e. thiazides may increase the responsiveness to tubocurarine. concomitant use of prostaglandin synthase inhibiting drugs, e.g., indomethacin, may decrease the hypotensive effects of beta blockers. lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. read prescribing information for lithium preparations before use of such preparations with atenolol and chlorthalidone. beta blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. if the two drugs are coadministered, the beta blocker should be withdrawn several days before the gradual withdrawal of clonidine. if replacing clonidine by beta-blocker therapy, the introduction of beta blockers should be delayed for several days after clonidine administration has stopped. while taking beta blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction. both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. concomitant use can increase the risk of bradycardia.

nsive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (eg, n angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. this fixed dose combination drug is not indicated for initial therapy of hypertension. if the fixed dose combination represents the dose appropriate to the individual patient's needs, it may be more convenient than the separate components.

ides may precipitate azotemia. since cumulative effects may develop in the presence of impaired renal function, if progressive renal impairment becomes evident, atenolol and chlorthalidone should be discontinued. in patients with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. atenolol and chlorthalidone should be used with caution in these patients. ischemic heart disease following abrupt cessation of therapy with certain beta-blocking agents in patients with coronary artery disease, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported. therefore, such patients should be cautioned against interruption of therapy without the physician’s advice. even in the absence of overt angina pectoris, when discontin­uation of atenolol and chlorthalidone is planned, the patient should be carefully observed and should be advised to limit physical activity to a minimum. atenolol and chlorthalidone should be reinstated if withdrawal symptoms occur. because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue atenolol and chlorthalidone therapy abruptly even in patients treated only for hypertension. concomitant use of calcium channel blockers bradycardia and heart block can occur and the left ventricular end diastolic pressure can rise when beta-blockers are administered with verapamil or diltiazem. patients with pre-existing conduction abnormalities or left ventricular dysfunction are particularly susceptible. (see precautions . ) bronchospastic diseases patients with bronchospastic disease should, in general, not receive beta blockers. because of its relative beta 1 -selectivity, however, atenolol and chlorthalidone may be used with caution in patients with bronchospastic disease who do not respond to or cannot tolerate, other antihypertensive treatment. since beta 1 -selectivity is not absolute, the lowest possible dose of atenolol and chlorthalidone should be used and a beta 2 -stimulating agent (bronchodilator) should be made available. if dosage must be increased, dividing the dose should be considered in order to achieve lower peak blood levels. major surgery chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. metabolic and endocrine effects atenolol and chlorthalidone may be used with caution in diabetic patients. beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. at recommended doses atenolol does not potentiate insulin-induced hypoglycemia and, unlike nonselective beta blockers, does not delay recovery of blood glucose to normal levels. insulin requirements in diabetic patients may be increased, decreased or unchanged; latent diabetes mellitus may become manifest during chlorthalidone administration. beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom atenolol and chlorthalidone therapy is to be withdrawn should be monitored closely. because calcium excretion is decreased by thiazides, atenolol and chlorthalidone 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. hyperuricemia may occur, or acute gout may be precipitated in certain patients receiving thiazide therapy. untreated pheochromocytoma atenolol and chlorthalidone tablets should not be given to patients with untreated pheochromocytoma. pregnancy and fetal injury atenolol can cause fetal harm when administered to a pregnant woman. atenolol crosses the placental barrier and appears in cord blood. administration of atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age. no studies have been performed on the use of atenolol in the first trimester and the possibility of fetal injury cannot be excluded. if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. neonates born to mothers who are receiving atenolol at parturition or breastfeeding may be at risk for hypoglycemia and bradycardia. caution should be exercised when atenolol and chlorthalidone is administered during pregnancy or to a woman who is breastfeeding. (see precautions, nursing mothers . ) atenolol and chlorthalidone was studied for teratogenic potential in the rat and rabbit. doses of atenolol/chlorthalidone of 8/2, 80/20 and 240/60 mg/kg/day were administered orally to pregnant rats with no evidence of embryofetotoxicity observed. two studies were conducted in rabbits. in the first study, pregnant rabbits were dosed with 8/2, 80/20 and 160/40 mg/kg/day of atenolol/chlorthalidone. no teratogenic effects were noted, but embryonic resorptions were observed at all dose levels (ranging from approximately 5 times to 100 times the maximum recommended human dose*). in the second rabbit study, doses of atenolol/chlorthalidone were 4/1, 8/2 and 20/5 mg/kg/day. no teratogenic or embryotoxic effects were demonstrated. atenolol 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 antihypertensive dose.* although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg/day or 12.5 times the maximum recommended human antihypertensive dose.* *based on the maximum dose of 100 mg/day in a 50 kg patient. chlorthalidone 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 possible hazards to the fetus. these hazards include fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult.

