagal dominance, if it occurs, may be corrected with atropine (1 to 2 mg i.v.).
Some patients receiving b-adrenergic blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported.
In emergency surgery, since atenolol is a competitive inhibitor of b-adrenergic receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol or norepinephrine.
Fluid or Electrolyte Imbalance: Patients receiving chlorthalidone should be carefully observed for clinical signs of fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis and hypokalemia). Periodic determination of serum electrolytes should be performed at appropriate intervals. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids or ACTH. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium supplements, potassium-sparing agents or foods with a high potassium content.
Any chloride deficit during chlorthalidone therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Because calcium excretion is decreased by chlorthalidone, Tenoretic should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy; however, the common complications of hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been seen.
Postsympathectomy Patients: The antihypertensive effects of thiazides may be enhanced in the postsympathectomy patient.
Hyperuricemia: Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving chlorthalidone.
Ethnic Populations: Atenolol appears to be effective and well-tolerated in most ethnic populations, although the response may be less in black patients than in Caucasians.
Pregnancy: Atenolol has been shown to produce a dose-related increase in embryo-fetal resorptions in rats at doses equal to or greater than 50 mg/kg or 25 or more times the maximum recommended human dose. Studies in humans have shown that transplacental passage of atenolol does occur in pregnant women with fetal drug serum levels equal to those of the mother. Thiazides also cross the placental barrier and appear in cord blood.
The safe use of Tenoretic in pregnancy has not been established. The use of Tenoretic in pregnancy or in women of childbearing potential requires that the anticipated benefit be weighed against possible risk to mother and/or fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia and, possibly, other adverse reactions which have occurred in the adult.
Lactation: In humans, there is a significant accumulation of atenolol in the breast milk of lactating women. Chlorthalidone also appears in human milk. If the use of Tenoretic is deemed essential, the patient should stop nursing.
Children: The safety of use of atenolol in children has not been established; therefore, Tenoretic is not recommended in the pediatric age group.
Occupational Hazards: Use of Tenoretic is unlikely to result in any impairment of the ability of patients to drive or operate machinery. However, it should be taken into account that dizziness or fatigue may occur.
Clonidine: b-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the b-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by b-blocker therapy, the introduction of b-blockers should be delayed for several days after clonidine administration has stopped. (Also see prescribing information for clonidine.)
Reserpine or Guanethidine: Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored because the added b-adrenergic blocking action of atenolol may produce an excessive reduction of sympathetic activity. Tenoretic should not be combined with other drugs containing b-blockers.
Antihypertensive Peripheral Vasodilator: The combination of Tenoretic with an antihypertensive peripheral vasodilator produces a greater fall in blood pressure than either drug alone. The same degree of blood pressure control can be achieved by lower than usual doses of each drug. Therefore, when using such concomitant therapy, careful monitoring of the doses is required until the patient is stabilized.
Norepinephrine: Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude the therapeutic effectiveness of the pressor agent in therapy.
Tubocurarine: Thiazide diuretics may increase the responsiveness to tubocurarine.
Lithium: Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. The Prescribing Information for lithium preparations should be read before use of such preparations with Tenoretic.
Alcohol, Barbiturates or Narcotics: Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates or narcotics.
Antiarrhythmic Agents: Care should be taken when atenolol is used concomitantly with Class I antiarrhythmic agents since these drugs may potentiate the cardiac depressing activity of atenolol. On rare occasions the concomitant administration of i.v. beta-adrenergic blocking agents with i.v. verapamil has resulted in serious adverse effects, especially in patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction.
Calcium Channel Blockers: Combined use of b-blockers and calcium channel blockers with negative inotropic effects can lead to prolongation of SA and AV conduction, particularly in patients with impaired ventricular function, conduction abnormalities, or diminished cardiac output. This may result in severe hypotension, bradycardia and cardiac failure. Concomitant therapy with dihydropyridines, e.g., nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.
Digitalis Glycosides: Digitalis glycosides may potentiate the bradycardia of b-blockade.
Nonsteroidal Anti-inflammatory Agents: The concomitant use of nonsteroidal anti-inflammatory agents may blunt the antihypertensive effects of b-blockers.
Anesthetic Agents: Anesthetics can produce a hypotensive state with associated reflex tachycardia. Since b blockade will inhibit reflex tachycardia, the hypotensive potential of anesthetic agents is increased with concomitant use of Tenoretic (see Contraindications and Precautions).
Adverse reactions that have been reported with the individual components are listed below.
Atenolol: The most serious adverse reactions encountered are congestive heart failure, AV block and bronchospasm.
The most common adverse reactions reported in clinical trials with atenolol in 2 500 patients are bradycardia (3%), dizziness (3%), vertigo (2%), fatigue (3%), diarrhea (2%) and nausea (3%).
Adverse reactions, occurring with an incidence of less than 1%, grouped by system, are as follows: Cardiovascular: congestive heart failure (see Warnings), heart block, palpitations, lengthening of PR interval, chest pain, lightheadedness, postural hypotension which may be associated with syncope, Raynaud’s phenomenon, intermittent claudication, or worsening of pre-existing intermittent claudication, leg pain and cold extremities, edema.
Respiratory: dyspnea, wheeziness, cough, bronchospasm.
CNS: faintness, ataxia, tiredness, lethargy, nervousness, depression, drowsiness, vivid dreams, insomnia, paresthesia, headache, tinnitus, mood changes, visual disturbances, psychoses and hallucinations.
