Tenoretic

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.

Clonidine: β-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the β-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by β-blocker therapy, the introduction of β-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 β-adrenergic blocking action of atenolol may produce an excessive reduction of sympathetic activity. TENORETIC should not be combined with other drugs containing β-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: Class I antiarrhythmic drugs (e.g. disopyramide) and amiodarone may have potentiating effect on atrial-conduction time and induce negative inotropic effect.

Calcium Channel Blockers: Combined use of β-blockers and calcium channel blockers with negative inotropic effects can lead to prolongation of S-A and A-V 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. 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.

Digitalis Glycosides: Digitalis glycosides may potentiate the bradycardia of β-blockade.

Nonsteroidal Anti-inflammatory Agents: The concomitant use of nonsteroidal anti-inflammatory agents may blunt the antihypertensive effects of β-blockers.

Anesthetic Agents: Anesthetics can produce a hypotensive state with associated reflex tachycardia. Since β-blockade will inhibit reflex tachycardia, the hypotensive potential of anesthetic agents is increased with concomitant use of TENORETIC, thus the anesthetic used should be an agent with as little negative inotropic activity as possible (see Contraindications and Precautions, Elective or Emergency Surgery).

Clinical studies of TENORETIC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic renal, or cardiac function, and concomitant diseases or other drug therapy.

Activities Requiring Mental Alertness: 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.

The safety of use of atenolol in children has not been established; therefore, TENORETIC is not recommended in the pediatric age group.

Each white, round, biconvex tablet, scored and embossed with 100/25 on one face and plain on the other, contains: atenolol 100 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.

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.

There is a significant accumulation of atenolol in breast milk.

Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORETIC is administered during pregnancy or to a woman who is breast-feeding. (See Warnings, Pregnancy.)

Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the placental barrier and appears in the cord blood.

No studies have been performed on the use of atenolol in the first trimester and the possibility of fetal injury cannot be excluded. Administration of atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age.

In a limited number of patients who were given atenolol during the last trimester of pregnancy, low birth weight, neonatal hypoglycemia, bradycardia in the fetus/newborn, and placental insufficiency were observed.

The use of atenolol in women who are, or may become pregnant requires that the anticipated benefit be weighed against the possible risks to mother and/or fetus.

The safe use of TENORETIC in pregnancy has not been established.

Neonates born to mothers who are receiving atenolol at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORETIC is administered during pregnancy or to a woman who is breast-feeding. (See Warnings, Lactation.)

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/day or 25 or more times the maximum recommended human dose.

Thiazides cross the placental barrier and appear in cord blood. The use of chlorthalidone and related drugs in pregnant women requires that the anticipated benefits of the drug be weighed against the possible risks to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia and, possibly, other adverse reactions, which have occurred in the adult.

anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis.

leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia.

laryngospasm, status asthmaticus and fever combined with aching and sore throat.

hyperglycemia, glycosuria, hyperuricemia, hyponatremia, muscle spasm, weakness, restlessness, impotence and hypokalemia.

dizziness, vertigo, paresthesias, headache, xanthopsia.

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.

The following adverse reactions have occurred with other β-blockers but have not been reported with atenolol:

purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell's syndrome (toxic epidermal necrolysis).

blurred vision, burning, and grittiness.

dyspnea, wheeziness, cough, bronchospasm.

During post-marketing experience with atenolol, cold extremities, gastrointestinal disturbances and fatigue were commonly reported. 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 beta blockers, has been associated with the development of antinuclear antibodies (ANA) and lupus syndrome.

In a long-term, well controlled trial of 1627 elderly patients with systolic hypertension, the incidence of dry mouth was significantly higher in patients taking atenolol (12.2%).

agranulocytosis.

exfoliative dermatitis.

The following adverse reactions have been reported:

Orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates or narcotics.

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 β-adrenergic blocking agent are congestive heart failure, hypotension, bronchospasm and/or hypoglycemia.

Chlorthalidone: Symptoms of chlorthalidone overdose include nausea, weakness, dizziness and disturbances of electrolyte balance.

Atenolol: 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 β-adrenoceptor stimulant such as dobutamine 2.5 to 10 µg/kg/min by i.v. infusion or isoproterenol 10 to 25 µg given as an infusion at a rate not exceeding 5 µg/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 β₂-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.