e atenolol elimination (ml/min/1.73 m 2 ) half-life (hrs) maximum dosage 15-35 16-27 50 mg daily <15 >27 50 mg every other day

12 5 postural hypotension 2 1 4 5 leg pain 0 0.5 3 1 central nervous system/ neuromuscular dizziness 4 1 13 6 vertigo 2 0.5 2 0.2 light-headedness 1 0 3 0.7 tiredness 0.6 0.5 26 13 fatigue 3 1 6 5 lethargy 1 0 3 0.7 drowsiness 0.6 0 2 0.5 depression 0.6 0.5 12 9 dreaming 0 0 3 1 gastrointestinal diarrhea 2 0 3 2 nausea 4 1 3 1 respiratory (see warnings ) wheeziness 0 0 3 3 dyspnea 0.6 1 6 4 during postmarketing experience, the following have been reported in temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin, hallucinations, headache, impotence, peyronie’s disease, postural hypotension which may be associated with syncope, psoriasiform rash or exacerbation of psoriasis, psychoses, purpura, reversible alopecia, thrombocytopenia, visual disturbance, sick sinus syndrome and dry mouth. atenolol, like other beta blockers, has been associated with the development of antinuclear antibodies (ana), lupus syndrome and raynaud’s phenomenon. chlorthalidone cardiovascular: orthostatic hypotension; gastrointestinal: anorexia, gastric irritation, vomiting, cramping, constipation, jaundice (intra­hepatic cholestatic jaundice), pancreatitis; cns: vertigo, paresthesia, xanthopsia; hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia; hypersensitivity: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) [cutaneous vasculitis], lyell’s syndrome (toxic epidermal necrolysis); miscellaneous: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness. clinical trials of atenolol and chlorthalidone conducted in the united states (89 patients treated with atenolol and chlorthalidone) revealed no new or unexpected adverse effects. to report suspected adverse events, contact actavis at 1-800-272-5525 or fda at 1-800-fda-1088 or h ttp://www.fda.gov/ for voluntary reporting of adverse reactions.

e. thiazides may increase the responsiveness to tubocurarine. concomitant use of prostaglandin synthase inhibiting drugs, e.g., indomethacin, may decrease the hypotensive effects of beta blockers. lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. read prescribing information for lithium preparations before use of such preparations with atenolol and chlorthalidone. beta blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. if the two drugs are coadministered, the beta blocker should be withdrawn several days before the gradual withdrawal of clonidine. if replacing clonidine by beta-blocker therapy, the introduction of beta blockers should be delayed for several days after clonidine administration has stopped. while taking beta blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction. both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. concomitant use can increase the risk of bradycardia.