Gastrointestinal: abdominal discomfort, indigestion, constipation, anorexia.
Miscellaneous: skin rash, itchy and/or dry eyes, psoriasiform skin reactions, exacerbation of psoriasis, decreased exercise tolerance, alopecia, epistaxis, flushes, impotence, decreased libido, sweating, general body aches, thrombocytopenia and purpura.
Postmarketing Experience: During postmarketing experience with atenolol, the following have been reported in temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin, headache, confusion, nightmares, impotence, Peyronie’s disease, psoriasiform rash or exacerbation of psoriasis, purpura, reversible alopecia and thrombocytopenia. Rare cases of hepatic toxicity including intrahepatic cholestasis have been reported. Atenolol, like other b-blockers, has been associated with the development of antinuclear antibodies (ANA) and lupus syndrome.
In a long-term, well controlled trial of 1 627 elderly patients with systolic hypertension, the incidence of dry mouth was significantly higher in patients taking atenolol (12.2%).
Potential Adverse Reactions: The following adverse reactions have occurred with other b-blockers but have not been reported with atenolol:
Cardiovascular: pulmonary edema, cardiac enlargement, hot flushes and sinus arrest.
CNS: aggressiveness, anxiety, short-term memory loss, and emotional lability with slightly clouded sensorium.
Allergic: laryngospasm, status asthmaticus and fever combined with aching and sore throat.
Dermatological: exfoliative dermatitis.
Ophthalmological: blurred vision, burning, and grittiness.
Gastrointestinal: mesenteric arterial thrombosis and ischemic colitis.
Chlorthalidone: The following adverse reactions have been reported:
Gastrointestinal: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis.
CNS: dizziness, vertigo, paresthesias, headache, xanthopsia.
Hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia.
Dermatologic-Hypersensitivity: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis).
Cardiovascular: Orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates or narcotics.
Other: hyperglycemia, glycosuria, hyperuricemia, hyponatremia, muscle spasm, weakness, restlessness, impotence.
Symptoms And Treatment Of Overdose:
No specific information is available with regard to overdosage of Tenoretic in humans.:
Atenolol: Overdosage with atenolol has been reported with patients surviving acute doses as high as 5 g. One death was reported in a man who may have taken as much as 10 g acutely.
The predominant symptoms reported following atenolol overdosage are lethargy, disorder of respiratory drive, wheezing, sinus pause, and bradycardia. Additionally, common effects associated with overdosage of any b-adrenergic blocking agent are congestive heart failure, hypotension, bronchospasm and/or hypoglycemia.
Treatment should be symptomatic and supportive and directed to the removal of any unabsorbed drug by induced emesis, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Further consideration should be given to dehydration, electrolyte imbalance and hypotension by established procedures.
Other treatment modalities should be employed at the physician’s discretion and may include:
Bradycardia: Atropine 1 to 2 mg i.v. If there is no response to vagal blockade, give isoproterenol cautiously. In refractory cases, a transvenous cardiac pacemaker may be indicated. Glucagon in a 10 mg i.v. bolus has been reported to be useful. If required, this may be repeated or followed by an i.v. infusion of glucagon 1 to 10 mg/h depending on response. If no response to glucagon occurs or if glucagon is unavailable, a b-adrenoceptor stimulant such as dobutamine 2.5 to 10 g/kg/min by i.v. infusion or isoproterenol 10 to 25 g given as an infusion at a rate not exceeding 5 g/min may be given, although larger doses may be required.
Heart Block (second or third degree): Isoproterenol or transvenous pacemaker.
Congestive Heart Failure: Digitalize the patient and administer a diuretic. Glucagon has been reported to be useful.
Hypotension: Vasopressors such as dopamine or norepinephrine. Monitor blood pressure continuously.
Bronchospasm: A b 2-stimulant such as isoproterenol or terbutaline, and/or i.v. aminophylline.
Hypoglycemia: I.V. glucose.
Electrolyte Disturbance: Monitor electrolyte levels and renal function. Institute measures to maintain hydration and electrolytes.
Based on the severity of symptoms, management may require intensive support care and facilities for applying cardiac and respiratory support.
Chlorthalidone: Symptoms of chlorthalidone overdose include nausea, weakness, dizziness and disturbances of electrolyte balance.
Dosage And Administration:
Dosage must be determined for individual patients by titration of each component separately. Where the fixed combination in Tenoretic supplies the dosage so determined, the combination product may be used for maintenance therapy. One tablet once daily can be used to administer up to 100 mg of atenolol and 25 mg of chlorthalidone.
If further lowering of the blood pressure is required, another antihypertensive agent may be added to the regimen.
In patients with renal impairment, the dose of the components should be carefully individualized. Recommendations for dosage adjustments for atenolol and chlorthalidone in renal disease are found in the Tenormin and Hygroton prescribing information.
If dosage adjustment is necessary during maintenance therapy, it is advisable to use the individual drugs.
Availability And Storage:
50/25: Each white, round, biconvex tablet, scored and embossed 50/25 on one face and plain on the other, contains: atenolol 50 mg and chlorthalidone 25 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. Calendar packs of 28.
100/25: Each white, round, biconvex tablet, scored and embossed with 100/25 on one face and plain on the other, contains: atenolol 100Â mg and chlorthalidone 25 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. Calendar packs of 28.
Protect from light and moisture. Store at room temperature.
TENORETIC® AstraZeneca Atenolol–Chlorthalidone Antihypertensive Agent