standard animal or human pharmacological tests, beta-adrenoreceptor blocking activity of atenolol has been demonstrated by: (1) reduction in resting and exercise heart rates and cardiac output, (2) reduction of systolic and diastolic blood pressure at rest and on exercise, (3) inhibition of isoproterenol induced tachycardia and (4) reduction in reflex orthostatic tachycardia. a significant beta-blocking effect of atenolol, as measured by reduction of exercise tachycardia, is apparent within one hour following oral administration of a single dose. this effect is maximal at about 2 to 4 hours and persists for at least 24 hours. the effect at 24 hours is dose related and also bears a linear relationship to the logarithm of plasma atenolol concentration. however, as has been shown for all beta-blocking agents, the antihypertensive effect does not appear to be related to plasma level. in normal subjects, the beta 1 -selectivity of atenolol has been shown by its reduced ability to reverse the beta 2 -mediated vasodilating effect of isoproterenol as compared to equivalent beta-blocking doses of propranolol. in asthmatic patients, a dose of atenolol producing a greater effect on resting heart rate than propranolol resulted in much less increase in airway resistance. in a placebo-­controlled comparison of approximately equipotent oral doses of several beta blockers, atenolol produced a significantly smaller decrease of fev 1 than nonselective beta blockers, such as propranolol and unlike those agents did not inhibit bronchodilation in response to isoproterenol. consistent with its negative chronotropic effect due to beta blockade of the sa node, atenolol in­creases sinus cycle length and sinus node recovery time. conduction in the av node is also prolonged. atenolol is devoid of membrane stabilizing activity, and increasing the dose well beyond that producing beta blockade does not further depress myocardial contractility. several studies have demonstrated a moderate (approximately 10%) increase in stroke volume at rest and exercise. in controlled clinical trials, atenolol given as a single daily dose, was an effective antihypertensive agent providing 24-hour reduction of blood pressure. atenolol has been studied in combination with thiazide-type diuretics and the blood pressure effects of the combination are approximately additive. atenolol is also compatible with methyldopa, hydralazine and prazosin, the combination resulting in a larger fall in blood pressure than with the single agents. the dose range of atenolol is narrow, and increasing the dose beyond 100 mg once daily is not associated with increased antihypertensive effect. the mechanisms of the antihypertensive effects of beta-blocking agents have not been established. several mechanisms have been proposed and include: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output, (2) a central effect leading to reduced sympathetic outflow to the periphery and (3) suppression of renin activity. the results from long-term studies have not shown any diminution of the antihypertensive efficacy of atenolol with prolonged use. pharmacokinetics and metabolism in man, absorption of an oral dose is rapid and consistent but incomplete. approximately 50% of an oral dose is absorbed from the gastrointestinal tract, the remainder being excreted unchanged in the feces. peak blood levels are reached between 2 and 4 hours after ingestion. unlike propranolol or metoprolol, but like nadolol, hydrophilic atenolol undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion. atenolol also differs from propranolol in that only a small amount (6-16%) is bound to proteins in the plasma. this kinetic profile results in relatively consistent plasma drug levels with about a fourfold interpatient variation. there is no information as to the pharmacokinetic effect of atenolol on chlorthalidone. the elimination half-life of atenolol is approximately 6 to 7 hours and there is no alteration of the kinetic profile of the drug by chronic administration. following doses of 50 mg or 100 mg, both beta-blocking and antihypertensive effects persist for at least 24 hours. when renal function is impaired, elimination of atenolol is closely related to the glomerular filtration rate; but significant accumulation does not occur until the creatinine clearance falls below 35 ml/min/1.73 m 2 (see prescribing information for atenolol). atenolol geriatric pharmacology in general, elderly patients present higher atenolol plasma levels with total clearance values about 50% lower than younger subjects. the half-life is markedly longer in the elderly compared to younger subjects. the reduction of atenolol clearance follows the general trend that elimination of renally excreted drugs is decreased with increasing age. chlorthalidone chlorthalidone is a monosulfonamyl diuretic which differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. it is an oral diuretic with prolonged action and low toxicity. the diuretic effect of the drug occurs within 2 hours of an oral dose. it produces diuresis with greatly increased excretion of sodium and chloride. at maximal therapeutic dosage, chlorthalidone is approximately equal in its diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics. the site of action appears to be the cortical diluting segment of the ascending limb of henle’s loop of the nephron.

ted at dose levels as high as 200 mg/kg/day or 100 times the maximum recommended human dose*) was unaffected by atenolol administration.